**The Women's Health Initiative (WHI) Clinical Trial of Estrogen plus
Progestin in Postmenopausal Women**

**Funded by the National Heart, Lung, and Blood Institute**

**Bethesda, Maryland**

**Conducted by 40 Clinical Centers and a Clinical Coordinating Center**

**(Investigator list appended)**

**[Speakers for WHI]{.underline}**

Background and Future Directions Jacques Rossouw, M.D.

NHLBI

Overview of Main Findings Marcia Stefanick, Ph.D.

Stanford

Breast Cancer Rowan Chlebowski, M.D.

Harbor-UCLA

> Garnet Anderson, Ph.D.

Fred Hutchinson Cancer

> Research Center

Osteoporosis and Fractures Jane Cauley, Ph.D.

U. Pittsburgh

> Garnet Anderson, Ph.D.
>
> Fred Hutchinson Cancer
>
> Research Center

**[Other WHI/NIH Representatives]{.underline}**

Barbara Alving, M.D.

NHLBI

(WHI Director)

Rebecca Jackson, M.D.

OHSU

(Osteoporosis)

Leslie Ford, M.D.

NCI

(Cancer)

**[Summary of the Women's health initiative (wHI)]{.underline}**

**Rationale for WHI Trials of Hormone Therapy**

The National Institutes of Health launched the WHI program in 1991 in
response to concerns about unanswered questions of importance to women's
health. A number of clinical trials were designed to provide clear
answers to promising but unproven prevention strategies. Two of these
trials centered on the efficacy and safety of long term hormone therapy
for prevention of chronic diseases.

While in prior decades these hormones were primarily used for the
treatment of (FDA-approved) menopausal symptoms and vaginal atrophy,
from the late 1980s and early 1990s long term hormone therapy was being
used with increasing frequency for the prevention of fractures and
coronary heart disease. For fracture prevention, this use was based on
the proven (and FDA-approved) benefit for osteoporosis prevention, and
on observational studies of fractures. For coronary heart disease
prevention, this use was based on improvements in lipids found in
clinical trials, observational studies, animal studies, and studies of
mechanism. However, there was no clinical trial evidence proving that
hormone therapy would prevent fractures, or prevent coronary heart
disease, and these indications were not approved by the FDA. Similarly,
there was no clinical trial evidence that any benefits would not be
offset by harms. It was known that estrogen increased the risk of
endometrial cancer (an effect which could be abrogated by progestins).
It was suspected that hormone therapy increased the risk of breast
cancer, based on observational and animal studies. At the time, the
effect of hormones on stroke was unknown, as was the effect on venous
thrombosis. In summary, the trials of hormone therapy were needed,
because use of hormone therapy for the prevention of chronic disease was
rising, and the diseases for which benefit was being assumed (or the
harms which it could cause) were of considerable public health
importance. The WHI trials were not designed to test the benefits and
risks of short term hormone therapy at the time of menopause, but did
include postmenopausal women in a wide age range in order to extend
their generalizability.

**Choice of Subjects and Drug Therapy**

The age range of postmenopausal women included in these trials was 50-79
to encompass the age range for which hormones were being prescribed for
prevention of chronic diseases. The choice of estrogen was dictated by
the knowledge that Premarin (conjugated equine estrogen) was the most
commonly prescribed hormone in the US in the early 1990s, that most of
the prescriptions were for the 0.625 mg daily dose, and by the fact that
most of the observational data suggesting benefit for coronary heart
disease were based on this drug at this dose. Premarin at this dose was
also the most commonly prescribed estrogen when used in combination with
a progestin. The most commonly prescribed progestin was
medroxyprogesterone, typically as cyclic therapy of 10 mg for 10-12 days
in the month, or (increasingly) as continuous-combined therapy with
daily 2.5 mg of medroxyprogesterone. Initially, continous-combined
therapy was prescribed as two separate pills, however from 1995 onwards
the combination pill Prempro became the dominant combination therapy.
Compared to epidemiologic data on Premarin alone, there was relatively
little data on Premarin combined with medroxyprogesterone. However, what
data existed appeared to support benefit for coronary heart disease of
about the same extent as for Premarin alone. Observational data from
Europe, where different estrogens and progestins predominate, were
consistent with the U.S. data. The scanty data also supported a risk for
breast cancer for the combination therapy, and a benefit for
osteoporosis prevention. After the WHI trials were launched, reports of
increased risk for venous thrombosis on estrogen alone or combined with
progestins surfaced, and in 1998 the Heart and Estrogen/Progestin Study
(HERS) published its findings of no benefit for coronary heart disease
prevention in women with existing coronary disease.

**Design and Timeline of Randomized Controlled Clinical Trials of
Hormone Therapy**

The trials were designed to test whether hormone therapy would prevent
coronary heart disease, and whether the benefits would outweigh the
risks, when given for several years to generally healthy postmenopausal
women aged 50-79. The primary outcome for benefit was coronary heart
disease, and the main outcome for harm was breast cancer. A global index
was constructed as a summary measure of overall benefit or harm. The
monitored outcomes included in the global index were coronary heart
disease, stroke, pulmonary embolism, hip fracture, breast cancer,
colorectal cancer, endometrial cancer (in women with a uterus), and
death from other causes.

A randomized controlled trial of estrogen (E-Alone) in 10,739 women who
had had a hysterectomy enrolled participants in the period 1993-1998 and
is planned to continue to 2005, after an average of 8.5 years of
follow-up. The estrogen is Premarin (conjugated equine estrogen) 0.625
mg daily, compared to matching placebo. A separate randomized controlled
trial of estrogen plus progestin (E+P) in 16,608 women who had an intact
uterus had the same timeline and was also originally planned to continue
to 2005. The drug used in the E+P trial was Prempro (conjugated equine
estrogen 0.626 mg plus medroxyprogesterone 2.5 mg daily). However, this
trial was stopped in July, 2002 after 5.2 years of follow up when the
independent Data and Safety Monitoring Board concluded that the
pre-designated boundary for harm from breast cancer had been crossed,
and that there was overall harm as assessed by a summary measure of
important clinical outcomes. Note that in 2000 and again in 2001 women
in the E-Alone as well as women in the E+P trials were notified of an
increased risk of coronary heart disease, stroke, and venous thrombosis
in the active treatment arms.

**[Main Findings from the Completed E+P Trial]{.underline}**

**These findings are summarized below, and links to abstracts of
published articles are provided. The first publication reported the
major locally adjudicated outcomes as of April 30, 2002, representing an
average of 5.2 years of follow-up. Subsequent publications include
centrally adjudicated outcomes reported up to the closing of the trial
on July 7, 2002 and represent an average of 5.6 years of follow up.
These subsequent publications also provide more detailed subgroup
analyses. The summary findings are reported here as hazard ratios (HR)
with the traditional nominal confidence (CI) intervals; however, the
various articles also report more conservative CIs adjusted for
sequential monitoring and/or multiple outcomes, as appropriate.**

**[Overall Risks and Benefits]{.underline}**

***Risks and Benefits of Estrogen Plus Progestin in Healthy
Postmenopausal Women***

***Principal Results From the Women\'s Health Initiative Randomized
Controlled Trial***

*Writing Group for the Women\'s Health Initiative Investigators*

*JAMA* 2002;288:321-333

After a mean of 5.2 years of follow-up, the trial was stopped because
because the test statistic for invasive breast cancer exceeded the
stopping boundary for this adverse effect and the global index statistic
supported risks exceeding benefits.

Hazard ratios (nominal 95% confidence intervals) were as follows:

-   CHD: 1.29 (1.02-1.63) with 286 cases

-   Breast cancer: 1.26 (1.00-1.59) with 290 cases;

-   Stroke: 1.41 (1.07-1.85) with 212 cases;

-   Pulmonary embolism: 2.13 (1.39-3.25) with 101 cases

-   Colorectal cancer: 0.63 (0.43-0.92) with 112 cases

-   Endometrial cancer: 0.83 (0.47-1.47) with 47 cases

-   Hip fracture: 0.66 (0.45-0.98) with 106 cases

-   Death due to other causes: 0.92 (0.74-1.14) with 331 cases

-   Total mortality: 0.98 (0.82-1.18)

-   Global index: 1.15 (1.03-1.28).

Absolute excess risks per 10 000 person-years attributable to estrogen
plus progestin were 7 more CHD events, 8 more strokes, 8 more pulmonary
emboli, and 8 more invasive breast cancers, while absolute risk
reductions per 10 000 person-years were 6 fewer colorectal cancers and 5
fewer hip fractures. The absolute excess risk of events included in the
global index was 19 per 10 000 person-years.

Overall health risks exceeded benefits from use of combined estrogen
plus progestin for an average 5.2-year follow-up among healthy
postmenopausal US women. All-cause mortality was not affected during the
trial. The risk-benefit profile found in this trial is not consistent
with the requirements for a viable intervention for primary prevention
of chronic diseases, and the results indicate that this regimen should
not be initiated or continued for primary prevention of CHD.

Abstract: <http://jama.ama-assn.org/cgi/content/abstract/288/3/321>

**[Coronary Heart Disease]{.underline}**

***Estrogen plus Progestin and the Risk of Coronary Heart Disease***

*JoAnn E. Manson, M.D., Dr.P.H., Judith Hsia, M.D., Karen C. Johnson,
M.D., M.P.H., Jacques E. Rossouw, M.D., Annlouise R. Assaf, Ph.D.,
Norman L. Lasser, M.D., Ph.D., Maurizio Trevisan, M.D., Henry R. Black,
M.D., Susan R. Heckbert, M.D., Ph.D., Robert Detrano, M.D., Ph.D., Ora
L. Strickland, Ph.D., Nathan D. Wong, Ph.D., John R. Crouse, M.D., Evan
Stein, M.D., Mary Cushman, M.D., for the Women\'s Health Initiative
Investigators*

*NEJM* 2003;349:523-534

> As noted above, this and all subsequent reports include the centrally
> adjudicated (rather than locally adjudicated) outcomes over the entire
> 5.6 year (rather than 5.2 year) duration of the trial.

-   A total of 335 cases of CHD were included in this final analysis,
    and with 188 vs 147 cases the HR was 1.24 (95% CI 1.00 - 1.54) for
    E+P compared to placebo

-   This corresponds to an excess of 6 cases CHD for every 10,000 women
    treated for one year, on average.

-   In adherent women the HR for CHD was 1.50 (1.14-1.97)

-   The elevation in risk was most apparent at one year with a HR of
    1.81 (1.09 - 3.01); the risks of CHD for years 2 through 6+ were
    1.34, 1,27, 1.25, 1,45, and 0.70

-   In year 6 and beyond, increased rates in the placebo group resulted
    in an apparent risk reduction

-   E+P did not increase or decrease the risks for angina, CABG or PTCA,
    and congestive heart failure

-   No subgroup (e.g., by age, years since menopause, presence of
    symptoms, BMI) with lowered risk of CHD on E+P could be identified

-   Higher base-line levels of low-density lipoprotein cholesterol were
    associated with an excess risk of CHD among women who received E+P,
    but higher base-line levels of C-reactive protein, other biomarkers,
    and other clinical characteristics did not significantly modify the
    treatment-related risk of CHD

Estrogen plus progestin does not prevent CHD, and may increase the risk
of CHD among generally healthy postmenopausal women, especially during
the first year after the initiation of hormone use. This treatment
should not be prescribed for the prevention of cardiovascular disease.

Abstract: <http://content.nejm.org/cgi/content/short/349/6/523>

**[Breast Cancer]{.underline}**

***Influence of Estrogen Plus Progestin on Breast Cancer and Mammography
in Healthy Postmenopausal Women***

***The Women\'s Health Initiative Randomized Trial***

*Rowan T. Chlebowski, MD, PhD; Susan L. Hendrix, DO; Robert D. Langer,
MD, MPH; Marcia L. Stefanick, PhD; Margery Gass, MD; Dorothy Lane, MD,
MPH; Rebecca J. Rodabough, MS; Mary Ann Gilligan, MD, MPH; Michele G.
Cyr, MD; Cynthia A. Thomson, PhD, RD; Janardan Khandekar, MD; Helen
Petrovitch, MD; Anne McTiernan, MD , PhD; for the WHI Investigators*

*JAMA* 2003:289;3243-3253

-   After a mean follow-up of 5.6 years, the hazard ratios (95%
    confidence intervals) for breast cancer associated with E+P compared
    to placebo were as follows:

    -   Total breast cancer (245 vs 185 cases), HR 1.24 (1.02-1.50),
        weighted *P*\<.001\*

    -   Invasive breast cancer (199 vs 150 cases), HR 1.24 (1.01-1.54),
        weighted *P* = .003

    -   In situ breast cancer (47 vs 37 cases), HR 1.18 (0.77-1.82),
        weighted *P* = 0.09.

-   The invasive breast cancers diagnosed in the E+P group were similar
    to those in the placebo group in respect of histology (including
    proportions of ductal and lobular cancers), estrogen and progestin
    receptor status, and grade of malignancy

-   However, the cancers in the E+P group were larger (mean \[SD\], 1.7
    cm \[1.1\] vs 1.5 cm \[0.9\], respectively; *P* = .04) and were at
    more advanced stage (regional/metastatic 25.4% vs 16.0%,
    respectively; *P* = .04) compared with those diagnosed in the
    placebo group.

-   For all study periods after the baseline examination, the
    percentages of women with abnormal mammograms were substantially
    higher in the E+P group than in the placebo group

-   In adherent participants, the HR for invasive breast cancer was 1.49
    (1.13-1.96), *P* \<.001

-   The findings were statistically consistent across multiple subgroups
    (e.g., by age, BMI, Gail Risk Assessment category)

-   Women with no prior menopausal hormone use had a HR for invasive
    breast cancer of 1.09 (0.86-1.39), while women with \<5 years prior
    use had a HR of 1.70 (0.99-2.91), and those with \>5 years prior use
    had a HR of 2.27 (1.00-5.15), weighted *P* value for interaction =
    0.15

-   In the placebo group, women with no prior menopausal hormone use
    appeared to have somewhat higher risk of breast cancer compared to
    women with prior use

-   On the other hand, the risk from E+P emerged later in women with no
    prior use; their HRs for invasive breast cancers were 0.48, 0.65,
    and 0.96 in years 1 through 3, and 1.45, 1.61, and 1.24 in years 4
    through 6+. In women with prior use, the HRs were 0.90, 1.10, 3.09,
    2.16, 3.56, and 1.99 in years 1 through 6+.

> Relatively short-term E+P use increases the risk for breast cancers,
> which are diagnosed at a more advanced stage compared with placebo
> use, and also substantially increases the percentage of women with
> abnormal mammograms. The results suggest E+P stimulates breast cancer
> growth and delays breast cancer diagnosis. Apparent differences by
> prior hormone use status need further investigation.
>
> \* weighting, as specified in the design, varied linearly from zero at
> time of randomization to a maximum of 1 beginning at follow up year 10
>
> Abstract: <http://jama.ama-assn.org/cgi/content/abstract/289/24/3254>

**[Stroke]{.underline}**

***Effect of Estrogen Plus Progestin on Stroke in Postmenopausal
Women***

***The Women\'s Health Initiative: A Randomized Trial***

*Sylvia Wassertheil-Smoller, PhD; Susan Hendrix, DO; Marian Limacher,
MD; Gerardo Heiss, MD; Charles Kooperberg, PhD; Alison Baird, MD, PhD,
MPH; Theodore Kotchen, MD; J. David Curb, MD; Henry Black, MD; Jacques
E. Rossouw, MD; Aaron Aragaki, MS; Monika Safford, MD; Evan Stein, MD,
PhD; Somchai Laowattana, MD; W. Jerry Mysiw, MD; for the WHI
Investigators*

*JAMA* 2003:289;2673-2684

-   All strokes were centrally adjudicated by stroke-trained
    neurologists for this report

-   151 participants in the E+P and 107 in the placebo groups had
    strokes.

-   For combined ischemic and hemorrhagic strokes, the HR for estrogen
    plus progestin vs placebo was 1.31 (95% CI, 1.02-1.68); with
    adjustment for adherence, the HR was 1.50 (95% CI, 1.08-2.08).

-   The excess risk for stroke appeared in the second year after
    randomization and persisted thereafter

-   Overall 79.8% of strokes were ischemic; the HR for ischemic stroke
    was 1.44 (95% CI, 1.09-1.90)

-   There was no effect of E+P on hemorrhagic stroke, HR 0.82 (95% CI,
    0.43-1.56)

-   Although E+P raised systolic blood pressure slightly (between 1 and
    2 mm Hg), this did not explain the excess risk

-   The excess risk of all stroke was apparent in all age groups, in all
    categories of baseline stroke risk, and in women with and without
    hypertension, prior history of cardiovascular disease, or prior use
    of hormones

-   Use of statins or aspirin did not modify the increased risk of
    stroke due to E+P

-   Years since menopause and presence or absence of hot flashes and/or
    night sweats did not modify the effect of E+P on stroke risk

-   Higher levels of inflammatory factors (IL-6, CRP, and E-selectin)
    predicted stroke, but did not modify the effect of E+P on stroke
    risk.

-   Other risk factors for stroke, including smoking, blood pressure,
    diabetes, lower use of vitamin C supplements, higher white blood
    cell count, and higher hematocrit levels also did not modify the
    effect of E+P on stroke risk

Estrogen plus progestin increases the risk of ischemic stroke in
generally healthy postmenopausal women. Excess risk for all strokes
attributed to estrogen plus progestin appeared to be present in all
subgroups of women examined. Inflammatory factors appear to play a role
in stroke, but did not modify the effect of E+P on stroke risk.

^Abstract:\ <http://jama.ama-assn.org/cgi/content/abstract/289/20/2673>^

**[DEMENTIA]{.underline}**

***Estrogen Plus Progestin and the Incidence of Dementia and Mild
Cognitive Impairment in Postmenopausal Women***

***The Women\'s Health Initiative Memory Study: A Randomized Controlled
Trial***

*Sally A. Shumaker, PhD; Claudine Legault, PhD; Stephen R. Rapp, PhD;
Leon Thal, MD; Robert B. Wallace, MD; Judith K. Ockene, PhD, MEd; Susan
L. Hendrix, DO; Beverly N. Jones III, MD; Annlouise R. Assaf, PhD;
Rebecca D. Jackson, MD; Jane Morley Kotchen, MD, MPH; Sylvia
Wassertheil-Smoller, PhD; Jean Wactawski-Wende, PhD; for the WHIMS
Investigators*

*JAMA* 2003:289;2651-2662

The Women's Health Initiative Memory Study (WHIMS) is an ancillary study
to WHI funded by Wyeth. It enrolled women aged 65 and older who were
participating in the WHI trial of E+P. WHIMS enrolled 92.6% of the 4894
WHI participants who were age-eligible and free of dementia in 39 of the
40 WHI clinical centers. WHIMS ascertained the incidence of probable
dementia (primary outcome) and mild cognitive impairment (secondary
outcome) through a structured clinical assessment. The mean (SD) time
between the date of randomization into WHI and the last Modified
Mini-Mental State Examination (3MSE) for all WHIMS participants was 4.05
(1.19) years.

-   Overall, 61 women were diagnosed with probable dementia, 40 (66%) in
    the estrogen plus progestin group compared with 21 (34%) in the
    placebo group.

-   The HR for probable dementia was 2.05 (95% CI, 1.21-3.48)

-   In adherent women the HR for probable dementia was 3.22 (95% CI,
    1.25-8.29)

-   Absolute rates were 45 vs 22 per 10 000 person-years, *P* = .01; on
    average, this increased risk would result in an additional 23 cases
    of dementia per 10 000 women per year of treatment with E+P.

-   Alzheimer disease was the most common classification of dementia in
    both study groups

-   Age, education, and baseline 3MSE score related to risk of probable
    dementia, but did not modify the effect of E+P

-   Prior use of hormones, statins, or aspirin did not modify the effect
    of E+P

-   Mild cognitive impairment did not differ between E+P and placebo
    groups (HR, 1.07; 95% CI, 0.74-1.55; 63 vs 59 cases per 10 000
    person-years; *P* = .72)

E+P therapy increased the risk for probable dementia in postmenopausal
women aged 65 years or older. In addition, estrogen plus progestin
therapy did not prevent mild cognitive impairment in these women. These
findings, in conjunction with previously reported WHI data, support the
conclusion that the risks of estrogen plus progestin outweigh the
benefits.

Abstract: <http://jama.ama-assn.org/cgi/content/abstract/289/20/2651>

**[COGNITIVE FUNCTION]{.underline}**

***Effect of Estrogen Plus Progestin on Global Cognitive Function in
Postmenopausal Women***

***The Women\'s Health Initiative Memory Study: A Randomized Controlled
Trial***

*Stephen R. Rapp, PhD; Mark A. Espeland, PhD; Sally A. Shumaker, PhD;
Victor W. Henderson, MD, MS; Robert L. Brunner, PhD; JoAnn E. Manson,
MD, DrPH; Margery L. S. Gass, MD; Marcia L. Stefanick, PhD; Dorothy S.
Lane, MD, MPH; Jennifer Hays, PhD; Karen C. Johnson, MD, MPH; Laura H.
Coker, PhD; Maggie Dailey, PhD; Deborah Bowen, PhD; for the WHIMS
Investigators*

*JAMA* 2003:289;2663-2672

The study population for this report was essentially the same as that
for the companion report on dementia, only excluding some 151
participants without a valid post-enrollment assessment of cognitive
function. WHIMS participants completed an annual assessment of global
cognitive function, as measured with the Modified Mini-Mental State
Examination (3MSE).

-   3MSE mean total scores in both groups increased slightly over time
    (mean follow-up of 4.2 years), probably due to the "learning effect"
    of repeated administration

-   Women in the estrogen plus progestin group had smaller average
    increases in total scores compared with women receiving placebo (*P*
    = .03), but these differences were not clinically important

-   Re-analysis after removing women by censoring them after adjudicated
    dementia, mild cognitive impairment, or stroke, and nonadherence to
    study protocol, did not alter the findings

-   Prior hormone therapy use and duration of prior use did not affect
    the interpretation of the results, nor did timing of prior hormone
    therapy initiation with respect to the final menstrual period

-   More women in the estrogen plus progestin group had a substantial
    and clinically important decline
    (![](media/image1.png){width="7.152777777777777e-2in"
    height="0.10486111111111111in"}2 SDs) in 3MSE total score (6.7%)
    compared with the placebo group (4.8%) (*P* = .008)

Among postmenopausal women aged 65 years or older, estrogen plus
progestin did not improve cognitive function when compared with placebo.
While most women receiving estrogen plus progestin did not experience
clinically relevant adverse effects on cognition compared with placebo,
a small increased risk of clinically meaningful cognitive decline
occurred in the estrogen plus progestin group.

Abstract: <http://jama.ama-assn.org/cgi/content/abstract/289/20/2663>

**[QUALITY OF LIFE]{.underline}**

***Effects of Estrogen plus Progestin on Health-Related Quality of
Life***

*Jennifer Hays, Ph.D., Judith K. Ockene, Ph.D., Robert L. Brunner,
Ph.D., Jane M. Kotchen, M.D., M.P.H., JoAnn E. Manson, M.D., Dr.P.H.,
Ruth E. Patterson, Ph.D., R.D., Aaron K. Aragaki, M.S., Sally A.
Shumaker, Ph.D., Robert G. Brzyski, M.D., Ph.D., Andrea Z. LaCroix,
M.P.H., Ph.D., Iris A. Granek, M.D., Barbara G. Valanis, M.D., for the
Women\'s Health Initiative Investigators*

*NEJM* 2003:348;1839-54

Quality-of-life measures were collected at base line and at one year in
all women and at three years in a subgroup of 1511 women enrolled in the
trial of E+P.

-   E+P treatment compared to placebo did not have any effects on
    general health, vitality, mental health, depressive symptoms, or
    sexual satisfaction

-   E+P treatment was associated with a statistically significant but
    small and not clinically meaningful benefits for sleep disturbance,
    physical functioning, and bodily pain after one year (for sleep
    disturbance the mean benefit was 0.4 point on a 20-point scale, for
    physical functioning 0.8 point on a 100-point scale, and for bodily
    pain it was 1.9 points on a 100-point scale)

-   These small benefits were no longer apparent at three years, and
    there were no significant benefits in terms of any of the other
    quality-of-life outcomes, in the subgroup with data at 3 years

-   The findings were similar in women aged 50-59 and in older women,
    and there were no differences in any subgroup (e.g., by body mass
    index, race or ethnicity, presence of menopausal symptoms, or
    previous use of hormone therapy)

-   Among 574 women aged 50 to 54 years with moderate-to-severe
    vasomotor symptoms at base line, E+P improved vasomotor symptoms and
    resulted in a small benefit for sleep disturbance but no benefit for
    the other quality-of-life outcomes

In this trial in postmenopausal women, estrogen plus progestin did not
have a clinically meaningful effect on health-related quality of life.
If present, symptoms of hot flashes and night sweats improved, but there
were no clinically significant improvements in other domains of quality
of life.

Abstract: <http://content.nejm.org/cgi/content/abstract/NEJMoa030311v1>

**[FRACTURES]{.underline}**

***The effects of Estrogen Plus Progestin on the Risk of Fracture and
Bone Mineral Density***

***The Women\'s Health Initiative Clinical Trial***

*Jane A. Cauley, Dr.PH; John Robbins, MD; Zhao Chen, PhD; Steven R.
Cummings, MD; Rebecca Jackson, MD; Adrea Z. LaCroix, PhD; Meryl LeBoff
MD; Cora E. Lewis, MD, MSPH; Joan McGowan, PhD; Joan Neuner, MD, MPH;
Mary Pettinger MS; Marcia L. Stefanick, PhD; Jean Wactawski-Wende, PhD;
Nelson B. Watts, MD; for the Women's Health Initiative Investigators*

*JAMA* 2003: 290;1729-1738

The trial was designed to test the effect of E+P on fractures in a
population of postmenopausal women otherwise at low risk of fracture.
All confirmed osteoporotic fractures that occurred during 5.6 years of
the trial were included in this report. Hip fractures were designated as
a secondary outcome of the trial, and were centrally adjudicated. Other
osteoporotic fractures were locally adjudicated, using radiology reports
to confirm initial self-report. Bone mineral density (BMD) was measured
in a subset of women (n=1024) at baseline and years 1 and 3.

-   733 women in the E+P group and 896 in the placebo group experienced
    a fracture, HR 0.76 (95% CI 0.69-0.83)

-   On average, 10,000 women treated for one year with E+P would
    experience 47 fewer osteoporotic fractures than women on placebo

-   52 women in the E+P group and 73 in the placebo group experienced a
    hip fracture, HR 0.72 (95% CI 0.47-0.96)

-   On average, 10,000 women treated for one year with E+P would
    experience 5 fewer hip fractures than women on placebo

-   The HRs in adherent women were similar to those in the groups
    overall; HR for total fracture was 0.71 (95% CI, 0.64-0.81), and HR
    for hip fracture was 0.63 (95% CI, 0.38-1.06)

-   The effect of E+P on fractures did not differ significantly by age,
    years since menopause, BMI, BMD, prior hormone use, or fracture risk
    score

-   For hip fracture, E+P reduced the risk more markedly in the subgroup
    of women with a baseline calcium intake of \>1200 mg/day than in
    women with a lower intake (*P* for interaction = 0.02); however,
    this was not true for total fracture

-   E+P lowered the risk of hip fracture in women with baseline BMIs of
    \<25 and 25-\<30, but not in women with a BMI of [\>]{.underline}30,
    but the interaction of therapy with baseline BMI was not
    statistically significant; E+P reduced the risk of total fracture to
    a similar degree across all groups of baseline BMI

-   Total hip BMD increased by 3.7% after 3 years, compared to 0.14% in
    the placebo group, p\<0.0001

-   The HR for the global index ranged from 1.20 in the lowest fracture
    risk tertile to 1.03 in the highest tertile (the global index
    includes coronary heart disease, stroke, pulmonary embolism, hip
    fracture, breast cancer, colorectal cancer, endometrial cancer, and
    death from other causes)

E+P increases BMD and reduces risk of osteoporotic fractures in healthy
postmenopausal women. However, even in the highest fracture risk tertile
there was no net benefit from treatment, as assessed by the global
index. Given the overall unfavorable risk/benefit ratio and the
availability of other agents to prevent and treat osteoporosis, E+P
cannot be recommended for the prevention or treatment of osteoporosis.

**[GYNECOLOGIC CANCERS]{.underline}**

***Gynecologic Cancers and Associated Diagnostic Procedures in the
Women's Health Initiative Randomized Trial of Estrogen Plus Progestin***

*Garnet L. Anderson, PhD; Howard Judd, MD; Andrew M. Kaunitz, MD; David
H. Barad, MD; Shirley A.A. Beresford, PhD; Mary Pettinger, MS; James
Liu, MD; S. Gene McNeeley, MD; Ana Maria Lopez, MD; for the Women's
Health Initiative Investigators*

*JAMA* 2003: 290;1739-1748

The effects of continuous combined E+P on gynecologic cancers have not
previously been described in a clinical trial setting. The main outcome
measures of this report were incident invasive cancer of the ovary and
endometrium.

-   The hazard ratio (HR) for invasive ovarian cancer in women assigned
    to estrogen plus progestin relative to placebo was 1.58 (95% CI:
    0.77-3.24) with 32 cases.

-   The HR for endometrial cancer was 0.81 (95% CI: 0.48-1.36) with 58
    cases.

-   No appreciable differences were found in the distributions of tumor
    histology, stage or grade for either cancer site

-   The HR for cervical cancer was 1.44 (95% CI 0.47-4.42) with 13
    cases, and the Pap smear results yielded slightly more mild
    displasia, low grade squamous intra-epithelial lesions, or atypia
    than the placebo arm and fewer normal results (p\<0.0001)

-   The incidence of other gynecologic cancers (uterus, other
    gynecologic organs) was low and did not differ by treatment arm

-   More women on E+P required endometrial biopsies (33% vs 6%,
    p\<0.0001)

The data suggest that continuous combined E+P may increase the risk of
ovarian cancer, but not that of endometrial cancer, over an average
follow up period of 5.6 years. The increased rates of endometrial biopsy
required to assess and manage vaginal bleed further limits the
acceptability of this treatment.

**[BIBLIOGRAPHY]{.underline}**

1.  Rossouw JE, Finnegan LP, Harlan WR, Pinn VW, Clifford C, McGowan JA.
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2.  Prentice R, Rossouw JR, Johnson, SR, Freedman LS, McTiernan A. \"The
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3.  Prentice RL, Anderson G, CummingsS, Freedman LS, Furberg C,
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4.  Shumaker SA, Reboussin BA, Espeland MA, Rapp SR, McBee WL, Dailey M,
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5.  Writing Group for the Women\'s Health Initiative Investigators.
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6.  Rapp S, Espeland M, Hogan P, Jones B, Dugan E. [Baseline experience
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7.  Rapp S, Espeland M, Shumaker S, Henderson V, Brunner R, Manson J,
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    *JAMA* 2003;289:2663-2672.

8.  Shumaker S, Legault C, Thal L, Wallace R, Ockene J, Hendrix S, Jones
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9.  Wassertheil-Smoller S, Hendrix S, Limacher M, Heiss G, Kooperberg C,
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    M, Stein E, Laowattana S, Mysiw WJ. [Effect of Estrogen Plus
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10. Jennifer Hays, Judith K. Ockene, Robert L. Brunner, Jane M. Kotchen,
    JoAnn E. Manson, Ruth E. Patterson, Aaron K. Aragaki, Sally A.
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    Barbara G. Valanis; for the Women\'s Health Initiative
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    Quality of Life]{.underline}. *NEJM* 2003:348;1839-54

11. Rowan T. Chlebowski, Susan L. Hendrix, Robert D. Langer, Marcia L.
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    Investigators. [Influence of Estrogen Plus Progestin on Breast
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    Health Initiative Randomized Trial.]{.underline}
    *JAMA*. 2003;289:3243-3253

12. JoAnn E. Manson, Judith Hsia, Karen C. Johnson, Jacques E. Rossouw,
    Annlouise R. Assaf, Norman L. Lasser, Maurizio Trevisan, Henry R.
    Black, Susan R. Heckbert, Robert Detrano, Ora L. Strickland,
    Nathan D. Wong, John R. Crouse, Evan Stein, Mary Cushman; for the
    Women\'s Health Initiative Investigators. [Estrogen plus Progestin
    and the Risk of Coronary Heart Disease.]{.underline} *NEJM*
    2003;349:523-534

13. Jane A. Cauley, John Robbins, Zhao Chen, Steven R. Cummings, Rebecca
    Jackson, Andrea Z. LaCroix, Meryl LeBoff, Cora E. Lewis, Joan
    McGowan, Joan Neuner, Mary Pettinger, Marcia L. Stefanick, Jean
    Wactawski-Wende, Nelson Watts; For the Women's Health Initiative
    Investigators. The Effects of Estrogen Plus Progestin on the Risk of
    Fracture and Bone Mineral Density. The Women's Health Initiative
    Clinical Trial. JAMA 2003: 290;1729-1738 *(In addition to this
    publication, Committee Members and Consultants also received the
    pre-publication manuscript to this publication.)*

14. Garnet L. Anderson, Howard Judd, Andrew M. Kaunitz, David H. Barad,
    Shirley A.A. Beresford, Mary Pettinger, James Liu, S. Gene McNeeley,
    Ana Maria Lopez. Gynecologic Cancers and Associated Diagnostic
    Procedures in the Women's Health Initiative Randomized Trial of
    Estrogen Plus Progestin. JAMA 2003:290;1739-1748 *(In addition to
    this publication, Committee Members and Consultants also received
    the pre-publication manuscript to this publication.)*

> **Further information on the WHI Program can be found at**
> <http://www.whi.org/> and at <http://www.nhlbi.nih.gov/whi/>

**[WHI INVESTIGATORS AND SITES]{.underline}**

Ross Prentice, Ph.D.

Fred Hutchinson Cancer

Research Center

Catherine I. Allen, Ph.D.

University of Wisconsin, Madison

Annlouise Assaf, Ph.D.

The Memorial Hospital

of Rhode Island

Tamsen Bassford, M.D.

University of Arizona, Health

Sciences Center

Shirley Beresford, M.D.

University of Washington

Henry R. Black, M.D.

Rush Presbyterian-St.Luke\'s

Medical Center

Gregory Burke. M.D., MS

Wake Forest University

Robert Burnner, Ph.D.

University of Nevada

Bette Caan, Dr.PH

Kaiser Division of Research,

Oakland

Rowan T. Chlebowski, M.D., Ph.D.

Harbor-UCLA Research

and Education Institute

David Curb, M.D.

University of Hawaii

Margery Gass, M.D.

University of Cincinnati

Jennifer Hays, Ph.D.

Baylor College of Medicine

Gerardo Heiss, M.D., Ph.D.

University of North Carolina,

Chapel Hill

Susan L. Hendrix, D.O.

Wayne State University

Barbara V. Howard, Ph.D.

MedStar Research Institute

Judith Hsia, M.D.

George Washington University

Allen Hubbell, M.D.

University of California, Irvine

Rebecca D. Jackson, M.D.

Ohio State University

Karen Johnson, M.D., M.P.H.

University of Tennessee, Memphis

Howard L. Judd, M.D.

UCLA

Jane Morley Kotchen, M.D., M.P.H.

Medical College of Wisconsin

Lewis Kuller, M.D., DrPH

University of Pittsburgh

Dorothy Lane, M.D.

SUNY at Stony Brook

Robert D. Langer, M.D., M.P.H.

University of California, San Diego

Norman Lasser, M.D., Ph.D.

University of Medicine and

Dentistry of N.J.

Cora Beth Lewis, M.D., MSPH

University of Alabama, Birmingham

Marian C. Limacher, M.D.

University of Florida

JoAnn Manson, M.D., DrPH

Brigham & Women's Health Hospital

Karen Margolis, M.D.

University of Minnesota

Judith K. Ockene, Ph.D.

University of Massachusetts

Medical College

Mary Jo O'Sullivan, M.D.

University of Miami

School of Medicine

Cheryl Ritenbaugh, Ph.D

Kaiser Center for Health

Research, Portland

John A. Robbins, M.D.

University of California, Davis

Robert S. Schenken, M.D.

University of Texas Health

Science Center, San Antonio

Marcia L. Stefanick, Ph.D.

Stanford University

Linda Van Horn, Ph.D., R.D.

Northwestern University

Jean Wactawski-Wende, Ph.D.

SUNY at Buffalo

Robert B. Wallace, M.D.

University of Iowa

Sylvia Wassertheil-Smoller, Ph.D.

Albert Einstein College of Medicine

Lawrence Phillips, M.D.

Emory University School of Medicine

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