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

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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

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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

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www.ahrq.gov

AHRQ Pub. No. 05-E016-1

March 2005

ISSN 1530-440X