Evidence Report/Technology Assessment

Number 120 

Management of Menopause-Related Symptoms 

Prepared for: 

Agency of Healthcare Research and Quality 

U.S. Department of Health and Human Services 

540 Gaither Road 

Rockville, MD 20850 

www.ahrq.gov

Contract No. 290-02-0024 

Prepared by: 

Oregon Evidence-based Practice Center 

Oregon Health & Science University 

Portland, Oregon 

Investigators 

Heidi D. Nelson, MD, MPH 

Elizabeth Haney, MD 

Linda Humphrey, MD, MPH 

Jill Miller, MD 

Anne Nedrow, MD 

Christina Nicolaidis, MD, MPH 

Kimberly Vesco, MD 

Miranda Walker, BA 

Christina Bougatsos, BS 

Peggy Nygren, MA 

AHRQ Publication No. 05-E016-2 

March 2005 
This report may be used, in whole or in part, as the basis for development of clinical practice 

guidelines and other quality enhancement tools, or a basis for reimbursement and coverage 

policies. AHRQ or U.S. Department of Health and Human Services endorsement of such 

derivative products may not be stated or implied. 

AHRQ is the lead Federal agency charged with supporting research designed to improve the 

quality of health care, reduce its cost, address patient safety and medical errors, and broaden access 

to essential services. AHRQ sponsors and conducts research that provides evidence-based 

information on health care outcomes; quality; and cost, use, and access. The information helps 

health care decisionmakers—patients and clinicians, health system leaders, and policymakers—

make more informed decisions and improve the quality of health care services. 
This document is in the public domain and may be used and reprinted without permission except 

those copyrighted materials noted for which further reproduction is prohibited without the 

specific permission of copyright holders. 

Suggested citation: 

Nelson HD, Haney E, Humphrey L, Miller J, Nedrow A, Nicolaidis C, Vesco K, Walker M, 

Bougatsos C, Nygren P. Management of Menopause-Related Symptoms. Evidence 

Report/Technology Assessment No. 120. (Prepared by the Oregon Evidence-based Practice 

Center, under Contract No. 290-02-0024.) AHRQ Publication No. 05-E016-2. Rockville, MD: 

Agency for Healthcare Research and Quality. March 2005. 

 ii 
Preface 

The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based 

Practice Centers (EPCs), sponsors the development of evidence reports and technology 

assessments to assist public- and private-sector organizations in their efforts to improve the 

quality of health care in the United States. The Office of Medical Applications of Research, 

National Institutes of Health, requested and provided funding for this report. The reports and 

assessments provide organizations with comprehensive, science-based information on common, 

costly medical conditions and new health care technologies. The EPCs systematically review the 

relevant scientific literature on topics assigned to them by AHRQ and conduct additional 

analyses when appropriate prior to developing their reports and assessments. 

To bring the broadest range of experts into the development of evidence reports and health 

technology assessments, AHRQ encourages the EPCs to form partnerships and enter into 

collaborations with other medical and research organizations. The EPCs work with these partner 

organizations to ensure that the evidence reports and technology assessments they produce will 

become building blocks for health care quality improvement projects throughout the Nation. The 

reports undergo peer review prior to their release. 

AHRQ expects that the EPC evidence reports and technology assessments will inform 

individual health plans, providers, and purchasers as well as the health care system as a whole by 

providing important information to help improve health care quality. 

We welcome comments on this evidence report. They may be sent by mail to the Task Order 

Officer named below at: Agency for Healthcare Research and Quality, 540 Gaither Road, 

Rockville, MD 20850, or by e-mail to epc@ahrq.gov. 

Carolyn M. Clancy, M.D. 

Director

Agency for Healthcare Research and Quality 

Barnett S. Kramer, M.D., M.P.H. 

Director

Office of Medical Applications 

 of Research 

National Institutes of Health 

Jean Slutsky, P.A., M.S.P.H. 

Director, Center for Outcomes and Evidence 

Agency for Healthcare Research and Quality 

Kenneth S. Fink, M.D., M.G.A., M.P.H. 

Director, EPC Program

Agency for Healthcare Research and Quality 

Carmen Kelly, PharmD

EPC Program Task Order Officer 

Agency for Healthcare Research and Quality 

The authors of this report are responsible for its content. Statements in the report 

should not be construed as endorsement by the Agency for Healthcare Research and 

Quality or the U.S. Department of Health and Human Services of a particular drug, 

device, test, treatment, or other clinical service. 

 iii 
Acknowledgments 

This systematic evidence review was developed for the National Institutes of Health State-of-theScience Conference on Management of Menopause-Related Symptoms. It was supported by the 

Office of Medical Applications of Research (OMAR) at the National Institutes of Health and the

Agency for Healthcare Research and Quality (AHRQ), and the investigators acknowledge the 

contributions of Carmen Kelly, PharmD, Task Order Officer, AHRQ, Lata Nerurka, PhD, 

OMAR, and Carol Mangione, MD, MSPH, Chair of the State-of-the-Science Conference Panel. 

The Women’s Health Fellowship at the Portland Veterans Administration Medical Center 

provided support for Kimberly Vesco, MD. Investigators thank the Technical Expert Panel 

members providing guidance for the project, expert reviewers commenting on the draft version, 

Andrew Hamilton, MLS, MS for conducting the literature searches, and Laurie Huffman, MS, 

and Korene Maceo, BS, for assisting with the project. 

 iv 
Structured Abstract 

Context: Although many symptoms have been attributed to the menopausal transition, it is 

unclear which symptoms are actually associated and how to effectively manage them. 

Objective: To describe the evidence about symptoms associated with menopause, factors that 

influence them, benefits and adverse effects of therapies, factors that influence therapies, and 

future research needs. 

Data Sources: Relevant studies were identified from multiple searches of MEDLINE®, 

PsycINFO, DARE, the Cochrane database, MANTIS, and AMED (1953 to November 2004); 

and from recent systematic reviews, reference lists, reviews, editorials, websites, and experts. 

Study Selection: Specific inclusion and exclusion criteria were developed to determine study 

eligibility. The target population includes adult women in the U.S. undergoing the menopausal 

transition. 

Data Extraction: All eligible studies were reviewed and relevant data were extracted, entered 

into evidence tables, and summarized by descriptive methods. Two reviewers independently 

rated the quality of studies using predefined criteria. 

Data Synthesis: Forty-eight studies conducted among 14 cohorts and 22 studies from other 

populations provide data about symptoms. Vasomotor symptoms and vaginal dryness are most 

consistently associated with menopause; sleep disturbance, somatic complaints, urinary 

complaints, sexual dysfunction, mood, and quality of life are inconsistently associated. No 

studies provide data on cognition and uterine bleeding problems, duration and severity of 

specific symptoms, or conclusive data on the influence of race/ethnicity, age of onset of 

menopause, body mass index, oophorectomy status, depression, or smoking. Results of 192 

randomized controlled trials of therapies indicate that for vasomotor symptoms, estrogen is 

effective; tibolone demonstrates benefit, but most studies are poor-quality; paroxetine, 

veralipride, gabapentin, soy isoflavones, and other phytoestrogens report benefit in some trials. 

Results for other symptoms are mixed, adverse effects are inadequately reported, and placebo 

effects are large. No trials describe the influence of bilateral oophorectomy, premature ovarian 

failure, use of potentially interacting agents, lifestyle and behavioral factors, recent 

discontinuation of hormones, or body mass index. For women with breast cancer, clonidine, 

venlafaxine, and megestrol acetate improve vasomotor symptoms, and results for other 

symptoms are mixed.

Conclusions: Vasomotor symptoms and vaginal dryness are most consistently associated with 

the menopausal transition. Results of treatment trials are consistent and conclusive only for 

estrogen. For other agents, the evidence base is limited by lack of studies demonstrating 

effectiveness, poor quality of existing studies, and incomplete information on adverse effects. 

Keywords: Menopause, menopause transition, menopause symptoms, treatment of menopause 

symptoms

 v 
Contents 

Chapter 1. Introduction ...................................................................................................................3

 Purpose........................................................................................................................................3 

 Menopausal Transition................................................................................................................4 

 Menopausal Symptoms...............................................................................................................4 

 Measures of Menopausal Symptoms..........................................................................................5

Chapter 2. Methods.........................................................................................................................7

 Analytic Framework and Key Questions....................................................................................7 

 Technical Expert Panel and Expert Reviewers...........................................................................7 

 Literature Search and Strategy....................................................................................................7 

 Inclusion and Exclusion Criteria.................................................................................................8 

 Key Questions 1 and 2 ...........................................................................................................8 

 Key Questions 3 and 4 ...........................................................................................................8 

 Date Extraction and Synthesis....................................................................................................8 

 Size of Literature.........................................................................................................................9 

Chapter 3. Results.........................................................................................................................11

 Key Question 1. Symptoms Associated With Menopause .......................................................11 

 What is the Evidence That the Symptoms More Frequently Reported By 

 Middle-aged Women are Attributable to Ovarian Aging and Senescence? .......................11 

 Summary...................................................................................................................................14 

 Key Question 2. Factors Influencing Symptoms......................................................................16 

 When do the Menopausal Symptoms Appear, How Long do They Persist and With 

 What Frequency and Severity, and What is Known About the Factors That Influence 

 Them? .................................................................................................................................16 

 Summary...................................................................................................................................18

 Key Question 3. Benefits and Adverse Effects of Therapies....................................................19 

 What Is the Evidence for the Benefits and Harms of Commonly Used Interventions 

 for Relief of Menopause-related Symptoms? . ...................................................................19 

 Summary...................................................................................................................................28

 Key Question 4. Therapies for Women With Specific Characteristics ...................................29 

 What are the Important Considerations in Managing Menopause-related Symptoms 

 in Women With Clinical Characteristics or Circumstances That May Complicate 

 Decision-making? ...............................................................................................................29 

 Summary...................................................................................................................................32

 Key Question 5. Future Research on Therapies.......................................................................32 

 What are the Future Research Directions for Treatment of Menopause Related 

 Symptoms and Conditions? .................................................................................................32 

Chapter 4. Discussion ...................................................................................................................35

References......................................................................................................................................37 

List of Excluded Studies................................................................................................................49

 vii 
Figures 

Figure 1. Normal Reproductive Aging in Women.........................................................................82 

Figure 2. Analytic Framework.......................................................................................................83 

Figure 3. Quality Rating Criteria ...................................................................................................84 

 

Tables 

Table 1. Measures of Menopause-Related Symptoms...................................................................86 

Table 2. Descriptions of Cohort Studies........................................................................................89 

Table 3. Results of Cohort Studies of Menopause-Related Symptoms.........................................91 

Table 4. Results of Cross-Sectional Studies of Menopause-Related Symptoms.........................105 

Table 5. Trials of Estrogen for Depression..................................................................................107

Table 6. Trials of Progestins........................................................................................................110 

Table 7. Trials of Androgens.......................................................................................................111 

Table 8. Trials of Tibolone ..........................................................................................................114 

Table 9. Trials of Antidepressant Drugs......................................................................................119 

Table 10. Trials of Clonidine ......................................................................................................121 

Table 11. Trials of Methyldopa, Bellergal, and Gabapentin........................................................124 

Table 12. Trials of Phytoestrogens and Isoflavones....................................................................125 

Table 13. Trials of Complementary and Alternative Therapies ..................................................130 

Table 14. Trials of Behavioral Interventions...............................................................................137 

Table 15. Summary of Benefits of Therapies..............................................................................139 

Table 16. Trials in Women with Breast Cancer...........................................................................141 

Appendixes 

Appendix A. Technical Expert Panel Members 

Appendix B. Expert Reviewers 

Appendix C. Literature Search Strategies 

Appendix D. Inclusion and Exclusion Criteria 

Appendix E. Literature Search Tree 

Appendix F. Evidence Tables 

Note: Appendixes and Evidence Tables are provided electronically at 

http://www.ahrq.gov/clinic/tp/menopstp.htm 

 

 viii 
Introduction

Menopause is defined as the permanent

cessation of menses resulting from reduced

ovarian hormone secretion that occurs naturally

or is induced by surgery, chemotherapy, or

radiation. Natural menopause is recognized after

12 months of amenorrhea that is not associated

with a pathologic cause. The average age of

menopause in the United States is 51 years, and

can vary normally between 40 and 58 years.1 The

menopausal transition can span over several years,

and often begins with variations in menstrual

cycle length in response to rising levels of follicle

stimulating hormone (FSH). The mean age of

onset of the menopausal transition is 47.5 years

and commonly lasts approximately 4 to 5 years.1

Stages and nomenclature of the menopausal

transition were defined by experts in 2001 at the

Stages of Reproductive Aging Workshop

(STRAW).2 The group recognized seven stages of

the reproductive aging continuum, and

acknowledged that most women do not progress

precisely through each stage. These stages are also

described by the following terms: 

• Premenopause: the time up to the beginning

of the perimenopause, but is also used to

define the time up to the last menstrual

period.

• Perimenopause: the time around menopause

during which menstrual cycle and endocrine

changes are occurring but 12 months of

amenorrhea has not yet occurred.

• Postmenopause: begins at the time of the last

menstrual period, although not recognized

until after 12 months of amenorrhea. 

A hot flash or flush refers to the spontaneous

sensation of warmth, often associated with

perspiration, resulting from a vasomotor response

to declining estrogen levels. Nightsweats are hot

flashes or flushes occurring at night, often while

sleeping. Other symptoms, such as vaginal

dryness, sleep disturbance, mood symptoms,

cognitive disturbances, somatic complaints,

urinary complaints, uterine bleeding problems,

sexual dysfunction, and reduced quality of life are

also attributed to the menopausal transition. 

Although many measures have been developed

to assess menopausal symptoms, few demonstrate

standardization, validity, or reliability. Some

measures are based on self-reports of the presence,

severity, and frequency of individual symptoms,

such as hot flashes. Others utilize cumulative or

global scores based on lists or scales of symptoms

attributed to menopause, such as mood,

cognition, quality of life, sexual function, and

somatic symptoms. Many studies base their

measures on study-specific checklists,

questionnaires, or scales. Ninety-two measures of

menopausal symptoms were reported by studies

included in this evidence review. 

Purpose

This systematic evidence review focuses on five

Key Questions relating to symptoms of

menopause and their management, as specified by

the Planning Committee for the National

Institutes of Health State-of-the-Science

Evidence Report/Technology Assessment

Number 120

Management of Menopause-Related Symptoms

Summary

Authors: Nelson HD, Haney E, Humphrey L, Miller J, Nedrow A, Nicolaidis C, Vesco K, 

Walker M, Bougatsos C, Nygren P

Agency for Healthcare Research and Quality

Advancing Excellence in Health Care • www.ahrq.gov

Agency for Healthcare Research and Quality Evidence-Based

Practice
2

Conference on Management of Menopause-Related Symptoms.

The target population includes adult women in the United

States undergoing the menopausal transition.

1. What is the evidence that the symptoms more frequently

reported by middle-aged women are attributable to

ovarian aging and senescence? These include vasomotor

symptoms, vaginal dryness, sleep disturbance, mood

symptoms, cognitive disturbances, somatic complaints,

urinary complaints, uterine bleeding problems, sexual

dysfunction, and reduced quality of life.

2. When do the menopausal symptoms appear, how long do

they persist and with what frequency and severity, and

what is known about the factors that influence them?

Factors include race and ethnicity, age at onset of the

menopause transition, body mass index (BMI), surgical

versus natural menopause, depression, and smoking.

3. What is the evidence for the benefits and harms of

commonly used interventions for relief of menopauserelated symptoms? Interventions include estrogens,

progestins, androgens, tibolone, antidepressants, other

drugs, phytoestrogens, complementary and alternative

medicine, and behavioral interventions.

4. What are the important considerations in managing

menopause-related symptoms in women with clinical

characteristics or circumstances that may complicate

decision-making? These include bilateral oophorectomy,

premature ovarian failure, breast cancer, concurrent use of

selective estrogen receptor modulators (SERMs) and other

interacting therapeutic agents, lifestyle and behavioral

factors, recent discontinuation of menopausal hormone

therapy, and very low or very high BMI.

5. What are the future research directions for treatment of

menopause-related symptoms and conditions?

Methods

A Technical Expert Panel was assembled to provide input

from experts and clinicians in the field to ensure that the scope

of the project addressed important clinical questions and issues.

The panel included obstetrician/gynecologists, internists,

naturopathic physicians, behavioral experts, and researchers.

The panel was convened for periodic conference calls during

the course of the project. Expert reviewers, including several

panel members, provided comments on the draft evidence

report. 

Literature Search and Strategy

Relevant studies were identified from multiple searches of

MEDLINE®, PsycINFO, DARE, the Cochrane database of

systematic reviews and controlled trials, MANTIS, and AMED

(1953 to November 2004); and from recent systematic reviews,

reference lists, reviews, editorials, websites, and experts.

Retrieved abstracts were entered into an electronic database

(EndNote®). 

Inclusion and Exclusion Criteria

Full text cohort studies with data on women experiencing

menopause and at least one of the symptoms listed in Key

Question 1 were initially reviewed and subsequently included if

the study enrolled 100 or more subjects, subjects represented

the target population, and data on symptoms associated with

menopause were provided. Exclusions included studies of

women not undergoing the menopausal transition and

experiencing menopause related symptoms, studies of aging

and its effects, and biologically based studies that did not report

epidemiological data relating to symptoms (e.g., studies of

hormone levels). Non-English language papers and studies of

animals or cadavers were also excluded. Cross-sectional studies

meeting similar inclusion/exclusion criteria were examined for

contributory data and included if they reported relevant data

about symptoms by menopausal stage, such as prevalence rates.

Full text randomized controlled trials and meta-analyses of

randomized controlled trials providing data on treatment of

menopausal symptoms, using one or more of the interventions

listed in Key Question 3, were included. Trials enrolling

women with breast cancer were considered separately from

those enrolling women without breast cancer. Exclusions

included studies of women not undergoing menopause and

experiencing menopause related symptoms during the course of

the study, studies of animals, and non-English language papers. 

Data Extraction and Synthesis

All eligible studies were reviewed and a “best evidence”

approach was applied, in which studies with the highest quality

and most rigorous design are emphasized.3 Data were extracted

from each study, entered directly into evidence tables, and

summarized descriptively. Benefits and adverse effects of

therapies were considered equally important and both types of

outcomes were abstracted. Trials of alternative and

complementary therapies were grouped according to the

National Center for Complementary and Alternative Medicine

categories4 most closely related to included topics. Results of
recently published meta-analyses on estrogens5-7 and isoflavones8

are included in this report. No new meta-analyses were

conducted because of heterogeneity of trials of other therapies.

Two reviewers independently rated the quality of

randomized controlled trials and cohort studies using criteria

specific to different study designs developed by the United

States Preventive Services Task Force.9 Similar criteria for crosssectional studies are not available. The overall rating is a

combination of internal and external validity scores. When

reviewers disagreed, a final rating was reached through

consensus. Studies reporting several different outcomes may

have different quality ratings for each outcome depending on

how completely it controlled for key confounders in multivariable models.

Size of Literature

A total of 10,059 unique citations were reviewed, including

6,342 about symptoms and factors influencing them (Key

Questions 1 and 2); 4,078 about therapies (Key Question 3);

and 806 about specific characteristics that may influence the

effects of therapies (Key Question 4).

Results

To address Key Questions 1 and 2, the review focused on

prospective studies of cohorts of midlife women transitioning

through the stages of menopause. Forty-eight studies

conducted among 14 cohorts met inclusion criteria. Seven

cohorts were based in the United States (Massachusetts

Women’s Health Study, Seattle Midlife Women’s Health Study,

Ohio Midlife Women’s Study, National Health Examination

Follow-up Study [NHANES], Study of Women’s Health Across

the Nation [SWAN], University of Minnesota/Tremin Trust

Longitudinal Study, and Pennsylvania Ovarian Aging Study).

Seven cohorts were based outside the United States

(Gothenburg, Sweden, Australian Longitudinal Study on

Women’s Health, Medical Research Council [MRC], U.K.,

Melbourne Women’s Midlife Health Project, Australia,

Manitoba Project on Women and Their Health in the Middle

Years, Canada, Copenhagen, Denmark, and Eindhoven,

Netherlands). An additional 22 cross-sectional studies from

other populations meeting similar inclusion criteria were

obtained to provide additional prevalence data.

Major limitations of studies include dissimilar methods for

evaluating and reporting symptoms and for assessing

menopausal change. Some cohort studies based results on

cross-sectional data reported at serial time points rather than

individual tracking of women over time. Some studies failed

to adjust or stratify for potentially important variables such as

age, race, BMI, life events, or history of depression when

attempting to attribute symptoms to change in menopausal

stage. Although most included studies were population-based,

in many cases, enrolled women were additionally selected from

the initial recruited cohort and may have been less

representative of the general population. Also, many studies

were based on cohorts recruited from community populations

and are more representative of volunteers than entire

communities.

Key Question 1. What is the evidence that the symptoms

more frequently reported by middle-aged women are

attributable to ovarian aging and senescence?

• Vasomotor symptoms: Evidence from population-based

cohort and cross-sectional studies supports the association

between vasomotor symptoms and menopausal stage.

Studies are consistent in reporting increasing prevalence

rates of vasomotor symptoms as women transition from

premenopause to either perimenopause or postmenopause,

affecting 50 percent or more of women. Studies suggest

that vasomotor symptoms persist for several years after

menopause for some women.

• Vaginal dryness: Vaginal dryness is associated with

menopause and prevalence rates increase as women

transition through the menopausal stages. Estimates

indicate that up to one third of perimenopausal and

postmenopausal women experience vaginal dryness.

• Sleep disturbance: Although results of studies are mixed,

two good-quality cohort studies indicate that women have

more difficulty sleeping as they transition through

menopausal stages, and this may be due to vasomotor

symptoms. Up to 40 percent to 60 percent of

perimenopausal and postmenopausal women experience

sleep disturbance, a slight increase from prevalence rates of

premenopausal women.

• Mood symptoms: The majority of studies from a large

literature report no associations between menopausal stage

and mood symptoms, development of a mental disorder,

or general mental health. Studies of prevalence rates

report wide ranges that are similar across menopausal

stages.

• Cognitive disturbances: No cohort studies are available.

Cross-sectional studies indicate no difference in

forgetfulness, memory, or concentration.

• Somatic complaints: Most studies report no association of

somatic symptoms with menopause, although somatic

symptoms were increased among perimenopausal women

3
4

compared with premenopausal women in one cohort and

two cross-sectional studies.

• Urinary complaints: Urinary leakage increased among

perimenopausal women compared with premenopausal

women in one study, and another reported no

associations. Studies of prevalence rates report wide

ranges that are similar across menopausal stages.

• Uterine bleeding problems: No studies meeting inclusion

criteria addressed uterine bleeding problems, most likely

because currently accepted definitions of menopause rely

historically on changes in uterine bleeding. 

• Sexual dysfunction: Women from one study cohort

reported declines in some or all of the measured sexual

parameters as they transitioned through menopausal

stages. Results of cross-sectional studies are mixed.

• Reduced quality of life: Results of available cohort and

cross-sectional studies are conflicting.

Key Question 2. When do the menopausal symptoms

appear, how long do they persist and with what frequency and

severity, and what is known about the factors that influence

them?

• Included studies do not provide adequate details to

characterize the onset, severity, and duration of specific

symptoms. Frequency is described by prevalence data in

Key Question 1. 

• Race and ethnicity: The influence of race and ethnicity on

menopausal symptoms has not been extensively studied.

Prevalence rates of vasomotor and mood symptoms vary

among race and ethnic groups in the large SWAN cohort.

• Age at onset of menopausal transition: Available studies are

inconclusive.

• Body mass index: Available studies are inconclusive.

• Surgical versus natural menopause: Studies present mixed

results regarding the impact of surgical menopause on

vasomotor symptoms, vaginal dryness, and mood.

Adjustment for confounders is necessary because women

undergoing hysterectomy differ from women with natural

menopause in ways that may also influence their

menopause related symptoms. 

• Depression: One cross-sectional study reported that prior

anxiety or depression did not predict menopausal

symptoms. Cohort studies show that a history of

depression predicts depression in the menopausal

transition. No studies evaluated depression in associaton

with other menopausal symptoms.

• Smoking: Available studies are inconclusive.

Key Question 3. What is the evidence for the benefits and

harms of commonly used interventions for relief of menopauserelated symptoms?

• A total of 192 randomized controlled trials of therapies for

managing menopause-related symptoms were evaluated,

including trials of estrogens, progestins, androgens

(testosterone and DHEA [dehydroepiandrosterone]),

tibolone, antidepressants (selective serotonin reuptake

inhibitors, moclobemide, veralipride), other drugs

(clonidine, methyldopa, gabapentin, Bellergal),

phytoestrogens (dietary and extract forms of soy

isoflavones, other forms of phytoestrogen, combinations),

complementary and alternative medicine (acupuncture,

Chinese herbs, red clover, black cohosh, combinations,

other types of supplements, manual therapies, energy

therapies), and behavioral interventions (exercise and other

types of interventions).

• Estrogen, in either opposed or unopposed regimens, is the

most consistently effective therapy for vasomotor

symptoms, and demonstrates benefit in most trials

evaluating urogenital symptoms. Some, but not all, trials

evaluating sleep, mood and depression, sexual function,

and quality of life outcomes also report benefit with

estrogen compared to placebo. 

• Breast tenderness and uterine bleeding are the most

commonly reported adverse outcomes in estrogen trials;

others include nausea and vomiting, headache, weight

change, dizziness, venous thromboembolic events,

cardiovascular events, rash and pruritus, cholecystitis, and

liver effects.

• Trials of progestin indicate mixed results for treatment of

vasomotor symptoms. 

• Few trials of testosterone are available; one trial indicated

no differences between testosterone/estrogen and estrogen

alone for hot flash severity, vaginal dryness, or sleep

problems. Sexual symptoms were improved with

testosterone/estrogen compared to estrogen alone or

placebo in two other trials.

• For women using testosterone combined with estrogen,

acne and hirsutism occur significantly more often than for

women using estrogen alone. 

• Based on only a few fair or good-quality trials, tibolone

demonstrated benefit for vasomotor symptoms, sleep, and

somatic complaints compared to placebo, and was similar

to estrogen for some, but not all, symptoms. 

• Uterine bleeding, body pain, weight gain, and headache

were more common in tibolone vs. placebo groups.
• Several agents demonstrate benefits in managing

vasomotor symptoms in some, but not all trials, or in only

a few available trials, including paroxetine, veralipride,

gabapentin, soy isoflavones, and other phytoestrogens. 

• Trials of soy isoflavones and other complementary and

alternative medicine therapies report benefits in improving

nonvasomotor symptoms, although results vary widely,

methods are lacking, and studies are typically small and

not generalizable.

• Placebo effects in trials are large reflecting underlying

fluctuations of symptoms.

• Although benefits and adverse effects of therapies were

equally important in this review, most trials did not report

adverse effects or reported them incompletely. 

Key Question 4. What are the important considerations in

managing menopause-related symptoms in women with clinical

characteristics or circumstances that may complicate decisionmaking?

• Evidence is not available to determine if the effectiveness

of therapy for menopause related symptoms or adverse

effects differ for women with bilateral oophorectomy,

premature ovarian failure, concurrent use of SERMs or

other potentially interacting agents, lifestyle and

behavioral factors, recent discontinuation of menopausal

hormone therapy, or very low or very high BMI.

• For women with breast cancer, results of 15 randomized

controlled trials indicate that clonidine, venlafaxine, and

megestrol acetate are associated with significantly

improved measures of hot flashes, and vitamin E, black

cohosh, isoflavones, magnets, and fluoxetine are not.

Results for nonvasomotor outcomes are mixed.

Key Question 5. What are the future research directions for

treatment of menopause-related symptoms and conditions?

In order to fill evidence gaps, future research could focus on:

• Determination of optimally effective doses, combination

regimens, durations of use, and timing of therapy.

• Evaluation of approaches to identify optimal candidates

for specific therapies (e.g., identification of

thrombophilias).

• Head-to-head and placebo comparisons of estrogen alone

and combined with other types of therapies including non

drug interventions.

• Trials demonstrating how to discontinue estrogen when

symptoms subside, including the effectiveness of tapering

doses and/or replacing with other therapies including non

drug interventions.

• Better reporting of adverse effects in trials and use of

standardized categories of adverse effects so data can be

combined across trials.

• Improved analysis of results including analysis by

hysterectomy and oophorectomy status, stage of

menopause, age, concurrent conditions and medications,

and other factors.

• More comprehensive trials to determine the role of regular

exercise, sleep management, optimal nutrition, healthy

relationships, social support, and relaxation; effects of

mind-body techniques such as biofeedback and breathing;

effects of a whole system approach with Chinese medicine. 

• Additional, well-designed and controlled trials of

phytoestrogens, botanicals, and bio-identical hormones,

especially estriol, estradiol, and progesterone. Further

study of antidepressants for vasomotor symptoms would

be justified based on evidence of currently available trials.

• Enrollment of women with specific characteristics who

have not previously been evaluated such as nonwhite

women, women with premature ovarian failure, those

using SERMs and other agents influencing symptoms

concurrently, women with very high or low BMI, and

those with lifestyle and behavioral factors influencing

symptoms. Trials should report data specific to these

groups in order to interpret their influence on therapy.

• Use of standard definitions, measures, outcomes, and

statistical methods for longitudinal data so results can be

compared across trials and population cohorts.

• Prevalence data in U.S. women.

• Details about onset, timing, and duration of symptoms in

relation to menopausal stage.

• Studies of symptoms after surgical menopause with and

without hormonal therapy.

Conclusions

Based on review of currently available cohort and crosssectional population studies, vasomotor symptoms and vaginal

dryness are symptoms most consistently associated with the

menopausal transition. Sleep disturbance, somatic complaints,

urinary complaints, sexual dysfunction, mood, and quality of

life are inconsistently associated. No cohort studies provide

data on cognition, but cross-sectional studies suggest no

association. There are no studies about uterine bleeding

problems, onset, duration, and severity of specific symptoms, or

conclusive data on the influence of race/ethnicity, age of onset

of menopause, BMI, oophorectomy status, presence of

5
depression, or smoking status. The literature is limited by

differences in how symptoms are defined and measured,

variability of study populations, and incompatibility of data

preventing direct comparisons between studies or pooling of

results. Future research using standard and validated measures

and uniform definitions for a more comprehensive array of

symptoms would improve knowledge of these associations.

Trials of therapy are conclusive only for estrogen and its use

in treating vasomotor and urogenital symptoms, although other

therapies may prove effective if further studied. Undertaking

trials to treat symptoms that are not clearly associated with the

menopausal transition would not be useful. Trials are limited in

many ways including use of highly selected small samples of

women; short durations; inadequate reporting of loss to follow

up, maintenance of comparable groups, contamination,

methods of analysis, and adverse events; use of dissimilar

measures and outcomes that are often not standardized or

validated; unclear inclusion and exclusion criteria; and industry

sponsorship. Future research addressing these deficiencies, as

outlined in Key Question 5, would guide patient and clinician

decision making when managing menopause related symptoms. 

The evidence review is limited in several ways. For Key

Questions 1 and 2, literature searches focused on population

studies of women undergoing the menopausal transition

reporting symptoms, and did not include epidemiologic or

biologically-based etiologic studies. In addition, studies that

may not have been identified by searches include those in

which menopause was not a primary focus of the study, but a

predictor variable included in a multivariable model evaluating

the outcome or symptom of interest. Studies potentially not

identified would be those that identified no association between

menopausal stage and the outcome of interest. Studies with a

positive association would probably have reported it in the

abstract and be identified by the searches. Also, the review was

limited to English-language randomized controlled trials of

therapies. Exploratory studies of agents may provide

contributory data that were not included in this report.

Availability of the Full Report

The full evidence report from which this summary was taken

was prepared for the Agency for Healthcare Research and

Quality (AHRQ) by the Oregon Evidence-Based Practice

Center, under Contract No. 290-02-0024. It is expected to be

available in March 2005. At that time, printed copies may be

obtained free of charge from the AHRQ Publications

Clearinghouse by calling 800-358-9295. Requesters should ask

for Evidence Report/Technology Assessment No. 120,

Management of Menopause-Related Symptoms. In addition,

Internet users will be able to access the report and summary

online through AHRQ’s Web site at www.ahrq.gov.

Suggested Citation

Nelson HD, Haney E, Humphrey L, Miller J, Nedrow A,

Nicolaidis C, Vesco K, Walker M, Bougatsos C, Nygren P.

Management of Menopause-Related Symptoms. Summary,

Evidence Report/Technology Assessment No. 120. (Prepared by

the Oregon Evidence-based Practice Center, under Contract

No. 290-02-0024.) AHRQ Publication No. 05-E016-1.

Rockville, MD: Agency for Healthcare Research and Quality.

March 2005.

References

1. North American Menopause Society. Available at:

www.menopause.org. Accessed 13 Dec, 2004.

2. Soules MR, Sherman S, Parrott E, al. e. Executive summary: stages of

reproductive aging workshop (STRAW) Park City, Utah, July 2001.

Menopause. 2001;8:402-407.

3. Slavin RE. Best practice synthesis: An alternative to meta-analytic and

traditional reviews. Education Research. 1986;15:5-11.

4. National Center for Complementary and Alternative Medicine.

http://nccam.nih.gov/health/whatiscam/. Accessed 10 Jan. 2005

5. Nelson HD. Commonly used types of postmenopausal estrogen for

treatment of hot flashes: scientific review. JAMA. 2004;291(13):

1610-1620.

6. MacLennan AH, Broadbent JL, Lester S, Moore V. Oral oestrogen

and combined oestrogen/progestogen therapy versus placebo for hot

flushes. Cochrane Database Syst Rev. 2004.

7. Nelson HD, Nygren P, Freeman M, Benjamin K. Drug Class Review

on Estrogens. Final report. http://www.ohsu.edu/drugeffectiveness/

reports/documents/Estrogens%20Final%20Report%20u2pdf.2004.

Accessed 10 Jan. 2005

8. Krebs EE, Ensrud KE, MacDonald R, Wilt TJ. Phytoestrogens for

treatment of menopausal symptoms: A systematic review. Obstet

Gynecol. 2004;104(4):824-836.

9. Harris RP, Helfand M, Woolf SH, et al. Current methods of the third

U.S. Preventive Services Task Force. Am J Prev Med. 2001;20(3S):

21-35.

6

www.ahrq.gov

AHRQ Pub. No. 05-E016-1

March 2005

ISSN 1530-440X
 

Evidence Report 
 
 3 

Chapter 1. Introduction 

Purpose 

This systematic evidence review focuses on five Key Questions relating to symptoms of 

menopause and their management, as specified by the Planning Committee for the National 

Institutes of Health State-of-the-Science Conference on Management of Menopause-Related 

Symptoms: 

1. What is the evidence that the symptoms more frequently reported by middle-aged women 

are attributable to ovarian aging and senescence? These include vasomotor symptoms, 

vaginal dryness, sleep disturbance, mood symptoms, cognitive disturbances, somatic 

complaints, urinary complaints, uterine bleeding problems, sexual dysfunction, and 

reduced quality of life. 

2. When do the menopausal symptoms appear, how long do they persist and with what 

frequency and severity, and what is known about the factors that influence them? Factors 

include race and ethnicity, age at onset of the menopause transition, body mass index 

(BMI), surgical versus natural menopause, depression, and smoking. 

3. What is the evidence for the benefits and harms of commonly used interventions for 

relief of menopause-related symptoms? Interventions include estrogens, progestins, 

androgens, tibolone, antidepressants, other drugs, phytoestrogens, complementary and 

alternative medicine, and behavioral interventions. 

4. What are the important considerations in managing menopause-related symptoms in 

women with clinical characteristics or circumstances that may complicate decisionmaking? These include bilateral oophorectomy, premature ovarian failure, breast cancer, 

concurrent use of selective estrogen receptor modulators (SERMs) and other interacting 

therapeutic agents, lifestyle and behavioral factors, recent discontinuation of menopausal 

hormone therapy, and very low or very high BMI. 

5. What are the future research directions for treatment of menopause-related symptoms and 

conditions? 

The target population includes adult women in the U.S. undergoing menopause. The 

evidence review emphasizes the patient’s perspective in assessment of symptoms, the choice of 

interventions, outcome measures, and potential adverse effects, and focuses on those that are 

applicable to clinical practice. It also considers the generalizability of efficacy studies performed 

in controlled settings. Although the evidence review attempts to assess research findings from 

the perspectives of clinicians and patients, it is not intended to propose practice 

recommendations. 
 4 

Menopausal Transition 

Menopause is defined as the permanent cessation of menses resulting from reduced ovarian 

hormone secretion that occurs naturally or is induced by surgery, chemotherapy, or radiation. 

Natural menopause is recognized after 12 months of amenorrhea that is not associated with a 

pathologic cause. The average age of menopause in the U.S. is 51 years, and can vary normally 

between 40 and 58 years.1 The menopausal transition can span over several years, and often 

begins with variations in menstrual cycle length in response to rising levels of follicle stimulating 

hormone (FSH). The mean age of onset of the menopausal transition is 47.5 years and 

commonly lasts approximately 4 to 5 years.1

 

Stages and nomenclature of the menopausal transition were defined by experts in 2001 at the 

Stages of Reproductive Aging Workshop (STRAW), sponsored by the American Society for 

Reproductive Medicine, the National Institute on Aging, the National Institute of Child Health 

and Human Development, and the North American Menopause Society.2 The group recognized 

seven stages of the reproductive aging continuum, and acknowledged that most women do not 

progress precisely through each stage (Figure 1). These stages are also described by the 

following terms: 

• Premenopause: the time up to the beginning of the perimenopause, but is also used to 

define the time up to the last menstrual period. 

• Perimenopause: the time around menopause during which menstrual cycle and endocrine 

changes are occurring but 12 months of amenorrhea has not yet occurred. 

• Postmenopause: begins at the time of the last menstrual period, although not recognized 

until after 12 months of amenorrhea. 

Menopausal Symptoms 

A hot flash or flush refers to the spontaneous sensation of warmth, often associated with 

perspiration, resulting from a vasomotor response to declining estrogen levels. Although the 

term “flash” indicates a prodromal phase and “flush” the vasomotor dilation phase, they are 

combined in this report because they are reported inconsistently in studies. Nightsweats are hot 

flashes or flushes occurring at night, often while sleeping. Other symptoms, such as vaginal 

dryness, sleep disturbance, mood symptoms, cognitive disturbances, somatic complaints, urinary 

complaints, uterine bleeding problems, sexual dysfunction, and reduced quality of life are also 

attributed to the menopausal transition. 
 5 

Measures of Menopausal Symptoms 

Although many measures have been developed to assess menopausal symptoms, few 

demonstrate standardization, validity, or reliability. Some measures are based on self-reports of 

the presence, severity, and frequency of individual symptoms, such as hot flashes. Others utilize 

cumulative or global scores based on lists or scales of symptoms attributed to menopause, such 

as mood, cognition, quality of life, sexual function, and somatic symptoms. Many studies base 

their measures on study-specific checklists, questionnaires, or scales. Ninety-two measures of 

menopausal symptoms were reported by studies included in this evidence review (Table 1). The 

most common measures are described below. 

The Kupperman Index, or Kupperman Blatt Index, assesses overall menopause symptoms, 

and is frequently used to determine severity of hot flashes. The Kupperman Index grades the 

self-reported severity of 11 symptoms (hot flashes, paresthesias, insomnia, nervousness, 

melancholia, vertigo, weakness, arthralgia or myalgia, headache, palpitations, and formication) 

on a scale from 0 to 3. Item scores are weighted to create a composite score. This measure has 

been validated and is responsive to change, however, it lacks statistical justification for weights.3

The Greene Climacteric Scale assesses the severity of 21 self-reported symptoms on a 4-point 

scale.4 Psychological, somatic, and vasomotor symptoms are assessed, along with one question 

on sexual dysfunction. The Women’s Health Questionnaire was developed for use primarily as a 

quality of life instrument, although it is also used to measure overall symptoms. It includes 36 

items with 4-point self-report response categories. It has demonstrated reliability, has undergone 

psychometric evaluation, and allows for cross-cultural comparisons.3

The Beck Depression Inventory and Hamilton Depression Rating Scale are widely-used and 

validated measures of depression that are highly correlated.5,6 The Hamilton Depression Rating 

Scale is the usual standard against which other depression rating scales are validated. The 

Psychological General Well-Being Index is less commonly used, and has demonstrated validity 

in assessing general psychological well-being.7

The Brief Index of Sexual Functioning for Women is a 22-item validated self-report 

instrument measuring current levels of female sexual functioning and satisfaction, assessing both 

quantitative and qualitative aspects.8

 The McCoy Sex Scale assesses sexual experience and 

responsiveness in the 30 days prior to testing utilizing 14 items on a 7-point scale.9

The Menopause Specific Quality of Life Questionnaire is a validated instrument that assesses 

physical, vasomotor, psychosexual, and sexual domains of life quality using a 7-point scale. A 

difference in one point on a domain score represents a 15 percent change.10 The Nottingham 

Health Profile includes 38 yes/no questions in six subsections (physical mobility, pain, sleep, 

energy, social isolation, and emotional reactions).11 The Short-Form 36 Health Survey measures 

eight health concepts and has been extensively tested and validated.12
7 

Chapter 2. Methods 

Analytic Framework and Key Questions 

The Key Questions for this evidence review were determined by the Planning Committee for 

the National Institutes of Health State-of-the-Science Conference on Management of 

Menopause-Related Symptoms. Key Questions examine a chain of evidence about symptoms 

commonly associated with menopause, factors that may influence the frequency, severity, or 

persistence of these symptoms, the effectiveness, benefits, and adverse effects of interventions 

for managing menopausal symptoms, and how the effects of interventions may differ for women 

with specific characteristics. The analytic framework (Figure 2) outlines the organization of key 

questions by identifying the target population, treatment interventions, health outcomes, and their 

relationships. 

Technical Expert Panel (TEP) and Expert Reviewers 

A Technical Expert Panel (Appendix 1) was assembled to provide input from experts and 

clinicians in the field to ensure that the scope of the project addressed important clinical 

questions and issues. The panel included obstetrician/gynecologists, internists, naturopathic 

physicians, behavioral experts, and researchers. The panel was convened for periodic conference 

calls during the course of the project. Expert reviewers, including several panel members, 

provided comments on the draft evidence report (Appendix 2). 

Literature Search and Strategy 

Relevant studies were identified from multiple searches of MEDLINE, PsycINFO, DARE, 

the Cochrane database of systematic reviews and controlled trials, MANTIS, and AMED (1953 

to November 2004) (Appendix 3). Additional articles were obtained from recent systematic 

reviews, reference lists, reviews, editorials, websites, and by consulting experts. Retrieved 

abstracts were entered into an electronic database (EndNote®). 
8 

Inclusion and Exclusion Criteria 

Key Questions 1 and 2 

Full text cohort studies with data on women experiencing menopause and at least one of the 

symptoms listed in Key Question 1 were initially reviewed and subsequently included if the 

study enrolled 100 or more subjects, subjects represented the target population, and data on 

symptoms associated with menopause were provided. Exclusions included studies of women not 

undergoing the menopausal transition and experiencing menopause related symptoms, studies of 

aging and its effects, and biologically based studies that did not report epidemiological data 

relating to symptoms (e.g., studies of hormone levels) (Appendix 4). Non-English language 

papers and studies of animals or cadavers were also excluded. Cross-sectional studies meeting 

similar inclusion/exclusion criteria were examined for contributory data and included if they 

reported relevant data about symptoms by menopausal stage, such as prevalence rates. 

Key Questions 3 and 4 

Full text randomized controlled trials and meta-analyses of randomized controlled trials 

providing data on treatment of menopausal symptoms, using one or more of the interventions 

listed in Key Question 3, were included. Trials enrolling women with breast cancer were 

considered separately from those enrolling women without breast cancer. Exclusions included 

studies of women not undergoing menopause and experiencing menopause related symptoms 

during the course of the study, studies of animals, and non-English language papers (Appendix 

4). For this report, abstracts of unpublished trials are included in evidence tables, but not in 

summary tables and text. 

Data Extraction and Synthesis 

All eligible studies were reviewed and a “best evidence” approach was applied, in which 

studies with the highest quality and most rigorous design are emphasized.13 Data were extracted 

from each study, entered directly into evidence tables, and summarized descriptively. Benefits 

and adverse effects of therapies were considered equally important and both types of outcomes 

were abstracted. Trials of alternative and complementary therapies were grouped according to 

the National Center for Complementary and Alternative Medicine categories14 most closely 

related to included topics. For this report, acupuncture and Chinese herbal treatments were 

categorized in the alternative healthcare systems category, and lifestyle modifications, such as 

exercise, counseling and education, were placed within the mind-body category. Additional 

categories include biologically based therapies (e.g., red clover), manual medicine (e.g., 

osteopathic manipulations), and energy therapies (e.g., reflexology). 

Results of recently published meta-analyses on estrogens15-17 and isoflavones18 are included 

in this report. No new meta-analyses were conducted because of heterogeneity of trials of other 

therapies.
9 

Two reviewers independently rated the quality of randomized controlled trials and cohort 

studies using criteria specific to different study designs developed by the U.S. Preventive 

Services Task Force (Figure 3).19 Similar criteria for cross-sectional studies are not available. 

The overall rating is a combination of internal and external validity scores. When reviewers 

disagreed, a final rating was reached through consensus. Studies reporting several different 

outcomes may have different quality ratings for each outcome depending on how well it 

measured the symptom and how completely it controlled for key confounders in multi-variable 

models. 

Size of Literature 

A total of 10,059 unique citations were reviewed, including 6,342 about symptoms and 

factors influencing them (Key Questions 1 and 2); 4,078 about interventions (Key Question 3); 

and 806 about specific characteristics that may influence the effects of interventions (Key 

Question 4) (Appendix 5). 
 11 

Chapter 3. Results 

To address Key Questions 1 and 2, 6,342 abstracts were reviewed to identify relevant studies 

evaluating menopause related symptoms and their associations with the menopausal transition. 

The review focused on prospective studies of cohorts of midlife women transitioning through the 

stages of menopause. Forty-nine studies conducted among 14 cohorts met inclusion criteria. 

Seven cohorts were based in the U.S. (Massachusetts Women’s Health Study, 20-25 Seattle 

Midlife Women’s Health Study,26-28 Ohio Midlife Women’s Study,29 National Health 

Examination Follow-up Study [NHANES],30 Study of Women’s Health Across the Nation 

[SWAN],31-39 University of Minnesota/Tremin Trust Longitudinal Study [includes a small 

subset from other countries],40 and Pennsylvania Ovarian Aging Study41,42). Seven cohorts were 

based outside the U.S. (Gothenburg, Sweden,43-45 Australian Longitudinal Study on Women’s 

Health,46,47 Medical Research Council [MRC], U.K.,48-51 Melbourne Women’s Midlife Health 

Project, Australia, 52-62 Manitoba Project on Women and Their Health in the Middle Years, 

Canada,63 Copenhagen, Denmark,64-66 and Eindhoven, Netherlands.67,68). Cohorts are described 

in Table 2, results are listed by symptoms in Table 3, and full details are provided in Appendix 6-

1. 

Major limitations of cohort studies include dissimilar methods for evaluating and reporting 

symptoms and for assessing menopausal change. Some studies based results on cross-sectional 

data reported at serial time points rather than individual tracking of women over time. Some 

studies failed to adjust or stratify for potentially important variables such as age, race, BMI, life 

events, or history of depression when attempting to attribute symptoms to change in menopausal 

stage. Although most included studies were population-based, in many cases, enrolled women 

were additionally selected from the initial recruited cohort and may have been less representative 

of the general population.44,52,53,55,57-59 Also, many studies were based on cohorts recruited from 

community populations and are more representative of volunteers than entire communities. 

A total of 51 cross-sectional studies meeting similar inclusion criteria were obtained to 

provide additional prevalence data including 29 studies from the 14 study cohorts21-25,27,30,33-

40,42,45,48-50,56,60-66,69 and 22 studies from other populations.70-91 Results of cross-sectional studies 

are summarized in Table 4. 

Key Question 1. Symptoms Associated with Menopause 

What is the evidence that the symptoms more frequently reported by 

middle-aged women are attributable to ovarian aging and 

senescence? 

Vasomotor Symptoms 

Four studies from four population-based cohorts evaluated the association between 

vasomotor symptoms and menopausal stage, including three rated good-quality46,51,53and one 
fair.

26 Women transitioning from premenopause to either perimenopause or postmenopause had 

increased vasomotor symptoms in the three good-quality studies.46,51,53 

The prevalence of hot flashes was reported in 33 cross-sectional studies.25,27,33,35-37,40,48,60,62,64,

66-67,69-76,78-85,87-90 Prevalence rates ranged from 14 percent to 51 percent for premenopausal 

women, were approximately 50 percent for perimenopausal women, and between 30 percent to 

80 percent for postmenopausal women, depending on the age and population studied. In one 

study, approximately 29 percent of women age 60 years reported hot flashes, suggesting only a 

modest decline in frequency with increasing time from menopause.66 

Vaginal Dryness 

Vaginal dryness was associated with menopause, and became more common with the 

transition from premenopause to postmenopause, in the one good-quality cohort study examining 

this relationship.53 Thirteen cross-sectional studies37,40,48,69,71,72,74-76,80,83-85 reported prevalence 

rates ranging from 4 percent to 22 percent for premenopausal women, 7 percent to 39 percent for 

perimenopausal women, and 17 percent to 30 percent for early postmenopausal women. Two 

cross-sectional studies showed either no association,84 or a weak association,83 between vaginal 

dryness and menopausal stage. 

Sleep Disturbance 

Three cohort studies evaluated the impact of menopausal status on sleep; two were rated 

good-quality46,53 and one fair.26 In the good-quality studies, women had more difficulty sleeping 

as they progressed through the menopausal stages,46,53 and sleeping difficulty was associated 

with the presence of hot flashes.53 The fair-quality study reported no association.26 

Eighteen cross-sectional studies evaluated the prevalence of sleep disturbance at different 

menopausal stages.25,35-38,48,60,69,78-82,84,85,87,90,92 Of these, eight reported prevalence rates ranging 

from 16 percent to 42 percent for premenopausal women, 39 percent to 47 percent for 

perimenopausal women, and 35 percent to 60 percent for postmenopausal women (including 

women with either surgical or natural menopause and hormone therapy users).37,60,78,80-82,85,90

Some studies,79,82,87 but not others,38,90 reported an association between hot flashes and sleep 

disturbance. When hot flashes/night sweats and insomnia were considered together in one study, 

27 percent of premenopausal women, 46 percent of perimenopausal women, and 38 percent of 

postmenopausal women reported disturbances.25

Four cross-sectional studies reported increased adjusted odds ratios for difficulty sleeping for 

menopausal women compared to premenopausal women37,48,69,92 In one study, an age-adjusted 

significant correlation between sleep problems and menopausal status was reported, but increases 

among perimenopausal and postmenopausal women were small, and social class was a stronger 

predictor.69 A factor analysis of sleep-related problems found sleep was not associated with 

menopausal status.84 In another study, sleep disordered breathing increased across the 

menopausal stages after multivariate adjustment and stratification by BMI and age.92

Mood Symptoms 

Fourteen studies from 11 cohorts evaluated the impact of menopausal stage on 

mood.20,24,26,28-30,41,44,47,51,54,55,63,68

 Of these, seven were rated good-quality,29,41,47,51,54,55,68 four 

 12 
fair,

20,26,28,63

 and three poor. 24,30,44 Symptoms included anxiety,29 depression,20,24,28-30,41,63,68

dysphoric or negative mood,26,54 and positive mood.55 Development of a mental disorder,44

psychological symptom reporting,51 and general mental health47 were also assessed. 

Twelve of the 14 studies, including five good-quality, four fair, and three poor, found no 

influence of menopausal stage on mood symptoms, development of a mental disorder, or general 

mental health.20,24,26,28-30,44,47,51,54,55,63 Two good-quality studies demonstrated a change in mood 

symptoms with the menopausal transition.41,68 A well-designed, nested case-control study of 

age-matched menopausal and premenopausal women from the Pittsburgh cohort found no 

differences between the groups in depression, anger, anxiety, or stress symptoms.

93

Twenty-four cross-sectional studies reported relevant data.22-24,33,35,36,48,50,60,63,64,66,67,69,70,72,

76,80-85,90

 The prevalence of depressed mood ranged from 8 percent to 37 percent for 

premenopausal women, 11 percent to 46 percent for perimenopausal women, 8 percent to 47 

percent for women with natural menopause, and 8 percent to 38 percent for women with surgical

menopause.23,66,67,80,85

Cognitive Disturbances 

No cohort studies longitudinally assessed cognitive symptoms. Eight cross-sectional studies 

showed no differences in the prevalence rates of memory or concentration problems by 

menopausal stage.37,48,67,69,80,81,84,85

Somatic Complaints 

Somatic complaints were evaluated in four studies conducted among three cohorts rated 

good-quality46,47,53 or fair-quality.26 Perimenopausal women had increased somatic symptoms

compared to premenopausal women in one cohort.46,47 Symptoms included back pain, severe 

tiredness, stiff or painful joints, bodily pain, and worse general health. Other studies reported 

reduced breast tenderness,53 or no association with somatic or neuromuscular symptoms.

26

Fourteen of 18 cross-sectional studies evaluating changes in somatic symptoms showed no 

significant increases as women transitioned from premenopause to postmenopause in adjusted 

analytic models.36,37,48,64,66,67,69,71,72,81-85,87 Three studies showed slight increases in somatic 

symptoms during perimenopause that decreased during postmenopause,78,89 or remained stable.67 

Another study showed significantly fewer somatic symptoms for women at menopause 

compared with those at premenopause.90

Urinary Complaints 

Three good-quality cohort studies evaluated the impact of menopausal stage on urinary 

symptoms.

46,53,56 In one study, women who were perimenopausal at baseline were more likely to 

report leakage of urine two years later than women who remained premenopausal.46 Two studies 

from the Melbourne cohort found no association of menopausal status with urinary 

symptoms.

53,56

 

Fourteen cross-sectional studies37,45,48,49,56,60,67,71,75,77,84-87 provided relevant data. Prevalence 

rates of urinary incontinence or leakage ranged from 10 percent to 36 percent for premenopausal 

women, 17 percent to 39 percent for perimenopausal women, 14 percent to 36 percent for 

 13 
 14 

women undergoing natural menopause, and 18 percent to 36 percent for women undergoing 

surgical menopause.37,46,56,67,86

Uterine Bleeding Problems 

No studies meeting inclusion criteria addressed uterine bleeding problems, most likely 

because currently accepted definitions of menopause rely historically on changes in uterine 

bleeding. 

Sexual Dysfunction 

Sexual dysfunction was evaluated in two fair-quality studies from the Melbourne cohort.57,58 

Sexual function was variably measured and included decreased responsivity, decreased libido, 

and/or decreased frequency of sexual activity. In that cohort, women demonstrated decreases in 

some or all of the sexual parameters as they transitioned from early to late perimenopause or 

postmenopause.57,58 

 Thirteen cross-sectional studies, including one from the Melbourne cohort, also evaluated 

sexual function.22,40,42,48,61,65,66,69,83,84,86,89 Five studies showed the prevalence of sexual 

disinterest, dysfunction, or discomfort to increase from premenopause to perimenopause to 

postmenopause,48,61,67,69,86 and four showed no change.40,65,84,89

Reduced Quality of Life 

 Four cohort studies addressed the impact of menopausal stage on quality of life, three rated 

good-quality47,52,59 and one poor.30 Two studies from the Melbourne cohort had conflicting 

results.52,59 One study showed declines in well-being across progressive menopausal stages 

(lowest for the one to two years postmenopause) that improved when women were more than 

two years postmenopause.52 A second study showed increased well-being from early to late 

perimenopause and postmenopause.59 In another good-quality study, women who remained 

perimenopausal over a two year follow-up period reported significant decreases in quality of life 

compared to women who remained premenopausal, although significant decreases were not 

reported by women in other stages.47 A poor-quality cohort study found that well-being was not 

associated with change in menopausal status.30 

Three cross sectional studies also evaluated quality of life.22,34,74 Satisfaction with life,22 and 

impaired functioning34 did not vary with menopausal stage in multivariate regression modeling 

of data from the Massachusetts Women’s Health Study. In another study, various aspects of 

general well-being were lower among postmenopausal women compared to premenopausal 

women.74

Summary 

• Vasomotor symptoms: Evidence from population-based cohort and cross-sectional 

studies supports the association between vasomotor symptoms and menopausal stage. 

Studies are consistent in reporting increasing prevalence rates of vasomotor symptoms as 

women transition from premenopause to either perimenopause or postmenopause, 
 15 

affecting 50 percent or more of women. Studies suggest that vasomotor symptoms 

persist for several years after menopause for some women. 

• Vaginal dryness: Vaginal dryness is associated with menopause and prevalence rates 

increase as women transition through the menopausal stages. Estimates indicate that up 

to one third of perimenopausal and postmenopausal women experience vaginal dryness. 

• Sleep disturbance: Although results of studies are mixed, two good-quality cohort 

studies indicate that women have more difficulty sleeping as they transition through 

menopausal stages, and this may be due to vasomotor symptoms. Up to 40 percent to 60 

percent of perimenopausal and postmenopausal women experience sleep disturbance, a 

slight increase from prevalence rates of premenopausal women. 

• Mood symptoms: The majority of studies from a large literature report no associations 

between menopausal stage and mood symptoms, development of a mental disorder, or 

general mental health. Studies of prevalence rates report wide ranges that are similar 

across menopausal stages. 

• Cognitive disturbances: The few studies evaluating cognitive disturbances in menopause 

have inadequate measures. 

• Somatic complaints: Most studies report no association of somatic symptoms with 

menopause, although somatic symptoms were increased among perimenopausal women 

compared with premenopausal women in one cohort and two cross-sectional studies. 

• Urinary complaints: Urinary leakage increased among perimenopausal women compared 

with premenopausal women in one study, and another reported no associations. Studies 

of prevalence rates report wide ranges that are similar across menopausal stages. 

• Uterine bleeding problems: No studies meeting inclusion criteria addressed uterine 

bleeding problems, most likely because currently accepted definitions of menopause rely 

historically on changes in uterine bleeding. 

• Sexual dysfunction: Women from two study cohorts reported declines in some or all of 

the measured sexual parameters as they transitioned through menopausal stages. Results 

of cross-sectional studies are mixed. 

• Reduced quality of life: Results of available cohort and cross-sectional studies are 

conflicting. 
 16 

Key Question 2. Factors Influencing Symptoms 

When do the menopausal symptoms appear, how long do they persist 

and with what frequency and severity, and what is known about the 

factors that influence them? 

Included studies do not characterize the severity and duration of specific symptoms, and 

frequency is described by prevalence data in Key Question 1.

Race and Ethnicity 

Two cohort studies38,41 addressed the influence of race and ethnicity on menopausal 

symptoms, while many adjusted for it in multivariable models. Depression was reported more 

often among African American women compared to Caucasian women,41 and sleep difficulties 

were reported more often among Caucasian and Hispanic women and less often among African 

American, Chinese, and Japanese women.38 

Seven cross-sectional studies conducted in the large SWAN cohort also evaluated symptoms 

by race or ethnicity.33-37,39,70 In SWAN, vasomotor symptoms were reported more often among 

African American women and less often among Hispanic, Chinese, and Japanese women 

compared with Caucasian women.33,37 Japanese, Chinese, African American, and Hispanic 

women reported fewer mood symptoms compared to Caucasian women,33,35,36 although 

“impaired social function” was reported among Hispanic women in two studies34,70 and among 

African American women in one study.34 Hispanic women also reported more bodily pain than 

Caucasian women.34 A cross-sectional study conducted outside the SWAN cohort found that 

Mexican American women had similar prevalence rates of vasomotor symptoms and vaginal 

dryness as Caucasian women.72 

Age at Onset of the Menopause Transition 

Long term studies evaluating menstrual cycles over many years among large cohorts of 

women showed the median onset of menstrual irregularity to begin between the ages of 45 and 

47.5 years with a mean duration of the menopausal transition lasting 5 years.94-96 Factors 

associated with earlier menopause include smoking,97-99 shorter cycle length during menstruating 

years,100 and shorter stature and leaner body weight.101 Factors associated with later age at 

menopause include higher gravidity or parity98,99 and higher BMI.99 

A cross-sectional study reported increased rates of hot flashes among women with 

menopause prior to age 53 after adjustment for other factors.88 Another found that earlier age of 

inception of perimenopause was related to a longer perimenopause stage.21

Body Mass Index (BMI) 

Two good-quality cohort studies evaluated BMI and its effect on symptoms among 

menopausal or perimenopausal women and found that BMI was a significant predictor of urinary 

incontinence,56 but not positive mood.55 A cross-sectional study reported a slight increase in 

vasomotor symptoms (15 percent) among women with a BMI of 27 or greater, although, 
 17 

vasomotor symptoms were less common at the extremes of BMI.37 Lower BMI was 

independently associated with increased hot flashes in another cross-sectional study.88 Three 

cross-sectional studies22,42,74 found no significant differences for increased BMI. Other studies 

evaluating menopausal symptoms adjusted for BMI in multivariate models but did not report the 

contribution of BMI to symptoms.46,47,53,92

Surgical Versus Natural Menopause 

Two good-quality29,56 and one fair-quality cohort studies63 reported data for women with 

surgical menopause. The Ohio Midlife Women’s Study found that hysterectomy was not a 

predictor of anxiety or depression.29 In contrast, a community-based study of women in 

Manitoba, Canada reported that women with hysterectomies had increased odds of depression.63

In the Melbourne Women’s Midlife cohort, surgical menopause was not a significant predictor of 

urinary incontinence.56 Other symptoms were not addressed in these studies. 

Sixteen cross-sectional studies reported symptoms among women with surgical and natural 

menopause.30,38,45,48,56,63-66,70,72,73,80,86,89,90 Four studies showed no significant differences in 

vasomotor symptoms,48,70,80,90 and three studies showed slightly higher rates of vasomotor 

symptoms among women with surgical menopause (seven percent to eight percent higher).64,66,73

Vasomotor symptoms were similar among Japanese and Canadian women with surgical and 

natural menopause in another study.70 Three studies evaluated vaginal dryness; two showed 

similar rates,48,72 and one reported a nine percent higher prevalence among women with surgical 

compared to natural menopause.80 One cross-sectional study found no differences in rates of 

sexual dysfunction by type of menopause,48 and another showed higher rates of urinary 

incontinence (36 percent vs. 22 percent) among women with surgical menopause.86

The prevalence of anxiety and depression was evaluated in four cross-sectional 

studies,66,70,80,89 and two showed higher prevalence rates among women with surgical 

menopause.66,80 In a cross-sectional study from the Massachusetts Women’s Health Study 

evaluating depression, women who had undergone surgical menopause in the previous three 

months were twice as likely as the rest of the cohort to have elevated depression scores.24 

Depression 

The interaction of baseline depression with menopausal stage and/or transition and the 

presence or absence of symptoms was not evaluated in any cohort study. A cross-sectional 

study reported that prior anxiety or depression did not predict menopausal symptoms.48 One 

other cross-sectional study evaluating menopausal symptoms adjusted for depression in a 

multivariate model but did not report the contribution of depression to symptoms.92

Smoking 

Three good-quality studies from the Melbourne Women’s Midlife cohort examined the 

association of smoking status with mood symptoms and urinary incontinence.54-56 In this cohort, 

current smoking was associated with negative mood,54 but not positive mood,55 and was not 

evaluated as an interaction term with menopausal transition or stage. Smoking was not a 

significant predictor of urinary incontinence.56 Two good-quality studies adjusted for smoking in 

multivariate models, but did not report any data for this variable.46,47
 18 

Five cross-sectional studies provide data on smoking and menopausal symptoms.35,37,48,62,88

Two studies showed no association between smoking and menopausal symptoms,37,62 one 

reported that smoking was associated with psychological distress but did not evaluate smoking as 

an interaction term,35 and another showed that smoking at anytime in the past predicted greater 

vasomotor symptoms during menopause.48 Another study reported no association between hot 

flashes and smoking, but identified higher rates of vasomotor symptoms among thin smokers 

than among thin non-smokers.88 Other studies evaluating menopausal symptoms adjusted for 

smoking status in multivariate models but did not report the contribution of smoking status to 

symptoms39,74,92

Summary 

• Included studies do not provide adequate details to characterize the onset, severity, and 

duration of specific symptoms. Frequency is described by prevalence data in Key 

Question 1. 

• Race and ethnicity: The influence of race and ethnicity on menopausal symptoms has not 

been extensively studied. Prevalence rates of vasomotor and mood symptoms vary 

among race and ethnic groups in the large SWAN cohort. 

• Age at onset of menopausal transition: Available studies are inconclusive. 

• Body mass index: Available studies are inconclusive. 

• Surgical versus natural menopause: Studies present mixed results regarding the impact of 

surgical menopause on vasomotor symptoms, vaginal dryness, and mood. Adjustment 

for confounders is necessary because women undergoing hysterectomy differ from 

women with natural menopause in ways that may also influence their menopause related 

symptoms. 

• Depression: Only one cross sectional study was included and reported that prior anxiety 

or depression did not predict menopausal symptoms. 

• Smoking: Available studies are inconclusive.
 19 

Key Question 3. Benefits and Adverse Effects of Therapies 

What is the evidence for the benefits and harms of commonly used 

interventions for relief of menopause-related symptoms? 

Estrogen 

Three recent good-quality systematic reviews and meta-analyses of randomized controlled 

trials of estrogen, alone (unopposed) or combined with progestin or progesterone (opposed), 

describe benefits and harms of various forms, doses, and regimens for treating menopausal 

symptoms. These include a Cochrane review of trials of oral estrogen for hot flashes,16,102,103 a 

meta-analysis of trials of oral conjugated equine estrogen (CEE) and oral and transdermal 

estradiol for hot flashes,15,104 and a review of commonly used types of estrogen for several 

menopausal symptoms.15 Trials were conducted predominantly in the U.S. or western Europe 

and recruited participants from primary care or gynecology practices. Most trials focused on 

healthy menopausal women in their early 50s with baseline symptoms that varied by study. All 

trials were double blind, of 12 weeks duration or more, and rated good or fair quality. 

Vasomotor symptoms. The Cochrane meta-analysis indicated a significant reduction in 

frequency of weekly hot flashes for oral estrogen compared to placebo with a pooled weighted 

mean difference of -17.9 hot flashes per week (95% confidence interval [CI], -22.9 to -13.0; nine 

trials), equivalent to a 75.3 percent reduction in frequency (95% CI, 64.3 percent to 82.3 

percent).16 Severity of symptoms was also significantly reduced compared to placebo (odds ratio 

[OR] 0.13; 95% CI, 0.07 to 0.23; 13 trials). Differences between types of estrogens were not 

determined, although trials of estradiol and CEE predominated. The review also found that the 

reduction in weekly hot flash frequency was similar for opposed and unopposed estrogen 

regimens compared to placebo (opposed: -19.9 per week; 95% CI, -26.7 to -12.6; three trials; 

unopposed: -14.7; 95% CI, -20.1 to -8.7; six trials). Symptom severity seemed to be better 

treated by opposed (OR 0.10; 95% CI, 0.06 to 0.19; 10 trials) than by unopposed estrogen (OR 

0.35; 95% CI, 0.22 to 0.56; four trials), although heterogeneity of trials could also explain this 

difference. 

Hot flash frequency, severity, or both improved in nine of 10 trials of oral estradiol and in all 

11 trials of transdermal estradiol compared to placebo in a review of these agents.15 The pooled 

weighted mean differences in hot flashes were -16.8 per week (95% CI, -23.4 to -10.2; five 

trials) for oral estradiol, and -22.4 per week (95% CI, -35.9 to -10.4; six trials) for transdermal 

estradiol. Results were similar when opposed and unopposed regimens were considered 

separately.15 All eight trials of oral CEE reported statistically significant improvements in hot 

flash frequency, severity, or both compared with placebo. One trial of CEE that provided data 

comparable to the estradiol meta-analyses reported a mean reduction of -19.1 hot flashes per 

week (95 percent CI, -33.0 to -5.1). Four trials comparing estrogen agents head-to-head (CEE 

compared with oral or transdermal estradiol) indicated improved number and severity of hot 

flashes for all treatment groups with no significant differences between them (pooled weighted 

mean difference in hot flashes -0.3; 95 percent CI, -3.4 to 2.7; three trials). 

In a review of 32 trials of estrogen for treatment of vasomotor symptoms, all but five were 

less than one year in duration and only three trials enrolled more than 500 participants, limiting 
 20 

evaluation of adverse effects.15 Trials reported multiple specific adverse effects including 

atypical bleeding and endometrial hypertrophy, nausea and vomiting, breast tenderness, 

headache, weight change, dizziness, venous thromboembolic events, cardiovascular events, rash 

and pruritus, cholecystitis, liver effects, and other adverse events. These outcomes were reported 

unevenly across studies and could not be combined in summary statistics. Trials included in the 

Cochrane review indicated similar adverse effects with breast tenderness and uterine bleeding 

most commonly reported.16

Urogenital symptoms/sexual dysfunction. In a systematic review of good and fair-quality 

trials of a variety of estrogen agents, urogenital symptoms improved in eight of nine trials, and 

sexual function (including pain during intercourse and responses to questionnaires) in eight of 11 

trials.15 Vaginal forms of estrogen were evaluated in five trials. In a placebo controlled trial, 

vaginal dryness and pain during intercourse improved with use of the estradiol intravaginal ring 

compared to placebo.105 A trial of the estradiol intravaginal ring and oral estradiol reported 

improved vaginal dryness, involuntary loss of urine, and pain during intercourse for both 

groups.106 Head-to-head trials comparing the intravaginal estradiol ring with CEE vaginal cream 

among women with signs and symptoms of urogenital atrophy indicated that the two agents were 

comparable for relief of vaginal dryness and pain during intercourse, resolution of atrophic signs, 

improvement in vaginal mucosal maturation indices, and reduction in vaginal pH.107,108 Similar 

findings were reported in a trial of the estradiol vaginal tablet and CEE cream.109

Four placebo controlled trials of transdermal estradiol indicated improvements in some, but 

not all, urinary and sexual symptoms. Two trials reported improvements in responses to the 

McCoy Sex Scale Questionnaire compared to placebo,9,110 although, another trial indicated no 

differences for symptoms of vaginal discomfort, loss of libido, and incontinence.111 Another trial 

of transdermal estradiol indicated improvement in vaginal dryness, but not pain during 

intercourse, frequent urination, dysuria, stress incontinence, and nocturia, compared to 

placebo.112 

A trial of oral CEE reported significantly improved vaginal dryness and urinary frequency, 

but no significant improvement on six other items related to sexual function on a General Health 

Questionnaire compared to placebo.113 A trial comparing oral CEE and transdermal estradiol 

indicated that the majority of women reported either no change or improvements in vaginal 

dryness and itching, pain during intercourse, and urinary pain and burning in all treatment groups 

with no major differences between groups.114 All treatment groups demonstrated improved 

vaginal cytology, measured by the maturation index, with the biggest improvement in the higher 

dose estradiol group (0.1 mg/day). 

Sleep disturbance. Improved measures of sleep were specifically reported in three trials 

included in the systematic review.15 Transdermal estradiol provided significant improvements 

in sleep quality, sleep onset, and decreased nocturnal restlessness and awakening compared to 

placebo.115 In a subanalysis of the Women’s Health Initiative (WHI) that considered women ages 

50 to 54 years old who reported moderate to severe vasomotor symptoms at baseline, there was a 

positive effect on sleep disturbance with CEE compared to placebo.116 In contrast, a trial of 

CEE in women with hot flashes and nighttime awakening at baseline indicated improvement in 

menopausal symptoms and measures of psychological well-being, but not in parameters of sleep 

quality such as total sleep time, sleep onset time, number of awakenings, and REM sleep 

duration compared to placebo.117 
 21 

Mood symptoms. Thirteen trials of estrogen reporting mood and depression outcomes met 

eligibility criteria (Table 5, Appendix 6-2), including three trials rated good-quality,118-120 four 

fair,121-124 and six poor.125-130 Trials compared placebo with CEE,119,121,124,126,128 oral 

estradiol,120,122,125 transdermal estradiol,118,126 piperazin oestrone sulphate,129,130 and estropiate.127

Head-to-head comparisons included estradiol and estradiol valerate,123 CEE and clonidine,128

CEE and raloxifene,119 and estradiol and raloxifene.120 

Two of the four good and fair-quality placebo controlled trials reporting between group 

differences found improved depressive symptoms among women using transdermal estradiol118

and oral estradiol with norethindrone acetate.122 No differences were found in trials comparing 

placebo with CEE/medroxyprogesterone acetate (MPA)121 or placebo with CEE.119 There were 

no differences in symptoms when comparing estradiol with estradiol valerate123 and estradiol 

with raloxifene.120 Another trial indicated improved anxiety with raloxifene vs. CEE, but no 

differences in depressed mood.119

Reduced quality of life. In a systematic review,15 four trials of transdermal estradiol,112,131-

133 two trials of oral estradiol,122,134 and one trial of esterified estrogens135 indicated improved 

health related quality of life and well-being compared to placebo, as measured by various 

instruments. In a subanalysis of the WHI that considered women ages 50 to 54 years old who 

reported moderate to severe vasomotor symptoms at baseline, there was no effect on healthrelated quality of life measures on the RAND 36-item Health Survey, despite significant 

improvements in vasomotor symptoms.116 A head-to-head comparison of CEE vs. transdermal 

estradiol utilizing the Menopause Specific Quality of Life Questionnaire indicated improvement 

in all areas with no significant differences between groups.136

Progestin/progesterone 

A total of 244 abstracts were identified and five randomized controlled trials met inclusion 

criteria (Table 6),137-141 including one rated good-quality,137 one fair,138 and three poor.139-141

Studies included transdermal progesterone,137,138 intramuscular progesterone,139

medroxyprogesterone acetate (MPA) tablet,141 and MPA injection.140 

Two trials of transdermal progesterone report conflicting results. A good-quality trial 

reported no differences between progesterone (32 mg/day) and placebo groups for vasomotor or 

somatic symptoms, mood, or sexual feelings as measured on previously validated instruments.137

A fair-quality trial of a lower dose (20 mg/day) reported significant reductions in vasomotor 

symptoms, but not depression scores, with progesterone compared to placebo (83 percent vs. 19 

percent; p<0.001).138 A poor-quality trial of intramuscular progesterone described small 

differences between groups, however, the clinical significance of these are unclear.139 Two poorquality trials of MPA did not provide adequate statistical comparisons.140,141

None of the trials reported adverse effects. 

Androgens 

Testosterone. A total of 1,095 abstracts were identified from a search for trials of androgens 

that included testosterone and dehydroepiandrosterone (DHEA). Of these, 10 trials of 

testosterone met inclusion criteria including one rated good-quality,142 four fair,144-146,148 and five 
 22 

poor143,147-149,151 (Table 7, Appendix 6-3). Major limitations of studies include few subjects, 

undefined inclusion and exclusion criteria, use of unclear outcome measures, and using open 

label rather than double blind methodology. Two additional studies were reported in abstract 

form and are included only in the evidence table (Appendix 6-3).152,153

Trials used methyltestosterone,142,143,145-149 testosterone undecanoate,150,151 and transdermal 

testosterone.144 All trials combined testosterone with estrogen and compared it head-to-head with 

estrogen, and two studies compared it with placebo.144,149 Outcomes included sexual 

dysfunction,142,144-146,150,151 hot flashes,143-149 mood,144,145,147,149,150 sleep disturbances,143,145,147-149

vaginal dryness,143,146-149 and quality of life.144,145,150

Only one good-quality and two fair-quality trials reported statistical comparisons between 

testosterone/estrogen and estrogen or placebo groups.142,143,144 One trial indicated no differences 

between testosterone/estrogen and estrogen alone for hot flash severity, vaginal dryness, or sleep 

problems.143 Sexual interest and responsiveness were improved with testosterone/estrogen 

compared to estrogen alone based on scores on the Sexual Interest Questionnaire in another 

trial.142 Sexual symptoms were also improved in a trial comparing testosterone/estrogen with 

placebo.144 

Adverse effects were reported in all 10 trials. Acne142,143,146,148 and hirsutism146,148 occurred 

significantly more often among women using methyltestosterone/estrogen than with estrogen 

alone. Adverse effects were not always separated by treatment group, making it difficult to 

determine which drug was responsible for the reported effect.144,149-151 

Dehydroepiandrosterone (DHEA). One fair-quality154 and one poor-quality155 randomized 

controlled trial met inclusion criteria (Table 7, Appendix 6-4). Studies were small, lacked clear 

exclusion criteria,155 and had high losses to follow up.154

Trials used dehydroepiandrosterone (DHEA)154 and dehydroepiandrosterone sulfate 

(DHEAS)155 alone154,155 or combined with transdermal estradiol.155 No significant differences 

between DHEA and placebo were determined on any measures of symptoms including hot 

flashes, vaginal dryness, insomnia, depression, urinary difficulties, libido, concentration, 

dizziness, forgetfulness, irritability, aches, anxiety, headaches, and fatigue in the one trial 

reporting between group differences.154 

Adverse effects were reported for DHEA only and included paresthesia of an upper 

extremity.154 

Tibolone 

A total of 162 abstracts were reviewed and 20 randomized controlled trials met inclusion 

criteria (Table 8, Appendix 6-5) including three rated good-quality,156-158 four fair,159-162 and 13 

poor.163-175 Four additional studies were reported in abstract form and are included only in the 

evidence table (Appendix 6-5).176-179

Trials compared tibolone with estrogen alone,169 estrogen combined with progestin or 

progesterone,158-160,162,163,166,170,171,173-175or placebo.156,157,161,164,165,167,168,172 Outcomes included hot 

flashes, sexual dysfunction, mood, uterine bleeding, somatic complaints, vaginal dryness, sleep 

disturbance, cognitive effects, urinary complaints, and quality of life. 

Three good or fair-quality trials reported between group differences for tibolone and 

placebo.156,157,161 Results indicated improved hot flashes,157 sleep,157 and somatic complaints156
 23 

with tibolone, but no differences between groups in Greene Climacteric Score,156 quality of 

life,157,161 or mood, energy, pain, social isolation, or urinary symptoms.157

Four good or fair-quality trials reported between group differences for tibolone and estrogen 

alone or estrogen combined with progestin or progesterone.158-160,162 Two trials indicated 

improved hot flashes with estrogen compared to tibolone.159,160 Sexual interest, drive, and/or 

performance were improved with tibolone compared to CEE/MPA in another trial.160 No 

differences between groups were determined for several other menopause related symptoms.158-

160,162 

Uterine bleeding was increased with tibolone in four trials,157,167,168,180 decreased in two,159,167

and was not significantly changed in four others.158,162,163,174 Uterine bleeding was dose related in 

two studies.168,180 Adverse effects that occurred significantly more often among women using 

tibolone than placebo were reported in 16 of 20 trials and included body 

pain,156,160,163,164,166,170,174,175 weight gain,156,158,160,164,166,169,175 and headache.156,160,163,166,167,170

Four studies did not report adverse effects.162,171-173

Antidepressant drugs 

A total of 184 abstracts were reviewed and eight randomized controlled trials met inclusion 

criteria including one trial rated good-quality,181 three fair,182,183,188 and four poor184-187 (Table 9, 

Appendix 6-6). Trials used paroxetine,181 venlafaxine,183 moclobemide,188 and veralipride.182,184-

187 Most studies were limited by small sample sizes, short durations of follow-up, lack of followup data, inadequate descriptions of inclusion criteria, and, in one trial, lack of blinding.187

Selective serotonin reuptake inhibitors (SSRIs). A good-quality trial of paroxetine 

reported statistically significant reductions in mean hot flash frequency and hot flash composite 

score at two doses compared with placebo.181 No differences were detected in sleep, depression, 

anxiety, sexual interest, disability, or side effects.181 A fair-quality trial of venlafaxine reported 

improvement on a single item measuring how significantly hot flashes interfered with daily 

activities compared to placebo, but no differences in hot flash frequency or severity as measured 

on daily diaries.183 The venlafaxine group also had improved mood and vitality compared with 

placebo.183 Other trials of SSRIs enrolled women with breast cancer and are described below. 

Moclobemide. A fair-quality trial evaluating two doses of moclobemide showed reduced 

hot flash composite scores with moclobemide at both doses, although comparisons with placebo 

were not reported.188 This trial was further limited by including only 30 participants and lasting 

only five weeks. 

Veralipride. Veralipride, an antidopaminergic drug, was evaluated in five trials; one rated 

fair-quality182 and four poor-quality.184-187 Two poor-quality trials comparing veralipride to 

placebo reported reduced rates of hot flashes with veralipride.184,185 Of the two studies comparing 

veralipride to estrogen, a poor-quality trial found that veralipride had less benefit,187 and a fairquality trial found it to be equivalent.182 

In four of the five studies, the side effects of mastodynia and/or galactorrhea occurred more 

frequently in the veralipride group. 
 24 

Other Drugs 

A total of 51 abstracts were identified and 15 randomized controlled trials met inclusion 

criteria (Appendix 6-7). Trials used clonidine,128,189-197 gabapentin,198 methyldopa,199-201 and 

Bellergal Retard.202 Major limitations of trials include few subjects, lack of clear inclusion and 

exclusion criteria, high attrition or loss to follow up, no washout period in crossover trials, lack 

of data for pre-crossover comparisons, and short treatment duration. 

Clonidine. Clonidine was compared to placebo in eight trials,189-195,197 and compared to 

other active drugs in trials with lisuride, sodium valproate, transdermal estradiol,195 and CEE and 

medrogestone128,196 (Table 10). Two trials were rated fair-quality,189,192 and eight were 

poor.128,190,191,193-197 Outcomes included hot flashes, insomnia, and mood symptoms.

Of the trials for which pre-crossover statistics were provided or could be calculated, there 

were no statistically significant differences between clonidine and placebo in the improvement of 

hot flash symptoms.189,191,192 In the non-crossover placebo controlled trials, one trial reported 

that clonidine was more effective than placebo in reducing hot flash frequency and intensity,195

and the other found no differences between groups in number of hot flashes, although women on 

clonidine were significantly more likely to report a decrease in subjective frequency, severity, 

and duration of hot flashes.197 Of the 3 remaining crossover studies reporting only summary 

statistics,190,193,194 one trial demonstrated that clonidine was more effective than placebo in 

reducing the number of hot flashes and improving subjective hot flash measures.193 Two headto-head trials found that estrogen, not clonidine, effectively decreased the number of hot flashes 

and improved measures of depression and anxiety.128,196 Two trials found no differences 

between clonidine and placebo in measures of psychological symptoms,191,192 and one found no 

difference in frequency of insomnia.192 

Adverse effects were reported in six of 10 trials; dry mouth occurred more frequently in 

women taking clonidine than placebo,189,191,193 and blood pressure was not affected by 

clonidine.189,190,192-194,197

Methyldopa. Three crossover trials, two rated fair-quality200,201 and one poor,199 compared 

methyldopa with placebo (Table 11). All trials provided pre-crossover statistics regarding 

improvement in hot flash frequency and none found significant differences between groups. A 

fair-quality study reporting post-crossover data separately found that methyldopa was more 

effective than placebo in reducing the number of hot flashes and improving Visual Analog 

Scores after crossover.201 

All trials noted substantially more adverse effects with methyldopa than placebo. Fatigue or 

drowsiness, dizziness, and dry mouth occurred more often among women using methyldopa than 

placebo. One patient on methyldopa developed a lupus-like rash.200 No significant changes in 

blood pressure were noted,199,201 however, one study reported orthostatic hypotension in one 

patient.200 

 

Gabapentin. In a good-quality study comparing gabapentin to placebo, hot flash frequency 

and a composite menopause symptom score were significantly improved with gabapentin (Table 

11).198 No significant differences in mood, quality of life, Patient Global Impression of Change 

scores, and sleep quality were detected.198 
 25 

Gabapentin use reduced levels of albumin, total protein, total bilirubin, blood urea nitrogen, 

and platelets compared to placebo. Somnolence, dizziness, rash, and peripheral edema were 

reported for gabapentin but not placebo. Fifty percent of the gabapentin group and 28 percent of 

the placebo group reported at least one adverse event. 

 

Bellergal. One poor-quality trial compared Bellergal Retard, a combination of 0.6 mg 

ergotamine, 40 mg phenobarbital, and 0.2 mg levorotatory alkaloids, with placebo (Table 11).20 

There were no statistically significant differences between Bellergal and placebo in measures of 

vasomotor symptoms, insomnia, nervousness, hyperirritability, headache, paresthesia, loss of 

libido, and dizziness. 

Adverse effects were similar between groups and included dry mouth, dizziness, and 

sleepiness. 

Phytoestrogens 

A total of 195 abstracts were identified and 21 randomized controlled trials met inclusion 

criteria (Table 12, Appendix 6-8). Trials used dietary soy isoflavones,203-213 soy isoflavone 

extracts,214-218 other forms of phytoestrogens,219-223 and phytoestrogens combined with other 

agents.224 Eight additional studies were reported in abstract form and are included only in the 

evidence table (Appendix 6-8).225-232 

Soy isoflavones—dietary. Dietary forms of soy isoflavones were compared to placebo in 10 

trials (Table 12) that included soy powder,203,204,211,213 cereal,205 drink,206,212 diet,208,211 flour,209

and tablets.207,210 Of these, seven were rated fair-quality,203,204,206,207,209-212 and three 

poor.205,208,213 Outcomes included hot flashes, sleep, mood or depression, vaginal dryness, sexual 

symptoms, scores on symptoms scales, and single trials reporting palpitations, headaches, and 

general health. 

Of the eight trials providing between group comparisons, one fair-quality and one poorquality trial reported improved hot flashes with soy compared to placebo203,204,213 and six 

reported no differences.205,206,209-212 A fair-quality trial of soy powder reported improved hot 

flash frequency with soy compared to placebo (44 percent vs. 31 percent, p<0.01), but no 

differences between groups on the Kupperman Index.203,204 A poor-quality trial of soy protein 

tablets indicated improved severity of hot flashes and improved hypoestrogenic symptoms score 

with soy, but no differences in number of hot flushes, night sweats, sleep disturbance, or general 

health score.213 In most trials, hot flashes improved in both soy and placebo groups,203,204,206,209-

212 although in two trials rated poor-quality, the placebo group reported improved symptoms 

while the soy group did not.205,208

Soy isoflavones—extract. Soy isoflavone extracts were compared to placebo in five trials 

(Table 12), including four rated fair-quality,214-216,218 and one poor.217 Outcomes included hot 

flashes, cognitive tests, scores on the Greene Climacteric Index, and mood. 

Of the three trials providing between group comparisons and hot flash outcomes, all reported 

improved hot flash frequency216,217 or severity218 with soy compared to placebo, and one trial 

reported no differences in frequency of night sweats.218 The Greene Climacteric Scale score was 

improved with soy compared to placebo in one trial,217 but not the other.215 Performance on 
 26 

cognitive tests, including tests of memory, improved with soy compared to placebo in the two 

trials evaluating this outcome.214,215 Mood was not improved with soy in one trial.215 

A trial reporting adverse effects of isoflavones indicated an increased rate of endometrial 

hyperplasia after five years of using 150 mg/day of isoflavone soy supplement.233

Other phytoestrogens. Phytoestrogens were compared to placebo in five trials (Table 12), 

including two rated fair-quality221,223 and three poor.219,220,222 Trials included diet,219 topical 

cream,220,222 and genistein tablets.221,223 One trial included a comparison group using estradiol 

and noresthisterone.221 Outcomes included hot flashes in all trials, vaginal dryness, scores on 

menopausal symptom scales, mood, sexual symptoms, and energy level. 

Three of five trials providing between group comparisons and hot flash outcomes reported 

improved hot flash severity219 or score221,223 with phytoestrogen compared to placebo. Two trials 

reported no differences compared to placebo in frequency and severity of hot flashes222 or 

Kupperman Index score,223 and another indicated that the hot flash score was better with 

estradiol and noresthisterone than genistein.221 Vaginal dryness was improved with 

phytoestrogen diet in one trial,219 but there were no significant differences in overall symptom 

scores.219 A trial of wild yam cream found no differences in mood, libido, or energy level.222

Combinations. A poor-quality trial of soy based isoflavones combined with C. racemosa

(black cohosh) reported improved hot flush symptoms with treatment compared to placebo, as 

reported on a questionnaire.224

Complementary and Alternative Medicine 

A total of 1,237 abstracts were identified and 28 randomized controlled trials met inclusion 

criteria (Table 13, Appendix 6-8). Trials used acupuncture,234-236 Chinese herbs,237-242 red 

clover,243-248 black cohosh,249 combinations,250 other supplements,251-259 manual therapies,260 and 

energy therapies.261 Four trials were reported in abstract form and are included only in the 

evidence table (Appendix 6-8).227,231,262,263 

Acupuncture. Four small trials compared a series of acupuncture treatments specific to 

menopausal symptoms with alternate nonspecific acupuncture procedures (Table 13).234-236,264 Of 

these, one trial was rated fair-quality264 and three poor.234-236 The fair-quality trial found no 

differences between groups in any measures,236 while a poor-quality study reported improved 

mood in the treatment group, but no differences in menopausal symptoms or well-being.235 A 

poor-quality trial compared acupuncture treatment specific to menopausal symptoms to both 

nonspecific acupuncture and estrogen and found a more pronounced improvement in hot flashes 

with estrogen than acupuncture.264 

Chinese herbs. Three fair-quality trials240-242 and three poor-quality trials237-239 of Chinese 

herbs met criteria for this review. Five trials compared herbs against placebo238-242 and two 

against CEE/MPA237,242 (Table 13). Treatments included specific formulations of herbs,237,238

ginseng,239,241 dong quai,240 and an herbal remedy (pueraria lobata) combined with isoflavone.242

Outcomes included hot flashes and other vasomotor symptoms, mood and depression, well-being 

and quality of life, memory, somatic symptoms, sexual symptoms, and general health. Studies 

were small, had short durations, and included highly selected populations. 
 27 

A fair-quality trial comparing ginseng with placebo reported significant improvements for 

depression, well-being, and health scores on the Psychological General Well Being Index, but no 

differences in hot flashes or scores on other instruments.241 Results of two other fair-quality 

placebo controlled trials indicated no differences between groups for menopausal 

symptoms,240,242 well-being,240,242 or rate of learning.242 

Red clover. Red clover isoflavone tablets (Promensil and Rimostil) were compared against 

placebo in six trials (Table 13) including one rated good-quality,247 four fair,243-245,248 and one 

poor.246 Outcomes included hot flashes and other vasomotor symptoms including measures from 

the Greene Climacteric Scale. One of five trials reporting between group comparisons indicated 

improved hot flashes with treatment compared to placebo,248 and no trials reported differences in 

scores on the Greene Climacteric Scale or symptom diary.243,244,246-248 

A good-quality meta-analysis of 25 trials of phytoestrogens for treatment of menopausal 

symptoms included an analysis of red clover using five of the six studies in this review.244-248

Results of the meta-analysis indicated no significant differences in hot flash frequency between 

treatment and placebo groups (weighted mean difference –0.60; 95 percent CI, -1.71 to 0.51).18

Black cohosh. One fair-quality trial compared C. racemosa preparation (black cohosh) with 

estrogen and placebo (Table 13).249 Between group comparisons indicated improved hot flushes 

with estrogen vs. placebo only. 

Combinations. A small poor-quality trial of a botanical formula (burdock root, licorice root, 

motherwort, dong quai, and wild yam) compared with placebo indicated no differences between 

groups in the number and severity of hot flashes (Table 13).250 Results indicated a significant 

decrease in the total number of other types of symptoms after three months of therapy for the 

botanical formula group compared to placebo (p<0.03).250 

Other supplements. Nine trials evaluated effects of other forms of supplements including 

melatonin,251 vitamin E,252 kavakava,253 evening primrose oil with vitamin E,254 guar gum,255

vaginal moisturizer,256,257 phospohlipid liposome injections,258 and S-adenosyl-L-methionine259

(Table 13). Of these, two trials were rated fair-quality253,258 and seven poor.251,252,254-257,259

Outcomes included hot flashes, mood or depression, vaginal dryness, and scores on symptom 

scales.

Between group differences for placebo controlled trials indicated improved symptoms with 

treatment compared to placebo for mood or depression (melatonin, S-adenosyl-Lmethionine),251,259 anxiety (kavakava, phospholipids liposomes),253,258 and scores on symptom 

scales (phospholipid liposomes).258 No differences between groups were found for hot flashes 

(guar gum),255 mood or depression (kavakava),253 and scores on symptom scales (kavakava).253

In a poor-quality trial of evening primrose oil, hot flashes were significantly improved with 

placebo compared to treatment.254 A poor-quality trial comparing vaginal moisturizer against 

dienoestrol vaginal cream reported improved vaginal dryness with dienoestrol.256

Manual therapies. A fair-quality trial of low force osteopathic manipulation of the pelvis, 

spine, and cranium was compared against sham low force touch in similar areas (Table 13).260

After 10 weeks of therapy, results indicated improved hot flashes and nights sweats, urinary 

frequency, depression, and insomnia with treatment compared with placebo.260
 28 

Energy therapies. A poor-quality trial of women undergoing nine sessions of reflexology 

provided over 19 weeks resulted in no differences in severity of hot flashes and night sweats or 

measures of health and well-being compared to women receiving standard foot massages (Table 

13).261

Behavioral Interventions 

A total of 436 abstracts were identified and eight randomized controlled trials met inclusion 

criteria (Table 14, Appendix 6-8). Trials consisted of exercise,265-267 relaxation, 268-270 low 

frequency sound wave audiotape,271 and education interventions.272 Of these, three trials were 

rated fair-quality,265,267,272 and five poor.266,268-271 One additional trial was reported in abstract 

form and is included only in the evidence table (Appendix 6-8).226 

Exercise. Two fair-quality studies evaluated the effects of aerobic exercise using 

comparison groups that underwent stretching activities265 or received usual care267 (Table 14). 

Outcomes included hot flashes and other vasomotor symptoms, mood and depression, cognitive 

function, sleep, well-being, and quality of life. Results of one trial indicated no differences in 

outcomes in the exercise group compared to the stretching group.265 A subset of women 

categorized as recently entering menopause showed improved memory in the aerobic vs. 

stretching group. 265 In a trial of exercise compared to usual care, exercisers showed significantly 

improved quality of life on the Nottingham Health Profile.267 

Other Interventions. A fair-quality trial compared health education with usual care and 

found no differences between groups for measures of mood, health, vaginal dryness, or sexual 

relationships.272 Knowledge of menopause increased in the intervention group, while the control 

group was more likely to attribute symptoms to menopause.272 Other trials rated poor-quality due 

to limitations in methods and/or small numbers of subjects evaluated biofeedback, relaxation, 

paced respiration, and use of audiotapes (Table 14).

Summary 

Results of trials of therapies providing between group comparisons are summarized in Table 

15. Although benefits and adverse effects of therapies were equally important in this review, 

most trials did not report adverse effects or reported them incompletely. Studies of estrogen 

provided the most information. It is unclear how applicable the adverse effects reported from 

other larger estrogen trials, such as the Women’s Health Initiative (WHI), are for younger, 

symptomatic women taking estrogen for brief periods.104 For women in the WHI who reported 

having menopausal symptoms, strokes and coronary heat disease events were not significantly 

elevated.273,274 Other important adverse outcomes, such as breast cancer, thrombosis, and gall 

bladder disease, have not been reported by age and symptom status in this trial. 

Main findings from trials of therapies include: 

• Estrogen, in either opposed or unopposed regimens, is the most consistently effective 

therapy for vasomotor symptoms, and demonstrates benefit in most trials evaluating 
 29 

urogenital symptoms. Some, but not all, trials evaluating sleep, mood and depression, 

sexual function, and quality of life outcomes also report benefit with estrogen compared 

to placebo. 

• Breast tenderness and uterine bleeding are the most commonly reported adverse 

outcomes in estrogen trials; others include nausea and vomiting, headache, weight 

change, dizziness, venous thromboembolic events, cardiovascular events, rash and 

pruritus, cholecystitis, and liver effects. 

• Trials of progestin indicate mixed results for treatment of vasomotor symptoms. 

• Few trials of testosterone are available; one trial indicated no differences between 

testosterone/estrogen and estrogen alone for hot flash severity, vaginal dryness, or sleep 

problems. Sexual symptoms were improved with testosterone/estrogen compared to 

estrogen alone or placebo in two other trials.

• For women using testosterone combined with estrogen, acne and hirsutism occur 

significantly more often than for women using estrogen alone. 

• Based on only a few fair or good-quality trials, tibolone demonstrated benefit for 

vasomotor symptoms, sleep, and somatic complaints compared to placebo, and was 

similar to estrogen for some, but not all, symptoms. 

• Uterine bleeding, body pain, weight gain, and headache were more common in tibolone 

vs. placebo groups. 

• Several agents demonstrate benefits in managing vasomotor symptoms in some, but not 

all trials, or in only a few available trials, including paroxetine, veralipride, gabapentin, 

soy isoflavones, and other phytoestrogens. 

• Trials of soy isoflavones and other complementary and alternative medicine therapies 

report benefits in improving nonvasomotor symptoms, although results vary widely, 

methods are lacking, and studies are typically small and not generalizable. 

• Placebo effects in trials are large reflecting underlying fluctuations of symptoms. 

Key Question 4. Therapies for Women with Specific 

Characteristics 

What are the important considerations in managing menopauserelated symptoms in women with clinical characteristics or 

circumstances that may complicate decision-making? 
 30 

Bilateral Oophorectomy 

A large number of studies reported data on women with bilateral oophorectomies, but did not 

stratify results by this characteristic.142,144-148,150,163,165,169,173,181,188,192,193,195,197,217,242,256 Trials of 

estrogen that exclusively enrolled women with oophorectomies to take unopposed estrogen 

reported similar improvements in vasomotor symptoms as trials of women without 

oophorectomies taking opposed estrogen.16
 31 

Premature Ovarian Failure 

Only one trial of soy isoflavones considered premature ovarian failure, but results were not 

reported specifically for women with this condition.217

Breast Cancer 

A total of 200 abstracts were identified and 15 randomized controlled trials met inclusion 

criteria (Table 16, Appendix 6-9).275-289 Of these, 3 trials were rated good-quality,278,280,285 10 

fair,275-277,279,281-284,287,288 and 2 poor.286,289 Major limitations of trials include small size, lack of 

sufficient detail regarding recruitment and randomization, non blinding, and lack of intention-totreat analyses. Two studies recruited women who either had a history of breast cancer or a 

perceived increased risk of breast cancer,282,283 and all other trials included women who had prior 

diagnoses of breast cancer but no residual disease and who were no longer receiving 

chemotherapy or radiation. Most studies included women taking tamoxifen, although tamoxifenusers represented varying proportions of the study populations (31 percent to 100 percent). 

Results for tamoxifen-users were presented separately in only one trial,276 and in three trials, all 

women were taking tamoxifen.284-286 Study designs did not allow ascertainment of whether 

treatments were addressing a side effect of tamoxifen therapy284-286 or vasomotor symptoms that 

occur naturally in women with a history of breast cancer. All studies recruited women from 

breast cancer clinics. 

Trials used conventional and complementary/alternative medical treatments including 

venlafaxine,282 fluoxetine,283 clonidine,284,285 megestrol acetate,280 various preparations of 

soy/isoflavone products,277-279,288 black cohosh,276,286 magnets,289 vitamin E,275 and a 

polycarbonphil-based vaginal moisturizer.281 All compared treatments with placebo or usual 

care. Outcomes included hot flashes, sleep disturbances, mood, somatic complaints, sexual 

dysfunction, vaginal dryness, quality of life, and overall menopausal symptoms. No trials 

evaluated cognitive symptoms, urinary symptoms, or uterine bleeding. 

Clonidine, venlafaxine, and megestrol acetate were associated with significantly improved 

measures of hot flashes.280,282,284,285 A good-quality trial of oral clonidine indicated a 38 percent 

decrease in hot flashes for clonidine (8 to 5 hot flashes/day) vs. 24 percent for placebo (7.4 to 5.7 

hot flashes/day).285 In a fair-quality trial of transdermal clonidine, hot flashes decreased 44 

percent with clonidine (6.1 to 3.4 hot flashes/day) compared to 27 percent for placebo (7 to 5.1 

hot flashes/day).284 Megestrol acetate reduced hot flashes by 74 percent compared to 27 percent 

for placebo in a good-quality trial.280 A fair-quality trial of venlafaxine reported a mean decrease 

in hot flashes of 30 percent to 58 percent for varying doses of venlafaxine vs. 19 percent for 

placebo.282 Vitamin E, black cohosh, isoflavones, magnets, and fluoxetine alone did not reduce 

hot flashes. 

Results for other outcomes were mixed. Sleep was improved in a fair-quality trial evaluating 

fluoxetine,283 but not in a fair-quality trial using black cohosh.276 None of the four fair-quality 

trials assessing mood (fluoxetine, venlafaxine, phytoestrogen and black cohosh) found them to 

be effective.276,279,282,283 Of the trials evaluating somatic complaints (headaches, palpitations, 

excessive sweating, nausea, fatigue), the only benefit reported was from a single fair-quality trial 

using black cohosh showing improvement of excessive sweating.276 Behavioral counseling with 

tailored therapies was effective at improving sexual functioning in one trial,287 but a fair-quality 

trial of venlafaxine found no difference in libido.282 The one trial evaluating polycarbophil-
 32 

based vaginal preparation found it no more effective than placebo in reducing vaginal dryness, 

but effective at improving dyspareunia scores.281 Of the four trials evaluating quality of life, 

clonidine improved measures,285while fluoxetine, magnets, and behavioral counseling did 

not.282,287,289 Three trials assessed overall menopausal symptoms, of which only behavioral 

counseling was effective.287 

Adverse effects were reported in 12 of 15 trials.275-285,289 Gastrointestinal adverse effects 

occurred more often among women using phytoestrogen products,278,279 particularly a soy 

beverage preparation.278 Two other trials reported no gastrointestinal adverse effects with soy 

preparations,277,288 although one trial excluded all women with intolerance to soy prior to 

randomization. 288 Fluoxetine was associated with worse appetite, nausea, constipation and dry 

mouth than placebo.283 The clonidine patch was associated with dry mouth, constipation, 

itchiness under the patch, and drowsiness.284 Clonidine tablets were associated with a trend 

toward more difficulty sleeping than placebo.285 Participants in the trial of magnets had difficulty 

with itching, redness, and perspiration at the site where magnets were affixed.289 Polycarbophilbased vaginal preparation was associated with an undesirable “wetness sensation.”281

Concurrent Use of Selective Estrogen Receptor Modulators (SERMs) and Other Agents 

Patients using tamoxifen were enrolled in most of the trials of therapies in women with breast 

cancer.275-279,282-287 One fair-quality study of black cohosh reported hot flash symptoms 

separately for tamoxifen users vs. non-users, but found no significant differences between 

groups.276 Other studies of treatment of menopausal symptoms did not describe how concurrent 

use of SERMs affects therapy. 

Lifestyle and Behavioral Factors 

Few trials considered lifestyle and behavioral factors such as smoking, alcohol use, diet, or 

others,161,162,169,170 and no trials reported results according to these factors. 

Recent Discontinuation of Menopausal Hormone Therapy 

Most trials required discontinuation of hormone therapy prior to enrollment, however, no 

results were specifically reported for women with recent discontinuation. 

Very Low or Very High Body Mass Index (BMI) 

Some trials specified a range of acceptable BMIs in their eligibility criteria thereby 

disallowing enrollment of women with very high or low BMI. No studies reported results 

according to BMI. 
 33 

Summary 

• Evidence is not available to determine if the effectiveness of therapy or adverse effects 

differ for women with bilateral oophorectomy, premature ovarian failure, concurrent use 

of SERMs or other potentially interacting agents, lifestyle and behavioral factors, recent 

discontinuation of menopausal hormone therapy, or very low or very high BMI. 

• For women with breast cancer, results of 15 randomized controlled trials indicate that 

clonidine, venlafaxine, and megestrol acetate are associated with significantly improved 

measures of hot flashes, and vitamin E, black cohosh, isoflavones, magnets, and 

fluoxetine are not. Result for nonvasomotor outcomes are mixed. 

Key Question 5. Future Research on Therapies 

What are the future research directions for treatment of menopauserelated symptoms and conditions? 

Although many trials of several types of interventions have been published, results are 

consistent and conclusive only for estrogen agents for the treatment of vasomotor and urogenital 

symptoms. Despite this evidence, many questions remain about the benefits and adverse effects 

of estrogen for treating menopause related symptoms long-term. For nonestrogen therapies, 

larger, more rigorous, and more comprehensive trials are needed in order to determine benefits 

and adverse effects. Funding for nonindustry sponsored trials would enable trials of non drug 

therapies, including head-to-head trials comparing several types of drug and non drug 

interventions. Future research should include: 

• Determination of optimally effective doses, combination regimens, durations of use, and 

timing of therapy. 

• Evaluation of approaches to identify optimal candidates for specific therapies (e.g., 

identification of thrombophilias). 

• Head-to-head and placebo comparisons of estrogen alone and combined with other types 

of therapies including non drug interventions. 

• Trials demonstrating how to discontinue estrogen when symptoms subside, including the 

effectiveness of tapering doses and/or replacing with other therapies including non drug 

interventions. 

• Better reporting of adverse effects in trials and use of standardized categories of adverse 

effects so data can be combined across trials. 
 34 

• Improved analysis of results including analysis by hysterectomy and oophorectomy 

status, stage of menopause, age, concurrent conditions and medications, and other factors. 

• More comprehensive trials to determine the role of regular exercise, sleep management, 

optimal nutrition, healthy relationships, social support, and relaxation; effects of mindbody techniques such as biofeedback and breathing; effects of a whole system approach 

with Chinese medicine. 

• Additional, well-designed and controlled trials of phytoestrogens, botanicals, and bioidentical hormones, especially estriol, estradiol, and progesterone. Further study of 

antidepressants for vasomotor symptoms would be justified based on evidence of 

currently available trials. 

• Enrollment of women with specific characteristics who have not previously been 

evaluated such as nonwhite women, women with premature ovarian failure, those using 

SERMs and other agents influencing symptoms concurrently, women with very high or 

low BMI, and those with lifestyle and behavioral factors influencing symptoms. Trials 

should report data specific to these groups in order to interpret their influence on therapy. 

• Use of standard definitions, measures, and outcomes so results can be compared across 

trials. 
35 

Chapter 4. Discussion 

Based on review of currently available cohort and cross-sectional population studies, 

vasomotor symptoms and vaginal dryness are symptoms most consistently associated with the 

menopausal transition. Sleep disturbance, somatic complaints, urinary complaints, sexual 

dysfunction, mood, and quality of life are inconsistently associated. No studies provide data on 

cognition and uterine bleeding problems, onset, duration, and severity of specific symptoms, or 

conclusive data on the influence of race/ethnicity, age of onset of menopause, BMI, 

oophorectomy status, presence of depression, or smoking status. The literature is limited by 

differences in how symptoms are defined and measured, variability of study populations, and 

incompatibility of data preventing direct comparisons between studies or pooling of results. 

Future research using standard and validated measures and uniform definitions for a more 

comprehensive array of symptoms would improve knowledge of these associations. 

Trials of therapy are conclusive only for estrogen and its use in treating vasomotor and 

urogenital symptoms, although other therapies may prove effective if further studied. 

Undertaking trials to treat symptoms that are not clearly associated with the menopausal 

transition would not be useful. Trials are limited in many ways including use of highly selected 

small samples of women; short durations; inadequate reporting of loss to follow up, maintenance 

of comparable groups, contamination, methods of analysis, and adverse events; use of dissimilar 

measures and outcomes that are often not standardized or validated; unclear inclusion and 

exclusion criteria; and industry sponsorship. Future research addressing these deficiencies, as 

outlined in Key Question 5, would guide patient and clinician decision making when managing 

menopause related symptoms. 

The evidence review is limited in several ways. For Key Questions 1 and 2, literature 

searches focused on population studies of women undergoing the menopausal transition 

reporting symptoms, and did not include epidemiologic or biologically-based etiologic studies. 

In addition, studies that may not have been identified by searches include those in which 

menopause was not a primary focus of the study, but a predictor variable included in a 

multivariable model evaluating the outcome or symptom of interest. Studies potentially not 

identified would be those that identified no association between menopausal stage and the 

outcome of interest. Studies with a positive association would probably have reported it in the 

abstract and be identified by the searches. Also, the review was limited to English-language 

randomized controlled trials of therapies. Exploratory studies of agents may provide 

contributory data that were not included in this report. 

 
 37 

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Figures 
Figure 1. Normal reproductive aging in women

Final Menstrual Period (FMP)

Stages -5 -4 -3 -2 -1 +2

Early Peak Late Early Late* Late

a b1yr 4yrs

82

Endocrine ↑ FSH

*Stages most likely to be characterized by vasomotor symptoms 

Terminology

Perimenopause

Duration of Stage variable variable until de

Reproductive Menopausal Transition

↑ FSH

Amen. x 12mos

Adapted from Menopause Practice: A Clinician's Guide available at: http://www.menopause.org/edumaterials/cliniciansguide/cliniciansguide

normal FSH

Menstrual

Cycles

↑ FSH

variable

to

regular regular

variable

cycle length

(>7 days 

different

from normal)

>2 skipped

cycles and 

an interval

of

amenorrhea

( > 60 days)

+1

Early*

Postmenopause

none
Interventions

Improvedsymptoms

Figure 2. Analytic framework

Women undergoing

Presence of symptoms attributed to menopausePresence of symptoms not attributed to menopause; or no symptoms

Adverse

Effects

2

1

Symptoms persistent, frequent, and severeMild symptoms

3B, 4B3A, 4A

3A, 4A

83
Figure 3. Quality rating criteria

 84

Internal Validity of Randomized Controlled Trials (RCTs) and Cohort Studies 

Criteria 

• Initial assembly of comparable groups: RCTs—adequate randomization, 

including concealment and whether potential confounders were distributed 

equally among groups; cohort studies—consideration of potential confounders 

with either restriction or measurement for adjustment in the analysis, 

consideration of inception cohorts. 

• Maintenance of comparable groups (includes attrition, cross-overs, adherence, 

contamination). 

• Important differential loss to follow-up or overall high loss to follow-up. 

• Measurements: equal, reliable, and valid (includes masking of outcome 

assessment). 

• Clear definition of interventions. 

• Important outcomes considered. 

• Analysis: adjustment for potential confounders for cohort studies, or intention-totreat analysis for RCTs. 

Definition of ratings based on above criteria 

Good: Comparable groups are assembled initially and maintained throughout the study 

(follow-up at least 80 percent); reliable and valid measurement instruments are 

used and applied equally to the groups; interventions are spelled out clearly; 

important outcomes are considered; and appropriate attention to confounders in 

analysis. 

Fair: Generally comparable groups are assembled initially but some question remains 

whether some (although not major) differences occurred in follow-up; 

measurement instruments are acceptable (although not the best) and generally 

applied equally; some but not all important outcomes are considered; and some 

but not all potential confounders are accounted for. 

Poor: Groups assembled initially are not close to being comparable or maintained 

throughout the study; unreliable or invalid measurement instruments are used or 

not applied at all equally among groups (including not masking outcome 

assessment); and key confounders are given little or no attention. 

External Validity 

Considerations 

• Similarities of the populations studied and target population. 

• Similarities of the test or intervention studied to those that would be routinely 

available or feasible. 

• Clinical or social environmental circumstances in the studies that could modify 

the results from those expected in the target population. 
Tables 
Table 1. Measures of menopause related symptoms

Measure

Vasomotor symptoms/Global menopausal symptoms

Blatt Menopausal Index191, 211, 252

Climacteric Index258

Clinical Global Impression Improvement Scale (CGI-I) 181, 227, 259

Daily Symptom Rating Calendar (DSR)154

General Health Questionnaire (GHQ)156, 161

Greene Climacteric Scale (GCS)137, 156, 160, 162, 174, 175, 179, 181, 212, 217, 237, 238, 244, 246, 253, 288

Hopkins Symptom Checklist130

Hot Flash Related Daily Interference Scale (HFRDIS) 289

Kupperman Index146, 148, 155, 203, 204, 220, 227, 236, 264

Measure Yourself Medical Outcome Profile (MYMOP)261, 263

Menopausal Rating Scale249

Menopausal Symptom Index276

Menopausal Symptom Scale263, 287

Menopausal Symptoms Questionnaire (MSQ)205, 219

Menopause Representation Questionnaire (MRQ)272

Neugarten-Kraines Menopausal Index Scale271

Nottingham Health Profile (NHP)126, 157, 267

Patient Global Impression of Change Scale198

Short Form-36 Health Survey (SF36)183, 198, 242, 287

Symptom Check List-90 (SCL-90)235, 266

Visual Analogue Scales (VAS)129, 151, 181, 199, 201, 235, 243, 261, 264, 266, 276, 279

Women's Health Questionnaire (WHQ) 119, 120, 162, 187, 241, 261, 272

Sleep disturbances

Epworth Sleepiness Scale215, 238

Pittsburgh Sleep Quality Index198

Sleep Dysfunction Test236

Sleep Problems Questionnaire187

Stanford Sleepiness Scale215, 238

Mood symptoms

Beck Anxiety Inventory II (BAI-II)181

Beck Depression Inventory (BDI)124, 214, 282, 283

Center of Epidemiological Studies Depression Scale (CES-D) 154

Eysenck Personality Inventory125

Hamilton Anxiety Scale (HAMA)129, 258

Hamilton Depression Rating Scale (HAM-D)129, 130, 154, 259

Hospital Anxiety and Depression Scale215, 238, 263

Irritability, Depression, and Anxiety (IDA)162

Leckie-Withers Test of Liability to Depressive Illness 128

Minnesota Multiphasic Personality Inventory (MMPI)124, 259

Personal Distress Scale (PDS)153

Profile of Mood Scale154

86
Table 1. Measures of menopause related symptoms (continued)

Measure

Mood symptoms (continued)

Profile of Mood States198

Psychological General Well-Being Index (PGWBI) 144, 150, 153, 160, 187, 241, 236

Rome Depression Inventory (RDI)259

Sabbatsberg Distress Self-Rating Scale (SDS) 125

Self-Evaluations Depression Scale253

South African Personality Questionnaire128

Spielberger State-trait Anxiety Inventory253, 269

Zung Self-Rating Depression Scale Questionnaire 138

Cognitive disturbances

Auditory Serial Addition Test215

Boston Naming Test242

Buschke Immediate Recall and Delayed Recall Tests 154

Digit Symbol Substitution Test154

Hong Kong List-Learning Test242

Logical Memory and Recall214

Mini-Biography Questionnaire128

Mini-Mental State Examination (MMSE)214, 242

National Adult Reading Test-Revised238

Neuropsychological Test Battery214

Symbol Copying Test154

Trail Making Test242

Wechsler Adult Intelligence Scales of Digit Span and Digit Symbol 124

Weschler Memory Scale215, 238

Work Ability Index279

Sexual dysfunction

Bem Sex Role Inventory128

Brief Index of Sexual Function for Women (BISF-W) 142, 144, 145

Local Urogenital Complaints Rating Scale (LUCRS) 160

McCoy Sex Scale150, 167, 171, 174

Profile of Female Sexual Function (PFSF) 152, 153

Sabbatsberg Revised Sexual Rating Scale (SRS)145

Sabbatsberg Sexual Self-Rating Scale (SSS)125

Sexual Activity Log (SAL)152, 153

Sexual Behavior Questionnaire187

Sexual Interest Questionnaire (SIQ)142, 145

Sexual Summary Scale287

Quality of life

Cancer Quality of Life Score (European Organization for Research and Treatment) 263

Menopause Specific Quality of Life Questionnaire (MENQOL) 137, 225, 229, 238

Quality of Life Menopause Scale (QUALMS)145

Quality of Life, Enjoyment and Satisfaction Questionnaire (Q-LES-Q) 160

SmithKline Beecham Quality of Life Self Report Questionnaire 154

87
Table 1. Measures of menopause related symptoms (continued)

Measure

Quality of life (continued)

Uniscale QOL instrument282, 283

Other

Collins and Landgren Rating Scale168

Dyadic Adjustment Scale (DAS)156

Finger Tapping Test242

Food Frequency Questionnaire242

Halstead-Reitan214

Heat Stress Test (HST)270

Karolinska Scale158

Kellner and Sheffield Rating Scale191

Profile of Adaptation to Life124

Sheehan Disability Scale181

Uken Motherliness Test128

Vaginal Dryness Index256

Vaginal Health Index257

88
Table 2. Descriptions of cohort studies

Cohort Description

Australian Longitudinal Study on Women's Health

8,236 Australian women 45 to 50 years old in 1996. 

Copenhagen 630 women 40 years old in 1976 selected from 4 municipalities and served by one hospital in 

Copenhagen, Denmark. Women using postmenopausal hormone therapy or who underwent premor surgical menopause were excluded. 

Eindhoven 8,503 women recruited based on responses to an osteoporosis screening study in Eindhoven, 

Netherlands. Women were excluded if non-Dutch White, had hysterectomy with or without oophorectomy, had bilateral oophorectomy, are using postmenopausal hormone therapy, or were noncompliant with one or more items in the questionnaire.

Gothenburg 1,462 women 38 to 60 years old randomly selected in 1968-69 and followed for over 25 years in 

Gothenburg, Sweden. Measures were assessed through periodic medical exams and interviews.

Manitoba Project on Women and Their Health in the Middle Years

A cross-sectional and longitudinal cohort study that enrolled 2,500 women aged 40-59 years old fthe general population of Manitoba, Canada.

Massachusetts Women's Health Study 2,500 premenopausal women from Massachusetts, U.S. Medical Research Council (MRC) National Survey for Health and Development

1,572 women identified from a socially stratified sample of all births in March 1943 in Britain. 

Melbourne Women's Midlife Health Project

Cross-sectional and longitudinal, community-based cohort that enrolled 2,000 women 45 to 55 yefrom Melbourne, Australia. Longitudinal follow up of 492 women has been ongoing since 1991. Tstudy assesses women's health during midlife and the menopause including well being, sexualitysymptoms, and bone density and their relationship to a range of variables including hormones, agstress, lifestyle, and other health experiences.

Minnesota/Tremin Trust Longitudinal Research Program on Women's Health

Longitudinal study that initially consisted of 2,350 University of Minnesota women. Between 1961a second group of 1,600 women was added, and in 1965, a third group of 1,000 native Alaskan wwere added. Women in the study range from teens to mid-nineties and represent fifty states and tfive foreign countries.

89
Table 2. Descriptions of cohort studies (continued)

Cohort Description

National Health Examination Follow-up Study

Sample of 3,049 U.S. women 40 to 60 years old from the National Health and Nutrition ExaminatiSurvey (NHANES).

Ohio Midlife Women's Study 208 women 40 to 60 years old, recruited with advertisements from a community in Ohio, U.S. Co

includes 57% Caucasian, 43% African-American women.

Pennsylvania Ovarian Aging Study Population-based cohort of 436 women from Philadelphia County, Pennsylvania, 35-47 years old 

baseline including 50% African American, 50% Caucasian. Ongoing longitudinal study.

Seattle Midlife Women's Health Study 11,222 women from within Seattle, U.S. census tracts, 35 to 55 years old, including multiple ethni

and income levels and followed for 3 years. All women had active menstrual periods at baseline were excluded if pregnant, using postmenopausal hormones, or non-English reading/speaking.

Study of Women's Health Across the Nation (SWAN)

U.S., community-based, multisite cross-sectional and longitudinal cohort study that enrolled 16,06women 40 to 55 years old. Longitudinal follow up of 3,306 women has been ongoing since 1995. goal of the study is to describe the chronology of the biological and psychosocial characteristics omenopausal transition and its effects on health and risk factors for age-related chronic diseases.

90
Table 3. Results of cohort studies of menopause related symptoms

Study, year Cohort Population N Symptom

Associated 

with change in 

menopausal 

stage? Directio

Vasomotor symptomsBrown, 200246 Australian Longitudinal 

Study on Women's Health

Mid-age (45-50 years) cohort selected from 41,500 Australian women with national health insurance.

8,236 Hot flashes,

night sweats

Yes Hot flashe

groups had ratio vs. prNight sweaodds ratio 

Dennerstein, 200053 Melbourne Women's 

Midlife Health Project

Community-based cohort of 492 women (45-55 years) living in Melbourne, Australia.

172 Hot flashes,

night sweats

Yes Increased 

menopaus

Hardy, 200251 Medical Research 

Council (MRC) 

Socially stratified sample of all births in 1 week in March 1943 in Britain.

1,572 Vasomotor 

symptoms

Yes 

Mitchell, 199626 Seattle Pre- and perimenopausal women 

(35-55 years) identified by census tract in Seattle, including minorities.

301 Vasomotor No 

Vaginal drynessDennerstein, 200053 Melbourne Women's 

Midlife Health Project

Community-based cohort of 492 women (45-55 years) living in Melbourne, Australia.

172 Vaginal 

dryness

Yes Increased 

postmenop

91
Table 3. Results of cohort studies of menopause related symptoms (continued)

Study, year Age at onset Body mass index Race/ ethnicity Smoking Depression

Sur

meno

Vasomotor symptoms (continued)Brown, 200246 NR Adjusted for but NR Adjusted for but NR Adjusted for but NR Adjusted for but NR N

Dennerstein, 200053 NE NR NE Yes, for hot flashes NE Exc

Hardy, 200251 NR NR NR NR NR N

Mitchell, 199626 NA NE NE NE NE Exc

Vaginal dryness (continued)Dennerstein, 200053 NE NR NE NR, presumed not 

significant

NE Exc

Modifiers

92
Table 3. Results of cohort studies of menopause related symptoms (continued)

Study, year Cohort Population N Symptom

Associated 

with change in 

menopausal 

stage? Directio

Sleep disturbanceBrown, 200246 Australian Longitudinal 

Study on Women's Health

Mid-age (45-50 years) cohort selected from 41,500 Australian women with national health insurance.

8,236 Difficulty 

sleeping

Yes Pre-peri, p

had signifipre-pre; onsignificant

Dennerstein, 200053 Melbourne Women's 

Midlife Health Project

Community-based cohort of 492 women (45-55 years) living in Melbourne, Australia.

172 Trouble 

sleeping

Yes Increased 

stages.

Mitchell, 199626 Seattle Pre- and perimenopausal women 

(35-55 years) identified by census tract in Seattle, including minorities.

301 Insomnia No 

Mood symptomsAvis, 199420 Massachusetts Women's 

Health Study

Cohort of premenopausal women sampled from Massachusetts, USA (born 1926-36).

2,565 Depression No Increased 

(2.05; 95% group. No with chang

Busch, 199430 National Health 

Examination Follow-up Study

U.S. women 40-60 years in NHANES.

573 Depression No 

Dennerstein, 199954 Melbourne Women's 

Midlife Health Project

Community-based cohort of 492 women (45-55 years) living in Melbourne, Australia.

354 Negative mood No 

Dennerstein, 200155 Melbourne Women's 

Midlife Health Project

Community-based cohort of 492 women (45-55 years) living in Melbourne, Australia.

267 Positive mood No 

Table 3. Results of cohort studies of menopause related symptoms (continued)

93
Table 3. Results of cohort studies of menopause related symptoms (continued)

Study, year Age at onset Body mass index Race/ ethnicity Smoking Depression

Sur

meno

Sleep disturbance (continued)Brown, 200246 NR Adjusted for but NR Adjusted for but NR Adjusted for but NR Adjusted for but NR N

Dennerstein, 200053 NE NR NE NR, presumed not 

significant

NE Exc

Mitchell, 199626 NA NE NE NE NE Exc

Mood symptoms (continued)Avis, 199420 NR NR NR NR Yes N

Busch, 199430 NR NR NR NR NR Dennerstein, 199954 NE NE NE No NE Exc

Dennerstein, 200155 NE NS NE NS NE ExcTable 3. Results of cohort studies of menopause related symptoms (continued)

ModifiersModifiers

94
Study, year Cohort Population N Symptom

Associated 

with change in 

menopausal 

stage? Directio

Mood symptoms (continued)Freeman, 200441 Pennsylvania Ovarian 

Aging Study

Cohort of 436 African American and Caucasian women age 35-47 years from Pennsylvania, recruited by random digit dialing.

332 Depression Yes Increased 

early and lodds of ma

Glazer, 200229 Ohio Midlife Women's 

Study

Community population based on media recruitment; 40-60 years.

208 Anxiety No 

Glazer, 200229 Ohio Midlife Women's 

Study

Community population based on media recruitment; 40-60 years.

208 Depression No 

Hallstrom, 198544 Gothenburg Systematic sampling of women age 

38-60 years using Taxation Office Register; psychiatric sample selected from this group.

899 Development 

of mental disorder

No 

Hardy, 200251 Medical Research 

Council (MRC) 

Socially stratified sample of all births in 1 week in March 1943 in Britain.

1,572 Psychological 

symptoms(anxiety or depression)

No 

Kaufert, 199263 Manitoba Community population of Manitoba, 

Canada 45-55 years.

469 Depression No 

Maartens, 200268 Eindhoven Women born between 1941-1947 

living in Eindhoven, The Netherlands, participating in Eindhoven Perimenopausal Osteoporosis Study.

2,103 Depression Yes Increase fr

postmenop

McKinlay, 198924 Massachusetts Women's 

Health Study

Cohort of premenopausal women sampled from Massachusetts, USA (born 1926-36).

2,466 Depression No Increased 

months of 

Table 3. Results of cohort studies of menopause related symptoms (continued)

95
Study, year Age at onset Body mass index Race/ ethnicity Smoking Depression

Sur

meno

Mood symptoms (continued)Freeman, 200441 NE NS Yes, increased odds 

of depression in 

African Americans 

vs. Caucasians

NR in multivariate 

model

Yes N

Glazer, 200229 NE NE NE NE Yes Y

Glazer, 200229 NE NE NE NE Yes YHallstrom, 198544 NR NR NR NR NR Exc

Hardy, 200251 NR NR NR NR NR NKaufert, 199263 NE NE NE NE NE Increase

being d

Maartens, 200268 NE NE NE NE NE Exc

McKinlay, 198924 NR NR NR NR NR Y

Table 3. Results of cohort studies of menopause related symptoms (continued)

Modifiers

96
Study, year Cohort Population N Symptom

Associated 

with change in 

menopausal 

stage? Directio

Mood symptoms (continued)Mishra, 200347 Australian Longitudinal 

Study on Women's Health

Mid-age (45-50 years) cohort selected from 41,500 Australian women with national health insurance.

8,623 General mental 

health (SF-36)

No 

Mitchell, 199626 Seattle Pre- and perimenopausal women 

(35-55 years) identified by census tract in Seattle, including minorities.

301 Dysphoric 

mood

No 

Woods, 199728 Seattle Pre- and perimenopausal women 

(35-55 years) identified by census tract in Seattle, including minorities.

347 Depressed 

mood

No 

Somatic complaintsBrown, 200246 Australian Longitudinal 

Study on Women's Health

Mid-age (45-50 years) cohort selected from 41,500 Australian women with national health insurance.

8,236 Back pain Yes Only peri-p

than pre-p

Brown, 200246 Australian Longitudinal 

Study on Women's Health

Mid-age (45-50 years) cohort selected from 41,500 Australian women with national health insurance.

8,236 Headache No All odds ra

97
Study, year Age at onset Body mass index Race/ ethnicity Smoking Depression

Sur

meno

Mood symptoms (continued)Mishra, 200347 NR Adjusted for weight 

but NR

NR Adjusted for but NR NR Exc

Mitchell, 199626 NA NE NE NE NE Exc

Woods, 199728 NE NE NE NE NE ExcSomatic complaints (continued)Brown, 200246 NR Adjusted for but NR Adjusted for but NR Adjusted for but NR Adjusted for but NR N

Brown, 200246 NR Adjusted for but NR Adjusted for but NR Adjusted for but NR Adjusted for but NR N

98
Table 3. Results of cohort studies of menopause related symptoms (continued)

Study, year Cohort Population N Symptom

Associated 

with change in 

menopausal 

stage? Directio

Somatic complaints (continued)Brown, 200246 Australian Longitudinal 

Study on Women's Health

Mid-age (45-50 years) cohort selected from 41,500 Australian women with national health insurance.

8,236 Severe 

tiredness

Yes Severe tire

and HT groodds ratios significant

Brown, 200246 Australian Longitudinal 

Study on Women's Health

Mid-age (45-50 years) cohort selected from 41,500 Australian women with national health insurance.

8,236 Stiff/painful 

joints

Yes Pre-peri, p

significantlpre; others 

Brown, 200246 Australian Longitudinal 

Study on Women's Health

Mid-age (45-50 years) cohort selected from 41,500 Australian women with national health insurance.

8,236 Constipation No Only HT g

odds ratios significant

Dennerstein, 200053 Melbourne Women's 

Midlife Health Project

Community-based cohort of 492 women (45-55 years) living in Melbourne, Australia.

172 Breast 

soreness

Yes Decreased 

menopaus

Dennerstein, 200053 Melbourne Women's 

Midlife Health Project

Community-based cohort of 492 women (45-55 years) living in Melbourne, Australia.

172 Somatic 

symptoms (other than breast soreness)

No 

Mishra, 200347 Australian Longitudinal 

Study on Women's Health

Mid-age (45-50 years) cohort selected from 41,500 Australian women with national health insurance.

8,623 Bodily pain 

(SF-36)

Yes Only peri-p

significantlvs. pre-pre

99
Table 3. Results of cohort studies of menopause related symptoms (continued)

Study, year Age at onset Body mass index Race/ ethnicity Smoking Depression

Sur

meno

Somatic complaints (continued)Brown, 200246 NR Adjusted for but NR Adjusted for but NR Adjusted for but NR Adjusted for but NR N

Brown, 200246 NR Adjusted for but NR Adjusted for but NR Adjusted for but NR Adjusted for but NR NBrown, 200246 NR Adjusted for but NR Adjusted for but NR Adjusted for but NR Adjusted for but NR NDennerstein, 200053 NE NR NE NR NE Exc

Dennerstein, 200053 NE NR NE NR NE ExcMishra, 200347 NR Adjusted for weight 

change and weight at baseline, but contribution NR

NR Adjusted for but NR NR Exc

Modifiers

100
Table 3. Results of cohort studies of menopause related symptoms (continued)

Study, year Cohort Population N Symptom

Associated 

with change in 

menopausal 

stage? Directio

Somatic complaints (continued)Mishra, 200347 Australian Longitudinal 

Study on Women's Health

Mid-age (45-50 years) cohort selected from 41,500 Australian women with national health insurance.

8,623 General health 

perception (SF-36)

Yes Only peri-p

significantlperception

Mitchell, 199626 Seattle Pre- and perimenopausal women 

(35-55 years) identified by census tract in Seattle, including minorities.

301 Neuromuscular No 

Mitchell, 199626 Seattle Pre- and perimenopausal women 

(35-55 years) identified by census tract in Seattle, including minorities.

301 Somatic No 

Urinary complaintsBrown, 200246 Australian Longitudinal 

Study on Women's Health

Mid-age (45-50 years) cohort selected from 41,500 Australian women with national health insurance.

8,236 Leaking urine Yes Only per-p

odds ratio significant

Dennerstein, 200053 Melbourne Women's 

Midlife Health Project

Community-based cohort of 492 women (45-55 years) living in Melbourne, Australia.

172 Urinary 

symptoms

No 

Sherburn, 200156 Melbourne Women's 

Midlife Health Project

Community-based cohort of 492 women (45-55 years) living in Melbourne, Australia.

373 Urinary incontinence No 

Sexual dysfunctionDennerstein, 200157 Melbourne Women's 

Midlife Health Project

Community-based cohort of 492 women (45-55 years) living in Melbourne, Australia.

283 Sexual 

dysfunction

Yes 

101
Table 3. Results of cohort studies of menopause related symptoms (continued)

Study, year Age at onset Body mass index Race/ ethnicity Smoking Depression

Sur

meno

Somatic complaints (continued)Mishra, 200347 NR Adjusted for weight 

change and weight at baseline but contribution NR

NR Adjusted for but NR NR Exc

Mitchell, 199626 NA NE NE NE NE Exc

Mitchell, 199626 NA NE NE NE NE ExcUrinary complaints (continued)Brown, 200246 NR Adjusted for but NR Adjusted for but NR Adjusted for but NR Adjusted for but NR N

Dennerstein, 200053 NE NR NE NR NE Exc

Sherburn, 200156 NE Yes NE Not significant NE YSexual dysfunction (continued)Dennerstein, 200157 NA NA NA NA NA Exc

Modifiers

102
Table 3. Results of cohort studies of menopause related symptoms (continued)

Study, year Cohort Population N Symptom

Associated 

with change in 

menopausal 

stage? Directio

Sexual dysfunction (continued)Dennerstein, 200258 Melbourne Women's 

Midlife Health Project

Community-based cohort of 492 women (45-55 years) living in Melbourne, Australia.

226 Sexual 

dysfunction

Yes Increased 

menopaus

Reduced quality of lifeBusch, 199430 National Health 

Examination Follow-up Study

U.S. women age 40-60 years in NHANES.

573 Quality of life No 

Dennerstein, 199752 Melbourne Women's 

Midlife Health Project

Community-based cohort of 492 women (45-55 years) living in Melbourne, Australia.

438 Quality of life Yes Decreased 

categories

Dennerstein, 200259 Melbourne Women's 

Midlife Health Project

Community-based cohort of 492 women (45-55 years) living in Melbourne, Australia.

226 Well-being Yes Increased 

post meno

Mishra, 200347 Australian Longitudinal 

Study on Women's Health

Mid-age (45-50 years) cohort selected from 41,500 Australian women with national health insurance.

8,623 Quality of life Yes, for peri-peri 

women only

Decreased

CI=Confidence Interval NE=Not Examined Pre=PremenopausalCES-D = Center for Epidemiologic Studies Depression Scale NR=Not Reported SF-36=Short Form-36 HealtHT=Hormone Replacement Therapy Peri=PerimenopausalNA=Not Applicable Post=Postmenopausal

Abbreviations

103
Table 3. Results of cohort studies of menopause related symptoms (continued)

Study, year Age at onset Body mass index Race/ ethnicity Smoking Depression

Sur

meno

Sexual dysfunction (continued)Dennerstein, 200258 NE NE NE NE NE Exc

Reduced quality of life (continued)Busch, 199430 NR NR NR NR NR 

Dennerstein, 199752 NR NR NR NR NR ExcDennerstein, 200259 NE NE NE NE NE Exc

Mishra, 200347 NR Similar body weight 

between groups

NR NR NR Exc

CI=Confidence Interval NE=Not Examined Pre=PremenopausalCES-D = Center for Epidemiologic Studies Depression Scale NR=Not Reported SF-36=Short Form-36 Health SHT=Hormone Replacement Therapy Peri=PerimenopausalNA=Not Applicable Post=Postmenopausal

Modifiers

Abbreviations

104
Table 4. Results of cross-sectional studies of menopause related symptoms

Study, year

Vasomotor

Vaginal 

dryness Sleep Mood

Cognitive Somatic Urinary Uterine bleeding

Sexual 

dysfunction Quality of life

Age at 

onset

Race/

ethnicity BMI

m

Data from study cohortsAvis, 199721

X

X

Avis, 200022 X XX X

Avis, 200133 XX x

Avis, 200334 X X

Bromberger, 200135 X XX X 

Bromberger, 200336 X XX X XBusch, 199430

Dennerstein, 199360 X XX X X

Dennerstein, 199461

X

Gold, 200037 XXX X X X XX 

Gracia, 200442 X XX

Guthrie, 199662

X

Hunter, 198969 X X XX X X X

Kaufert, 199263

X

Koch, 199540 XX X X

Koster, 199364 X XX

Koster, 199365 X Koster, 200266 X XX X 

Kravitz, 200338 

X X 

Kuh, 199748 X X XX X X X X 

Kuh, 199949 X X

Kuh, 200250

X

McKinlay, 198723

X

McKinlay, 198924

X

McKinlay, 199225 X X

Milsom, 199345 X 

Mitchell, 200127

X

Randolph, 200339 XX 

Sherburn, 200156 X X

Main Outcomes

105
Table 4. Results of cross-sectional studies of menopause related symptoms (continued)

Study, year

Vasomotor

Vaginal 

dryness Sleep Mood

Cognitive Somatic Urinary Uterine bleeding

Sexual 

dysfunction Quality of life

Age at 

onset

Race/

ethnicity BMI

m

Data from other populationsAvis, 199370 X X X

Bardel, 200271 XX X XBell, 199572 XX X X X Feldman, 198573

X

Groeneveld, 199374 XX X X 

Hagstad, 198675 XX XHammar, 198476 XX XHording, 198677

X

Jansson, 200379 X X

Jaszmann, 196978 XX XKeenan, 200380 X X XX X X Li, 200281 X XX X XMcKinlay, 197482 X XX XO'Connor, 199583 XX X X XOlofsson, 200084 X X XX X X X XPorter, 199685 X X XX X X XReckers, 199286 XX 

Rybo, 197187 X X XX X

Schwingl, 199488

X X 

Slaven, 199889 X XX X 

Thompson, 197390 X XX X

Young, 200392

X X 

KeyX=statistically significant association between symptom and menopausal stage.

Main Outcomes

106
Table 5. Trials of estrogen for depression

Study, year N

Mean 

age 

(range) Therapy Comparison Duration

Between group 

differences

W

Bech, 1998122

151 Not 

reported

1. Estradiol 2 mg/day and NETA 1 mg/day2. Estradiol 2 mg/day for 22 days, 1 mg/day for 6 days and NETA 1 mg/day for 10 days of cycle 

Placebo 12 

months

Improved scores on Beck Depression Inventory (12 & 21 item scales) with both estrogen groups vs. placebo (p<0.05).

Improved for estrog

Ditkoff, 1991124

36 53

(45-60)

1. CEE 0.625 mg/day days 1 to 25; cyclic2. CEE 1.25 mg/day days 1 to 25; cyclic

Placebo 3 months Not reported Improved 

Depressincome m(p<0.05 fdoses of other meProfile of WechsleScales).

Furuhjelm, 1984125

58

(48 

analyzed)

54

(44-64)

1. Estradiol 1-2 mg/day, estriol 0.5-2 mg/day, and norethisterone acetate 1 mg/day; cyclic2. Estradiol 2-4 mg/day, estriol 0.5-2 mg/day, and norethisterone acetate 1 mg/day; cyclic3. Estradiol 2 mg/day, estriol 1 mg/day All groups combined in analysis

Placebo Crossover; 4

2-month 

phases

Not reported Improved 

distress (p<0.01)depresseimproved (p<0.001General Distress Sexual SEysenck Inventory

Main results

107
Table 5. Trials of estrogen for depression (continued)

Study, year N

Mean 

age 

(range) Therapy Comparison Duration

Between group 

differences

W

Gerdes, 1982128

38 Not 

reported

CEE 1.25 mg/day for 21 days and medrogestrone 5 mg/day from day 16 to 21 followed by 7 days of placebo; cyclic

1. Placebo2. Clonidine 25 mcg twice daily

20 weeks Improved cheerfulness, health, and 

energy with CEE vs. placebo (p<0.001); improved moodiness, feeling relaxed, feeling understood, and self-confidence with CEE vs. placebo (p<0.01).Improved depression score (p<0.01) (Mini-Biography Questionnaire) and less moodiness in CEE vs. clonidine group (p<0.05); no difference in moodiness with clonidine vs. placebo.

Hall, 1998126 60 44-75 1. CEE 0.625 mg/day and 

MPA 5 mg/day; cyclic2. Estradiol 50 mcg patch and MPA 5 mg/day; cyclic

Placebo 1 year Not reported Improved 

in all grodepresseCEE groin estradgroups.

Khoo, 1998121

105 46

(40-52)

CEE 0.625 mg/day and MPA 10 mg/day days 14 to 27; cyclic

Placebo Crossover; 6 

months 

each 

phase

No differences between groups in depressive symptoms during first phase.

Klaiber, 1996127

38 53

(45-65)

Estropiate 1.5 mg/day and norethindrone 1 mg/day 

Placebo Crossover; 56 

days each 

phase

Improved mood symptoms while on estropiate only vs. placebo (anxiety p<0.001, depression and anger p<0.01); no differences while on estropiate and norethindrone.

Main results

108
Table 5. Trials of estrogen for depression (continued)

Study, year N

Mean 

age 

(range) Therapy Comparison Duration

Between group 

differences

W

Saure, 2000123

376 49 Estradiol 1.5 mg/day for 24 

days and desogestrel 0.15 mg/day for 12 days each cycle

Estradiol valerate 2 mg/day for 21 days and MPA 10 mg/day for 10 days of cycle

6 months No differences in mood 

disturbances between groups at end of study.

Improved (self repo

Soares, 2001118

50 49 estradiol, 50 

placebo; 

(40-55)

Estradiol 100 mcg/day transdermal

Placebo 12 weeks Improved depressive symptoms in 

depressed women using estradiol vs. placebo (p<0.001); (Montgomery-Asberg Depression Rating Scale.) 

Improved in both gtreatmen

Strickler, 2000119

373 55

(47-60)

CEE 0.625 mg/day 1. Raloxifene 60 

mg/day2. Raloxifene 150 mg/day3. Placebo

1 year No differences in depressed mood 

between groups. Improved anxiety with raloxifene 60 mg/day vs. placebo (p=0.03), and raloxifene 60 mg/day vs. CEE (p=0.003). No differences with raloxifene 150 mg/day.

Thomson, 1977129

42 49

(45-55)

Piperazin oestrone sulphate 1.5mg twice a day

Placebo 8 weeks No difference in depression, 

anxiety or hot flashes. Improved sleep on estrogen (p<0.05).

Both groimprovemanxiety, 

Voss, 2002120

1008 56 Estradiol 2 mg/day and 

norethisterone acetate 1 mg/day

1. Raloxifene 60 mg/day

6 months Improved depressed mood with 

raloxifene vs. estradiol (p=0.004). No differences in anxiety or fears.

Wheatley, 1977130

58 50

(45-60)

Piperazin oestrone sulphate 1.5 mg twice a day (with amitriptyline)

Placebo (with amitriptyline)

4 weeks No difference in depression 

between groups.

Both groimprovem

AbbreviationsCEE=Conjugated equine estrogensMMPI=Minnesota Multiphasic Personality InventoryMPA=Medroxyprogesterone acetateNETA=Norethindrone acetate

Main results

109
Table 6. Trials of progestins

Study, year N

Mean 

age 

(range) Therapy Comparison Duration Between group differences Within g

Progesteronede Wit, 2001139 10 50-72 Progesterone 

intramuscular injections 25, 50, or 100 mg weekly

Placebo 4 weeks No differences in mood, cognition, or 

behavior. Higher rating of sluggishness in 100 mg group.

Not reporte

Leonetti, 1998231, 

1999138

102 52 Progesterone 

transdermal cream 20 mg/day

Placebo cream 12 months 

in 4 month phases

Improved vasomotor symptoms with progesterone vs. placebo (p<0.001). No differences in depression scores.

Not reporte

Wren, 2003137 80 54 

(43-69)

Progesterone transdermal cream 32 mg/day

Placebo cream 12 weeks No differences between groups on 

measures of vasomotor or somatic symptoms, mood, or sexual feelings.

Not reporte

Medroxyprogesterone acetateMorrison, 1980140

48 45 

(27-59)

Medroxy-progesterone acetate injection 50 mg, 100 mg, or 150 mg weekly

Placebo injection 12 weeks Improved number of hot flashes and 

subjective symptoms with MPA vs. placebo; higher satisfaction with MPA.

Not reporte

Schiff, 1980141 27 50 

(28-67)

Medroxy-progesterone acetate tablet 20 mg/day

Placebo 12 weeks Improved hot flashes in MPA vs. 

placebo (p value not given).

Improved hMPA (74%) groups.

AbbreviationsMPA=Medroxyprogesterone acetate

Main Results

110
Table 7. Trials of Androgens

Study, year N

Mean age 

(range) Therapy Comparison Duration Between group differences Within g

BarrettConnor, 1999146

311 45 (21-65) 1. Esterified estrogen 

0.625 mg/day and MT 1.25 mg/day 2. Esterified estrogen 1.25 mg/day and MT 2.5 mg/day 

1. CEE 0.625 mg/day 2. CEE 1.25 mg/day 

2 years Not reported Improved ho

dryness in asignificant trimprovemensexual intereno differencesymptoms (MScale).

Dobs, 2002145

40 57 (41-76) Esterified estrogen 1.25 

mg/day and MT 2.5 mg/day 

Esterified estrogen 1.25 mg/day

16 weeks Not reported Improved sy

groups. Sigwith MT/estr(Quality of LScale), sexusomatic symmood and co

Floter, 2002150

50 54 (45-60) Estradiol valerate 2 

mg/day and testosterone undecanoate 40 mg/day

Estradiol valerate 2 mg/day 

24 weeks 

cross 

over

Improved enjoyment of sex, satisfaction with frequency, interest in sex, and total McCoy Sex Scale score with testosterone/estrogen vs. estrogen. No significant different in psychological well-being.

Improved moGeneral Wesymptoms (Mand quality oGeneral Wegroups.

Hickok, 1993143

26 52 

treatment; 

50 

comparison

Esterified estrogen 0.625 mg/day and MT 1.25 mg/day

Esterified estrogen 0.625 mg/day

6 months No differences between groups 

in hot flash symptom severity, vaginal dryness, sleep problems (4-point menopausal symptom scale). 

Improved hoseverity, vagproblems in menopausal 

Lobo, 2003142

218 53 (40-65) Esterified estrogen 

0.625 mg/day and MT 1.25 mg/day

Esterified estrogen 0.625 mg/day

4 months Improved frequency sexual 

interest/desire, responsiveness and total Sexual Interest Questionnaire score with MT/ estrogen vs. estrogen, p<0.02.

Improved seresponsivenInterest Queboth groups

Main results

Testosterone

111
Table 7. Trials of Androgens (continued)

Study, year N

Mean age 

(range) Therapy Comparison Duration Between group differences Within g

Penotti, 2001*, 151

40 57 

treatment; 

55 

comparison

Estradiol 50 mcg/day transdermal and MPA 10 mg/day for 12 days/month and testosterone undecanoate 40 mg/day 

Estradiol 50 mcg/day transdermal and MPA 10 mg/day for 12 days/month

8 months No differences between groups 

in sexual symptoms (Visual Analogue Scores). 

Improved sesatisfaction oScale in both 

Raisz, 1996*, 147

18 60 

treatment; 

66 

comparison

Esterified estrogen 1.25 mg/day and MT 2.5 mg/day

CEE 1.25 mg/day 9 weeks Not reported Improved ps

psychologicaMT/estrogen flashes, vagsomatic sym(Modified Kuscale).

Shifren, 2000144

75 47 (31-56) 1. Testosterone 150 

mcg/day transdermal and CEE 2. Testosterone 300 mcg/day transdermal and CEE 

CEE at various doses (0.625, 0.9, 1.25, 1.8, or 2.5 mg/day)

36 weeks 

cross 

over

Improved composite score (p=0.04), depressed mood (p=0.03), and positive well-being (p=0.04) (Psychological General Well-Being Index), and improved sexual symptoms (Brief Index of Sexual Function for Women) with testosterone 300 mcg/day vs. 

placebo (p=0 03)

Not reported 

Simon, 1999149

93 54 1. Esterified estrogen 

0.625 mg/day and MT 1.25 mg/day2. Esterified estrogen 1.25 mg/day and MT 2.5 mg/day

1. Esterified estrogen 0.625 mg/day2. Esterified estrogen 1.25 mg/day3. Placebo

3 months Not reported Improved so

vaginal drynin all nonplaeffect on sle(Kupperman effect for psypsychologica

Watts, 1995148

66 21-60 Esterified estrogen 1.25 

mg/d + MT 2.5 mg/day 

Esterified estrogen 1.25 mg/day 

2 years No differences between groups 

for hot flashes, vaginal dryness, or sleep (modified Kupperman Index with 0-7 scale).

Improved hodryness and (modified Ku7 scale).

Main results

Testosterone (continued)

112
Table 7. Trials of Androgens (continued)

Study, year N

Mean age 

(range) Therapy Comparison Duration Between group differences Within g

Barnhart, 1999154

60 48 (45-55) DHEA 50 mg/day Placebo 3 months No differences between groups 

in hot flashes, vaginal dryness, sleep, mood, cognition, somatic symptoms, urinary symptoms, sexual symptoms, and quality of life

Improved tothealth-relateboth groups

Stomati, 1999155

22 50-55 1. DHEAS 50 mg/day

2. DHEAS 50 mg/day and estradiol 50 mg/day transdermal

Estradiol 50 mg/day transdermal

3 months Not reported Similar impro

Index score (p<0.01).

Main results

*Open label trialAbbreviationsMPA=Medroxyprogesterone acetateCEE=Conjugated equine estrogenMT=MethyltestosteroneDehydroepiandrosterone (DHEA)

113
Table 8. Trials of tibolone

Study, year N

Mean age 

(range) Therapy Comparison Duration Between group differences Within g

Baracat, 2002*, 163

85 51 

treatment; 

53 

comparison

(45-65)

Tibolone 2.5 mg/day CEE 0.625 mg/day 

and MPA 5 mg/day 

12 months No differences between groups in 

intensity and mean number hot flashes, sleep, mood, cognition, somatic complaints, and sexual symptoms.

Improved intenumber hot flcognition, somsexual sympt

BenedekJaszmann, 1987164

60 44-61 Tibolone 2.5 mg/day Placebo 12 months Improved hot flashes, irritability, 

and psychic instability with tibolone vs. placebo. No consistent differences between groups in depression, sleep, somatic complaints.

Not reported 

De Aloysio, 1987*, 165

168 Not reported Tibolone 2.5 mg/day 1. Placebo injection 

2. No treatment

4 months Improved hot flashes with tibolone 

vs. placebo; no differences between groups for sleep and somatic symptoms.

"Spontaneouimprovementsymptoms in value given).

Egarter, 1996*, 166

129 54 Tibolone 2.5 mg/day CEE 0.625 mg/day 

and medrogestone 10 mg/day for 12 days/month

6 months No differences between groups in 

hot flashes, vaginal dryness, sleep, mood, somatic complaints, and sexual symptoms.

Improved hot dryness, sleecomplaints, ain both group

Hammar, 1998159

437 55 Tibolone 2.5 mg/day Estradiol 2 mg/day 

and NETA 1 mg/day 

48 weeks Improved hot flushes with 

estrogen/NETA vs. tibolone (p<0.001); no differences between groups in sweating episodes or vaginal dryness; tibolone group had less vaginal bleeding.

Improved hot episodes, and both groups (scale).

Huber, 2002160

501 55 Tibolone 2.5 mg/day CEE 0.625 mg/day 

and MPA 5 mg/day 

1 year No difference between groups in 

total Greene Climacteric Score, or vaginal or urinary symptoms; vasomotor subscore slightly more improved with CEE/MPA vs. tibolone. Reduced vaginal bleeding and improved sexual interest, drive, and/or performance in tibolone group. 

Improved totaScore in both Improvement symptoms in 

Main results

114
Table 8. Trials of tibolone (continued)

Study, year N

Mean age 

(range) Therapy Comparison Duration Between group differences Within g

Hudita, 2003167

162 56 (40-65) 1. Tibolone 1.25 

mg/day2. Tibolone 2.5 mg/day

Placebo 24 weeks Improved hot flashes, vaginal 

dryness, and sexual symptoms with both doses of tibolone vs. placebo; greater improvement in hot flashes and vaginal dryness with 2.5 mg vs. 1.25 mg doses (Modified McCoy Sex Scale, menopausal symptoms scale). Increased bleeding with both doses of tibolone.

Improved hot dryness in bonot in placebo

Lam, 2004156

100 50 Tibolone 2.5 mg/day Placebo 6 months 

in each 

arm

Improved somatic complaints in tibolone group. No difference in total Greene Climacteric Score or any other subscales.

Improved vasand sexual sugroups; improsomatic compgroup; (GreenGeneral HealDyadic Adjuschange in psyin either grou

Landgren, 2002168

775 52 (40-60) 1. Tibolone 

0.625 mg/day 2. Tibolone 1.25 mg/day 3. Tibolone 2.5 mg/day 4. Tibolone5 mg/day

Placebo 12 weeks Improved frequency of hot flashes 

and sweating at 1.25 mg, 2.5 mg, and 5.0 mg doses of tibolone vs. placebo (Collins and Landgren Rating Scale). Dose related vaginal bleeding.

Not reported 

Lloyd, 2000161

29 61 Tibolone 2.5 mg/day Placebo 6 months No differences between groups in 

quality of life (General Health Questionnaire).

Not reported 

Main results

115
Table 8. Trials of tibolone (continued)

Study, year N

Mean age 

(range) Therapy Comparison Duration Between group differences Within g

Meeuwsen, 2002157

85 54 Tibolone 2.5 mg/day Placebo 1 year Improved hot flashes and sleep 

with tibolone vs. placebo (p<0.05); no differences between groups for mood, energy, pain, social isolation, urinary symptoms, or quality of life (Nottingham Health Profile). Increased vaginal bleeding with tibolone.

Not reported 

Mendoza, 2000*, 169

76 <50 Tibolone 2.5 mg/day Estradiol 50 

mcg/day transdermal

1 year No differences between groups in 

hot flashes, mood, and sexual symptoms (Kupperman Index).

Improved hot sexual sympt(no p-values comparisons)

Mendoza, 2002*, 170

165 50 Tibolone 2.5 mg/day 1. Estradiol 50 

mcg/day transdermal and progesterone 200 mg twice weekly2. Estradiol 50 mcg/day transdermal for 14 days, then Estradiol 50 mcg/day transdermal and NETA 0.25 mg/day for 14 days 

1 year No differences between groups for 

hot flashes, sleep, mood, cognition, somatic symptoms, and sexual symptoms.

Improved hot groups (ModiIndex).

NathorstBöös, 1997171

437 >53 Tibolone 2.5 mg/day Estradiol 2 mg/day 

and NETA 1 mg/day

48 weeks Improved sexual frequency, 

satisfaction, and enjoyment with tibolone vs. estradiol/NETA (p<0.05); (McCoy Sex Scale; Swedish version).

Improved sexand vaginal dgroups. Improsexual sympt

Palacios, 1995*, 172

28 50-60 Tibolone 2.5 mg/day Calcium 500 

mg/day

12 months Improved sexual symptom score 

with tibolone vs. placebo (p<0.05) (10 item questionnaire scored on a 7 point scale).

Improved sextibolone grou

Main results

116
Table 8. Trials of tibolone (continued)

Study, year N

Mean age 

(range) Therapy Comparison Duration Between group differences Within g

Ross, 1999162

36 52 (45-65) Tibolone 2.5 mg/day CEE 0.625 mg/day 

and norgestrol 150 mg/day for 12 days of cycle

3 months No differences between groups for 

hot flashes, mood, cognition, somatic symptoms, uterine bleeding, and sexual symptoms (Women's Health Questionnaire, Irritability, Depression, and Anxiety, Greene Climacteric Scale).

Not reported 

Volpe, 1986173

113 Not reported Tibolone 2.5 mg/day 1. Placebo

2. CE 0.625 mg/day for 21 days/mo and NETA 5 mg/day for 10 days/mo2. CE 0.625 mg/day for 21days/mo and CPA 12.5 mg/day for 10 days/mo3. Estradiol valerate 2 mg/day for 21 days/mo and NETA 5 mg/day for 10 days/mo4. Estradiol valerate 2 mg/day for 21 days/mo and CPA 12.5 mg/day for 10 days/mo5. Estriol 2-4 mg/day

6 months Not reported. Improved hot 

treatment gro

Winkler, 2000158

60 54 (45-70) Tibolone 2.5 mg/day 1. Estradiol 2 

mg/day and Estriol 1 mg/day and NETA 1 mg/day

24 weeks No differences between groups in 

hot flashes and vaginal dryness (Karolinska Scale).

Improved hot dryness in all (Karolinska S

Main results

117
Table 8. Trials of tibolone (continued)

Study, year N

Mean age 

(range) Therapy Comparison Duration Between group differences Within g

Wu, 2001*, 

174

48 51 (38-56) Tibolone 2.5 mg/day CEE 0.625 mg/day 

and MPA 5 mg/day

3 months Improved sexuality with tibolone. 

No differences between groups in hot flashes, mood, and somatic complaints.

Climacteric sylife, and sexu(McCoy Sex Climacteric S

Yang, 1999*, 

175

40 51 Tibolone 2.5 mg/day CEE 0.625 and 

MPA 5 mg/day 12 days/month

6 months No differences between groups in 

hot flashes, mood, cognition, somatic complaints, and sexual symptoms.

Improved hot cognition, somsexual sympt(Greene Clim

AbbreviationsCE=Conjugated estrogenCEE =Conjugated equine estrogenCPA=Cyproterone acetateMPA=Medroxyprogesterone acetateNETA=Norethidrone acetate*Not a double-blind study (single blind or open).

Main results

118
Table 9. Trials of antidepressant drugs 

Study, year N

Mean age 

(range) Therapy Comparison Duration Between group differences Within group 

David, 1988186

50 32-81 Veralipride

100 mg/day

Placebo Four 20 

day 

courses

Not reported Improved hot flash 

severity with veralip

Evans 2005183

80 51 Venlafaxine XR, 

37.5mg/day for 1 week, then 75mg/day

Placebo 12 weeks No difference in hot flash frequency 

or severity as measured by daily diaries. Greater reduction in "selfperceived hot flash score" in venlafaxine group. (p<0.001; single item on interference of hot flash with daily living). Greater improvement in mood and vitality in venlafaxine group (p=0.005; SF-36 scales). 

Both groups noted thot flash severity screported.)

LimouzineLamothe, 1994*,187

499 Not 

reported

Veralipride 100 mg/day first 20 days of each month

Estraderm TTS 50 transdermal and chlormandinon first 12 days of each month 

6 months Improved numbers of hot flashes in 

estrogen vs. veralipride group (41% vs. 81%; p<0.001). Improved measures of quality of life, sleep, sexual function, depression, anxiety, general psychological well being, somatic complaints, cognitive difficulties, social life, family life, professional life, and vitality with estrogen vs. veralipride (Women's Health Questionnaire, Psychological General Well-Being Index, Sleep Problems Questionnaire, Sexual Behavior Questionnaire, symptom scale).

Not reported 

Main results

119
Table 9. Trials of antidepressant drugs (continued)

Study, year N

Mean age 

(range) Therapy Comparison Duration Between group differences Within group 

Melis, 1988184

40 48-56 Veralipride

100 mg/day

Placebo 30 days Improved hot flash composite score 

with veralipride vs. placebo (66% vs. 26%; p<0.5); more women noted improvement with veralipride vs. placebo (85% vs. 50%; p<0.05).

Both groups showehot flash composite p<0.05; veralipride 

Stearns, 2003181

165 >35 Paroxetine

12.5 mg/day or25 mg/day

Placebo 6 weeks Improved mean hot flash frequency 

with paroxetine 25 mg and 12.5 mg vs. placebo (3.2 and 3.3 vs. 1.8; p=0.01); improved composite score with paroxetine vs. placebo (65% and 62% vs. 38%; p=0.03) (daily hot flash composite score, Greene Climacteric Scale 21). No differences in sleep, depression, anxiety, sexual interest, or disability (Visual Analogue Scale, Beck Anxiety Inventory II, Sheehan Disability Scale, Clinical Global Impression). 

Not reported 

Tarim, 2002188

30 51

(35-55)

Moclobemide150 mg/day or300 mg/day

Placebo 5 weeks Not reported All groups had decr

composite scores (6150 mg/day, 35% mmg/day, 24% place

Wesel, 1984182

43 40-60 Veralipride 100 

mg/day

CEE 1.25 mg/day

20 days No differences between groups in hot 

flash frequency or composite score.

Improved hot flash composite score in 

Zichella, 1986185

75 45-55 Veralipride

100 mg/day

Placebo 20 days Improved hot flash composite score 

with veralipride vs. placebo (-2.3 vs. -0.6; p<0.5).

Improved hot flash with veralipride (p<0(p<0.05)

AbbreviationsCEE=Conjugated equine estrogen*Non blinded trial

Main results

120
Table 10. Trials of Clonidine

Study, year N

Mean 

age

(range) Therapy Comparison Duration Between group differences Within 

Bolli, 1975190† 20 51 1. Clonidine tablet 

0.0375 mg twice daily2. Clonidine tablet 0.075 mg twice daily 

Placebo crossover 2 weeks 

each 

phase

No differences between groups in mean number of hot flashes or subjective measures of severity and duration. Results same for both doses.

Reductioflashes wthe 0.075 (p<0.02) (p<0.05) 

Clayden, 1974189 100 50 

(41-62)

Clonidine tablet 0.025 mg twice daily; increased if needed to maximum 0.075 mg twice daily 

Placebo crossover 4 weeks 

each 

phase

Prior to crossover: no differences between groups in mean change in number of hot flashes.After crossover: improved subjective scores of hot flash severity (p=0.05) and duration 

Greater flashes w(p<0.05) Improved hot flash and dura

Edington, 1980193†

93 47

(27-71)

Clonidine tablet 0.05 mg twice daily 

Placebo crossover 4 weeks 

each 

phase

Improved mean number of flushing episodes (averaged over all 4 trials) with clonidine vs. placebo (p<0.05). 

Gerdes, 1982128

(Same as Sonnendecker 1980)

38 Not 

reported

Clonidine tablet 0.050 mg twice daily for 28 days + placebo tablets for CEE and medrogestone

CEE 1.25 mg daily for 21 days + medrogestone 5 mg daily from day 16 to 21 + placebo for clonidine

20 weeks Improved depression score (MiniBiography Questionnaire, p<0.01) 

and moodiness (p<0.05) with CEE vs. clonidine; no difference in moodiness with clonidine vs. placebo.

Improved depressi(p<0.05) group on

Lindsay, 1978191 100 46 

(35-60)

Clonidine tablet 0.050 mg twice daily; increased if needed to maximum of 0.05 mg three times daily 

Placebo crossover 6 weeks 

each 

phase

No differences between groups in hot flashes (Blatt Menopausal Index, flushing attacks scale) or psychological symptoms (Kellner and Sheffield Scale).

Main results

121
Table 10. Trials of Clonidine (continued)

Study, year N

Mean 

age

(range) Therapy Comparison Duration Between group differences Within 

Nagamani, 1987197

30 41 

(25-58)

Clonidine transdermal 0.1 mg/day, patch changed weekly

Placebo 8 weeks No differences between groups in 

mean reduction in hot flashes (diary) at weeks 4 and 8.* More women in the clonidine group reported improvement on subjective measures of frequency (p<0.04), severity (p<0.04), and duration (p<0.03). 

Significanumber both clonplacebo 

Nappi, 1991195 35 44 

(30-50)

Clonidine tablet 0.075 mg twice daily

1. Sodium valproate tablet 200 mg twice daily2. Lisuride tablet 0.2 mg twice daily3. Transdermal 17B estradiol 0.050 mg daily4. Placebo

4 weeks Improved hot flash frequency and 

intensity in the estradiol, clonidine, and lisuride vs. placebo groups (p<0.01). 

Salmi, 1979192 40 51 

(41-57)

Clonidine tablet 0.025 mg twice daily; increased if needed to maximum 0.075 mg twice daily

Placebo crossover 6 weeks 

each 

phase

No differences between groups in frequency of hot flushes, insomnia, depression or anxiety.

Sonnendecker, 1980196

38 Not 

reported

Clonidine tablet 0.050 mg twice daily for 28 days + placebo tablets for CEE and medrogestone

CEE 1.25 mg daily for 21 days + medrogestone 5 mg daily from day 16 to 21 + placebo for clonidine

20 weeks No differences between groups in 

reduction of number of hot flashes.

Number decreaseCEE groin the clo

Wren, 1986194† 19 51 

(46-56)

Clonidine tablet 0.05 mg twice daily

Placebo crossover 4 weeks No differences between groups in 

mean number of hot flashes.

No chaninsomniairritability 

AbbreviationsCEE=Conjugated equine estrogen*Calculated p-value; not reported in study

Main results

122
†Pre-crossover data not reported

123
Table 11. Trials of methyldopa, Bellergal, and gabapentin

Study,year N

Mean 

age 

(range) Therapy Comparison Duration Between group differences Within gr

Andersen, 1986199

40 51 

(46-60)

Methyldopa 375 mg nightly; increased by 1 tablet every 2 weeks as needed to maximum dose of 1,125 mg nightly

Placebo crossover

 Up to 8 

weeks 

each 

phase

No differences between groups in median number of hot flashes; women on methyldopa felt less troubled by hot flashes (Visual Analogue Scale) vs. placebo (p<0.05).

Number of hot both placebo (1methyldopa (14

Bergmans, 1987202

71 Not 

reported

Bellergal Retard 1 tablet twice daily (0.6 mg ergotamine, 40 mg phenobarbital, 0.2 mg levorotatory alkaloids)

Placebo 8 weeks No differences between groups at week 8 

in mean number and severity of hot flashes, sweating, or any other symptom.

For both groupimprovement wflashes, sweatihyperirritability(p<0.05). Headand dizziness iand loss of libidplacebo (p<0.0

Guttuso, 2003198

59 53 Gabapentin 300 mg 

three times daily

Placebo 12 weeks Improved hot flash frequency at weeks 4 

(p=0.03) and 12 (p=0.02), composite score at weeks 4 (p=0.01) and 12 (p=0.01), and sleep (Pittsburgh Sleep Quality Index) at week 4 (p=0.01) for gabapentin vs. placebo group. No differences between groups in Profile of Mood States score, quality of life (Short Form-36 Health Survey), or Patient Global Impression of Change Scale.

Hammond, 1984200

10 46 

(36-54)

Methyldopa 250 mg twice daily; increased after one week to 3 times daily

Placebo crossover

4 weeks 

each 

phase

No difference between placebo and methyldopa in mean decrease in number of hot flashes prior to crossover.

Improved hot flmethyldopa anphase but only (p<0.02) during 

Nesheim, 1981201

40 Not 

reported

Methyldopa 250 mg twice daily; increased if needed to maximum of 500 mg twice daily 

Placebo crossover

30 days 

each 

phase

Improved hot flash frequency in methyldopa vs. placebo group in the second phase (p=0.01) but not the first (p=0.06); improved Visual Analogue Score in methyldopa vs. placebo group (p=0.002).

Significant reduwith methyldop

Main results

124
Table 12. Trials of phytoestrogens and isoflavones 

Study, year N

Mean age 

(range) Therapy Comparison Duration Between group differences Within g

Soy isoflavones—dietaryAlbertazzi, 1998203, 

1999204

104 53

(48-61)

Soy powder 60 grams (76 mg isoflavones) 

60 grams casein powder

12 weeks Improved hot flash frequency 

with soy vs. casein at 12 weeks (p<0.01); no differences between groups on Kupperman Index.

Improved hoboth groups with soy, 31changes in K

Balk, 2002205 27 57 soy; 

58 placebo

Soy and corn flour cereal (100 mg/day isoflavones) 

Wheat cereal (Grapenuts)

6 months No differences between groups 

in hot flushes, night sweats, palpitations, headache, depression, vaginal dryness, or decreased libido over 6 months (Menopause Symptoms Questionnaire); soy group had greater insomnia than placebo (p=0.017).

Improved hosweats, and with placebo 

Burke, 2003206 241 51

(45-55)

1. Soy drink with 42 mg/day isoflavones2. Soy drink with 58 mg/day isoflavones

Soy drink with isoflavones removed

24 months No differences between groups 

in frequency and severity of hot flashes and night sweats (selfreported symptom diary).

Improved hoand severity (p<0.0001).

Dalais, 1998208 52 54 soy; 

55 linseed; 

54 wheat;

(45-65) 

1. Soy diet (high in isoflavones)2. Linseed diet (high in isoflavones)

Wheat diet (low in isoflavones) cross over

12 weeks 

each 

phase

Not reported Improved ra

(diary) with ldecrease) odecrease), b

Han, 2002207 82 48 

isoflavone; 

49 placebo; 

(45-55) 

Soy isoflavone (50 mg soy protein and 33 mg isoflavones)

Placebo 5 months Not reported Improved ho

mood, and Kscores in so

Main results

125
Table 12. Trials of phytoestrogens and isoflavones (continued) 

Study, year N

Mean age 

(range) Therapy Comparison Duration Between group differences Within g

Soy isoflavones—dietary (continued)Knight, 2001212 24 52 soy; 

54 placebo; 

(40-65)

Soy isoflavone powder beverage 60 g/day (134.4 mg/day isoflavones) 

Casein powder 12 weeks No differences between groups 

in flushing frequency or Greene Menopause Symptom Scores.

Improved fluboth groups

Murkies, 1995209

58 54 soy; 

56 wheat

Soy flour 45 grams/day

Wheat flour 45 grams/day 

14 weeks No differences between groups 

for hot flashes and general symptom scores.

Improved hogeneral symgroups at 12 

Penotti, 2003210 62 53

(45-60)

Soy tablet (36 mg/day isoflavone and 48 mg/day soy saponine)

Placebo 6 months No difference between groups 

in hot flashes (hot flush daily dairy)

40% reductioverall in bo

St. Germain, 2001211

69 42-62 1. Soy protein (80 

mg/day isoflavone)2. Soy protein (4.4 mg/day isoflavone) 

Placebo (whey protein)

24 weeks No differences between groups 

in hot flush frequency or severity, mood, vaginal dryness, urinary or sexual symptoms (Menopausal Index).

Improved hogroups (p=0

Washburn, 1999213

51 51

(45-55)

1. Soy protein 20 grams (34 mg/day phytoestrogen)2. Soy protein 20 grams (34 mg/day phytoestrogens) in 2 doses

Placebo 6 weeks Improved severity of hot flashes 

(diary) with soy vs. placebo (p<0.001); hypoestrogenic symptom score was improved with soy vs. placebo (p<0.05); no differences in number of hot flushes, night sweats, sleep disturbance, or general health score. 

Main results

126
Table 12. Trials of phytoestrogens and isoflavones (continued) 

Study, year N

Mean age 

(range) Therapy Comparison Duration Between group differences Within g

Soy isoflavones—extractDuffy, 2003215 36 59 soy; 

57 placebo; 

(50-65)

Soy isoflavone supplement (60 mg/day) 

Placebo 12 weeks No differences between groups 

on the Greene Climacteric Score or mood. Improved memory with soy vs. placebo (delayed recall of pictures, p<0.03; immediate story recall, p<0.06; reversal of the simple discrimination rule, p=0.05;improved time to learn complex tasks, p<0.05).

No changes symptoms.

Faure, 2002216 75 53 soy; 

54 placebo 

Soy isoflavone extract (70 mg genistin/daidzin/ day)

Placebo 16 weeks Improved hot flush frequency 

(diary) with soy vs. placebo (p=0.01);no effect on other symptoms (not described). 

Improved ho(61% reductgroups (21% 

KritzSilverstein, 2003214

56 61

(55-74)

Soy extracted supplement (isoflavone 100 mg/day) 

Placebo 6 months Improved cognitive test 

(category fluency) for soy vs. placebo (p=0.05); no differences between groups for 2 tests of verbal memory and Trails B test.

Improved coboth groups

Scambia, 2000217

39 54 soy; 

53 placebo; 

(29-63)

Soy extract (400 mg/day with 50 mg/day isoflavone) followed by CEE 0.625 mg/day for 4 weeks

Placebo followed by CEE 0.625 mg/day for 4 weeks

12 weeks Improved mean number of hot 

flushes/week (score card) and Greene Climacteric Scale score with soy vs. placebo at 6 weeks (p<0.01).

Improved hoin both grou

Upmalis, 2000 

218

177 55 soy; 

54 placebo 

Soy isoflavone extract tablet 50 mg/day 

Placebo 12 weeks Improved average hot flush 

severity (diary) with soy vs. placebo (p=0.01); no difference in frequency of night sweats. 

Improved hosweats in bo

Main results

127
Table 12. Trials of phytoestrogens and isoflavones (continued) 

Study, year N

Mean age 

(range) Therapy Comparison Duration Between group differences Within g

PhytoestrogensBrzezinski, 1997219

145 54 phytoestrogen; 

51 placebo; 

(43-65) 

Phytoestrogen rich diet (tofu, soy drink, miso, flax seed, approx 182 mg daidzein, 255 mg genistein, 4 mg lignans) 

Regular Israeli diet 12 weeks Improved hot flush severity 

(p=0.004) and vaginal dryness severity (p=0.005) with phytoestrogen vs. control; no difference in Menopause Symptom Questionnaire score.

Both groups Menopause Questionnai

Carranza-Lira, 2001220

30 52 phytoestrogen, 

51 placebo

Phytoestrogen cream (4 mg/day) 

Placebo (identical cold cream) 

1 month No differences in Kupperman 

Index score between groups.

Improved Kuscore in both 

Crisafulli, 2004221

90 52 

genistein; 

52 estrogen 

progesterone 

treatment; 

51 placebo; 

(47-57)

Genistein (54 mg/day)

1. Placebo2. Estradiol (1 mg/day) combined with noresthisterone 

1 year Genistein group, hot flush score 

decreased by 22% vs. placebo at 3 months (p<0.01), 29% at 6 months (p<0.001), and 24% at 12 months (p<0.01). Estrogen group, hot flush score decreased by 53% vs. placebo at 3 months (p<0.001) and maintained at 6 and 12 months.Improvement with estrogen greater than genistein at all measurements (p<0.05).

Komesaroff, 2001222

50 54

(45-60)

Wild yam cream preparation (Biogest, one teaspoonful twice daily to arms, legs or abdomen) 

Placebo cross over 3 months No differences between groups 

(diary) including flushing frequency, severity, mood, breast tenderness, libido, and energy level.

Improved fluscore, and egroups; impyam cream. 

Main results

128
Table 12. Trials of phytoestrogens and isoflavones (continued) 

Study, year N

Mean age 

(range) Therapy Comparison Duration Between group differences Within g

Phytoestrogens (continued)Sammartino, 2003*,223

70 51 Genistein 36 mg/day Placebo 12 months Improved Kupperman Index 

score with genistein vs. placebo (p<0.05).

Improved Kuscore with g

CombinationsRusso, 2003224 50 53

(48-54)

Soy based isoflavones (80 mg/day) with C. racemosa (black cohosh) (30 mg/day) 

Placebo 3 months Improved hot flush symptoms 

(questionnaire) in treatment vs. placebo group (p<0.05).

AbbreviationsCEE=Conjugated equine estrogen*Not double blinded (open).

Main results

129
Table 13. Trials of complementary and alternative therapies 

Study, year N

Mean 

age 

(range) Therapy Comparison Duration Between group differences Within gro

AcupunctureCohen, 2003234

18 47

(43-53)

6 acupuncture treatments specific to menopausal symptoms 

6 general tonic acupuncture treatments (shen mein)

9 weeks Not reported Improved mean 

severity (diary) months in treatcontrol. Improvdisturbance in Improved mood treatment, not c

Sandberg, 2002235

30 54

(48-60)

14 electro-acupuncture treatments specific to menopausal symptoms 

Superficial needle insertion (sham) 

12 weeks Treatment group mood (MOOD 

Scale) improved vs. control at 8 (p=0.05) and 12 weeks (p=0.01). No differences in climacteric or well-being between groups.

Improved mood treatment grousymptoms (Visand well-being in both groups.

Wyon, 1995236

24 54

(47-62)

10 electro-acupuncture (2 Hz) treatments specific to menopausal symptoms over 8 weeks

Superficial needle insertion (sham) 

8 weeks No differences between groups on 

any measure.

Number of flusdecreased in bclimacteric symAnalogue Scaletreatment grouKupperman Indboth groups; no being for either 

Wyon, 2004264

45 51-55 (43-

59)

14 electro-acupuncture treatments specific to menopausal symptoms 

Superficial needle insertion (sham) vs. conjugated estrogen 0.625 mg/day

12 weeks For flushes, more pronounced 

effect in estrogen group vs. electroacupuncture (p<0.001).

All three groups improvement in Visual Analogureported daily s

Main results

130
Table 13. Trials of complementary and alternative therapies (continued)

Study, year N

Mean 

age 

(range) Therapy Comparison Duration Between group differences Within gro

Chinese herbsChen, 2002235

62 50-52 (45-

65)

Chinese herbs (JWSYS=a collection of thirteen herbs) 

CEE 0.625 mg/day and MPA 2.5 mg/day

16 weeks No differences between groups in 

total symptom score, anxiety, depression, somatic symptoms, and vasomotor symptoms (Greene Climacteric Score). Improved sexual symptoms with CEE/MPA vs. JWSYS (p<0.05).

Improved psycsomatic measu(Greene Climac

Davis, 2001238

78 54-56 (45-

70)

Chinese medicinal 12 herb formula 

Placebo 12 weeks No differences between groups in 

vasomotor symptoms (daily diary) or Menopause Specific Quality of Life Questionnaire scores. Those having previously not used natural therapies for menopausal symptoms showed improved physical, vasomotor, and sexual domains compared to placebo (p<0.05).

Improved vaso(daily diary) anSpecific Quality Questionnaire sgroups. 

Hartley, 2003239

34 58-59

(53-65)

Ginseng; ginkgo tablet 120 mg/day containing 25% ginkgo flavonoids and 6% terpenoids 

Placebo 1 week No difference between groups on 

menopausal symptoms, mood, or sleepiness (Greene Climacteric Scale). No difference on 7 of 8 memory tests. Improved nonverbal memory and sustained attention in treatment group.

Improved sympClimacteric Sca(p<0.001).

Hirata, 1997240

71 52

(44-69) 

4.5 grams/day of dong quai from root material 

Placebo 24 weeks No differences in symptoms 

between groups (Kupperman Index).

Improved sympIndex) in both g

Main results

131
Table 13. Trials of complementary and alternative therapies (continued)

Study, year N

Mean 

age 

(range) Therapy Comparison Duration Between group differences Within gro

Chinese herbs (continued)Wiklund, 1999241

384 53-54 (45-

65) 

Standardized ginseng extract (Ginsana, containing 100 mg of the standardized ginseng extract G115; 2 capsules/day)

Placebo 16 weeks Improved depression, well-being, 

and health scores with ginseng vs. placebo (p<0.05) (Psychological General Well Being index). No differences between groups on Women's Health Questionnaire, Visual Analog Scale, or hot flushes.

Improved vasoand sleep in bo

Woo, 2003242 136 56-57 (50-

65)

Pueraria lobata (PL) (a traditional Chinese herbal remedy) and isoflavone 100 mg/day 

1. Placebo2. CEE 0.625 mg/day and MPA 5 mg/day during second 14 days of the month

3 months No differences between groups in 

menopausal symptoms or well being measures. No differences in word finding or rate of learning.CEE or PL vs. placebo: Cognitive tests and digital symbol improvement for both treatments (p<0.05).PL vs. placebo: Flexible thinking improved for PL group (p<0.05). CEE vs. placebo: Motor skills worsened in the CEE group. 

No differences 

Red cloverAtkinson, 2004243

205 55

(49-65)

Red clover isoflavone tablet (Promensil) 40 mg/day 

Placebo 12 months No differences between groups in 

number of hot flushes or menopausal symptoms score (diary).

Improved numband symptoms groups.

Baber, 1999244

51 45-65 Red clover isoflavone 

tablet (Promensil) 40 mg/day 

Placebo 7 months 

cross-over

No differences in symptoms between groups (Greene Climacteric Score, hot flush frequency).

Improved sympgroups (Greene Score, hot flush 

Main results

132
Table 13. Trials of complementary and alternative therapies (continued)

Study, year N

Mean 

age 

(range) Therapy Comparison Duration Between group differences Within gro

Red clover (continued)Jeri, 2002245 30 51-52 Red clover isoflavone 

tablet (Promensil) 40 mg/day 

Placebo 16 weeks Not reported Improved frequ

of hot flushes in (p<0.001).

Knight, 1999246

37 54.5

(40-65)

1. Red clover isoflavone tablet (Promensil) 40 mg/day 2. Red clover isoflavone tablet (Promensil) 160 mg/day 

Placebo 12 weeks No differences between groups in 

flushing frequency or Greene Climacteric Scale.

Flushing frequeall groups.

Tice, 2003247 252 52

(45-60)

1. Red clover isoflavone tablet (Promensil) 82 mg isoflavones/day 2. Red clover isoflavone tablet (Rimostil) 57 mg isoflavones/day

Placebo 12 weeks No differences between groups in 

Greene Climacteric Scale or number of hot flushes (p<0.001). Reduction in hot flashes was faster for Promensil compared to placebo (p=.03).

Improved GreeScale and numin all groups.

van de Weijer, 2002248

30 53-54 (49-

65)

Red clover isoflavone tablet (Promensil) 80 mg/day 

Placebo 12 weeks Improved hot flushes with 

isoflavone vs. placebo (p=0.0154); no difference in Greene Climacteric Scale score.

Improved hot flgroup; no chanClimacteric Sca

Black cohoshWuttke, 2003249

62 40-60 C. racemosa 

preparation (CR BNO 1055;Klimadynon/Menofem) 40 mg herbal drug/day

1. Placebo2. Conjugated estrogen 0.6 mg/day

12 weeks Improved hot flushes (menopause 

rating scale) with estrogen vs. placebo (p=0.046).

Improved symp(menopausal ra

Main results

133
Table 13. Trials of complementary and alternative therapies (continued)

Study, year N

Mean 

age 

(range) Therapy Comparison Duration Between group differences Within gro

CombinationsHudson, 1998250

13 Not 

reported

Botanical formula 500 mg 2 capsules three times per day (combined dry herb including burdock root [2 parts], licorice root [2 parts], motherwort [1 part], Dong Quai root [2 parts] and Mexican wild yam root [1 part]) 

Placebo 3 months No differences between groups in 

number and severity of hot flashes (diary).

Improved numbhot flashes for 

Other supplementsBellipanni, 2001251

79 42-62 Melatonin 3 mg/day Placebo 6 months Improved mood and morning 

depression (questionnaire) in melatonin vs. placebo group (p<0.05);no differences between groups for other symptoms.

Blatt, 1953252 748 Not 

reported

1. Vitamin E 50-100 mg 3 times daily2. Ethinyl estradiol 0.05 mg/day 3. CEE 1.25 mg/day4. Phenobarbital 15 mg 3 times daily

Placebo 3 years Not reported Improved hot fl

CEE and ethinywomen), phenoVitamin E (13%(16%). 

Bygdeman, 1996*, 256

39 58

(43-76)

Vaginal moisturizer (Replens) 3 times per week 

Dienoestrol vaginal cream 0.5 mg/day for 2 weeks, then 3 times per week

3 months Improved vaginal dryness index 

with dienoestrol vs. moisturizer (p=0.0001).

Improved vaginboth groups.

Main results

134
Table 13. Trials of complementary and alternative therapies (continued)

Study, year N

Mean 

age 

(range) Therapy Comparison Duration Between group differences Within gro

Other supplements (continued)Cagnacci, 2003253

80 50-52 (47-

53)

1. Kava kava 100 mg/day + calcium 1g/day2. Kava kava 200 mg/day + calcium 1g/day

Calcium 1g/day 3 months Improved anxiety with treatment 

vs. placebo; no differences between groups in Greene Climacteric Score or depression score.

Improved GreeScore, anxiety, score in both tr

Chenoy, 1994254

56 54

(45-67) 

Evening primrose oil (gamolenic acid) 2,000 mg/day with natural vitamin E 10 mg/day

Placebo 6 months Improved maximum number of 

daytime hot flushes (diary) with placebo vs. treatment (p<0.05). 

Makkonen, 1993255

30 52-54

(44-60)

Guar gum 5 grams three times daily 

Placebo 6 months No differences between groups in 

Kupperman Index scores.

Improved Kuppscores in both g

Nachtigall, 1994*, 257

30 Not 

reported

Vaginal moisturizer (Replens) 3 times/week 

CEE vaginal cream 2 grams/day

12 weeks Not reported Improved vagin

fluid volume, angroups.

Rachev, 2001258

64 50-52 

(41-59)

Phospholipid liposomes (Liposom Forte) 28 mg/2ml intramuscular injection every other day

Placebo injection every other day

60 days Improved climacteric index 

(p=0.0013) and anxiety (Hamilton Anxiety Scale) (p<0.001) with treatment vs. placebo.

Improved climaanxiety for both for both).

Salmaggi, 1993259

80 51

(45-59)

S-adenosyl-Lmethionine (SAMe) 1600 mg/day

Placebo 30 days Improved depression in treatment 

vs. placebo group (Hamilton Depression Rating Scale; Rome Depression Inventory; Clinical Global Impression Improvement Scale; Psychoasthenia Scale of the MMPI).

Main results

135
Table 13. Trials of complementary and alternative therapies (continued)

Study, year N

Mean 

age 

(range) Therapy Comparison Duration Between group differences Within gro

Manual therapiesCleary, 1994260

30 50-60 Low force osteopathic 

manipulation of pelvis, spine, and cranium 

Sham low force touch in similar areas

10 weeks 

treatment

Improved hot flushes and night sweats (questionnaire), urinary frequency, depression, and insomnia in treatment vs. control group. 

Energy therapiesWilliamson, 2002261

80 50.8

(45-60)

Reflexology with 9 sessions over 19 weeks 

Standard foot massage

9 sessions 

of 

treatment 

over 19 

weeks

No differences between groups in severity of hot flushes and night sweats (Women's Health Questionnaire, Visual Analogue Scale, and a self-completed measure of quality of life).

AbbreviationsMPA=Medroxyprogesterone acetateCEE=Conjugated equine estrogenMMPI = Minnesota Multiphasic Personality Inventory*Not double blind study (open).

Main results

136
Table 14. Trials of behavioral interventions 

Study, year N

Mean 

age 

(range) Therapy Comparison Duration Between group differences Within gro

Aiello, 2004265

173 61 Aerobic exercise 

225 minutes/ week 

Stretching 45 minutes/week 

12 months No differences between groups in 

hot flash frequency, sleep, depressive mood, or cognitive function. A subset of women with recent menopause showed improved memory in aerobic vs. stretching group.

Not reported 

Freedman, 1995268

24 53 Paced respiration 

training in 8 1-hour biweekly treatment sessions

Alpha-EEG biofeedback in 8 1-hour biweekly treatment sessions 

4 weeks Not reported Decreased hot f

the paced-respir(p<0.001) but nofeedback group.

Germaine, 1984270

14 50

(44-61) 

Progressive muscle relaxation in 6 1-hour weekly trainings 

Alpha-EEG biofeedback in 6 1-hour weekly trainings 

6 months Improved time for onset of hot flush 

(p<0.01) (physiological laboratory testing) in progressive muscle relaxation vs. biofeedback group. 

Reduced hot flarelaxation group up (p<0.01).

Hunter, 1999272

86 Over 50 Health/ menopause 

and stress relief education 

Usual care 5 year 

follow-up

Control group more likely to contribute aches and pains to menopause than intervention group (p<0.01). No differences between groups on mood, health, vaginal dryness or sexual relationships. Knowledge of menopause increased in the intervention group. 

Improved mainteknowledge, less menopause, moless estrogen usgroup. More wogroup lost intere

Main results

137
Table 14. Trials of behavioral interventions (continued)

Study, year N

Mean 

age 

(range) Therapy Comparison Duration Between group differences Within gro

Irvin, 1996269 45 49-53 

(44-66)

Relaxation (diaphrag-matic breathing 20 minutes/day) and charting hot flashes

1. Reading and charting hot flashes2. Charting hot flashes only 

10 weeks Not reported Significant impro

intensity, tensiondepression for th(p<0.05). Reducand confusion in (p<0.05). No difffrequency in any changes in cont

LindhAstrand, 2004266

30 51-54

(48-63)

Exercise 3 sessions/ week 

1. Estradiol 2 mg/day for 12 weeks minimum2. Wait listed controls

38 weeks Not reported Improved hot flu

Index, symptom Analogue Scorewith estrogen; imIndex, symptom Analogue Score 

Rankin, 1989271

40 49

(40-58)

Low frequency sound wave audiotape; 20 minutes 3 times/week for 2 weeks 

Usual care 2 weeks No differences between groups in 

menopausal, somatic, and psychological symptoms.

Improved freque(Neugarten-KraiIndex Scale), sopsychological sywaves in menop

Teoman, 2004267

81 51

(45-65)

Aerobic exercise 3 times/week 

Usual care (taking hormone therapy)

6 weeks Improved quality of life measures 

(Nottingham Health Profile) in exercise vs. control group.

Exercise group squality of life; no group.

Main results

138
Table 15. Summary of benefits of therapies 

Therapy

Included in 

report 

Reported 

comparisons Good Fair Poor Improved vs. placebo

Improved or 

same vs. 

other 

therapy

Other 

therapy

Improved 

vs. placeb

EstrogenVasomotor symptoms*

Estradiol (oral) 10 10 9/10

Estradiol (transdermal) 11 11 11/11Conjugated equine estrogen 8 8 8/8

Urogenital symptoms* 9 9 3/4 

Sexual function* 11 11 3/6 Sleep* 3 3 2/3Mood and depression 13 10 3 3 4 4/8 Quality of life* 9 9 7/8 Progestin

Progesterone 3 3 1 1 1 1/2 0/3Medroxyprogesterone acetate 22 2 2/2 1/2

Androgen

Testosterone with estrogen 10 6 1 4 1 2/2 E 1/1 Dehydroepiandrosterone 2 1 1 0/1 0/1

Tibolone 20 19 3 4 12 5/5 8/10 E +/- P 6/7 Antidepressants

Paroxetine 1 1 1 1/1 0/1Moclobemide 1 0Venlafaxine 1 1 1 0/1 1/1Veralipride 5 4 1 3 2/2 1/2 E +/- P 1/2 

Other Drugs

Clonidine 10 10 1 9 3/8 1/2 E + P Methyldopa 3 3 2 1 1/3Gabapentin 1 1 1 1/1 0/1Bellergal 1 1 1 0/1 1/1

Number of trials reporting benefit/total 

Hot flashes

Total number of trials

Quality rating

11

39

1011

89

139
Table 15. Summary of benefits of therapies (continued)

Therapy

Included in 

report 

Reported 

comparisons Good Fair Poor Improved vs. placebo

Improved or 

same vs. 

other 

therapy

Other 

therapy

Improved 

vs. placeb

Phytoestrogens

Soy isoflavones—dietary 10 8 6 2 2/8 1/5Soy isoflavones—extracts 5 5 4 1 3/3 2/2Phytoestrogen 5 5 2 3 4/5 0/1 E + P 1/2Combinations 1 1 1 1/1

Complementary and Alternative Medicine

Acupuncture 4 3 1 2 0/3 0/1 E 1/3Chinese herbs 6 6 3 3 0/5 2/2 E + P 3/4 Red clover 6 5 1 3 1 1/5 0/5Black cohosh 1 1 1 0/1 0/1 ECombinations 1 1 1 0/1 1/1Other supplements 9 7 2 5 2/4 3/3 Manual therapies 1 1 1 1/1 1/1Energy therapies 1 1 1 0/1 0/1

Behavioral Interventions 8 5 3 2 0/5 1/3 1/4AbbreviationsE=EstrogenP=ProgestinR=RaloxifeneC=Clonidine*Trials from published systematic reviews 15, 17

Total number of trials Number of trials reporting benefit/total 

Quality rating Hot flashes 

140
Table 16. Trials in women with breast cancer

Study, year N Population Therapy Comparison Duration

Between group 

differences

Barton, 1998275

125 18 and older with 

previous breast cancer; 54% taking tamoxifen

Vitamin E succinate 800 IU daily 

Placebo crossover

4 weeks 

each 

phase

Prior to cross-over and in summary: No differences between groups in hot flash frequency or severity (diary questionnaire).

Improgroupsignif

Carpenter, 2002289

15 18 and older with 

previous breast cancer

6 magnetic devices attached to participants' skin over acupuncture/acupressure sites used to balance energy and treat hot flashes

Placebo crossover; placebo was identical but blinding not effective because of magnet properties 

72 hours 

+ 2 days 

follow-up 

each 

phase

Summary statistics: Improved hot flash frequency with placebo (10.5 to 6.6) vs. magnet (9.6 to 8.3) (p=0.02); improved "bothersome" hot flashes with placebo (4.4 to 3.2) vs. magnets (4.2 to 4.1) (p=0.02). No differences between groups for hot flash severity, interference scale, or overall quality of life. 

Ganz, 2000287

76 Mean age 54.5; 

all have breast cancer; 56% taking tamoxifen

Counseling by nurse practitioner, tailored therapy, and support. Therapy includes any of the following: hot flashes—bellergal, clonidine patch, megestrol; behavioral symptoms—slow abdominal breathing; vaginal dryness—moisturizer or lubricant; urinary symptoms—Kegel's, Replens, phenylpropanolamine; psychosocial—referral for counseling or group support.

Usual care 4 months Improved adjusted mean change in 

menopause symptoms (p=0.0004) and adjusted mean change in sexual functioning with intervention vs. usual care (p=0.04); no differences between groups for vitality score. 

Main results

141
Table 16. Trials in women with breast cancer (continued)

Study, year N Population Therapy Comparison Duration

Between group 

differences

Goldberg, 1994284

116 54 (30-76);

all have breast cancer and taking tamoxifen

Clonidine transdermal 0.1 mg/day 

Placebo cross over

4 weeks 

each 

phase

Prior to cross-over: Improved median hot flash frequency (p<0.04), severity (p<0.03), and score (p<0.04) for clonidine vs. placebo. Summary statistics: No difference between clonidine and placebo for hot flash frequency, severity or score. Patients preferred clonidine vs. placebo (p=0.02).

Hernandez Munoz, 2003286

136 >35 years; 

all have estrogen receptor positive breast cancer and taking tamoxifen 

Black cohosh 20 mg one tablet twice daily

Usual care 60 day Improved hot flashes with treatment 

(47% free of hot flashes) vs. usual care (0% free of hot flashes) (p<0.01).

Jacobson, 2001276

85 18 and older; 

all have breast cancer; 69% taking tamoxifen

Black cohosh 1 tablet twice daily

Placebo 60 days Improved sweating in black cohosh 

vs. placebo group (p=0.04). No differences between groups in mean number of hot flashes, hot flash severity, sleep, irritability, nervousness, depression, headaches, and palpitations.

Impronervoheadexcesboth of wechan

Main results

142
Table 16. Trials in women with breast cancer (continued)

Study, year N Population Therapy Comparison Duration

Between group 

differences

Loprinzi, 1994280

97 Women with 

history of breast cancer; 

Megestrol acetate 20 mg twice daily.

Placebo crossover 4 weeks each 

phase

Prior to cross-over: Improved hot flash frequency (26% of baseline for megestrol vs. 73% of baseline for placebo, p<0.001). Improved median hot flash score (17% of baseline for megestrol vs. 73% of baseline for placebo, p<0.001). Reduction of 50% in hot flash frequency: 71% of megestrol group vs. 24% of placebo group, p<0.001. From baseline hot flash frequency of 6.1 hot flashes/day (range 0.9-21.4).

Loprinzi, 1997281

52 Women > 18 

with history of breast cancer and persistent vaginal dryness and/or itching for > 2 months

Polycarbophil-based vaginal moisturizer

Placebo (watersoluble 

lubricating)

4 weeks 

each 

phase

Not reported Vagin

impro(decrReplein plawks, Dyspdecreafter Replein pla

Loprinzi, 2000282

229 Women >18 with 

have breast cancer or perceived high risk; 69% taking tamoxifen

Venlafaxine 37.5 mg/day, 75 mg/day, 150 mg/day

Placebo 4 weeks 

each 

phase

Prior to cross-over: Improved hot flash frequency and score with all doses of venlafaxine vs. placebo (p<0.001); improved quality of life with venlafaxine vs. placebo (p=0.02). No differences between groups in depression score or libido.

Main results

143
Table 16. Trials in women with breast cancer (continued)

Study, year N Population Therapy Comparison Duration

Between group 

differences

Loprinzi, 2002283

87 18 and older; 

have breast cancer or perceived high risk; 54% taking tamoxifen

Fluoxetine 20 mg/day Placebo 

crossover

 4 weeks 

each 

phase

Prior to cross-over: Fewer reports of trouble sleeping sleep with fluoxetine vs. placebo (p=0.03). No significant decrease in hot flash frequency (p=0.54) or score (p=0.35).Summary statistics: Improved hot flash frequency (p=0.01), hot flash score (p=0.02) with combined data at end of both cross over periods; No overall differences between groups for sleep, quality of life, depression, or libido. 

Nikander, 2003279

62 Mean age 54 (35-

69); all have breast cancer; 5% had used tamoxifen>5 months prior

Phytoestrogen tablet 114 mg; 3 twice daily

Placebo crossover

3 months 

each 

phase

Prior to cross-over: No differences between groups in Kupperman Index, or hot flashes.

ImproIndex improinteneffecabilityin eit

Pandya, 2000285

198 Mean age 53-55 

(35-77); all have breast cancer and taking tamoxifen

Clonidine 0.1 mg/day Placebo 8 weeks 

treatment 

+ 4 weeks 

follow-up

Improved mean hot flash frequency, hot flash score, and duration with clonidine vs. placebo. Improved quality of life score with clonidine vs. placebo. No differences between groups in hot flash severity. Increased difficulty sleeping with clonidine vs. placebo.

Main results

144
Table 16. Trials in women with breast cancer (continued)

Study, year N Population Therapy Comparison Duration

Between group 

differences

Quella, 2000277

182 women >18; 

previous breast cancer; 78% on tamoxifen

Soy isoflavone 600 mg tablet one three times daily (each contains 50 mg of soy isoflavones: 40-45% genistein, 40-45% diadzein, and 10-20% glycitein)

Placebo crossover

4 weeks 

each 

phase

Summary statistics: No differences in hot flash score or frequency between groups. For outcome of reduction by half in hot flash frequency, 36% for placebo vs. 24% for soy (p=0.01).

Secreto, 2004288

262 >35; women with 

breast cancer included (<25%); none on tamoxifen

1. Isoflavones 40 mg midday, and isoflavones 40 mg with melatonin 3 mg evening2. Isoflavones 40 mg midday and evening3. Placebo midday, and melatonin 3 mg evening

Placebo midday and evening

3 months No differences between groups in 

the total score or sub scores of Greene Climacteric Scale.

ImproClimain all placealonealoneand m

Van Patten, 2002278

157 Mean age 55-56; 

all have breast cancer; 31% taking tamoxifen

Soy beverage totaling 90 mg/day isoflavones

Placebo 12 weeks No differences between groups in 

frequency and intensity of hot flashes.

Improfrequboth 

Main results

145
U.S. Department of Health and Human Services 

Mike Leavitt, Secretary 

Office of Public Health and Science 

Richard H. Carmona, M.D., M.P.H., F.A.C.S., Surgeon General of the United States

Agency for Healthcare Research and Quality 

Carolyn M. Clancy, M.D., Director 
Appendix A. Technical Expert Panel Members 

 A-1 

Technical Expert Panel Members 

Robert R. Freedman, PhD 

Professor 

Wayne State University School of Medicine 

Detroit, Michigan 

Tori Hudson, ND 

Medical Director 

A Women’s Time 

Portland, Oregon 

Fredi Kroenenburg, PhD 

Professor of Clinical Physiology in Rehabilitation Medicine 

The Richard & Hinda Rosenthal Center for Complementary & Alternative Medicine 

New York, New York 

Kurt Kroenke, MD 

Regenstrief Institute for Health Care 

Indianapolis, Indiana 

Diana Petitti, MD, MPH 

Director, Research and Evaluation Clinical Services 

Kaiser Permanente Southern California 

Pasadena, California 

Sally Shumaker, PhD 

Department of Public Health Sciences 

Wake Forest University School of Medicine 

Winston-Salem, North Carolina 

Leon Speroff, MD 

Professor, Department of Obstetrics and Gynecology 

Oregon Health and Science University 

Portland, Oregon 
Appendix B. Expert Reviewers 

 B-2 

Expert Reviewers

Deborah I. Allen, MD 

Representing American Academy of Family Physicians 

Tori Hudson, ND 

Medical Director, A Women’s Time 

Portland, Oregon 

Barbara L. Kass-Bartelmes, MPH, CHES 

Agency for Healthcare, Research, and Quality 

Carmen Kelly, Pharm D 

Agency for Healthcare, Research, and Quality 

Alastair MacLennan, MD 

Professor, Department of Obstetrics & Gynecology 

Women's and Children's Hospital 

Adelaide University, Australia 

Susan Meikle, MD 

Agency for Healthcare, Research, and Quality 

Diana Petitti, MD, MPH 

Director, Research and Evaluation Clinical Services 

Kaiser Permanente Southern California 

Pasadena, California 

Leon Speroff, MD 

Professor, Department of Obstetrics and Gynecology 

Oregon Health and Science University 

Portland, Oregon 

Stanley Zinberg, MD, MS 

Representing American College of Obstetricians and Gynecologists 

 
Appendix C. Literature Search Strategies 

 C-1 

Literature Search Strategies 

KQ1 MEDLINE 

Searched 1966 through mid-November 2004

Cognitive 

Database: Ovid MEDLINE(R) 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 CLIMACTERIC/ 

2 MENOPAUSE/ 

3 1 or 2 

4 exp Neurobehavioral Manifestations/ 

5 3 and 4 

6 cognit$.mp. [mp=title, original title, abstract, name of substance, mesh subject 

heading] 

7 3 and 6 

8 exp Delirium, Dementia, Amnestic, Cognitive Disorders/ 

9 3 and 8 

10 5 or 7 or 9 

11 limit 10 to english language 

12 10 not 11 

13 limit 12 to abstracts 

14 11 or 13 

Depression 

Database: Ovid MEDLINE(R) 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 CLIMACTERIC/ 

2 MENOPAUSE/ 

3 1 or 2 

4 CLIMACTERIC/px [Psychology] 

5 MENOPAUSE/px [Psychology] 

6 4 or 5 

7 DEPRESSION/ 

8 exp Depressive Disorder/ 

9 7 or 8 

10 6 or 9 

11 3 and 10 

12 limit 11 to english language 

13 11 not 12 

14 limit 13 to abstracts 

15 12 or 14 
Appendix C. Literature Search Strategies (continued)

 C-2 

Mood 

Database: Ovid MEDLINE(R) 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 CLIMACTERIC/ 

2 MENOPAUSE/ 

3 1 or 2 

4 exp Affect/ 

5 exp Mood Disorders/ 

6 mood$.mp. 

7 4 or 5 or 6 

8 3 and 7 

9 exp EMOTIONS/ 

10 3 and 9 

11 8 or 10 

12 limit 11 to english language 

13 11 not 12 

14 limit 13 to abstracts 

15 12 or 14 

Ovarian Aging 

Database: Ovid MEDLINE(R) 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 climacteric/ or menopause/ 

2 exp OVARY/ 

3 exp AGING/ or exp CELL AGING/ 

4 senescen$.mp. 

5 3 or 4 

6 1 and 2 and 5 

Quality of Life 

Database: Ovid MEDLINE(R) 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 CLIMACTERIC/ 

2 MENOPAUSE/ 

3 1 or 2 

4 "Quality of Life"/ 

5 3 and 4 

6 (qualit$ adj5 (life or living)).mp. [mp=title, original title, abstract, name of substance, 

mesh subject heading] 

7 3 and 6 

8 5 or 7 

9 exp Life Change Events/ 
Appendix C. Literature Search Strategies (continued)

 C-3 

10 3 and 9 

11 8 or 10 

12 limit 11 to english language 

13 11 not 12 

14 limit 13 to abstracts 

15 12 or 14 

Sexual Function 

Database: Ovid MEDLINE(R) 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 CLIMACTERIC/ 

2 MENOPAUSE/ 

3 1 or 2 

4 exp sex disorders/ 

5 3 and 4 

6 exp "Sexual and Gender Disorders"/ 

7 3 and 6 

8 (sex$ adj3 (disorder$ or dysfunctio$ or function$)).mp. [mp=title, original title, 

abstract, name of substance, mesh subject heading] 

9 3 and 8 

10 (sex$ adj3 activ$).mp. [mp=title, original title, abstract, name of substance, mesh 

subject heading] 

11 3 and 10 

12 exp Sexual Behavior/ 

13 3 and 12 

14 5 or 7 or 9 or 11 or 13 

15 limit 14 to english language 

16 14 not 15 

17 limit 16 to abstracts 

18 15 or 17 

Sleep 

Database: Ovid MEDLINE(R) 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 CLIMACTERIC/ 

2 MENOPAUSE/ 

3 1 or 2 

4 exp Sleep Disorders/ 

5 3 and 4 

6 exp SLEEP/ 

7 3 and 6 

8 5 or 7 

9 (sleep$ or slept).mp. [mp=title, original title, abstract, name of substance, mesh 

subject heading] 
Appendix C. Literature Search Strategies (continued)

 C-4 

10 3 and 9 

11 insomn$.mp. [mp=title, original title, abstract, name of substance, mesh subject 

heading] 

12 3 and 11 

13 5 or 8 or 10 or 12 

14 limit 13 to english language 

15 13 not 14 

16 limit 15 to abstracts 

17 14 or 16 

Somatic 

Database: Ovid MEDLINE(R) 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 CLIMACTERIC/ 

2 MENOPAUSE/ 

3 1 or 2 

4 exp pain/ 

5 somat$.mp. 

6 4 or 5 

7 3 and 6 

8 limit 7 to english language 

9 7 not 8 

10 limit 9 to abstracts 

11 8 or 10 

Urination 

Database: Ovid MEDLINE(R) 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 CLIMACTERIC/ 

2 MENOPAUSE/ 

3 1 or 2 

4 exp Urination Disorders/ 

5 3 and 4 

6 incontinen$.mp. [mp=title, original title, abstract, name of substance, mesh subject 

heading] 

7 3 and 6 

8 5 or 7 

9 urinat$.mp. [mp=title, original title, abstract, name of substance, mesh subject 

heading] 

10 3 and 9 

11 8 or 10 

12 limit 11 to english language 

13 11 not 12 

14 limit 13 to abstracts 
Appendix C. Literature Search Strategies (continued)

 C-5 

15 12 or 14 

Uterine Bleeding 

Database: Ovid MEDLINE(R) 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 CLIMACTERIC/ 

2 MENOPAUSE/ 

3 1 or 2 

4 exp Uterine Hemorrhage/ 

5 3 and 4 

6 (((uterine or uterus) adj5 (bleed$ or bled or hemorrhag$)) or menorrhag$).mp. 

7 3 and 6 

8 5 or 7 

9 limit 8 to english language 

10 8 not 9 

11 limit 10 to abstracts 

12 9 or 11 

Vaginal Dryness 

Database: Ovid MEDLINE(R) 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 CLIMACTERIC/ 

2 MENOPAUSE/ 

3 1 or 2 

4 (vagina$ adj5 dry$).mp. [mp=title, original title, abstract, name of substance, mesh 

subject heading] 

5 3 and 4 

6 exp VAGINA/mi, bs, ph, pp, en, se, ir, me [Microbiology, Blood Supply, 

Physiology, Physiopathology, Enzymology, Secretion, Innervation, Metabolism] 

7 3 and 6 

8 5 or 7 

9 limit 8 to english language 

10 8 not 9 

11 limit 10 to abstracts 

12 9 or 11 

Vasomotor 

Database: Ovid MEDLINE(R) 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 MENOPAUSE/ 

2 CLIMACTERIC/ 

3 1 or 2 

4 vasomotor.mp. or exp vasomotor system/ 
Appendix C. Literature Search Strategies (continued)

 C-6 

5 3 and 4 

6 (hot flash$ or hot flush$ or night sweat$).mp. [mp=title, original title, abstract, name 

of substance, mesh subject heading] 

7 Body Temperature Regulation/ or SWEATING/ 

8 6 or 7 

9 3 and 8 

10 5 or 9 

11 limit 10 to english language 

12 10 not 11 

13 limit 12 to abstracts 

14 11 or 13 

KQ1 PSYCHINFO 

Searched 1974 through May 2004 

Cognitive 

Database: PsycINFO 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word, 

table of contents, key concepts] 

2 (cognit$ or memor$ or dement$).mp. [mp=title, abstract, heading word, table of 

contents, key concepts] 

3 1 and 2 

Mood 

Database: PsycINFO 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word, 

table of contents, key concepts] 

2 exp emotional states/ 

3 (mood$ or depress$ or anxi$ or irritab$).mp. [mp=title, abstract, heading word, table 

of contents, key concepts] 

4 2 or 3 

5 1 and 4 

Quality of Life 

Database: PsycINFO 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word, 

table of contents, key concepts] 

2 exp "quality of life"/ or exp life satisfaction/ or exp lifestyle/ or exp lifestyle changes/ 

or exp well being/ 
Appendix C. Literature Search Strategies (continued)

 C-7 

3 (qualit$ adj3 life).mp. [mp=title, abstract, heading word, table of contents, key 

concepts] 

4 2 or 3 

5 1 and 4 

Sexual Function 

Database: PsycINFO 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word, 

table of contents, key concepts] 

2 exp Sexuality/ or exp Psychosexual Behavior/ 

3 (sex$ adj3 (function$ or dysfunction$ or activ$)).mp. [mp=title, abstract, heading 

word, table of contents, key concepts] 

4 2 or 3 

5 1 and 4 

Sleep 

Database: PsycINFO 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word, 

table of contents, key concepts] 

2 sleep$.mp. [mp=title, abstract, heading word, table of contents, key concepts] 

3 (insomn$ or hypersomn$).mp. [mp=title, abstract, heading word, table of contents, 

key concepts] 

4 (awak$ or wak$).mp. [mp=title, abstract, heading word, table of contents, key 

concepts] 

5 2 or 3 or 4 

6 1 and 5 

Somatic 

Database: PsycINFO 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word, 

table of contents, key concepts] 

2 somat$.mp. [mp=title, abstract, heading word, table of contents, key concepts] 

3 exp pain/ 

4 (pain$ or ache$).mp. [mp=title, abstract, heading word, table of contents, key 

concepts] 

5 2 or 3 or 4 

6 1 and 5 

Urination 

Database: PsycINFO 
Appendix C. Literature Search Strategies (continued)

 C-8 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word, 

table of contents, key concepts] 

2 (urinat$ or urinar$ or incontin$).mp. [mp=title, abstract, heading word, table of 

contents, key concepts] 

3 1 and 2 

Uterine Bleeding 

Database: PsycINFO 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word, 

table of contents, key concepts] 

2 (uterin$ or uterus).mp. [mp=title, abstract, heading word, table of contents, key 

concepts] 

3 (hemorrhag$ or menorrhag$ or bleed$).mp. [mp=title, abstract, heading word, table 

of contents, key concepts] 

4 2 or 3 

5 1 and 4 

Vaginal Dryness 

Database: PsycINFO 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word, 

table of contents, key concepts] 

2 vagin$.mp. [mp=title, abstract, heading word, table of contents, key concepts] 

3 1 and 2 

Vasomotor 

Database: PsycINFO 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word, 

table of contents, key concepts] 

2 fl#sh$.mp. [mp=title, abstract, heading word, table of contents, key concepts] 

3 sweat$.mp. [mp=title, abstract, heading word, table of contents, key concepts] 

4 vasomotor$.mp. [mp=title, abstract, heading word, table of contents, key concepts] 

5 body temperature.mp. [mp=title, abstract, heading word, table of contents, key 

concepts] 

6 2 or 3 or 4 or 5 

7 1 and 6 
Appendix C. Literature Search Strategies (continued)

 C-9 

KQ2 MEDLINE 

Searched 1966 through mid-November 2004 

Age of Onset 

Database: Ovid MEDLINE(R) 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 CLIMACTERIC/ 

2 MENOPAUSE/ 

3 1 or 2 

4 "Age of Onset"/ 

5 (age adj3 onset).mp. [mp=title, original title, abstract, name of substance, mesh 

subject heading] 

6 (age adj2 menopause).mp. [mp=title, original title, abstract, name of substance, mesh 

subject heading] 

7 (menopaus$ adj2 transit$).mp. [mp=title, original title, abstract, name of substance, 

mesh subject heading] 

8 4 or 5 or 6 or 7 

9 3 and 8 

10 exp Age Factors/ 

11 exp Time Factors/ 

12 10 or 11 

13 9 and 12 

14 limit 13 to english language 

15 13 not 14 

16 limit 15 to abstracts 

17 14 or 16 

18 from 17 keep 1-458 

BMI 

Database: Ovid MEDLINE(R) 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 CLIMACTERIC/ 

2 MENOPAUSE/ 

3 1 or 2 

4 (body mass index or bmi).mp. [mp=title, original title, abstract, name of substance, 

mesh subject heading] 

5 3 and 4 

6 limit 5 to english language 

7 5 not 6 

8 limit 7 to abstracts 

9 6 or 8 
Appendix C. Literature Search Strategies (continued)

 C-10 

Depression 

Database: Ovid MEDLINE(R) 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 CLIMACTERIC/ 

2 MENOPAUSE/ 

3 1 or 2 

4 CLIMACTERIC/px [Psychology] 

5 MENOPAUSE/px [Psychology] 

6 4 or 5 

7 DEPRESSION/ 

8 exp Depressive Disorder/ 

9 7 or 8 

10 Depress$.mp. 

11 6 and 10 

12 3 and 9 

13 11 or 12 

14 limit 13 to english language 

15 13 not 14 

16 limit 15 to abstracts 

17 14 or 16 

Ethnicity 

Database: Ovid MEDLINE(R) 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 CLIMACTERIC/ 

2 MENOPAUSE/ 

3 ((perimenopaus$ or menopaus$) adj3 (sign$ or symptom$)).mp. 

4 1 or 2 or 3 

5 eh.fs. 

6 exp Population Groups/ 

7 Cross-Cultural Comparison/ 

8 5 or 6 or 7 

9 4 and 8 

10 limit 9 to english language 

11 9 not 10 

12 limit 11 to abstracts 

13 10 or 12 

Surgical 

Database: Ovid MEDLINE(R) 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 CLIMACTERIC/ 

2 MENOPAUSE/ 
Appendix C. Literature Search Strategies (continued)

 C-11 

3 1 or 2 

4 surgical menopause.mp. 

5 exp OVARIECTOMY/ 

6 3 and 5 

7 (oophorectom$ or ovariectom$).mp. [mp=title, original title, abstract, name of 

substance, mesh subject heading] 

8 (ovar$ adj3 remov$).mp. [mp=title, original title, abstract, name of substance, mesh 

subject heading] 

9 7 or 8 

10 3 and 9 

11 4 or 6 or 10 

12 limit 11 to human 

13 limit 12 to english language 

14 12 not 13 

15 limit 14 to abstracts 

16 13 or 15 

KQ2 PSYCHINFO 

Searched 1974 through May 2004 

Depression 

Database: PsycINFO 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word, 

table of contents, key concepts] 

2 exp emotional states/ 

3 (mood$ or depress$ or anxi$ or irritab$).mp. [mp=title, abstract, heading word, table 

of contents, key concepts] 

4 2 or 3 

5 1 and 4 

KQ3 AMED 

Searched 1985 through August 2004 

Menopause 

Database: AMED (Allied and Complementary Medicine) 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=abstract, heading words, 

title] 
Appendix C. Literature Search Strategies (continued)

 C-12 

KQ3 COCHRANE 

Searched through 2nd Quarter 2004 

Alternative 

Database: EBM Reviews - Cochrane Central Register of Controlled Trials 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 (exp menopause/ and climacterium/) or exp climacteric/ or (menopaus$ or climacter$ 

or premenopaus$ or postmenopaus$ or perimenopaus$).mp. 

2 exp medicinal plant/ or exp plants, medicinal/ or exp plant medicinal product/ or exp 

plant extracts/ or (botanical$ or herb or herbal or red clover or black cohosh or primrose 

or yam or ginseng or dong quai or progesterone cream).mp. [mp=title, original title, 

abstract, mesh headings, heading words, keyword] 

3 exp traditional medicine/ or exp alternative medicine/ or exp complementary 

therapies/ or ((Alternative or complement$) adj5 (medic$ or treat$ or therap$)).mp. 

[mp=title, original title, abstract, mesh headings, heading words, keyword] 

4 (homeopath$ or naturopath$ or Ayurvedic).mp. [mp=title, original title, abstract, 

mesh headings, heading words, keyword] 

5 (acupunct$ or reflexol$ or magnet$ or electromagnet$ or tradition$ or folk).mp. 

[mp=title, original title, abstract, mesh headings, heading words, keyword] 

6 2 or 3 or 4 or 5 

7 1 and 6 

Androgens 

Database: EBM Reviews - Cochrane Central Register of Controlled Trials 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 (exp menopause/ and climacterium/) or exp climacteric/ or (menopaus$ or climacter$ 

or premenopaus$ or postmenopaus$ or perimenopaus$).mp. 

2 exp androgens/ or androgen$.mp. or testosteron$.mp. [mp=title, original title, 

abstract, mesh headings, heading words, keyword] 

3 (dhea or dihydroepitestosteron$).mp. [mp=title, original title, abstract, mesh 

headings, heading words, keyword] 

4 dihydrotestosteron$.mp. 

5 2 or 3 or 4 

6 1 and 5 

7 from 6 keep 1-384 

Antidepressants 

Database: EBM Reviews - Cochrane Central Register of Controlled Trials 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 (exp menopause/ and climacterium/) or exp climacteric/ or (menopaus$ or climacter$ 

or premenopaus$ or postmenopaus$ or perimenopaus$).mp. 
Appendix C. Literature Search Strategies (continued)

 C-13 

2 exp antidepressant agents/ or exp antidepressive agents/ or Antidepress$.mp. 

[mp=title, original title, abstract, mesh headings, heading words, keyword] 

3 fluoxetine.mp. 

4 venlafaxine.mp. 

5 paroxetine.mp. 

6 2 or 3 or 4 or 5 

7 1 and 6 

8 exp depression/ 

9 exp depressive disorder/ 

10 8 or 9 

11 1 and 10 

12 7 or 11 

Exercise 

Database: EBM Reviews - Cochrane Central Register of Controlled Trials 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 (exp menopause/ and climacterium/) or exp climacteric/ or (menopaus$ or climacter$ 

or premenopaus$ or postmenopaus$ or perimenopaus$).mp. 

2 exp Exercise Movement Techniques/ or exp kinesiotherapy/ or exp exercise/ 

3 (aerobic$ or exercis$ or yoga or tai chi or pilates).mp. [mp=title, original title, 

abstract, mesh headings, heading words, keyword] 

4 ((exp psychophysiology/ or exp feedback system/ or exp Mind-Body/) and 

Relaxation Techniques/) or (biofeedback$ or feedback$).mp. [mp=title, original title, 

abstract, mesh headings, heading words, keyword] 

5 ((pace or paced or pacing) adj3 (breath$ or respirat$)).mp. [mp=title, original title, 

abstract, mesh headings, heading words, keyword] 

6 2 or 3 or 4 or 5 

7 1 and 6 

Hormones (covers estrogen and progestin) 

Database: EBM Reviews - Cochrane Central Register of Controlled Trials 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 exp pain/ or (Pain or pains or painful or ache or aching or ached or aches or headach$ 

or migrain$ or somat$).mp. 

2 exp urination disorders/ or exp urinary dysfunction/ or ((vagina$ adj5 dry$) or 

enuresis or polyuria or oliguria or incontinen$ or (urin$ adj3 frequen$) or urinat$ or 

vaginit$ or vulvovaginit$).mp. [mp=title, original title, abstract, mesh headings, heading 

words, keyword] 

3 exp Delirium, Dementia, Amnestic, Cognitive Disorders/ or exp memory disorder/ or 

exp memory disorders/ or exp cognitive defect/ or (Cognit$ or amnes$ or deliri$ or 

dement$ or memor$ or remember$ or think$).mp. [mp=title, original title, abstract, mesh 

headings, heading words, keyword] 

4 exp sexuality/ or exp Sexual behavior/ or exp sex disorders/ or exp sexual 

dysfunction/ or ((sex$ adj3 (disorder$ or dysfunctio$ or function$ or activ$ or desir$)) or 
Appendix C. Literature Search Strategies (continued)

 C-14 

Dyspareuni$ or vaginismus).mp. [mp=title, original title, abstract, mesh headings, 

heading words, keyword] 

5 exp sleep/ or exp sleep disorders/ or exp sleep disorder/ or (Sleep$ or slept or 

insomn$ or awak$).mp. [mp=title, original title, abstract, mesh headings, heading words, 

keyword] 

6 exp uterine bleeding/ or exp uterus bleeding/ or (((uterine or uterus) adj5 (bleed$ or 

bled or hemorrhag$)) or menorrhag$).mp. 

7 exp affect/ or exp mood disorders/ or exp mood disorder/ or exp mood/ or exp 

temperament/ or (mood$ or emotion$ or depression or depressive or irritat$ or anxi$ or 

Affective).mp. [mp=title, original title, abstract, mesh headings, heading words, keyword] 

8 exp quality of life/ or (qualit$ adj5 (life or living)).mp. 

9 exp body temperature regulation/ or exp body temperature disorder/ or exp 

vasomotor disorder/ or exp vasomotor system/ or exp adrenergic system/ or (Vasomotor 

or fl#sh$ or sweat$).mp. [mp=title, original title, abstract, mesh headings, heading words, 

keyword] 

10 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 

11 (exp menopause/ and climacterium/) or exp climacteric/ or (menopaus$ or 

climacter$ or premenopaus$ or postmenopaus$ or perimenopaus$).mp. 

12 exp estrogens/ or exp estrogen/ or estrogen$.mp. 

13 exp hormone replacement therapy/ or exp hormone substitution/ or (hormone 

replacement therapy or hormone substitution).mp. 

14 exp progesterone/ or exp progestins/ or exp gestagen/ or (progestin$ or 

progesterone$ or gestegen$ or neta or mpa or megestrol).mp. 

15 12 or 13 or 14 

16 10 and 11 and 15 

Other Drugs 

Database: EBM Reviews - Cochrane Central Register of Controlled Trials 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 (exp menopause/ and climacterium/) or exp climacteric/ or (menopaus$ or climacter$ 

or premenopaus$ or postmenopaus$ or perimenopaus$).mp. 

2 gabapentin.mp. 

3 clonidine.mp. 

4 methyldopa.mp. or exp METHYLDOPA/ 

5 exp Ergotamine/ or bellergal.mp. 

6 2 or 3 or 4 or 5 

7 1 and 6 

Phytoestrogens 

Database: EBM Reviews - Cochrane Central Register of Controlled Trials 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 (exp menopause/ and climacterium/) or exp climacteric/ or (menopaus$ or climacter$ 

or premenopaus$ or postmenopaus$ or perimenopaus$).mp. 
Appendix C. Literature Search Strategies (continued)

 C-15 

2 exp phytoestrogen/ or exp isoflavones/ or exp isoflavone derivative/ or 

(phytoestrogen$ or isflavone$ or soy or soya or soybean$ or genistein or flax).mp. 

[mp=title, original title, abstract, mesh headings, heading words, keyword] 

3 1 and 2 

Tibolone 

Database: EBM Reviews - Cochrane Central Register of Controlled Trials 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 (exp menopause/ and climacterium/) or exp climacteric/ or (menopaus$ or climacter$ 

or premenopaus$ or postmenopaus$ or perimenopaus$).mp. 

2 tibolone.mp. 

3 1 and 2 

KQ3 MANTIS 

Searched 1880 through July 2004 

Menopause 

Database: Mantis 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, descriptors] 

KQ3 MEDLINE 

Searched 1966 through mid-November 2004 

Alternative 

Database: Ovid MEDLINE(R) 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 exp CLIMACTERIC/ or (climacter$ or menopaus$).mp. 

2 limit 1 to complementary medicine 

3 (botanical$ or red clover or black cohosh or primrose or yam or ginseng or dong quai 

or progesterone cream).mp. [mp=title, original title, abstract, name of substance, mesh 

subject heading] 

4 exp Complementary Therapies/ 

5 (homeopath$ or naturopath$ or Ayurvedic).mp. [mp=title, original title, abstract, 

name of substance, mesh subject heading] 

6 3 or 4 or 5 

7 1 and 6 

8 2 or 7 

9 limit 8 to english language 

10 8 not 9 

11 limit 10 to abstracts 
Appendix C. Literature Search Strategies (continued)

 C-16 

12 9 or 11 

13 limit 12 to (guideline or meta analysis or randomized controlled trial) 

14 from 13 keep 1-310 

Androgens 

Database: Ovid MEDLINE(R) 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 exp CLIMACTERIC/ or (climacter$ or menopaus$).mp. 

2 exp androgens/ or androgen$.mp. or testosteron$.mp. [mp=title, original title, 

abstract, name of substance, mesh subject heading] 

3 (dhea or dihydroepitestosteron$).mp. [mp=title, original title, abstract, name of 

substance, mesh subject heading] 

4 dihydrotestosteron$.mp. 

5 2 or 3 or 4 

6 1 and 5 

7 limit 6 to female 

8 limit 7 to english language 

9 7 not 8 

10 limit 9 to abstracts 

11 8 or 10 

12 limit 11 to (guideline or meta analysis or randomized controlled trial) 

Antidepressives 

Database: Ovid MEDLINE(R) 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 exp CLIMACTERIC/ or (climacter$ or menopaus$).mp. 

2 exp Antidepressive Agents/ 

3 fluoxetine.mp. 

4 venlafaxine.mp. 

5 paroxetine.mp. 

6 exp DEPRESSION/de, dt [Drug Effects, Drug Therapy] 

7 exp Depressive Disorder/dt [Drug Therapy] 

8 2 or 3 or 4 or 5 or 6 or 7 

9 1 and 8 

10 limit 9 to (guideline or meta analysis or randomized controlled trial) 

Estrogen/Progestin 

Database: Ovid MEDLINE(R) 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 CLIMACTERIC/ 

2 MENOPAUSE/ 

3 (climacter$ or menopaus$ or perimenopaus$).mp. [mp=title, original title, abstract, 

name of substance, mesh subject heading] 
Appendix C. Literature Search Strategies (continued)

 C-17 

4 1 or 2 or 3 

5 exp Hormone Replacement Therapy/ 

6 exp ESTROGENS/ 

7 exp PROGESTINS/ 

8 5 or 6 or 7 

9 4 and 8 

10 limit 9 to (guideline or meta analysis or randomized controlled trial) 

11 limit 10 to (guideline or meta analysis or randomized controlled trial) 

12 limit 11 to english language 

13 11 not 12 

14 limit 13 to abstracts 

15 12 or 14 

Exercise 

Database: Ovid MEDLINE(R) 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 exp CLIMACTERIC/ or (climacter$ or menopaus$).mp. 

2 exp Exercise Movement Techniques/ 

3 (aerobic$ or exercis$ or yoga or tai chi or pilates).mp. [mp=title, original title, 

abstract, name of substance, mesh subject heading] 

4 (biofeedback$ or feedback$).mp. [mp=title, original title, abstract, name of 

substance, mesh subject heading] 

5 ((pace or paced or pacing) adj3 (breath$ or respirat$)).mp. [mp=title, original title, 

abstract, name of substance, mesh subject heading] 

6 2 or 3 or 4 or 5 

7 1 and 6 

8 limit 7 to english language 

9 7 not 8 

10 limit 9 to abstracts 

11 8 or 10 

12 limit 11 to (guideline or meta analysis or randomized controlled trial) 

Other Drugs 

Database: Ovid MEDLINE(R) 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 exp CLIMACTERIC/ or (climacter$ or menopaus$).mp. 

2 gabapentin.mp. 

3 clonidine.mp. 

4 methyldopa.mp. or exp METHYLDOPA/ 

5 exp Ergotamine/ or bellergal.mp. 

6 2 or 3 or 4 or 5 

7 1 and 6 

8 limit 7 to english language 

9 7 not 8 
Appendix C. Literature Search Strategies (continued)

 C-18 

10 limit 9 to abstracts 

11 8 or 10 

12 limit 11 to (guideline or meta analysis or randomized controlled trial) 

Phytoestrogen 

Database: Ovid MEDLINE(R) 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 exp CLIMACTERIC/ or (climacter$ or menopaus$).mp. 

2 exp Isoflavones/ 

3 (phytoestrogen$ or isflavone$ or soy or soya or flax).mp. [mp=title, original title, 

abstract, name of substance, mesh subject heading] 

4 2 or 3 

5 1 and 4 

6 limit 5 to english language 

7 5 not 6 

8 limit 7 to abstracts 

9 6 or 8 

10 limit 9 to (guideline or meta analysis or randomized controlled trial) 

Tibolone 

Database: Ovid MEDLINE(R) 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 exp CLIMACTERIC/ or (climacter$ or menopaus$).mp. 

2 tibolone.mp. 

3 1 and 2 

4 limit 3 to english language 

5 3 not 4 

6 limit 5 to abstracts 

8 limit 7 to (guideline or meta analysis or randomized controlled trial) 

KQ3 PSYCHINFO 

Searched 1974 through May 2004 

Alternative 

Database: PsycINFO 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word, 

table of contents, key concepts] 

2 exp alternative medicine/ or exp dietary supplements/ or exp "medicinal herbs and 

plants"/ 

3 (red clover or cohosh or herb or herbal$ or acupunct$ or reflex$).mp. [mp=title, 

abstract, heading word, table of contents, key concepts] 
Appendix C. Literature Search Strategies (continued)

 C-19 

4 holist$.mp. [mp=title, abstract, heading word, table of contents, key concepts] 

5 (complementar$ adj2 (medic$ or therap$)).mp. [mp=title, abstract, heading word, 

table of contents, key concepts] 

6 (alternat$ adj2 (medic$ or therap$)).mp. [mp=title, abstract, heading word, table of 

contents, key concepts] 

7 2 or 3 or 4 or 5 or 6 

8 1 and 7 

Antidepressants 

Database: PsycINFO 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word, 

table of contents, key concepts] 

2 exp Antidepressant Drugs/ 

3 (fluoxetine or venlafaxine or paroxetine).mp. [mp=title, abstract, heading word, table 

of contents, key concepts] 

4 exp Serotonin Reuptake Inhibitors/ 

5 ssri.mp. [mp=title, abstract, heading word, table of contents, key concepts] 

6 antidepress$.mp. [mp=title, abstract, heading word, table of contents, key concepts] 

7 2 or 3 or 4 or 5 or 6 

8 1 and 7 

Exercise 

Database: PsycINFO 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word, 

table of contents, key concepts] 

2 exp exercise/ or exp movement therapy/ 

3 (exercis$ or (physical$ adj3 activ$)).mp. [mp=title, abstract, heading word, table of 

contents, key concepts] 

4 (pac$ adj2 respir$).mp. [mp=title, abstract, heading word, table of contents, key 

concepts] 

5 biofeed$.mp. [mp=title, abstract, heading word, table of contents, key concepts] 

6 (meditat$ or relax$).mp. [mp=title, abstract, heading word, table of contents, key 

concepts] 

7 2 or 3 or 4 or 5 or 6 

8 1 and 7 
Appendix C. Literature Search Strategies (continued)

 C-20 

Hormones (covers estrogen, progestin, and androgen) 

Database: PsycINFO 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word, 

table of contents, key concepts] 

2 exp sex hormones/ 

3 (estrogen$ or progestin$ or progesterone$ or estradiol$ or mpa or neta or megestrol 

or androgen$ or testosteron$ or dhea).mp. [mp=title, abstract, heading word, table of 

contents, key concepts] 

4 (hormon$ adj2 therap$).mp. [mp=title, abstract, heading word, table of contents, key 

concepts] 

5 2 or 3 or 4 

6 1 and 5 

Other Drugs 

Database: PsycINFO 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word, 

table of contents, key concepts] 

2 (gabpentin or clonidine or methyldopa or bellergal).mp. [mp=title, abstract, heading 

word, table of contents, key concepts] 

3 1 and 2 

Phytoestrogens 

Database: PsycINFO 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 (menopaus$ or climacter$ or perimenopaus$).mp. [mp=title, abstract, heading word, 

table of contents, key concepts] 

2 (phytoestrogen$ or soy or soya or flax or isoflavon$).mp. [mp=title, abstract, heading 

word, table of contents, key concepts] 

3 (phytoestrogen$ or soy or soya or flax or isoflavon$ or genistein$).mp. [mp=title, 

abstract, heading word, table of contents, key concepts] 

4 1 and 3 

Tibolone 

Database: PsycINFO 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 tibolone.mp. 
Appendix C. Literature Search Strategies (continued)

 C-21 

KQ4 MEDLINE 

Searched 1966 through mid-November 2004 

Breast Cancer 

Database: Ovid MEDLINE(R) 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 exp Breast Neoplasms/co [Complications] 

2 (menopaus$ or perimenopaus$ or premenopaus$).mp. [mp=title, original title, 

abstract, name of substance, mesh subject heading] 

3 1 and 2 

4 (breast adj (cancer$ or tumor$ or malignan$) adj3 survivor$).mp. [mp=title, original 

title, abstract, name of substance, mesh subject heading] 

5 2 and 4 

6 3 or 5 

7 limit 6 to english language 

8 6 not 7 

9 limit 8 to abstracts 

10 7 or 9 

SERMS 

Database: Ovid MEDLINE(R) 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 MENOPAUSE/ 

2 CLIMACTERIC/ 

3 1 or 2 

4 exp Selective Estrogen Receptor Modulators/ad, ae, ct, tu, to [Administration & 

Dosage, Adverse Effects, Contraindications, Therapeutic Use, Toxicity] 

5 3 and 4 

6 limit 5 to english language 

7 5 not 6 

8 limit 7 to abstracts 

9 6 or 8 

All KQ’s DARE 

Searched through 2nd Quarter 2004 

Menopause 

Database: EBM Reviews - Database of Abstracts of Reviews of Effects 

Search Strategy: 

-------------------------------------------------------------------------------- 

1 menopaus$.mp. [mp=title, full text, keywords] (73) 

2 perimenopaus$.mp. [mp=title, full text, keywords] (4) 

3 climacter$.mp. [mp=title, full text, keywords] (6) 
Appendix C. Literature Search Strategies (continued)

 C-22 

4 postmenopaus$.mp. [mp=title, full text, keywords] (63) 

5 1 or 2 or 3 or 4 (106) 

6 from 5 keep 1-10 (10) 

7 from 6 keep 1-10 (10) 

8 from 6 keep 1-10 (10)
Appendix D. Inclusion and Exclusion Criteria

D-1 

Inclusion and Exclusion Criteria 

Criteria for Reviewing Abstracts 

Key Question 1 (Symptoms)

Include Relevant to question 

Cohort, cross-sectional, review, meta-analysis, or unclear study design 

Community or population based 

U.S. applicable 

Appropriate sample size 

Mid-aged females 

Undergoing menopause 

Exclude Not relevant to question 

Wrong design 

No data 

Wrong population 

Paper only available in non-English language 

Comment or opinion 

Key Question 2 (Symptom characteristics and influencing factors) 

Include Relevant to question 

Cohort, cross-sectional, review, meta-analysis, or unclear study design 

Community or population based 

U.S. applicable 

Appropriate sample size 

Mid-aged females 

Undergoing menopause 

Exclude Not relevant to question 

Wrong design 

No data 

Wrong population 

Paper only available in non-English language 

Comment or opinion 
Appendix D. Inclusion and Exclusion Criteria (continued) 

 D-2 

Key Question 3 (Benefits and adverse effects of treatments) 

Include Relevant to question 

RCT, review, or meta-analysis 

One or more listed interventions 

One or more menopause-related outcomes 

Perimenopausal or menopausal women 

Exclude Not relevant to question 

Wrong study design 

No data 

Wrong population: premenopausal or postmenopausal women or men 

Available in non-English language 

Nonhuman/animal 

Methodological fatal flaw 

Comment or opinion 

Key Question 4 (Specific characteristics and treatments) 

Include Relevant to question 

RCT, review, or meta-analysis 

One or more listed interventions 

One or more menopause-related outcomes 

Perimenopausal or menopausal women 

Exclude Not relevant to question 

Wrong study design 

No data 

Wrong population: premenopausal or postmenopausal women or men 

Available in non-English language

Nonhuman/animal

Methodological fatal flaw 

Comment or opinion 
Appendix D. Inclusion and Exclusion Criteria (continued) 

 D-3 

Criteria for Reviewing Full-Text Papers 

Key Question 1 (Symptoms) 

Include Cohort, cross-sectional, review, or meta-analysis

Peri, currently menopausal women, or early postmenopausal women 

with symptoms 

Describes one of the symptoms in key question 1 

Population based 

Data specific to women 

Appropriate outcomes measures 

N > 100 

Exclude Major concurrent disease 

Key Question 2 (Symptom characteristics and influencing factors) 

Include Cohort, cross-sectional, review, or meta-analysis

Peri, currently menopausal women, or early postmenopausal women 

with symptoms 

Describes one of the symptoms in key question 1 and/or one of the 

factors in key question 2 

Population based 

Data specific to women 

Appropriate outcomes measures 

N > 100 

Exclude Major concurrent disease 

Key Question 3 (Benefits and adverse effects of treatments) 

Include RCT, review, or meta-analysis 

Peri, currently menopausal women, or early postmenopausal women 

with symptoms 

Describes one of the treatments in key question 3

Appropriate agent (currently available, non-injectable, etc.) 

Dose explicitly stated 

Appropriate length of treatment (e.g. > 12 weeks for estrogen use) 

Data specific to women 

Appropriate outcome measures 

Appropriate power (N) 

Exclude No major concurrent disease 
Appendix D. Inclusion and Exclusion Criteria (continued) 

 D-4 

Key Question 4 (Specific characteristics and treatments) 

Include RCT, review, or meta-analysis 

Peri, currently menopausal women, or early postmenopausal women 

with symptoms 

Describes one of the specific characteristics in key question 4 

Appropriate agent (currently available, non-injectable, etc.) 

Dose explicitly stated 

Appropriate length of treatment (e.g. > 12 weeks for estrogen use) 

Data specific to women 

Appropriate outcome measures 

Appropriate power (N)

Exclude No major concurrent disease
Appendix E. Literature Search Tree

* MANTIS was searched starting in 1880, and only for KQ 3g, h, i† COCHRANE database was not searched for KQ’s 1, 2, & 4 ‡ Citations may overlap among key questions § Only cohort and cross-sectional from cohort studies could be quality rated

Literature Search Tree

E-1 KQ 1 & 2† Symptoms and 

Factors 

KQ 3 

Interventions 

Review with 6,342 4,078 

eligibility criteria‡

Read full text; apply 

eligibility criteria‡

440 428

Full text, quality rated 

and included in 

evidence report‡

71§ 134 

MEDLINE, PsycINFO, COCHRANE, AMED, MANTIS*, and DARE 

Searched 1966–November 2004 

Total Number of Citations 

10,059 

KQ 4†

Characteristics

806 

9415 

E-1 
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

Avis, 1994 Massachusett's 

Women's Health Study

2565 Cohort Internal 5 years Random sample of 8,050 

women ages 45-55 in Massachusetts, from which 2,565 were identified as having menstruated in the past 3 months, having a uterus and > one ovary

Population barecruitment opremenopaus

Avis, 1997 Massachusett's 

Women's Health Study

454 (131 

for some 

analyses)

Crosssectional analyses from cohort

Internal 4.5 years Sample was part of larger 

cohort of 8,050 women randomly selected; 2,565 were pre- or early menopausal

Community-bMassachuset

F-1
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearAvis, 1994Avis, 1997

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

_ _ __ 

45-55 in 1982 (baseline)

For this analysis, women who were premenopausal at baseline and naturally post-menopausal at the last study f/u (4 yrs later, 6th clinic visit).

Telephone and mailed questionnaires

94-95% retention over 6 contacts focohort of 2,565 prand early menopausal women

F-2
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearAvis, 1994Avis, 1997

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

CES-D for depressionSeven measures of health care utilizationSelf-assessed health, physical symptoms, restricted activity and chronic conditions.Surgical menopause included either hysterectomy or BSO.

_ ___ 

hot flashes and night sweats (frequency and bothersomeness)consult with MD regarding menopause

All women in this analysis progressed from pre to post menopausal (natural) over the course of the f/u period

Excluded Excluded NR 

F-3
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearAvis, 1994Avis, 1997

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

_ __ _ _ 

Current smoking at baseline 41%

Excluded NR 23% were not bothered 

by HF/NS at any of the six interviews.HF and NS bothersomeness were highly correlated.Length of perimenopause was not correlated with number or bothersomeness of symptoms.Women with more negative attitude toward menopause report HF/NS more frequently.

F-4
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearAvis, 1994Avis, 1997

Mood Cognitive Somatic Urinar

y

_ _ _ _

F-5
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearAvis, 1994Avis, 1997

Sexual Dysfunc-tion Quality of Life Other Outcomes

_ __

F-6
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearAvis, 1994Avis, 1997

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

_ Used CES-D score of <16 vs. 

>16 as dichotomous outcome 

variable. Logistic regression model adjusted for HRT, menopausal symptoms at T2, T1-T2 menopausal transition and T1 CES-D score.

_

Smoking (;<0.05), physical symptoms (p<0.01), psychological symptoms (p<0.001), having had a surgery for a benign breast cyst, greaster alcohol consumption and agreeing with the statement "many women think they are no longer "real" women after the menopause" were related to FH/NS bothersomeness.

Stepwise logistic regression. "Smoking (;<0.05), physical symptoms (p<0.01

symptoms (p<0.001), having had a surgery for greaster alcohol consumption and agreeing witwomen think they are no longer ""real"" women were related to FH/NS bothersomeness.Primary variables predicting frequncy of HF/NS premenopausal symptoms and attitudes towarAge at inception of peri-menopause was assocperimenopause (r=-0.16, p=0.0005).

F-7
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearAvis, 1994Avis, 1997

RR or OR Comments

_ Depression at baseline was most predictive of subsequent 

depression (OR 9.12, p<0.0001). A menopausal symptoms variable was also significant contributor (OR=3.55, <0.0001). The menopausal transition was significant as a single variable but the individual variables were not. (OR 0.59 to 1.28, all CI crossing 1).Comparing the prevalence of depression among groups, the peak prevalence of depression for those not depressed at baseline, was for those who were peri-peri. For those who were depressed at baseline, the peak prevalence of depression occurred in the pre/peri-post group (see figure in paper, no numbers given in text).

OR for HF/NS frequency from stepwise logistic regression:smoking 1.44 (CI 1.02, 2.05)tubal ligation 0.47 (CI 0.29, 0.78)any college 0.59 (0.42, 0.84)physical symptoms 1.47 (1.18, 1.83)psychological symptoms 2.14 (1.38, 3.35)length of perimenopause 1.24 (1.07, 1.44).

F-8
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

Avis, 2000 Massachusett's 

Women's Health Study

2000 Crosssectional 

analyses from cohort

Intenral 5 years 

(1986-91)

Random pop-based sample of 8,050 women in Mass. 2,569 women ages 45-55 selected for f/u. Of these 427 (78.6% of 543) were eligible for this study. 200 included in this analysis.

Community-bMassachuset

F-9
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearAvis, 2000

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

51-61, mean age 54

Inclusion criteria:1. Intact uterus and 1 ovary2. No HRT in past 2 yrs3. Current sexual partner4. Living within 1 hr of Boston5. <12 months consecutive ammenorrhea6. No major cancer in last 5 years.

Questionnaires RR 77% from initi

recruitement. 

F-10
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearAvis, 2000

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

Sexual activity questionnaire adapted for Amssachusetts male Agin StudySatisfaction with current sexual relationshipFrequency of sexual intercourseSexual desireBelief that interest in sex declines with ageLevel of arousal Difficulty reaching organsmPelvic area pain

Exlcuded Excluded Excluded if 

within 5 ye

F-11
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearAvis, 2000

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

Current smoking 22%

Excuded (n=51)

BMI range 17-49, mean+SE=27.9+5.

5

F-12
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearAvis, 2000

Mood Cognitive Somatic Urinar

y

Overall: 12.6% had CES-D score >16.

39.8% had psychological symptoms

F-13
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearAvis, 2000

Sexual Dysfunc-tion Quality of Life Other Outcomes

Fewer perimenopausal women reported never having difficulty reaching orgasm (NS).Level of sexual desire was lower among postmenopausal women compared with premenopausal women (p<0.05).Frequency of sexual intercourse and pain during intercourse did not vary by menopausal status.

Satisfaction with life did not vary by menopausal status.

F-14
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearAvis, 2000

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

The following variables were unrelated to any aspect of sexual functioning: employment status, vasomotor symptoms, parter stress, alcohol , exercise and BMI

Multiple regression Sexual Function:

Recent vaginal dryness was related to pain du(OR 3.86) and difficulty reaching orgasm (OR 2Menoapausal status was not related to either pdifficulty reaching orgasm.Age was negatively related to difficulty reachin

F-15
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearAvis, 2000

RR or OR Comments

F-16
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

Avis, 2001 SWAN 14,906 Crosssectional __ _ _ 

F-17
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearAvis, 2001

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

47.1 (40-55) Exclusion:

450 missing race/ethnicity data341 uncertain menopausal status55 pregnant or breastfeeding313 incomplete data on symptoms or covariates 

_ 87.70% 

F-18
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearAvis, 2001

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

_ Surgical 20.8%

Postmenopausal 14.6%Perimenopausal 27.2%Premenopausal 29.7%Hormone user 7.7%

___ 

F-19
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearAvis, 2001

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

_ __ _ _ 

F-20
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearAvis, 2001

Mood Cognitive Somatic Urinar

y

_ _ _ _

F-21
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearAvis, 2001

Sexual Dysfunc-tion Quality of Life Other Outcomes

_ _ Factor 1 - psychosomati

symptomsFactor 2 - vasomotor symptomsSymptoms had to load > 

on a factor for all ethnic groups.

F-22
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearAvis, 2001

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

Age, education, selfassessed health, economic strain, geographic siteinteraction terms for race/ethnicity and menopausal status

Multiple linear regression model for Factors 1 and multiple logistic regression for Factor 2.

Factor 1: Psychosomatic symptoms

Significant predictors (p<0.0001)AgeEducation (reference postgraduate degree) - hdegree/equivalentSelf-assessed health (reference excellent) - veDifficult to pay for basics (reference not at all hvery hardRacial/ethnic group (reference Caucasian) - AAHispanicMenopausal status (reference premenopausal) menopause, HRT usersGeographic site (reference Detroit) - Boston, NFactor 2: Vasomotor symptoms (1 vs. 0)Education (ref postgraduate degree) - college education Self-assessed health (ref excellent) - very goodDifficult to pay for basics (ref not at all hard) - shardRacial ethnic group (ref Caucasian) -  AA: Chicago; AA: Detroit; Chinese; JapanesMenopausal status (ref premenopausal) - peri, usersFactor 2: Vasomotor symptoms (2 vs. 0)Age; Education (ref postgraduate degree) - coleducation;Self-assessed health (ref excellent) - very goodRacial ethnic group (ref Caucasian) AA (all sites); Chinese, Japanese, HispanicMenopausal status (ref premenopausal) - peri, Geographic site (ref Detroit) - Pittsburgh, L.A.

F-23
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearAvis, 2001

RR or OR Comments

1.22-1.29; 1.38-2.58; 1.15-1.301.41; 1.59; 0.60; 0.65; 1.69-1.961.05; 1.53-1.79; 1.69-3.72; 1.18-1.551.28-1.82; 0.25-0.77; 3.35-3.81; 0.74-0.75

Psychosomatic symptom reporting differs by both race/ethnicity and by menopausal status. All other racial/ethnic groups report significantly fewer symptoms than Caucasian women. Perimenopausal women, HRT users and women with surgical menopause report more symptoms than premenopausal women.Vasomotor symptom reporting also varies by race/ethnicity and menopausal status. Effects are greater when looking 2 symptoms vs. none. AA were more likely and Hispanic, Japanese, Chinese were less likely than Caucasian women to report vasomotor symptoms. All menopausal groups reported significantly more symptoms than premenopausal women.

F-24
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

Avis, 2003 SWAN 3,193 Crosssectional _ _ _ _ 

Bromberger, 2001

SWAN 10,374 Crosssectional N/A N/A _ _ 

F-25
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearAvis, 2003Bromberger, 2001

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

46.2 (42-52) Data on menopausal status and SF-36 outcomes 

missing for 109 of 3302

_ 96.70% 

40-55mean 45.9 with distressmean 46.4 without distress

5213 of 16065 were excluded for 1) exogenous hormone use preceding 3 months, 2) pregnancy, 3) hysterectomy, 4) no menses past 12 months due to pregnancy, breast-feeding, severe weight loss, or illness

_ 64.57% 

F-26
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearAvis, 2003Bromberger, 2001

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

5 subscales of SF-36 as measures of health related quality of life (HRQL): bodily pain, role limitations due to physical health, role limitations due to emotional problems, social functioning and vitalitymenopausal status, sociodemographic and lifestyle variables, health variablespsychosocial variables including the Center for Epidemiological Studies (CES-D) scale, Perceived Stress Scale, Medical Outcomes Study Social Support Survey

Premenopause 53.82 %Early perimenopause 46.18%Late perimenopause 0%Post-menopause 0%

___ 

12-item questionnaire of physical and psychological symptomsPsychological distress = presence of all 3 symptoms feeling tense or nervous, feeling blue or depressed, feeling irritable or grouchy (categorical - present or absent)

Premenopause 43.2 %Early perimenopause 34Late perimenopause 5.8Post-menopause 16.8Proportion with psychological distress:Premenopause 20.9 %Early perimenopause 28.9Late perimenopause 25Post-menopause 22

Ineligible NR NR 

F-27
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearAvis, 2003Bromberger, 2001

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

_ __ _ _ 

Smoking:current 22.5%past 23never 53.6

_ _ Yes 32.5%

No 67Those with vasomotor flushes (36.6%) were more likely than those without (18.0%) to have psychological distress (p<0.001).

NR Diff

Yes No Thosleemowithpsy(p<

F-28
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearAvis, 2003Bromberger, 2001

Mood Cognitive Somatic Urinar

y

_ _ _ _

Psychological distress:Yes 24.1%No 75.9

NR NR NR 

F-29
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearAvis, 2003Bromberger, 2001

Sexual Dysfunc-tion Quality of Life Other Outcomes

_ __

NR NR The following variable w

significantly associated wpsychological distress (p<0.001): menopause status, race/ethnicity, educationmarital status, smoking, availability of perceived support, number close friends/relatives, paying basics, perceived health

F-30
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearAvis, 2003Bromberger, 2001

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

SES, sociodemographic, health, lifestyle and social circumstance variables

Adjusted models for impaired function (women at or below the 25th percentile) on the SF-36 scales 

In unadjusted models, early perimenopause ansignificantly associated with Impaired FunctionIn models adjusted for health conditions, impaiby menopausal status.In adjusted models, Hispanic women were moreport bodily pain and impaired social functionilikely than Whites to report impaired social fun

Significant: menopause status, race/ethnicity, education, smoking, availability of perceived social support, close friends/relatives, paying for basics, perceived health, health limitations, difficulty sleeping, vasomotor symptoms, ageNot significant:employment status, marital status, site, physical activity, number of reported medical conditions,

Multivariate association of psychological distress with menopausal status

Early perimenopause as compared to premenowith increased odds of psychological distress (AA, H, J, Chinese race as compared to W race decreased odds of psychological distress (OR The presence of vasomotor symptoms was assodds of psychological distress (OR1.96).

F-31
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearAvis, 2003Bromberger, 2001

RR or OR Comments

_ "Symptoms are important mediators between physiological 

conditions and HRQL."

_ Early perimenopause and vasomotor symptoms were associated 

with increased odds of psychological distress. Late perimenopause and post-menopause were not associated with increased odds of psychological distress.

F-32
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

Bromberger, 2003

SWAN 3,161 Crosssectional N/A N/A _ _ 

F-33
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearBromberger, 2003

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

42-52mean 46.2

White or site-predetermined ethnicity, menses within the previous 3 month, have uterus and at least one ovary, not pregnant, no use of reproductive hormones or birth control pills within the previous 3 months.141 excluded because of missing data for dysphoric mood and menopausal status

_ 95.73% 

F-34
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearBromberger, 2003

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

Symptom checklists, SF-36 Role Emotional scale, Medical Outcomes Study Social Support Survey, modification of Psychiatric Epidemiology Research Interview, adapted Baecke questionnaireDysphoric mood = summary scale 0-16 (dichotomized 0-6 v 7-16) of the 4 mood measures feeling blue, feeling irritable, feeling nervous, or experiencing mood changes on > 6 

days in preceding 2 weeks.

Premenopausal 53.4 %Early perimenopausal 46.6 %

Ineligible Ineligible NR 

F-35
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearBromberger, 2003

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

Nonsmokers

82.9 % 

N/A NR None 89% NR Dis

F-36
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearBromberger, 2003

Mood Cognitive Somatic Urinar

y

Use of medication for nervous condition 10%possible PMS 15.3%

NR Pain:

severe/very severe 7.1%moderate 22%very mild/mild 54.2%

NR 

F-37
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearBromberger, 2003

Sexual Dysfunc-tion Quality of Life Other Outcomes

NR NR _

F-38
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearBromberger, 2003

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

Study site, menopausal status, ethnicity, age, difficulty of paying for basic necessities, use of medication for nervous conditions, pain, disturbed sleep, vasomotor symptoms, possible premenstrual syndrome, social support, number of upsetting events, relationship presence/quality, recreational/sport activity, study site

Logistic regression models for each of four mood symptoms:Feeling blue, irritable, nervous, or experiencing mood changes on >= 6 days in preceding 2 weeks.Logistic regression model of dysphoric mood. Menopausal status, study site, age, race/ethnicity forced into all adjusted models.

In comparison to premenopause, early perimewith increased odds of :feeling irritable (OR 1.33)feeling nervous (OR 1.54)experiencing mood changes (OR 1.52). dysph(OR 1.8) dysphoric mood in previous 2 weeks (OR 1.62In comparison to W women, AA had decreased feeling blue (OR 0.62)feeling irritable (OR 0.61)feeling nervous (OR 0.46)Chinese women had decreased odds of: feeling blue (OR 0.35)feeling irritable (OR 0.30); J women had decreased odds of:feeling blue (OR 0.44) feeling nervous (OR 0.51).Vasomotor symptoms were associated with all (p<0.001).Lower education level was associated with incmood:some college (OR 2.04) high school or less (OR 2.35)

F-39
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearBromberger, 2003

RR or OR Comments

_ Early perimenopause was associated with increased odds of 

mood symptoms and dysphoric mood particularly among women with lower educational attainment.

F-40
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

Brown, 2002Australia

Australian Longitudinal Study on Women's Health

8,236 Cohort Internal 2 years 41,500 women selected from 

all over Australia using national Medicare health insurance database with overrepresentation of women living in rural and remote areas. The mid-age cohort (age 45-50 years) was targeted for survey 2 in 1998. 

_ 

Busch, 1994 National 

Health Examination Follow-up Study

395 naturally menopausal women + 178 surgically menopausal women. Drawn from a sample of 3,049 women age40-60 in NHANES

Cohort 

(also has 

crosssectional 

data)

Internal 10 years NHANES (stratified probability 

sample of U.S.)

U.S. 

F-41
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearBrown, 2002AustraliaBusch, 1994

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

Mean age 49.7 (sd 1.5) yreas at survey 2

_ _ 14,065 mid-age 

women responded to the mailed survey; 54% of them agreed. For survey 2, 92% of 12,328 women responded (12,32represents women who consented to further contact anhad not died). 

40-60 Women who had participated in NHANES at 

baseline and the 10 year follow-up study. Included those who were not menopausal at the baseline assessment.Exclusions:1. Insufficient data to determine menopausal status2. Cessation of menstruation for reasons other than natural or surgical menopause3. Reporting surgical menopause but still having a uterus and ovaries4. Reporting continued menstruation after age 58.

__ 

F-42
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearBrown, 2002AustraliaBusch, 1994

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

Menopausal status: self-reported bleeding history or HRT (4 categories); 6 change categories.

_ ___ 

 Women were selected at random to receive the CES-D and the GWB (Global Well-Being) questionnaires. Sleep disturbance measures by three NHEFS items summed to form a scale: "How often do you have trouble falling asleep?"; "How often to you have trouble with waking up during the night?"; "How often do you have trouble with waking up too early and not being able to fall sleep again?"

_ 178/573 had 

"surgical menopause"

NR NR 

F-43
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearBrown, 2002AustraliaBusch, 1994

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

_ _ _ Relative to pre-pre:

Pre-peri: OR 1.3 (1.1, 1.5)Peri-peri: 1.3 (1.1, 1.5)Pre/peri-Post: 1.0 (0.8, 1.2) Not significantPost-post: 0.9 (0.7, 1.2) not significantHRT: 1.5 (1.3, 1.8)

_ Diff

PrePerPre1.8Posnot HR

NR NR NR NR NR No 

betdiffchabetsurme

F-44
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearBrown, 2002AustraliaBusch, 1994

Mood Cognitive Somatic Urinar

y

_ _ Stiff or painful joints 

(compared to pre-pre):Pre-peri: 1.3 (1.1, 1.5)Peri-peri: 1.6 (1.4, 1.9)Pre/peri-Post: 1.1 (0.9, 1.4) Post-post: 1.3 (1.0, 1.7)HRT: 1.4 (1.2, 1.7)Back pain (compared to pre-pre):Pre-peri: 1.2 (1.0, 1.4)Peri-peri: 1.3 (1.1, 1.5)Pre/peri-Post: 1.0 (0.8, 1.2) Post-post: 1.1 (0.9, 1.4)HRT: 1.2 (1.0, 1.4)

Leaking urine (comparto pr-pre):Pre-peri: 1.0 (0.8, 1.2) not significantPeri-peri: 1.3 (1.1, 1.6)Pre/peri-Post: 1.0 (0.81.3) not significantPost-post: 0.8 (0.6, 1.1not significantHRT: 1.0 (0.8, 1.2) not significant

No significant differences between women in different menopausal change groups, or between those of surgical vs. natural menopause (Mean CES-D score (s.d.) time 1 vs. time 2) :Pre-pre: 8.9 (9.1) vs. 7.8 (9.0), n=172Pre-Peri: 10.3 (9.4 vs. 7.8 (6.5), n=58.Pre-Natural Menopause: 8.4 (8.1vs 7.8 (7.5), n=114.Pre-Surgical Menopause: 9.6 (7.5)vs 9.4 (11.1) n=50

NR NR NR 

F-45
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearBrown, 2002AustraliaBusch, 1994

Sexual Dysfunc-tion Quality of Life Other Outcomes

_ __

NR No significant differences between 

women in different menopausal change groups, or between those of surgical vs. natural menopause (mean (s.d.) at time 1 vs. time 2):pre-pre:48.0 (10.9)vs 49.3(11.1), n=352.Pre-peri: 47.1 (12.6)vs. 47.7 (11.1), n=125.pre-Natural Menopause: 49.2(10.7) vs. 49.5 (10.1), n=281.pre-Surgical Menopause: 45.8 (12.3) vs. 47.0 (13.1).

_

F-46
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearBrown, 2002AustraliaBusch, 1994

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

_ Adjusted for symptom score at 

survey 1, physical activity , weight, weight change, life events, smoking status, occupation, country of birth, marital status, and area of residence and age. 

_

None No MV modeling _

F-47
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearBrown, 2002AustraliaBusch, 1994

RR or OR Comments

_ Using pre-pre as the reference group, 1. Headache: OR were 

not significantly different between groups (all CI crossed 1) 2. Eyesight problems: OR were not significantly different between groups (all CI crossed or included 1), 3. Severe tiredness: OR were highest for HRT (OR 1.5, CI 1.3-1.8), then per-peri (OR 1.3, CI 1.1-1.5) and peri-peri (OR 1.3, CI 1.1-1.5) and lowest for pre/peri-post (OR 0.9, 0.7-1.1) and postpost (OR 1.0, CI 0.7-1.3).4. Stiff or painful joints5. Back pain6. Leaking urine7. Constipation8. Difficulty sleeping9. Hot flashes10. Night sweats

NA Assume that the categories used to report symptoms are those 

ascertained at 10 year assessment, because everyone was premenopausal at baseline in order to be included.

F-48
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

Dennerstein, 1993Australia

Melbourne Women's 

1,897 Crosssectional __ _ _ 

Dennerstein, 1994Australia

Melbourne Women's 

1,879 Crosssectional __ _ _ 

Dennerstein, 1997

Melbourne Women's

405 Longitudinal _ 4 years _ _ 

F-49
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 1993AustraliaDennerstein, 1994AustraliaDennerstein, 1997

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

_ _ _ 1897/2001 (94.8%

were available for analysis

_ Current oc users excluded. _ _ 

45-55 Inclusion:

Women who were still experiencing menstrual cycles, or who had no more than 3 months of amenorrhea, who were not taking hormone therapy, or oral contraceptives, had an intact uterus, and at least one ovaryExclusions:HRT use, surgical removal of uterus and/or ovaries, women who refused blood draws

Face to face interview

Subset of cohort o2001 women

F-50
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 1993AustraliaDennerstein, 1994AustraliaDennerstein, 1997

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

_ _ ___ 

Sexual interest, frequency, dyspareuniasociodemographic and lifestyle variableshealth status, menopausal status

_ ___ 

Affectometer 2 (modified)E2

FSHTotal Testosterone (T)SHBGFree Androgen Index (FAI)

Pre 37%Early Peri 34%Late Peri 17%1-2 years post 9%> 2 years post 3%Mean age increased across the menopausal categories from 49.4 (pre) to 54.4 (> 2 years post), p<0.001.

Excluded NR NR 

F-51
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 1993AustraliaDennerstein, 1994AustraliaDennerstein, 1997

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

_ _ _ By menstrual status:

Post 39.4%Peri 31.5%Pre 9.8%

_ Tro

by PosPerPre 

_ __ _ _ _ NR _ (% in the last 2 weeks)

12.618.4 (p<0.05)54.3 (p<0.001)57.0 (p<0.001)48.8 (0.001)p values as compared to pre-menopausal group

_ 

F-52
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 1993AustraliaDennerstein, 1994AustraliaDennerstein, 1997

Mood Cognitive Somatic Urinar

y

Feeling sad or downheartedby menstrual status:Post 48.7%Peri 33%Pre 24.7%

Difficulty in concentratingby menstrual status:Post 18.3%Peri 27.5%Pre 20.3%

_ Problems with urine 

control by menstrual status:Post 14%Peri 16%

Pre 9.2%

_ _ _ _

Positive affect increased with age (p<0.05) and negative affect decreased with age (p<0.05) only in the postmenopausal categories.In the pre- and peri-menopausal categories, there were no significant age effects.

_ _ _

F-53
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 1993AustraliaDennerstein, 1994AustraliaDennerstein, 1997

Sexual Dysfunc-tion Quality of Life Other Outcomes

_ ___ ___ __

F-54
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 1993AustraliaDennerstein, 1994AustraliaDennerstein, 1997

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

__ _

Age, menopausal status, well-being, employment status, years of education, vasomotor symptoms, cardiopulmonary symptoms, skeletal symptoms

Logistic regression model of decrease in sexual interest over the preceding year

Natural menopauseOn HRTwell-beingpart-time employmentno employment11-12 years of educationvasomotor symptomscardiopulmonary symptomsskeletal symptoms

_ Data from years 1-4 was pooled 

an analyzed as a whole.Generalized linear regression, forward stepwise approach.

Significant coefficients after adjustment for age None were significant for positive affect in any groups compared with premenopausal group.The mean negarive affect score was higher in p<0.01) and 1-2 year post menopause (Beta 0compared to premenopausal group.Overall, well being tended to decrease with incstatus, with the lowest in the 1-2 years postmefollowed by an increase in levels of well being postmenopause group.

F-55
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 1993AustraliaDennerstein, 1994AustraliaDennerstein, 1997

RR or OR Comments

_

1.93 (1.22-3.06)2.27 (1.42-3.63)0.76 (0.67-0.87)1.81 (1.34-2.45)1.56 (1.16-2.10)0.65 (0.50-0.87)1.25 (1.05-1.48)0.72 (0.61-0.84)1.32 (1.11-1.50)

Decline in sexual interest was associated with natural menopause, decreased well-being, decreasing employment, vasomotor symptoms, skeletal symptoms, and cardiopulmonary symptoms. It was not associated with age.

_

_

F-56
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

Dennerstein, 1999Australia

Melbourne Women's

354 Longitudinal _ 6 years _ _ 

Dennerstein, 2000Australia

Melbourne Women's

172 Longitudinal _ 7 year 

follow-up

_ _

F-57
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 1999AustraliaDennerstein, 2000Australia

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

48.1 at baseline

Exclusions: dropouts (49), surgical menopause (29), oral contraceptive use at any year (6).

Questionnaires, physical exam, blood samples, telephone interview

Retention rate for longitudinal arm 90% at 6 years. Percentage of original cohort eligible for this analysis 80.8%.

50.3 172 women of the 438 in the longitudinal cohort 

were included. They were premenopausal at baseline and either perimenopausal or postmenopausal at follow-up. For women who had hysterectomy, bilateral oophorectomy, endometrial ablation (n=10) or took HRT (n=53), only information prior to the intervention was used.

Questionnaires, physical exam, blood samples, telephone interview

89% for longitudincohort at 7year follow-up.Percentage of original cohort eligible for this study 39%.

F-58
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 1999AustraliaDennerstein, 2000Australia

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

Affectometer-2sociodemographic variables, menopausal status, 22 symptom checklist, self-rated health, lifestyle factors, blood samples FSH, E2, Inhibin, Factor 1 of Personal Experiences Questionnaire

_ ___ 

North American symptom checklist, sociodemographic, health and wellbeing, menstrual calendars, blood samples E2, FSH

By post-menopause, the average total number of symptoms reported increased by 17% from 4.2 to 4.9 (p<.001)

___ 

F-59
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 1999AustraliaDennerstein, 2000Australia

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

_ __ _ _ _ _ 33.6% BMI>25 Night sweats (p<0.01) 

and hot flushes (p<0.001) increased in the late peri and postmenopause . Magnitude of change between early and late perimenopause +27% for hot flushes, +17% for night sweats.

Vaginal dryness increased in late perimenopause and postmenopause (P<0.001). 

Magnitude of change between early and late perimenopause +17%.

TroscopermeMa+6% late (grame

F-60
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 1999AustraliaDennerstein, 2000Australia

Mood Cognitive Somatic Urinar

y

Significant decrease in negative mood with time (p=.005)

_ _ _

_ _ Somatic symptoms 

(other than breast soreness) did not change significantly with transition to late-peri or post-menopause.

Urinary symptoms did not change significantwith transition to late-por post-menopause.

F-61
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 1999AustraliaDennerstein, 2000Australia

Sexual Dysfunc-tion Quality of Life Other Outcomes

_ ___ Breast soreness severity 

scores were reduced in peri and post-menopauscompared to pre and eaperimenopause (p<0.00Magnitude of change -2E2 decreased sharply aFSH increased sharply between early and late perimenopause.

F-62
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 1999AustraliaDennerstein, 2000Australia

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

_ _ Significant predictors of Magnitude of Negative 

0.02):premenstrual complaints, negative attitudes to parity of one child, number of symptoms, poor negative feelings for the partner, lack of a partnexercising < once a week, >3 daily hassles, mo

interpersonal stressSignificant predictors of Change in Negative Mfactor changes) (p < 0.001 to p=0.05):symptoms, self-rated health, feelings for partneinterpersonal stress

FSH, E2, all predictors used in the model are not listed

Logistic regression to determine predictors of symptoms in late perimenopause

Hot flash model: number of symptoms > 4 occupation professional  occupation sales/white collar smoking pack years at early perimenopause >10 estradiol at late perimenopause 30-100 estradiol at late perimenopause <30Night sweats model: change in E2 from early to late perimenopausVaginal dryness model: education >12 yTrouble sleeping model: well-being at early perimenopause 1.7-2.3 well-being at early perimenopause >2.3 Agree to statement of beliefs about menopau Hot flushes at late perimenopause - yes

F-63
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 1999AustraliaDennerstein, 2000Australia

RR or OR Comments

_ No direct link between the menopausal transition and negative 

mood level.However, menopausal transition interacts (amplifies negative effects of these variables on mood) with paid work, self-rated health, daily hassles.

6.20.10.27.020.55.01.10.30.30.15.55.0

E2 is the best predictor for vasomotor symptoms.

F-64
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

Dennerstein, 2001aAustralia

Melbourne Women's

283 Longitudinal Internal 8 years _ _ 

Dennerstein, 2001bAustralia

Melbourne Women's

267 Longitudinal _ 8 years _ _ 

F-65
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 2001aAustraliaDennerstein, 2001bAustralia

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

48.5 at baseline

Included:Group M = 197 women who transitioned through menopauseGroup A = 44 stayed pre-or early perimenopausalGroup B = 42 stayed postmenopausal between years 3 and 8Excluded: dropouts, surgical menopause, oral contraceptive use at any year, had not passed through enough menopausal categories.

Questionnaires, blood samples, telephone interview

88% retention at 8 years, percentage eligible for this study 64.6%.

48.8 years at baseline

Excluded: dropouts (57), surgical menopause (36), oral contraceptive use at any year (5), lack of baseline data on some measures (5), failure to reach late perimenopause during 8 years of study (26), HRT use before reaching late perimenopause (42).

Questionnaires, physical exam, blood samples, telephone interview

88% retention at 8 years, percentage eligible for this study 61%.

F-66
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 2001aAustraliaDennerstein, 2001bAustralia

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

Personal Experiences Questionnaire (SPEQ, based on the McCoy Female Sexuality Questionnaire). PEQ factors include: feelings for partner, sexual responsivity, frequency of sexual activities, libido, partner problems, vaginal dryness/dyspareuniaFSH, E2, menopausal status/menstrual diaries

_ ___ 

Affectometer-2, menstrual status,sociodemographic variables, lifestyle variables

_ ___ 

F-67
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 2001aAustraliaDennerstein, 2001bAustralia

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

_ __ _ _ _ __ _ _ 

F-68
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 2001aAustraliaDennerstein, 2001bAustralia

Mood Cognitive Somatic Urinar

y

_ _ _ _

Mean positive mood scores by study year did not show any linear trend with time.No significant change in positive mood over the menopausal transition.Premenopausal positive mood scores correlated significantly with late perimenopausal (r=0.61) and postmenopausal (r=0.66) positive mood scores.Late perimenopause positive mood scores correlated with postmenopause positive mood scores 

(r=0.68)

_ _ _

F-69
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 2001aAustraliaDennerstein, 2001bAustralia

Sexual Dysfunc-tion Quality of Life Other Outcomes

Total SPEQ scores fell from early to late perimenopause (p<0.001). Sexual responsivity (SPEQ2) decreased signifi-cantly (p<0.0001). Sexual frequency, libido, and vaginal dyspareunia did not change significantly.Partner's problems with sexual performance increased significantly (p<0.001) and women's positive feelings for partner declined significantly (p<0.05).From late peri to postmenopause total SPEQ score declined further (p<0.01) as did scores for sexual responsivity (p<0.01), libido (p<0.01), and frequency of sexual activities (p<0.05).Significant increase in vaginal dyspareunia (p<0.01) and partner's problems with sexual performance (p<0.05).

_ In control group A (pre- 

early perimenopausal), tonly parameter to show change with time (1st to year) was sexual respon(mean change-0.67, p=0.0005). FSH increased (+19.3, p<0.0between years 1-7, E2 ldecreased (-212, p<0.01) between 3-8.In control group B (postmenopausal), the only parameter to show chanwas sexual responsivity change-0.42, p=0.036). No sig

_ __

F-70
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 2001aAustraliaDennerstein, 2001bAustralia

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

__ __ General linear model of factors 

affecting positive moods during midlife.Final model: Predictors of Positive Mood Late in the Menopausal Transition

Premenopausal positive mood scores were sigbaseline interpersonal stress (B=-0.113, p=0.0attitudes to aging (B=0.054, p=0.026).Postmenopausal positive mood scores were sipremenopausal positive mood scores (B=0.717symptom change (B=-0.085, p=0.000), chang(B=0.342, p=0.007), major life events (B=-0.12hassles (B=-0.016, p = 0.014), work satisfactioPremenopausal positive mood scores (B=0.73dysphoric symptom change (B=-0.108, p=0.00status (B=0.353, p=0.004) major life events (Bdaily hassles (B=-0.015, p = 0.011)work satisfaction (B=0.456, p=0.000). 

F-71
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 2001aAustraliaDennerstein, 2001bAustralia

RR or OR Comments

_ Sexual responsivity (SPEQ2) decreases with time across all 

groups. The other five domains of sexual functioning were not affected by time but changed with the menopausal transition.

_ The most important predictor of positive mood in late peri- and 

post-menopause is positive mood in pre- and early perimenopause.BMI was not a significant predictor of positive mood.Smoking was not a significant predictor of positive mood.

F-72
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

Dennerstein, 2002aAustralia

Melbourne Women's

226 Longitudinal _ 8 years _ _ 

F-73
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 2002aAustralia

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

Participants included in this analysis could provide at least one measure of well-being during early menopausal transition, late transition and postmenopause. Yearly measures associated with HRT were excluded. The original longitudinal cohort of 438 had 57 drop out, 36 had surgical menopause, 5 used oral contraceptives. 226 of 340 eligible participants were included.

Questionnaires, physical exam, blood samples, telephone interview

Retention rate for longitudinal arm 88% at 8 years. Percentage of original cohort (438) used in this study 51.6%. Percentage of those eligible for this analysis 66.5%

F-74
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 2002aAustralia

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

Well-being using Affectometer-2symptomsdemographicslifestyle factors BMImenopausal statusFSH, E2, Testosterone

_ ___ 

F-75
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 2002aAustralia

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

_ __ _ _ 

F-76
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 2002aAustralia

Mood Cognitive Somatic Urinar

y

No significant change in positive mood scores with menopausal transition. Significant decrease in negative mood and significant improvement in well-being scores between early and late perimenopause and early and post-menopause.

_ _ _

F-77
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 2002aAustralia

Sexual Dysfunc-tion Quality of Life Other Outcomes

_ __

F-78
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 2002aAustralia

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

14 predictors including baseline measures of physical and mood symptoms, lifestyle measures, and well-being

Multifactor model of well-being change during midlife - late menopausal transition model.Influence of vasomotor symptoms and vaginal dryness on well-being.Influence of hormone levels on well-being.Final model of well-being in the late menopausal transition using findings from the previous models.(Results were the same for postmenopause.)Regression analysis on change in well-being from early to late menopausal transition.

Well-being in the early menopause was the oninfluenced well-being in the late menopause.Well-being before late menopause (B 0.72, p 0dysphoric symptoms (B -0.20, p 0.00)changing marital status (becoming married or tp 0.02)change in satisfaction with work (B 0.63, p 0.00experiencing a severe life event (B -0.2, p 0.03increase of hassles (B -0.02, p 0.04).No significant effect of vasomotor symptoms, vhormones on well-being.Well-being before late menopause (B 0.63, p 0changing marital status (becoming married or tp 0.01)change in satisfaction with work (B 0.71, p 0.00experiencing a severe life event (B -0.17, p 0.0increase of hassles (B -0.03, p 0.00)Changing marital status (becoming married or p 0.00)change in satisfaction with work (B 0.80, p 0.00experiencing a severe life event (B -0.23, p 0.0

F-79
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 2002aAustralia

RR or OR Comments

_ As women transition from early to late perimenopause and postmenopause there is an improvement in measures of well-being. 

Well-being appears to be influenced by psychosocial factors.

F-80
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

Dennerstein, 2002bAustralia

Melbourne Women's

226 Longitudinal _ 8 years _ _ 

Freeman, 2004 Penn 

Ovarian Aging Study

332 Longitudinal _ 4 years Random digit dialing to all 

households in Philadelphia County

African Ame

White w

F-81
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 2002bAustraliaFreeman, 2004

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

Year 1 - mean age of women in early menopausal transition was 49.1 years.Year 8 - mean age of postmenopausal women was 57.1 years.

Women were excluded from analysis if they dropped out, had surgical menopause, took oral contraceptives or hormones, or did not complete the sexuality measure or blood sampling. 226 of original 438 were available for analysis.

Questionnaires, physical exam, blood samples, telephone interview

88% retention at 8 years, percentage eligible for this study 51.6%.

35-47 75% of eligible participants were enrolled in the full 

cohort (218 AA, 218 W), 353 of these provided data for this study, 332 did not have usable blood samples and were thus excluded

Questionnaire and interview

75% 

F-82
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 2002bAustraliaFreeman, 2004

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

Personal Experiences Questionnaire (SPEQ, based on the McCoy Female Sexuality Questionnaire), Affectometer 2, FSH, E2, T (testosterone), DHEAS, SHBG (sex hormone-binding globulin, menopausal status/menstrual diaries

_ Excluded _ _ 

CES-D, DSM-IV criteria for MDD Women were initially all 

premenopausal (n=332), by yearBreakdown:Pre 227/312Early transition 64/312Late transition 10/312Post 11/312

Excluded _ _ 

F-83
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 2002bAustraliaFreeman, 2004

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

_ __ _ _ _ __ _ _ 

F-84
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 2002bAustraliaFreeman, 2004

Mood Cognitive Somatic Urinar

y

Positive and negative mood did not correlate with any of the hormone measures. Positive mood increased with age (B 0.01, p 0.042) and negative mood decreased with age (B -0.009, p 0.012).

_ _ _

CES-D scores of 16 or higher incrased during the transition to menopause and were lower after menopause (p=0.047)MDD present in 10-13% of premenopausal and < 4% in 

transition phases

_ _ _

F-85
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 2002bAustraliaFreeman, 2004

Sexual Dysfunc-tion Quality of Life Other Outcomes

42% of women in early menopausal transition at year 1 had SPEQ scores in-dicating sexual dysfunction com-pared with 88% of postmenopausal women at year 8 of follow-up.

_ _

_ __

F-86
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 2002bAustraliaFreeman, 2004

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

_ "Repeated-measures linear 

regression was used to model total and domain scores on SPEQ and mood scores as a function of age, log of free testosterone index, and log of free estradiol index."

Total SPEQ score:age (B -0.2, p 0.0)log estradiol (B 0.13, p 0.01)log free estradiol index (B 0.12, p 0.014)Sexual responsivity:age (B -0.07, p 0.0)log estradiol (B 0.04, p 0.052)Frequency of sexual activities:age (B -0.05, p 0.0)Libido:age (B -0.45, p 0.0)log estradiol (B 0.087, p 0.001)log free estradiol index (B 0.08, p 0.001)No aspect of sexual functioning was correlaandrogen measures.

Race, age, history of depression, menopausal status, severe PMS, poor sleep, not employed, hot flashes, FSH, antidepressant medications

Multivariate models of CES-D scores and MDD

CES-DMenopausal status (pre is reference group)Early transition OR 1.55 (CI 1.04-2.32)Late transition OR 2.89 (CI 1.29-6.45)Postmenopausal OR 0.78 (CI 0.1-6.17)Race (White is reference)AA OR 1.89 (CI 1.35-2.63)History of depression OR 2.45 (CI 1.61-3.72)MDDRace (White is reference)AA OR 1.52 (1.03-2.24)Menopausal status NSHistory of depression OR 4.75 (CI 3.17-7.13) 

F-87
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearDennerstein, 2002bAustraliaFreeman, 2004

RR or OR Comments

_ "Female sexual functioning declines with the natural menopause 

transition." No association of androgen levels with sexual functioning. However, there was an association of decreasing estrogen levels with decline in sexual functioning.

See Significant Predictors 

column

Only relevant significant predictiors listed for these models. There were other significant predictors in the models.

F-88
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

Glazer, 2002 Ohio 208 Cohort Internal 27 months Community recruitment NR Gold, 2000 SWAN 12,425 Crosssectional

(baseline survey 1995-7)

N/A N/A _ _ 

F-89
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearGlazer, 2002Gold, 2000

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

40-60 (mean 

48)

Reported Kupperman Index 208 recruited

175 to 1st follow-u165 completed

40-55range %:40-43 28.3%44-47 31.0%48-51 24.0%52-55 16.7%

3640 of 16065 were excluded because 1) menses had stopped because of medication, radiotherapy, pregnancy/lactation, or extreme weight change, 2) reported use of exogenous female hormones in the past 3 months, 3) reported race/ethnicity as mixed/other.

_ 77.34%

F-90
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearGlazer, 2002Gold, 2000

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

Coping ScaleKaufert and Syrotvik IndexHobfoll Core EvaluationBowles Menopause Attitude ScaleDepression ScaleHealth Promoting Activities

Pre: 38%Peri: 17%Post: 14%SMP: 33%

NR NR NR 

Yes/No questions regarding presence of vasomotor, psychological, and physical symptoms during the previous 2 weeks

Surgical 16%Postmenopausal 14.2Late perimenopausal 4.9Early perimenopausal 28.6premenopausal 36.3

1988/12425

(16%)

NR NR 

F-91
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearGlazer, 2002Gold, 2000

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

Evaluated NR _ _ _ 

Smoking:current 23.4%past 23.3never 53.3

_ BMI:

<19 6.4%19-26.9 42.7%27-31.9 21.5%>=32 19.4%Compared to BMI 19-26.9, OR for hot flashes (p<0.05):27-31.9 OR 1.15> 32 OR 1.18

By menstrual status:surgical 46.9% post 48.8%late peri 56.8%early peri 36.9%pre 19.4%Compared to premenopausal status (p<0.05):surgical OR 2.4 post OR 2.81late peri OR 4.32early peri OR 2.06

By menstrual status:surgical 19.4%post 21.2%late peri 18.2%early peri 12.9%pre 7.1%Compared to premenopausal status (p<0.05):surgical OR 2.39 post OR 2.57late peri OR 2.30early peri OR 1.77

Diffby surposlate earpre Compausurposlate ear

F-92
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearGlazer, 2002Gold, 2000

Mood Cognitive Somatic Urinar

y

_ _ _ NR _ Forgetfulness

by menstrual status:surgical 43.8%post 42%late peri 44.8% early peri 44%pre 31.2%Compared to premenopausal status (p<0.05):surgical OR 1.27post OR 1.28late peri OR 1.43early peri OR 1.44

Stiff/soreby menstrual status:surgical 59.4%post 54.8%late peri 58.4%early peri 57.9%pre 45.8%Compared to premenopausal status (p<0.05):surgical OR 1.50post OR 1.31late peri OR 1.48early peri OR 1.48

Urine leakageby menstrual status:surgical 22.1%post 17.7%late peri 19.6% early peri 20.6%pre 12.3%Compared to premenopausal status (p<0.05)surgical OR 1.64post OR 1.24late peri OR 1.42early peri OR 1.67

F-93
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearGlazer, 2002Gold, 2000

Sexual Dysfunc-tion Quality of Life Other Outcomes

NR NR Menstrual irregularity an

hysterectomy associated significant level of increaanxiety in univariate anabut not multivariate anal

NR NR _

F-94
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearGlazer, 2002Gold, 2000

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

Menopausal status included in modelsEducation coping effectiveness of resourcesAttitude toward menopauseCoping useAgeRaceJobIncomeMarital statusReligion

Multivariate with 3 outcomes Predictors of anxiety:

Loss of resourcesEducation levelCoping effectivenessPredictors of depression:Loss of resourcesEducationPredictors of health promoting activities:Coping effectivenessAttitude towards menopause

Age, education, employment status, difficulty paying for basics, race/ethnicity, marital status, parity, menstrual status, BMI, smoking, physical activity, study site, parity

Several multiple logistic regression models for the following symptoms:hot flashes/night sweats, urine leakage, vaginal dryness, stiff/sore, heart pounding, forgetful, difficulty sleeping.

See Table 3 p.468 (Key points)-All symptoms were more frequent in women wpremenopausal (p<0.05).-Hot flashes/night sweat prevalence was assoc(p<0.05). -Vaginal dryness was not associated with BMI.-Hot flashes were not associated with an increaperimenopausal and postmenopausal women -Compared to W women, J and Chinese had dflashes (OR 0.63, 0.65), AA women had increahad increased odds of vaginal dryness (OR 1.8

F-95
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearGlazer, 2002Gold, 2000

RR or OR Comments

__

F-96
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

Gracia, 2004 Penn 

Ovarian Aging Study

326 Crosssectional 

analyses from cohort

Internal 4 years Women in Philadephia County 

indentified through random digit dialing

Community-bPhiladephia

Guthrie, 1996Australia

Melbourne Women's 

453 Crosssectional _ 3rd year of follow-up _ _

F-97
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearGracia, 2004Guthrie, 1996Australia

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

35-47 Excluded:

Serious illness with potential to effect hormone levelsAny hormone use in past 3 monthsPreganancy, lactation, or use of psychotropic drugsUse of alcohol/illicit drugs in past 1 yr

Serum blood samplesQuestionnaires

Of 578 eligible, 75% agreed to participate. Of those participating326 were eligible for this analysis.

By menstrual group

Longitudinal cohort, excluded if they had undergone hysterectomy by the time of follow-up

__ 

No change 50.2Change in flow 50.1

F-98
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearGracia, 2004Guthrie, 1996Australia

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

CES-DTotal testosterone, DHEASFSH, LH, E2Libido assessed with one question "Have you experience a decrease in libido?"

Premenopausal 147 (45%)Early menopausal (variable cycle lengths) 140 (42%)Late menopausal (3-11 mo of ammenorrhea)Post-menopausal 14 (4.3%)

Excluded Excluded NR 

_ _ ___ 

12%19%

F-99
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearGracia, 2004Guthrie, 1996Australia

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

NR Excluded if 

HRT or any hormone within past 3 months

Mean BMI 28

No significant difference in smoking status between women who did and did not have hot flashes for the whole cohort and by menstrual group.

_ BMI in kg/m2 did 

not differ across menstrual groups (p=.239)

> 1 in last 2 weeks by 

menstrual status (p<.001):post 62%peri 37%pre 13%HRT users 15%As the frequency of hot flash reporting increased the FSH levels increased and E2 levels decreased.

_ 

26.627.4

F-100
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearGracia, 2004Guthrie, 1996Australia

Mood Cognitive Somatic Urinar

y

_ _ _ _

F-101
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearGracia, 2004Guthrie, 1996Australia

Sexual Dysfunc-tion Quality of Life Other Outcomes

At 4 years (6th assessment): 27% (87 of 326 women) reported a decreased in libido or sexual interest vs 73% (239) reported no change.Women with decreased libido were more likely to report vaginal dryness (38% vs 13%) and depressive symptoms (52% vs 28%)

_ _ FSH, E2, and inhibin (IN

levels by menstrual grouCompared to no change (p<0.05): FSH levels wehigher in all groups but cin flow and change in frequency. E2 and INH lower in both amenorrhegroups, INH was lower igroup.FSH 13E2 249.3Inhibin 187.4FSH 13.8E2 243.7Inhibin 189.6

F-102
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearGracia, 2004Guthrie, 1996Australia

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

Variables in the model: age, BMD, race, marital status, depression (CES-D), presence of child <18 yr old at home, vaginal dryness, mean testosterone level.

multivariate models In MV analysis, vaginal dryness was strongly a

decreased libido (OR 3.5, CI 1.8, 6.6), as was 1.9, 6.1)Depression remained a significant predictor of after excluding women on anti-depressantsFluctuation in testosterone was associated with Overal levels of testostertone and DHEAS werthose with decrease in libido and those with no Fluctuation of other hormones was not relatex Age, BMI and Causasian race were not associlibido.

Hormonal, physical, and lifestyle variables

Effect of variables on presence of vasomotor symptoms multiple linear logistic regression conducted in periand post-menopausal women.

Peri:premenstrual complaints 1.42 (1.04-1.93)FSH 1.71 (1.15-2.55)Estradiol NSPost:premenstrual complaints NSFSH NSEstradiol NS

F-103
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearGracia, 2004Guthrie, 1996Australia

RR or OR Comments

Significant predictors of decreased libido were:Having children < age 18 at home OR 1.4 (CI 1.1, 1.7), p=0.014Depression OR 3.4 (1.9, 6.1), p<0.0001Vaginal dryness OR 3.5 (1.8, 6.6), p<0.0001Degreee of testosterone fluctuation was divided into quartiles. All quartiles 

No results for hormone levels or libido by menoapusal status. No adjustment for menopausal status in the MV analysis.

_

F-104
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

Guthrie, 1996Australia(continued)

F-105
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearGuthrie, 1996Australia(continued)

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

Change in frequency 59.8Change in flow and frequency 51.2Amenorrhea >3<12 months 52.4Amenorrhea >12 months 53.7Hormone therapy 52.7

F-106
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearGuthrie, 1996Australia(continued)

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

6%

20%15%15%24%

F-107
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearGuthrie, 1996Australia(continued)

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

25.625.926.726.225.3

F-108
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearGuthrie, 1996Australia(continued)

Mood Cognitive Somatic Urinar

y

F-109
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearGuthrie, 1996Australia(continued)

Sexual Dysfunc-tion Quality of Life Other Outcomes

FSH 19.7E2 196.8Inhibin 170.2FSH 19.5E2 256.9Inhibin 165.2FSH 69.2E2 81.4Inhibin 98.9FSH 93.9E2 37.9Inhibin 76.2FSH 26E2 357.4Inhibin 89.5

F-110
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearGuthrie, 1996Australia(continued)

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

F-111
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearGuthrie, 1996Australia(continued)

RR or OR Comments

F-112
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

Hallstrom, 1985Sweden

Gothenburg 899 Cohort Internal 6 years Systematic sampling of 

Gothenburg Sweden population using Taxation Office Register. Sampling methods described elsewhere. Unclear in this paper how the "psychiatric population" was selected from the larger sample

_ 

F-113
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearHallstrom, 1985Sweden

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

38-60 _ _ 899 participated in 

the first wave, of these 800 were examined. Of those 800 677 (84.6%) were examined in the second wave

F-114
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearHallstrom, 1985Sweden

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

<age 38 considered pre-climactericage>44 and regularly menstruating= premenopausalirregular menstruations=perimenopausalamenorrhea for 12-35 months=early menopauseamenorrhea for 36 months=postmenopause.Global assessment of functioning, disability grade, diagnostic interview for diagnoses of major depression, anxiety states, neurastenic state, phobic disorder, obsessive compulsive disorder, psychoses, alcoholism.

_ ___ 

F-115
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearHallstrom, 1985Sweden

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

_ __ _ _ 

F-116
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearHallstrom, 1985Sweden

Mood Cognitive Somatic Urinar

y

Cross-sectional data at baseline:Major depression N=55 (6.9%)anxiety N=18 (2.3%)Neurasthenic state N=14 (1.8%)Phobic disorder N=10 (1.3%)Obsessive compulsive disorder N=2 (0.3%)Pyschosis N=4 (0.5%)Alcoholism N=2 (0.3%)1 year onset rate of any psychiatric symptoms:Pre climacteric: N=78 (15.5%) age <38Pre menopause: N=190 (37.8%)Peri: N=126 (25.1%)Early Post menopasue: N=54 (10.8%) (12-35 months after menopause)Late postmenopause: N=54 (10.8%) (menopause > 3 years ago)

_ _ _

F-117
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearHallstrom, 1985Sweden

Sexual Dysfunc-tion Quality of Life Other Outcomes

_ __

F-118
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearHallstrom, 1985Sweden

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

_ No MV modeling _

F-119
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearHallstrom, 1985Sweden

RR or OR Comments

_ Proportion of women developing a mental disorder within one 

year after the menopause compared with the proportion of women developing a mental disorder without life events one year before: 9 (15.8%) after menopause vs. 15 (12.8%) prior to menopause and without a life event (NS by Fisher's exact).Lumped all mental disorders together.

F-120
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

Hardy, 2002Britain

Medical Research Council (MRC) National Survey for Health and Development

1572 Cohort Internal 52 years Socially stratified sample of all 

births in March 1943 in Britain

Socially straticohort in Britainterviewed in (age 43) were representative native populaage. 

F-121
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearHardy, 2002Britain

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

52 _ _ 2548 women 

enrolled at birth (March1946).1778 still in contacas of 1993.1572 women returned at least one questionnaire (84-90% RR) ovethe next 4 years fothis study.

F-122
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearHardy, 2002Britain

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

Checklist of 20 health problems (1-4 for each symptom)

_ ___ 

F-123
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearHardy, 2002Britain

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

_ _ _ Vasomotor symptom 

score:Peri-peri: 12.31 (10.44, 14.18)Post-post: 0.29 (-1.55, 2.12)Hysterectomyhysterectomy: 3.46 (1.72, 5.19)HRT-HRT: -2.93 (-4.6, -1.26)Pre-peri: 8.44 (6.11, 10.79)Vasomotor change in % score:Pre-post: 17.3 (6.33, 29.13)Pre-HRT: 19.25 (12.96, 25.52)Pre-hysterectomy: 9.87 (-0.37, 20.10) Pre-Peri: 8.44 (6.11, 10.76)Post-Post: 0.29 (-1.55, 2.12)

_ 

F-124
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearHardy, 2002Britain

Mood Cognitive Somatic Urinar

y

Psychological change score: Pre-post: 4.74 (-1.74, 11.23)Pre-HRT: 6.4 (2.12, 10.69)Peri-HRT: 4.38 (1.54, 7.21)Pot-post: -0.12 (-1.40, 1.15)Peri-Hysterectomy: -1.12 (-8.36, 6.15)Peri-Post: 1.58 (-0.65, 3.81)Peri-peri: 0.98 (-0.30, 2.26)Hysterectomy-hysterectomy: 0.41 (-0.75, 1.57)Pre-peri: 1.57 (-0.15, 3.29)Pre-hysterectomy: 2.43 (-4.78, 9.63)

_ _ _

F-125
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearHardy, 2002Britain

Sexual Dysfunc-tion Quality of Life Other Outcomes

_ _ Found the largest chang

percentage vasomotor symptom score between women who were premenopausal and becpostmenopausal (17.73) those who were premenopausal and starHRT (19.25). Change swere high among those were peri-menopausal aremained peri-menopauafter 6 years (12.31). Thwho were post-menopauand remained postmenopausal had the lowchange score (0.29).Change in percentage psychological symptom was highest among thoswomen who were premenopausal and becpost-menopausal (4.74)who were pre-menopauwent on HRT (6.4), and who were peri-menopauand went on HRT (4.38)Lowest psychological chscores were found in thowho were post- and rem

post (-0.12) and those w

F-126
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearHardy, 2002Britain

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

_ MV models adjusted for prior 

psychological status and personality (neuroticism score at age 16, present state examination (PSE) for anxiety and depression at age 36), health related behaviors, socioeconomic status (highest education, job held at age 43), attitude to menopause, smoking, BMI at age 36, age and baseline score.

Change in menopausal status.Change in work stress.Change in family stress.(true for both HR and psychological outcomes)

F-127
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearHardy, 2002Britain

RR or OR Comments

_

F-128
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

Hunter, 1989London

None 682 Crosssectional _ _ Newspaper ads, radio program, volunteers for 

ovarian cancer screening

Women aged years predomfrom London East England

F-129
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearHunter, 1989London

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

52.3 (45-65) Excluded: Women receiving estrogen therapy, 

women who had undergone hysterectomy

Questionnaires 78% (850/1090) to 

initial postal surve62.6% after exclusions

F-130
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearHunter, 1989London

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

"Women's Health Questionnaire" developed by the authorsPilowsky Hypochondriasis QuestionnaireGeneral Health Questionnaire

Premenopausal 18%Perimenopausal 26% Postmenopausal 56%

Excluded _ _ 

F-131
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearHunter, 1989London

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

_ _ _ Vasomotor symptoms 

increased with menopausal status. 55% of peri- and postmenopausal vs. 15% premenopausal women (p<0.000). 

Vaginal dryness increased with menopausal status. 25% of pre- and perimenopausal vs. 45% postmenopausal women (p NR).

Sleincme<0.con

F-132
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearHunter, 1989London

Mood Cognitive Somatic Urinar

y

Depressed Mood category of symptoms increased with transition to peri- and postmenopause (p<0.002) but there were only two items in this group that increased significantly "lack of enjoyment'' and "no feelings of well-being, reported by 5% of premenopausal and 15% of periand postmenopausal women.

No significant difference by menopausal status.

No significant difference by menopausal status.

_ 

F-133
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearHunter, 1989London

Sexual Dysfunc-tion Quality of Life Other Outcomes

Sexual problems increased with menopausal status (p<0.04). Sexual interest decreased significantly in periand post-menopausal women even when controlling for age. Sexual satisfaction did not change with menopausal status.

_ _

F-134
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearHunter, 1989London

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

Menopausal status, age, reported current illness, marital status, social class, employment status (only 45-54 year olds included).

Multiple regression for each factor score (symptom group)

Symptoms groups with menopausal status as a (p<0.05). Depressed Mood:

menopausal statusSomatic symptoms:menopausal statusVasomotor symptoms:menopausal statusSexual problems:menopausal statusSleep problems:menopausal statusMenopausal status was not a significant predicdifficulties and anxiety/fears.

F-135
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearHunter, 1989London

RR or OR Comments

B 0.17B 0.17B 0.29B 0.16B 0.11

Factor analysis done prior to use of scores for ANCOVA and regression analysis.

F-136
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

Kaufert, 1992 Manitoba 469 Crosssectional 

and longitudional

_ 3 years Mail survey of women from 

general population of Manitoba, CanadaAge 40-59 years

Manitoba, Ca

Koch, 1995 University of 

Minnesota and Tremin Trust Longitudinal Study

391 Crosssectional 

from cohort

Internal Prevalence College class 852 eligible p

from college c1963 and the Trust Longitu505 surveys r391 eligible

F-137
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKaufert, 1992Koch, 1995

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

45-55 (mean 48.4)

Inclusion: menstruated in the last 3 months, or had previously had a hysterectomy, age 45 or older

Mail and telephone surveys

68% to mail surve87% of those eligible for longitudional follow up agreed to participate

Mean 46 Specified Survey 

F-138
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKaufert, 1992Koch, 1995

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

CES-DModified Worsley's 'Role Problem Checklist'Questions regarding recent life events, menses, 4 health conditions (arthritis, allergies, high blood pressure, thyroid problems), and present state of health (good, fair, or poor)

_ 136 (no 

differentiation by oophorectomy status)

NR NR 

Survey Excluded NR NR NR 

F-139
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKaufert, 1992Koch, 1995

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

_ __ _ _ 

NR NR 24% reported

Significantly related to age and menopausal status

36% in perimenopausal group

NR 

F-140
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKaufert, 1992Koch, 1995

Mood Cognitive Somatic Urinar

y

Depression26% of all women were depressed at one interview or another. Across all 5 interviews, the percentage of women with CES-D > 16 was 9-11%. All depression 

data was collapsed across the 5 interviews to look at the association between depression and transition from one menopausal status to another. A woman's menopausal status does not significantly alter the likelihood of her becoming depressed (hysterectomized women excluded). Hysterectomized women who were not depressed at baseline were more likely than women in any other menopausal category to become depressed 

(OR 1.7, CI 1.15, 2.6).

_ _ _

NR NR NR NR 

F-141
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKaufert, 1992Koch, 1995

Sexual Dysfunc-tion Quality of Life Other Outcomes

_ __

NR NR Age

Marital statusMenopausal statusVaginal drynessHot flashes

F-142
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKaufert, 1992Koch, 1995

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

__ _

Change in desire, marital status, vaginal dryness, enjoyment with partner, age.Menopausal status not related to reduced desire, reduced orgasm, or less 

j t

Logistic regression Only Betas and x2 reported for each predictor v

F-143
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKaufert, 1992Koch, 1995

RR or OR Comments

_ __ Premenopausal: 21%

Perimenopausal: 79%

F-144
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

Koster, 1993a Copenhagen 621 Crosssectional 

from cohort

Internal 4 years NR Danish wome

1936, from 4 municipalities Copenhagen

Koster, 1993b Copenhagen 621 Crosssectional 

from cohort

Internal 11 years NR Danish wome

1936, from 4 municipalities Copenhagen

F-145
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKoster, 1993aKoster, 1993b

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

51 year olds Inclusion:

In 1976, all 40 year old women born in 1936, resident in 4 municipalitites in Copenhagen, in good general health

Questionnaire 526 (88%) 

40-51 year olds Inclusion:

In 1976, all 40 year old women born in 1936, resident in 4 municipalitites in Copenhagen, in good general health

Questionnaire and 

interview

NR 

F-146
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKoster, 1993aKoster, 1993b

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

Postal questionniare and telephone 

contact

In 1987Pre 47 (9%)Peri 91 (7%)Post 129 (25%)HRT 175 (33%)SM 84 (16%)In 1986Pre 66 (13%)Peri 121 (23%)Post 93 (18%)HRT 163 (31%)SM 83 (16%)In 1985Pre 135 (26%)Peri 95 (18%)Post 129 (25%)HRT 144 (27%)SM 81 (15%)In 1984Pre 205 (39%)Peri 67 (13%)Post 51 (10%)HRT 125 (24%)

SM 7

8 (15%)

Examined _ _ 

Questionnaire, interview, clinical 

assessment from a trained 

psychiatrist using diagnostic criteria 

developed by Bollerup for The 

Glostrup Population Studies 

(psychological health status), criteria 

from The Danish National Institute of 

Scoial Research (social status) 

See Koster 1993 Examined _ _ 

F-147
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKoster, 1993aKoster, 1993b

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

_ Excluded _ Increased prevalence 

within groupsPre to peri: beta 0.81 (p<0.0001) OR 2.24 (1.90-2.64)Peri to post: beta 0.41 (p<0.0001) OR 1.51 (1.25-1.81)

_ 

_ Excluded _ _ _ 

F-148
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKoster, 1993aKoster, 1993b

Mood Cognitive Somatic Urinar

y

Increased prevalence of moodiness within groupsPre to peri: beta 0.17 (p<0.017) OR 1.19 (1.03-1.37)

_ Increased prevalence of 

fatigue within groupsPre to peri: beta 0.24 (0.004) OR 1.27 (1.08-1.49)Peri-post: beta 0.21 (p<0.041) OR 1.23 (1.01-1.50)

_ 

_ _ _ _

F-149
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKoster, 1993aKoster, 1993b

Sexual Dysfunc-tion Quality of Life Other Outcomes

_ __

Anticipation of decreased sexuality at 40 years was only significant predictor of decreased sexual desire (p<0.01) at 51 years.

_ _

F-150
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKoster, 1993aKoster, 1993b

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

Not significant:Headache, depression, moodiness from peri - post menopausal status

Logistic regression models _

Not significant:Social background (education, marital, and social status), life-style (smoking, alcohol-intake, physical fitness)

Multiple logistic regression models

AgeMarital statusEmplyment statusSocial status

F-151
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKoster, 1993aKoster, 1993b

RR or OR Comments

OR (see symtom 

columns)

Prevalence data reported.

F-152
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

Koster, 2002Denmark

Copenhagen 621 invited

548 initially 

enrolled

Crosssectional Internal 20 years NR Women in De

Age 40 in 197

F-153
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKoster, 2002Denmark

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

40 at baseline NR Survey

Telephone questionnaires or personal interview

65-88% 

F-154
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKoster, 2002Denmark

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

Survey evaluating sociodemographic, attitudes, symptoms, general health, sexualty, body image, medication, life events, aging.

Assessed by numbers NR

NR NR 

F-155
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKoster, 2002Denmark

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

Assessed (see 

measures used 

column)

NR NR Prevalence by age (%):

40: NR45: NR51: 5660: 29Prevalence by menopausal status (%):Pre: 31Peri: 46Post: 68HRT: 56Surgical menopause: 61

NR

F-156
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKoster, 2002Denmark

Mood Cognitive Somatic Urinar

y

Depression by age (%):40: NR45: NR51: 1860: 20Depression by menopausal status (%):Pre: 12Peri: 21Post: 16HRT: 28Surgical menopause: 38Moodiness by age (%):51: 2860: 31Moodiness by menopausal status (%):Pre: 33Peri: 34Post: 32HRT: 49Surgical menopause: 60

_ Headache by age (%):

40: 5651: 4960: 38Headache by menopausal status (%):Pre: 44Peri: 49Post: 38HRT: 56Surgical menopause: 61Fatigue by age (%):

41: 4151: 3460: 29Fatigue by menopausal 

status (%):Pre: 21Peri: 30Post: 26HRT: 35Surgical menopause: 56

NR 

F-157
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKoster, 2002Denmark

Sexual Dysfunc-tion Quality of Life Other Outcomes

Decreased sexuality by age (%):51: 3760: 67

_ _

F-158
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKoster, 2002Denmark

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

Strongest predictor of woman's menopause experience was prior health. Sexuality depended on prior sexual experiences. No association between menopausal/perimenopausal and depression/moodiness, but hot flashes and fatigue correlated with transition. Also, hot flashes with fatigue associated with various psychosocial factors, which explained much variation in symptoms.

_ _

F-159
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKoster, 2002Denmark

RR or OR Comments

_ _

F-160
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

Kravitz, 2003 SWAN 12,603 Crosssectional Internal N/A Random digit dialing Random sele

women from sites (Los AngPittsburgh, NeBoston, ChicaDetroit, and O

F-161
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKravitz, 2003

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

40-44 (N=4,233)45-49 (N=4,600)50-55 (N=3,770)

_ Self report 

questionnaires and interviews

81% 

F-162
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKravitz, 2003

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

12-item symptom questionnaire Pre=4,425

Early peri=3,521Late peri=607Natural post=1,739Surgical post=701Post on HRT=1,610

701/12,603 NR NR 

F-163
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKravitz, 2003

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

NR NR NR _ _ Ove

sleeMosurLeapreCauHisrepslee

F-164
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKravitz, 2003

Mood Cognitive Somatic Urinar

y

_ _ _ _

F-165
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKravitz, 2003

Sexual Dysfunc-tion Quality of Life Other Outcomes

_ __

F-166
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKravitz, 2003

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

Ethnicity and age Bivariate associations 

bewtween each covariate and sleep difficulty were examined using X2 tests.

Multivariate associations ere examined using a multiple logistic regression.

EthnicityAge

F-167
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKravitz, 2003

RR or OR Comments

Surgical post = 1.55 (1.25-1.92)Late peri = 1.33 (1.07-1.65)Natural post = 1.21 (1.03-1.43)Post on HRT = 1.12 (0.95-1.31)Early peri = 1.11 (0.99-1.24)Pre = 1 00

_

F-168
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

Kuh, 1997Britain

Medical Research Council (MRC)

1498 (84% of those who were sent the questionnaire)

Crosssectional Internal N/A National prospective birth cohort in England, Scotland 

and Wales

Socially straticohort in Britainterviewed in (age 43) were representative native populaage. 

F-169
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKuh, 1997Britain

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

NR _ Mailed questionnaire 84% 

F-170
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKuh, 1997Britain

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

Symptom checklist All women in study (all age 

47)

215 (14.3%) 

salpingo 

hysterectomy, 

analyzed 

separately

NR NR 

F-171
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKuh, 1997Britain

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

NR 172 

(11.4%) on 

HRT, 

analyzed 

separately

NR Hot flashes (n=1465):

bothered a lot: 7%bothered a little: 24.4%none or not bothered: 68.7%Cold/night sweats (n=1454):bothered a lot: 6.2%bothered a little: 20.0%none/not bothered:73.8%

Vaginal Dryness (n=1399):bothered a lot: 4.2%bothered a little 15.7%none or not bothered 80.1% 

Trobotbotnon50.

F-172
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKuh, 1997Britain

Mood Cognitive Somatic Urinar

y

Anxiety or depression (n=1427):bothered a lot:16.8%bothered a little: 36.0%none/not bothered:50.5%irritability (n=1419):bothered a lot:14.6%bothered a little: 40.2%none/not bothered: 45.2%tearfulness (n=1414)bothered a lot:11.7%bothered a little:30.1%none/not botherred:58.1%feelings of panic (1392):bothered a lot: 7.2%bothered a little: 17.2%none/not bothered: 75.6%

Forgetfulness:bothered a lot: 13.1%bothered a little: 31.2%none/not bothered: 55.7%

Aches and pains (n=1422):bothered a lot:17.1%bothered a little: 42.5%none/not bothered: 39.7%severe headaches (n=1413):bothered a lot: 10.9%bothered a little: 20.9%none/not bothered: 68.2%breast tenderness (n=1422):bothered a lot: 10.1%bothered a little:33.4%none/not bothered: 56.5%palpitations (1406):bothered a lot: 6.3%bothered a little:22.4%none/not bothered: 71.3%pins and needles (n=1399):bothered a lot: 5.4%

bothered a little:20.2%

Urinary frequency (n=1410):bothered a lot:7.9%bothered a little:18.6%none/not bothered: 73.5%

F-173
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKuh, 1997Britain

Sexual Dysfunc-tion Quality of Life Other Outcomes

Difficulties with intercourse (n=1381):bothered a lot: 3.9%bothered a little: 9.1%none/not bothered: 87.0%

NR Skin crawling sensations 

(n=1383):bothered a lot: 3.3%bothered a little: 11.1%none/not botherred:85.5skin wrinkling (n=1389)bothered a lot: 3.3%bothered a little:15.5%none/not bothered: 81.6hair loss (1383):bothered a lot: 2.1%bothered a little:5.9%none/not botherred:92.0

F-174
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKuh, 1997Britain

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

__ _

F-175
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKuh, 1997Britain

RR or OR Comments

_ Women were all aged 47 years; anxiety and depression 

(assessed by PSE), and health status was assessed at age 36.

F-176
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

Kuh, 1997Britain(continued)

_ __ _ _ _ _ 

Kuh, 1997Britain(continued)

_ __ _ _ _ _ 

Kuh, 1997Britain(continued)

_ __ _ _ _ _ 

F-177
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKuh, 1997Britain(continued)Kuh, 1997Britain(continued)Kuh, 1997Britain(continued)

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

_ _ __ _ _ __ _ _ __ 

F-178
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKuh, 1997Britain(continued)Kuh, 1997Britain(continued)Kuh, 1997Britain(continued)

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

_ Premenopausal women _ _ _ _ _ ___ _ _ ___ 

F-179
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKuh, 1997Britain(continued)Kuh, 1997Britain(continued)Kuh, 1997Britain(continued)

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

_ _ _ Bothered by hot flashes 

(p<0.001): 

pre: 17%peri: 40%post: 60%HRT: 40%**hysterectomy:42%**bothered by cold/night sweats (p<0.001)pre: 16%peri: 32%post: 45%HRT: 34%**hysterectomy: 36%**

_ 

_ _ _ _ Bothered by vaginal 

dryness (p<0.01)pre: 11%peri:25%post:35%HRT:25%hysterectomy: 28%

_ _ _ _ _ Diff

(p<preperposHRhys

F-180
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKuh, 1997Britain(continued)Kuh, 1997Britain(continued)Kuh, 1997Britain(continued)

Mood Cognitive Somatic Urinar

y

_ _ _ __ _ _ __ _ _ _

F-181
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKuh, 1997Britain(continued)Kuh, 1997Britain(continued)Kuh, 1997Britain(continued)

Sexual Dysfunc-tion Quality of Life Other Outcomes

_ __

Difficulties with intercourse (bothered a little or a lot, p<0.001)pre: 8%peri: 13%post: 24%HRT:19%hysterectomy: 19%

_ _

_ __

F-182
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKuh, 1997Britain(continued)Kuh, 1997Britain(continued)Kuh, 1997Britain(continued)

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

_ Logistic regression models to 

predict bothered a little/lot adjusting for menopausal status, life stress at age 36, physical and emotional health at age 36, smoking behavior in earlier adult life, educational background.

For vasomotor symptoms: significant predictostatus, educational qualifications, work stress wsmoking at any time in past, 3+health problemfamily life was not a significant predictor. 

_ _ Significant predictors include: menopausal sta

previous history of 2+health problems at age 3education, smoking, anxiety/depression in pas

_ _ Significant predictors: menopausal status, cur

at work, poorer physical and emotional health 

F-183
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKuh, 1997Britain(continued)Kuh, 1997Britain(continued)Kuh, 1997Britain(continued)

RR or OR Comments

Adjust OR for vasomotor symptoms (post compared to pre)=4.7 (95%CI 2.6, 8.5). Other groups: peri 2.5**, hysterectomy 2.5**, HRT 3.4** compared to pre.

** data approximated from histogram or OR figure, referred to generally in text.

Adjusted OR for sexual dysfunction (combines vaginal dryness and difficulties with intercourse=~4**; Also increased were OR for peri (2.2)**, hysterectomy (3.2)**, and HRT (2.4)** 

** data approximated from figure showing Ors for groups. Referred to in text as "almost fourfold increase post vs. pre. 

Adjusted OR for trouble sleeping: post=3.4 (95% CI 1.9, 6.2); peri =1.5 (95% CI 1.1-02.0); hysterectomy 2.6 (95% CI 1.8, 3.7); and hysterectomy 2.3 (95% CI 1.5, 3.4) compared to pre.

_

F-184
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

Kuh, 1999Britain

MRC 1378 Crosssectional 

from cohort

__ _ _ 

F-185
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKuh, 1999Britain

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

48 years All women with whom the investigators were still in 

contact from the original cohort of 2548 women

Postal questionnaire sent to 1486 women when they were 48 years old

93% to 

questionnaire

F-186
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKuh, 1999Britain

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

Questionnaire regarding incontinence (incont) symptoms (no statement of questionnaire validation)

Stress incont symptoms by menopausal status:Pre 49.8%Peri 52.7%Post 36.3 % Hyst 53.7%HRT 47.9%Urge incont symptoms by menopausal statusPre 18.1%Peri 23.8%Post 18.6% Hyst 28.8%HRT 21.0%Severe incont symptoms by menopausal statusPre 7.3%Peri 6.0%Post 9.8% Hyst 9.8%HRT 5.0%

___ 

F-187
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKuh, 1999Britain

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

_ __ _ _ 

F-188
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKuh, 1999Britain

Mood Cognitive Somatic Urinar

y

_ _ _ 55% in the cohort 

reported incontinence, see menopausal statufor breakdown by grouodds of stress symptowere lower in the postmenopausal versunot menopausal group (OR 0.57, CI 0.33-0.95no association of urge symptoms or severe incontinence with menopausal status

F-189
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKuh, 1999Britain

Sexual Dysfunc-tion Quality of Life Other Outcomes

_ __

F-190
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKuh, 1999Britain

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

__ _

F-191
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKuh, 1999Britain

RR or OR Comments

_ _

F-192
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

Kuh, 2002Britain

Medical Research Council (MRC) National Survey of Health & Development

2547 women in initial cohort. 1023 were available and completed all six questionnaires between 1993-1998

Cohort with 

Crosssectional 

data

Internal _ All births to non-manual and 

agricultural workers and one in four births to manual workers in the 2nd week of march 1946.

Britain, Scotla

Maartens, 2001Netherlands

Eindhoven 2450 Cohort Internal _ Invitation, method NR All women liv

Eindhoven reto screening rage 46-53 at (n=8503; 664to participate)

F-193
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKuh, 2002BritainMaartens, 2001Netherlands

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

52 _ Mailed 

questionnaires

_ 

46-53 Inclusion:

1. Dutch, Caucasian women2. Natural menopause3. No HRTExclusion:1. Women with hysterectomy or bilateral oophorectomy2. HRT without surgical menopause3. Non-compliance with questionnaire

Questionnaires 2450 responded 

and eligible

F-194
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKuh, 2002BritainMaartens, 2001Netherlands

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

_ Pre 272

Peri 309Post 208Hysterectomy 240HRT 255

240/1284 NR NR 

Population Survey _ Excluded _ _ 

F-195
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKuh, 2002BritainMaartens, 2001Netherlands

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

_ HRT users 

255/1284

NR _ _ 

NR NR NR Prevalence

HF OR 5.9 comparing pre to peri menopausal status and OR 1.9 comparing peri to post menopausal status and OR 13.4 comparing pre to post menopausal status

Prevalenceperi vs. post OR 1.6

Preper(ins

F-196
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKuh, 2002BritainMaartens, 2001Netherlands

Mood Cognitive Somatic Urinar

y

_ _ _ _

Multivariate adjusted OR for change (increase) in depression scoreTransition: Pre to peri: not significantPre to post: 0.57 (statistically significant)

No statistical difference No statistical difference No urinary symptoms 

stage

F-197
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKuh, 2002BritainMaartens, 2001Netherlands

Sexual Dysfunc-tion Quality of Life Other Outcomes

_ __

Pain with intercourse:Pre-peri: not significantPeri-post: 1.86 (statistically significant)Pre-post: 2.13

NR NR

F-198
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKuh, 2002BritainMaartens, 2001Netherlands

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

_ _ Menopausal status was not a significant predic

stress in multivariate modeling, adjusting for chand psychological factors.

Physical symptomsDemographicCognitive/Mental Symptoms

Chi squareLogistic regression

_

F-199
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearKuh, 2002BritainMaartens, 2001Netherlands

RR or OR Comments

Age adjusted OR for psychological symptom score: "Women reporting higher levels of psychological symptoms in midlife were much more likely than their less symptomatic peers to have had health problems previously during their adult life. There was no variation in psychological symptoms according to menopausal stage but HRT users had a higher level of (psychological) symptoms." OR shown on Table 3, all cross 1 except OR for HRT users (Regression Coefficient=0.44 (0.20, 0 69)

Tables report regression coefficients rather than OR.

_ _

F-200
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

Maartens, 2002Netherlands

Eindhoven 6648 Prevalence 

and 

prospective 

cohort

Internal 5 years Invitation to all women in 

Eindhoven of which 6648 (78%) participated

All women livEindhoven reto screening rage 46-53 at (n=8503; 664to participate)

McKinlay, 1987 Massachusett's 

Women's Health Study

2500 Crosssectional 

analyses from cohort

Internal 27 months Random sample of 8,050 

women ages 45-55 in Massachusetts; 2,500 identified as premenopausal. 77% RR

Population barecruitment opremenopaus

F-201
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMaartens, 2002NetherlandsMcKinlay, 1987

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

46-53 Inclusion:

1. Dutch, Caucasian women2. Natural menopause3. No HRTExclusion:1. Women with hysterectomy or bilateral oophorectomy2. HRT without surgical menopause3. Non-compliance with questionnaire

Questionnaire Prevalence: 78%

Follow-up of 2748 with natural menopause and nHRT: 76%2103 (76%) participated

_ _ CES-D given once 

during 1st 27 months; combined into single cross sectional data set "after determining that depression scores did not depend on the followup in which the CESD scale was administered.

77% 

F-202
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMaartens, 2002NetherlandsMcKinlay, 1987

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

Mailed Edinburgh depression scaleGynecologic historyGeneral medical historyDemographic data

_ Excluded NR NR 

CES-D _ _ NR NR 

F-203
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMaartens, 2002NetherlandsMcKinlay, 1987

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

Evaluated Evaluated NR NR NR 

_ __ _ _ 

F-204
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMaartens, 2002NetherlandsMcKinlay, 1987

Mood Cognitive Somatic Urinar

y

Prevalence depression at baselineMean Score:pre - 5.6per - 6.5post - 7.8Prevalence depresssion at followuppre - 6.8per - 7.0post - 7.8

NR NR NR 

Percentage of women with CES-D score>16 (estimated from figure 

1):pre: 7.5% (n=527)peri: 10.5% (n=1632)natural menopause: 8% (n=262)surgical menopause 18% (n=78)

_ Women reporting > 2 

physical symptoms are about 4 times as likely to be depressed as women reporting < 1 symptom 

(15.7% vs. 4.3%).

_ 

F-205
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMaartens, 2002NetherlandsMcKinlay, 1987

Sexual Dysfunc-tion Quality of Life Other Outcomes

NR NR _

_ __

F-206
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMaartens, 2002NetherlandsMcKinlay, 1987

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

DemographicMajor life eventsPrior episodes depressionTime between baseline and follow-up exam

T tests for change Multivariate adjusted OR for depression:

Transition peri-post 1.8 (1.3-2.6)Transition pre-peri 1.8 (1.10-3.3)Prior depression 2.2 (1.6-3.0)Unemployment 2.4 (1.2-4.6)Death of partner 2.4 (1.1-5.6)Financial problems 3.4 (1.5-7.8)

1. sociodemographic variables:marital status, education, age, employment status, total number of persons in household2. health status: selfassesssed health, physical symptoms, restricted activity and chronic conditions.3. utilization behavior: formal and informal health resources, lay consultations, medication use

Logistic regression with CES-D >16 as outcome

Education and marital status were significantly D score of >16; personal stress caused by othe

worry); number of health problems; use of tran

F-207
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMaartens, 2002NetherlandsMcKinlay, 1987

RR or OR Comments

_ Not adjusted for sleep disturbance

Not given. RR presented for each of the significant variables in predictor model.

"menstrual change associated with the menopause appears to have no significant effect on depression ... those with a recent surgical menopause were the most depressed group." 

F-208
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

McKinlay, 1989 Massachusett's 

Women's Health Study

2,466 Crosssectional 

and prospective cohort

Internal 4.5 years Random sample 8051 women 

CommonweaMassachuset1926-1936.

F-209
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMcKinlay, 1989

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

45-55 in 1982 A cohort of premenopausal women was chosen 

from the entire sample of women (8050)

Questionnaires 77% to initial 

survey, 85% overain follow-up

F-210
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMcKinlay, 1989

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

CES-D Change in menstrual status 

over 3 years of follow-up (T0-T3, n=2466):menses in 3 months prior to T3 42.9%menses changed to irregular 16.9%amenorrhea < 12 months 15.5%amenorrhea > 12 months 

20.4%Surgical menopause 4.4%

___ 

F-211
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMcKinlay, 1989

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

_ __ _ _ 

F-212
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMcKinlay, 1989

Mood Cognitive Somatic Urinar

y

CES-D score related crosssectionally to menstrual status reveals women who have undergone surgical menopause in previous 3 months were twice as likely as the rest of the cohort to have CES-D scores >16 (19% v 

10%).

_ _ _

F-213
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMcKinlay, 1989

Sexual Dysfunc-tion Quality of Life Other Outcomes

_ __

F-214
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMcKinlay, 1989

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

__ _

F-215
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMcKinlay, 1989

RR or OR Comments

_ "Change in menstrual status associated with the menopause 

appears to have no significant effect on depression, as defined by a CES-D score of 16 or greater."(Minimal data available for this finding.)Some data reported in this study is the same as that reported in McKinlay, 1992

F-216
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

McKinlay, 1992 Massachusett's 

Women's Health Study

2,570 Longitudinal 

and crosssectional analysis of cohort data

Internal 5 years Random sample of 8,050 

women ages 45-55 in Massachusetts, derived from census lists. Of these, 2,570 were identified as having menstruated in the past 3 months, having a uterus and > one ovary

8050 women CommonweaMassachuset1926-1936.

Milsom, 1993 Goteberg, 

Sweden

7,459 Crosssectional _ _ Random sampling of population register Birth cohorts 

1905, 1910, 11930, 1940 frSweden

F-217
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMcKinlay, 1992Milsom, 1993

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

45-55 in 1982 Premenopausal women selected from initial sample 

of 8,050

Questionnaires or telephone interviews if questionnaires not received.

77% of 8,050 responded. Had 9

99% retention of the 2,570 premenopausal cohort

46-86 _ Questionnaire 

regarding urinary incontinence

74.60% 

F-218
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMcKinlay, 1992Milsom, 1993

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

Symptoms checklist (any in past 2 weeks): hot flashes, cold sweats, vertigo, feeling blue or depressed, headaches, insomnia, palpitations, lack of energy, diarrhea and/or constipation, persistent cough, backaches, upset stomach, aches/stiffness in joints, shortness of breath, sore throat, loss of appetite, menstrual problems, fluid retention, difficulty in concentrating, nervous tension, urinary tract/bladder infections and "pins and needles" in hand or feet.

_ Excluded Excluded NR 

_ _ Hysterectomy 

was 

associated 

with increased 

risk of 

incontinence 

in the whole 

cohort, but not 

within the 

individual age 

__ 

F-219
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMcKinlay, 1992Milsom, 1993

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

33.5% of premenopausal cohort (n=1178) were current smokers

1% of premenopausal cohort (n=1178) were using HRT

NR 13.4% of premenopausal 

cohort had HF (n=1178) at baseline.For women 27 mo prior to perimenopause: 10% had HFs; Following the cessation of menses 50% have HF; 4yrs postmenopause 20% have HF.

NR NR 

with 

_ __ _ _ 

F-220
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMcKinlay, 1992Milsom, 1993

Mood Cognitive Somatic Urinar

y

NR NR NR NR 

_ _ _ Menopausal status wa

not associated with incontinence (postmenopausal verspremenopausal)

F-221
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMcKinlay, 1992Milsom, 1993

Sexual Dysfunc-tion Quality of Life Other Outcomes

NR NR Lumped HF, sweats and 

insomnia into "menopausymptoms," and all othesymptoms into nonmenopausal symptoms: that at Time 6, the followproportions of women reboth types of symptomspre - 27%peri - 46.3%post - 37.7%"Women who were perimenopausal for only contact were consistentllikely to report hot flashebefore, during and after menopause than were wwith a longer perimenopWomen with short or no perimenopause: 39% hvs. remainder of women 

of whom had HF

_ __

F-222
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMcKinlay, 1992Milsom, 1993

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

__ ___ _

F-223
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMcKinlay, 1992Milsom, 1993

RR or OR Comments

__ Prevalence data is by birth cohort, not by menopausal status.

F-224
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

Mishra, 2003Australia

Australian Longitudinal Study on Women's Health

8,623 Cohort Internal 2 years Mailed questionnaires Random sele

Australian wo45-50 in 1996 completed questionnaireand 1998

F-225
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMishra, 2003Australia

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

Mean age at baseline 47.7

Exclusions: 1. Women salpingo hysterectomy or oophorectomy (n=3014)

Survey 1996 and 1998, mail (long version, n=11,637) and phone (shorter for those who couldn't/didn't complete the mailed version, n=691)

90.4% response rate for those who were alive at the time of the second survey.

F-226
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMishra, 2003Australia

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

SF-36 scores Defined on the basis of selfreported bleeding history.

Pre: bleeding in last 12 months and with same frequency as in the previous year (55.1% at BL).Peri: bleeding in last 12 months but not in last 3 months (25.4% at BL)Post: no bleeding in past 12 months (7.0% at BL)HRT: on HRT (12.1% at BL; 20.2 at 2 years)

Excluded NR NR 

F-227
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMishra, 2003Australia

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

Current smokingpre: 12.5%peri: 17.9%post: 23.1%HRT: 20.6% (p<0.0001)

NR Similar body 

weights among groups.Proportion overweight or obese:pre: 42.4%peri: 45.6%post: 43.6%HRT: 44.7%

NR NR 

F-228
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMishra, 2003Australia

Mood Cognitive Somatic Urinar

y

Adjusted mean score (s.e.) for "general mental health" from the SF-36 at baselinepre: 73.4 (0.5)peri: 70.7 (0.6)*post: 71.0 (0.8)*HRT 68.1 (0.7)** ;<0.01 in mean adjusted for multiple comparisons when compared to pre-pre group.Adjusted mean change score (s.e.) for "general mental health" from the SF-36 after 2 years.pre-pre: -0.7pre-peri: -0.4 (0.7)peri-peri: -1.2 (0.7)pre/peri-post: -1.0 (0.8)post-post: 0.0 (0.9)HRT -2.1 (0.6)** ;<0.01 in mean change adjusted for multiple comparisons when compared to pre-pre group.

NR Adjusted mean score for 

bodily pain from the SF36 at baselinepre: 72.5 (0.7)peri: 68.2 (0.8)*post: 70.3 (1.1)*HRT 65.0 (0.9)** ;<0.01 in mean adjusted for multiple comparisons when compared to pre-pre group.Adjusted mean change score (s.e.) for "bodily pain" from the SF-36 after 2 yearspre-pre: 0.6 (0.7)pre-peri: -0.5 (0.8)peri-peri: -1.8 (0.8)*pre/peri-post: -1.2 (1.0)post-post: -0.6 (1.2)HRT: -2.7 (0.8)** ;<0.01 in mean change adjusted for multiple comparisons when compared to pre-pre 

group.

NR 

F-229
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMishra, 2003Australia

Sexual Dysfunc-tion Quality of Life Other Outcomes

NR Adjusted mean score (s.e.) for 

"general health perception" at baselinepre: 73.4 (0.6)peri: 68.2 (0.8)*post: 70.3 (1.1)HRT: 65. (0.9)** ;<0.01 in mean adjusted for multiple comparisons when compared to pre-pre group.Adjusted mean change score (s.e.) for "general health perception" from SF-36 after 2 years.Pre-pre: 0.6 (0.5)pre-peri: -0.2 (0.6)peri-peri: -1.5 (0.6)*pre/peri-post:-0.7 (0.7)post-post:-0.8 (0.8)HRT:-1.8 (0.5)** ;<0.01 in mean change adjusted for multiple comparisons when compared to pre-pre group.

_

F-230
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMishra, 2003Australia

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

All mean scores calculated after adjusting after adjusting for age, physical activity level, weight, number of life events, smoking status, occupation, country of birth, marital status, and area of residence.All mean changes calculated 

after adjusting for SF-36 scores at baseline, physical activity levels at baseline and follow-up, weight at baseline, change in weight, change in number of life events, age smoking status, occupation, country of birth, marital status, and area of residence.

MV modeling only reported in terms of adjustments

NR

F-231
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMishra, 2003Australia

RR or OR Comments

_

F-232
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

Mitchell, 1996 Seattle 508 

entered study301 year 1215 year 2200 year 3

Cohort N/A 3 years Women in households within 

census tracts with mixed ethnicity and income contacted by phone 11,222 - from which 820 eligible

Census tracts 

Mitchell, 2001 Seattle 230 Crosssectional Internal Preva- lence Women in households within census tracts with mixed 

ethnicity and income contacted by phone

Census tracts 

F-233
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMitchell, 1996Mitchell, 2001

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

35-55 Exclusion:

1. Amenorrhea > 1 year2. Pregnant3. TAH BSO4. Could not read or speak English5. Irregular menstrual cycles6. HRT use

Interview, cycle diary, health update

11,222 phone contacts820 eligible508 entered study

Mean 46.7 Exclusion:

1. Amenorrhea > 1 year2. Pregnant3. TAH BSO4. Could not read or speak English5. Irregular menstrual cycles6. HRT use

Interviews 508 initially; this 

survey conducted among women stiparticipating 96-97N=230

F-234
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMitchell, 1996Mitchell, 2001

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

Washington Women's Health Diary _ Excluded NR NR 

Cycle analysis NR NR NR NR 

F-235
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMitchell, 1996Mitchell, 2001

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

NR NR NR NR NR NR NR NR NR NR 

F-236
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMitchell, 1996Mitchell, 2001

Mood Cognitive Somatic Urinar

y

At baseline dysphoric mood explained 23.8% of variance among symptom clusters - highly stable over 3 years.

NR Somatic symptoms 

explain 6.5% of variance -

highly stable over 3 years.

NR 

142 women reported memory change compared with 88 without memory change.No association with age, education, income between the 2 groups.

_ _ NR 

F-237
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMitchell, 1996Mitchell, 2001

Sexual Dysfunc-tion Quality of Life Other Outcomes

NR NR _NR NR _

F-238
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMitchell, 1996Mitchell, 2001

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

Factor analysis Important factors identified included dysphoric mood, vasomotor symptoms, insomnia, neuromuscular symptoms, somatic symptoms.Dysphoric mood very stable over 3 years (explained 77% of variance).Neuromuscular symptoms stable (explained 74% of variance).Vasomotor symptoms moderately stable over 3 years.

_ NA

__ _

F-239
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearMitchell, 1996Mitchell, 2001

RR or OR Comments

NA All premenopausal or early perimenopausal.

Findings suggest that many symptoms described at baseline are stable over time and MP transition explains none over 3 years.

This study really only evaluates women's attributions of causes for change in memory (selfreported). Stress, physical health, and aging most frequently cited as attributing to memory 

change.

Based on cycle analysisPremenopausal: early menopause transition stage (MTS) 53Mid-menopausal: MTS 54Late menopausal: MTS 27Postmenopausal: MTS 1296 on hormones or hysterectomy or were not classifiable

F-240
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

Randolph, 2003 SWAN 2,930 Crosssectional _ _ _ _ 

Rodstrom, 2002Sweden

Gothenburg 1462 Cohort Internal 25+ years Randomly selected from 

population

1968-69 1462 aged 38-601302 re-exam75 (89%)1154 re-exam81 plus 47 neborn in 19304th exam 199

F-241
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearRandolph, 2003Rodstrom, 2002Sweden

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

46.3 253 of 3302 were excluded because of missing data _ 92.30%

Initially 38-60 None specified other than those with surgical 

menopause

Standardized 

interview

_ 

F-242
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearRandolph, 2003Rodstrom, 2002Sweden

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

Height, weight, demographic and lifestyle data.Menopausal status, FSH, DHEAS, SHBG and E2 from venipuncture on day 2-7 of a spontaneous menstrual cycle occurring within 60d of recruitment then annually.

Premenopausal 54.3%early perimenopausal 45.7%

___ 

_ Excluded NR NR 

F-243
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearRandolph, 2003Rodstrom, 2002Sweden

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

Smoking:never 57.6%past 25.4%current <10/d 5.0%current >10/d

12.1%Higher mean FSH, testosterone, and SHBG levels for current compared to never smokers in unadjusted analyses (p<0.0001)

_ Mean 28 kg/m2

For all ethnic groups, SHBG, FSH, E2, and DHEAS levels declined with increasing BMI, and testosterone levels increased with increasing BMI.For SHBG only did 

BMI and ethnicity interact.BMI distribution varied across 

ethnicities

__

NR NR NR Prevalence of hot 

flashes increased in linear manner from 11% at age 38, to maximal prevalence of 60% at ages 52-54, to 30% at age 60, 15% at age 66, 9% at age 72.Hot flashes reported significantly less often among women aged 50 in 1980-81 cohort than the age 50 women in the 1968-69 cohort.Cohort differences 

t ti ti ll i ifi t

NR 

F-244
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearRandolph, 2003Rodstrom, 2002Sweden

Mood Cognitive Somatic Urinar

y

_ _ _ _

NR NR NR NR 

F-245
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearRandolph, 2003Rodstrom, 2002Sweden

Sexual Dysfunc-tion Quality of Life Other Outcomes

_ _ Unadjusted mean hormo

levels by menopausal stE2 pg/ml (p NS):pre 74 early peri 77FSH IU/L (p <0.0001):

pre 19.7early peri 29.8Testosterone ng/ml (p Npre 46early peri 48DHEAS mcg/dl (p<0.05)pre 135early peri 128SHBG nM (p NS):pre 45early peri 46

NR NR NR

F-246
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearRandolph, 2003Rodstrom, 2002Sweden

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

Ethnicity, menopausal status, study site, day of cycle, BMI, age, smoking, and alcohol

Adjusted models for mean serum hormone concentrations

E2:No affect of menopausal status and ethnicityFSH:Ethnicity (p<0.05)Menopausal status (p<0.0001) 

T:Ethnicity (p<0.05)No affect of menopausal statusDHEAS:Ethnicity (p<0.0001)

No affect of menopausal status

Only age, MP status, and 

cohort

Chi Square _

F-247
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearRandolph, 2003Rodstrom, 2002Sweden

RR or OR Comments

_ Adjusted FSH levels were significantly higher in AA and H than 

W and Asian women.Adjusted FSH levels were significantly higher in early perimenopausal than premenopausal women.Adjusted DHEAS levels were 73% higher in Chinese than AA.Adjusted testosterone levels were slightly lower in in AA and H than W and Asian women.

_ _

F-248
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

Sherburn, 2001Australia

Melbourne Women's 

1897,373

Crosssectional, longitudinal

_ 7 year 

follow-up

_ _

F-249
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearSherburn, 2001Australia

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

_ _ __ 

F-250
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearSherburn, 2001Australia

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

_ Baseline % noted above.

At 7 year follow-up n=373:stayed pre/peri 13.7%became post 54.7%HRT user 22.8%had surgical menopause 8.8%

___ 

F-251
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearSherburn, 2001Australia

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

_ __ _ _ 

F-252
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearSherburn, 2001Australia

Mood Cognitive Somatic Urinar

y

_ _ _ Urinary incontinence a

baseline by menopausstatus:pre 10.4%peri 17.3%*post 14%HRT 19%*surgical 17.7%* Total 15.3%*p<0.005 compared to pre.Incidence rate (%) at 7 yr:stayed pre/peri 34%became post 37%HRT user 27%surgical menopause 54%total 35%

F-253
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearSherburn, 2001Australia

Sexual Dysfunc-tion Quality of Life Other Outcomes

_ __

F-254
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearSherburn, 2001Australia

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

_ Logistic regression model of 

factors associated with urinary incontinence

BMIOther gynecologic surgeryparticipating in lawn bowlsurinary tract infectiondiarrhea or constipationparityarthritisnegative mood score(menopausal status was not significant in this m

F-255
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearSherburn, 2001Australia

RR or OR Comments

1.52.172.264.751.951.471.551.64

"Urinary incontinence in middle-aged women is more closely associated with mechanical factors than with menopausal transition."

F-256
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/Year Umbrella N

Study 

Design

Type 

Control 

Group

Length of 

FollowUp Recruitment (Data source) Population

Sowers, 2000 (methods paper for SWAN)

SWAN 16,065

Crosssectional

3306

longitudinal

Crosssectional and multisite longitudinal study

Ongoing 

since 

1995

Census data, lists, randomdigit dialing, "snow-balling" Community b

Pittsburgh, BoDetroit, ChicaAngeles, OakNewark

Woods, 1997 Seattle 347 Cohort Internal 2 years 822 eligible

508 participated in interviews347 completed years 1 and 2 surveys

SeattlePopulation-basample choserepresent minSampling framon phone num

F-257
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearSowers, 2000 (methods paper for SWAN)Woods, 1997

Age (range) Inclusion/Exclusion Criteria

Ascertainment of Symptoms Response Rate 

40-55 Eligibility criteria for cross-sectional study:

1) primary residence in designated geographic area, 2) ability to speak English or other designated language, 3) age 40-55 years at time of contact, 4) cognitive ability to provide verbal informed consent, 5) membership in a specific site's targeted ethnic groupsEligibility criteria for longitudinal study:

1) aged 42-52 years, 2) no surgical removal of the uterus and/or both ovaries, 3) not currently using exogenous hormone preparations affecting ovarian function, 4) at least one menstrual period in the previous 3 months, 5) self-identification with one of each site's designated race/ethnic group

Interview, written/oral survey, questionnaires, clinic measurements, specimen data, menstrual calendars, abstract medical records for hysterectomy. Materials available in all relevant languages.

46.6% crosssectional50.7% longitudina

35-45 (median 

41)

Inclusion criteria:1) Non-lactating2) Non-pregnant3) Menses within last year4) English reading5) No hysterectomy6) Had at least 1 ovary

_ 508 of 820 of whic

75% completed firyear and 90% second year

F-258
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearSowers, 2000 (methods paper for SWAN)Woods, 1997

Measures Used Menopausal status

Hysterectomy or

BSO (#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cance

(#/n)

Too extensive to list _ None at 

enrollment

By definition ineligible for longitudinal study

NR 

CES-D ScaleMenopausal ChangesNorbechs LES (Stressful Life Context)Feminine SocializationSocialization for MidlifeHealth StatusFamily Resources

_ Excluded NR NR 

F-259
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearSowers, 2000 (methods paper for SWAN)Woods, 1997

Behavior or 

Lifestyle Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or Low BMI

(#/n) Hot Flashes

Vaginal Dryness 

_ __ _ _ 

NR NR NR NR NR 

F-260
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearSowers, 2000 (methods paper for SWAN)Woods, 1997

Mood Cognitive Somatic Urinar

y

_ NR NR NR 

Patterns (chronic, resolved, emerging) of depressed mood related to stressful life context, past/present health status, and social learning about midlife.Menopausal status did not differentiate woen with depression from non-depressed.

_ _ _

F-261
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearSowers, 2000 (methods paper for SWAN)Woods, 1997

Sexual Dysfunc-tion Quality of Life Other Outcomes

_ ___ _

F-262
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearSowers, 2000 (methods paper for SWAN)Woods, 1997

Predictors studied

(significant/not significant) Statistical Models

Significant predictors in mu

(adjusted models)

__ __ Factors prediction Social learning about midlife

Stress life contextPast/present health status

F-263
Appendix F: Evidence table 6-1. Key Question 1 and 2 cohort studies

Study/YearSowers, 2000 (methods paper for SWAN)Woods, 1997

RR or OR Comments

_

NA Baseline: all premenopausal

At year 2 follow up: 22% perimenopausal, 31% hot flashes

F-264
Appendix F. Evidence table 6-1. Key Question 1 and 2 cohort studies

AA = African American

peri = Perimeno

pausal

BL = Baseline PHS = Perceived health statusBMI = Bod

y mass inde

x PMS = Premenstrual s

yndrome

BSO = Bilateral Sal

pin

go Oo

pherectom

y

post = Postmeno

pausal

CES-D = Center for E

pidemiolo

gic Studies De

pression Scale

pre = Premeno

pausal

DHEAS = Deh

ydroe

piandrosterones PSE = Present state examination

E2 = Estradiol RR = Relative risk

GWB = Global well-bein

g sd = Standard deviation

H = His

panic SES = Socioeconomic status

HF = Hot flash SPEQ = Sexualit

y

questionnaire of Personal Ex

perien

HRQL = Health related 

qualit

y of lif

e SWAN = Stud

y of Women's Health Across the Nation

HRT = Hormone re

placement therapy T = Testosterone

INH = Inhibin T0 = Time zeroISRO = Index of Sex Role Orientation T1 - Time oneJ = Ja

panese T2 = Time two

LES = Life event stress T3 = Time threeMRC = Medical Research Council TAH = Total abdominal h

ysterectom

y

MTS = Meno

pausal transition sta

ge W = White

MV = Multivariat

e

NA = Not applicable

NHANES = National Health and Nutrition Examination Surve

y

NHEFS = National Health Examination Follow-u

p Stud

y

NR = Not re

ported

NS = Not si

gnificant

oc =Oral contrace

ptives 

OR = Odds ratioPEQ = Personal Ex

periences Questionnaire

Ke

y/Abbreviations

F-265
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion C

Ditkoff, 1991 36 RCT P 3 

months

Asymptomatic American-born Latina women, aged 45-60, Salpingo hysterectomy, living in East LA. Recruitment info NR.

Inclusion:1. Age 45-602. Previous hysterectomy3. American born Latina4. Estradiol <205. No subjective HF6. No HRT for 2 months7. No medical illnesses8. No hypnotics or mood altering 

Furuhjelm, 1984 48 Crossover P 4 2-month 

periods

Postmenopausal women with climacteric complaints attending outpatient clinic in SwedenGroup 1: N=28 with high depression/mental distress scoresGroup 2: N=9 with mild depression/mental distress scoresGroup 3: N=11 with no depression/mental distress

Inclusion:1. No clinical or laboratory signs obiliary, GI or renal malfunction2. No HRT for at least 2 months3. Complaints of various climacte4. > 1-year post-menopausal

F-266
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/YearDitkoff, 1991Furuhjelm, 1984

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or 

Lifestyle 

Factors

(#/n)

d

1. Minnesota Multiphasic Personality Inventory-1682. Profile of Adaptation to Life3. Beck Depression Inventory4. Wechsler Adult Intelligence Scales of digit span and digit symbol

36/36 NR NR 0 NR NR 

1. Sabbatsberg General Symptom Scale (for somatic and mental disturbances)2. Sabbatsberg Distress SelfRating Scale (for depression)3. Eysenck Personality Inventory 4. Sabbatsberg Sexual SelfRating Scale5. Hormone levels, chemistry, physical exam, pap

NR NR NR NR NR NR 

Specific Characteristics of Population

F-267
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/YearDitkoff, 1991Furuhjelm, 1984

Main Drug type; dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal 

Dryness S

CEE, 0.625mg or 1.25mg, PO qd for days 1-25 each month

Placebo None in either group NR 

Period A: 2mg estradiol17B and 1mg estriol for 12 days, then 2mg estrodiol 17B, 1mg estriol, and 1mg noretristone acetate for 10 days, then 1mg estradiol17B and 0.5mg estriol;Period B: 4mg estradiol-17B and 2mg estriol for 12 days, then 4mg estrodiol 17B, 2mg estriol, and 1mg noretristone acetate for 10 days, then 1mg estradiol17B and 0.5mg estriol; Period C: 2mg estrodiol-17B and 1mg estriol for 28 days

Period D: placebo

All groups improved in prepost comparison during hormone treatment; placebo did not change; no comparison to placebo given. All regimens grouped together.

NR 

Treatment Main Outcomes

F-268
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/YearDitkoff, 1991Furuhjelm, 1984

Mood Cognitive Somatic Urinar

y 

1. No change in Minnesota Multiphasic Personality Inventory;2. Significant decrease in Beck Depression Inventory for both doses of CEE pre-post; scores increased with placebo, but change not significant; no comparison between CEE and placebo given.3. Significant improvement in income management scale pre-post in both CEE groups; no change with placebo; no comparison between CEE and placebo.

No change NR NR 

All groups improved in pre-post comparison of mental distress during hormone treatment (p<0.01). Only depressed group had improvement in depression scores during hormone treatment (p<0.001); non-depressed groups and placebo did not change; no direct comparison to placebo given. All regimens grouped together.

NR NR NR 

Main Outcomes (continued)

F-269
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/YearDitkoff, 1991Furuhjelm, 1984

Sexual 

Dysfunction Quality of Life Other Outcomes Withdrawals Withdrawals due to AEs Advers

Effects 

NR NR NR NR 0 NoneNR NR NR 10/58 3/58 3 with heav

bleeding

F-270
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion C

Hall, 1998 60 RCT P & HH 1 year Postmenopausal women aged 44-

75 with CAD in Sweden. Recruitment info NR

NR

F-271
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/YearHall, 1998

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or 

Lifestyle 

Factors

(#/n)

d

Specific Characteristics of Population

Nottingham health profile and "others evaluated by Wiklund et. al."

NR NR NR NR NR NR 

F-272
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/YearHall, 1998

Main Drug type; dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal 

Dryness S

Treatment Main Outcomes

CEE 0.625mg, alone for 18 days, in combo with medroxyprogesterone 5mg for 10 days

Patch TTS E2 50 mcg alone for 18 days, in combo with medroxyprogesterone 5mg for 10 days

NR NR No chang

F-273
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/YearHall, 1998

Mood Cognitive Somatic Urinar

y 

Main Outcomes (continued)

Significant improvement in depressed moods (p=0.054) in CEE group; no change in E2 or placebo; no comparison given between groups. Overall improvement in mood reported in all groups with no difference between groups.

Improved in all 3 groups; no difference between groups.

NR NR 

F-274
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/YearHall, 1998

Sexual 

Dysfunction Quality of Life Other Outcomes Withdrawals Withdrawals due to AEs Advers

Effects 

NR NR NR 14/60 7/60 Heavy 

bleeding, edema, allergic skireaction, palpitationsheadache. (Numbers given for ththat withdrenot total sample.)

F-275
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion C

Hlatky, 2002 2,763 RCT P 36 

months

Postmenopausal women with CAD in HERS study from 20 US clinical centers

Inclusion:1. < 802. Postmenopausal: a) age >55 and no menses for 5 

 b) no menses for 1 year and FS c) documented bilateral oophor d) reported oophorectomy and E2 < 253. CAD: a) prior MI b) angiography showing >50% major vessel c) prior coronary revascularizatExclusion:1. MI or revascularization procedmonths2. Prior hysterectomy3. Contraindication to HRT4. HRT within 3 months5. Other life-threatening illnesses6. Unable to return for follow-up v

F-276
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/YearHlatky, 2002

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or 

Lifestyle 

Factors

(#/n)

d

Specific Characteristics of Population

1. Duke Activity Status;2. RAND 4-item scale on energy/fatigue;3. RAND mental health inventory;4. 8-item depression scale developed for National Study of Medical Outcomes;

0 NR NR NR NR NR 

F-277
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/YearHlatky, 2002

Main Drug type; dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal 

Dryness S

Treatment Main Outcomes

CEE, 0.625mg and medroxyprogesterone acetate 2.5mg PO qd

Placebo Reported elsewhere Reported 

elsewhere

Reported 

F-278
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/YearHlatky, 2002

Mood Cognitive Somatic Urinar

y 

Main Outcomes (continued)

RAND mental health inventory had small decline in all patients over time (p=0.05); no significant interaction between treatment group and time (p=0.10).Depressive symptoms decreased more over time among patients on HRT (p=0.005).In women with flushing at entry, HRT group had improved mental health (+2.6 vs. -0.5, p=0.04) and depressive symptoms (-0.5 vs. +0/007, p=0.01) compared to placebo. No significant change in women without flushing.

NR NR Reported 

elsewhere

F-279
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/YearHlatky, 2002

Sexual 

Dysfunction Quality of Life Other Outcomes Withdrawals Withdrawals due to AEs Advers

Effects 

NR More rapid decline over time 

in physical function scores in women on HRT (p=0.03). In women without flushing, HRT had greater decline in physical function (-4.2 vs. -3.3, p=0.04) and worsening of energy/fatigue (-4.6 vs. -3.1, p=0.03) compared to placebo. No significant difference in women with flushing.

Energy/fatigue scores declined overall (P<0.001); faster declines in energy/fatigue in women on HRT (p=0.05). 

1/2763 missing all data; 169/1383 on P and 180/1380 on HRT missing some data.

NR Reported 

elsewhere

F-280
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion C

Strickler, 2000 398 

(373 in 

analysis)

RCT P and HH 1 year Asymptomatic postmenopausal 

women aged 47-60; 2-8 years after last menses; 32 study sites; recruitment info NR; 

Inclusion:1. Age 47-602. 2-8 years with no menses3. E2 < 204. BMD within 2.5 SD of premenowomen.Exclusion:1. Intolerable menstrual symptomtreatment2. Uterine bleeding of unknown c3. BMI < 18 or >314. History of DVT5. Use of corticosteroids, estroge6 months6. Chronic illness.

F-281
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/YearStrickler, 2000

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or 

Lifestyle 

Factors

(#/n)

d

Specific Characteristics of Population

Women's Health Questionnaire NR NR NR NR NR NR 

F-282
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/YearStrickler, 2000

Main Drug type; dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal 

Dryness S

Treatment Main Outcomes

CEE 0.625 Raloxifene 60mg or 

150mg qd or placebo

HRT improved vasomotor symptoms compared to Raloxifene (p<0.001) and placebo (p<0.001).

NR No signif

difference

F-283
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/YearStrickler, 2000

Mood Cognitive Somatic Urinar

y 

Main Outcomes (continued)

No significant difference in depressed mood. Anxiety improved in Raloxifene 60mg (0.165) compared with placebo (0.028, p=0.03) and estrogen (-0.017, p=0.003). No difference with Raloxifene 150mg (0.076).

No difference in memory/ concentration

No difference in somatic symptoms

NR 

F-284
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/YearStrickler, 2000

Sexual 

Dysfunction Quality of Life Other Outcomes Withdrawals Withdrawals due to AEs Advers

Effects 

No difference in sexual behavior

NR NR 25/398 NR NR 

F-285
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion C

Thomson, 1977 42 RCT P 8 weeks 45-55 yo women referred by local 

general practitioners. 

Inclusion: 1. 45-55 years old2. Amenorrhea > 3 months

3. Symptoms of insomnia, depresand hot flashesExclusion: 1. Other medications, contraindicaestrogen therapy

F-286
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/YearThomson, 1977

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or 

Lifestyle 

Factors

(#/n)

d

Specific Characteristics of Population

Daily visual analogue scales for mood and anxiety and number of hot flashes. Hamilton anxiety and depression scales.

NR NR NR NR 0 NR 

F-287
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/YearThomson, 1977

Main Drug type; dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal 

Dryness S

Treatment Main Outcomes

Piperazin oestrone sulphate 1.5mg BID

Placebo No significant difference NR Improved 

(intervenwakefulnfrequencawakeninstage of scompare(p<0.05)

F-288
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/YearThomson, 1977

Mood Cognitive Somatic Urinar

y 

Main Outcomes (continued)

No difference between groups; both groups improved (p<0.001)

NR NR NR 

F-289
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/YearThomson, 1977

Sexual 

Dysfunction Quality of Life Other Outcomes Withdrawals Withdrawals due to AEs Advers

Effects 

NR NR No difference in 

anxiety between groups; both groups improved (p<0.001).

8 of 42 NR NR

F-290
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion C

Vestergaard, 2002

1,006 RCT 

(Open 

label)

No HRT 5 years 45-58 year old women; recruited 

by mailing to random sample.

Inclusion:1. Women aged 45-58  a) 3-24 months past last perio b) experiencing perimenopaus(irregular menses) with elevated F2. Women aged 45-52 Salpingo hwith elevated FSH.Exclusion:1. Metabolic bone disease / osteo2. HRT within 3 months3. Current or past treatment with > 6 months4. Malignancy5. Newly diagnosed or uncontrolldisease6. Alcohol or drug addiction.

F-291
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/YearVestergaard, 2002

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or 

Lifestyle 

Factors

(#/n)

d

Specific Characteristics of Population

Modified Greene scale (visual analogue scale from 0-4 for severity of symptoms.) 

192/1006 NR NR 0 NR NR 

F-292
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/YearVestergaard, 2002

Main Drug type; dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal 

Dryness S

Treatment Main Outcomes

First line: E2 2mg days 1-12; E2 mg and norethisterone 1mg days 13-22; E2 1mg days 23-28 for women with uterus. E2 2mg po qd for women without uterus. Women allowed to use other regimens if they requested change.

None HRT reduced severity of 

HF compared to placebo (p<0.01).

HRT less vaginal dryness (p<0.01)

Less sleedifficultieHF on HRNo differesleeping unrelated (p=0.17).

F-293
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/YearVestergaard, 2002

Mood Cognitive Somatic Urinar

y 

Main Outcomes (continued)

No significant difference in mood swings. NR No significant 

difference in headaches.

No significant difference in voiding frequency or incontinence.

F-294
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/YearVestergaard, 2002

Sexual 

Dysfunction Quality of Life Other Outcomes Withdrawals Withdrawals due to AEs Advers

Effects 

Trend toward less reduction in libido with HRT (p=0.08)

NR Blood pressure 

decreased overall; no difference with HRT.

54/502 on HRT; 55/504 not on HRT

NR; 40% changed HRT regimen or terminated HRT due to AEs 

39 headac14 edema/retention; 2mood swindepression

F-295
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion C

Voss, 2002 1,008 RCT HH 6 month Healthy postmenopausal women 

in 129 gynecological practices in Europe, South Africa and Israel.

Inclusion:1. Healthy ambulatory women ag

2. Natural menopause > 2 years 

3. Elevated FSH in women age < Exclusion:1. Hysterectomy, ovariectomy, brestrogen-dependant cancer2. Any other cancer within 5 year3. DVT, liver disease, thyroid dise4. Did not qualify for therapy accoprescribing information for E2 or N5. Endometrial pathology6. Severe postmenopausal sympHRT7. Treatment with estrogens withi8. Treatment with hypolipidemic dmonthsNote: intravaginal estrogens and 

Wheatley, 1977 58 RCT P 4 weeks Depressed women NR

F-296
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/YearVoss, 2002Wheatley, 1977

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or 

Lifestyle 

Factors

(#/n)

d

Specific Characteristics of Population

Women's Health Questionnaire 0 0 NR 0 0 NR Global rating; Hamilton Depression Scale; Hopkins S

y

m

ptom Checklist

NR NR NR NR NR NR 

F-297
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/YearVoss, 2002Wheatley, 1977

Main Drug type; dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal 

Dryness S

Treatment Main Outcomes

Oestradiol 2mg and norethisterone acetate 1mg

Raloxifene 60mg qd HRT: -0.21

R: -0.03p<0.001 favoring HRT

NR HRT: -0.

R: -0.04p=0.086

Piperazin oestrone sulphate 1.5mg BID (with amitryptline)

Placebo (with amitryptiline)

NR NR 

F-298
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/YearVoss, 2002Wheatley, 1977

Mood Cognitive Somatic Urinar

y 

Main Outcomes (continued)

Depressed mood: HRT +0.03, R:-0.02, p=0.004 favoring Raloxifene.Anxiety/fears: HRT 0.00; R: -0.01; p=0.6.

Memory/concentration: HRT: -0.04;R: +0.02; p=0.02 favoring HRT

HRT: -0.02; R: -0.01; p=0.3.

NR 

No difference between groups; both groups improved.

NR NR NR 

F-299
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

Study/YearVoss, 2002Wheatley, 1977

Sexual 

Dysfunction Quality of Life Other Outcomes Withdrawals Withdrawals due to AEs Advers

Effects 

HRT: -0.11R:-0.02; p=0.007 favoring HRT

NR Greater treatment 

satisfaction (p=0.004) and compliance (p<0.01) with R than HRT 

54/495 on R; 116/513 on HRT

24/495 on R; 65/513 on HRT

Vaginal bleeding (R 6.8%, HRT 55%, p<0.0

NR NR NR NR NR NR

F-300
Appendix F: Evidence table 6-2. Key Question 3A Estrogens for depression

Study/YearVoss, 2002Wheatley, 1977

Sexual 

Dysfunction Quality of Life Other Outcomes Withdrawals Withdrawals due to AEs Advers

Effects 

HRT: -0.11R:-0.02; p=0.007 favoring HRT

NR Greater treatment 

satisfaction (p=0.004) and compliance (p<0.01) with R than HRT 

54/495 on R; 116/513 on HRT

24/495 on R; 65/513 on HRT

Vaginal bleeding (R 6.8%, HRT 55%, p<0.0

NR NR NR NR NR NR

F-298
Appendix F. Evidence table 6-2. Key Question 3A Estrogens for depression

AbbreviationsAE = Adverse Effect

CEE = Conjugated E

quine Estro

gens

E2 = EstrodialHH = Head to headHRT = Hormone Re

placement Therapy

NETA=norethidrone acetateNR = Not re

ported

P = PlaceboRCT = Randomized Controlled TrialHF = Hot flashGI = GastrointestinalSD = Standard deviationMI = Myocardial infarctionCAD = Coronary artery diseas

e

DVT = Deep vein thrombosisR = RaloxifeneHERS = Heart and Estrogen/Progestin Replacement Stud

y

RAND = RAND Mental Health Inventor

y

BMI = Body mass inde

x

SERMs = Selective Estrogen Receptor Modifiers BMD = Bone mineral densit

y

F-299
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year N

Study 

design

Comparison Length of Trial Population Inclusion/Exclusion Crite

BarrettConnor, 1999 311 in 4 

groups

DB 

RCT

HH 2 years Surgically menopausal 

White women. Mean age approx 45 (21-65)

Inclusion:1. White women 2. 21-65 years old3. Surgically menopausal: Undergone bilateral oohysterectomy > 3 months before but < 5 years pri4. Within 75-125% of ideal body weight5. In stable relationship for > 6 monthsExclusion:1. Receiving estrogens or HRT in previous 6 wee2. Receiving psychotropic drugs in the previous 4 3. History of pelvic or breast malignancy4. Dependence on alcohol, tobacco, or illicit drugs

Braunstein, 2003(abstract only)

447 DB 

RCT

P 24 

weeks

Surgically menopausal women with hypoactive sexual desire

Inclusion:1. Surgically menopausal women2. Had Hypoactive Sexual Desire Disorder

Davis, 2003 (abstract only)

77 DB 

RCT

P 24 

weeks

Surgically menopausal women with hypoactive sexual desire

Inclusion:1. Surgically menopausal women2. Had Hypoactive Sexual Desire Disorder

F-300
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

BarrettConnor, 1999Braunstein, 2003(abstract only)Davis, 2003 (abstract only)

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or Lifestyle 

Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or 

Low BMI

(#/n)

Modified Kupperman Scale

311 311 NR 0 NR NR No HRT in 

prior 6 weeks

Approximately 25 

SALPFSF

447/447 NR NR NR NR NR 0 NR 

SALPFSFPGWBPDS

77/77 77/77 NR NR NR NR 0 NR 

S

pecific Characteristics of Po

pulation

F-301
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

BarrettConnor, 1999Braunstein, 2003(abstract only)Davis, 2003 (abstract only)

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal 

Dryness Sleep Mood Cognitive 

E2 0.625 mg + MT 1.25 mg/day oral (E+ A-L); E2 1.25 mg + MT 2.5 mg/day oral (E + A)

Improved in all treatment groups (p value not reported)

Improved in all treatment groups (p value not reported)

NR NR NR 

Oral estrogen NR NR NR NR NR Transdermal estrogen

NR NR NR NR NR 

Main Outcomes

F-302
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

BarrettConnor, 1999Braunstein, 2003(abstract only)Davis, 2003 (abstract only)

Urinar

y

Uterine 

Bleeding Sexual Dysfunction Quality of Life Other Outcomes

NR NR Non-significant trend toward greater 

improvement in well-being and sexual interest in the E + A groups (data on Kupperman scale.)

NR Significantly increased BMD 

group at lumbar spine and hicomparison to the CEE group months. No statistically signifdifferences in hirsutism scoretreatment groups (Ferriman-Gscale)

NR NR In the 300 mcg/d group, a 30% increase in 

satisfying sexual activity observed in T vs. P (p<0.05) and 81% increase from baseline (p<0.05) on SAL. Sexual desire score also increased (p<0.05) on PFSF.

NR Increased mean concentratio

and bioavailable T.

NR NR Increase in sexual desire score on PFSF in 

T group compared to P, p<0.05

NR Increased mean concentratio

and bioavailable T.

Main Outcomes continued

F-303
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

BarrettConnor, 1999Braunstein, 2003(abstract only)Davis, 2003 (abstract only)

Withdrawals

Withdrawals 

due to AEs

Adverse Effects Commen

112 (non drug related-24, protocol violation-21, loss to follow-up-22)

45 Nausea (6% E+A-L; 3% E+A; 11% CEE-L 

and 22% CEE) Acne/hirsutism/chloasma (3 in E+A-L; 4 in E+A;1 CEE)

Participants in study not selpresence/severity of menop

NR NR NRNR NR NR

F-304
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year N

Study 

design

Comparison Length of Trial Population Inclusion/Exclusion Crite

Dobs, 2002 40 DB 

RCT

HH 16 

weeks

Menopausal womenMean age 56.9 (41.4-76.3)

Inclusion:1. Surgically or naturally menopausal women2. Required to have been on HRT for > 3 months remove confounding hypoestrogenic symptomsExclusion:1. Uncontrolled hypertension or hyperlipidemia2. Medication known to affect lipids3. Poorly controlled diabetes mellitus4. Unstable angina or congestive heart failure5. Myocardial infarction < 3 months of study6. Preexisting liver disease7. Renal impairment8. Hepatic adenoma9. History of breast or uterine cancer10. Gall bladder disease11. History of thromboembolic events

F-305
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

Dobs, 2002

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or Lifestyle 

Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or 

Low BMI

(#/n)

S

pecific Characteristics of Po

pulation

BISF -WSRSSIQQUALMS

NR 21/40 NR NR NR NR 0 NR 

F-306
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

Dobs, 2002

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal 

Dryness Sleep Mood Cognitive 

Main Outcomes

E2 1.25 mg/day oral Improved in 

E2/MT at week 4 (p=0.024) and week 10 (p=0.003) QUALMS Scale

NR Improved in 

E2/MT at week 4 (p=0.024) and week 10 (p=0.003) QUALMS Scale

No significant change

No significant change

F-307
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

Dobs, 2002

Urinar

y

Uterine 

Bleeding Sexual Dysfunction Quality of Life Other Outcomes

Main Outcomes continued

NR NR Frequency/psycho-sexual (p=0.05) and 

pleasure/orgasm (p=0.041) scores of BISFW increased.Total SRS score improved in E2/MT (p value not reported).Improved SIQ score in E2/MT at week 10 (p=0.031) and week 16 (p=0.014).

See QUALMS data

Sex hormone levels

F-308
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

Dobs, 2002

Withdrawals

Withdrawals 

due to AEs

Adverse Effects Commen

3 3 

(E2/MT - 2 E2 - 1)

Bloating/weight gain (E2/MT)Migraine (E2/MT)Hirsutism (E2/MT)Insomnia, breast swelling, headache (E2)

Sexual function and quality outcome.Healthier baseline sexual fugroup compared to E2/MT (reported)

F-309
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year N

Study 

design

Comparison Length of Trial Population Inclusion/Exclusion Crite

Floter, 2002 50 in 2 

groups

RCT

Crossover

HH 24 

weeks

Surgically menopausal womenMean age 54 (45-60)

Inclusion:1. 45-60 years old2. History of hysterectomy and bilateral salpingo odisorders3. Body mass index between 18 and 29 kg/m24. Blood pressure > 170 mmHg systolic and/or 105. Normal mammogram within past yearExclusion:1. Previous use of HRT within past 2 months2. Other medication within past 2 months (other ssteroids, corticosteroids, danazol, calcium antagoagents, barbiturates, carbamazepines, griseofulviherbal/homeopathic therapy)3. History of or present premalignancies/malignan4. Liver disease5. Cardiovascular, cerebrovascular, or thromboem6. Present psychiatric disease7. Regular use of tranquillizers and/or antihistamismoking of > 10 cigarettes/day was allowed

F-310
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

Floter, 2002

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or Lifestyle 

Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or 

Low BMI

(#/n)

S

pecific Characteristics of Po

pulation

McCoy's Sex ScalePGWB-I

50/50 50/50 NR 0/50 NR NR NR Mean 

25.7

F-311
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

Floter, 2002

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal 

Dryness Sleep Mood Cognitive 

Main Outcomes

Estradiol valerate 2 mg/day + testosterone undecanoate 40 mg/day

NR NR NR Both treatment 

groups with significant improvement, p< 0.001PGWB Index

NR 

F-312
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

Floter, 2002

Urinar

y

Uterine 

Bleeding Sexual Dysfunction Quality of Life Other Outcomes

Main Outcomes continued

NR NR Both treatment groups with significant 

improvement (p< 0.01) on McCoy Sex Scale.

Both treatment groups with significant improvement on PGWB Index, p< 0.05

Sex hormone levels

F-313
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

Floter, 2002

Withdrawals

Withdrawals 

due to AEs

Adverse Effects Commen

6 1 Migraine

AcneHirsutismBody swelling

F-314
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year N

Study 

design

Comparison Length of Trial Population Inclusion/Exclusion Crite

Hickok, 1993 26 in 2 

groups

DB 

RCT

HH 6 

months

Postmenopausal White women 40-60 yearsMean age:E2=50E2 + MT= 52

Inclusion:1. Women from Department of Obstetrics and GyHealth and Science University2. Caucasian 3. 40-60 years oldExclusion:1. Menstrual bleeding in the last 12 months2. History of steroid ingestion in 4 weeks prior to s3. Receiving adrenergic agonists or antagonists, pcholesterol-lowering agents, beta-blockers, beta-mhormones4. Smoking within the past 12 months5. History of genital tract disease6. Current or previous estrogen-dependent malign7. History of jaundice or elevated liver enzymes, gcardiovascular disease8. Current hypertriglyceridemia or severe hyperte

F-315
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

Hickok, 1993

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or Lifestyle 

Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or 

Low BMI

(#/n)

S

pecific Characteristics of Po

pulation

4 point menopausal symptom scale (0-3)

NR NR NR NR NR Nonsmokers NR NR 

F-316
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

Hickok, 1993

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal 

Dryness Sleep Mood Cognitive 

Main Outcomes

E2 0.625 mg/day oral

Decrease in symptom severity in both groups, p<.01. No significant difference between groups.

Decrease in symptom severity in both groups, p<.01. No significant difference between groups.

Decrease in symptom severity in both groups, p<.01. No significant difference between groups.

NR NR 

F-317
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

Hickok, 1993

Urinar

y

Uterine 

Bleeding Sexual Dysfunction Quality of Life Other Outcomes

Main Outcomes continued

NR NR NR NR Decreased symptom severity 

symptoms measured.No significant differences betgroups.

F-318
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

Hickok, 1993

Withdrawals

Withdrawals 

due to AEs

Adverse Effects Commen

0 0 Acne (E2 + MT - 5)

Facial hair (E2 + MT - 2; E2 - 1)

Menopausal symptoms meascale (0=absent to 3=severesweats, vaginal dryness, cobreast pain or tenderness, ntingling, skin crawls, edemabody hair, voice deepening, sleeping, heart pounding, dior tightness in head or body

F-319
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year N

Study 

design

Comparison Length of Trial Population Inclusion/Exclusion Crite

Lobo, 2003 218 in 

2 groups

DB 

RCT

HH 4 

months

Postmenopausal women with hypoactive sexual desire. Mean age approx 53 (40-65)

Inclusion:1. Healthy postmenopausal women (natural or su2. 40-65 years old3. Receiving estrogen (0.625 mg of conjugated eqmonths or equivalent of 0.9 mg if dose decreased study)4. Experienced hypoactive sexual desire associatmenopause (not overt mood disorders) scoring hiThoughts/Desire Dimension of the BISF-W 5. History of adequate sexual interest before onseExclusion:1. Dyspareunia2. Unresolved or recent sexual abuse3. Depressive or anxiety symptoms 4. Physical limitations that interfered with normal s5. Abnormal mammogram6. Relevant clinical laboratory test abnormalities7. Recent previous high-dose HRT or other sex h8. Lipid-lowering agents9. Antidepressants (including SSRI's)10. Anxiolytics11. Thyroid replacement medication (unless a sta12. Antihypertensive drugs

F-320
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

Lobo, 2003

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or Lifestyle 

Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or 

Low BMI

(#/n)

S

pecific Characteristics of Po

pulation

SIQBISF-W

NR Approximately 

68/218 (30.8 % EE/MT and 31.5% EE)

NR NR NR NR None E2 26.7 + 

5.4 and E2/MT 25.5 + 4.6

F-321
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

Lobo, 2003

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal 

Dryness Sleep Mood Cognitive 

Main Outcomes

NR NR NR NR NR NR 

F-322
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

Lobo, 2003

Urinar

y

Uterine 

Bleeding Sexual Dysfunction Quality of Life Other Outcomes

Main Outcomes continued

NR NR SIQ scores for mean sexual interest/desire 

and responsiveness significantly increased, p=.047 and p=.002, respectively.

NR Mean bioavailable T levels in

E2/MT group, p< .010, decreHDL in EE/MT, p<.010.

F-323
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

Lobo, 2003

Withdrawals

Withdrawals 

due to AEs

Adverse Effects Commen

E2 16/111 E2/MT 20/107

E2: 5 E2/MT: 9

Headache (E2/MT 9.3% vs. E2 7.2%) Infection (E2/MT 9.3% vs. E2 6.3%) Acne (E2/MT 5.6% vs. E2 2.7%) Hot flushes (E2/MT and E2 7%)Breast pain (E2/MT 3.7% vs. E2 7%)Acne (E2/MT 5.6% vs. E2 3%)Rhinitis (E2/MT 4% vs. E2 6%)

F-324
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year N

Study 

design

Comparison Length of Trial Population Inclusion/Exclusion Crite

Penotti, 2001 40 in 2 

groups

Open 

RCT

HH 8 

months

Postmenopausal women. Mean age: HRT + T 57.4HRT 55.3

Inclusion:1. Attending the Menopause Clinic of the Second Obstetrics and Gynecology, University of Milan2. Receiving HRT > 1 year3. Receiving Transdermal E2 (50 ug/d) for betweemedroxyprogesterone acetate (10 mg/d) for 12 daExclusion:1. Suffering from any major disease including hypdiabetes, renal or peripheral vascular diseases2. Undergone surgical removal of the uterus or ov

Raisz, 1996 18 in 2 

groups

Open 

RCT

HH 9 weeks Postmenopausal 

women. Mean age:CEE 65.7E2/MT 59.8

Inclusion:1. Postmenopausal women (last spontaneous me5 years)2. Within 25% of ideal body weight3. Non-smoker4. Negative mammogram and Pap smear within 1 electrocardiogramsExclusion:1. Receiving estrogens within last 6 months2. Prior history of estrogen-dependent cancer, hyhyperthyroidism, or metabolic bone disease3. Any prior treatment with drugs that might affect than calcium supplements and estrogens, or with hepatic enzymes (including excess vitamin A and cholesterol-lowering agents, heparin, anticonvulsanonsteroidal anti-inflammatory drugs, and high doreplacement

F-325
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

Penotti, 2001Raisz, 1996

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or Lifestyle 

Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or 

Low BMI

(#/n)

S

pecific Characteristics of Po

pulation

VAS 0 0 NR NR NR NR None HRT + T 

=24.1 and HRT =24.9

Modified Kupperman with 0-3 scale

0 CEE 3/15 NR 0 NR Nonsmokers 

only

No estrogen for 6 months prior

CEE =25.1 and E2/MT =26.5

F-326
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

Penotti, 2001Raisz, 1996

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal 

Dryness Sleep Mood Cognitive 

Main Outcomes

HRT: E2 50 mcg/day Transdermal + MPA 10 mg/day for 12day/month

NR NR NR NR NR 

Oyster shell calcium tablet (Oscal) 500 mg 1 or 2 tablets/day oral

Decreased in both groups, p<.05

Decreased in both groups, p<.05

Improved in E + A group, p<.05

Improved in E2/MT group, p<.05

NR 

F-327
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

Penotti, 2001Raisz, 1996

Urinar

y

Uterine 

Bleeding Sexual Dysfunction Quality of Life Other Outcomes

Main Outcomes continued

NR NR No difference observed between the 2 

groups of VAS scores at any of the time points (baseline, 4 months, 8 months)

NR NR

NR CEE 5

E2/MT 4 

NR NR Markers of bone formation an

resorption, lipids, and SHBG

F-328
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

Penotti, 2001Raisz, 1996

Withdrawals

Withdrawals 

due to AEs

Adverse Effects Commen

HRT 2/20 and HRT + T 5/20

HRT + T: 3 Hyperandrogenism 

Nausea, nervousness, and Aggressiveness in 2 patients

VAS (visual analogue scale changes in psychological wedesire and satisfaction

NR NR Headache (6 CEE; 2 E2/MT) 

Breast pain (6 CEE; 3 E2/MT)Acne (1 CEE; E2/MT)Bleeding (CEE 5; E2/MT 4)

Results reported by 3 group

Somatic symptoms: hot flasepisodes, vaginal drynessPsychosomatic symptoms: fpalpitationsPsychological symptoms: irrnervousness, depression, aconcentration.

F-329
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year N

Study 

design

Comparison Length of Trial Population Inclusion/Exclusion Crite

Shifren, 2000 75 DB 

RCT

P 36 

weeks

Surgically menopausal women with impaired sexual function. Mean age 47 (31-56)

Inclusion:1. Women 31-56 years old at nine clinics in the U2. Undergone bilaterial salpingo-oophorectomy annatural menopause between 1-10 years earlier3. Had serum testosterone concentrations < 30 ngtestosterone concentrations < 3.5 pg/milliliter4. Received CEE of > 0.625/day orally for > 2 mo5. Been in stable, monogamous, heterosexual rel6. Had BMI between 19.5 - 33.57. Impaired sexual function determined by questioBrief Index of Sexual Functioning for Women)Exclusion:1. Received oral, topical, or vaginal androgen themonths, or injectaable or implantable androgen thmonths2. Had > 20 moderate or severe hot flashes per w3. Had severe acne (grade 3 on Palatsi et al scale4. Mild or severe hirsutism (score of > 6 on Loprin5. Hyperlipidemia6. Psychiatric illness7. Dyspareunia8. Physical limitations that interferred with norma9. Receiving glucocorticoids, selective serotonin-rinhibitors, tricyclic antidepressants, antiandrogen ginseng, yohimbine, phytoestrogens, dehydroepiaor melatonin

F-330
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

Shifren, 2000

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or Lifestyle 

Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or 

Low BMI

(#/n)

S

pecific Characteristics of Po

pulation

BISF-WPGWB

75/75 75/75 NR NR NR NR 0 25.8 

(19.5-33.5)

F-331
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

Shifren, 2000

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal 

Dryness Sleep Mood Cognitive 

Main Outcomes

Oral CEE 0.625 mg/day - 41CEE 0.9 mg/day - 12CEE 1.25 mg/day - 20CEE 1.8 mg/day - 1CEE 2.5 mg/day - 1

No change from baseline

NR NR Significant 

increase in depressed - mood measure of PGWBI in testosterone 300 mcg/d group only, p=0.03

NR 

F-332
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

Shifren, 2000

Urinar

y

Uterine 

Bleeding Sexual Dysfunction Quality of Life Other Outcomes

Main Outcomes continued

NR NR Composite score of BISF increased for all 

treatment groups, p=0.05

Mean composite score of PGWBI increased for all treatment groups, p=0.04

No significant effects on total cholesterol, HDL, LDL, triglycfasting glucose or insulin, bloor LFT's.

F-333
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

Shifren, 2000

Withdrawals

Withdrawals 

due to AEs

Adverse Effects Commen

18 4 Anxiety - 2

Nipple discharge - 1Skin reaction - 1

Participants on variable dos

F-334
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year N

Study 

design

Comparison Length of Trial Population Inclusion/Exclusion Crite

Simon, 1999 93 in 5 

groups

RCT P 3 

months

Naturally menopausal women with mild to moderate vasomotor symptoms.Mean age 53.7

Inclusion:1. Naturally menopausal women with both ovaries 2. Recruited from Georgetown University (WashinWorcester Foundation for Experimental Biology (WMiddleton Foundation (Olympia, WA)3. Experienced amenorrhea > 6 months duration years) prior to study4. Had follicle-stimulating hormone levels > 55 mIlaboratory test results (biochemistry, hematology, profile), normal Pap smear, EKG, and mammogra5. Experienced mild to moderate vasomotor symp6. Non-smoker7. Within + 25% of ideal body weight (based on MInsurance tables)8. In heterosexual relationships of > 1 year duratioExclusion:1. Receiving estrogens, progestins, androgens, o8 weeks of study enrollment2. Active breast, uterine, or ovarian cancer or hist3. Recent history of vaginal bleeding

Watts, 1995 66 in 2 

groups

DB 

RCT

HH 2 years Surgically menopausal 

women

Inclusion:1. 21-60 years old2. Surgically menopausal: Undergone bilateral oohysterectomy at least 4 weeks before study entry Exclusion:1. Had concomitant illness

F-335
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

Simon, 1999Watts, 1995

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or Lifestyle 

Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or 

Low BMI

(#/n)

S

pecific Characteristics of Po

pulation

Kupperman 0 0 NR 0 0 100% nonsmokers NR Mean 27.1 

Modified Kupperman with 0-7 scale

66/66 66/66 NR 0 NR NR NR E2-24.9

E2/MT25.8

F-336
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

Simon, 1999Watts, 1995

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal 

Dryness Sleep Mood Cognitive 

Main Outcomes

E2 0.625 mg/dayE2 1.25 mg/day

All active treatment groups shared significant improvement (p < 0.05)

All active treatment groups shared significant improvement (p < 0.05)

No treatment effect

No treatment effect

NR 

E2 1.25 mg/day + MT 2.5 m/day oral

No difference between treatment groups at baseline or after treatment

No difference between treatment groups at baseline or after treatment

No difference between treatment groups at baseline or after treatment

NR due to small numbers of symptomatic patients

NR 

F-337
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

Simon, 1999Watts, 1995

Urinar

y

Uterine 

Bleeding Sexual Dysfunction Quality of Life Other Outcomes

Main Outcomes continued

NR NR NR Sex hormone levelsNR NR NR NR Lipids and Spinal bone miner

F-338
Appendix F. Evidence table 6-3. Key Question 3C Testosterone

Study/Year

Simon, 1999Watts, 1995

Withdrawals

Withdrawals 

due to AEs

Adverse Effects Commen

3 1 - high dose 

estratest

Rash Only somatic symptoms rep

E2 3E2/MT 7

E2 3E2+MT 5

Headache (E2 16; E2/MT 9)Hot flashes (E2 7; E2/MT 3)Rdema (E2 10; E2/MT 10)Breast pain (E2 9; E2/MT 13)Hair disorder (E2 1; E2/MT 12)Acne (E2 2; E2/MT 10)

Modified Kupperman scale umenopause symptoms.

F-339
Appendix F: Evidence table 6-3. Key Question 3C Testosterone

Key/Abbreviations

A = Androgen

BISF-W = Brief Index of Sexual Function for WomenBMD = Bone mineral densit

y

BMI = Body mass inde

x

CEE= Conjugated equine estrogensDB = Double blindE = EstrogenE2 = EstradiolEE = Esterified EstrogenHH = Head to headHRT = Hormone replacement therapyMT = MethyltestosteroneNR = Not reportedP = PlaceboPDS = Personal Distress ScalePFSF = Profile of Female Sexual FunctionPGWB = Psychological General Well-BeingPGWB-I = Psychological General Well-Being IndexQUALMS = Quality of Life Menopause Scal

e

RCT = Randomized controlled trialSAL = Sexual Activity Lo

g

SERMs = Selective Estrogen Receptor Modifiers SIQ = Sexual Interest QuestionnaireSRS = Sabbatsberg Revised Sexual Rating Scal

e

SSRI = Selective Serotonin Reuptake InhibitorT = TestosteroneVAS = Visual Analogue Scal

e

F-340
Appendix F. Evidence table 6-4. Key Question 3C DHEA

Study/Year N

Study 

design

Comparison Length of Trial Population Inclusion/Exclusion Criteria

Barnhart, 1999

60 in 2 

groups

DB

RCT

P 3 months Perimenopausal 

women with altered mood and wellbeing.Mean age 48 (45-55)

Inclusion:1. Perimenopausal women2. 45-55 years old3. Symptoms include fatigue, lack of energy, anxietydepression, insomnia, forgetfulness, concentration dlibido, or global reports of a decreased sense of welExclusion:1. Any contraindication to HRT2. Exposure to injectable or implantable sex steroid systemic steroid within 90 days of treatment3. Used antidepressants and/or antianxiolitics4. Current diagnosis of major psychiatric disorder, dhypercholesterolemia, or cardiovascular disease5. Abnormal renal or liver function

Stomati, 1999 22 in 3 

groups

RCT HH 3 months Postmenopausal 

women (50-55 years)

Inclusion:1. Postmenopausal women2. 50-55 years old3. Climacteric complaints4. Normal body mass index5. Basal plasma DHEA levels < 5 ug/mlExclusion:1. Previous or current estrogen-dependent neoplasiadisease, liver, pancreatic or renal disease, and diabe

F-341
Appendix F. Evidence table 6-4. Key Question 3C DHEA

Study/YearBarnhart, 1999Stomati, 1999

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or 

Lifestyle 

Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

High or 

Low BMI

(#/n)

t

DSR (0-4 scale), Profile of Mood Scale, Ham-D, SmithKline Beecham Quality of Life Self-Report Questionnaire, Buschke Immediate Recall and Delayed Recall, Symbol Copying and Digit Symbol Substitution Tests

NR NR NR NR NR NR NR NR D

m

Kupperman (0-3 scale, where 0=none and 3=marked)

NR NR NR NR NR NR NR NR D

m

Specific Characteristics of Population 

F-342
Appendix F. Evidence table 6-4. Key Question 3C DHEA

Study/YearBarnhart, 1999Stomati, 1999

Hot Flashes

Vaginal 

Dryness Sleep Mood Cognitive Somatic Urinary

Uterine 

Bleeding

Sexual 

Dysfunc

tion 

No significant difference between study groups

No significant difference between study groups

No significant difference between study groups

No significant difference between study groups

No significant difference between study groups

No significant difference between study groups

No significant difference between study groups

NR No 

significant difference between study groups

NR NR NR NR NR NR NR NR NR 

Outcomes

F-343
Appendix F. Evidence table 6-4. Key Question 3C DHEA

Study/YearBarnhart, 1999Stomati, 1999

Withdrawals

Withdrawals 

due to AEs Adverse Effects Comments

6 3 Rash (placebo)

Abdominal pain/fatigue (placebo)Paresthesia (DHEA)

Subjects from both study groups had decreased total perimenopausal symptoms and improvements in components of health-related quality of life, p<0.01.

0 0 NR Similar significant progressive 

improvement in Kupperman score with all treatment groups (p<0.01). Specific components of Kupperman score not reported individually.

F-344
Appendix F: Evidence table 6-4. Key Question 3C DHEA

Key/Abbreviations

BMI = Body mass indexDB = Double blindDHEA = DehydroepiandrosteroneDSR = Daily Symptom Rating CalendarHAM-D = Hamilton Depression Rating ScaleHH = Head to headHRT = Hormone replacement therapyNR = Not reportedP = PlaceboRCT = Randomized controlled trialSERMs = Selective Estrogen Receptor Modifiers 

F-345
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year N

Study 

design

Comparison Length of Trial Population Inclusion/Exclusion Criteria

Baracat, 2002 85 in 2 

groups

open 

RCT

HH 12 

months

Postmenopausal women with intact uterus. EE/MPA mean age: 53 (45-65)Tibolone mean age: 51

Inclusion:1. Ages 45-65 years2. Intact uterus3. Natural menopause > 6 months prior4. > 4 hot flushes/dayExclusion:1. History or presence of clinically significant phyundiagnosed vaginal bleeding, hypertension, obsmoking, alcohol or drug abuse2. >Pap smear class III3. Use of estrogens, progestins, androgens, Tiblowering agents within 90 days of evaluation4. Known sensitivity to an investigational or a re

BenedekJaszmann, 1987 60 in 2 groups DB RCT P 12 months Post-menopausal women attending a 

menopause clinic. Age 44-61

Inclusion: 1. Menopausal Exclusion: 1. Current or past h/o cancer or thromboembolic 

Berning, 2000 94 in 3 

groups

RCT P 2 years Post-menopausal (1-

3years), non-smoking, White, with a BMI < 27. Mean age 52.7

Inclusion: 1. White2. Non-smoking3. BMI<27Exclusion:1. No disease2. No medication that influences calcium metabo

F-346
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Baracat, 2002BenedekJaszmann, 1987Berning, 2000

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior or 

Lifestyle 

Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

H

4 point scale, hot flashes calculated separately

0 1/85 NR 0 NR NR Excluded C

25Ti

4 point scale NR NR NR 0/60 NR NR NR 

NR 0/94 0/94 NR NR NR NR NR M

S

pecific Characteristics of Po

pulation

F-347
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Baracat, 2002BenedekJaszmann, 1987Berning, 2000

Main Drug type; dose;

regimen

Other Drugs type; dose; 

regimen Hot Flashes

Vaginal Dryness 

Tibolone 2.5 mg/day oral CEE/MPA 0.625/5 mg/day 

oral

Decreased intensity and mean number hot flashes in both groups. No significant difference between groups

Significant improvement in both treatment groups, p value not reported.

Impin bNo diffebetwtreagro

Tibolone 2.5 mg/day Placebo Improved in Tibolone 

group throughout study, p<.05

NR Imp

Tibogromonp<.0

Tibolone 1.25 mg/day n=36Tibolone 2.5 mg/day n=35Placebo n=23

Placebo NR NR 

Main Outcomes

F-348
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Baracat, 2002BenedekJaszmann, 1987Berning, 2000

Mood Cognitive Somatic Urinar

y Uterine Bleeding Sexual Dysfun

Improvement in both groups. No significant difference between treatment groups.

Improvement in both groups. No significant difference between treatment groups.

Improvement in both groups. No significant difference between treatment groups.

NR No significant difference between 

treatment groups.

Improvement in bgroups. No signidifference betweetreatment groups

Improved in Tibolone group at month 6 only, p<.05

NR NR NR NR NR 

NR NR NR NR Compared to placebo, Increased 

number bleeders in Tibolone 2.5 mg group, p<.05. Non significantly increased number bleeders in Tibolone 1.25 mg group. Total number bleeding episodes significantly increased in Tibolone 2.5 mg compared to Tibolone 1.25 mg, p<.05 and placebo, p<.01.

NR 

Main Outcomes

F-349
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Baracat, 2002BenedekJaszmann, 1987Berning, 2000

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse Effects Co

Cholesterol levelsWeight gain

CEE/MPA: 5

Tibolone: 4

CEE/MPA: 4

Tibolone: 3

HeadacheT-2.5%, CEE 6.7%NauseaBreast pain T 2.5%, CEE 11%Vaginal bleeding CEE onlyPelvic pain T5%, CEE4.4%, Fatigue/HTN/leg cramps/low back pain -T2.5% CEE2.2%, Dysuria-7.5%, 

4 point scale: 0 (absflushes per cycled canumber of hot flusherespective score 0 (a

Cholesterol, Irritability improved in Tibolone group at months 1, 6, 12, p<.05. Psychic instability improved in Tibolone group at months 1, 3, 6, 12, p<.05.

Tibolone: 6

Placebo: 11

Tibolone: 4 

Placebo: 4

Weight gain (T-2, P-1) Limb pain (T-2, P-1) Skin problem (P-1) Nausea (P-1)

4 point scale: 0 (absparameters measure

Estradiol levels and endometrial morphology

Tibolone 

1.25: 3 

Tibolone 2.5: 

3 Placebo: 4

Tibolone 1.25: 

2

Vaginal bleeding (T1.25-1), Skin reaction (T1.25-1)

This study not designTibolone on menopa

F-350
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year N

Study 

design

Comparison Length of Trial Population Inclusion/Exclusion Criteria

Dansuk, 2002(Abstract only)

140 in 

2 

groups

RCT HH 3 

months

Hysterctomized postmenopausal women

Inclusion:1. Women who were hysterectomized > 1 year pExclusion:1. Previous estrogen use2. Use of lipid lowering drugs

De Aloysio, 1987

124 in 

3 

groups

Open 

RCT

P 4 

months

Post-menopausal women attending a menopause clinic.

Inclusion:1. Post-menopausalExclusion:1. No endometriosis, fibrocystic mastitis, estrogeanemia, thromboembolic or liver disease, HT premonths, medications, early menopause

Egarter, 1996 129 in 

2 

groups

Unblinded 

RCT

HH 6 

months

Postmenopausal women on no HRT for at least 6 months. Mean age approximately 53.5

Inclusion:1. Spontaneous menopause > 12 months prior2. No use of HRT in last 6 monthsExclusion:1. Use of short-acting hormones within 3 months 2. Hysterectomy3. Injection of long-acting estrogens within 6 mo4. Existing or suspected hormone-dependent tumbleeding of unknown etiology, severe liver disordprevious cardiovascular or cerebrovascular diso

F-351
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Dansuk, 2002(Abstract only)De Aloysio, 1987Egarter, 1996

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior or 

Lifestyle 

Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

H

S

pecific Characteristics of Po

pulation

Kupperman 140/140 NR NR NR NR NR 0 

NR 24/124 24/124 NR 0/124 NR NR No HRT in 

prior 6 months

TiapPlapCoap

Kupperman 

Index

0/129 NR NR 0 NR NR No HRT in 

past 6 months

F-352
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Dansuk, 2002(Abstract only)De Aloysio, 1987Egarter, 1996

Main Drug type; dose;

regimen

Other Drugs type; dose; 

regimen Hot Flashes

Vaginal Dryness 

Main Outcomes

Tibolone 2.5 mg/day oral E2 0.05 mg/day 

Transdermal

NR NR 

Tibolone 2.5 mg/day n=35 Placebo IM injection n=46

Control n=43

Improved in Tibolone group, p<.01

NR No 

diffebetwtreaplaccon

Tibolone 2.5 mg/day oral CEE 0.625 mg/day + 

medrogestone 10 mg/day for 12 days/month

Improvement in both groups. No difference between groups.

Improvement in both groups. No difference between groups.

Impin bNo betwgro

F-353
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Dansuk, 2002(Abstract only)De Aloysio, 1987Egarter, 1996

Mood Cognitive Somatic Urinar

y Uterine Bleeding Sexual Dysfun

Main Outcomes

NR NR NR NR NR NR NR NR NR NR NR NR 

Improvement in both groups. Higher significance level in Tibolone group, p<0.001 vs. p<0.01.

NR Overall, 

improvement in both groups with no significant difference between groups.

NR NR Improvement in b

groups. Higher significance level Tibolone, p<0.00CEE/medrogestop<0.05.

F-354
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Dansuk, 2002(Abstract only)De Aloysio, 1987Egarter, 1996

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse Effects Co

Cholesterol levels 0 0 NR No difference in clim

between the 2 treatmcategories not report

Cholesterol, BMI, BP, electrolytes, coagulation, gonadal hormones

Tibolone: 21 

Placebo: 10 

Control: 13

Tibolone: 5 

Placebo: 2

Uterine bleeding (T-3), Weight gain (P-1), Anxiety (P-1), GI distress (T-2)

Endometrial thickness Tibolone: 15

CEE/medrog

e-stone: 18

Tibolone: 3

CEE/medrogestone: 6

Weight gain T-2, HRT-4Bleeding HRT-4Headache T-2, HRT-2 Leg pain T-4

Treatment groups webaseline with regard 

F-355
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year N

Study 

design

Comparison Length of Trial Population Inclusion/Exclusion Criteria

Hammar, 1998 437 in 

2 

groups

DB

RCT

HH 48 

weeks

Symptomatic menopausal women

Inclusion:1. Physically and mentally healthy women2. > 1 year since last menstrual bleeding3. Menopausal complaints4. Intact uterus5. BMI < 30kg/m2Exclusion:1. Usual exclusion criteria for HRT applied

Huber, 2002 501 in 

2 

groups

DB

RCT

HH 1 year Postmenopausal 

women with intact uterus < 65. Mean age: 55

Inclusion:1. Postmenopausal women with last period > 12 2. Under the age of 65 years3. If date of natural menopause is unknown due women must be > 53 years and received HRT foending with progestin phase4. Intact uterus5. BMI of 18-29 kg/m2Exclusion:1. Presence or history of hormone-dependent mknown or suspected hypercholesterolemia, hypedisease, endometrial hyperplasia, undiagnosed prophyria, haemoglobinopathie2. Presence or history of cardiovascular, cerebrothromboembolic disorders3. Use of HRT during last month prior to start4. Previous use of implantable or injectable HRT5. Concomitant use of sex hormones or any druinterfere with trial medication6. Drinking > 4 glass of alcohol/day

F-356
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Hammar, 1998Huber, 2002

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior or 

Lifestyle 

Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

H

S

pecific Characteristics of Po

pulation

5 point scale 0/437 NR NR NR NR NR NR Ti

E224

Q-LES-QPGWBIGCSLUCRS

0/501 NR NR NR NR < 4 alcoholic 

beverages per day

No HRT one month prior to trial

TiC24

F-357
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Hammar, 1998Huber, 2002

Main Drug type; dose;

regimen

Other Drugs type; dose; 

regimen Hot Flashes

Vaginal Dryness 

Main Outcomes

Tibolone 2.5 mg/day oral E2 NETA 2 mg/day oral Improvement with both 

treatments. Significantly greater decrease with E2/NETA at last visit, p<0.001.

Improvement with both treatment groups, p<0.0001.

Tibolone 2.5 mg/day oral CEE 0.625 mg/day + MPA 5 

mg/day oral

No significant difference between groups on GCS

No significant difference between groups on GCS

No diffebetwgroGC

F-358
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Hammar, 1998Huber, 2002

Mood Cognitive Somatic Urinar

y Uterine Bleeding Sexual Dysfun

Main Outcomes

NR NR NR NR Decreased in Tibolone group, 

p<0.0001.

NR 

No significant difference between groups on PGWBI or GCS

NR No 

significant difference between groups on GCS

No significant difference between groups on LUCRS

Significantly decreased in Tibolone group during cycles 1-3, p=0.002 and 4-6, p=0.004.

Significantly imprsexual interest, dand/or performanTibolone group amonths, p=0.017 LES-Q).

F-359
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Hammar, 1998Huber, 2002

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse Effects Co

NR Tibolone: 54

E2/NETA: 68

Tibolone: 34

E2/NETA: 55

Breast tenderness T-44, E2-119Edema T-72, E2-61Nausea T-51, E2-63Bleeding T-9, E2-37

Menopausal symptom(1 = none; 5 = very s

Economic status score of Q-LES-Q higher at 3 months for CEE/MPA group, p=0.029.

Tibolone: 62

CEE/MPA: 

50

Tibolone: 38

CEE/MPA: 33

Vaginal bleeding T-20, HRT15Breast tenderness T-6, HRT43HeadacheT-22, HRT-17; Back pain T-13, HRT-11; Body pain T-4, HRT-12; Depression T11, HRT-10; Weight gain T-9, HRT-8; Anxiety T-8, HRT-3, Uterine bleeding T-20, HRT15

F-360
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year N

Study 

design

Comparison Length of Trial Population Inclusion/Exclusion Criteria

Hudita, 2003 162 in 

2 

groups

DB

RCT

P 24 

weeks

Non-obese postmenopausal women with intact uterus. Mean age approximately 56 (40-65).

Inclusion: 1. Age 40-65, intact uterus2. Amenorrhea for 12 months3. FSH >30 mIU/ml4. 17 beta-estradiol <50pg/ml Exclusion:1. History of VTE disease2. GYN cancer3. Uncontrolled DM4. Abnormal mammogram/pap/ lab values5. History of kidney/liver disease6. Use of hormones 8 weeks prior to study7. Other criteria

Johannes, 1997 (abstract only)

770 in 

4 

groups

DB

RCT

P 12 

weeks

Non-hysterectomized post-menopausal women. Mean age: 52

Inclusion:1. Postmenopausal women2. Non-hysterectomized

Kö kçü, 2000(abstract only)

50 in 2 

groups

RCT HH 1 year Women with natural 

menopause. Mean age not reported.

Inclusion:1. Women with natural menopauseExclusion:1. Contraindication for HRT

F-361
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Hudita, 2003Johannes, 1997 (abstract only)Kö kçü, 2000(abstract only)

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior or 

Lifestyle 

Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

H

S

pecific Characteristics of Po

pulation

McCoy Sex Scale (modified), 5 point scale for menopausal symptoms

0/162 NR NR 0/162 0/162 NR No 

hormones 8 weeks prior to study

Mapy 

NR 0/770 NR NR NR NR NR NR 

Questionnaire NR NR NR NR NR NR NR 

F-362
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Hudita, 2003Johannes, 1997 (abstract only)Kö kçü, 2000(abstract only)

Main Drug type; dose;

regimen

Other Drugs type; dose; 

regimen Hot Flashes

Vaginal Dryness 

Main Outcomes

Tibolone 1.25 mg/dayTibolone 2.5 mg/day

Placebo Significant 

improvement in both treatment groups at 4, 12, and 24 weeks, p<.01. Greater improvement at 4 weeks with Tibolone 2.5 mg than Tibolone 1.25 mg, p<.05

Significant improvement in both treatment groups at 4, 12, and 24 weeks, p<.01. Greater improvement at 4 and 8 weeks with Tibolone 2.5 mg than Tibolone 1.25 mg, p<.05

Tibolone 0.625 mg/day1.25 mg/day2.5 mg/day5.0 mg/day oral

Placebo Significant decrease in 

incidence with 1.25, 2.5, and 5.0 mg/d dose, p<0.05.

NR 

Tibolone2.5 mg/day oral

CEE 0.625 + MPA 2.5 mg/day oral

NR NR 

F-363
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Hudita, 2003Johannes, 1997 (abstract only)Kö kçü, 2000(abstract only)

Mood Cognitive Somatic Urinar

y Uterine Bleeding Sexual Dysfun

Main Outcomes

NR NR NR NR Significantly increased bleeding at 

week 12 in both treatment groups, p<.05

Significant improvin both treatment groups at weeks and 24, p<.05. 

Tibolone 1.25 mg greater improvemweek 12 than Tib2.5 mg, p<.05. Tibolone 2.5 mg greater improvemweek 24, p<.05.

NR NR NR NR Higher incidence in 5.0 mg/d group 

in comparison to other doses and placebo, p value not reported.

NR 

NR NR NR NR NR Significantly incre

sexual desire in Tibolone group, p

F-364
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Hudita, 2003Johannes, 1997 (abstract only)Kö kçü, 2000(abstract only)

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse Effects Co

Cholesterol levels 42 NR Breast discomfort (Tibolone 

1.25-2, Tibolone 2.5-4) Fluid retention (Tibolone 1.25-3, Tibolone 2.5-2) Vaginal spotting (Placebo-2, Tibolone 1.25-4, Tibolone 2.5-2) Headache (Placebo-2, Tibolone 1.25-3, Tibolone 2.5-2) Nausea (Placebo-1)

NR NR NR Bleeding

Both treatment groups with significant improvement in subjective well-being and vasomotor symptoms, p<0.05.

NR NR NR No significant differe

treatment groups. Sreported.

F-365
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year N

Study 

design

Comparison Length of Trial Population Inclusion/Exclusion Criteria

Lam, 2004 100 in 

2 

groups

DB 

RCT 

crossover

P 13 

months

Postmenopausal Chinese women from Hormone Replacement Clinics. Mean age approx 50.

Inclusion: 1. Married2. Intact uterus3. FSH> 30 IU/L4. Estradiol < 100 pmol/L Exclusion: 1. Breast/endometrial cancer2. Liver/kidney disease3. Thromboembolic disease

F-366
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Lam, 2004

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior or 

Lifestyle 

Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

H

S

pecific Characteristics of Po

pulation

GCS, GHQ, DAS (Dyadic Adjustment Scale)

0/100 NR NR 0/100 0/100 NR No 

hormones in prior 6 months

F-367
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Lam, 2004

Main Drug type; dose;

regimen

Other Drugs type; dose; 

regimen Hot Flashes

Vaginal Dryness 

Main Outcomes

Tibolone 2.5 mg/day Placebo Both groups with 

significantly reduced vasomotor sub score of GCS; p<.05

Both groups with significantly reduced urogential sub score of GCS, p<.05

F-368
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Lam, 2004

Mood Cognitive Somatic Urinar

y Uterine Bleeding Sexual Dysfun

Main Outcomes

Significantly reduced depression sub score of GCS in treatment group, p<.05

NR Significant 

reduction in somatic sub score of GCS in treatment group, p<.05

Both groups with significantly reduced urogential sub score of GCS, p<.05

NR Both groups with 

significantly reducsexual sub score GCS, p<.05

F-369
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Lam, 2004

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse Effects Co

Marital quality of couples assessed by DAS

Tibolone: 4 

Placebo: 2

NR Muscle/bone pain (T-2; P-1) 

Weight gain (T-2, P-1) Headache (T-1)

Modified McCoy Sex system. GCS score both treatment group

F-370
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year N

Study 

design

Comparison Length of Trial Population Inclusion/Exclusion Criteria

Landgren, 2002 775 in 

5 

groups

DB

RCT

P 12 

weeks

Healthy post menopausal women with hot flushes and sweating. Mean age approximately 52 (40-60).

Inclusion:1. Non-hysterectomized women aged 40-60 yea2. Absence of spontaneous vaginal bleeding for prior to start3. > 1 moderate-severe hot flush/day4. Body weight between 80%-130% of ideal weiExclusion:1. History or presence of any malignant disorderor cerebrovascular disease, thromboembolism/thepatic or renal disease, epilepsy or classical mbleeding of unknown etiology, hypertension, rhediabetes mellitus, hyperlipidaemia, any serious dpsychiatric disorder, hypersensitivity to oestrogeprogestin, disease for which exogenous hormoncontraindicated2. Use of sex steroids within 6 weeks3. Ethinyloestradiol within the last 6 months4. Hormone implants at any time5. One or more of the following drugs during the hydantion, barbiturates, primidone, carbamazepgriseofulbin, drugs for treating climacteric sympt6. Alcohol abuse and/or drug abuse within the la7. Smoking > 10 cigarettes/day

F-371
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Landgren, 2002

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior or 

Lifestyle 

Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

H

S

pecific Characteristics of Po

pulation

Collins and Landgren Rating Scale

0/775 NR NR 0/775 NR NR NR Pl

250.gr1.gr2.

245.24

F-372
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Landgren, 2002

Main Drug type; dose;

regimen

Other Drugs type; dose; 

regimen Hot Flashes

Vaginal Dryness 

Main Outcomes

Tibolone0.625 mg/day1.25 mg/day2.5 mg/day5 mg/day

Placebo Significant decrease in 

frequency with 1.25 mg, 2.5 mg, and 5.0 mg doses, p<0.0125

NR 

F-373
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Landgren, 2002

Mood Cognitive Somatic Urinar

y Uterine Bleeding Sexual Dysfun

Main Outcomes

NR NR NR NR Dose-related increased vaginal 

bleeding and spotting. Highest incidence in the 5 mg/d group. Observed throughout 12 week study.

NR 

F-374
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Landgren, 2002

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse Effects Co

Sweating episodes significantly decreased in the 1.25, 2.5, and 5mg/d groups, p<0.0125.

99 36 Vaginal bleeding (T and P)

others not reported

F-375
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year N

Study 

design

Comparison Length of Trial Population Inclusion/Exclusion Criteria

Lloyd, 2000 29 in 2 

groups

DB

RCT

P 6 

months

Hypertensive postmenopausal women. Mean age approximately 61

Inclusion:1. Women with hypertension2. > 1 year postmenopausalExclusion:1. Intrinsic renal disease, insulin dependent diabof an oestrogen dependent tumor2. Use of sex steroid compounds, previous HRTTibolone, or tamoxifen within previous 3 months

Meeuwsen, 2002

85 in 2 

groups

DB

RCT

P 1 year Health women 

postmenopausal for 1-15 years. Mean age approximately 54.

Inclusion:1. > 1 year but < 15 years after natural menopauExclusion:1. Presence or history of sex hormone depende2. Use of HRT or other steroid medication or muaffecting drugs during last 6 months3. Hypertension, active liver disease4. Presence or history of endometrial hyperplasiatypia, undiagnosed vaginal bleeding5. Presence or history of cardiovascular, cerebrothromboembolic disorders6. Consumption of > 4 alcoholic drinks/day7. Pophyria, haemoglobinopathy8. Use of sex hormones, anabolcs, corticosteroicoagulants or enzyme-inducing drugs9. Participating in a clinical trial during the last 3 10. BMI below 18 kg/m2 or above 29 kg/m211. Concomitant medication that could interfere 

F-376
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Lloyd, 2000Meeuwsen, 2002

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior or 

Lifestyle 

Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

H

S

pecific Characteristics of Po

pulation

GHQ NR NR NR NR No 

tamoxifen within prior 3 months

3/30 No HRT 

within prior 3 months

TiPl

NHP Tibolone: 4

Placebo: 5

0/85 NR NR NR NR No HRT 6 

months prior to trial

25 gr

F-377
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Lloyd, 2000Meeuwsen, 2002

Main Drug type; dose;

regimen

Other Drugs type; dose; 

regimen Hot Flashes

Vaginal Dryness 

Main Outcomes

Tibolone 2.5 mg/day oral Placebo NR NR Tibolone 2.5 mg/day oral Placebo Significantly 

decreased in Tibolone at cycle 12 in comparison to placebo, p<0.05

NR Sig

impin Tgrocomplacp<0NH

F-378
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Lloyd, 2000Meeuwsen, 2002

Mood Cognitive Somatic Urinar

y Uterine Bleeding Sexual Dysfun

Main Outcomes

NR NR NR NR NR NR 

No significant difference between treatment groups by NHP score.

NR No 

significant difference between treatment groups in energy, pain, social isolation.

No significant difference between treatment groups.

Overall increased frequency in Tibolone group, p<0.05.

NR 

F-379
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Lloyd, 2000Meeuwsen, 2002

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse Effects Co

Blood pressure and lipids

Tibolone: 2

Placebo: 2

Tibolone: 1

Placebo: 1

Headache (numbers not reported)Nausea (numbers not reported)Flushing (numbers not reported) , Uterine bleeding T4 P-1

Primary outcome wablood pressure and brisk factors in hypertelife reported as a sec

NR Tibolone: 1

Placebo: 2

Tibolone: 1

Placebo: 0

Malaise T-2Vaginal bleeding (but no Withdrawal due to vaginal bleeding) T-16, P-4; Abnormal mammogram P-1

NHP used to assess organized into 6 domenergy, pain, physicasocial isolation.

F-380
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year N

Study 

design

Comparison Length of Trial Population Inclusion/Exclusion Criteria

Mendoza, 2000 76 in 2 

groups

RCT HH 1 year Surgically menopausal 

women < 50. Mean age not reported

Inclusion:1. Women who underwent a hysterectomy or biloophorectomy for benign gynecologic process2. 3-4 months from surgery to study entryExclusion:1. Prior use of HRT2. Previous malignant gynecologic process, oestumor, endocrinological or metabolic problems, cdisease, uncontrolled hypertension, active hepaserious skin illness, intestinal sickness or chronirespiratory disease3. Psychiatric problems or receiving anxiolytic or drugs

Mendoza, 2002 165 in 

3 

groups

RCT HH 1 year Postmenopausal 

women with intact uterus amenorrhea 1-5 years. Mean age approximately 50.

Inclusion:1. Intact uterus2. Amenorrhea for 1-5 years3. Under 60 years of ageExclusion:1. Hysterectomized women2. Use of HRT within 3 months prior to start3. History of a malignant gynecological processeproducing tumor, serious endocrine or metabolic insulin dependent diabetes, obesity (BMI > 32 kghypertension, active liver disease, serious skin dobstructive pulmonary disease4. Psychiatric disturbance or use of anxiolytics o

F-381
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Mendoza, 2000Mendoza, 2002

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior or 

Lifestyle 

Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

H

S

pecific Characteristics of Po

pulation

Kupperman Index

76/76 76/76 NR 0 0 Alcohol:

Tibolone 1/36Estradiol 0/37Smoking:Tibolone 11/36Estradiol 10/37

0 

Modified Kupperman Index

0/165 NR NR NR NR No alcohol 

use.Smoking Tibolone 18%.Cyclic combined 23.6%.Intermittent progesterone 20%.

No HRT 3 months prior to trial.

N

F-382
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Mendoza, 2000Mendoza, 2002

Main Drug type; dose;

regimen

Other Drugs type; dose; 

regimen Hot Flashes

Vaginal Dryness 

Main Outcomes

Tibolone 2.5 mg/day oral Estradiol 50 mcg/day 

Transdermal

No significant difference between treatments. Both groups improved.

NR 

Tibolone 2.5 mg/day oral orEstradiol 50 mcg/day x 14 days, then Estradiol 50 mcg/day + NETA 0.25mg/day x 14 days Transdermal

Estradiol 50 mcg/day Transdermal + progesterone 200 mg 2x/week oral.

No significant difference between treatment groups (all improved)

NR No 

diffetreabetwgro

F-383
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Mendoza, 2000Mendoza, 2002

Mood Cognitive Somatic Urinar

y Uterine Bleeding Sexual Dysfun

Main Outcomes

No significant difference between treatments. Both groups improved.

NR NR NR NR No significant diff

between treatme

No significant difference treatment between groups.

No significant difference treatment between groups.

No significant difference treatment between groups.

NR NR No significant diff

treatment betweegroups.

F-384
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Mendoza, 2000Mendoza, 2002

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse Effects Co

Lipids NR Tibolone: 3

Estradiol: 1

Headache E2-1Nausea T-4, E2-1Skin irritationBreast tenderness E2-4Weight gain T-1, E2-2Edema T-1, E2-1Hirsutism T-1Nervousness T-1Endometriosis T-1

Lipid profiles Tibolone: 4

Intermittent 

progesterone

: 3

Cyclic 

combined: 1

Tibolone: 4

Intermittent 

progesterone: 

3

Cyclic 

combined: 1

Vaginal bleeding T-3, HRT-25Headache T-4, HRT-2Skin irritation HRT-11Varicose veinsHypertension T-1Stomach pain T-3Anxiety HRT-1Dysmenorrheal HRT-1Mastalgia HRT-3

Symptoms on Kuppefrequency of occurreoccasional, never). Scategories: vasomotoosteoarticular, and se

F-385
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year N

Study 

design

Comparison Length of Trial Population Inclusion/Exclusion Criteria

Nathorst-Bö ö s, 1997

437 in 

2 

groups

DB

RCT

HH 48 

weeks

Postmenopausal women of at least one year or using HRT more than 2 years. All participants > 53

Inclusion:1. Healthy women 2. > 1 year postmenopausal or using HRT > 2 ye3. > 53 years old at study entry4. Suffered from hot flushes and sweating5. Had BMI < 306. Had intact uterusExclusion:1. Receiving HRT < 1 month prior to study2. History of atypical endometrial hyperplasia3. Had severe metabolic or endocrine disease

Palacios, 1995 28 in 2 

groups

SB 

RCT

HH 12 

months

Menopausal women, ages 50-60, with no history of HRT, married once, in a stable marriage

Inclusion:1. Postmenopausal women2. 50-60 years old3. Intact uterus and ovaries4. Married only once and in stable relationship5. Normal bone densitometryExclusion:1. Received hormone therapy during menopaus2. Had known associated diseases

Ross, 1999 36 in 2 

groups

RCT HH 3 

months

Peri- and postmenopausal women with climacteric symptoms. Mean age 52 (45-65)

Inclusion:1. English speaking women > 45 years of age2. Intact uterus3. Amenorrhea > 3 months4. No past psychotic history nor current use of apsychotherapeutic agents5. No contraindications to estrogen therapy

F-386
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Nathorst-Bö ö s, 1997Palacios, 1995Ross, 1999

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior or 

Lifestyle 

Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

H

S

pecific Characteristics of Po

pulation

McCoy Sex Scale (Swedish version)

0/437 NR NR NR NR NR 437/437 

discontinued one month prior

7 point scale 0 0 NR NR NR NR 0 WHQIDAGCS

0/36 NR NR NR NR Smokers:

Tibolone 9/18CEE 14/18

NR 

F-387
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Nathorst-Bö ö s, 1997Palacios, 1995Ross, 1999

Main Drug type; dose;

regimen

Other Drugs type; dose; 

regimen Hot Flashes

Vaginal Dryness 

Main Outcomes

Tibolone 2.5 mg/day oral E2 2 mg/day + NETA 1 

mg/day oral

NR Improvement with 

both treatment groups. No significant difference between groups.

Tibolone 2.5 mg/day oral Calcium 500 mg/day oral NR NR Tibolone 2.5 mg/day CEE 0.625 mg/day

Norgestrol 150 mg/day12 days of cycle

No significant difference between the treatment groups on GCS.

NR 

F-388
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Nathorst-Bö ö s, 1997Palacios, 1995Ross, 1999

Mood Cognitive Somatic Urinar

y Uterine Bleeding Sexual Dysfun

Main Outcomes

NR NR NR NR NR Greater improvem

the Tibolone grouregard to the freqand enjoyment, p

NR NR NR NR NR Improved total sc

Tibolone group, p

No significant difference between the treatment groups (WHQ).

No significant difference between the treatment groups (WHQ).

No significant difference between the treatment groups (WHQ).

NR No significant difference between 

the treatment groups (WHQ).

No significant diffbetween the treatgroups (WHQ).

F-389
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Nathorst-Bö ö s, 1997Palacios, 1995Ross, 1999

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse Effects Co

NR 122 NR NRNR 4 0 NR One primary goal of 

validity of sexual queinvestigators. (10 itea 7 point scale.) 

Tibolone: 2

CEE: 6

Tibolone: 2

CEE: 4

NR

F-390
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year N

Study 

design

Comparison Length of Trial Population Inclusion/Exclusion Criteria

Volpe, 1986 113 in 

7 

groups

RCT P 6 

months

Postmenopausal women

Inclusion:1. Postmenopausal women2. Physiological menopause or hysterectomy an3. Last menstrual period occurred 1-5 years prioExclusion:1. Received hormone preparations < 8 weeks pr2. Histories or conditions which would contraindtherapy

Winkler, 2000 60 in 2 

groups

DB

RCT

HH 24 

weeks

Healthy postmenopausal women. Mean age approximately 54 (45-70)

Inclusion:1. Healthy postmenopausal women aged 45-70 2. Spontaneous menopause with last period > 3artificial menopause with FSH >30IU/LExclusion:1. Presence of cardiovascular, cerebrovascular thromboembolic disorders, hypertension, hypercliver, renal, thyroid, parathyroid or adrenal disorddependent diabetes, undiagnosed vaginal bleednot cured for > 10 years2. History or presence of hormone-dependent m3. Chronic use of medication that might affect msteroid4. Drug or alcohol abuse within last 12 months5. Use of investigational drugs with the last 3 mo6. Cigarette smoking

F-391
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Volpe, 1986Winkler, 2000

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior or 

Lifestyle 

Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

H

S

pecific Characteristics of Po

pulation

4 point scale 32/113 32/113 NR NR NR NR NR Karolinska Scale 24/60 NR NR NR NR 0 smokers NR Ti

H

F-392
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Volpe, 1986Winkler, 2000

Main Drug type; dose;

regimen

Other Drugs type; dose; 

regimen Hot Flashes

Vaginal Dryness 

Main Outcomes

1. CE 0.625mg/day for 21 days/month + NETA 5mg/day for 10 days/month2. CE 0.625 mg/day for 21days/month + CPA 12.5 mg/day for 10 days/month3. Estradiol valerate 2 mg/day for 21 days/month + NETA 5 mg/day for 10 days/month4. Estradiol valerate 2 mg/day for 21 days/month + CPA 12.5 mg/day for 10 days/month5. Estnol 2-4 mg/da

y

Placebo Improved in all 

treatment groups

NR 

Tibolone 2.5 mg/day Estradiol 2 mg/day + 

Estradiol 1mg/day + norethindrone acetate 1 mg/day

Improved in both groups. No significant difference between groups, p values not reported.

Improved in both groups. No significant difference between groups, p values not reported.

F-393
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Volpe, 1986Winkler, 2000

Mood Cognitive Somatic Urinar

y Uterine Bleeding Sexual Dysfun

Main Outcomes

NR NR NR NR NR NR NR NR NR NR No significant difference between 

treatment groups.

NR 

F-394
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Volpe, 1986Winkler, 2000

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse Effects Co

Cholesterol levels 11 NR NR Hot flushes scored o

(absent), 3 (mild), 6 (other menopausal syscale: 0 (absent) to 3 

Hemostasis measurements

Tibolone: 4

HRT: 4

Tibolone: 

HRT: 3

Weight gain T-2Sleep disturbance T-1Breast tenderness T-3.4%, HRT 25.8%Vaginal bleeding HRT-1

Climacteric symptomoutcome. Primary oueffect on clotting cas

F-395
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year N

Study 

design

Comparison Length of Trial Population Inclusion/Exclusion Criteria

Wu, 2001 48 in 2 

groups

SB

RCT

HH 3 

months

Postmenopausal women with at least one climacteric symptom. Mean age 51 (38-56).

Inclusion:1. Women who were 12-36 months postmenopa2. > 1 climacteric symptom

Yang, 1997 (abstract only)

40 in 2 

groups

RCT HH 6 

months

Women 1-3 years postmenopause Inclusion: 1. Postmenopausal women (1-3 years)

Yang, 1999 40 in 2 

groups

open 

RCT

HH 6 

months

Symptomatic postmenopausal women. CEE/MPA mean age: 52Tibolone mean age: 51

Inclusion:1. Women 1-3 years postmenopausal with signifmenopausal symptomsExclusion:1. Any of the following: known or suspected tumbone diseases; cardiovascular, cerebrovascular thromboembolic disorders; vaginal bleeding of u2. Active gastrointestinal or liver disease or gastsurgery likely to influence drug absorption3. Diabetes, renal disease, epilepsy or history of rheumatic arthritis, osteoarthritis, or other arthritseverely restricting mobility, thyroid function disodisorders4. Abuse of drugs or alcohol5. Medication use that may affect bone/calcium 6. Uncontrolled hypertension7. Heavy smokers

F-396
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Wu, 2001Yang, 1997 (abstract only)Yang, 1999

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior or 

Lifestyle 

Factors

(#/n)

Recent 

discontinuation of 

HRT

(#/n)

H

S

pecific Characteristics of Po

pulation

Mc Coy Sex ScaleGCS

NR NR NR NR NR NR NR 

GCS NR NR NR NR NR NR NR GCS NR NR NR 0 NR NR NR Ti

C22

F-397
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Wu, 2001Yang, 1997 (abstract only)Yang, 1999

Main Drug type; dose;

regimen

Other Drugs type; dose; 

regimen Hot Flashes

Vaginal Dryness 

Main Outcomes

Tibolone 2.5 mg/day oral CEE 0.625 mg/day + MPA 5 

mg/day

No significant difference between treatment groups.

Improved in Tibolone group, p<0.05 (GCS).

Tibolone 2.5 mg/day oral Premarin 0.625 mg/day oral

Provera 5 mg/day day 1-12 months oral

NR NR 

Tibolone 2.5 mg/day oral CEE 0.625 + MPA 5 mg/day 

12 days/month

Improvement in both treatment groups, p<0.05

NR 

F-398
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Wu, 2001Yang, 1997 (abstract only)Yang, 1999

Mood Cognitive Somatic Urinar

y Uterine Bleeding Sexual Dysfun

Main Outcomes

No significant difference between treatment groups

NR No 

significant difference between treatment groups

NR At 3 months, Tibolone 2/16

HRT 6/16

Improved in Tibogroup, p<0.05 (MSex Scale).

NR NR NR NR Reported for both treatment 

groups, p value not reported.

NR 

Improvement in both treatment groups, p<0.05.

Improvement in both treatment groups, p<0.05

Improvement in both treatment groups, p<0.05

NR NR Improvement in b

treatment groupsp<0.05

F-399
Appendix F. Evidence table 6-5. Key Question 3D Tibolone

Study/Year

Wu, 2001Yang, 1997 (abstract only)Yang, 1999

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse Effects Co

Hormone and 

cholesterol levels

12 7 (3 Tibolone, 

4 HRT)

Body discomfort T-3, HRT-4

Improvement of climacteric symptoms reported in both treatment groups, p value not reported.

NR NR NR

Bone metabolismBone densityCholesterol levelsEffect on endometrium.

4 NR Weight gain T-1

Uterine bleeding T-6, HRT-20Insomnia T-2, HRT-2Backache T-1, HRT-1 (All Effects in first 3 months)

F-400
Appendix F: Evidence table 6-5. Key Question 3D Tibolone

Ke

y/Abbreviation

s

BMI = Bod

y mass inde

x

BP = Blood 

pressure

CE = Conjugated estro

gens

CEE= Conjugated e

quine estro

gens

CPA = Cyproterone acetat

e

DAS = D

yadic Adjustment Scale

DB = Double blindDM = Diabetes mellitusE2 = EstradiolEE = Esterified Estro

gen

GCS = Greene Climacteric ScaleGHQ = General Health QuestionnaireHH = Head to headHRT = Hormone re

placement therapy

HTN = Hypertension

IDA = Irritabilit

y, De

pression, and Anxiet

y

LUCRS = Local Uro

genital Com

plaints Ratin

g Scal

e

MPA = Medroxyprogesterone acetat

e

NETA=norethidrone acetateNHP = Nottin

gham Health Profile

NR = Not re

ported

P = PlaceboPGWB-I = Psychological General Well-Being IndexQ-LES-Q = Qualit

y of Life, Enjo

yment and Satisfaction Questionnaire 

RCT = Randomized controlled trialSB = Sin

gle blind

SERMs = Selective Estro

gen Rece

ptor Modifiers 

T = TiboloneVTE = Venous thromboembolismWHQ = Women's Health Questionnaire

F-401
Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugs

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusi

David 1988 50 RCT P 4 20-

day 

courses

Patients from menopause clinic in Israel; aged 32-81; many postmenopausal for many years

NR

Evans 2005 80 RCT P 12 

weeks

Postmenopausal, symptomatic women. Recruited through newspapers, radio, direct mailings, and flyers posted in physicians' offices.

Inclusion:1. Natural or surgical menopaus2. > 14 hot flashes per week

Exclusion:1. Known adverse reactions to a2. Receiving estrogens, progestchemotherapy

F-402
Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugs

Study/YearDavid 1988Evans 2005

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or 

Lifestyle 

Factors*

(#/n)

d

u

HF frequency; severity of perspiration; FSH, LH, testosterone, E2

NR NR NR NR NR NR 

Modified Health Survey Short Form 36 mood scale; single-item 5-point scale about hot flashes interfrerence with daily living; daily hot flash diary (severity 1-4). 

16/80 NR NR NR NR Alcohol 

use 14/40 in controls and 25/40 in treatment

Specific Characteristics of Population

F-403
Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugs

Study/YearDavid 1988Evans 2005

Main Drug 

type; dose;

regimen

Other Drugs 

type; dose; 

regimen

Reduction in Hot Flash 

Frequency

Reduction 

in Hot 

Flash 

Severity

Reduction in Hot Flash 

Composite Score

Other 

M

Veralipride 100mg PO qd (V)

Placebo Pre-post comparisons only:

Group 1 (V x 4): 80% reported almost complete disappearance of HF.Group 2 (Px2, Vx2): HF frequency 18 at baseline; 12 with P, almost complete resolution with V.Group 3 (Vx2, Px2): baseline 15, almost complete resolution with V; up to 6-12.

NR NR 

Venlafaxine XR, 37.5mg daily for 1 week, then 75mg daily

Placebo No difference between 

groups.

No difference between groups.

No difference between groups. Both groups had reduction in HF score (no p-value given).

Venlafaxreduction perceivescore; Plreduction(single itinterferenwith daily 

Treatment Hot Flash Outcomes

F-404
Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugs

Study/YearDavid 1988Evans 2005

Other Outcomes

Vaginal 

Dryness Sleep Mood Cognitive Somatic 

All groups had decrease in insomnia and depression with no significant differences.

NR All groups had 

decrease in insomnia

All groups had decrease in depression

NR NR 

NR NR NR Mental health 

improved in tx vs. P on SF36 (p=0.005)

NR NR 

Outcomes

F-405
Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugs

Study/YearDavid 1988Evans 2005

Sexual 

Dysfunc-tion Quality of Life Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse Effec

NR NR LH, testosterone, 

Prolactin, DHEA

3 0 NR

Possibly more sexual dysfunction in tx than P (p=0.11)

Vitality improved in tx vs. P on SF36 (p=0.005)

NR 11/40 in tx; 

8/40 in P

Difficulty sleeping decreased libido, nausea and anxiety in tx group

Greater dry mouth, sleeplessness, and decreased appetite in P, but dizziness, tremanxiety, diarrhea, and less in tx than P.

Outcomes (cont.)

F-406
Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugs

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusi

LimouzinLanothe, 1994 499 Non-blind RCT HH 6 months Enrolled by 101 physicians in France; all literate and "enjoyed a 

comfortable standard of living"

Inclusion:1. Natural or surgical menopaus

months but < 3 years

2. >4 HF/day and nocturnal swe

Exclusion:1. HRT since beginning of meno2. Symptomatic TX within 1 mon3. "Estrogen-dependent patholo

Melis, 1988 40 DB RCT P 30 days Recruitment info NR; Italy Inclusion:

1. Postmenopausal women aged 2. Physiologic menopause >1 y

3. Experiencing hot flashesExclusion:1. HRT within 30 days

F-407
Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugs

Study/YearLimouzinLanothe, 1994Melis, 1988

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or 

Lifestyle 

Factors*

(#/n)

d

u

Specific Characteristics of Population

Women's Health Questionnaire, Psychological General Well-Being Index, Sleep Problems Questionnaire; Sexual Behavior Questionnaire.10 symptoms on a 4-point scale

NR NR NR NR NR Similar 

Education

1. HF frequency; HF severity (0-3); and vasomotor score (frequency x severity) by diary;2. "Objective HF" by skin temp (for 6 hours for 8 women in each group); 3. Plasma LH, FSH, PRL, E2; 

NR NR NR NR NR NR 

F-408
Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugs

Study/YearLimouzinLanothe, 1994Melis, 1988

Main Drug 

type; dose;

regimen

Other Drugs 

type; dose; 

regimen

Reduction in Hot Flash 

Frequency

Reduction 

in Hot 

Flash 

Severity

Reduction in Hot Flash 

Composite Score

Other 

M

Treatment Hot Flash Outcomes

Veralipride 100mg/day first 20 days of each month (V)

Estraderm TTS 50 and chlormandinone 1st 12 days of each month

NR NR NR 1 or no H

HRT: 18V: 94/23(p<0.001Efficacy "very gooclinician:HRT: 12V: 39/21(p<0.001

Veralipride 100mg/day (V)

Placebo NR NR Frequency (0-3) x 

intensity (0-3)V: 3.0-1.0=2 (66% red)P: 3.1-2.3=0.8 (26% red)p<0.05(note: interpreted from figure)

# of womexperienimprovemV: 17/20 P: 10/20 p<0.05

F-409
Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugs

Study/YearLimouzinLanothe, 1994Melis, 1988

Other Outcomes

Vaginal 

Dryness Sleep Mood Cognitive Somatic 

Outcomes

Measures of quality of life, sleep, sexual function, depression, anxiety, general psychological well being, somatic complaints, cognitive difficulties, social life, family life, professional life, and vitality significantly better with HRT than V, but both groups improved over 6 months

NR HRT group 

improved more than Veralipride group (p<0.001)

HRT group improved more than Veralipride group (p<0.001)

HRT group improved more than Veralipride group (p<0.01)

HRT group improved more than Veralipride group (p<0.001)

NR NR NR NR NR NR 

F-410
Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugs

Study/YearLimouzinLanothe, 1994Melis, 1988

Sexual 

Dysfunc-tion Quality of Life Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse Effec

Outcomes (cont.)

HRT group improved more than Veralipride group (p<0.01)

Clinical efficacy for measures of quality of life, sleep, sexual function, depression (general psychological well being) all significantly better with HRT but both groups improved over 6 months

Attractiveness, social life, and vitality all improved more in the HRT group than in Veralipride group

No follow-up data in 10/250 of HRT and10/249 of V;Discontinued TX: 21 of HRT and 36 of V.

NR HRT: 67 local skin re

26 systemic reactionV: 23 systemic react

NR NR LH levels opioids

Veralipride group had increased PRL and LH

0 NR 0 in placebo group

3 mastodynia in Veragroup

F-411
Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugs

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusi

Stearns, 2003 165 DB RCT P 6 weeks Menopausal women (recruited 

from 17 US sites using newspaper ads, women's groups and professional referral networks)

Inclusion:1. Women over 18 years2. Menopausal a. Amenorrhea > 12 months

 b. 6 months amenorrhea with or  c. Surgical menopause3. 2-3 hot flashes/day or > 14/we

Exclusion:1. Recent psychotropic medicati2. Major depression or "significasymptoms"3. HRT within 6 weeks4. Active cancer, current chemo 5. Active psychiatric disorder6. Intolerance to SSRIs7. Substance dependence

Tarim, 2002 30 DB RCT P 5 weeks Consecutive patients presenting to 

outpatient menopause clinic of U in Turkey

Inclusion:1. Aged 35-55 years2. Post menopausal with ameno3. FSH > 40

4. At least 14 hot flashes a weekExclusion:1. CAD2. Any psychiatric disorders

F-412
Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugs

Study/YearStearns, 2003Tarim, 2002

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or 

Lifestyle 

Factors*

(#/n)

d

u

Specific Characteristics of Population

Daily hot flash composite score (frequency x severity; severity is 1-4); Greene Climacteric Scale 21; sleep disturbance Visual Analogue Scale; Beck anxiety inventory II; Sheehan Disability Scale; Clinical Global Impression global improvement item.

50/165 25/165 NR 12/165 12/165 NR 

HF weekly severity score (frequency x severity 1-4)

NR P: 4/9

M 150: 

1/10

M 300: 

4/11

NR NR NR NR 

F-413
Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugs

Study/YearStearns, 2003Tarim, 2002

Main Drug 

type; dose;

regimen

Other Drugs 

type; dose; 

regimen

Reduction in Hot Flash 

Frequency

Reduction 

in Hot 

Flash 

Severity

Reduction in Hot Flash 

Composite Score

Other 

M

Treatment Hot Flash Outcomes

Paroxetine 12.5Paroxetine 25

Placebo Paroxetine 12.5 = 3.3

Paroxetine 25 = 3.2Placebo = 1.8(p=0.01)

NR Paroxetine 12.5 = 62.2%

Paroxetine 25 = 64.6%Placebo = 37.8% (p<0.03)

Meclopomide 150mg (M 150) or 300mg (M 300)

Placebo NR NR "Weekly severity score" 

(frequency x severity 1-4)Mean reduction:M150: 69.8%M300: 35.0%P: 24.4%;no p-value given

Decreasthan 50% composiM150: 8M300: 5/P: 2/9 (2no p-valu

F-414
Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugs

Study/YearStearns, 2003Tarim, 2002

Other Outcomes

Vaginal 

Dryness Sleep Mood Cognitive Somatic 

Outcomes

No significant difference in sleep, depression, anxiety, sexual interest, or disability for the groups

NR

Adjusted mean 

difference from baseline in sleep disturbance VAS:12.5mg: -1.38, 25mg: -1.6 P: -1.0 (not significant)

Depression (BDI-I) 12.5mg: -0.73; 25mg: -0.006; P: -0.33 (not significant); Anxiety (BAI-II) 12.5mg: -0.7325mg: -1.23P: -1.11 (not significant)

NR NR 

NR NR No sleep 

disturbances reported by any group

NR NR NR 

F-415
Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugs

Study/YearStearns, 2003Tarim, 2002

Sexual 

Dysfunc-tion Quality of Life Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse Effec

Outcomes (cont.)

Sexual Interest GCS 12.5mg: -0.0225mg: -0.02P: -0.07 (not significant)

NR Global climacteric 

score improvedDisability (SDS):12.5mg: 0.8325mg: 0.01P: 0.06 (not significant)

12.5mg: 7/51 25mg: 14/58P: 5/56 

12.5mg: 

4/51; 

25mg: 8/58; 

P: 2/56 

Headaches, dizzinesnausea, dyspnea, insconstipation, lethargysomnolence - none significant difference placebo.

NR NR NR 1 in P and 1 

in M due to somnolence

1 in P and 1 in M due to somnolence

Somnolence: 1 in eacgroup; No dizziness, nausea, sleep disturb

F-416
Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugs

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusi

Wesel, 1984 43 DB RCT HH 20 days Women attending a OB-GYN 

hospital in France

Inclusion:1. Aged 40-60 years2. Spontaneous amenorrhea > 6 

Exclusion:1. Genital or mammary cancer2. Oophorectomy3. HRT within 30 days

Zichella, 1986 75 (5 

groups 

of 15)

RCT HH 20 days Postmenopausal women 

Recruiting information NRAged 45-55

Inclusion:1. Physiologic menopause 1-2 y2. Severe vasomotor symptomsExclusion:1. Endocrinologically active drug

F-417
Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugs

Study/YearWesel, 1984Zichella, 1986

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or 

Lifestyle 

Factors*

(#/n)

d

u

Specific Characteristics of Population

HF frequency; HF severity (1-4); HF duration (1-6); 

0 0 NR 0/43 NR NR > 

d

HF frequency (0-3); HF severity (0-3); 

0 0 NR NR NR NR 

F-418
Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugs

Study/YearWesel, 1984Zichella, 1986

Main Drug 

type; dose;

regimen

Other Drugs 

type; dose; 

regimen

Reduction in Hot Flash 

Frequency

Reduction 

in Hot 

Flash 

Severity

Reduction in Hot Flash 

Composite Score

Other 

M

Treatment Hot Flash Outcomes

Veralipride 100mg/day (V)

CEE 1.25mg V: 54.1-15.6 = 38.5 (71% 

reduction)CEE: 65.2-14.0 = 51.2 (79% reduction)Not significant

NR # x intensity (1-4)

V: 73-17=56 (77% red.)CEE: 108-18=90 (83% red.)Not significant

Veralipride 100mg qd (V)

Bromocriptine 3.75; Liposom 40mg Imqd; domperidone 10mg qd

NR NR HF score: V: 3.5 + 0.3 

to 1.2 + 0.1; P: 3.0 + 0.2 

to 2.4 + 0.1 (p<0.05)

F-419
Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugs

Study/YearWesel, 1984Zichella, 1986

Other Outcomes

Vaginal 

Dryness Sleep Mood Cognitive Somatic 

Outcomes

NR NR NR NR NR NR NR NR NR NR NR NR 

F-420
Appendix F. Evidence table 6-6. Key Question 3E Antidepressant drugs

Study/YearWesel, 1984Zichella, 1986

Sexual 

Dysfunc-tion Quality of Life Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse Effec

Outcomes (cont.)

NR NR NR 3 in CEE 

group

NR V: 2 mastodynia, 2 se

4 headache, 3 nauseasthenia, 1 pelvic pavenous disorderCEE: 4 sedation

NR NR NR 0 0 V: mastodynia 10; 

galactorhea 2. 0 with placebo

F-421
Appendix F: Evidence table 6-6. Key Question 3E Antidepressant drugs

Ke

y/Abbreviation

s

AE = Adverse Effect

BAI-II = Beck Anxiety Inventory II BCT = BromocriptineBDI = Beck Depression Inventor

y

BMI = Bod

y mass inde

x

CAD = Coronary artery diseas

e

CEE= Conjugated e

quine estro

gens

DB = Double blindDHEA = Dehydroepiandrosteron

e

DOM = DomperidoneE2 = EstradiolGCS = Greene Climacteric ScaleHF = Hot flashHH = Head to headHRT = Hormone re

placement therapy

NR = Not re

ported

P = PlaceboRCT = Randomized controlled trialSDS = Sheehan Disability Scal

e

SERMs = Selective Estro

gen Rece

ptor Modifiers 

SF-36 = Modified Health Survey Short Form 36 SSRI = Selective Serotonin Reuptake Inhibitor

tx = TreatmentVAS = Visual Analogue Scal

e

F-422
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/ex

Andersen 1986 40 DB RCT 

with 

crossover

P Unclear.

1 week run-in. 2 week wash-out then cross-over. Each treatment period could last up to 8 weeks total or until "troublesome side effects".

Women experiencing hot flushes in the climacteric.Mean age 51 years (range 46-60).Duration of symptoms 0.5-16 years (mean 4 years).Norway

Bergmans 1987

71 DB RCT

(meds 

were 

randomized)

P 8 weeks

(4 week open study followed)

Women reporting hot flashes and sweats. No mean age reported.Patients from 3 general teaching hospitals.Netherlands.

Description of women inAll reported hot flushes a

several other somatic coExclusion:ovariectomized patients, conditions

F-423
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearAndersen 1986Bergmans 1987

Measures

Hysterectomy

+/- UO 

(#/n)

Hysterectomy

BSO

(#/n)

BSO

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Rec

discontin

H

(#

Patients recorded the number of hot flashes experienced daily (run-in week and last week of each treatment period).Visual analogue scales used to denote trouble caused by hot flashes and general well-being.Interviewed about side effects and which treatment they preferred.Labs: creatinine, AST, ALT, GGT< WBC, Hgb, Direct Coombs', blood pressure, weight.

NR NR NR NR None 9/40 had pr

been treatehormones. treatment foflushes for prior to enropatients on estrogen dr

Body weight, blood pressure.Symptoms rated as absent, slight, moderate, or severe.Efficacy rated by participant and investigator as poor, fair, acceptable, good or excellent.

NR Ovariectomized 

patients excluded.

Excluded NR NR N

Specific Characteristics of Population

F-424
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearAndersen 1986Bergmans 1987

Main Drug type; dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes (correc

Alpha-Methyldopa 375 mg tab nightly, increased by 1 tab every 2 weeks as needed to maximum dose of 1,125 mg nightlyDose adjusted every 2 weeks if needed to maximum dose then maintained for 4 weeks. 

Placebo Prior to crossover:

No difference in median number between M Improved number of hot flashes for both P (1pNR).Summary statistics:M group felt less troubled by hot flashes than General well-being was slightly disfavors M (

Bellergal Retard (BR) 1 tablet twice dailyBR = 0.6 mg ergotamine, 40 mg Phenobarbital, 0.2 mg levorotatory alkaloids

Placebo Decrease in mean number for both BR and P

between BR and P (p<0.001) at week 12.

Decrease in severity for both BR and P. No between BR and P at week 12.Decrease in sweating for both BR and P. No between BR and P (p<0.001) at week 12.

Treatment

F-425
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearAndersen 1986Bergmans 1987

Hot Flashes

Vaginal 

Dryness Sleep Mood Soma

No significant difference between alpha-methyldopa and placebo in median number of hot flashes. Patients on alpha-methyldopa felt less troubled by hot flashes (p<0.05).

NR NR NR NR 

Similar number of baseline hot flashes, mean 14.48/day for BR and 14.55/day for P.The mean number of hot flushes decreased in both BR and P. The only significant difference between BR and P was noted at week 2 (p<=0.001).Hot flush severity decreased in both BR and P. The only significant difference between BR and P was noted at week 2 (p<=0.008).Sweating decreased in both BR and P. The only significant difference between BR and P was noted at week 2 (p<=0.04).

NR Insomnia was 

improved for both BR (p=0.002) and P (p=0.03).Statistically significant differences between BR and P for insomnia were only seen at weeks 2 and 4. (BR 

Statistically significant decreases in nervousness and hyperirritability were noted for BR and P. No significant between group differences.

Statisticasignificancrease in 

ache, pathesia, adizziness noted for No signifdifferencbetween and P.

Main Outcomes

F-426
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearAndersen 1986Bergmans 1987

QoL Other Outcomes Withdrawals

Withdrawals 

due to AEs

W

A

No significant difference in feeling of wellbeing (tendency is to feel worse on M).

No significant change in blood pressure or body weight.No abnormal hematological measures.

16/40(14 dropouts and 2 excluded because flushing not severe enough)

8/40 (4 M, 4P)drowsiness, dry mouth, headache, skin rash

"Substanwith M.drowsineand depr

NR Overall efficacy assessed by 

participant and investigator at the end of the double blind and open study. BR was assessed as excellent or good in 51% of cases, placebo 21%, the difference was statistically significant in favor of BR.

33/715 dropped out for personal reasons prior to starting treatment, 12 dropped out from BR and 16 from P.

10/33 BR group6/33 P group

19/33 in Badverse r18/33 in P adverse r

Main outcomes (cont.)

F-427
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearAndersen 1986Bergmans 1987

Adverse Effects Reported Comments Overall findings

Distribution of symptoms appears quite different for drop-outs than for those completing the study.

Measures questionable. The authors conclude that M is efficacious for hot flashes. However, there was no difference in the number of hot flashes and overall it appears that participants tended to feel worse when on M. What is the significance of a visual analog score of the degree to which you are troubled by hot flashes? This measure and 62.5% participant preference for M is what drives the author's conclusion.

Question-able benefit for M with significant side effects noted.

Complaints included dry mouth, dizziness, sleepiness, headache, and nausea.

Early in the study some benefit of BR over P noted but effect gone by the end of the 8 week trial.

Bellergal was not more effective than placebo.

F-428
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/ex

Bolli 1975 12 DB RCT 

with 

crossover

P 2 trials 4 weeks 

each;2 weeks C or P then cross-over (n=12);2 weeks higher dose C or P then cross-over (n=8)

Hypertensive women with menopausal flushing.Duration of flushing was 1-16 months (mean 4 months).Mean age 51 years.Dunedin Hypertension Clinic, New Zealand

Carranza-Lira 2001

75

(5 

groups 

15 each)

SB RCT HH 3 months Healthy postmenopausal 

(> 1-5 years) women with vasomotor symptoms and insomnia.No hormones or other treatment for hot flushes, FSH and estradiol in the postmenopausal range. Mean age not reported.Mexico

F-429
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearBolli 1975Carranza-Lira 2001

Measures

Hysterectomy

+/- UO 

(#/n)

Hysterectomy

BSO

(#/n)

BSO

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Rec

discontin

H

(#

Specific Characteristics of Population

Daily number of hot flushes, changes in the severity and duration of hot flushes (more, same, less), severity of concomitant perspiration.Side effects.

NR NR NR NR NR None had 

Number of hot flashes per day, intensity of hot flashes on visual scale 0-10, duration in minutes, insomnia and sweating (absent or present).

NR NR NR NR NR None had u

other tre

their sy

F-430
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearBolli 1975Carranza-Lira 2001

Main Drug type; dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes (correc

Treatment

C 0.0375 mg tab twice daily for first trialC 0.075 mg tab twice daily for second trial

Placebo Prior to crossover:

NRSummary statistics:Results were the same for Trials 1 and 2.No significant difference in mean number betNo significant difference between C and P in 

C 0.10 mg tab every 12 hours CEE 0.0625 mg tab daily 

(hysterectomized patients only)propranolol 20 mg tab every 12 hoursveralipride 100 mg tab daily from Monday-FridayPlacebo tab every 12 hours

F-431
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearBolli 1975Carranza-Lira 2001

Hot Flashes

Vaginal 

Dryness Sleep Mood Soma

Main Outcomes

Appears that data presented compares patients' Clonidine trials to their placebo trials.No significant difference in mean # of hot flashes between P and C in trial one or two, although both showed significant decrease from baseline.

NR NR NR NR 

Hot flash frequency decreased in the CEE and C groups compared to the propranolol, veralipride and placebo groups.Hot flash intensity and duration in CEE users decreased in comparison to the other four groups.Hot flash intensity was lower in C compared to propranolol and P.The presence of sweating was lower in CEE and C compared to propranolol and P.

NR Insomnia 

presence was greater in the propranolol group when compared to CEE, clonidine and veralipride. Frequency of presentation of insomnia was greater in propranolol than in CEE and C.

NR NR 

F-432
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearBolli 1975Carranza-Lira 2001

QoL Other Outcomes Withdrawals

Withdrawals 

due to AEs

W

A

Main outcomes (cont.)

NR No change in blood pressure with 

C.

None None 

NR NR 4/75

(1 CEE, 2 propranolol, 1 veralipride)

2/75 (1 CEE and 1 veralipride for drug intolerance)

F-433
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearBolli 1975Carranza-Lira 2001

Adverse Effects Reported Comments Overall findings

Nausea in 1 patient on C. Data not reported clearly. Summary 

states significant difference between C and P at higher dose C (150 mcg), but discussions states results of this trial did not reach statistical significance.

No difference between clonidine and placebo.

NR Method of randomization not 

disclosed. States patients with contraindication to CEE were randomly distributed to the other 4 four groups. No statement that the patients were blinded.Limited information given. Summary table is essentially uninterpretable.

F-434
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/ex

Clayden 1974 100 DB RCT 

with 

crossover

P 9 weeks

(1 week of no treatment to assess baseline then4 weeks C or P then cross-over)

Women with menopausal flushing of sufficient severity to warrant treatment.Duration of flushing ranged from two weeks to 23 years.42 received C first

Inclusion:1. No other complicating 

Edington 1980 93 DB RCT 

crossover

(4 weeks 

C or P 

then 

cross)

P 16 weeks

(4 phases each 4 weeks, first 2 trials conducted by the same investigator)

Women with dilatation of blood vessels in all areas of the skin and profuse sweating. Mean age 47 years (range 27-71).

Inclusion:1. Dilatation of blood vesand profuse sweating. 2. > 30 attacks per week

3. Symptoms for > 3 mo

Exclusion:1. Other interfering illnes

F-435
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearClayden 1974Edington 1980

Measures

Hysterectomy

+/- UO 

(#/n)

Hysterectomy

BSO

(#/n)

BSO

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Rec

discontin

H

(#

Specific Characteristics of Population

Patient diary recording each attack of flushing.Nine visits throughout trial. At each visit, questions were asked about frequency, severity, and duration of attacks. 5 point scale ("much more" to "much less").Side effects question "Any problem with the tablets?"Blood pressure/pulse.

NR NR NR NR NR States all p

medication was stoppebefore entry 

Patient diary of the time, extent, severity and duration of flushing, and side effects.Blood pressure, pulse.

NR NR 10/66 NR NR N

F-436
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearClayden 1974Edington 1980

Main Drug type; dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes (correc

Treatment

C 0.025 mg tabs 1 twice daily, increased to maximum of 3 tabs twice daily depending on effect or presence of side effects.

Placebo Prior to crossover:

No difference in mean change from baseline between C and P (p=0.7)*.Summary statistics:Greater reduction in number while on C(C first p<=0.05, P first p<=0.001).Compared to their own P trial, the number of scores of frequency, severity, and duration w(p=0.1, p=0.05, P=0.01).P response greater in those with flushing for <1 year (p NR).

C 0.05 mg twice daily Placebo Prior to crossover:

NRSummary statistics:Mean number of flushing attacks (averaged osignificantly lower with C therapy (p<0.05).Subjective assessment of frequency, severityas much less or less in (50-89%) of all particcrossover.

F-437
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearClayden 1974Edington 1980

Hot Flashes

Vaginal 

Dryness Sleep Mood Soma

Main Outcomes

Appears that data presented compares patients' Clonidine trials to their placebo trials, rather than doing the two trials separately.Reduction in number of hot flashes was greater during clonidine period than placebo period (C first p<=0.05, P first p<=0.001).During first treatment period, more patients on C than P improved in scores of frequency, severity, and duration (p values listed by week). During the second treatment period, there was no difference between C and P.Greater placebo response noted in those with flushing for less than 1 year.

NR NR NR NR 

Mean number of flushing attacks (averaged over all 4 trials) was significantly lower with C therapy (p<0.05).

NR NR NR NR 

F-438
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearClayden 1974Edington 1980

QoL Other Outcomes Withdrawals

Withdrawals 

due to AEs

W

A

Main outcomes (cont.)

NR Blood pressure and pulse. No 

significant changes over the study period (p NR).

14 excluded for several reasons (Table 1). 4/14 were for side effects

3C,1P

NR Blood pressure and pulse. No 

significant changes over the study period (p NR).

27/936 due to symptoms, 1 nonmedical, 8 lost to follow up, 12 patients did not keep proper diaries 

6/93 2/93 on P 

1 double withdrew depressionausea)

F-439
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearClayden 1974Edington 1980

Adverse Effects Reported Comments Overall findings

56 participants reported side effects. 34 while on C, 36 while on P.Effects nonspecific (Table V) and "well distributed" between C and P except dry mouth which was more frequent on C.

No stats provided prior to cross-over. No significant 

difference between C and P prior to crossover. After crossover, C was more effective than P in reducing number of hot flashes.

Headache 12C, 10PDry mouth 11C, 4PInsomnia 8C,4PFatigue 3C, 5PNausea 2C, 3POther 30C, 28P(p NR)

Study done in 4 trials of 4 weeks each. Trial 3 was a single-blinded placebo only trial. "The findings were averaged" from the 4 trials.I don't think this study can be used. 

Clonidine was more effective than placebo. However, statistical method is questionable.

F-440
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/ex

Gerdes 1982 38

(15/38 

defaulted)

There 

were 

also 10 

asymptomatic 

controls

DB RCT HH 20 weeks Menopausal women with symptoms. 

No mean age noted.Climacteric Clinic Johannesburg Hospital

Inclusion: 1. Elevated FSH (>18mI2. Hot flushesExclusion:1. Several medical cond

F-441
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearGerdes 1982

Measures

Hysterectomy

+/- UO 

(#/n)

Hysterectomy

BSO

(#/n)

BSO

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Rec

discontin

H

(#

Specific Characteristics of Population

South African Personality Questionnaire, Leckie-Withers Test of Liability to Depressive Illness, Bem Sex Role Inventory, Items from Uken Motherliness Test, Mini-Biography Questionnaire, subjective assessment concerning pretreatment to post treatment change on 5 point scale.

NR NR NR Excluded NR N

F-442
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearGerdes 1982

Main Drug type; dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes (correc

Treatment

Opposed Estrogen group: CEE 1.25 mg daily for 21 days + medrogestone 5mg daily from day 16 to 21, then 7 days off, + placebo C 2 tab twice daily for 28 days

C group:placebo CEE daily 21 days + placebo medrogestone days 16-21, then 7 days off, + C 0.025 mg 2 tab twice daily for 28 days

Reported in Sonnendecker 1980

F-443
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearGerdes 1982

Hot Flashes

Vaginal 

Dryness Sleep Mood Soma

Main Outcomes

Reported in Sonnendecker 1980 NR NR Significant decrease in MBQ 

depression score for CEE compared to C (p<0.05). A significant decrease in indirect and direct depression, MBQ depression and anxiety scores was seen in CEE but not C (p<0.05). 

NR 

F-444
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearGerdes 1982

QoL Other Outcomes Withdrawals

Withdrawals 

due to AEs

W

A

Main outcomes (cont.)

NR 38 women entered the study 

but 15 defaulted (7 from estrogen and 8 from clonidine group) leaving only 23 remaining.

NR 

F-445
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearGerdes 1982

Adverse Effects Reported Comments Overall findings

NR 10 asymptomatic postmenopausal 

controls (not included in n)

Only estrogen/progesterone combination was associated with improvement in measures of depression and anxiety (p<0.05).

F-446
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/ex

Guttuso 2003 59

(246 

screene

d 187 

were 

ineligible

)

DB RCT P 12 weeks

(followed by a 5 week open-label treatment phase)

Postmenopausal women with hot flashes. Mean age 52.7 G, 53 P.Randomization was stratified by surgical menopause status.Recruited by advertisement.New York

Inclusion:1. Average > 7 hot flash

sweating2. Amenorrhea for > 12 with FSH>40 mIU/mL anstatus post bilateral oopExclusion:multiple 

Hammond 1984

10 DB RCT 

with 

crossover

P 14 weeks

(1 week baseline, 4 weeks study drug, 1 week baseline, 4 weeks alternate medication)

Menopausal women with vasomotor symptoms.Mean age 45.6 years (range 36-54).7 natural menopause, 3 surgical menopause (6 months to 6 years post menopause).North Carolina

All women had > 30 vas

serum FSH > 40 mIU/m

States women were "noand had no medical con

F-447
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearGuttuso 2003Hammond 1984

Measures

Hysterectomy

+/- UO 

(#/n)

Hysterectomy

BSO

(#/n)

BSO

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Rec

discontin

H

(#

Specific Characteristics of Population

4 patient clinic visits, bimonthly phone calls and patient diaries.Serum FSH and estradiol, LH, CBC with differential, platelets, chemistry-14 panel, phosphate. Vitals signs, height, weight.Hot flash diary of frequency and severity (scale 1-7) symptoms noted at occurrence. Composite hot flash score,Pittsburgh Sleep Quality Index, Profile of Mood States, Short Form-36 Health Survey, Patient Global Impression of Change Scale. Adverse events.

NR NR 8/30 G

6/29 P

NR 1/30 G

5/29 P

States coulHRT, leuprotamoxifen fprior to stud

Diary of number of vasomotor flushes and objective 5 hour study periods of continuous temperature monitoring and sampling for serum LH.

NR NR NR NR NR States no H

for 6 monthstudy.

F-448
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearGuttuso 2003Hammond 1984

Main Drug type; dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes (correc

Treatment

G 300 mg tab 3 times daily (900 mg daily).Participants allowed to decrease dose if side effects.In the open label trial the dose of G could be increased to maximum of 2700 mg/day.

Placebo Statistically significant decrease between G a

weeks 4 (p=0.03) and 12 (p=0.02) and comp(p=0.01) and 12 (p=0.01). Results not altered by adjusting for baseline duration of hot flashes and Total Mood Distu

Methyldopa 250 mg tab twice daily, increased after 1 week to 3 times daily

Placebo Prior to crossover:

Both M and P resulted in decrease in hot flasdifference in mean decrease in number betwSummary statistics:Compared to baseline, significant decrease iNo significant difference in objective measure

F-449
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearGuttuso 2003Hammond 1984

Hot Flashes

Vaginal 

Dryness Sleep Mood Soma

Main Outcomes

Statistically significant decrease between G and P in hot flash frequency at weeks 4 (p=0.03) and 12 (p=0.02) and composite score at weeks 4 (p=0.01) and 12 (p=0.01). Results not altered by adjusting for baseline group differences in duration of hot flashes and Total Mood Disturbance scores.

NR Pittsburgh 

Sleep Quality Index improved with G at week 4 (p=0.01) but not at week 12 (p=0.09).

No significant difference between G and P in Profile of Mood States.

NR 

In the first study period (i.e. before crossover) there was no significant difference between M and P in mean decrease of hot flashes.In the second study period there was a significant decrease in vasomotor flushes for M but not P (p<=0.02).Objective measures of hot flashes by skin temperature changes did not show any significant difference in either treatment phase.

NR NR NR NR 

F-450
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearGuttuso 2003Hammond 1984

QoL Other Outcomes Withdrawals

Withdrawals 

due to AEs

W

A

Main outcomes (cont.)

No significant difference between G and P in Short Form-36 Health Survey.

No significant difference between G and P in Patient Global Impression of Change Scale. Several lab studies done. Significant differences were seen in albumin, total protein, total bilirubin, blood urea nitrogen, and platelets.

5 withdrawals from doubleblind study, 4 withdrawals from open-label study

4/30 in G (dizziness, rash, heart palpitations, and peripheral edema)1/29 in P (diarrhea)Two withdrawals for AE's from the open- label study (dizziness, peripheral edema).

NR Statistically significant decrease in 

the mean number of LH peaks per hour during M therapy (p<=0.05).

1/10 1/10 No side e

1 patient like rash.Fatigue, wnausea wpatients.Bradycarhypotens

F-451
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearGuttuso 2003Hammond 1984

Adverse Effects Reported Comments Overall findings

Somnolence, dizziness, rash and peripheral edema were reported in G but not P.15 (50%) in G and 8 (27.6%) in P reported at least one adverse event.

A few patients were taking raloxifene or antidepressants during the study.81.5% of patients requested to continue G after completion of the open-label study.

G was more effective than P throughout the study.

"Significant side effects occurred in 6/10 patients receiving methyldopa."

Authors conclude that "because of significant side effects and minimal symptomatic improvement, M is not likely to be an acceptable therapy."

No significant effect of M. Significant side effects.

F-452
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/ex

Lindsay 1978 100 DB RCT 

with 

crossover

P 13 weeks (6 

weeks P or C then cross-over, 1 week free in between)

Menopausal women with symptoms. States all experienced "natural" menopause.Mean duration of symptoms 1.6 years (1 month-5 years).Mean age 46.4 years (35-60)Patients selected from referrals on a random basis. Glasgow.

Nagamani 1987

30 DB RCT P 10 weeks

(2 weeks to assess baseline, 8 weeks C or P)

Symptomatic women (6 spontaneous menopause, 24 surgical).Mean age 41 (range 25-58)Texas

Exclusion:1. Previous treatment wi2. Other medical exclusi

Nappi 1991 35

(5 

groups 

of 7 

each)

RCT HH 4 weeks Menstruating women undergoing 

TAH-BSO for benign indications.Mean age 43.5 years (range 30-50)

Not more explicitly spec

F-453
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearLindsay 1978Nagamani 1987Nappi 1991

Measures

Hysterectomy

+/- UO 

(#/n)

Hysterectomy

BSO

(#/n)

BSO

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Rec

discontin

H

(#

Specific Characteristics of Population

No diaries. Interviews at weeks 4, 7, and 12.Blatt Menopausal Index (4 points scale).Flushing attacks assessed separately (4 point scale).Kellner and Sheffield rating scale for psychological symptoms.

NR NR NR NR NR # NR, state

treatment ostopped at weeks befo

Patient diary noting occurrence of hot flashes and side effects of treatment.

At visit, patients were questioned about

frequency, severity (decrease or same), and duration (decrease or same) of hot flashes.Blood pressure, pulse, LH levels.

NR NR 24/30 NR NR NR, states 

treatment fosymptoms f30 days beinclusion

Plasma LH and FSH.Patient diaries of frequency (0, <5/day, >5-<10/day, >10/day scored 0-3) and intensity of hot flushes (0, mild, moderate, severe scored 0-3).

None 35/35 35/35 NR NR N

F-454
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearLindsay 1978Nagamani 1987Nappi 1991

Main Drug type; dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes (correc

Treatment

0.025 mg tab, 2 tablets twice daily, increased to 2 tabs three times daily after 1 week if needed

Placebo Prior to crossover:

Significant decrease in Blatt score for C (p<0flush score for C (p<0.005) and P (p<0.001).No significant difference between C and P on Summary statistics:After crossover, no significant improvement ino difference between C or P.

C Transdermal 0.1 mg/day, patch changed weekly

Placebo No significant difference between C and P in 

(p=0.28)* and 8 (p=0.25)*.

Significant decrease in mean number for C (pweek 8.Proportion of women reporting a decrease in (p<0.04), severity (p<0.04), and duration (p<than P.

C 0.075 mg tab twice daily Sodium Valproate 200 

mg tab twice dailyLisuride 0.2 mg tab twice dailyTransdermal 17B estradiol 0.050 mg dailyplacebo

Hot flash frequency and intensity were lower and Lisuride treated groups compared to P (p

F-455
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearLindsay 1978Nagamani 1987Nappi 1991

Hot Flashes

Vaginal 

Dryness Sleep Mood Soma

Main Outcomes

Blatt Menopausal Index. Significant decrease in first 6 weeks for C (p<0.05) and P (p<0.05). No difference between C and P."Flushing attacks".Significant decrease in first 6 weeks for C (p<0.005) and P (p<0.001)No difference between C and P.

NR NR Kellner and 

Sheffield initial scores higher in women with menopausal symptoms for >1 year (p<0.01) compared to those with symptoms for < 1 year

NR 

Mean number of hot flashes significantly decreased from baseline at each weekly assessment (p<0.001-0.03) for C and only at weeks 5 (p<0.05), 6 (p< 0.05), and 8 (p<0.04) for P. (Results for direct comparison of C and P NR, graphic display only.)Subjective comparison of frequency (decrease or same) (p<0.04), severity (p<0.04), and duration (p<0.03) of hot flushes significantly decreased in the clonidine compared to the P groups.

NR NR NR NR 

Hot flash frequency and intensity were lower in the estradiol, clonidine, and Lisuride treated groups compared to P (p<0.01). 

NR NR NR NR 

F-456
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearLindsay 1978Nagamani 1987Nappi 1991

QoL Other Outcomes Withdrawals

Withdrawals 

due to AEs

W

A

Main outcomes (cont.)

NR NR 62/100 2 2 withdra

mouth an

NR LH levels measured in 2 

participants without C and after 2 weeks of C. No change in LH pulsatile secretion noted with C.No significant changes in blood pressure and pulse.

1/30 (excluded from analysis, dropped out after 2 weeks of treatment)

None 

NR FSH, LH levels NR NR 

F-457
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearLindsay 1978Nagamani 1987Nappi 1991

Adverse Effects Reported Comments Overall findings

2 reported nocturia on C, 1 reported nausea on P

100 initially to be included. States only 41 completed treatment in the trial. Three additional withdrawals noted, one did not return after initial assessment, 2 withdrew because of side effects. Results are reported for the remaining 38.

No difference between clonidine and placebo.

Skin reactions (erythema and/or itching) 4C, 3 P(no dryness of mouth or dizziness reported)

How useful are the results of limited subjective measures? 

C was more effective than P in subjective measures but not for mean decrease in number of hot flashes.

NR All treatments started on the first day 

after surgery.Method of randomization not disclosed. No report of blinding. One small paragraph on hot flash results, more time spent discussing LH/FSH results.

Estrogen, clonidine, and Lisuride decreased hot flash frequency and intensity compared to placebo.

F-458
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/ex

Nesheim 1981 40 DB RCT 

with 

crossover

P Not clearly stated 

but inferred; 1 week baseline; 30 day M or P then 14 day washout then cross-over

Women with menopausal hot flushes.Mean age or age range NR.Patients referred by General Practitioners in Akershus County, Norway.

Exclusion:1. Use of antihypertensivsedating drugs 

Salmi 1979 40 DB RCT 

crossover

(not true 

RCT, 

medication 

packs 

made in 

random 

order)

P

each 

patient 

is her 

own 

control

12 weeks,cross-over at 6 weeks

Women with menopausal symptoms. 10 still menstruating, 18 spontaneous menopause. Mean age 50.5 years (range 41-57).Mean duration of symptoms 21.5 months (range 1-131 months).Outpatients from Department of Ob/Gyn, University Central Hospital, Finland.

Inclusion: 1. Hot flushes, sweating

F-459
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearNesheim 1981Salmi 1979

Measures

Hysterectomy

+/- UO 

(#/n)

Hysterectomy

BSO

(#/n)

BSO

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Rec

discontin

H

(#

Specific Characteristics of Population

Patient recorded number of hot flashes per day. Patients were contacted weekly by phone and asked to use a VAS to record degree they were troubled by hot flashes.Blood pressure.

NR NR NR NR NR Participants 

allowed to testrogen fobefore the s

Patient records and visits (3).Frequency of sweating episodes/hot flushes (none, <5, >5, >10)Incidence of insomnia and depression, occurrence of possible anxiety states (none, less than before the medication, the same as before, more than before)Blood pressure, pulse, AST, cholesterol.Side effects.

 2/37 7/37 NR 1 of the 

patients was excluded at the beginning because of cancer in a mammary node.

NR N

F-460
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearNesheim 1981Salmi 1979

Main Drug type; dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes (correc

Treatment

l-methyldopa 250 mg tab twice dail

y

increased if needed to maximum of 2 tabs twice daily 

Placebo Prior to crossover:

NRSummary statistics:Median reduction in number 38% P (pNS), 6Between groups M superior to P (p=0.06 M f22 M, 15 P improved. Overall, greater reduc(p=0.004)Median improvement on VAS score 5 M, 2.4 Median improvement 77% M, 30% P.

0.025 mg tab twice daily, increased every 2 weeks by 1 tab twice daily, if needed, to max 0.075 mg twice daily

No concurrent use of HRT, psychopharmaceutics or antihypertensive.

Prior to crossover:No significant difference between C (14/20) aasymptomatic at 6 weeks (p=0.0975)*.

Summary statistics:No significant difference between C and P in NR).

F-461
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearNesheim 1981Salmi 1979

Hot Flashes

Vaginal 

Dryness Sleep Mood Soma

Main Outcomes

Median number of hot flashes per week prior to medication was 58 (14-315). 16 participants received M first, 12 P first.Median number of hot flashes for M first was 42 (14-140 and for P first was 70 (28-315). (Not reported if this was significantly different at baseline.)Hot flash frequency was reduced by both M and P, favoring M in both the first phase (p=0.06) and the second phase (p =0.01) Combined results from both phases favors M (p=0.004).Median VAS score prior to treatment 8.4 cm (2.9-10)Improvement in score was greater with M than P (p=0.002) (patients compared to themselves). Median improvement 77% with M, 30% with P.

NR NR NR NR 

Sweating and hot flushes (day and night). No statistical difference (p NR) between C and P.

NR Insomnia. No 

statistical 

difference (p 

NR) between 

C and P.

Disturbances of depression and anxiety states. No statistical difference (p NR) between C and P.

NR 

F-462
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearNesheim 1981Salmi 1979

QoL Other Outcomes Withdrawals

Withdrawals 

due to AEs

W

A

Main outcomes (cont.)

NR No significant change in blood 

pressure.

12/40 (various reasons reported)2 additional patients were unable to keep record of their hot flashes, only VAS data available

2/40 (specific effects not stated)

NR No changes in blood pressure and 

pulse during the trial.

3 were excluded from initial 40, unclear if this was prior to randomization. 1 for cancerous node, 1 for psychiatric treatment, 1 for interruption of medication.

none 

F-463
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearNesheim 1981Salmi 1979

Adverse Effects Reported Comments Overall findings

Tiredness 15 M, 3 PDry mouth 10 M, 7PSlight edema 3 MDiarrhea 1 M, 1PExanthem and Arthralgia 1 M

Some results appeared to be combined across both treatment periods (i.e. patients compared to themselves).

No significant differences between C and P in side effect occurrence.(Various side effects listed Table 1)

Serum aspartate amniotransferase and cholesterol readings were done in all and there were no elevated values noted.

No difference between clonidine and placebo.

F-464
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/ex

Sonnendecker 1980

38

(15/38 

defaulted)

DB RCT HH 20 weeks Menopausal women with symptoms. 

No mean age noted.Climacteric Clinic Johannesburg Hospital

Inclusion: 1. Elevated FSH (>18mI2. Hot flushesExclusion:1. Several medical cond

Wren 1986 19 DB RCT 

with 

crossover

P 10 weeks

(2 weeks placebo, then 4 weeks C or P then cross-over)

Postmenopausal women with symptoms (all spontaneous menopause).Mean age 50.6 (range 46-56)Menopause clinic at the royal Hospital for Women, New South Wales

Inclusion:1. Spontaneous menopa2. Symptoms > 3 month

Exclusion: 1. Hysterectomy2. Previous C or anti-hyp

F-465
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearSonnendecker 1980Wren 1986

Measures

Hysterectomy

+/- UO 

(#/n)

Hysterectomy

BSO

(#/n)

BSO

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Rec

discontin

H

(#

Specific Characteristics of Population

Mammography, hot flushes in number per day, FSH, LH, 17B-estradiol, progesterone, prolactin.

NR NR NR Excluded NR N

Frequency, severity, and duration of vasovagal symptoms. Patient diaries of number of flushes/sweats, insomnia, anxiety, libido, headache, irritability, and depression.Exam and biochemical investigation every 2 weeks.

Excluded Excluded NR NR NR Excluded if 

use C, antihypertensivsedative, tror hypnotic 

F-466
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearSonnendecker 1980Wren 1986

Main Drug type; dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes (correc

Treatment

Opposed Estrogen group: CEE 1.25 mg daily for 21 days + medrogestone 5mg daily from day 16 to 21, then 7 days off, + placebo C 2 tab twice daily for 28 days

C group:placebo CEE daily 21 days + placebo medrogestone days 16-21, then 7 days off, + C 0.025 mg 2 tab twice daily for 28 days

Mean change in number from pre- to post-triasignificantly with CEE (p<0.05) but not C.No significant difference in mean change bet

C 0.025 mg tabs 2 twice daily Placebo Prior to crossover:

NRSummary statistics:No significant difference in mean number betNo data reported for severity and duration.

F-467
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearSonnendecker 1980Wren 1986

Hot Flashes

Vaginal 

Dryness Sleep Mood Soma

Main Outcomes

Number of hot flashes experienced daily was decreased significantly in the estrogen group (p<0.05) but not in the clonidine group.

NR NR NR NR 

Crossover design, each patient is her own control.No significant difference in mean # of hot flashes. (p NR)

No change with C or P

No change in insomnia or tiredness with C

No change in anxiety, panic, or irritability with C

NR 

F-468
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearSonnendecker 1980Wren 1986

QoL Other Outcomes Withdrawals

Withdrawals 

due to AEs

W

A

Main outcomes (cont.)

NR FSH, LH, and estradiol, 

progesterone and prolactin levels were assessed. Mammography was performed.

38 women entered the study but 15 defaulted (7 from estrogen and 8 from clonidine group) leaving only 23 remaining.

NR 

NR No change in blood pressure or 

gonadotropin levels

5/19 (not included in analysis, states withdrawal due to frustration with lack of benefit)

None No adver

F-469
Appendix F. Evidence table 6-7. Key Question 3F other drugs

Study/YearSonnendecker 1980Wren 1986

Adverse Effects Reported Comments Overall findings

NR Only 

estrogen/progesterone combination was effective for decreasing hot flashes.

NR No p values reported in this paper No difference between 

clonidine and placebo.Statistical method is question-able.

F-470
Appendix F: Evidence table 6-7. Key Question 3F other drugs

Ke

y/Abbreviation

s

*p value not reported by the authors

AE = Adverse Effect

BMI = Body mass inde

x

BR = Beller

gal Retard

BSO = Bilateral Sal

pin

go Oo

phorectom

y

C = ClonidineCEE = Conjugated E

quine Estro

gens

DB = Double-blindECOG = Eastern Coo

perative Oncology Grou

p Scal

e

G = Gaba

pentin

HH = Head to headHRT = Hormone re

placement therapy

M = Meth

yldopa

MBQ = Mini-Bio

gra

phy Questionnaire 

NR = Not re

ported

P = PlaceboQoL = Qualit

y of Life

RCT = Randomized Controlled TrialSERMs = Selective Estrogen Receptor Modifiers TAH = Total abdominal h

ysterectom

y

UO = Unilateral Oo

phorectom

y

VAS = Visual Analogue Scal

e

F-471
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Aiello, 2004 173 RCT HH 12 

months

Postmenopausal women recruited from the greater Seattle area (50-75 years of age) through mass mailings and media placements.Average age 60.7 and 60.6 SD (6.6 and 6.7years). Approximately 60% had some menopausal symptoms.

Inclusion:1. Sedentary at baseline (<60 min/weevigorous exercise)2. BMI>25.0 or over 24.0 with body fatExclusion:1. Taking HRT2. Smoker

Albertazzi, 1998 &1999

104 RCT P 12 

weeks

Mean age 53, range of 48-61.Women postmenopausal requesting treatment for severe hot flushes.

Inclusion:1. > 6 months since the last menstrual 

weeks since bilateral oophorectomy w2. Seven moderate to severe hot flushsweats/24 hours during at least the lasweek prestudy period3. FSH>50 and estradiol <35Exclusion:1. HRT or any other drug for the treatmsymptoms, such as Vitamin E, clonidin

F-472
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearAiello, 2004Albertazzi, 1998 &1999

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Adherance to exercise via daily activity logs, food frequency questionnaire, information on menopause symptoms and their severity was collected at 0,3,6,9, and 12 months with a selfadministered questionnaire, which was a modified version of a questionnaire used by the Women's Health Initiative, DEXA was conducted at baseline and 12 months for leanness

13-18% NR NR NR NR NR 

Daily diary; Kupperman Index NR NR NR NR Allowed NR 

Specific Characteristics of Population

F-473
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearAiello, 2004Albertazzi, 1998 &1999

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

45 minutes of moderate-intensity exercise, 5 days/week for 12 months

Control was invitation to attend 45 minute weekly stretching session for 12 months

No change in frequency over the year

NR No 

gro

Casein 60 grams daily for 12 weeks

Soy powder (Supro Brand Protein Technologies, St. Louis, MO) 60 grams/day; this contained 76 mg of isoflavones (aglycone units)

Hot flash reduction was seen in both group (43.6 % reduction in soy group compared with 31.3% reduction in placebo group). Soy group had greater reduction than casein group at 12 weeks (p<0.01)

Vaginal maturation indices did not increase in the soy group, but did significantly increase in the casein group

Treatment Main Outcomes

F-474
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearAiello, 2004Albertazzi, 1998 &1999

Mood Cognitive Somatic Urinar

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No change in depressive feelings in either group over the year (only 13% had a baseline)

No change in either group over the year; when analyzed by time since menopause those within 5 years of menopause had a significant decrease in memory problems in the exercise group compared to the controls (OR at 6 mo=0.2; 95% CI, 0.08-0.6). This was sustained at 9 and 12 months.

NR NR NR NR 

NR NR NR NR NR NR 

Main Outcomes (cont.)

F-475
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearAiello, 2004Albertazzi, 1998 &1999

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

When analyzing the subset of moderate/severe menopausal symptoms (n=11 exercisers, 10 controls), a significant decrease in hot flashes was seen over the year in the control group (p=0.02 but not in the exercisers)

6/87 in the exercise group; 2/86 controls 

None None Mind-body Only RC

Kupperman index values as a whole did 'not change'

25/51; 11 in the soy group and 14 in the casein group

14 patients, 7 in each group dropped due to gastrointestinal side effects; lack of efficacy caused 3 patients in the casein group and 1 person in the soy group to withdraw

Gastrointestinal - constipation 48%

Biologically based therapies

F-476
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Anarte, 1998 73 RCT HH 6 

months

45-55 year old postmenopausal women with less than 3 years evolution, no previous treatment; all attending a Menopause Unit in Southern Spain

None reported other than population dthat patients in whom hormonal treatmcontraindicated were excluded

Atkinson, 2004 205 DB RCT P 1 year Women recruited from a 

breast clinic in Cambridge, UK

Exclusion:1. History of breast cancer, major brea2. Use of HRT

F-477
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearAnarte, 1998Atkinson, 2004

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Kupperman Index, plus the emotional alternation, anxiety and depression scales of the Granada Gynecological Questionnair of Salvatierra et al.

NR NR NR Those with 

contraindication to HRT excluded

NR NR 

28 day menopausal symptom diary at baseline and 12 months; severity and frequency of 21 symptoms associated with menopause

NR NR NR Excluded NR NR 

F-478
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearAnarte, 1998Atkinson, 2004

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

Transdermal estrogen with cyclical progesterone

HRT plus Psychological counseling(Education, counseling and behavioral element)

In both groups there was significant improvement in vasomotor symptoms (p<0.0001

NR Ins

sigimco(Hp=babeInssigimgro

Promensil 1/day; 26 mg biochanin, 16 mg formononetin, 1 mg genistein, 0.5mg diadzein derived from red clover

Placebo Interaction between treatment 

group and menopausal status for changes in menopausal symptom score and number of hot flashes was not statistically significant p<0.05 

NR 

F-479
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearAnarte, 1998Atkinson, 2004

Mood Cognitive Somatic Urinar

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Main Outcomes (cont.)

Combined treatment group has significant benefit in nervousness (p=0.0001), anxiety, depression, emotional alteration, melancholia (p=0.0001) over HRT only group, however, both groups had significant improvement in these parameters from baseline. HRT only nervousness (p=0.0001) and anxiety (p=0.0002); combined group both had p = 0.0001. 

NR NR NR NR NR 

NR NR NR NR NR NR 

F-480
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearAnarte, 1998Atkinson, 2004

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

Weakness and fatigue improved in combined group over HRT alone group (p=0.0001); same with palpitations. Neither group had improvement in joint and muscle pain or headache symptoms. 

NR NR NR Mind-body

NR 16/102 

withdrew from Promensil group and 12 /103 from placebo withdrew

None reported; most withdrew to go on HRT

None Biologically 

based therapies

F-481
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Baber, 1999 51 DB RCT P 7 

months

Unpaid female volunteers Inclusion:

1. Aged 45-652. > 3 hot flushes/dayExclusion:1. Intercurrent medical problems2. HRT or antibiotics in previous 3 mon3. FSH<304. Menstruation in previous 6 months5. Hysterectomy6. Vegetarian (>10g legumes per day)

Baird, 1995 97 RCT Control

Usual 

care

4 weeks Volunteers recruited through 

newspaper ads, flyers, and radio

Inclusion:1. Age less than 65 2. No menses for > 2 years

3. No use of estrogen or antibiotics > 

4. No use of prescription drugs known outcomes, such as corticosteroids. 

F-482
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearBaber, 1999Baird, 1995

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Greene Climacteric Scale Excluded NR NR NR NR Vegeta

> 10g legumeday exclude

Health habits and history questionnaire, Luteinizing hormone, follicle stimulating hormone, vaginal cytology, urinary phytoestrogen

NR NR NR NR NR NR 

F-483
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearBaber, 1999Baird, 1995

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

Promensil (Novogen Ltd, Sydney); Promensil is a standardized isoflavone supplement prepared from red clover extract in 500mg tablet form containing 40 mg/tablet; contains genistein, daidzein, biochanin, and formononetin

Placebo Greene score and flush frequency 

decreased in both placebo and active groups during the 3 months of treatment (p=0.003); no difference between groups

NR 

1/3 of calories to come from soy flour

Control was usual care diet

NR No change in 

vaginal maturation index

F-484
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearBaber, 1999Baird, 1995

Mood Cognitive Somatic Urinar

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Main Outcomes (cont.)

NR NR NR NR NR NR NR NR NR NR NR NR 

F-485
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearBaber, 1999Baird, 1995

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

Significantly different (p=<0.001) in urinary isoflavones between baseline and 3 months in the supplemented group; not the case in the placebo group

8/51 withdrew 7 withdrew for 

personal reasons; 1 withdrew for medical reasons not related to the study

NR Biologically 

based therapies

After urperformthat magroup disoflavo

No change in FSH, LH, 6/97 withdrew, 

3 were found ineligible after screening, 2 from other family emergencies and 1 could not tolerate soy foods

None None Biologically 

based therapies

F-486
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Balk, 2002 27 RCT P 6 

months

Postmenopausal women were recruited from clinics and private gynecology, family practice, and internal medicine offices in Pittsburgh. Advertisements were placed in newspapers, on radio, and on the web site for Magee-Women's Research Institute home page.

Inclusion:1. Over 40 years, postmenopausal, no for 1 year or >30 years old with BSO o2. Omnivore3. Intact uterusExclusion:1. HRT in past year2. Use of SERMs

F-487
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearBalk, 2002

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Endometrial biopsyMenopausal Symptoms Questionnaire by Brzeginski, et al

NR NR NR NR Excluded NR 

F-488
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearBalk, 2002

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

100 mg soy/cereal/day N/A No difference No difference So

ins

F-489
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearBalk, 2002

Mood Cognitive Somatic Urinar

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Sexual D

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Main Outcomes (cont.)

No difference (depression)

N/A N/A No difference N/A No differe

(decrease

F-490
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearBalk, 2002

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

Headache, palpitation, night sweats, no difference

2/13 from 

placebo and 

6/14 from the 

soy group

YesNumber not stated

Flatulence, poor taste - no improvement

Biologically based therapies

F-491
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Bellipanni, 2001 79 RCT P 6 

months

No relevant pathologies, taking no drugs, hormones or herba preparation and conducting a normal lifestyle with typical Mediterranean diet rich of carbohydrates and fresh vegetables

Inclusion:1. Age 42-62

F-492
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearBellipanni, 2001

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Questionnaire in which life habits, physiological data, data concerning previous pathologies, treatment-related side-effects, treatment-induced alterations, effects on perimenopausal symptoms (neurovegetative, sleep, psychological) werer recorded at time 0 and at 3 and 6 months. Questions concerned duration and character of their menstrual cycle and/or psychosomatic, peri- and menopause related symptoms such as irritability, morning mood and depreession, insomnia, night sweatings, headache, stypsis, amnesia, hot flushes, palpitations, and body weight increase. 

NR NR NR NR NR All non

smokerand no alcohol abuse

F-493
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearBellipanni, 2001

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

3 mg melatonin/day Placebo No significant difference between 

groups

NR No 

difgro

F-494
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearBellipanni, 2001

Mood Cognitive Somatic Urinar

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Main Outcomes (cont.)

After analysis of all answers, the evaluation of different typical perimenopause or menopause-related symptoms or alternations did not disclose a clear-cut difference between the two groups, with the notable exception of a very significant improvement of mood and complete disappearance of morning depression in the melatonintreated women. 

NR NR NR Only episodical 

improvement of regularity and duration of menstrua cycles were reported. Six menopausal women (at 1 and 2 years after total cessation of the menses) reported a re-acquisition of normal (bleeding and duration) menstrual cycles

NR 

F-495
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearBellipanni, 2001

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

Information on LH, thyroid and FSH results

NR NR NR Biologically 

based

Poor st

F-496
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Blatt, 1953 748 DB RCT 5 arms 

with 

controls 

and 

placebo

3 years Climacteric women NR

Boblitz, 2003(Abstract Only)

179 RCT P 6 weeks Women with menopausal 

symptoms

NR

F-497
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearBlatt, 1953Boblitz, 2003(Abstract Only)

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Menopausal index, a validated scale that represents a numerical conversion of the severity of the 11 most common menopausal symptoms.

NR NR NR NR NR NR 

Kupperman Menopause Index; CGI scores for anxiety, impaired drive, depressive mood and nervousness/irritability

NR NR NR NR NR NR 

F-498
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearBlatt, 1953Boblitz, 2003(Abstract Only)

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

Vitamin E 50-100mg tid (n=82) vs. ethinyl estradiol 0.05mg (n=107) vs. conjugated equine estrogen 1.25mg (n=173) vs. phenobarbital 15mg tid (n=88).

Placebo (n=298)

All results reported by menopausal 

index of which several questions pertain to vasomotor symptoms. No p values are given in paper due to date of publication. However, 66.5% of both estrogen groups had an excellent response to treatment (as compared to 13.4% of Vitamin E, 23.6% of phenobarbital and 15.6% of placebo patient)

NR 

Remifemen Plus; 20 mg black cohosh, 250 mcg of hypericin

Placebo NR NR 

F-499
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearBlatt, 1953Boblitz, 2003(Abstract Only)

Mood Cognitive Somatic Urinar

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Main Outcomes (cont.)

NR NR NR NR NR NR 

In all Greene Climacteric Index items referring to psychological symptoms, Remifemin Plus was superior to placebo (p<0.001) 

NR NR NR NR NR 

F-500
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearBlatt, 1953Boblitz, 2003(Abstract Only)

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

NR NR NR NR Biologically 

based

A decrease in Kupperman Index total 

score demonstrated significant superiority of the active to placebo (p<0.001)

NR 6 withdrew in 

each group due to adverse events, none serious

NR Biologically 

based

F-501
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Brzezinski, 1997 145 RCT Control 

Israeli diet 

(usual 

care)

12 

weeks

Women who were peri and postmenopausal (43-65 years) with climacteric complaints from the outpatient menopause clinic at Hadassah Medical Center, Jerusalem, Israel

Inclusion:1. Natural or surgical menopause (> 3 

amenorrhea)2. FSH>30, LH>20, and low plasma es3. > 1 of the following symptoms: hot f

sweats, insomnia, depression, vaginal dyspareuniaExclusion:1. Evidence of acute medical illness2. Use of gonadal hormones or any minfluence menopausal symptoms or en3. Known or suspected allergic reactioitems. 

Burke, 2003 241 DB

RCT

HH 24 

months

Women aged 45-55 were recruited from the community and seen at Wake Forest University.White: 88%Married: 79%High school diploma: 96%>$30,000 annual income: 

79%

Inclusion:1. Perimenopausal (only 1 period in pr2. At least 1 vasomotor symptom a da3. No use of HRT for 3 months prior to Exclusion:1. Acute myocardial infarction or strok2. History of breast or endometrial can3. History of invasive cancer within 5 y4. Active thromboembolic disease5. Previous osteoporosis fractures beihormones6. Low bone density7. Previous exposure to diethylstilbest8. An endometrial biopsy showing hyp

F-502
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearBrzezinski, 1997Burke, 2003

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Menopause symptoms questionnaire (MSQ); evaluates hot flashes, night sweats, palpitations, headache, depression, vaginal dryness, urinary discomfort, insomnia, and decreased libido on a four point scale. Serum phytoestrogen concentrations

Included Included NR NR NR NR 

Self report in symptom diaries. 56/241 NR NR Excluded NR NR 

F-503
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearBrzezinski, 1997Burke, 2003

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

Phytoestrogen rich diet, approximately 1/4 of their calories (PE group)

Regular Israeli diet; told to avoid soy products and flax seed

Significantly reduced in PE group over controls (p=0.004)

Significantly reduced in PE group over control (p=0.005)

25g of soy with 42mg a day of isoflavonesor25g of soy with 58mg a day of isoflavones

25g of soy, alcohol washed to remove isoflavones (Control)

Rapid reduction in all groups, including control. No difference between groups.Significant reduction for all groups from baseline (p<0.0001) but no difference between groups (p=0.10).

NR 

F-504
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearBrzezinski, 1997Burke, 2003

Mood Cognitive Somatic Urinar

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Main Outcomes (cont.)

NR NR NR NR NR NR NR NR NR NR NR NR 

F-505
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearBrzezinski, 1997Burke, 2003

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

Average of 100-fold increase in the phytoestrogen serum levels of the PE group; no change in the control group

31/145 4/95 in the PE 

group due to intolerance of diet; 2/95 in soy group and 7/50 in control group withdrew due to unbearable menopausal symptoms; other dropouts were due to personal reasons

NR Biologically 

based therapies 

Interesttofu, so

NR NR NR NR Biologically 

based therapies 

170/24

F-506
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Bygdeman, 1996

40 RCT HH 3 

months

Postmenopausal women complaining of vaginal dryness (aged 43-76, mean 58.28 years)

Exclusion:1. Hormonal-dependent tumors2. Known or suspected other serious dgenital bleeding, past history of active disorder, vaginal infection3. HRT in the last 3 months4. Vaginal use of any douche or lubric

Cagnacci, 2003 80 RCT, 

open

HH 3 

months

Women (age 47-53) in perimenopause referred to the Menopause Center were enrolled; mean age was 50.2, 51.5 and 51.8

Exclusion:1. Organic or neurological pathologies2. Used hormones, neuroactive or psythe 3 months preceeding

F-507
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearBygdeman, 1996Cagnacci, 2003

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Self diary and vaginal dryness index (Bachmann)

NR 2/40 NR NR NR NR 

State Trait Anxiety Inventory, SelfEvaluations Depression Scale, Greene's Climacteric Scale

NR NR NR NR NR NR 

F-508
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearBygdeman, 1996Cagnacci, 2003

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

Replens: 1 vaginal application three times/week for 3 months

Dienoestrol vaginal cream (0.01%) 0.5mg daily for 2 weeks then three times a week for 3 months

NR Both groups 

resulted in a significant increase in the vaginal dryness index with compared to baseline values

Kava-Kava (KK) 100m/day (15 women) vs. Kava-Kava 200mg/day (19 women)

Control was 1000mg Calcium/day (34 women)

Both KK groups had significant decline in Greene's score from baseline, but not significantly different from control group.

NR 

F-509
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearBygdeman, 1996Cagnacci, 2003

Mood Cognitive Somatic Urinar

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Main Outcomes (cont.)

NR NR NR NR NR NR 

Anxiety; significant decrease compared to control in both KK groups (p<0.009); Depression scores were significantly decreased from baseline in KK groups, however, not significant from controls

NR NR NR NR NR 

F-510
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearBygdeman, 1996Cagnacci, 2003

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

NR 1/40 NR NR Biologically 

based

NR 12/80; 6 in the 

control group, and 5 in the 100mg KK group and 1 in the 200mg KK group

2 for nausea and gastric pain

nausea and gastric pain

Biologically based

F-511
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Carranza-Lira, 2001

30 DB RCT P 1 month Postmenopausal women 

who attended the Climacteric Clinic of the hospital studied

Inclusion:1. No current or previous exposure to 2. FSH >30 and estradiol <30

Chen, 2003 52 RCT HH 16 

weeks

Non-hysterectomized postmenopausal women, aged 45-65 with climacteric complaints were recruited from outpatients attending this Taiwan Hospital

Inclusion:1. Last menstruation > 6 months previ

2. No HRT for > 6 months

Exclusion:1. Severe metabolic, endocrine, or GI concomitant heart disease, uncontrolle(>160/95), diabetes, endometriosis, unbleeding and psychiatric illness2. Surgically induced menopause3. Previous or current estrogen-depencurrent malignant or life-threatening di4. Previous or concomitant serious or conditions. 5. Taking tranquilizers or antidepressa

F-512
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearCarranza-Lira, 2001Chen, 2003

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Modified Kupperman Index NR NR NR NR NR NR 

Greene Climacteric Scale Excluded Excluded Excluded Excluded NR NR 

F-513
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearCarranza-Lira, 2001Chen, 2003

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

Phytoestrogen cream 4mg/day aloe vera; wild yam root extract; almond oil; cartamo oil; jojoba oil; tocopheryl acetate; chamomile extract; sheepshkin root extract oil of ass herb; siberian ginseng extract; to alternating forearms/day

Cold cream control A significant decrease in 

Kupperman Index Score was found in both groups at the end of treatment (p<0.001), no other significant differences between groups

NR 

JWSYS (Sun Ten Pharmaceutical Co., Taipei, Taiwan); 4 grams tid; includes angelica Radix, Atractylodis rhizoma, Paeoniae Radix; Bupleuri Radix; Hoelen; Glycyrrhizae Radix; Moutan Bark; Gardeniae Fructus; Zingiberis Rhizoma, Menthae Herba

Premelle 0.625/2.5 (Wyeth Medica, Newbridge, Co. Kildare, Ireland); one tablet q d

JWSYS had significant reduction (p<0.01) in vasomotor symptoms on Greene scale and Premelle did not. 

NR 

F-514
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearCarranza-Lira, 2001Chen, 2003

Mood Cognitive Somatic Urinar

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Main Outcomes (cont.)

NR NR NR NR NR NR 

Both groups had significant improvement in anxiety and depression (p<0.01)

NR Both groups had 

significant improvement from baseline (p<0.01)

NR See withdrawals Premelle 

had signifimprovem(p<0.01), JWSYS gnot

F-515
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearCarranza-Lira, 2001Chen, 2003

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

A significant decrease in KI was found in both groups at the end of the treatment (p<0.001) in both groups from baseline

NR NR NR Biologically 

based therapies

Both JWSYS and Premelle induced a significant reduction of prevalence and severity of menopausal symptoms. (p<0.01)

13/37 JWSYS; 11/25 HRT

3/37 from Chinese herb group due to vaginal bleeding and abdomenal disturbances; 5/25 from HRT group due to vaginal bleeding and breast tenderness

See withdrawals

Biologically based therapies

No true 

F-516
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Chenoy, 1994 56 DB RCT P 6 

months

56 women were recruited from the general gynecology clinic of North Staffordshire Hospital Center, London; from general practitioners' surgeries, and by self referral of volunteers. 

Inclusion:1. Menopausal women who had hot flutimes/day2. Elevated FSH and LH or had amenomonths, or both. Exclusion:1. Received estrogen replacement or esupplements in the previous 2 months2. Taking any form of HRT or other drusymptoms during the study, or systemsteroidal anti-inflammatory agents, antclonidine, and phenothiazides. 

Chiechi, 2003 187 RCT Usual 

care

6 

months

Healthy postmenopausal asymptomatic woman aged 39-60, living in Southern Italy; mean age was 52.7 years

Inclusion:1. Spontaneous menopause of > 6 mo

2. FSH>30, or bilateral oophorectomyExclusion:1. Age >602. Heavy drinkers3. Treatment with HRT, cholesterol-lowantiosteoporotic or other interfering dru4. Diabetes or history of cancer5. In vegetarian or macrobiotic diet6. Presence of menopausal symptoms 

F-517
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearChenoy, 1994Chiechi, 2003

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Self reported symptom diary Excluded NR NR NR NR NR 

Karyopycnotic index and maturation value of the vagina, FSH, estradiol, urinary daidzein, vaginal smears

Included NR NR NR NR NR 

F-518
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearChenoy, 1994Chiechi, 2003

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

Six months of treatment with either four 500mg evening primrose oil with 10mg natural Vitamin E

Placebo was 500mg liquid paraffin; four capsules twice daily

All women given placebo showed a significant positive difference between control cycle and last cycle (p<0.05). Women given gamolenic acid, however, did not show a significant improvement between the control cycle and last available treatment cycle except for a reduction in the maximum number of night time flushes (p0.014). 

NR 

Women were given soy increased diet, adding a soy food every day, and two meals twice/week based on phytoestrogen rich food; isoflavone intake of 20-30mg/day

Usual care; and HRT These women were asymptomatic Statistically 

significant improvement from baseline in vaginal indices in both the HRT (p<0.01) and soy groups (p=0.03), most in the HRT group; not seen in control group

F-519
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearChenoy, 1994Chiechi, 2003

Mood Cognitive Somatic Urinar

y Uterine Bleeding

Sexual D

tio

Main Outcomes (cont.)

NR NR NR NR NR NR NR NR NR NR NR NR 

F-520
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearChenoy, 1994Chiechi, 2003

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

NR 11/28 from 

placebo and 10/28 from gamolenic acid group

2/11 from placebo due to nausea; however main reason stated was lack of clinical response

Lack of clinical response

Biologically based therapies

Significbut not 

NR 22 out of 

control group; 44 out of diet group; 31 out of HRT group

NR NR Biologically 

based therapies

Too higreliable

F-521
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Cleary, 1994 30 RCT P 15 

weeks

Women age 50-60 years with menopausal symptoms recruited through local and national newspapers

Inclusion:1. < 4 periods in the previous 12 mont2. Abnormal FSH/LH analysis Exclusion:1. Current or past HRT in last 18 mont2. Any debilitating medical condition 3. Any facial or spinal surgery 4. Taking medication likely to affect thesympathetic systems, such as thyroxin5. Any past or present patient of the re

Cohen, 2003 18 RCT HH 12 

weeks

Women were recruited by flyers and by advertisements in local newspapers in a New England ; 11/17 women had ceased having menstrual cycles within the past 2 years and the remaining 6 women had not had a period in 3-4 months; Mean age was 47.3 years (43-53)

Inclusion:1. Ability of self-identification of menop2. Ceased previous treatment of menowith hormones, other medications, herat least 3 months prior to enrollment in for a sufficient cleansing periodExclusion:1. Women with hormonal supplementapharmacologic therapies, herbal remeacupuncture (including acupressure). 

F-522
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearCleary, 1994Cohen, 2003

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

1. Weekly 1-10 scale Symptom questionnaire during study 2. Pre-, Week 5, and Week 15 blood levels of estradiol, FSH, LH, thyroxine, testosterone, sex hormone binding globulin, prolactin, cortisol, IGF/1, TSH, and GH 

NR NR NR Excluded NR NR 

4 scale daily symptom diary NR NR NR NR NR NR 

F-523
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearCleary, 1994Cohen, 2003

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

The spine and pelvis of each subject was treated by a low-force osteopathic technique developed by Fox, and the cranium by cranial techniques following mechanical principles weekly for 10 weeks, followed by a 5 week observation period.

Placebo: low-force technique delivered to a joint adjacent to a restricted joint, where it will have no effect; force is so low in both groups that they are unaware they have received treatment weekly for ten weeks followed by five week observation period

Reduction in study group of hot flashes (p=0.016) at ten weeks and (p=0.007) at 15 weeks; Reduction in study group of night sweats (p=0.021) at ten weeks and (p=0.016) at 15 weeks

NR Re

insgroten (p=we

9 week acupuncture treatment protocol consisting of 1/week for 3 weeks then once every other week for a total of 6 treatments followed by 3 nontreatment weeks (20-30 minutes/ treatment) (EA group)

UB15, 23, 32; GV 20, H7; pericardium 6; SP6, 9; L3 for experimental group; comparison is general tonic (shen mein) L4;K7 and ear points (7)

EA group showed a decrease in mean monthly hot flush severity (30%) for site-specific acupuncture from baseline to month 2 (p=0.05), baseline to month 3 (p=0.005) and baseline to posttreatment month 4 (p-0.019). The comparison acupuncture treatment group had no change in severity from baseline over the treatment phase.

NR Sle

in destustasig(0.in moacco

F-524
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearCleary, 1994Cohen, 2003

Mood Cognitive Somatic Urinar

y Uterine Bleeding

Sexual D

tio

Main Outcomes (cont.)

Reduction in depression in study group compared to controls (p = 0.042) at ten weeks and (p=0.290) at 15 weeks; Reduction in irritability is study group compared to controls (p = 0.184) at ten weeks and (p=0.271) at 15 weeks

NR NR Reduction in 

urinary frequency in study group over controls (p=0.021) at ten weeks and (p=0.168) at 15 weeks

NR NR 

Mood changes decreased in both groups between baseline and posttreatment month of the study; EA group p=0.05; comparison acupuncture group (0.056) 

NR NR NR NR NR 

F-525
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearCleary, 1994Cohen, 2003

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

Of the 11 hormones studied there was a significant difference in testosterone levels (decreased in study group) (p=0.028); Reduction in pain was greater in the study group: (p=0.04) for neck pain, and (p=0.06) for back pain

NR NR NR Manual 

Medicine

NR 1/18 Withdrew prior 

to randomization

None Alternative 

Health Systems

F-526
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Crisafulli, 2004 90 RCT P, HH 1 year Healthy, ambulatory women, 

referred by the Department of Internal Medicine and the Department of OB/GYN at University of Messina, Italy, age 47-57

Inclusion:1. No surgical menopause patients2. No period for 12 months, FSH>50 a<100.Exclusion:1. Clinical or lab abnormalities suggescardiovascular, hepatic, renal disorder2. Use of oral or transdermal estrogenandrogen or other steroids in the prece3. Smoking >10 cigarettes/day

Dalais, 1998 52 DB RCT HH 7 

months

52 postmenopausal women were recruited

Inclusion:1. Age 45-652. FSH > 403. > 14 hot flashes/week4. 12 months of amenorrhea5. No antibiotic or hormone replacemethe preceding 3 months6. Non-smoker and non-vegetarian

F-527
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearCrisafulli, 2004Dalais, 1998

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Self-reported diary of the number of hot flushes, 14 days before each assessment; only number used, not severity

Not 

allowed

Not 

allowed

NR NR NR Not 

allowed smoked > 10 cigarettday

Hot flush diary NR NR NR NR NR Non 

smokernon vegetars

F-528
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearCrisafulli, 2004Dalais, 1998

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

1mg/day estradiol combined with noresthisterone; genistein (n=30) at 54mg/day

Placebo Estrogen group, flush score 

decreased by 53% (p<0.001) compared to placebo at 3 months. This was maintained at 6 and 12 months. Genistein group decreased by 22% (p<0.01) after 3 months; 29% at 6 months (p<0.001) and 24% at 12 months (p<0.01) compared to placebo. The difference between the estrogen group and the genistein group was significant at all measurements (p<0.05)

NR 

45 grams of soy (high phytoestrogen), linseed (high phytoestrogen), or wheat diet; dosage of isoflavones (daidzein, genistein) was 52.64 + 

8.68 mg/day

Wheat diet In women consuming linseed and 

wheat, a significant decrease in hot flush rate was observed following 12 weeks of ingestion (41% decrease, p<0.009; 51% decrease, p<0.001 respectively) compared to baseline. No significant decrease in hot flush rate was detected during soy ingestion.

Women ingesting soy showed signicant increase in vaginal cytology maturation index (p0.03); none for other two groups

F-529
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearCrisafulli, 2004Dalais, 1998

Mood Cognitive Somatic Urinar

y Uterine Bleeding

Sexual D

tio

Main Outcomes (cont.)

NR NR NR NR NR NR NR NR NR NR NR NR 

F-530
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearCrisafulli, 2004Dalais, 1998

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

NR 7 None None Biologically 

based therapies 

Funding importa

Urinary excretion of daidzein, genistein, enterodiol and enterolactone increased significantly (10-30 fold) during soy and linseed ingestion, respectively (p<0.01). No such changes in wheat group

8/52 Personal 

reasons

NR Biologically 

based therapies 

F-531
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Davis, 2001 55 DB RCT P 12 

weeks

Women, age 45-70 years were recruited through the Jean Hailes Foundation Newsletter, newspapers, radio station interviews and the medical unit of the Jean Hailes Foundaion

Inclusion:1. Non-Asian women who had lived in least ten years2. Postmenopausal (>12 months amen>25)3. Reported at least 14 hot flushes or nExclusion:1. Use of HRT, Chinese medicinal hernatural therapies during the eight wee2. Preexisting gastrointestinal, renal, odiabetes mellitus requiring treatment, uhypertension, undiagnosed vaginal bleglucocorticosteroid use3. Undergoing cancer therapy4. Women who had consumed a high for the four weeks before baseline

F-532
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearDavis, 2001

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Daily diary of the frequency of hot flushes and night sweats for four weeks before treatment and for the entire 12 weeks of the study period. The Menopause Specific Quality of Life Questionnaire (MENQOL) and urinary phytoestrogen excretion

NR NR NR NR NR NR 

F-533
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearDavis, 2001

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

Both placebo and CMH produced by Ningbo Daekang Herbs Co Ltd (Ningbo, China)

Placebo was cornstarch with a bitter taste enhancer

Frequency of vasomotor symptoms were reduced in both CMH and placebo groups. Difference between groups was not significant (p =0.09) A progressive decline in the frequency of vasomotor symptoms with treatment duration was seen in both groups

NR 

F-534
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearDavis, 2001

Mood Cognitive Somatic Urinar

y Uterine Bleeding

Sexual D

tio

Main Outcomes (cont.)

NR NR NR NR NR NR 

F-535
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearDavis, 2001

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

Women with more than four years of ammenorrhea had a significantly greater response to placebo than to CMH; significant greater reduction in score was seen with CMH compared with placebo in the vasomotor domain of the MENQOL for age <55, BMI <25, and previous nonusers of natural therapies (p<0.05)

14/42 in Chinese herbal group; 9/36 in placebo group. 

Most withdrew in the first week after randomization due to the taste of both products

In CMH group, two became asymptomatic before study began and withdrew, and on started HRT; 7 withdrew due to taste intolerance, 2 were lost to follow-up, and 2 withdrew due to other illness; in placebo group, one withdrew before the study commenced due to lack of symptoms, 2 withdrew due to no benefit, one withdrew due to other illness, one was lost to follow-up and 3 

withdrew due

Biologically based therapies (specifically comments in article that this is not assessing TCM)

Herbs iglutinosDioscororientalPoria coLycium julibrissprostara

F-536
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Duffy, 2003 36 DB RCT P 12 

weeks

36 postmenopausal women aged 50-65 were recruited by circular email at King's College London from a database of those who had previously participated in a study on bone mineral density at Guy's Hospital.

Inclusion:1. No menstruation for the previous 12 Exclusion:1. Had used HRT in previous 12 mont2. Use of antibiotics in the previous 3 m3. Current illness or use of psychoactivThree subjects were excluded during ttreatment, two because they started tramitryptiline and one because she sta

Faure, 2002 75 DB RCT P 4 

months

Postmenopausal women requesting treatment for hot flushes.

Inclusion:1. > 6 months out from last menses

2. FSH >403. > 7 moderate to severe hot flashes 4. > 6 weeks since last HRT use

F-537
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearDuffy, 2003Faure, 2002

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Hospital Anxiety & Depression Scale; Greene Climmacteric Scale; Stanford Sleepiness Scale; Epworth Sleepiness Scale; paced Auditory Serial Addition test; plus short-term memory test from the Weschler Memory Scale; plus samples from the Cambridge neuropsychological Test Automated Battery 'list all the animals they could think of in 1 minute'

13-22% Included NR NR NR All 

nonsmos; caffeand alcassessplus diealcohol intake significy less isoy gro(p<0.05high IQ both groups (118 an115)

Self report by diary. NR NR NR NR NR NR 

F-538
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearDuffy, 2003Faure, 2002

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

Soya isoflavone supplement used was Solgen 40 (Solbar Plant Extracts, Ashdod, Israel). Each capsule contained 30 mg total isoflavone equivalents. Dose was two capsules/day for 12 weeks

Identical looking placebo capsules; told to avoid Soya foods and food products containing Soya for the duration of the study, and for the two weeks prior

No significant effects of treatment on any of the menopausal symptoms assessed by the Greene Climacteric Scale

NR No 

70mg/day of Genisten and Diadzin (Phytosoya) 325mg four/day = 70mg of G/D

Placebo The Intention-to-treat analysis 

indicated treatment effect on the change in frequency of hot flashes for the intervention group (p=0.01).

NR 

F-539
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearDuffy, 2003Faure, 2002

Mood Cognitive Somatic Urinar

y Uterine Bleeding

Sexual D

tio

Main Outcomes (cont.)

No difference Significant 

improvement in memory in Solgen group (delayed recall of pictures (p<0.03); immediate story recall (p<0.06); corrected for practice effect; also learning the reversal of the simple discrimination rule (p=0.05)

No difference NR NR NR 

NR NR NR NR NR NR 

F-540
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearDuffy, 2003Faure, 2002

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

Improved time to learn complex tasks greater in Solgen group than placebo (p<0.05 and <0.003)

3/36 None None Biologically 

based therapies

NR 6 soy group

14 placebo

NR NR Biologically 

based therapies

F-541
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Freedman, 1992 33 RCT HH 4 weeks 33 women were recruited 

from newspaper advertisements; mean age in years was 50.7 + 8.6 in 

paced respiration group; 53.1 + 6.0 in muscle relaxation 

group; and 53.9 + in alpha 

wave feedback group

Inclusion: 1. Amenorrheic > 1 year 

2. > 5 hot flashes/day

Freedman, 1995 24 RCT HH 4 weeks Women recruited from 

newspaper advertisement; age was 52.5 years + 1.6 for 

paced respiration group; 52.7 + 1.6 years for alpha 

feedback group

Inclusion: 1. Amenorrheic > 1 year 

2. > 5 hot flashes/day

F-542
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearFreedman, 1992Freedman, 1995

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Ambulatory monitoring of sternal skinconductance level and abdominal and thoracic ventilation; in addition thoracic and abdominal ventilation were recorded on two additional channels of the Medilog using inductance plethysmography (Respitrace); serum epi

Included Included NR NR NR NR 

Ambulatory monitoring of sternal skinconductance level and abdominal and thoracic ventilation; in addition thoracic and abdominal ventilation were recorded on two additional channels of the Medilog using inductance plethysmography (Respitrace); serum epinephrine and norepinephrine

Included Included NR NR NR NR 

F-543
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearFreedman, 1992Freedman, 1995

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

8 1-hour biweekly treatment sessions of paced respiration training

8 1-hour treatment sessions of alpha-EEG biofeedback, or Patients were taught muscle relaxation by a research assistant using previously published methods

Hot flash frequency declined significantly (p<0.02) for the pacedrespiration group but not for the 

muscle relaxation (p>0.2) or alpha wave feedback group (p>0.5). 

NR 

8 1-hour biweekly treatment sessions of paced respiration training

8 1-hour treatment sessions of alpha-EEG biofeedback

Hot flash frequency declined significantly (p<0.001) for the paced-respiration group but not for the alpha wave feedback group. 

NR 

F-544
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearFreedman, 1992Freedman, 1995

Mood Cognitive Somatic Urinar

y Uterine Bleeding

Sexual D

tio

Main Outcomes (cont.)

NR NR NR NR NR NR NR NR NR NR NR NR 

F-545
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearFreedman, 1992Freedman, 1995

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

Analysis of vafriance on respiration rate showed a significant (p<0.02) Group x Pretreatment/Posttreatment interaction effect. Simple effects tests showed a significant pretreatment/posttreatment increase in tidal volume for the paced respiration group (p<0.03) but not for the muscle relaxation group (p>0.8) or alpha wave feedback (p>0.5)

NR NR NR Mind-body 

interventions

The 24-hour patern of skinconductance level of significantly altered for the paced respiration group (p<0.001); no significant change in any of the biochemical measures

NR NR NR Mind-body 

interventions

F-546
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Germaine, 1984 26 RCT HH 6 

months

Menopausal women, 44-61 years (Mean=50.3 years); 12 premenopausal women, all reporting regular menstrual periods from 22-45 served as controls

Inclusion:1. > 2 hot flashes/day

2. No HRT3. No periods

Han, 2002 82 DB RCT P 5 

months

Women, age 45-55 years Inclusion:

1. Intact uterus 2. FSH > 25 3. Estradiol < 20 4. Presence of hot flashes5. 'in menopause' at least 12 months E1. Using lipid-lowering drugs, antidiabesoybean-derived products, or herbal s2. History of uncontrolled hypertension3. Cancer diagnosed less than 5 years 4. Previous myocardial infarction

F-547
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearGermaine, 1984Han, 2002

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Heat stress test (HST); this is 2 circulating water pads maintained at 42° C to the subjects torso whild supine on a bed in a 23° C room. Subjects were instructed to signal the earliest perception of a hot flash by pushing a hand-held button; following the HST 1 the 14 menopausal women were randomly assigned to receive 6 weekly sessions of progressive musle relaxation or alpha EEG biofeedback; HSTs were then administered 1 week later and then final test at the end of training.

NR NR NR NR NR NR 

Kupperman Index; height, weight, blood pressure, lipid, and hormone levels, transvaginal sonography

Excluded NR NR Excluded if 

within past 5 years

NR All 

exercisless thathree times/w; 30% smokerplacebo group; smokerisoflavogroup; 

F-548
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearGermaine, 1984Han, 2002

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

Progressive muscle relaxation (PMR)

Alpha EEG biofeedback

Increase in heart rate during the heating period, whereas premenopausal women declined in heart rate. Significant reduction in PMR group compared to controls during third HST (Significant test p<0.0003, and Group X Test p<0.002) were found. Also time was significantly longer (p<0.01) for onset of hot flush in the PMR group compared to control group. This change was significant between HST 2 and HST 3 for the PMR group but not the control group (p<0.01). 

NR 

Soy isoflavone 83.3 mg/day; soy protein 50.3 mg and isoflavone 33.3mg. Genistein, daizein, and glycitein in aglycone form 23.3.mg, 6.2mg, and 3.8 mg, respectively.

Placebo was 83.3 mg composed of purified soy protein 50.3mg without isoflavones and glucose 33.3mg

Isoflavone group declined more than placebo group (p<0.01)

NR Ins

deisomogro

F-549
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearGermaine, 1984Han, 2002

Mood Cognitive Somatic Urinar

y Uterine Bleeding

Sexual D

tio

Main Outcomes (cont.)

NR NR NR NR NR NR 

Isoflavone group improved score over placebo in melancholia, nervousness (p<0.01)

NR NR NR NR NR 

F-550
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearGermaine, 1984Han, 2002

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

NR NR NR NR Mind-body 

interventions

Novel wpresenc

All measures of Kupperman scale (vasomotor, paresthesia, insomnia, nervousness, melancholia, vertigo, weakness, arthralgia and myalgia, headache, palpitation, formication) showed individual statistical improvement in isoflavone group over placebo (p<0.01)

1 out of 41 in each group; 1 for 'poor response' and 1 for 'nausea'

NR NR Botanically 

based

Soy isoeugenbKorea

F-551
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Hartley, 2003 34 DB RCT P 1 week Postmenopausal women 

aged 53-65 were recruited from those responding to articles in national and local press

Inclusion:1. No period for 12 months and healthExclusion:1. Use of HRT within the previous 12 m2. Smoking more than 20 cigarettes/da3. Current illness or use of psychoactivincluding soya supplements, Ginkgo owere allowed)

Hirata, 1997 71 DB RCT P 24 

weeks

Women (mean age 52.4 + 6 

years) were solicited through radio, television, and newspaper and magazine information; age range was from 44.7-69.3 years in the placebo group and from 44.5 to 59.6 years in the dong quai group.

Inclusion:1. FSH > 30 2. 'troublesome' hot flushes >14/week 3. 'post menopausal' for > 6 months 

4. No HRT for 3 months Exclusion:1. Weight >30% or < 15% of ideal weig2. Previous hysterectomy, serious illne3. Use of herbal therapy during the pre4. Gastrointestinal disorders that resuldiarrhea or malabsorption5. History of breast cancer, pelvic irrad6. Tobacco use, or consumption of > 2 per day7. Active liver disease8. Chronic use of antibiotics9. Use of vaginal creams or corticoste

F-552
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearHartley, 2003Hirata, 1997

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

National Adult Reading Test-Revised version; Hospital Anxiety and Depression Scale, Greene Climacteric ScaleStanford Sleepiness Scale, Epworth Sleepiness Scale, Immediate and delayed paragraph recall from the Weschler Memory ScaleRevised, and several other brain function measures

Included Included NR NR NR Smoke

include

Kupperman Index; symptom diary; serum estradiol, estrone, and sex hormonebinding globulin levels; vaginal cells, endometrial ultrasounography

Excluded NR NR Excluded NR Smoke

excludemore th2 alcohdrinks/dexclude57% weregular exercis

F-553
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearHartley, 2003Hirata, 1997

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

Ginkyo One-A-Day 120mg tablet/day containing 25% Ginkgo flavonoids and 6% terpenoids

Placebo No significant effect of treatment 

on any of the menopausal symptoms assessed by the Greene Scale, however all improved from baseline (p<0.001)

NR No 

4.5 grams/day of dong quai from root material

Maltodextrin placebo 29.4% of the placebo group and 

33.3% of the dong quai group reported good or excellent control of their vasomotor symptoms

40% of subjects complained of moderate to severe vaginal dryness at baseline; 12 weeks later, about 30% still had this symptom

F-554
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearHartley, 2003Hirata, 1997

Mood Cognitive Somatic Urinar

y Uterine Bleeding

Sexual D

tio

Main Outcomes (cont.)

No difference between groups

Not significant between groups

NR NR NR One para

Greene's that did noimprove o

NR NR NR NR NR NR 

F-555
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearHartley, 2003Hirata, 1997

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

NR 3 One in the 

placebo group because of brief menstrual period and two in the Ginkgo group because testing was too demanding

NR Biologically 

based

Both groups has significant decrease in Kupperman scale from baseline at 6, 12, and 24 months (p<0.0001); No significant changes were seen in serum estradiol level, estrone level, SHBG level, blood pressure, or weight were seen during the study

6/36 in the placebo group; 4/35 in dong quai group

Placebo: 2 dropped due to lack of efficacy; 2 developed 'minor side effects'; 1 lost interest; 1 developed 'other health problems'; dong quai; 2 due to lack of efficacy; 1 due to minor side effects and 1 due to other health problems

Side effects: burping, gas, and headache in both groups, with no statistically significant difference between groups

Botanically based

Dong qcrushed by East OR). Pomateria0.5mg/korange materiathe don

F-556
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Hochanadel, 1999

11 DB RCT P 12 

weeks

Naturally postmenopausal women over age 45

NR

Hudson, 1998 13 DB RCT P 3 

months

Women recruited from a one sentence article in The Oregonian (local newspaper)

Inclusion:1. Hhot flashes and one additional me2. No HRT for the previous 3 months3. Natural physiologic menopause with 3 months4. No serious acute or chronic disease5. No cariovascular disease and norm

Hunter, 1999 86 RCT P 5 years All women were over 50 

years who had been randomized to two 90 minute education groups or no intervention at age 45; 

Inclusion:1. Premenopausal at age 45, from the of five general practices in south LondDetailed exclusion/inclusion criteria ou1998:29:215-24

F-557
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearHochanadel, 1999Hudson, 1998Hunter, 1999

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Somatic symptoms, mood and verbal learning performance of naturally postmenopausal women were measured

Excluded NR NR NR NR NR 

Self-reported symptom diary (frequency and severity)

NR Excluded NR NR NR NR 

1. Sociodemographic and health information survey2. Knowledge about menopause questionnaire3. Menopause Representation Questionnaire (MRQ)4. Women's Health Questionnaire (WHQ)

NR NR NR NR NR Smoke

exercis

F-558
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearHochanadel, 1999Hudson, 1998Hunter, 1999

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

100 mg/day of encapsulated soy isoflavone

Placebo No improvement No improvement 

Botanical formula that contained 500mg combined dry herb: burdock root (2 part), licorice root (2 part), motherwort (1 part), Dong Quai root (2 part) and Mexican wild yam root (1 part) 2 capsules tid

Rice bran placebo with similar smell and appearance also 2 tid. 

100% improvement in severity symptom score in verum group (n=7) and 67% improvement in placebo group (n=6). 71% in verum group had improvement in number of symptoms and 17% had improvement in number of symptoms in placebo group. One sided Z-test showed p<0.03, but two-sided Z test did not reveal this to be statistically significant

NR 

Education N/A HRT users reported fewer hot 

flashes (p<0.04).

No difference No 

F-559
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearHochanadel, 1999Hudson, 1998Hunter, 1999

Mood Cognitive Somatic Urinar

y Uterine Bleeding

Sexual D

tio

Main Outcomes (cont.)

No significant difference between groups

No significant differences between groups

No significant differences between groups

No improvement NR No improv

NR NR NR NR NR NR 

No difference in depression or anxiety

Significant difference in knowledge of menopause (p<0.01)

Control group more likely than intervention group to believe aches & pains (p<0.01) & skin problems (p<0.05) are due to menopause, no difference as a category

NR No difference Improved 

function in interventio(p<0.06)Controls hinterest in more (p<0

F-560
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearHochanadel, 1999Hudson, 1998Hunter, 1999

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

None of the statistical comparisons between the active and placebo conditions yielded findings in support of the hypothesis that soy isoflavones may be useful fo the treatment of these post-menopausal cognitive or somatic changes

NR NR NR Botanically 

based

Poster. 

NR None None NR Botanically 

based

Size of 

Women in intervention group maintained better knowledge & did not attribute so many things to menopause.Women in prepared group took more exercise (p<0.01) and had lower prevalence of HRT (p<0.01).

NR N/A N/A Mind-body 

interventions

F-561
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Hyde, 1983(Abstract Only)

30 RCT HH NR Menopausal women NR

Irvin, 1996 45 RCT HH, P 10 

weeks

Postmenopausal women from the greater Boston area recruited through media sources of public service announcements and newspaper advertisements, and through posted notices at appropriate medical sites, age 44-66

Inclusioin:1.General good health2. > 6 months without a menstrual per

3. Experiencing > 5 hot flashes per 24 

4. Willingness to monitor flashes and aprotocol

F-562
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearHyde, 1983(Abstract Only)Irvin, 1996

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Menopausal symptoms checklist for frequency, intensity and duration of menopausal symptoms; Galvanic skin responses

NR NR NR NR NR NR 

Spielberger State-trait Anxiety Inventory; Profile of Mood States; daily hot flash diary

NR NR NR NR NR NR 

F-563
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearHyde, 1983(Abstract Only)Irvin, 1996

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

12 contingent Galvanic Skin Response feedback conditioning sessions and progressive relaxation training

12 non-contingent feedback sessions and were told simply to relax

Both groups improved; No significant difference between groups was observed

NR 

Relaxation group (RR); reading group (R) which served as the placebo intervention group, or the charting group which was the control group

Reading group was instructed to read leisure material; relaxation group instructed in diaphragmatic breathing and breath awareness; both 20 minutes/day

All three groups had a change in flash frequency, but these did not reach statistical significance. The RR group did have a significant decrease (p<0.046) in intensity of hot flashes from baseline.

NR 

F-564
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearHyde, 1983(Abstract Only)Irvin, 1996

Mood Cognitive Somatic Urinar

y Uterine Bleeding

Sexual D

tio

Main Outcomes (cont.)

NR NR NR NR NR NR 

On the POMS the RR group demonstrated a significant decrease in tension-anxiety (p<0.044) and depressiondejection (p<0.013)

The reading group showed significant decrease in confusionbewilderment (p<0.013) on the POMS

NR NR NR NR 

F-565
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearHyde, 1983(Abstract Only)Irvin, 1996

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

NR NR NR NR Mind-body 

interventions

NR 12/45 4 left because 

they found charting to be too intrusive in their lives, 3 dropped out due to snow; 2 because they started their menses again, 2 lack of interest, and 1 who went on estrogen treatment

See withdrawals

Mind-body interventions

Inclusio1. Postsympto

flushes/2. > 6 m

bilateraExclusi1. HRT weeks2. Allergcontain 3. Curreliver or 4. Diab5. Maligcancers6. Contvegetar

product 

F-566
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Jeri, 2002 30 DB RCT P 16 

weeks

Nonvegetarian Peruvian women who had been postmenopausal for more than 1 year; median age was 52 + 0.7 years for treatment 

group and 51 + 0.8 years for 

control group

Inclusion:1. < 60 with FSH>30, having > 5 hot fl

averaged for more than 1 week2. Not using HRT, antidepressants, or or soy or other estrogen-active plan pr

Knight, 1999 37 DB RCT HH, P 12 

weeks

Women, age 40-65, were recruited through the University Department of OB/GYN at St. George Hospital, Sydney, Australia

Inclusion:1. Postmenopausal women symptoma

flushes/day2. > 6 months of amenorrhea or bilate

FSH >40Exclusion:1. HRT within the previous 6 weeks2. Allergy to foodstuffs known to conta3. Current history of active bowel, liver disease4. Diabetes requiring drug therapy5. Malignancy (excluding skin cancers6. Contraindications to HRT use, vegeregular soy product users,7. Receiving medications that result in induction

F-567
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearJeri, 2002Knight, 1999

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Self reported diary of frequency and severity of hot flushes

NR NR NR NR NR NR 

Greene Menopause Scale;self-reported diary of hot flushes

NR Included NR Excluded NR NR 

F-568
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearJeri, 2002Knight, 1999

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

Promensil (40 mg standardized isoflavones (genistein, daidzein, formononetin and biochanin))/day

Placebo Reduction in both frequency and 

severity of hot flushes was reported by women in the treatment group; 14 Promensil women had a 48% reduction from baseline in frequency of hot flashes (p<0.001), controls had a 10.5% reduction. P value not given between groups or for control group; Regarding severity index, 47% reduction in Promensil group from baseline (p<0.001) and no change in placebo form baseline. 

NR 

Placebo vs. 40mg of Promensil vs. 160mg of Promensil

Promensil is a standardized isoflavone supplement prepared from red clover extract, in tablet form; each tablet contains 40 mg of total isoflavones; genistein (4.0), daidzein (3.5mg) and their methylated precursors biochanin (24.5mgg) and formononetin (8.0mg)

Flushing frequency decreased in all groups over the 12 week trial period. There was not difference in flushing frequency between the active and placebo groups. (average 29-34% reduction)

NR 

F-569
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearJeri, 2002Knight, 1999

Mood Cognitive Somatic Urinar

y Uterine Bleeding

Sexual D

tio

Main Outcomes (cont.)

NR NR NR NR NR NR NR NR NR NR NR NR 

F-570
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearJeri, 2002Knight, 1999

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

Significant reduction in FSH in Promensil group from baseline (59.27 to 48.60) P<0.001)

1/15 Promensil group

NR NR Biologically 

based

None of the biological parameters of estrogen activity measured, including FSH, SHBG and climacteric symptom scores, showed any change with time, compared to placebo. (average 26% -160mg group to 46% - placebo group reduction in Greene Score over the twelve weeks)

2/37 Intervention by 

their general practitioner

NR Biologically 

based

F-571
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Knight, 2001 24 DB RCT P 12 

weeks

24 subjects were recruited through the University Departments of Obstetrics and Gynecology , Sydney Australia

Inclusion:1. Postmenopausal women, having > 3 

amenorrhea for 6 months, FSH >40 or oophorectomy2. Aged 40-65Exclusion:1. HRT within the previous 6 weeks2. Current history of active bowel, liver disease; diabetes requiring drug theracontraindications to HRT use3. Vegetarians and regular soy-produc

F-572
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearKnight, 2001

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Daily flush diary; Green Menopause Scale

Included Included NR Excluded NR NR 

F-573
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearKnight, 2001

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

Isoflavone powder, TakeCare, 60g/day; isoflavones 134.4mg/day; (aglycone formulations 77.4mg/day)

Casein based powdered drink

Flushing frequency decreased in both groups, but there was not difference in flushing frequency between the active and placebo groups; no difference in Greene Menopause Symptom Scores

NR 

F-574
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearKnight, 2001

Mood Cognitive Somatic Urinar

y Uterine Bleeding

Sexual D

tio

Main Outcomes (cont.)

NR NR NR NR NR NR 

F-575
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearKnight, 2001

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

NR 4/24 3/12 in the 

isoflavone group..could not tolerate taste

None Biologically 

based

F-576
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Komesaroff, 2001

50 DB RCT P 3 

months

Healthy menopausal women 45-60 years, currently experiencing symptoms of the menopause, recruited from the Baker Institute Menopause Clinic, and from the local community by advertisements placed in local newspapers and discussion in the electronic media. Mean age was 53.3 + 1.1 years

Inclusion:1. No HRT for > 6 weeks

2. Last period > 12 months before, FS<130Exclusion:1. Significant cardiac, renal or hepatic psychiatric disease, inflammatory condthyroid disease, diabetes, or a history 

F-577
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearKomesaroff, 2001

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Symptom diary self reported including number of episodes of flushing and scores for specific symptoms. Symptom scores were combined to produce values for 'total', flushing', and total non-flushing' scores. This approach made possible analysis of specific scores relating to mood, breast symptoms, libido and energy levels. 

3/50 NR NR NR NR NR 

F-578
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearKomesaroff, 2001

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

Wild yam preparation (Biogest) supplied in 100gram tubs. Participants were asked to apply one teaspoonful twice daily to the arms, legs or abdomen (manuractures claim that each 1 gram of bioGest contains Dioscorea villosa extract 100mg, Linum usitatissmum oil 2 grams, Perlargonium graveolens oil 100mg, Salvia officinalis oil 100mg and alpha tocopheryl acetate 10mg in a vegetable cream base).

Placebo No significant difference between 

the yam cream and placebo in any of the three cases

NR 

F-579
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearKomesaroff, 2001

Mood Cognitive Somatic Urinar

y Uterine Bleeding

Sexual D

tio

Main Outcomes (cont.)

NR NR NR NR NR NR 

F-580
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearKomesaroff, 2001

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

NR 19/25 in the 

Biogest group attributed to unrelieved symptoms and unspecified personal circumstances. 8/25 in the placebo group for same reasons

No adverse effects

NR Biologically 

based

F-581
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Kotsopoulos, 2003

94 DB RCT P 3 

months

Women were recruited from a larger trial.Average age: 59-60 years

Inclusion:1. Aged 50-75 years2. Non smokers3. Non vegetarians4. > 12 months amenorrheic

5. FSH >20Exclusion:1. On HRT in previous 12 months2. On phytoestrogens or soy based pr3. On antibiotics in previous 3 months

Kritz-Silverstein, 2003

56 DB RCT P 6 

months

Women were recruited through mass mailings based on voter registration lists, newspaper ads, and presentations at local organizations.Average age: 61 yearsAverage age at menopause: 49 years

Inclusion:1. Postmenopausal women aged 55-7

Leonetti, World Congress on Fertility, 1998(Abstract Only)

90 RCT P 1 year 5 years of menopause, 

surgical or natural

NR

F-582
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearKotsopoulos, 2003Kritz-Silverstein, 2003Leonetti, World Congress on Fertility, 1998(Abstract Only)

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Validated questionnaire of menopauseassociated symptoms (measure not stated by name).

NR NR NR NR NR 0/94 

Beck Depression Inventory (BDI)The Mini-mental Status Examination (MMSE)Trials A & B of the Halstead-Reitan Neuropsychological Test BatteryCategory FluencyLogical Memory and Recall

NR NR Yes 

exact number not stated

NR NR 2/56 dr

soy beveraevery d

NR NR NR NR NR NR NR 

F-583
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearKotsopoulos, 2003Kritz-Silverstein, 2003Leonetti, World Congress on Fertility, 1998(Abstract Only)

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

118mg Isoflavones Placebo No change between groups. No change between 

groups. Intervention group had a significant improvement (p=0.01).

110mg/day of Isoflavones

Placebo NR NR 

20mg/day of natural progesterone cream

Placebo 83% of natural progesterone 

cream patients had improvement or resolution of vasomotor symptoms compared with 14% of placebo group (p<0.001)

NR 

F-584
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearKotsopoulos, 2003Kritz-Silverstein, 2003Leonetti, World Congress on Fertility, 1998(Abstract Only)

Mood Cognitive Somatic Urinar

y Uterine Bleeding

Sexual D

tio

Main Outcomes (cont.)

No change within groups for psychological outcomes

NR No change 

between groups

No change within groups.

NR No chang

between gboth interand placegroups im(p=0.009 p=0.015, respective

NR Women in the 

treatment group showed improvement on four of five tests compared to controls (p=0.03)

NR NR NR NR 

NR NR NR NR NR NR 

F-585
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearKotsopoulos, 2003Kritz-Silverstein, 2003Leonetti, World Congress on Fertility, 1998(Abstract Only)

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

Both intervention and placebo groups had a significant improvement in facial hair (p=0.04 and p=0.014, respectively) and dry skin (p=0.0027 and p=0.011, respectively).

19/9410 in treatment group9 in placebo group

Gastrointestinal side effectsAll were due to AEs (19)

None seriousTreatment group: 7 - intolerable; 1 - weight gain; 1 - menopausal symptoms; 1 - unrelatedPlacebo group: 6 - intolerable; 2 - constipation; 1 -

allergies

Biologically based

NR NR NR NR Biologically 

based therapies

Outcomperform

NR NR NR NR Biologically 

based

F-586
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Lewis, 2002(Abstract Only)

99 DB RCT HH, P 16 

weeks

Postmenopausal women NR

Lindh-Astrand, 2004

75 RCT HH 12 

weeks

75 postmenopausal sedentary women with vasomotor symptoms, 48-63 years of age, recruited by advertisement in the local papers and at the gynecological outpatient clinic of a hospital in Sweden; mean age of exercise group was 54 years with BMI of 24.6; estrogen treated women had mean age of 50.9 years and BMI of 25.6

Inclusion:1. Spontaneous menopause > 6 mont

Exclusion:1. Severe endocrine, metabolic or throdisease, uncontrolled hypertension, or sedatives, anxiolytic or antidepressant 2. Exercising regularly more than 1 ho

F-587
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearLewis, 2002(Abstract Only)Lindh-Astrand, 2004

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Menopause Specific Quality of Life (MENQOL), plus daily diary of frequency and severity of hot flashes

NR NR NR NR NR NR 

Number of flushes during the last day and night in a log-book which was filled in at bedtime for two weeks before and during the 12 week treatment. Also measured the severity of flushes (0-10); also completed questionnaires on aspects of quality of life at baseline, 4,8,12, and 24 weeks, Kupperman Index, VAS to general summary of the total climacteric symptom intensity and distress, MOOD Scale, SCL-90

4 None NR NR NR NR 

F-588
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearLewis, 2002(Abstract Only)Lindh-Astrand, 2004

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

Flaxseed muffin vs. soy flour muffin

Wheat flour muffin NR NR 

3 times weekly exercise (15 women); also compared to 8 wait listed women and 4 women being observed in a parallel study on hot flushes in women with breast cancer

Oral estrogen (15 women); 45 other women randomized to three additional arms (2mg/day)

The severity of flushes decreased significnatly p=0.041 in the 5 exercising women, who continued the complete follup-up time of 36 weeks (exercising the entire time period). In the estrogen group the mean number of flushes decreased (p<0.001) after 12 weeks and remained at this level; in the waiting list group of 12 untreated women the number of flushes did not change during a period of 8 weeks. 

NR 

F-589
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearLewis, 2002(Abstract Only)Lindh-Astrand, 2004

Mood Cognitive Somatic Urinar

y Uterine Bleeding

Sexual D

tio

Main Outcomes (cont.)

NR NR NR NR NR NR NR NR NR NR NR NR 

F-590
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearLewis, 2002(Abstract Only)Lindh-Astrand, 2004

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

ANOVA on 4 domains showed no significant time by dietary group interaction in quality of life: vasomotor, psychosocial, sexual, physical or in combined score, hot flash frequency of hot flash severity. No MENQOL domains or hot flash symptoms showed significant group differences: however, all groups showed improvement with time

7/33 from flax, 3/33 from soy;3/33 from wheat

NR NR Biologically 

based therapies

SCL-90, Kupperman's and VAS all changed significantly p<0.01) at 36 weeks, and mood scale only in the estrogen group

5/15 in the first 12 weeks, 5/15 additional in the second 12 weeks in the exercise group; 6/15 in the first 12 weeks from the estrogen group; 0/15 in the second 12 weeks

1 from estrogen group

Vaginal bleeding

Mind-body interventions

F-591
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Makkonen, 1993 30 DB RCT P 6 

months

Women, mean age of 52.3 + 

2.7 years for guar gum group; mean age of 53.6 + 4.0 in placebo group

Exclusion:1. Uncontrolled hypertension, diabetes disease or thromboembolic disease2. Hormone therapy taken during prev

Murkies, 1995 58 DB RCT HH 14 

weeks

Women were recruited from interested patients in a general practice in Melbourne, Australia and newspaper advertisements

Inclusion:1. > 12 months of amenorrhea, and FS

2. Hot flushes > 14/week3. Non-smokers4. Stopped antibiotics or hormonal rep

months prior

Nachtigall, 1994 30 RCT HH 12 

weeks

Post menopausal women Inclusion:

1. > 1 year past their last menstrual pe2. Not on any other HRT3. Cancer free4. Experiencing vaginal discomfort or d

F-592
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearMakkonen, 1993Murkies, 1995Nachtigall, 1994

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Kupperman Index, weight, height, blood presuure, serum estrone, estradiol, testoserone, androstenedione, FSH, LH, SHBG, TSH, total cholesterol, HDL cholesterol, triglycerides and fasting blood glucose

NR NR NR NR NR 3 were 

smokerguar gugroup; none in placebo

Diet diary; flush diary to record daily number of flushes; subjective four point scale of 'general menopause symptoms' (flushes, sweats, palpitations, headache, sleep disturbance, depression, tiredness, irritability/nervousenss, frequency/urge to urinate, vagninitis, loss of libido, dyspareunia; vaginal smears

NR NR NR NR NR Non 

smoker

Pap smear done every 4 weeks with specific criteria for atrophy; Vaginal fluid pH; Vaginal health index

NR NR NR NR NR NR 

F-593
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearMakkonen, 1993Murkies, 1995Nachtigall, 1994

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

Guar gum (Guarem, Orion Pharmaceutica, Espoo, Finland) 5 grams 3 times daily for 6 months

Placebo was wheat flour granules

Both groups improved significantly on the Kupperman scale (p<0.001) at 3 and 6 months from baseline. No difference between groups

NR 

45 grams of 'soy flour' 45 grams of refined 

wheat flour

At 6-weeks there was a significant decrease in hot flashes and general symptom score from baseline in the soy treated group (p<0.05). At 12-weeks there was a significant decrease in hot flashes and general symptom group in both groups (p<0.05) and no significant difference between the 2 flour groups.

Vaginal maturation score did not change within or between flour groups

Replens (a nonhormonal bioadhesive local vaginal mosturizer) 3 times/week for 12 weeks

2 grams of Premarin Vaginal cream daily for 12 weeks

NR Vaginal moisture 

showed significant improvement in both groups at 12 weeks (p<0.005)

F-594
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearMakkonen, 1993Murkies, 1995Nachtigall, 1994

Mood Cognitive Somatic Urinar

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Sexual D

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Main Outcomes (cont.)

NR NR NR NR NR NR NR NR NR Urinary daidzein 

excretion increased signifiantly over 12 weeks in the majority of women in the soy group with signicant difference between groups (p<0.001)

NR NR 

NR NR NR NR NR NR 

F-595
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearMakkonen, 1993Murkies, 1995Nachtigall, 1994

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

See note under hot flashes regarding Kupperman Index scores

3 withdrawals from the placebo group, one due to depression and exhaustion, and two due to travelling. No withdrawals from the guar 

NA NA Biologically 

based therapies

No change in lipid panels between groups

5/28 withdrew from soy group; 6/30 withdrew from wheat group

NR NR Biologically 

based therapies

Soy Prodebitterrefined 

Vaginal elasticity improved in both groups (p <0.02) from baseline; vaginal pH and vaginal fluid volume improved from baseline (p<0.05)

None None None Biologically 

based

F-596
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Nassef, The 10th World Congress on the Menopause. 2002(Abstract Only)

37 RCT P 3 

months

Postmenopausal Egyptian females

NR

Penotti, 2003 62 DB RCT P 6 

months

Women patients attending the outpatient Menopause Clinic at the University of Mulan

Inclusion:1. High FSH and low BE22. LDL < 1603. > 7 hot flashes/day

4. Post menopausal for > 6 months

5. Aged 45-60 years6. T score > -2.5Exclusion:1. Osteoporosis

F-597
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearNassef, The 10th World Congress on the Menopause. 2002(Abstract Only)Penotti, 2003

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

NR NR NR NR NR NR NR Daily diary for hot flash recording NR NR NR NR NR NR 

F-598
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearNassef, The 10th World Congress on the Menopause. 2002(Abstract Only)Penotti, 2003

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

Cimicifuga rhizome 40mg/day

Placebo No difference (p>0.05) between 

groups

NR 

36mg Soy Isoflavones a day

N/A No change between groups, both 

groups had a 40% reduction in hot flashes

NR 

F-599
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearNassef, The 10th World Congress on the Menopause. 2002(Abstract Only)Penotti, 2003

Mood Cognitive Somatic Urinar

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Main Outcomes (cont.)

NR NR NR No difference in 

dysuria or stress urinary incontinence between groups (p>0.05)

NR NR 

NR NR NR NR NR NR 

F-600
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearNassef, The 10th World Congress on the Menopause. 2002(Abstract Only)Penotti, 2003

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

Bone aches were significantly improved in phytoestrogen group (p<0.001); no significant difference between groups in vaginal cytology, bone mineral density, or endometrial thickness (p>0.05)

NR NR NR Biologically 

based

NR 6 in soy group

7 in placebo group

1 from soy group due to diarrheaPersistent hot flashes in the rest

Diarrhea Biologically 

based

F-601
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Rachev, 2001 64 DB RCT P 60 days Women age 40-60 from the 

'maternity ward' of the University Hospital in Sofia, Bulgaria; mean age was 51.5 in LF group and 49.5 in placebo group.

Inclusion:1.Evident anxious-depressive symptomphysiological menopause lasting for at 2. No treatment with phospholipids > 4 

3. No antidepressant or anxiolytic therstudyExclusion:1. Sensory organ deficiency not propeartificial aids 2. Signs or symptoms of foci of cerebr3. Signs or symptoms of other neurolopsychiatric diseases requiring treatmedrugs and/or other antidepressants4. Liver or kidney impairment, severe cdiseases, past or ongoing neoplastic dsever ongoing internal or surgical path5. Proven hypersensitivity to phosphol

Rankin, 1989 40 RCT No 

treatment

2 weeks Women, age 40-60 who 

stated they were experiencing menopausal symptoms; referred to the study by other health professionals and recruited from church groups and various women's organizations. Mean age was 49.3 years, range from 40-58

Inclusion:1. Understand and write English

F-602
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearRachev, 2001Rankin, 1989

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Hamilton Anxiety Scale (HAMA) and the Climacteric Index

NR NR NR NR NR NR 

Neugarten-Kraines Menopausal Index Scale, Sound Wave Audiotapes

41% NR NR NR NR NR 

F-603
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearRachev, 2001Rankin, 1989

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

Liposom Forte (phospholipid liposomes) 28mg/2ml as a single intramuscular injection every other day for a period of 60 days

Placebo injection every other day for 60 days

Significant decline in the climacteric index in LF and P groups from baseline (p<0.001); however more significant decline in LF group (p=0.0013) than P group (NOTE: did include questions of asthenia (p=0.05), dizziness (p=0.024) and restlessness (p=0.019)

NR 

20 minute long low frequency sound wave audiotape developed by Halpern (1978); 3 times/week for 2 weeks

No treatment The sound wave group has 

significant improvement over no treatment in decreased frequency of symptoms (p=0.01), somatic symptoms were decreased (p=0.03) and psychological symptoms were decreased (p=0.029). 

NR 

F-604
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearRachev, 2001Rankin, 1989

Mood Cognitive Somatic Urinar

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Sexual D

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Main Outcomes (cont.)

Decrease in the total HAMA score in both groups was noted (p<0.001); however significantly greater decline in the LF group than the P group (p<0.001); specifically anxious mood (p=0.006), tension (p=0.024) and fear (p=0.009) were significant between groups as well.

NR NR NR NR NR 

NR NR NR NR NR NR 

F-605
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearRachev, 2001Rankin, 1989

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

NR 6/64 Allergy = 1

anxiety = 1; asthenia = 1; drowsiness = 2; hypertension = 1; petechia = 1; increased sweating = 1; paroxysmal tachycardia = 1; weight increase = 1

NR Biologically 

based therapies

Not sur

confirmto meno

NR 6/20 in sound 

group; 7/20 in the control group

4 completed the protocol late, others did not follow instructions, or did not have time.

None Mind-body Poor st

F-606
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Rao, 2003 30 RCT P 2 

months

Women with menopausal symptoms

NR

Russo, 2003 50 DB RCT P 3 

months

Women who were referred to a clinic in Rome, Italy.Average age: 53 yearsAverage age at onset of menopause: 51 years

Inclusion:1. Aged 48-54 years2. Recent menopause (1-2 years LMP3. Symptomatic4. Caucasian5. Negative PAP testExclusion:1. Currently on HRT or off <6 months2. Arterial hypertension or cardiovascu3. Endocrinological pathologies4. Nicotinism5. Obesity6. Alcohol or drug abuse

F-607
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearRao, 2003Russo, 2003

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Menopause-specific Quality of Life NR NR NR NR NR NR Self report questionnaire. NR NR NR Excluded NR Smoke

exclude

F-608
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearRao, 2003Russo, 2003

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

Biogest cream (wild yam)

Placebo Significant effects were noted with 

symptoms of hot flushes, night sweats, and emotional symptoms with dramatic reductions in these symptoms occurring in the BioGest group when compared with placebo.

NR 

32mg/day of Soy (Fitormil)- Specific formulation described in paper

Placebo 11/25 in soy group and 6/25 in 

placebo group described improvement in symptoms (p<0.05)

No significant reductions for either group.

No redgro

F-609
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearRao, 2003Russo, 2003

Mood Cognitive Somatic Urinar

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Sexual D

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Main Outcomes (cont.)

NR NR NR NR NR NR 

No significant reductions for either group on anxiety.

NR NR NR NR NR 

F-610
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearRao, 2003Russo, 2003

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

NR NR NR NR Biologically 

based

Abstrac

NR 3 1 due to 

spotting after 15 days

Spotting Biologically 

based

Cross ofrom firsover.

F-611
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Salmaggi, 1993 80 DB RCT P 30 days Age 45-59 (mean age is 51) 

women patients consecutively referred to an Ob/Gyn department in Italy

Inclusion: 1. Major depression within 6 to 36 monsurgical or natural menopause2. Free of antidepressants for > 1 wee

Exclusion:1. Considered at risk for suicide2. On estrogen therapy 3. Major medical illness or bipolar illne

Sammartino, 2003

70 RCT HH 12 

cycles 

of 28 

days

Women attending Menopause Clinic.Average Age: 51 yearsAverage time since menopause: 17 monthsAverage BMI: 24-26

Inclusion:1. At least 12 months after spontaneou2. FSH > 40 3. Estradiol < 204. At least 7 hot flashes of moderate to 24 hours during last 2 weeksExclusion:1. Neoplastic, metabolic and infectious 2. Concomitant use of any drug3. BMI < 304. Past or concomitant use of HRT or treatment of climacteric symptoms5. Endometrial thickness of >5mm or eabnormalities

F-612
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearSalmaggi, 1993Sammartino, 2003

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

HAM-D-21 (Hamilton Depression Rating Scale) and the RDI (Rome Depression Inventory); MMPI (Minnesota Multiphasic Personality Inventory); CGI-I (Clinical Global Impression Improvement Scale)

Included Included NR NR NR NR 

Kupperman scale - Baseline and 6, 12 months

0 0 0 0 NR NR 

F-613
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearSalmaggi, 1993Sammartino, 2003

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

1600mg SAMe per day divided into 4 doses

Placebo NR NR 

36mg/day of Genistein Calcium supplements Significant decline in Kupperman 

Score for Genistein group (p<0.05).

NR 

F-614
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearSalmaggi, 1993Sammartino, 2003

Mood Cognitive Somatic Urinar

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Sexual D

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Main Outcomes (cont.)

HAM-D-21 decreased significantly (p<0.01) at both day 10 and 30 compared to placebo; also found in RDI (p<0.01), CGII (p<0.01) and depression and psychoasthenia scale of MMPI (p<0.01) compared to placebo.

NR Questions 11-16 

on the HAM-D-21 pertaining to somatic symptoms improved significantly from placebo at both day 10 and 30 (p<0.01)

NR NR NR 

NR NR NR NR NR NR 

F-615
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearSalmaggi, 1993Sammartino, 2003

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

NR 10/40 from 

each group due to poor compliance

NR NR Biologically 

based

All women in Genistein group had decreased climacteric symptoms (but not specified by symptom).

3 in Genistein4 in Calcium

None None Biologically 

based

F-616
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Sandberg, 2002 30 RCT HH 14 

weeks, 

Followup at 6 

months

Women age 48-60, natural menopause of at least 6 months were recruited through advertisements in the local press and at gynecological outpatient clinics.

Inclusioin:1. FSH and estradiol levels confirms pstate2. Natural menopause of > 6 months

3. Aged 48-60 years Exclusion:1. Severe metabolic, thromboemboic, malignant disease, uncontrolled hyper2. Use of medication that could interfesymptoms

Scambia, 2000 39 DB RCT P 12 

weeks

Women who were outpatients at Italian hospital (mean age was 54 + 7.1 

years)

Inclusion:1. Spontaneous amenorrhea > 12 mon

2. Surgical or early menopause3. Normal endometrial thickness by ultmammography, and metabolic and biowithin normal range

F-617
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearSandberg, 2002Scambia, 2000

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Visual Analog Scale (VAS)SCL-90

Unclear Not 

included

Not 

included

NR NR Similar 

rates of smokinexercis

Vasomotor symptoms were evaluted usina a special score card and the Greene climacteric scale. Special score card was filled out daily to evaluate the number and severity of hot flushes and brought it to each visit

NR 1/50 1/50 NR NR NR 

F-618
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearSandberg, 2002Scambia, 2000

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

Electro acupuncture (EA)

Extremely superficial needle insertion

Both groups showed improvement in VAS at 3 and 6 months

NR 

Standardized soy extract containing 12% isoflavones and 35% saponins in a tablet which was 200mg SOYSELECT 2/day which would correspond to 50mg/day of isoflavones. After 6 weeks of treatment Premarin was also given to each participant at a dose of 0.625 for 4 weeks

Placebo tablet containing lactose

In the first 6-weeks of treatment, participants who were taking the standardized soy extract had a significant reduction (p<0.01) in the mean number of hot flushes/week as compared with placebo. Once the Premarin was started both groups had a decrease in hot flushes and there was no significant difference between groups. 

After 6 weeks of treatment, the group that was taking the standardized soy extreact had a significant reduction (p<0.001) in the mean point values 19 and 20 of Greene scale (hot flushes and night sweats) compared with placebo.

F-619
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearSandberg, 2002Scambia, 2000

Mood Cognitive Somatic Urinar

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Main Outcomes (cont.)

Significant improvement in mood at 12 weeks in EA group compared to baselineBoth groups improved in SCL-90

NR NR NR NR NR 

NR NR NR NR NR NR 

F-620
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearSandberg, 2002Scambia, 2000

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

NR 4/15 

Superficial needle insertion4/15 EA

Hot flashes Hot flashes Alternative 

health care systems

NR 20 were 

analyzed in soy extract group suggesting no withdrawals

Nausea in 1 placebo member

NR Biologically 

based

F-621
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

SimkinSilverman, 2003 535 RCT Lifestyle vs. 

assessment only

5 years Women were recruited from 

the WHLP clinical trials and were seen at the Health Studies Clinic at the University of Pittsburg.

Inclusion:1. Aged 44-50 years2. Premenopausal by self report3. Not taking HRT4. BMI was 20-34Exclusion:1. Women taking lipid-lowering medicaantihypertensive medication, insulin, thor psychotropic medications

St. Germain, 2001

69 RCT Placebo 24 

weeks

Telephone interviews of age 42-62 year old women; 

Inclusion:1. > 10 hot flushes and/or night sweats

months of their last menstrual cycle2. Free from chronic diseases (cardiovosteoporosis) or chronic medication us3. Not taking HRT or ERT at the time omonths previously4. 1 or both ovaries remaining5. BMI 20-316. FSH>30.

F-622
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearSimkinSilverman, 2003St. Germain, 2001

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Weight, BMI and body fat were measured.Paffenbarger Activity QuestionnaireThe Block Food Frequency Questionnaire

NR NR NR NR NR NR 

5 day Menopausal Index (modified from the Blatt instrument, 1953) at baseline, week 12 and week 24

11 

with 

intact 

ovaries

Excluded NR NR NR Non 

smok

F-623
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearSimkinSilverman, 2003St. Germain, 2001

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

Behavioral, dietary and physical activity intervention

N/A NR NR 

SPI+ (Supro 675 HG; Protein Technologies International, St. Louis, MO = 80.4 mg/day aglycone components which are the unconjugated parent forms of isoflavones)

SPI- (Supro 675 IF; Protein Technologies International) = 4.4 mg/day aglycone components; Group 3 consumed whey protein (control) produced by ProMod; Ross Laboratories, Columbus, Ohio 

No treatment effect on the change in frequency of hot flushes; time of study from baseline did have a significant effect on hot flush frequency in all groups (p.0.003)

No significant difference among the three groups at any time point

F-624
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearSimkinSilverman, 2003St. Germain, 2001

Mood Cognitive Somatic Urinar

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Main Outcomes (cont.)

No signs of increased stress or depressive symptoms in intervention group

NR NR NR NR NR 

No significant difference among the three groups at any time point

NR NR No significant 

difference among the three groups at any time point

NR No signific

difference the three at any tim

F-625
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearSimkinSilverman, 2003St. Germain, 2001

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

Women lost significantly more weight in the intervention group (p<0.001), remained more active (p<0.001) and consumed fewer calories (p<0.01) than the control group.

14/260 Intervention12/275 Control

NR NR Mind-body 5 year p

intense (cognitiand low of weig

NR 1/69 None NR Biologically 

based therapies

F-626
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Teoman, 2004 81 RCT Control 

Usual 

care

6 weeks Volunteer postmenopausal 

women (average age 51.0 + 

3.9 years)

Inclusion:1. Natural menopause2. Taking HRT > 1 year (0.625 mg est

medroxyprogesterone/day)3. Aged 45-65 years old4. No health problems that may prevenexercise5. No high cardiac risk

Thompson, 2002(Abstract only)

53 DB RCT P 16 

weeks

Women with breast cancer with menopausal symptoms

NR

F-627
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearTeoman, 2004Thompson, 2002(Abstract only)

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

6 minute walking test, vertical jump test, static back extension test, sit up test, side bending test, sit and reach test, balance test, quality of life using the Nottingham Health Profile

NR Excluded NR NR NR NR 

Measure Yourself Medical Outcome Profile (MYMOP), Hospital Anxiety and Depression score, European Organization for Research and Treatment in Cancer Quality of Life Score, Menopausal Symptom Scale

NR NR NR Included NR NR 

F-628
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearTeoman, 2004Thompson, 2002(Abstract only)

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

6 weeks aerobic exercise programme

Non-exercise control group

NR NR 

Homeopathic intervention

Placebo Both groups showed significant 

improvement over the study period by an average of 80%. No statistically significant difference betweeen groups

NR 

F-629
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearTeoman, 2004Thompson, 2002(Abstract only)

Mood Cognitive Somatic Urinar

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tio

Main Outcomes (cont.)

NR NR NR NR NR NR NR NR NR NR NR NR 

F-630
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearTeoman, 2004Thompson, 2002(Abstract only)

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

NR NR NR NR Exercise

Mind/body

Turkey

NR 8/43 NR NR Biologically 

based therapies

Abstrachomeopfound. 

F-631
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Tice, 2003 252 DB RCT HH 12 

weeks

Women were recruited from 3 academic clinical research sites in Oakland, CA; Minneapolis, MN, and Iowa City, Iowa from the general population through newspaper and radio advertising, flyers posted in clinics and at health fairs, and directed mailings

Inclusion:1. Age 45-60 years old2. Experiencing > 35 hot flashes/week

3. FSH > 304. > 2 consecutive months of amenorr

enrollment with > 6 months of amenor

prior to entry, or documented bilateral Exclusion:1. Vegetarians2. Consumed soy products more than 3. Took medications affecting isoflavon(antibiotics, antacids) or hormonal prethe three months prior to enrollment4. Significant gastrointestinal disease5. > 2 alcoholic beverages/day6. Allergic to red clover7. Regular users of dietary supplemenisoflavones8. Consumed less than 80% of the exptablets during the 2-week placebo run-

Unfer, 2004 376 DB RCT P 5 years Healthy voluntary 

postmenopausal women; mean age was 49 + 4.3 

years in soy group; 50 + 3.9 

years in placebo group

Inclusion:1. Intact uterus2. Absence of menses for > 12 months

3. FSH >304. Body weight range within 20% of noExclusion:1 Use of medication containing estrogandrogens within 8 weeks of the begin2. Presence of endometrial hyperplasi

F-632
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearTice, 2003Unfer, 2004

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Greene Climacteric Scale; used the psychological (anxiety and depression), somatic, vasomotor, and sexual desire; hot flash diary cards

NR Allowed NR NR NR Exclude

drank >alcoholbeveraday

Endometrial biopsies at the beginning of the study, after 30 months, and at the end of the study

Excluded Excluded NR NR NR NR 

F-633
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearTice, 2003Unfer, 2004

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

Promensil contains an average of 41.0 mg of total isoflavones/tablet (red clover containing a higher proportion of biochanin A and genistein); Rimostil contains average of 28.6 mg of total isoflavones and a higher proportion of formononetin and daidzein. Participants took two tablets daily.

Placebo that had less than 0.04 mg total isoflavone

Decrease in hot flush count was significant for all three groups (p<0.001), however, the hot flash reductions in the phytoestrogen groups were not statistically different from placebo at 12 weeks (p>0.20).

NR 

Soy tablets (3/day) equaled 150mg/day of isoflavones; isoflavones were 40-45% genistein, 40-45% diadzein, and 10-20% glycitein

Placebo NR NR 

F-634
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearTice, 2003Unfer, 2004

Mood Cognitive Somatic Urinar

y Uterine Bleeding

Sexual D

tio

Main Outcomes (cont.)

NR NR NR NR NR NR NR NR NR NR NR NR 

F-635
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearTice, 2003Unfer, 2004

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

Greene Symptom Scales; over the 12-week treatment period, there were significant improvements from baseline in all three groups, but there was no statistically significant differences between groups on any of the Greene scales

6/252 withdrew 2 from each of the 3 arms; 84 participants were in Promensil group; 83 participants were in Rimostil group; 85 participants were in placebo group

1 from the Rimostil group

There was no statistically significant association of either of the dietary supplements with adverse events

Biologically based

No cases of endometrial hyperplasia or malignancy were detected at 30 months; at 5 years, 6 cases of endometrial hyperplasia were detected in Group A (soy), none in Group B (p<.05) (control)

7 withdrew at 30 months; and 50 more withdrew by 5 years

NR NR Biologically 

based

Significyears

F-636
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Upmalis, 2000 177 DB RCT P 12 

weeks

Postmenopausal women age > 50 years

Inclusion:1. Overall good health2. Body weight within +/- 35% range fo3. FSH >404. Estradiol levels of 25 pg/mL or less5. Average of > 5 vasomotor symptom

6. No menses for at least 6 months 7. Discontinued HRT use at least 60 dentryExclusion:1. History of breast cancer, hyperplasicarcinoma, or cervical neoplasia2. Positive pregnancy test3.Undiagnosed abnormal vaginal blee4. Bilateral oophorectomy or hysterect5. Thromboembolic disorders6. History of cardiovascular disease7. Liver disease8. History of chronic alcoholism9. Medication hypersensitivity, or allergsupplement ingredients10. Uncontrolled addiction or severe d11. Acute systemic infection12. Abnormal laboratory values

Valente, 10 world congress on the menopause, 2000

(Abstract Only)

100 RCT HH NR Menopausal women NR

F-637
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearUpmalis, 2000Valente, 10 world congress on the menopause, 2000(Abstract Only)

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Daily symptom dairy cards for recording the number and severity of hot flushes and night sweats

Excluded Excluded NR Excluded NR NR 

Neurovegetative symptoms, vaginal dryness, endometrial pattern, lipids, bone density

NR NR NR NR NR NR 

F-638
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearUpmalis, 2000Valente, 10 world congress on the menopause, 2000(Abstract Only)

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

Soy isoflavone extract tablet. The extract was standardized for total content of genistin and daidzin (approximately 50% each). The dose contained in two tablets taken once daily was approximately 50mg in total of genistin and daidzin

Placebo There was a significant (p<0.05) 

change from baseline in both the number and the severity of hot flushes in both treatment groups. Analysis showed a statistically significant reduction (p=0.01) in average hot flush severity over the 12 weeks in the soy isoflavone extract tablet group compared with the placebo group. Marginally significant (p=0.078) reduction in the number of hot flushes in the soy isoflavone extract tablet group compared with the placebo group; No statistically significant difference between the two groups at 12 weeks (p>0.05) in frequency of night sweats

NR 

50 women treated with phytoestrogens (25 with oral and 25 with patch, 75mg/day)

50 with HRT, patch (Estradiol 2.5mg and Levonorgestrel 1mg)

"Phytoestrogen therapy cannot be considered as valid as HRT"

NR 

F-639
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearUpmalis, 2000Valente, 10 world congress on the menopause, 2000(Abstract Only)

Mood Cognitive Somatic Urinar

y Uterine Bleeding

Sexual D

tio

Main Outcomes (cont.)

NR NR NR NR NR NR NR NR NR NR NR NR 

F-640
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearUpmalis, 2000Valente, 10 world congress on the menopause, 2000(Abstract Only)

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

NR 31/90 those 

randomized to soy group withdrew; 24/87 withdrew from placebo group

Failure to meet inclusion/exclusion criteria; protocol violations; voluntary discontinuation;

NR Biologically 

based therapies

Odd sturandomscreenicriteria

NR NR NR NR Biologically 

based

F-641
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

van de Weijer, 2002

30 DBRCT P 12 

weeks

Symptomatic postmenopausal women, age 49-65

Inclusion:1. > 5 hot flushes/day 

2. > 12 months amenorrhea Exclusion:1. HRT or antibiotics within 12 weeks o2. Undiagnosed vaginal bleeding, activdisease3. History of allergy for foodstuffs4. Previous history of malignancy, cardor thromboembolism

Washburn, 1999 51 DB RCT HH 6 weeks 

then 

crossover

Perimenopausal women aged 45-55 years; women were recruited through advertisements in a local newspaper

Inclusion:1. Presence of menopausal symptoms 

or night sweat daily)2. Not currently using HRT (or any HRmonths)3. Missing > 3 menstrual periods in the 

and having last menstrual period not > participating in the study

F-642
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Yearvan de Weijer, 2002Washburn, 1999

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Greene Climacteric Scale; self-reported diaryUrinary isoflavone levels

NR NR NR Excluded NR NR 

Self reported symptom diary of hot flashes and night sweats; both frequency and severity; A health related quality of life questionnaire was administered at baseline and at the end of each 6 week intervention period. Using the health related quality of life questionnaire data, an overall symptoms core was calculated by using the Likert scale information for the following content specific areas: estrogenic symptoms, general health, sleep disturbances, and gastrointestinal symptoms. Specifically, the estrogen symptom score was calculated to provide a continuous estimate of the intensity/frequency of symptoms known to be estrogen-dependent (vasomotor symptoms, vaginal dryness, sleep disturbances, breast tenderness, mood 

NR NR NR NR NR NR 

F-643
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Yearvan de Weijer, 2002Washburn, 1999

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

Red clover (Promensil) 80 mg/day

Identical placebo No difference in the hot flush 

count between the 2 groups at baseline 1. At week 12 there had been a significant decline in hot flushes in the isoflavone users (p=0.0154)

NR 

Group 1: 20 grams complex carbohydrated supplement containing no phytoestrogen; Group 2: 20 grams of soy protein supplement containing 34 mg phytoestrogen/day; Group 3: 20 grams soy protein supplement containing 34 mg phytoestrogens split into two equal doses consumed twice daily.

All supplements were provided by Protein Technologies International, St. Louis, Missouri. All identical appearing packets

No significant differences were observed in the number of hot flushes or night sweats/week; however, severity of hot flashes was lower in the soy groups vs. the carbohydrate group (p<0.001)

NR separately No 

difgro

F-644
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Yearvan de Weijer, 2002Washburn, 1999

Mood Cognitive Somatic Urinar

y Uterine Bleeding

Sexual D

tio

Main Outcomes (cont.)

NR NR NR NR NR NR NR NR NR NR NR NR 

F-645
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Yearvan de Weijer, 2002Washburn, 1999

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

Isoflavone urinary excretion increased significantly for women in the active treatment group (p=0.027). (p=0.0005) from baseline of 4 week washout period

3/16 red clover group; 3/14 control group

ZeroWithdrawals were due to lack of efficacy

N/A Biologically 

based therapies

Red clofrom thusing a and bleproprietgenisteformono

Estrogenic symptom score' was significantly different from the comparison group (p<0.05)

9/51 5 had personal 

reasons; 1 did not want to use aspartame, 1 remembered she was allergic to soy and 1 had a recurrence of acne rosacea

NR Biologically 

based

F-646
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Wiklund, 1999 384 DB RCT P 16 

weeks

Women were recruited through advertisements in newspapers. Women seeking medical assistance due to climacteric symptoms were asked to participate in the trial as well.

Inclusion:1. Healthy postmenopausal women, a2. No HRT for the previous 2 months 3. No bleeding during the previous 6 m4. 6 episodes of hot flushes during at ldays. Exclusion:1. Previous or concomitant serious or conditions2. Uncontrolled hypertension (>160/953. Psychiatric illness4. Unable to understand and complete questionnaires5. Taking tranquilizers

Williamson, 2002

80 RCT HH 19 

weeks

Women age 45-60 with no period for 3 months.Recruited by means of notices placed in primary care surgeries.

Exclusion:1. Current HRT use or psychoactive m2. Severe pathology of feet3. Previous reflexology treatment4. Current CAM treatment for menopa5. History of severe psychological illne

F-647
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearWiklund, 1999Williamson, 2002

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Women's Health Questionnaire; Psychological General Well-being Index; Visual Analog Scales (VAS); selfreported diary

NR NR NR Excluded NR NR 

Women's Health Questionnaire; VAS for severity of flushes and night sweats, MYMOP, a validated, self-completed measure of quality of life

NR NR NR NR NR NR 

F-648
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearWiklund, 1999Williamson, 2002

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

Standardized ginseng extract (Ginsana, containing 100mg of the standardized ginseng extract G115; Pharmaton SA, Lugano, Switzerland); 2 capsules/day

Placebo Both treatments improved 

vasomotor symptoms compared with baseline (p<0.05), with no indication that the ginseng was superior to placebo; No statistically significant difference between treatments was observed in vasomotor symptoms even though a considerable decrease in these symptoms was noted for both treatments

NR 

Reflexology weekly for 6 weeks then monthly for 3 months

N/A No change between groups NR No 

gro

F-649
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearWiklund, 1999Williamson, 2002

Mood Cognitive Somatic Urinar

y Uterine Bleeding

Sexual D

tio

Main Outcomes (cont.)

Statistically significant differences (p<0.05) were detected for depression, wellbeing and health subscales of the PGWB in favor of the ginseng extract compared to placebo

NR NR NR NR NR 

AnxietyDepression no change between groups

No change between groups on memory/ concentration

No change between groups

NR NR NR 

F-650
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearWiklund, 1999Williamson, 2002

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

NR 3/193 ginseng 

group; 2/191 placebo group

1/193 in the ginseng group due to nausea and lack of efficacy

See withdrawals

Biologically based

Feelings of attractiveness no change.p>0.2 for time-group interaction.p<0.001 - strong time effect evidence

5/38 control6/42 reflexology

No reasons stated

None reported Energy 

Therapy

F-651
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Woo, 2003 136 RCT HH 3 

months

50-65 year old women with no periods for the past 12 months; contacted as part of a territorywide survey and random sampling of housing estates, and participants who are registered with the Family Medicine clinic of the Chinese University of Hong Kong

Inclusion:1. No period for 12 monthsExclusion:1. Hypertension, ischemic heart diseasdementia, diabetes, thyrotoxicosis, brelump/malignancy, or abnormal Pap sm2. Taking lipid lowering drugs or HRT

Wuttke, 2003 62 DB RCT HH, P 12 

weeks

NR Inclusion:

1. Postmenopausal women, 40-60 yea2. BMI < 303. Last menstrual bleeding at least 6 m4. FSH>255. > 3 hot flushes/day

6. Menopause rating scale (MRS) itemscores >1.7 at visits 1 and 2; MRS item >0.3 at visits 1 and 2. 

F-652
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearWoo, 2003Wuttke, 2003

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Menopausal symptoms questionnaire; MMSE, plus four neuropsychological tests covering measurement of memory (Hong Kong List-Learning test, attention (Trail Making test), motor speed (Finger Tapping Test), and word-finding ability (Boston Naming Test), quality of life (SF36), Food Frequency Questionnaire; lipid profile; urinary deoxypyridinoline; dietary phytoestrogen intake and urinary phytoestrogen; estradiol; FSH and LH

24% 18% NR Excluded NR 100% 

smoke

Menopausal rating scale NR NR NR NR NR NR 

F-653
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearWoo, 2003Wuttke, 2003

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

Pueraria lobata (PL)Isoflavone 100mg/day; plus a control group where women were given no treatment

HRT; Premelle (Wyeth) containing conjugated equine estrogen (o.625 mg) for first 14 days followed by 14 days of combination of estrogen plus progesterone (5mg)

No significant change in menopausal symptoms between baseline and 3 months in any of the groups

NR 

Cimicifung racemosa (CR BNO 1055) brand name Klimadynon/Menofem, correlating to 40mg herbal drug/day; and placebo

Conjugated estrogen 0.6mg/day

MRS items 1-3 (#1 related to hot flashes) were significantly reduced by the CE compared to placebo (p=0.0461). CR BNO 1055 showed a marked difference to placebo, without reaching the level of significance. 

NR 

F-654
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearWoo, 2003Wuttke, 2003

Mood Cognitive Somatic Urinar

y Uterine Bleeding

Sexual D

tio

Main Outcomes (cont.)

NR 1. No change in any 

group except MMSE increased for both HRT & PL2. Delayed recall improved in HRT vs. control3. Attention span better in HRT & PL4. Performance in flexible thinking best in PL group

NR NR NR NR 

NR NR Factor 3 

(questions 7-10 on the MRS scale) which relate to urinary and sexual symptoms did show significant improvement with the black cohosh vs placebo (p=0.0218); CE approached significance (p=0.0503)

NR NR NR 

F-655
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearWoo, 2003Wuttke, 2003

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

NR 5/48 HRT

2/47 PL2/41 control

HRT = abdominal pain, distension, and acne or too busy; PL group = urticaria and being too busy; control group = being too busy

Abdominal pain, distention, acne, too busy, urticania

Biologically based

p valueregardiprobab

NR NR NR NR Biologically 

based

This stuone stuas effecestrogesymptomisquostatisticany on only cosignifica

F-656
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/Year N

Type of 

Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Wyon, 1995 24 RCT P 3 

months

"Ordinary" women patients who attended the outpatient clinic because of vasomotor symptoms and were primarily interested in HRTMedian age was 54 with a range from 47-62

Inclusion:1. Healthy women with vasomotor sym2. Natural menopause at least 1 year pExclusion:1. Severe metabolic, thromboembolic, disease2. Uncontrolled hypertension (>95mg 

Wyon, 2004 45 RCT HH, P 12 

weeks 

with 6 

month 

followup

Local newspaper and gynecological clinic in Sweden

Inclusion: 1. Healthy women with vasomotor sym2. Age 48-63 years3. Natural menopause > six months pr

hysterectomy, however, none had bilaoophorectomy)Exclusion: 1. Severe metabolic, thrombo-embolicdisorders2. Severe hypertension (>95mg Hg dia3. Use of sedatives, anxiolytics, or antnarcotics. 

Yoles, 2002 (Abstract Only)

102 RCT P 6 

months

NR NR

F-657
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearWyon, 1995Wyon, 2004Yoles, 2002 (Abstract Only)

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behav

or 

Lifest

Facto

(#/n

Specific Characteristics of Population

Daily symptom dairy; Psychological General Well-Being Index; Sleep Dysfunction Test; modified Kupperman Index

Excluded Excluded Excluded NR NR NR 

Kupperman Index; visual analog scale; self-reported daily symptom diary of frequency and severity of menopausal symptoms

4/45 Excluded NR NR NR Exclude

exercis> 1 hour/we20-31% smoker

Detailed questionnaire regarding patients 15 variables of patients menopausal complaints

NR NR NR NR NR NR 

F-658
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearWyon, 1995Wyon, 2004Yoles, 2002 (Abstract Only)

Main Drug type; 

dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Vaginal Dryness 

Treatment Main Outcomes

Acupuncture to VB 15, 

23, 32; GV20; H7; P6; LIV3; SPG, Each treatment given twice a week for 2 weeks and once week for 6 weeks for 30 minutes each.

Superficial needle insertion

No significant differences were found between groups on any measure, before, during, or 3 months after treatment; Number of hot flushes/day decreased significantly in both groups from before to the first as well as the second treatment period (p=0.013 and 0.0033 in the EA group, p = 0.005 and 0.0093 in the SNI group)

NR 

Electro acupuncture (EA) 14 treatments over 10 weeks sites BL 15, 23, 32, HT 7, SP 6, 9 LR 3, PC 6, GV 20

Conjugated estrogen 0.625mg/day vs. superficial needle insertion (SNI) (sham acupuncture) at Baseline, Week 15, 23, and 32

Hot flushes decreased in all 3 groups over the 12 weeks (p<0.001); these results persisted at the 6 month followup.

NR 

Tofu based concentrated phytoestrogen

Placebo Hot flushes decreased in 76% of 

the patients treated by phytoestrogen vs 19% of placebo group (p<0.001)

NR Sle

imtakph16(p<

F-659
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearWyon, 1995Wyon, 2004Yoles, 2002 (Abstract Only)

Mood Cognitive Somatic Urinar

y Uterine Bleeding

Sexual D

tio

Main Outcomes (cont.)

PGWB index did not change significantly in any group during treatment

NR NR NR NR NR 

NR NR NR NR NR NR 

Nervousness improved in 56% taking phytoestrogen vs 14% placebo (p<0.001)

NR NR NR NR NR 

F-660
Appendix F. Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Study/YearWyon, 1995Wyon, 2004Yoles, 2002 (Abstract Only)

Other Outcomes Withdrawals

Withdrawals 

due to AEs

Adverse 

Effects

NCCAM 

Category 

Visual analog scale decreased significantly in the EA group but not the SNI group (p=0.008); Kupperman Index decreased significantly in both groups (p<0.05) and persisted for 3 months after treatment

3/24 due to noncompliance with log books

None None Alternative 

Health Systems

All 3 groups had significant improvement in Kupperman Index and visual analog scale (p<0.001); these results persisted at the 6 month followup

4/15 in electroacupunc-ture group; 3/15 in superficial needle insertion group; 6/15 in estrogen group

None None Alternative 

Systems

77% decrease in PE group vs 17% in placebo group (p<0.001); no change in endometrial thickness

NR NR NR Biologically 

based

Done in 

F-661
Appendix F: Evidence table 6-8. Key Question 3G-I complementary and alternative therapies

Key/Abbreviations

AE = Adverse effects PMR = Progressive muscle relaxation

BDI = Beck Depression Inventor

y POF = Premature ovarian failure

BMI = Body mass inde

x POMS = Profile of Mood States

BSO = Bilateral Salpingo Oophorectom

y QoL = Quality of life

CAM = Complimentary and Alternative Medicin

e R = Reading

CE = Conjugated estrogen RCT = Randomized controlled trialCGI = Clinical Global Impression Improvement Scale RDI = Rome Depression Inventor

y

CMH = Chinese medicinal herbs RR = RelaxationDB = Double blind SAMe = S-adenosyl-L-methionin

e

EA = Electro acupuncture SD = Standard deviationERT = Estrogen replacement therap

y SERMs = Selective Estrogen Receptor M

G/D = Genisten and Diadzin combination therap

y SNI = Superficial needle insertion

GI = Gastrointestinal TCM = Traditional chinese medicineHAMA = Hamilton Anxiety Scal

e TIA = Transient ischemic attack

HAM-D-21 = Hamilton Depression Rating Scale VAS = Visual Analogue Scal

e

HH = Head to head WHLP = Women's Healthy Lifestyle ProjeHRT = Hormone replacement therapy WHQ = Women's Health QuestionnaireHST = Heat stress testKK = KavaKav

a

LF = Liposom Forte (phospholipid liposomes)LMP = Last menstrual period MENQOL = Menopause Specific Quality of Life Questionnair

e

MMPI = Minnesota Multiphasic Personality Inventor

y

MMSE = Mini-mental Status ExaminationMRQ = Menopause Representation QuestionnaireMRS = Menopause rating scaleMSQ = Menopause symptoms questionnaireMYMOP = Measure Yourself Medical Outcome ProfileNA = Not applicableNHP = Nottingham Health ProfileNR = Not reportedOC = Oral Contrace

ptives

P = PlaceboPE = PhytoestrogenPGWB-I = Psychological General Well-being IndexPL = Pueraria lobata

F-662
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year N Type of Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Barton, 1998 125 RCT crossover P 9 weeks Women over age 18 with a history of breast cancer. Inclusion: 1. Hot flashes for > 1 month with a freque

week.2. Life expectancy > 6 months.

3. ECOG performance status of 0 or 1.4. Tamoxifen allowedExclusion:1. Current or planned therapy with corticoprogestational agents, estrogens, androgany other agen used for treating hot flashof vit E daily.2. Pregnant or lactating women.3. Women with a history of bleeding tenddeficiencies or thrombophlebitis.

Barton, 2002 (abstract)

80 Open trial HH 4 weeks NR NR

F-663
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Barton, 1998Barton, 2002 (abstract)

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or 

Lifestyle 

Factors

(#/n)

Rece

discon

uation 

HRT

(#/n

Documentation of hot flashes number and severity using a diary questionnaire (cites Bergman, Loprinzi studies).

NR NR NR 100% 54% Vitamin 

use in Table 1

NR 

Hot flash diary: frequency and score (daily frequency x score)

NR NR NR 100% NR NR NR 

S

pecific Characteristics of Po

pulation

F-664
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Barton, 1998Barton, 2002 (abstract)

Main Drug type; dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Va

Vitamin E succinate 800 IU daily for 4 weeks followed by placebo 

Placebo for 4 weeks followed by vitamin E

At the end of 4 weeks, HF frequency decreased 25% in vitamin E group as compared to 22% in the P (p=0.90). HF score decreased 28% with vitamin E and 20% with P (p=-0.68). Both groups had statistically significant within group decreases by Wilcoxon's sign rank.At the end of 9 weeks, vitamin E/P group had decrease in HF frequency and HF score that was greater than the P/vitamin E group, P<0.05, no data given

Venlafaxine, nefazodone, citalopram, mirtazapine

Venlafaxine decreased HF score to 47% of baseline (n=47)Nefazadone decreased HF score to 37% of baseline (n=6)Citalopram decreased HF score to 40% of baseline (n=14)Mirtazapine decraesed HF score to 38% of baseline

Treatment Main Outcomes

F-665
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Barton, 1998Barton, 2002 (abstract)

Mood Cognitive Somatic Urinar

y

Uterine 

Bleeding Sexual Dysfunc-tion 

NR NR NR NR NR NR NR NR NR NR NR NR 

Main Outcomes (contiued)

F-666
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Barton, 1998Barton, 2002 (abstract)

Other Outcomes Withdrawals Withdrawals due to AEs Adverse Effects 

102 women responded to question about preference at the conclusion of the study:32% preferred vitamin E; 29% preferred placebo; 38% did not have a preference.

4 prior to initiation of drug.

None No significant 

differences in reporting of:1. headaches16/120 in vitamin E; 17/120 in P (p=0.85)2. nausea 11/120 in vitamin E; 11/120 in P (p=0.99)3. fatigue 20/120 in vitamin E; 25/120 in P (p=0.31)4. other: 18/120 in vitamin E; 13/120 in P (p=0.43).

125 women raplacebo group their medicatioRCT cross-oveage (18-49 vs tamoxifen use(>/< 9 mo), avflushes and cu

"these antidepressants appear to ameliorate other menopausal related symptoms such as difficulty sleeping, anger and depression."

NR NR NR Pilot of 4 anti-d

(venlafaxine, nmirtazapine)

F-667
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year N Type of Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Bertelli, 1999 (abstract)

71 Open label 

Randomized 

HH 6 weeks NR 71 post-menopausal breast cancer surviv

HF/week.

Carpenter, 2002

15 RCT crossover P 72 hours ecah 

arm 

followed 

by 2 

days 

observat

ion 

period 

and 10 

day 

washout

Postmenopausal women >18 years (some 

postmenopausal at early age due to chemotherapy)

Inclusion:1. Women > 18 years

2. 1st time diagnosis of breast cancer3. No other type of cancer4. Currently free of cancer or competing t5. > 12 months of ammenorrhea6. Expereincing HF7. Able to speak, write, and read EnglishExclusion:1. Contraindication to magnets (i.e. impla2. Concurrent use of magnets for other sy3. Concurrent use of other HF treatments

F-668
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Bertelli, 1999 (abstract)Carpenter, 2002

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or 

Lifestyle 

Factors

(#/n)

Rece

discon

uation 

HRT

(#/n

S

pecific Characteristics of Po

pulation

HF frequency and score NR NR NR 100% NR NR NR 1. HF monitor - ambulatory sternal skin conductance monitoring2. HF diary (number of HF, date/time, severity 0-10, degree of bothered 0-10)3. HF related daily interference scale (HFRDIS) - 10 item scale measures degree to which HF interferes with 9 daily activities and overall quality of life

NR NR NR 100% NR NR NR 

F-669
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Bertelli, 1999 (abstract)Carpenter, 2002

Main Drug type; dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Va

Treatment Main Outcomes

Depot IM medroxyprogesterone acetate (MPA) 500 mg IM on days 1, 14, and 28 vs oral megestrol acetate (MA) 40 mg/day for 6 weeks.

MPA vs MA HF frequency was reduced by 87% and 

HF score was reduced by 89% as compared to baseline, with no significant diffferences between groups.Response (>50% reduction in HF) observed in 28/37 (75%) off MPA and 22/34 (64%) of MA groups, p=0.7Follow-up 6 months after randomization:25/28 (89%) of MPA vs 10/22 (42%) MA maintained response (p<0.001).

6 magnetic devices attached to participants skin over accupuncture/accupressure sites used to balance energy and treat HF.Accupressure sites located by 2 licensed accupuncturists. Study nurses affixed devices and covered with gauze and tegaderm magnetic device (hard plastic outer layer with 4 separate magnets of alternating polarity (+,-,+,-). Magna Bloc.

Placebo was identical in size, shape and weight (but blinding was not possible due to the distinctive magnetic properties of the treatment devices).

HF frequency decreased from 9.55 + 6.7 

to 8.27 + 6.56 in the magnet group and 

from 10.45 + 5.89 to 6.64 + 5.82 in the P 

group (p=0.02).HF severity showed no significant difference between groups.HF botherersome decreased from 4.18 + 

2.41 to 4.07 + 2.68 for the magent group 

and from 4.4 + 2.34 to 3.21 + 2.85 in the P 

group (p=0.02)HF interference scale was reduced in both groups, but no signficicant differences were found between groups.

F-670
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Bertelli, 1999 (abstract)Carpenter, 2002

Mood Cognitive Somatic Urinar

y

Uterine 

Bleeding Sexual Dysfunc-tion 

Main Outcomes (contiued)

NR NR NR NR NR NR NR NR NR NR NR NR Ov

siggro

F-671
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Bertelli, 1999 (abstract)Carpenter, 2002

Other Outcomes Withdrawals Withdrawals due to AEs Adverse Effects 

NR NR NR "less side effects 

were reported with MPA than MA"2 MPA vs 7 MA pts had vaginal bleeding.0 MPA vs 6 MA stopped treatment early for toxicity.

NR Only 11 

participants (of 15) completed both arms of the study.

Reasons for 4 not completing the 2nd arm of the study.Perspiration (unable to keep device attached to skin) = 1Lack of interest = 2Itching from tape = 1

Several problems were reported in both placebo and magnet arms in first week (27%)1 - Perspiration1 - Redness1 - ItchingBy end of 2nd week 6 reported itching.Willingness to continue with placebo was 8.2 vs. treatment at 9.3

Data not preseNo wash out parms of cross-

F-672
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year N Type of Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Ganz, 2000 76 RCT Usual 

Care

4 

months

Mean age: 54.5 yearsDisease-free, female breast cancer patients between 8 months and 5 years after diagnosis of stage I or II disease

Inclusion:1. Perimenopausal or postmenopausal (dammenorrhea > 6 months)2. All chemotherapy or radiation therapy 

prior to enrollment, but could be taking ta3. Presence of > 1 target symptom that w

severe in intensity4. Willing to accept behavioral or pharma> 1 target symptom

Exclusion:1. History of other cancers except non-m2. Serious medical conditions that might assessment of helath related quality of life3. An abnormal Pap smear showing dyspchanges4. curent symptoms of majoy psychiatric being treated or were not being controlled 5. Inability to read and write English6. Active alcohol or substance abuse7. Use of ERT within the past 3 months8. Major cognitive impairment or inability consent

F-673
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Ganz, 2000

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or 

Lifestyle 

Factors

(#/n)

Rece

discon

uation 

HRT

(#/n

S

pecific Characteristics of Po

pulation

1. Menopausal Symptom Scale Score adapted from the Breast Cancer Prevention Trial Symptom Checklist2.Vitality Scale from the RAND 36 Item Health Survey 1.0 (also known as the Medical Outcomes Study SF36)3. Sexual Summary scale from the Cancer Rehabilitation Evaluation System (CARES)

NR NR NR 100% 40 (56%) 

on 

Tamoxifen

NR Exclud

any ERuse witlast 3 months

F-674
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Ganz, 2000

Main Drug type; dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Va

Treatment Main Outcomes

NP counselling, tailored therapy and support.1. Assessment: symptom diary, indepth interview focused on symptoms and influencing factors, and a standardized psychosocial evaluation.2. Symptom Management: With help of nurse, patient chose 1 of 3 symptoms to focus on, developed an individualized plan of care that included education, counseling and specific pharmologic and/or behavioral interventions (for HF: pharmacologic = bellergal, clonidine patch, or megestrol; behavioral = slow abdominal breathing; for vaginal dryness: moisturizer or lubricant; for SUI: behavior = Kegel's; pharm = replens, phyenylpropanolamine; for psychosocial problems = referral for counseling or group support3. Follow-up: telephone call 2 weeks after intervention, visits at 2 months and 4 months. Patients had ability to change or alter treatment until symptom relief achieved.

Usual Care (UC) NR 

F-675
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Ganz, 2000

Mood Cognitive Somatic Urinar

y

Uterine 

Bleeding Sexual Dysfunc-tion 

Main Outcomes (contiued)

NR NR NR NR NR Intervention group had 

significantly higher change score in CARES sexual functioning scale both unadjusted and adjusted (unadjusted mean change score 0.11 UC vs 0.46 Int, p=0.03)

No chavitaINT 0.8afteadja c

F-676
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Ganz, 2000

Other Outcomes Withdrawals Withdrawals due to AEs Adverse Effects 

Change in overall menopause symptom scale was significantly greater in the intervention group (reduced symptoms) as compared to the usual care group (true both for unadjusted scores and score adjusted for age, tamoxifen use, prior chemotherapy, race, partner status ad RAND score): unadjusted mean change score: 0.09 UC vs 0.57 INT, p<0.0001 

4 people dropped out, all from the intervention group: 2 had family member's illness, 2 developed metastatic disease and became inelligible

None NR 1. Groups we

equivalent at bgroup had lowscores and hig(p=0.05 for bo2. Also, cannointerventions, choose from a the course of t3. There was usual care grosome kind of t

F-677
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year N Type of Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Goldberg, 1994

116 DBRCTX P 9 weeks

(1week 

of P to 

assess 

baseline

4 weeks 

C or P 

then X)

Adult women on tamoxifen for breast cancer with hot flashes.Median age 54 years (30-76).Stratified by age, duration of tamoxifen use, duration of hot-flash symtpoms, and average frequency /severity of hot flashes.

Inclusion:1. Hot flashes present >1 month and > 7 

2. Life expectancy of > 6 months

3. ECOG performance status of 0 or 1.Exclusion:1. Many listed

Hernandez Munoz, 2003

136 RCT HH 12 

months 

Women > 35 years attending a breast cancer clinic in Venezuela

Inclusion:1. Women > 35 years who were premens2. Diagnosis of ER+ breast cancer treated 3. Hot flush symptoms

F-678
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Goldberg, 1994Hernandez Munoz, 2003

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or 

Lifestyle 

Factors

(#/n)

Rece

discon

uation 

HRT

(#/n

S

pecific Characteristics of Po

pulation

Self administered questionnaires of number of hot flashes, severity (mild, mod, severe, or very severe graded 1-4), and drug toxicities.Composite score of mean frequency times mean severity. Contacted by nurses every 2-3 weeks to assess compliance, toxicities, and answer questions.

NR NR NR 116/116 116/116 NR NR

multip

dru

exclus

includ

hormo

therap

HF diary (number and intensity)

10% (with retention of the adnexae). 

NR NR 100% 100% on 

tamoxifen

NR NR 

F-679
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Goldberg, 1994Hernandez Munoz, 2003

Main Drug type; dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Va

Treatment Main Outcomes

Clonidine transdermal 0.1 mg/day, patch changed weekly

Patients were on tamoxifen for treatment of breast cancer.

No baseline differences in severity, frequency or hot flash score between C and P groups.Statistically significant decrease in median frequency (p<0.04), severity (p<0.03), and hot-flash score (p<0.04) between C and P after first treatment period. (These findings remained significant after crossover.)

1 tab bid ofCR BNO 1055 (C racemosa). Each tablet contained 20 mg of the herbal supplement.

All on tamoxifen; appears that control group did not have placebo

At the end of 6 months there was no significant difference in the control group for either moderate or severe HF (5-9% decline, p=0.71 compared to baseline). Results for intervention group are only reported in post-treatment, no comparison to pre treatment rates of symptoms

F-680
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Goldberg, 1994Hernandez Munoz, 2003

Mood Cognitive Somatic Urinar

y

Uterine 

Bleeding Sexual Dysfunc-tion 

Main Outcomes (contiued)

NR NR NR NR NR NR NR NR NR NR NR NR 

F-681
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Goldberg, 1994Hernandez Munoz, 2003

Other Outcomes Withdrawals Withdrawals due to AEs Adverse Effects 

Patient preferences for treatment option noted at the end of the study. 2-to-1 advantage for clonidine was significantly different than 50:50 odds (x2 p=0.02).

6/116 omitted from analyses (1 ineligible, 1 didn't understand study, 4 failed to submit data)

C was associated with significant increase in dry mouth (p<0.001), constipation (p<0.02), itchiness under the patch (p<0.01) and drowsiness (p<0.05) compared to the week before treatment. 

21/116 omitted from efficacy analyses due lack of data or patch came off Despite unequal losses, baseline characteristics of hot flashes were similar (table 2).

Does not appemenopausal w

NR Of 150 that 

entered the study, 14 decided not to participate in the rest of the study.

NR 11 "minor" adverse 

events occurred: 7 in the usual care group and 4 in the intervetnion group." No serious events reported. No list of what the events were.

No placebo in The control grother therapie

F-682
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year N Type of Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Jacobson, 2001

85 RCT, 

stratified by 

tamoxi-fen 

use

P 60 days Women over age 18 

previously treated for breast cancer, who reported experiencing daily hot flases

Inclusion:1. Completion of primary therapy includinradiation > 2 months prior.

Exclusion:1. HRT for HF2. Pregnancy3. Major psychiatric illness4. Known recurrent or metastatic breast c

F-683
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Jacobson, 2001

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or 

Lifestyle 

Factors

(#/n)

Rece

discon

uation 

HRT

(#/n

S

pecific Characteristics of Po

pulation

1. Menopausal symptom index2. Changes in LH and FSH from start to end of study3. Visual analog scale of overall health and well-being.4. HF diary

NR NR NR 100% 59/85 on 

tamoxifen at baseline

NR NR 

F-684
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Jacobson, 2001

Main Drug type; dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Va

Treatment Main Outcomes

Black cohosh, 1 tablet bid with meals Women permitted to 

use other nonhormonal medication while in study, but asked not to initiate new therapy for HF.

1. mean HF number at end of study (no significant difference by ANOVA):tam+tx:27.9tam+placebo: 31.6tx alone: 26.7placebo alone: 29.82. mean HF intensity (no significant difference by ANOVA):tam+tx: 1.94tam+placebo:2.06tx alone: 1.97placebo alone: 1.74

F-685
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Jacobson, 2001

Mood Cognitive Somatic Urinar

y

Uterine 

Bleeding Sexual Dysfunc-tion 

Main Outcomes (contiued)

Irritability and nervousness and depression included in menopausal symptom scale, both goups improved, not significantly difference from each other

NR 1. Headaches and 

palpitations included in menopausal symptom scale, both goups improved, not significantly difference from each other2. Excessive sweating improved in both groups but the treatment group reported more improvement that placebo group (p=0.04, wilcoxon test)

NR NR NR NR

F-686
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Jacobson, 2001

Other Outcomes Withdrawals Withdrawals due to AEs Adverse Effects 

Safety outcomes were changes in mean levels of FSH and LH: both tamoxifen groups had lower FSH than the nontamoxifen groups but not statistically significant, and no signficant change; no significant changes in LH levels

9 participants declined further participation after baseline assessments.16 (includes the 9) failed to complete the HF diary at the end of the study.reasons for drop outs:1. Adverse effect 3 tx; 1 placebo2. Forgot pills while traveling 1 tx; 1 placebo3. unknown 5 tx, 5 placebo

4 Lack of change in LH 

and FSH levels reported.3 serious AE's occurred: hysterectomy (tam+tx), breast cancer recurrence (tam+tx), appendectomy (tam+placebo)10 minor AE's occurred: constipation (tam+tx), swolllen finger (tam+placebo), arrhythmia (tx alone), weight gain (tam+tx), endometrial hyperplasia(tam+tx), diliation and currettage(tam+tx), cramping (tx alone), indigestion(tam+tx), vaginal bleeding(tam+tx), and rash on abdomen (tam+placebo).

Randomization 

F-687
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year N Type of Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Kimmick, 2001 (abstract)

62 DBRCT

Cross-over

P 6 weeks Data from 47 women

mean age 53.9 (range 36.6-77.1)89% post-menopausal85.5% Caucasian

Inclusion:1. Women on tamoxifen experiencing > 1 

Loprinzi, 1994 97 DBRCT P 4 weeks 

each period, no wash out period between

97 women with history of breast cancer, 66 men with prostate cancer who had undergone androgendeprivation therapy. 

Inclusion: 1. Breast or prostate cancer with either suorchiectomy2. Bothersome hot flashes

F-688
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Kimmick, 2001 (abstract)Loprinzi, 1994

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or 

Lifestyle 

Factors

(#/n)

Rece

discon

uation 

HRT

(#/n

S

pecific Characteristics of Po

pulation

HR frequency and score (frequency x severity)

NR NR NR 100% 100% on 

tamoxifen

NR NR 

HF frequency NR NR NR 100% 78/97 

women (80%) were using tamoxifen

NR NR 

F-689
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Kimmick, 2001 (abstract)Loprinzi, 1994

Main Drug type; dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Va

Treatment Main Outcomes

Sertraline 50 mg qAM Placebo At 6 weeks:

36% of women on sertraline (N=25) vs 27% of women on placebo (N=22)reported a decrease in the frequency of HF by 50% (p=0.7)At 13 weeks:Women were asked which tablet/period worked best for their HF: 28% had no preference; 49% preferred sertraline; 11% preferred placebo.

Megestrol acetate 20 mg twice daily. Placebo After 4 weeks (results for women only):

HF frequency was 26% of baseline in megestrol group vs 73% in placebo group, p<0.001.Median HF score was 17% of baseline in megestrol acetate group vs 73% of baseline in placebo group, p<0.001.Reduction of 50% in HF frequency: 71% of megestrol group vs 24% of placebo group, p<0.001. Baseline frequency of HF was 6.1 HF/day (range 0.9-21.4) for women.

F-690
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Kimmick, 2001 (abstract)Loprinzi, 1994

Mood Cognitive Somatic Urinar

y

Uterine 

Bleeding Sexual Dysfunc-tion 

Main Outcomes (contiued)

NR (in process analyzed according to abstract)

NR NR NR NR NR NR 

acc

NR NR NR NR NR NR 

F-691
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Kimmick, 2001 (abstract)Loprinzi, 1994

Other Outcomes Withdrawals Withdrawals due to AEs Adverse Effects 

NR NR NR NRNR Of 100 women 

enrolled in the trial, 2 were ineligible and 1 withdrew before starting any medication. Approximately 82% of women provided usable data for the analysis of efficacy.

NR Assessed weekly for 

vaginal symptoms (dryness, irritation or discharge), change in appetite, fluid retnetion.vaginal bleeding reported as a side effect by 15(31%) women, who got megestrol first and had bleeding while on placebo. No suggestion that megestrol acetate was related to other vaginal symptoms, fluid retention or apetite change.

Stratified by dumonths), type of androgen atamoxifen use 

F-692
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year N Type of Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Loprinzi, 1997 52 DBRCT

Cross-over 

P 4 weeks 

each period with 1 week washout between

NR Inclusion:

1. Women > 18 years with a history of bresignificant vaginal complaints defined as dryness and/or itching2. Symptoms present for > 2 months.Exclusion:1. Evidence of active vaginal infection2. Current anti-neoplastic therapy with es3. Pregnancy or lactation4. Previous use of Replens5. Planned use of any vaginal preparation 6. Use of any vaginal product during prior 

Loprinzi, 2000 229 

(191 

with 

data

)

RCT P 4 weeks Breast cancer or perceived 

high risk of breast cancer

Inclusion:1. > 14 bothersome hotflashes per week f

menopause criteria needed)2. Age 18 or over3. Breast cancer or perceived increased r4. Performance status of 0-1 on ECOG5. Tamoxifen and raloxifene o.k. if started study and continued for 5 weeks6. Not on chemo, estrogens, androgens, antidepressants, clonidine, Bellergal. Exclusion: 1. Venlafaxine ever2. Antidepressants past 2 years3. Pregnancy, breastfeeding4. Other hot flash treatments in past 2 we5. Uncontrolled HTN.

F-693
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Loprinzi, 1997Loprinzi, 2000

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or 

Lifestyle 

Factors

(#/n)

Rece

discon

uation 

HRT

(#/n

S

pecific Characteristics of Po

pulation

Vaginal atrophy index: summed score of vaginal elasticity, secretions, mucosal integrity and moisture collected from pelvic exam.Questionnaire grading symptoms of vaginal dryness, itching and discomfort during intercourse.

NR NR NR 100% NR NR NR 

Daily hot flash score (frequency x severity 1-4); hot flash frequency; Beck depression inventory; uniscale QOL instrument

NR NR NR NR NR NR NR 

F-694
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Loprinzi, 1997Loprinzi, 2000

Main Drug type; dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Va

Treatment Main Outcomes

Replens daily for 5 days in 1st week, then 3x/week for next 3 weeks.During washout period, placebo was given 3x/week.

Placebo consisting of hydroxymethylcellulose, glycerindelta lactone, hydrogenated palm oil glyceride and water.

NR Vag

scorboth (decin Rand group=0No fsubschandrynstud

Venlafaxine 37.5mg (V 37.5)Venlafaxine 75mg (V 75)Venlafaxine 150mg (V 150)

Placebo See table 1. 

(Reduction in score and frequency for all arms compared to placebo)

F-695
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Loprinzi, 1997Loprinzi, 2000

Mood Cognitive Somatic Urinar

y

Uterine 

Bleeding Sexual Dysfunc-tion 

Main Outcomes (contiued)

NR NR NR NR NR Dyspareunia scores decreased 

in both groups after 4 weeks: decreased 60% in Replens group and 41% in placebo group, p=0.05.During cross-over period, there were no further substantial changes in either arm for dyspareunia scores compared with the end of the first 4-week period.

BDI reduction: P = 1.6; V 37.5 = 2.4; V 75 = 4.8; V 150 = 3.2. NS

NR NR NR NR All improved; NS between 

arms. See figure 5.

Tx: P:-

F-696
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Loprinzi, 1997Loprinzi, 2000

Other Outcomes Withdrawals Withdrawals due to AEs Adverse Effects 

Vaginal itching: not present at baseline in the majority of women and no significant impact of either Replens or placebo on this symptom.Participants asked which lubricant worked best: of 36 responding, 41% chose Replens, 24% chose placebo and 35% had no preference (p=0.68).

Of 52 patients entering trial, 1 patient canceled before receving any therapy and 6 patients did not answer any of the weekly questionnaires.

7 of the 45 patients terminated their participation before the end of full 9-week period. Anecdotal evidence suggests that patients did not like "feeling wet" and that amount of agent and/or discomfort with applicator contirubted to their decision to quit the study.

NR Patients stratif

they were recehormonal therof vaginal symsevere).

8 prior to study; P - 6; V 37.5 - 7; V 75 - 12; V 150 - 5

NR Dry mouth, decreased 

appetite, nausea, and constipation more in tx. No difference in tiredness, dizziness, nervousness, mood changes, sweating, sleepiness or sleep trouble.

F-697
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year N Type of Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Loprinzi, 2002 81 RCT - crossover P 2 periods; 

4 weeks 

per 

period

Breast cancer or perceived high risk of breast cancer

Inclusion:1. > 14 bothersome hotflashes per week f

menopause criteria needed)2. Breast cancer or perceived increased r3. No current evidence of malignant disea4. Not on chemo, estrogens, androgens, coumadin5. Tamoxifen or raloxifene ok as long as pfor duration of study6. No previous use of fluoxetine7. No antidepressants for 2 years8. No other treatments of hot flashes

Nikander, 2003

62 RCT crossover P 3 months Women being treated for beast cancer at university 

hospital who volunteered for study.Mean age: 54+6, range 35-

69.Age at diagnosis of breast cancer 49.9+7.8 (range 29.9-

68.1).

Inclusion:1. No residual malignant disease2. Incapacitiating climacteric complaints3. FSH>30 U/LExclusion:1. Use of sex steroids including tamoxife2. Use of natural products with possible e3. Use of drugs possibly affecting climacmetabolism or absorption of drug (ie abx)

F-698
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Loprinzi, 2002 Nikander, 2003

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or 

Lifestyle 

Factors

(#/n)

Rece

discon

uation 

HRT

(#/n

S

pecific Characteristics of Po

pulation

Daily hot flash score (frequency x severity 1-4); hot flash frequency; Beck depression inventory; uniscale QOL instrument

NR NR NR NR NR NR NR 

1. Kuperman Index2. Severity of menopausal symptoms with 10 cm long visual analogue scale.3. Self-rating 1-5 of 5 physical and mental working capacity, and present overall work capacity (scale of 1-10) in relation to lifetime best. These all factored into Work Ability Index.4. Depressive mood5. Anxiety6. Self-confidence

10 (18%) NR NR 100% 3/56 

(5.4%) used tamoxifen >5 months 

prior

13 (23%) smoking

22/56 (39.3%had usHRT at some p>5 mon

prior

F-699
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Loprinzi, 2002 Nikander, 2003

Main Drug type; dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Va

Treatment Main Outcomes

Fluoxetine 20mg Placebo Not significant at end of 4-week period

Cross-over analysis: median Hot Flash frequency reduction 1.5 (19%, p=0.01) and score reduction 3.1 (24%, p=0.02)

114 mg phytoestrogen (6 tab/day total, 3 bid)

Placebo Kupperman Index decreased significantly 

in both groups compared to baseline: by 4.2+9.6 (15.5%) in phytoestrogen group 

and by 4.0+8.1 (14.7%) in the P group. 

Not significantly different between groups. HF not different when evaluated separately.Intensity of HF was significantly decreased in P group (-0.3, p=0.006) but not in phytoestrogen group.

F-700
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Loprinzi, 2002 Nikander, 2003

Mood Cognitive Somatic Urinar

y

Uterine 

Bleeding Sexual Dysfunc-tion 

Main Outcomes (contiued)

Trend for lower BDI scores with Fluoxetine (p=0.08); dichotomous analysis NS

NR NR NR NR Fluoxetine: 1 decreased, 11 

increased; Placebo: 3 decreased, 9 increased.

NS 

No significant decrease in anxiety among either P or phytoestrogen group.

NR NR NR NR NR No 

sel

F-701
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Loprinzi, 2002 Nikander, 2003

Other Outcomes Withdrawals Withdrawals due to AEs Adverse Effects 

6 prior to study; 9 had no baseline data (5 placebo, 4 tx); 5 hadno 5 week data (1 P, 4 tx); 2 had no 9 week data (1 P, 1 tx). 

NR Dry mouth (45 vs 

23%, p=0.07); no difference in appetite, nausea, dizziness, constipation, nervousness, mood changes, fatigue, abnormal sweating. Sleep improved in period one on tx.

No change in overall severity of menopausal symptoms by VAS: 55.7+20 before (all); 

46.5+26.5 after phytoestrogen; 49.3+23 

after placebo (p=0.469).25 (44.6%) preferred the phytoestrogen; 15 (26.8%) preferred placebo; 16 (28.6%) had no preference

6 people withdrew: 4 phytoestrogen group (2 stomach ache, 1 recurrent breast cancer, 1 personal); 2 in placebo group (1 lack of effect, 1 vaginal bleeding)

2 women in phytoestrogen group withdrew because of GI AE (stomach ache); 1 woman in the P group withdrew because of vaginal bleeding

Stomach ache Serum values 

genistein, equRCT cross-ovout between eperiod

F-702
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year N Type of Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Pandya, 2000 198 RCT P 12 

weeks

(8 

weeks 

of 

intervention and 

follow 

up 4 

weeks 

later)

Postmenopausal women on tamoxifen for breast cancer with hot flushes. Mean age 53 in C group, 55 in P group (p=0.15) Range 35-77Stratified by time since menopause, duration of tamoxifen therapy, and baseline frequency of hot flushes.Recruited from clinical practices of medical oncologists from participating NCI Community Clinical Oncology Programs.

Inclusion: 1. Postmenopausal women on tamoxifen 

1 month with > 1 hot flash daily.

Exclusion:1. Premenopausal women2. Women on chemotherapy or other endbreast cancer3. Multiple other exclusions

F-703
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Pandya, 2000 

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or 

Lifestyle 

Factors

(#/n)

Rece

discon

uation 

HRT

(#/n

S

pecific Characteristics of Po

pulation

Patient diary daily at baseline, and weeks 4, 8 and 12. Number, severity (mild, moderate, severe, or very severe, grade 1-4) and duration of hot flashes. Combined score (mean frequency x mean severity).Symptom checklist for 18 potential side effects (grade 0-4).Quality of life on a scale from 1 (worst possible life) to 10 (best possible life).Blood pressure.

NR NR NR 198/198 198/198 NR

multiple drug exclusions including hormonal therapies

NR

F-704
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Pandya, 2000 

Main Drug type; dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Va

Treatment Main Outcomes

Clonidine 0.1 mg tab at bedtime Patients were on 

tamoxifen for at least one month for treatment of breast cancer.

No baseline differences in severity, frequency or hot flash score between C and P groups.Statistically significant decrease in mean frequency at weeks 4 (p=0.001) and 8 (p=0.006) and hot flash score at weeks 4 (p=0.002) and 8 (p=0.006).Statistically significant difference in hot flash duration at week 12 (p=0.023).No siginifcant difference in hot flash severity at weeks 4, 8, or 12.

F-705
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Pandya, 2000 

Mood Cognitive Somatic Urinar

y

Uterine 

Bleeding Sexual Dysfunc-tion 

Main Outcomes (contiued)

NR NR NR NR NR NR Qu

in tat w(p=me

F-706
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Pandya, 2000 

Other Outcomes Withdrawals Withdrawals due to AEs Adverse Effects 

Effects of clonidine by the stratification variables duration of tamoxifen use and years past menopause.States blood pressure was not adversely affected.

States patient withdrawals were due to patient preference

45/198 did not complete the full 12 weeks of the study, 31/198 did not complete the 8-week intervention.4/198 randomized but did not provide baseline data and were considered unevaluable.

Participants were asked to complete a symptom checklist including 18 potential side effects. The only diffference was in difficulty sleeping.

Alternate analyaccount for padata. The resu1) QOL at 8 wsignificantly grflash symptom

F-707
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year N Type of Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Quella, 1998 132 Retrospective None 

(open label for long term follow-up)

Contact was 3 years after end of initial study

74 men; 58 women55 (93%) had been on megestrate continually for 3 years.

Inclusion:1. Female breast cancer survivors and msurvivors who underwent androgen depre

F-708
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Quella, 1998

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or 

Lifestyle 

Factors

(#/n)

Rece

discon

uation 

HRT

(#/n

S

pecific Characteristics of Po

pulation

Telephone interview, unclear how data elicited

NR NR NR NR NR NR NR 

F-709
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Quella, 1998

Main Drug type; dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Va

Treatment Main Outcomes

Megestrol acetate: doses ranged from <20mg/day to 160 mg/day.

N/A Of 59 patients taking megestrol:

7 women were experiencing break through HF; 6 women stated that HF were infrequent and mild; 10 patients (M and W) were experiencing daily HF and 3 notes several HF/day which were occasionally severe

F-710
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Quella, 1998

Mood Cognitive Somatic Urinar

y

Uterine 

Bleeding Sexual Dysfunc-tion 

Main Outcomes (contiued)

NR NR NR NR NR NR 

F-711
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Quella, 1998

Other Outcomes Withdrawals Withdrawals due to AEs Adverse Effects 

NR NR Reasons for 

discontinuation of the drug (men and women combined):no benefit: 17 vaginal spotting/bleeding/carmping: 14taking too many other drugs: 13HF resolved: 12wt gain/appetite stimulation : 9chills: 5drug too expensive: 4depression: 4severe hand/wrist numbness/tingling: 3Hand/wrist numbness/tingling was attributed to carpal tunnel, a syndrome previously associated with megestrol.Symptoms resolved within 4-6 weeks of withdrawing the drug.

Toxicity:3 women (17%) had chillls once their HF were eliminated.5 women reported appetite stimulation16 men and women listed weight gain as a possible side effect (8 reported wt gain of <10 lbs; 8 reported 10-

20 lb weight gain).5 women (28%) reported abnormal vaginal bleeding3 women (17%) complained of intermittent mild fluid retention, bloating and cramping without bleeding.1 womean experienced an increase in blood pressure.

Retrospective participating in controlled trial the end of that given option to megestrol at thto control HF.Where given dOther SE occuheadaches, 1 thromboembonot broken dowand W. 

F-712
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year N Type of Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Quella, 2000 182 RCT, crossover after 4 

weeks

P 9 weeks Women age 18 and older 

with history of breast cancer but no residual maligant disease. 

Inclusion:1. Tamoxifen or raloxifene allowed if startplanning to continue through the trial. 2. All suffering from HF > 14 times/wk an

warrant intervention" and HFfor > 1 month

3. Life expectancy > 6 months

4. ECOG=0 or 1.Exclusion:1. Curent treatment with antineoplasitc candrogens, estrogens, prgestational ages2. Use of any other agent to treat hot flasmegestrol acetate, vitamin E and belladoergotamine tartrate, or other soy products

Secreto, 2004 262 DB RCT HH & P 3 

months

Women age 49-57 years in Italy

Inclusion:1. Postmenopausal women aged > 352. Last menstrual flow > 6 months before 

3. Any condition for which classic HRT is 4. Written informed consentExclusion:1. Breast cancer therapy (hormone or cheduring the previous 3 months2. Overt endocrinopathy (diabetes mellituetc.)3. Intolerance to soy

F-713
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Quella, 2000Secreto, 2004

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or 

Lifestyle 

Factors

(#/n)

Rece

discon

uation 

HRT

(#/n

S

pecific Characteristics of Po

pulation

1. Frequency and intensity of hot flashes2. Toxicity: diarrhea, nausea, vomitting, gas/bloating, other3. Compliance

NR NR NR 100% 68 (78%) 

on 

tamoxifen

NR Exclud

Greene Climacteric Scale Included Included NR Included Excluded NR None fo

months prior

F-714
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Quella, 2000Secreto, 2004

Main Drug type; dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Va

Treatment Main Outcomes

600 mg tablets containging 50 mg of soy isoflavones: 40-45% genistein, 40-45% diadzein, and 10-20% glycitein. Subjects instructed to take 1 tablet TID (total of 150mg isoflavones/day). Soy phytoestrogen and placebos provided by pharmavite, Mission Hills, CA.

Placebo ANOVA for HF score and frequency 

produced non-significant p values for all treatment effect comparisons, regardless of period, sequence, or week of observation. Among pateints receviving placebo, 36% reported that HF frequency had been cut in half compared with only 24% of patients receiving soy (p=0.01).

Group 1: midday, isoflavones 40mg; evening, isoflavones 40mg+melatonin 3 mg; Group 2: midday and evening, isoflavones 40mg; Group 3: midday, placebo; evening, melatonin 3mg

Group 4: midday and evening, placebo

NR 

F-715
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Quella, 2000Secreto, 2004

Mood Cognitive Somatic Urinar

y

Uterine 

Bleeding Sexual Dysfunc-tion 

Main Outcomes (contiued)

NR NR NR NR NR NR NR NR NR NR NR NR 

F-716
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Quella, 2000Secreto, 2004

Other Outcomes Withdrawals Withdrawals due to AEs Adverse Effects 

No difference in percent of patients reporting daily use of medications (compliance) and percentage reporting having missed <10% of pills for soy vs. placebo.

149 (85%) had usable data at the end of 9 weeks.

None No difference in 

toxicity between the two study arms: diarrhea, nausea, vomiting or bloating/gas

1. Authors do separately aftecross over. Thcombined groutreatment grouwould have biapositive (and teven with com2. There was between cross 

Greene Climacteric Scale as a whole and subscales were nearly identical between groups at baseline. Decrease of 30% in Greene Score in placebo group; 25% in melatonin alone group; 32% in isoflavone alone group; and 34% in isoflavones and melatonin group; No statistically significant difference between groups in the total score or sub scores. 

4/65 withdrew from isoflavone + melatonin group; 5/64 withdrew from isoflavone group; 12/66 withdrew from melatonin + placebo group; 9/67 withdrew from placebo group

3/65 from isoflavone and melatonin group; 2/64 from isoflavone alone group; 4/66 from melatonin group; and 3/67 from placebo group; 9 were lost to follow-up; 8 discontinued for other reasons

Not stated Each isoflavon

300mg of soy 40mg of isoflarations: daidzeand genistein BV, 4283 ZG G

F-717
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year N Type of Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Thompson, 2002 (abstract only)

53 DB RCT P 16 

weeks

Women with breast cancer with menopausal symptoms

Not listed

F-718
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Thompson, 2002 (abstract only)

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or 

Lifestyle 

Factors

(#/n)

Rece

discon

uation 

HRT

(#/n

S

pecific Characteristics of Po

pulation

Measure Yourself Medical Outcome Profile (MYMOP), Hospital Anxiety and Depression score, European Organization for Research and Treatment in Cancer Quality of Life Score, Menopausal Symptom Scale

NR NR NR Included NR NR NR 

F-719
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Thompson, 2002 (abstract only)

Main Drug type; dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Va

Treatment Main Outcomes

Homeopathic intervention Placebo Both groups showed significant 

improvement over the study period by an average of 80%. No statistically significant difference betweeen groups

F-720
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Thompson, 2002 (abstract only)

Mood Cognitive Somatic Urinar

y

Uterine 

Bleeding Sexual Dysfunc-tion 

Main Outcomes (contiued)

NR NR NR NR NR NR 

F-721
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Thompson, 2002 (abstract only)

Other Outcomes Withdrawals Withdrawals due to AEs Adverse Effects 

NR 8/43 NR NR Abstract only; 

homeopathic R

F-722
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year N Type of Trial

Comparison Length of Trial Population Inclusion/Exclusion Cr

Van Patten, 2002

157 RCT P 12 

weeks

263 eligible women; 157 randomized; 123 completed the study (59 soy, 64 placebo).Age at study entry 55.5+6.3; P 54.9+6.5.Conducted in Canada

Inclusion:1. Breast cancer with completion of treatm2. No use of HRT for >4 months3. Tamoxifen allowed4. Troublesome HF: score>10/wk (freque5. Other medications + CAM allowed if nmonths.Exlusion:1. Smokers2. Use of abx3. Diagnosis of IBD, liver impairment or rcancer4. Allergy to or regular consumption of so

F-723
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Van Patten, 2002

Measures Used

Hysterectomy 

(#/n)

Bilateral 

Oophorectomy

(#/n)

Premature 

Ovarian 

Failure

(#/n)

Breast 

Cancer

(#/n)

Use of 

SERMS

(#/n)

Behavior 

or 

Lifestyle 

Factors

(#/n)

Rece

discon

uation 

HRT

(#/n

S

pecific Characteristics of Po

pulation

1. Frequency and intensity (0-5 scale) of HF, daily diary.

"Hysterectomy + oophorectomy"soy 23 (39%)P 28 (44%)

NR NR 100% Tamoxifen 

use:soy - 9(15%)P - 6 (9%)

NR (No use 

4 montprior to start of study): soy 26 (44%)placebo (44%)

F-724
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Van Patten, 2002

Main Drug type; dose;

regimen

Other Drugs type; 

dose; regimen Hot Flashes

Va

Treatment Main Outcomes

Average concentration of isoflavone in the soy veberage was 45 +13mg/250mL; isoflavones were undetectable in the rice beverage. Total isoflavones consumed by soy women: 90 mg/day.

Placebo None of the HF reductions were 

significantly different between groups.24 hour HF number and score baseline vs final 4 weeks of treatment: number: soy (7.1+ 4.3 vs 5.3 +4.1); placebo (7.4+6.4 vs 4.9+3.9).Score (intensity x frequency): soy (18.0+13.9 vs 12.6+13.4); placebo 18.9+18.9 vs 11.4+11.3).(also reported for day and night, also NS change).

F-725
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Van Patten, 2002

Mood Cognitive Somatic Urinar

y

Uterine 

Bleeding Sexual Dysfunc-tion 

Main Outcomes (contiued)

NR NR NR NR Only 

reported as an adverse effect of treatment with soy (see AE column).

NR 

F-726
Appendix F. Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Study/Year

Van Patten, 2002

Other Outcomes Withdrawals Withdrawals due to AEs Adverse Effects 

On the study exit questionnaire, a large number of women in both soy and placebo groups perceived a marginal decrease in HF number in the day (54%soy vs 58%P) and night (48%soy vs 56%P), and in the severity of HF in the day (50%soy vs 56%P) and night (52%soy vs 55%placebo).At completion, only half of the women in the soy and placebo groups (48% and 52% respectively) could correctly identify wich beverage they were consuming.

After randomization 34 (22%) women dropped out of the study.

10 women dropped out because of intolerance to study beverage (7 from soy group; 3 from placebo).25 dropped out because of time committment6 dropped out for other reasons9 women became inellgible after randomization (6 had insufficient HF, 2 had regular consumption of soy; 1 had IBD).

Frequent and severe gastrointestinal side effects in soy group: overall 28 soy women reported GI AE; 14 P women reported GI AE (list includes abdominal bloating, gas/flatulence, constipation, gastritis, diarrhea, nausea, vomiting, heartburn). This does not include the 10 women who dropped out of the study for intolerance (7 soy; 3 P). Weight gain occurred equally in both groups (5 soy vs 4 P).Vaginal spotting was reported by 4 women consuming soy and 1 consuming placebo.

No mention of negative study Other CAM ancommmon in bcohosh, wild yflaxsee and SSprimrose oil mboth groups.Serum values 

F-727
Appendix F: Evidence table 6-9. Key Question 4C therapies in women with breast cancer

Abbreviation

s

AE = Adverse Effect

BMI = Body mass inde

x

C = ClonidineCAM = Complimentary and alternative medicineECOG = Eastern Coo

perative Oncology Grou

p Scal

e

ER + = Estrogen Receptor PositiveERT = Estrogen replacement therap

y

GI = GastrointestinalHF = Hot flashHH = Head to headHRT = Hormone Re

placement Therapy

HTN = HypertensionIBD = Irritable Bowel DisorderINT = InterventionMVI = Multivariat

e

NR = Not reportedNS = Not significantP = PlacebOQoL = Quality of lifeRAND = RAND Mental Health Inventor

y

RCT = Randomized Controlled TrialSD = Standard deviationSERMs = Selective Estrogen Receptor Modifiers tam = Tamoxifenetx = TreatmentUC = Usual care

F-728