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Original Investigation |

Effects of Conjugated Equine Estrogen on Health-Related Quality of Life in Postmenopausal Women With Hysterectomy:  Results From the Women’s Health Initiative Randomized Clinical Trial FREE

Robert L. Brunner, PhD; Margery Gass, MD; Aaron Aragaki, MS; Jennifer Hays, PhD; Iris Granek, MD; Nancy Woods, PhD, RN; Ellen Mason, MD; Robert Brzyski, MD, PhD; Judith Ockene, PhD; Annlouise Assaf, PhD; Andrea LaCroix, MPH, PhD; Karen Matthews, PhD; Robert Wallace, MD; Women’s Health Initiative Investigators
[+] Author Affiliations

Author Affiliations: Department of Family and Community Medicine, University of Nevada School of Medicine, Reno (Dr Brunner); Department of Obstetrics/Gynecology, University of Cincinnati, Cincinnati, Ohio (Dr Gass); Clinical Coordinating Center, Fred Hutchinson Cancer Research Center (Mr Aragaki and Dr LaCroix), and University of Washington School of Nursing, Center for Women’s Health Research (Dr Woods), Seattle; Women’s Health Center, Department of Medicine, Baylor College of Medicine, Houston, Tex (Dr Hays); Department of Preventive Medicine, State University of New York at Stony Brook (Dr Granek); Department of Obstetrics and Gynecology, John H. Stroger Jr Hospital of Cook County, Chicago, Ill (Dr Mason); Department Obstetrics and Gynecology, University of Texas Health Science Center, San Antonio (Dr Brzyski); Division of Preventive and Behavioral Medicine, University of Massachusetts Medical School, Worcester (Dr Ockene); Department of Community Health, Brown University, Providence, RI (Dr Assaf); Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pa (Dr Matthews); and Department of Epidemiology, University of Iowa, Iowa City (Dr Wallace).


Arch Intern Med. 2005;165(17):1976-1986. doi:10.1001/archinte.165.17.1976.
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Published online

Background  The Women’s Health Initiative (WHI) clinical trial of conjugated equine estrogens (CEEs), involving 10 739 postmenopausal women with hysterectomy, aged 50 to 79 years, was stopped early owing to lack of overall health benefit and increased risk of stroke. Because CEE is still prescribed for treatment of menopausal symptoms and prevention of osteoporosis, it is important to understand the overall impact of this therapy on health-related quality of life (HRQOL).

Methods  All participants completed 6 specific measures of quality of life at baseline and 1 year, and a subsample (n = 1189) also completed the questions 3 years after randomization. Changes in scores were analyzed for treatment effect.

Results  Randomization to CEE was associated with a statistically significant but small reduction in sleep disturbance at year 1 compared with baseline (mean benefit, 0.4 points on a 20-point scale) and a statistically significant but small negative effect on social functioning (mean effect, −1.3 points on a 100-point scale). There were no significant improvements due to CEE in the areas of general health, physical functioning, pain, vitality, role functioning, mental health, depressive symptoms, cognitive function, or sexual satisfaction at year 1. A subgroup examined 3 years after baseline had no significant benefits for any HRQOL outcomes. Among women aged 50 to 54 years with moderate to severe vasomotor symptoms at baseline, CEE did not improve any of the HRQOL variables at year 1.

Conclusion  In this trial of postmenopausal women with prior hysterectomy, oral CEE did not have a clinically meaningful effect on HRQOL.

Results of recently published large, randomized clinical trials have failed to support protective effects of oral estrogen therapy alone or estrogen plus progestin therapy on cardiovascular disease when administered to postmenopausal women.13 Findings of the Women’s Health Initiative (WHI)4 demonstrated that, compared with placebo, women taking conjugated equine estrogens (CEEs) were at increased risk for stroke and deep vein thrombosis and at decreased risk for osteoporotic fractures. The global risk-benefit profile was neutral in the CEE treatment group, and the planned 8.5-year randomized clinical trial (RCT) was stopped after an average of 6.8 years of follow-up (range, 5.7-10.7 years). Although the parallel WHI trial of CEE and medroxyprogesterone acetate (CEE + MPA) and other results showed that active treatment produced relief from vasomotor symptoms, the health-related quality of life (HRQOL) effects were limited to modest changes in physical functioning, sleep disturbance, and bodily pain that were considered too small to be of clinical significance on a population basis.57

The origin of the HRQOL concept has often been attributed to the World Health Organization position that health is a “state of complete physical, mental and social well-being and not merely the absence of infirmity and disease.”8 Health-related quality of life (QOL) limits the influences on QOL to medical conditions and/or their treatment.9

Typical self-assessment of HRQOL examines aspects of functioning that may relate to disease symptoms, disability, and outcome.10 Many HRQOL instruments target symptoms for specific medical conditions.11 However, the concept is also more broadly defined as encompassing multiple domains such as physical health and functioning, emotional functioning, social functioning, and role limitations.12 This approach and a single summary measure, ie, “global” QOL, were used herein and in the earlier CEE + MPA RCT. They have been widely validated.1315 Quality-of-life benefit is a consideration in the decision to use hormone therapy.16,17

Several recent reports have found some domains of HRQOL to be affected by the transition from before to after menopause, with depressive symptoms tending not to be affected.1823 Women before the menopause transition compared with women who had begun the transition differed in reports of pain, role limitations, and vitality, but adjustments for symptoms (leaking urine, vaginal dryness, night sweats, and hot flashes) and other variables reduced differences in HRQOL to nonsignificance in a large cross-sectional study.23,24 Estrogen alone as a postmenopausal hormone treatment continues to be offered for vasomotor symptom reduction, with collateral improvement reported in depression,25 sexual functioning,26 and cognitive functioning,27 all of which are components of HRQOL and an influence on global QOL. However, objective evidence of efficacy, particularly from longitudinal studies of menopause28 or randomized trials, have been inconsistent.29,30 The present RCT is a randomized, double-blind, placebo-controlled study conducted in women with prior hysterectomy, which eliminates a major adverse effect of hormone therapy (uterine bleeding). Other adverse effects such as breast tenderness, bloating, and moodiness, which are sometimes attributed to the use of a progestin, also are reduced because progestin was not used in this study. Thus, the WHI CEE trial provides an excellent opportunity to evaluate HRQOL benefits of estrogen in a large, diverse population of relatively healthy, postmenopausal women, some with symptoms associated with estrogen therapy withdrawal and others nonsymptomatic.

The eligibility criteria, recruitment procedures, and main study outcomes have been published previously.4,31,32 Briefly, women aged 50 to 79 years with hysterectomy more than 3 months earlier (with or without oophorectomy) were potentially eligible for this RCT. Participation in the WHI was precluded if a medical condition predicted survival of less than 3 years or if there were diagnoses of previous breast cancer or melanoma, other cancer within the past 10 years (except nonmelanoma skin cancer), low hematocrit or platelet counts, or any condition that would interfere with acceptable adherence and retention (eg, alcoholism or dementia). A 3-month washout of any prevailing hormone therapy was required before starting data collection, screening, and enrollment. Women who reported moderate or severe menopausal symptoms during the washout period were not excluded but were discouraged from participating.

Initial consent forms, questionnaires, fasting blood draws, physical measurements, and breast and pelvic examinations were completed at 3 screening visits. As part of the screening process, women took placebo pills for at least 4 weeks to assess compliance with pill taking. Then, eligible participants were randomized to CEE (0.625 mg) or matching placebo treatment. Participants and clinic staff were blinded to the study pill assignments. Clinic visits occurred 6 and 12 months (year 1 visit) after randomization, and annually thereafter. The baseline questionnaires were completed at the year 1 visit for all participants and, for an 8.6% subsample (n = 1189), at the year 3 visit. The 8.6% subsample was selected to have a larger proportion of ethnic minority participants than the overall cohort. The National Institutes of Health, Bethesda, Md, and the institutional review boards of all participating institutions approved the protocol and consent forms.

ASSESSMENT OF HRQOL AND FUNCTIONAL STATUS

Quality of life/functional status was assessed using the RAND 36-Item Health Survey (RAND36).33,34 The RAND36 has 8 subscales, each with a score range of 0 to 100 (with higher scores being better), that assess general health, physical functioning, role limitations due to physical health, bodily pain, energy and fatigue (vitality), role limitations due to emotional/mental problems, social functioning, and emotional/mental health and a stand-alone health transition question. Although the RAND36 contains the same items as the 36-item Medical Outcomes Study Short Form, it uses a slightly different scoring algorithm for 2 of the 8 subscales.

GLOBAL QOL

Global QOL was assessed by a single item (“Overall, how would you rate your quality of life?”) with an 11-point response scale (0 indicates “as bad or worse than being dead” and 10, “best quality of life”) that was reduced, for analysis, to 4 categories corresponding to poor (0-4), moderate (5-7), good (8), and excellent (9-10). The categories were chosen a priori and mirror those used in the Study of Women Across the Nation HRQOL.23

SLEEP QUALITY

Sleep quality was assessed by the 5-item Women’s Health Initiative Insomnia Rating Scale that was developed and validated for use in the WHI.35 Items in this survey referenced sleep during the past 4 weeks. Four items assessed sleep initiation and maintenance using a 5-point response scale (not in past 4 weeks; <1 time/wk; 1-2 times/wk; 3 or 4 times/wk; ≥5 times/wk). A fifth item assessed sleep quality, also using a 5-point scale (very sound or restful, sound or restful, average quality, restless, and very restless). Scores ranged from 0 (worst) to 20 (best).

SEXUAL SATISFACTION

Sexual satisfaction (“How satisfied are you with your current sexual activities, either with a partner or alone?”) was assessed by a single item with a 4-point response scale (very unsatisfied, a little unsatisfied, somewhat satisfied, or very satisfied). Scores ranged from 1 (worst) to 4 (best).

COGNITIVE FUNCTIONING

Cognitive functioning was assessed in participants 65 years or older by the Modified Mini-Mental State Examination,36 a scale used in the Cardiovascular Health Study.37 The Modified Mini-Mental State Examination has 15 parts with 46 separately scored items. Maximum (best) scores per item range from 1 to 8 (with a total of 100). The functions tested are orientation to time, place, and person; short-term memory; reading; writing; naming; verbal fluency; praxis; and graphomotor performance.

DEPRESSIVE SYMPTOMS

Depressive symptoms were assessed by means of an 8-item scale38 developed to screen for depressive disorders (major depression and dysthymia). It included 6 items from the Center for Epidemiological Studies Depression Scale39 and 2 items from the Diagnostic Interview Schedule.40 Scores may range from −8.2 (best) to 4.0 (worst). In this questionnaire, a lower score is desirable.

STATISTICAL ANALYSES

All primary analyses focused on changes in HRQOL from baseline to year 1 in relation to CEE randomization assignment. For each of the 13 HRQOL measures, we fit a linear model to test whether CEE had a significant treatment effect on HRQOL change score. To examine whether the CEE effect was moderated by baseline variables, we fit a series of linear models. Each pair, a baseline variable and the corresponding CEE interaction, was added one at a time, followed by a test of the interaction. Baseline characteristics included age, body mass index, ethnicity, moderate or severe vasomotor symptoms, previous hormone therapy use, years since menopause, bilateral oophorectomy status, history of cardiovascular disease, and socioeconomic variables (education, income, and health insurance status). Menopause was defined as the lowest age according to last menses, age at bilateral oophorectomy, or age when hormone therapy was started. If the ovaries were partially removed/intact, menopause was defined as the lower of the age hormone therapy was started or the age at first menopausal symptoms. Similar analyses were performed on data available at year 3 for the 8.6% subsample.

Statistical significance of the effect of CEE on HRQOL and of the tests of interactions were judged by Bonferroni-corrected αs of 0.005 (0.05/13, approximately 0.005) and 0.0005 (approximately 0.05/[13 × 11]), respectively. Actual P values, unadjusted for multiple comparison, are reported exclusively throughout the text and tables.

A post hoc analysis examined participants aged 50 to 54 years who reported moderate to severe night sweats or hot flashes at baseline. Because P values of treatment effects from subgroups can be misleading,41 we did not use a Bonferroni-adjusted α level for this analysis and caution readers to carefully interpret their values. All analyses were based on the intention-to-treat principle using SAS version 9.1.42

Overall, 5310 women were randomized into the CEE group and 5429 into the placebo group. The intervention groups were balanced on key demographic characteristics except for a slight statistical difference in bilateral oophorectomy status (Table 1). There were 2.5% fewer women in the CEE group with bilateral oophorectomy than in the placebo group. The mean age in the cohort was 63.6 years; 75.3% were white; 23.9% had a college education; 48.4% had some previous hormone use; and 17.3% had moderate/severe vasomotor symptoms at baseline. Baseline scores on the RAND36 were similar to scores observed in other healthy populations.43 The scores were somewhat lower than those seen in the WHI CEE + MPA trial among women with a uterus.5

Table Graphic Jump LocationTable 1. Baseline Characteristics by Treatment Assignment (Missing Excluded)

This analysis focused on changes in HRQOL measures during the first year of taking study drugs. At year 1, vital status was known for 100% of participants, including the 0.4% who died, and none were lost to follow-up. During the first year, study therapy was stopped for various reasons by 8.4% of women randomized to CEE and 8.0% of women randomized to placebo. Overall, 78% of women randomized to CEE and 82% of women randomized to placebo were adherent (defined as taking ≥80% of pills) at year 1. At year 3, in the subsample, adherence was 59% for both treatment groups.

In examining the change in HRQOL measures from baseline to year 1, few differences were observed between the CEE and placebo groups (Table 2). There was a small (0.40 difference on the 20-point scale) but statistically significant positive effect of CEE, relative to placebo, on sleep disturbance (P<.001). Based on Cohen’s44 rule of thumb, the effect size on sleep (0.4/3.88 = 0.1) does not even achieve the threshold for a small (≥0.2) effect size. There was also a small but statistically significant negative effect of CEE on social functioning (P = .003). At year 1, there were no other HRQOL variables for which a clinically meaningful or statistically significant improvement was observed with CEE.

Table Graphic Jump LocationTable 2. Change in QOL Scores From Baseline to Year 1

Differences from baseline to year 1 in the approximately 8.6% random subsample of women whose measures were repeated at year 3 (n = 577 in the CEE group; n = 612 in the placebo group) are displayed in Table 3. Treatment with CEE did not produce a statistically significant improvement in any HRQOL variables at year 1 or year 3 in this subsample. Further analyses explored whether there were substantive effects of CEE on HRQOL that depended on demographic, health, or other measures taken at baseline. There were no significant interactions of intervention assignment and any of the following: age, race/ethnicity, education, income, insurance status, body mass index, vasomotor symptoms (moderate or severe night sweats/hot flashes), years since menopause, previous use of any type of hormone therapy, bilateral oophorectomy status, or history of cardiovascular disease. Analyses of the following 3 subgroups were of particular interest: (1) women who had undergone bilateral oophorectomy, (2) women who reported moderate or severe vasomotor symptoms at baseline (hot flashes or night sweats), and (3) the youngest age group (with symptoms). These subgroups may have experienced greater improvements in QOL from relief of symptoms by CEE. There was no significant difference in the effect of CEE on HRQOL among women who had undergone bilateral oophorectomy compared with those who had not. Apart from HRQOL, we examined the effects of CEE on relief of symptoms specifically among women who reported moderate or severe vasomotor symptoms at baseline (913 women in the CEE and 917 in the placebo groups). At the 1-year follow-up, 72.4% of women reporting moderate or severe vasomotor symptoms at baseline in the CEE group no longer reported them, compared with 55.6% of women in the placebo group (P<.001). As shown in Table 4, an additional restriction to women aged 50 to 54 years reporting moderate or severe vasomotor symptoms at baseline does not magnify any positive effect of CEE on HRQOL variables. For 7 of the 13 HRQOL changes (baseline to year 1), these youngest participants in the CEE group had worse scores than the placebo group. A higher proportion of participants in the placebo group (39%) reported, at year 1, much better or somewhat better health than participants in the CEE group (23%) (Table 5).

Table Graphic Jump LocationTable 3. Change in QOL Scores at Years 1 and 3 Compared With Baseline in CEE Subgroup of 1189 Participants
Table Graphic Jump LocationTable 4. Changes in QOL Scores From Baseline to Year 1 Among Subjects Aged 50 to 54 Years With Moderate or Severe Vasomotor Symptoms
Table Graphic Jump LocationTable 5. Change in Rating of General Health*

The single global item asked: “Overall, how would you rate your quality of life?” The distributions of global scores did not differ between the CEE and placebo groups (data not shown). In both groups, less than 3% reported poor and 40% reported excellent global QOL. The CEE and placebo groups were very similar in the proportions of participants who rated their global QOL in the moderate and good categories (26%-30%). Table 6 offers a sense of the metric for HRQOL (eg, RAND36 scores) by showing differences that are associated with categorical increments in global QOL. As examples, the HRQOL mean scores were approximately 1 SD higher for women who rated their global QOL as excellent compared with those who rated it as moderate. The HRQOL sleep disturbance score was 3 points higher (less disturbance) for women rating their global QOL as excellent compared with those who rated it as moderate. Higher ratings of global QOL were associated with higher scores on each of the RAND36 subscales and lower scores on the depression measures, all suggesting that this global item is sensitive to symptoms and functioning. Also, regardless of treatment assignment, moderate to severe menopausal symptoms and adverse effects of hormone therapy were significantly associated with worse global QOL.

Table Graphic Jump LocationTable 6. Relationship of Vasomotor Symptoms, Adverse Effects of Treatment, and RAND36 Scores to Global QOL at Year 1 Collapsed by Treatment Assignment

Because of the slight imbalance of bilateral oophorectomy status by treatment assignment, we performed a sensitivity analysis of our primary results. Adjustment of bilateral oophorectomy status did not change conclusions regarding sleep disturbance; the mean difference between the CEE and placebo groups changed from 0.40 to 0.38 and remained statistically significant (P≤.001). However, oophorectomy adjustment slightly attenuated the effect of CEE on social functioning; after adjustment, the mean difference changed from −1.31 to −1.16 (P = .01) and consequently did not reach the Bonferroni-corrected α level. None of the other results were changed after adjusting for bilateral oophorectomy status.

In the WHI RCT of CEE alone,4 a clinically meaningful benefit of CEE treatment on HRQOL was not found in an ethnically diverse population of postmenopausal women who had undergone hysterectomy before entering the study. Failure to demonstrate global improvement in HRQOL occurred, despite absence of uterine bleeding or other progestin-associated adverse effects.

These results were similar to results reported for women with a uterus in the WHI CEE + MPA trial.5 In both trials, a statistically significant, small improvement in average sleep disturbance score was found after 1 year of hormone treatment. Women with vasomotor symptoms experienced a significant decline in these symptoms, but the positive effects on physical functioning and bodily pain seen in the WHI CEE + MPA trial were not found here.

Several baseline differences in HRQOL were noted between women in the CEE + MPA trial (with a uterus) and women in the CEE trial (without a uterus). The average bodily pain score at baseline was significantly more negative (more pain) in the CEE trial than in the CEE + MPA trial (P≤.001). Similarly, women in the CEE trial had worse physical functioning scores at baseline (P≤.001). Also, in the CEE + MPA trial, at baseline, fewer women reported poor and more reported excellent global QOL than in the present trial (P<.001). However, after 1 year, the CEE and CEE + MPA groups did not differ from their respective placebo groups in global QOL. The subsample with HRQOL undergoing reassessment 3 years from baseline provided no evidence that longer-term use of CEE improves HRQOL measures compared with a shorter-term use. It could be argued that the limited effects of CEE on HRQOL resulted from a too conservative α level probability threshold, one that had been adjusted for multiple comparisons. However, we have presented actual (unadjusted) P values, so the reader may decide what they consider statistically significant. For example, applying a liberal α value of .05 would only add a statistically significant improvement in physical functioning from CEE, which then is perhaps offset by a significant negative change in cognitive functioning.

The minimal benefit of CEE on HRQOL (2% improvement in sleep disturbance symptoms) does not challenge the current treatment guidelines. The findings suggest that asymptomatic women using estrogen therapy, eg, for prevention of osteoporosis, are unlikely in the short term to experience a meaningful improvement in HRQOL.

Overall, our results are consistent with other recent randomized trials46,47 and epidemiological studies.48 The WHI and other studies indicate that some menopausal vasomotor symptoms improve with estrogen treatment. There is little or no benefit of systemic hormone treatment for most other physical, functional, and psychosocial conditions, with some, like nocturnal urinary frequency, worsening.49,50 The HRQOL measures may be considered subjective aggregates that are complexly influenced by the combination of estrogen replacement’s improvement in vasomotor symptoms (and/or other unspecified positive effects), adverse effects, and consequences for disease processes and end points. Part of the rationale for the original study design was that estrogen would have health benefits (bone, heart, and cognition) that would be reflected in HRQOL measures. The absence of an improvement with estrogen in the global index, the study’s overall risk-benefit health profile,4 may help explain the weak response of HRQOL measures.

As a randomized clinical trial of relatively healthy women after menopause, it might be argued that the potential for positive health differences was limited by a “ceiling” that effectively reduced the range of scores at the upper end of the spectrum. This may be the case for the 2-item social functioning subscale (mean score lower in the CEE group) of the RAND36, which has a coarse Likert scale. Most participants attained the maximum score on social functioning. For other subscales, average scores were well below the possible maximum. For example, only 1% of subjects had maximum vitality scores, and baseline HRQOL scores were generally lower in this population than in the previously reported CEE + MPA trial in women without a hysterectomy. We attribute the latter difference largely to more health risk factors and lower socioeconomic status in the women with hysterectomy.

Some reports suggest that estrogen therapy might play a role in the management of severe emotional and mental changes in the postpartum or perimenopausal periods.51,52 The impact of estrogen treatment in clinical mood disorders may be very different than its population effects in healthy women not selected for such disturbances.

Estrogen therapy alone in women with a hysterectomy did not produce clinically meaningful improvements in HRQOL measures compared with placebo, despite reduction of some vasomotor symptoms resulting from the active treatment, albeit in the relatively small proportion of women in the cohort who were symptomatic. Any overall impact may have been lessened by the size of the specific effect on sleep disturbance, which, as one of the more widely reported and enduring problems in this age group, had only a small average improvement, perhaps because nocturnal urinary frequency may worsen with hormone treatment.49 Moreover, recent reviews have suggested that subjectively reported sleep dis turbance during and after menopause has multiple causes and that its relationship to hormone changes is complex.53,54 In the WHI, health risks and benefits were relatively balanced after more than 6 years of CEE use. Individual women may experience some improvement in their vasomotor and urogenital atrophy symptoms, but these may be partly offset by adverse effects associated with postmenopausal hormone treatment. We find no evidence of an HRQOL benefit for the general postmenopausal population.

Correspondence: Robert L. Brunner, PhD, Department of Family and Community Medicine, University of Nevada School of Medicine, MS145, Reno, NV 89557 (bbrunner@whi.org).

Accepted for Publication: May 19, 2005.

Financial Disclosure: Dr Assaf is an employee of Pfizer, which during part of the conduct of the study, made a competing drug to conjugated estrogens (Premarin), the study drug made by Wyeth-Ayerst. Pfizer has since divested the company of the subsidiary that made the hormone drug.

Funding/Support: The Women’s Health Initiative is funded by the National Heart, Lung, and Blood Institute, US Department of Health and Human Services, National Institutes of Health (NIH), Bethesda, Md.

Role of the Sponsor: The National Heart, Lung, and Blood Institute funded the Women’s Health Initiative. Scientists from the NIH participated in the design of the study but did not participate in data collection or analysis and are not among the authors of this article.

Box Section Ref ID

WHI Investigators

Program Office

National Heart, Lung, and Blood Institute, Bethesda, Md: Barbara Alving, Jacques Rossouw, Linda Pottern, Shari Ludlam, and Joan McGowan.

Clinical Coordinating Center

Fred Hutchinson Cancer Research Center, Seattle, Wash: Ross Prentice, Garnet Anderson, Andrea LaCroix, Ruth Patterson, Anne McTiernan, Barbara Cochrane, Julie Hunt, Lesley Tinker, Charles Kooperberg, Martin McIntosh, C. Y. Wang, Chu Chen, Deborah Bowen, Alan Kristal, Janet Stanford, Nicole Urban, Noel Weiss, and Emily White. Wake Forest University School of Medicine, Winston-Salem, NC: Sally Shumaker, Ronald Prineas, and Michelle Naughton. Medical Research Laboratories, Highland Heights, Ky: Evan Stein and Peter Laskarzewski. University of California–San Francisco: Steven Cummings, Michael Nevitt, and Maurice Dockrell. University of Minnesota, Minneapolis: Lisa Harnack. McKesson BioServices, Rockville, Md: Frank Cammarata and Steve Lindenfelser. University of Washington, Seattle: Bruce Psaty and Susan Heckbert.

Clinical Centers

Albert Einstein College of Medicine, Bronx, NY: Sylvia Wassertheil-Smoller, William Frishman, Judith Wylie-Rosett, David Barad, and Ruth Freeman. Baylor College of Medicine, Houston, Tex: Jennifer Hays, Ronald Young, Jill Anderson, Sandy Lithgow, and Paul Bray. Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass: JoAnn Manson, Julie Buring, Kathryn Rexrode, Claudia Chae, and Caren Solomon. Brown University, Providence, RI: Annlouise R. Assaf, Carol Wheeler, Charles Eaton, and Michelle Cyr. Emory University, Atlanta, Ga: Lawrence Phillips, Margaret Pedersen, Ora Strickland, Margaret Huber, and Vivian Porter. Fred Hutchinson Cancer Research Center, Seattle, Wash: Shirley A. A. Beresford, Vicky M. Taylor, Nancy F. Woods, Maureen Henderson, and Robyn Andersen. George Washington University, Washington, DC: Judith Hsia, Nancy Gaba, and Joao Ascensao. Harbor/University of California–Los Angeles Research and Education Institute, Torrance: Rowan Chlebowski, Robert Detrano, Anita Nelson, and Michele Geller. Kaiser Permanente Center for Health Research, Portland, Ore: Evelyn Whitlock, Patricia Elmer, Victor Stevens, and Njeri Karanja. Kaiser Permanente Division of Research, Oakland, Calif: Bette Caan, Stephen Sidney, Geri Bailey and Jane Hirata. Medical College of Wisconsin, Milwaukee: Jane Morley Kotchen, Vanessa Barnabei, Theodore A. Kotchen, Mary Ann C. Gilligan, and Joan Neuner. MedStar Research Institute/Howard University, Washington, DC: Barbara V. Howard, Lucile Adams-Campbell, Lawrence Lessin, Monique Rainford, and Gabriel Uwaifo. Northwestern University, Chicago/Evanston, Ill: Linda Van Horn, Philip Greenland, Janardan Khandekar, Kiang Liu, and Carol Rosenberg. Rush-Presbyterian St Luke’s Medical Center, Chicago: Henry Black, Lynda Powell, Ellen Mason, and Martha Gulati. Stanford Center for Research in Disease Prevention, Stanford University, Stanford, Calif: Marcia L. Stefanick, Mark A. Hlatky, Bertha Chen, Randall S. Stafford, and Linda C. Giudice. State University of New York at Stony Brook: Dorothy Lane, Iris Granek, William Lawson, Gabriel San Roman, and Catherine Messina. The Ohio State University, Columbus: Rebecca Jackson, Randall Harris, Electra Paskett, W. Jerry Mysiw, and Michael Blumenfeld. University of Alabama at Birmingham: Cora E. Lewis, Albert Oberman, James M. Shikany, Monika Safford, and Brian K. Britt. University of Arizona, Tucson/Phoenix: Tamsen Bassford, Cyndi Thomson, Marcia Ko, and Ana Maria Lopez. University at Buffalo, Buffalo, NY: Jean Wactawski-Wende, Maurizio Trevisan, Ellen Smit, Susan Graham, and June Chang. University of California at Davis, Sacramento: John Robbins and S. Yasmeen. University of California at Irvine, Orange: Allan Hubbell, Gail Frank, Nathan Wong, Nancy Greep, and Bradley Monk. University of California at Los Angeles: Howard Judd, David Heber, and Robert Elashoff. University of California at San Diego, LaJolla/Chula Vista: Robert D. Langer, Michael H. Criqui, Gregory T. Talavera, Cedric F. Garland, R. and Elaine Hanson. University of Cincinnati, Cincinnati, Ohio: Margery Gass, Suzanne Wernke, and Nelson Watts. University of Florida, Gainesville/Jacksonville: Marian Limacher, Michael Perri, Andrew Kaunitz, R. Stan Williams, and Yvonne Brinson. University of Hawaii, Honolulu: David Curb, Helen Petrovitch, Beatriz Rodriguez, Kamal Masaki, and Santosh Sharma. University of Iowa, Iowa City/Davenport: Robert Wallace, James Torner, Susan Johnson, Linda Snetselaar, and Jennifer Robinson. University of Massachusetts/Fallon Clinic, Worcester: Judith Ockene, Milagros Rosal, Ira Ockene, Robert Yood, and Patricia Aronson. University of Medicine and Dentistry of New Jersey, Newark: Norman Lasser, Baljinder Singh, Vera Lasser, and John Kostis. University of Miami, Miami, Fla: Mary Jo O’Sullivan, Linda Parker, R. Estape, and Diann Fernandez. University of Minnesota, Minneapolis: Karen L, Margolis, Richard H. Grimm, Donald B. Hunninghake, June LaValleur, and Sarah Kempainen. University of Nevada, Reno: Robert Brunner, Michael Bloch,William Graettinger, and Vicki Oujevolk. University of North Carolina, Chapel Hill: Gerardo Heiss, Pamela Haines, David Ontjes, Carla Sueta, and Ellen Wells. University of Pittsburgh, Pittsburgh, Pa: Lewis Kuller, Jane Cauley, and N. Carole Milas. University of Tennessee, Memphis: Karen C. Johnson, Suzanne Satterfield, Raymond W. Ke, Stephanie Connelly, and Fran Tylavsky. University of Texas Health Science Center, San Antonio: Robert Brzyski, Robert Schenken, Jose Trabal, Mercedes Rodriguez-Sifuentes, and Charles Mouton. University of Wisconsin, Madison: Gloria Sarto, Douglas Laube, Patrick McBride, Julie Mares-Perlman, and Barbara Loevinger. Wake Forest University School of Medicine, Winston-Salem, NC: Denise Bonds, Greg Burke, Robin Crouse, Mara Vitolins, and Scott Washburn. Wayne State University School of Medicine/Hutzel Hospital, Detroit, Mich: Susan Hendrix, Michael Simon, and Gene McNeeley.

Former Principal Investigators

Baylor College of Medicine: John Foreyt, PhD. Emory University: Dallas Hall, MD. George Washington University: Valery Miller, MD. Kaiser Permente Division of Research, Oakland: Robert Hiatt, MD. Kaiser Permente Center for Health Research, Portland: Barbara Valanis, DrPh. University of California, Irvine: Frank Meyskens, Jr, MD. University of Cincinnati: James Liu, MD. University of Miami: Marianna Baum, PhD. University of Minnesota: Richard Grimm, MD. University of Nevada: Sandra Daugherty, MD.† University of North Carolina, Chapel Hill: David Sheps, MD. University of Tennessee, Memphis: William Applegate, MD. University of Wisconsin: Catherine Allen, PhD.†

Deceased.

Grady  DHerrington  DBittner  V  et al. HERS Research Group, Cardiovascular disease outcomes during 6.8 years of hormone therapy: heart and estrogen/progestin replacement study follow-up (HERS II). JAMA 2002;28849- 57
PubMed Link to Article
Herrington  DMReboussin  DMKlein  KP  et al.  The Estrogen Replacement and Atherosclerosis (ERA) Study: study design and baseline characteristics of the cohort. Control Clin Trials 2000;21257- 285[published correction appears in Control Clin Trials. 2000;21:414]
PubMed Link to Article
WHI Writing Group, Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002;288321- 333
PubMed Link to Article
Anderson  GLLimacher  MAssaf  AR  et al. Women’s Health Initiative Steering Committee, Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative Randomized Controlled Trial. JAMA 2004;2911701- 1712
PubMed Link to Article
Hays  JOckene  JKBrunner  RL  et al. Valanis BG for the Women’s Health Initiative Investigators, Effects of estrogen plus progestin on health-related quality of life: results from the Women's Health Initiative Randomized Clinical Trial. N Engl J Med 2003;3481839- 1854
PubMed Link to Article
Greendale  GAReboussin  BAHogan  P  et al.  Symptom relief and side effects of postmenopausal hormones: results from the postmenopausal estrogen/progestin interventions trial. Obstet Gynecol 1998;92982- 988
PubMed Link to Article
Barnabei  VMGrady  DStovall  DW  et al.  Menopausal symptoms in older women and the effects of treatment with hormone therapy. Obstet Gynecol 2002;1001209- 1218
PubMed Link to Article
World Health Organization, World Health Organization constitution. Basic Documents. Geneva, Switzerland World Health Organization1948;
Cella  DFBonomi  AE Measuring quality of life: 1995 update. Oncology (Williston Park) 1995;9 ((11 suppl)) 47- 60
PubMed
Guyatt  GHNaylor  DJuniper  EHeyland  DKJaeschke  RCook  DJEvidence-Based Medicine Working Group, Users’ guide to the medical literature, XII: how to use articles about health-related quality of life. JAMA 1997;2771232- 1237
PubMed Link to Article
Cella  DNowinski  CJ Measuring quality of life in chronic illness: the functional assessment of chronic illness therapy measurement system. Arch Phys Med Rehabil 2002;83S10- S17
PubMed Link to Article
Hunt  SM The problem of quality of life. Qual Life Res 1997;6205- 212
PubMed
Dempster  MDonnelly  MFitzsimons  D Generic, disease-specific and individualised approaches to measuring health-related quality of life among people with heart disease: a comparative analysis. Psychol Health 2002;17447- 457
Link to Article
Alder  EM How to assess quality of life: problems and methodology. Schneider  HPGed.Hormone Replacement Therapy and Quality of Life. New York, NY Parthenon Publishing Group Inc2002;
Stansfeld  SARoberts  RFoot  SP Assessing the validity of the SF-36 General Health Survey. Qual Life Res 1997;6217- 224
PubMed Link to Article
Rothert  MPadonu  GHolmes-Rovner  M  et al.  Menopausal women as decision makers in health care. Exp Gerontol 1994;29463- 468
PubMed Link to Article
Zethraeus  NJohannesson  MHenriksson  PStrand  R The impact of hormone replacement therapy on quality of life and willingness to pay. Br J Obstet Gynaecol 1997;1041191- 1195
PubMed Link to Article
Avis  NEStellato  RCrawford  S  et al.  Is there a menopausal syndrome? menopausal status and symptoms across racial/ethnic groups. Soc Sci Med 2001;52345- 356
PubMed Link to Article
Avis  NEBrambilla  DMcKinlay  SMVass  K A longitudinal analysis of the association between menopause and depression: results from the Massachusetts Women’s Health Study. Ann Epidemiol 1994;4214- 220
PubMed Link to Article
Kaufert  PAGilbert  PTate  R The Manitoba Project: a re-examination of the link between menopause and depression. Maturitas 1992;14143- 155
PubMed Link to Article
Hardy  RKuh  D Change in psychological and vasomotor symptom reporting during the menopause. Soc Sci Med 2002;551975- 1988
PubMed Link to Article
Dennerstein  LLehert  PBurger  HDudley  E Mood and the menopausal transition. J Nerv Ment Dis 1999;187685- 691
PubMed Link to Article
Avis  NEOry  MMatthews  KASchocken  MBromberger  JCovin  A Health-related quality of life in a multiethnic sample of middle-aged women: study of women’s health across the nation. Med Care 2003;411262- 1276
PubMed Link to Article
Avis  NEAssmann  SFKravitz  HMGanz  PAOry  M Quality of life in diverse groups of midlife women: assessing the influence of menopause, health status and psychosocial and demographic factors. Qual Life Res 2004;13933- 946
PubMed Link to Article
Zweifel  JO’Brien  W A meta-analysis of the effect of hormone replacement therapy upon depressed mood. Psychoneuroendocrinology 1997;22189- 212
PubMed Link to Article
Sarrell  PM Effects of hormone replacement therapy on sexual psychophysiology and behavior in postmenopause. J Womens Health Gend Based Med 2000;925- 32
Link to Article
Paganini-Hill  AHenderson  V Estrogen deficiency and risk of Alzheimer’s disease in women. Am J Epidemiol 1994;140256- 261
PubMed
Meyer  PMPowell  LHWilson  RS  et al.  A population-based longitudinal study of cognitive functioning in the menopausal transition. Neurology 2003;61801- 806
PubMed Link to Article
Espeland  MRapp  SShumaker  S  et al.  The effect of estrogen on global cognitive function in postmenopausal women: results from the Women’s Health Initiative Memory Study. JAMA 2004;2912959- 2968
PubMed Link to Article
Bagger  YZTanko  LBAlexandersen  PQin  GChristiansen  CPERF Study Group, Early postmenopausal hormone therapy may prevent cognitive impairment later in life. Menopause 2005;1212- 17
PubMed Link to Article
Women’s Health Initiative Study Group, Design of the Women’s Health Initiative clinical trial and observational study. Control Clin Trials 1998;1961- 109
PubMed Link to Article
Matthews  KAShumaker  SABowen  DJ  et al.  The Women’s Health Initiative: why now? what is it? what’s new? Am Psychol 1997;52101- 116
PubMed Link to Article
Ware  JE  JrSherbourne  CD The MOS 36-Item Short-Form Health Survey (SF-36), I: conceptual framework and item selection. Med Care 1992;30473- 483
PubMed Link to Article
Hays  RDSherbourne  CDMazel  RM The RAND 36-Item Health Survey 1.0. Health Econ 1993;2217- 227
PubMed Link to Article
Levine  DWKaplan  RMKripke  DFBowen  DJNaughton  MJShumaker  SA Factor structure and factor invariance of the Women’s Health Initiative Insomnia Rating Scale. Psychol Assess 2003;15123- 136
PubMed Link to Article
Teng  ELChui  HC The Modified Mini-Mental State (3MS) examination. J Clin Psychiatry 1987;48314- 318
PubMed
Lyketsos  CGLopez  OJones  BFitzpatrick  AIBreitner  JDeKosky  S Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the Cardiovascular Health Study. JAMA 2002;2881475- 1483
PubMed Link to Article
Burnam  MAWells  KBLeake  BLandsverk  J Development of a brief screening instrument for detecting depressive disorders. Med Care 1988;26775- 789
PubMed Link to Article
Radloff  LS The CES-D Scale: a self-report depression scale for research in the general population. App Psychol Measurement 1977;1385- 401
Link to Article
Robins  LNHelzer  JECroughan  JRatcliff  KS National Institute of Mental Health Diagnostic Interview Schedule: its history, characteristics, and validity. Arch Gen Psychiatry 1981;38381- 389
PubMed Link to Article
Pocock  SJAssman  SEEnos  LEKasten  LE Subgroup analysis, covariate adjustment and baseline comparisons in clinical trial reporting: current practice and problems. Stat Med 2002;212917- 2930
PubMed Link to Article
SAS Institute, Inc, Statistical Analysis System.  Cary, NC SAS Institute Inc2002-2003;
McHorney  CAWare  JERaczek  AE The MOS 36-Item Short-Form Health Survey (SF-36), II: psychometric and clinical tests of validity in measuring physical and mental health constructs. Med Care 1993;31247- 263
PubMed Link to Article
Cohen  J Statistical Power Analysis for the Behavioral Sciences.  Orlando, Fla Academic Press Inc1988;
Barnabei  VMCochrane  BBAragaki  AK  et al. Women's Health Initiative Investigators, Menopausal symptoms and treatment-related effects of estrogen and progestin in the Women's Health Initiative. Obstet Gynecol 2005;105 ((pt 1)) 1063- 1073
PubMed Link to Article
Haines  CJYim  SFChung  TK  et al.  A prospective, randomized, placebo-controlled study of the dose effect of oral oestradiol on menopausal symptoms, psychological well being, and quality of life in postmenopausal Chinese women. Maturitas 2003;44207- 214
PubMed Link to Article
Polo-Kantola  PErkkola  RHelenius  HIrjala  KPolo  O When does estrogen replacement therapy improve sleep quality? Am J Obstet Gynecol 1998;1781002- 1009
PubMed Link to Article
Kritz-Silverstein  DVon Muhlen  DGGaniats  TGBarrett-Connor  E Hysterectomy status, estrogen use and quality of life in older women: the Rancho Bernardo Study. Qual Life Res 2004;1355- 62
PubMed Link to Article
Cardozo  LLose  GMcClish  DVersi  E A systematic review of the effects of estrogens for symptoms suggestive of overactive bladder. Acta Obstet Gynecol Scand 2004;83892- 897
PubMed Link to Article
 Executive summary. Obstet Gynecol 2004;104 ((suppl)) 1S- 4S
PubMed Link to Article
Schmidt  PJNieman  LDanaceau  MA  et al.  Estrogen replacement in perimenopause-related depression: a preliminary report. Am J Obstet Gynecol 2000;183414- 420
PubMed Link to Article
Ahokas  AAito  MRimon  R Positive treatment effect of estradiol in postpartum psychosis: a pilot study. J Clin Psychiatry 2000;61166- 169
PubMed Link to Article
Krystal  ADEdinger  JWohlgemuth  WMarsh  OR Sleep in peri-menopausal and post-menopausal women. Sleep Med Rev 1998;2243- 253
PubMed Link to Article
Moline  MLBroch  LZak  RGross  V Sleep in women across the life cycle from adulthood through menopause. Sleep Med Rev 2003;7155- 177
PubMed Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics by Treatment Assignment (Missing Excluded)
Table Graphic Jump LocationTable 2. Change in QOL Scores From Baseline to Year 1
Table Graphic Jump LocationTable 3. Change in QOL Scores at Years 1 and 3 Compared With Baseline in CEE Subgroup of 1189 Participants
Table Graphic Jump LocationTable 4. Changes in QOL Scores From Baseline to Year 1 Among Subjects Aged 50 to 54 Years With Moderate or Severe Vasomotor Symptoms
Table Graphic Jump LocationTable 5. Change in Rating of General Health*
Table Graphic Jump LocationTable 6. Relationship of Vasomotor Symptoms, Adverse Effects of Treatment, and RAND36 Scores to Global QOL at Year 1 Collapsed by Treatment Assignment

References

Grady  DHerrington  DBittner  V  et al. HERS Research Group, Cardiovascular disease outcomes during 6.8 years of hormone therapy: heart and estrogen/progestin replacement study follow-up (HERS II). JAMA 2002;28849- 57
PubMed Link to Article
Herrington  DMReboussin  DMKlein  KP  et al.  The Estrogen Replacement and Atherosclerosis (ERA) Study: study design and baseline characteristics of the cohort. Control Clin Trials 2000;21257- 285[published correction appears in Control Clin Trials. 2000;21:414]
PubMed Link to Article
WHI Writing Group, Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002;288321- 333
PubMed Link to Article
Anderson  GLLimacher  MAssaf  AR  et al. Women’s Health Initiative Steering Committee, Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative Randomized Controlled Trial. JAMA 2004;2911701- 1712
PubMed Link to Article
Hays  JOckene  JKBrunner  RL  et al. Valanis BG for the Women’s Health Initiative Investigators, Effects of estrogen plus progestin on health-related quality of life: results from the Women's Health Initiative Randomized Clinical Trial. N Engl J Med 2003;3481839- 1854
PubMed Link to Article
Greendale  GAReboussin  BAHogan  P  et al.  Symptom relief and side effects of postmenopausal hormones: results from the postmenopausal estrogen/progestin interventions trial. Obstet Gynecol 1998;92982- 988
PubMed Link to Article
Barnabei  VMGrady  DStovall  DW  et al.  Menopausal symptoms in older women and the effects of treatment with hormone therapy. Obstet Gynecol 2002;1001209- 1218
PubMed Link to Article
World Health Organization, World Health Organization constitution. Basic Documents. Geneva, Switzerland World Health Organization1948;
Cella  DFBonomi  AE Measuring quality of life: 1995 update. Oncology (Williston Park) 1995;9 ((11 suppl)) 47- 60
PubMed
Guyatt  GHNaylor  DJuniper  EHeyland  DKJaeschke  RCook  DJEvidence-Based Medicine Working Group, Users’ guide to the medical literature, XII: how to use articles about health-related quality of life. JAMA 1997;2771232- 1237
PubMed Link to Article
Cella  DNowinski  CJ Measuring quality of life in chronic illness: the functional assessment of chronic illness therapy measurement system. Arch Phys Med Rehabil 2002;83S10- S17
PubMed Link to Article
Hunt  SM The problem of quality of life. Qual Life Res 1997;6205- 212
PubMed
Dempster  MDonnelly  MFitzsimons  D Generic, disease-specific and individualised approaches to measuring health-related quality of life among people with heart disease: a comparative analysis. Psychol Health 2002;17447- 457
Link to Article
Alder  EM How to assess quality of life: problems and methodology. Schneider  HPGed.Hormone Replacement Therapy and Quality of Life. New York, NY Parthenon Publishing Group Inc2002;
Stansfeld  SARoberts  RFoot  SP Assessing the validity of the SF-36 General Health Survey. Qual Life Res 1997;6217- 224
PubMed Link to Article
Rothert  MPadonu  GHolmes-Rovner  M  et al.  Menopausal women as decision makers in health care. Exp Gerontol 1994;29463- 468
PubMed Link to Article
Zethraeus  NJohannesson  MHenriksson  PStrand  R The impact of hormone replacement therapy on quality of life and willingness to pay. Br J Obstet Gynaecol 1997;1041191- 1195
PubMed Link to Article
Avis  NEStellato  RCrawford  S  et al.  Is there a menopausal syndrome? menopausal status and symptoms across racial/ethnic groups. Soc Sci Med 2001;52345- 356
PubMed Link to Article
Avis  NEBrambilla  DMcKinlay  SMVass  K A longitudinal analysis of the association between menopause and depression: results from the Massachusetts Women’s Health Study. Ann Epidemiol 1994;4214- 220
PubMed Link to Article
Kaufert  PAGilbert  PTate  R The Manitoba Project: a re-examination of the link between menopause and depression. Maturitas 1992;14143- 155
PubMed Link to Article
Hardy  RKuh  D Change in psychological and vasomotor symptom reporting during the menopause. Soc Sci Med 2002;551975- 1988
PubMed Link to Article
Dennerstein  LLehert  PBurger  HDudley  E Mood and the menopausal transition. J Nerv Ment Dis 1999;187685- 691
PubMed Link to Article
Avis  NEOry  MMatthews  KASchocken  MBromberger  JCovin  A Health-related quality of life in a multiethnic sample of middle-aged women: study of women’s health across the nation. Med Care 2003;411262- 1276
PubMed Link to Article
Avis  NEAssmann  SFKravitz  HMGanz  PAOry  M Quality of life in diverse groups of midlife women: assessing the influence of menopause, health status and psychosocial and demographic factors. Qual Life Res 2004;13933- 946
PubMed Link to Article
Zweifel  JO’Brien  W A meta-analysis of the effect of hormone replacement therapy upon depressed mood. Psychoneuroendocrinology 1997;22189- 212
PubMed Link to Article
Sarrell  PM Effects of hormone replacement therapy on sexual psychophysiology and behavior in postmenopause. J Womens Health Gend Based Med 2000;925- 32
Link to Article
Paganini-Hill  AHenderson  V Estrogen deficiency and risk of Alzheimer’s disease in women. Am J Epidemiol 1994;140256- 261
PubMed
Meyer  PMPowell  LHWilson  RS  et al.  A population-based longitudinal study of cognitive functioning in the menopausal transition. Neurology 2003;61801- 806
PubMed Link to Article
Espeland  MRapp  SShumaker  S  et al.  The effect of estrogen on global cognitive function in postmenopausal women: results from the Women’s Health Initiative Memory Study. JAMA 2004;2912959- 2968
PubMed Link to Article
Bagger  YZTanko  LBAlexandersen  PQin  GChristiansen  CPERF Study Group, Early postmenopausal hormone therapy may prevent cognitive impairment later in life. Menopause 2005;1212- 17
PubMed Link to Article
Women’s Health Initiative Study Group, Design of the Women’s Health Initiative clinical trial and observational study. Control Clin Trials 1998;1961- 109
PubMed Link to Article
Matthews  KAShumaker  SABowen  DJ  et al.  The Women’s Health Initiative: why now? what is it? what’s new? Am Psychol 1997;52101- 116
PubMed Link to Article
Ware  JE  JrSherbourne  CD The MOS 36-Item Short-Form Health Survey (SF-36), I: conceptual framework and item selection. Med Care 1992;30473- 483
PubMed Link to Article
Hays  RDSherbourne  CDMazel  RM The RAND 36-Item Health Survey 1.0. Health Econ 1993;2217- 227
PubMed Link to Article
Levine  DWKaplan  RMKripke  DFBowen  DJNaughton  MJShumaker  SA Factor structure and factor invariance of the Women’s Health Initiative Insomnia Rating Scale. Psychol Assess 2003;15123- 136
PubMed Link to Article
Teng  ELChui  HC The Modified Mini-Mental State (3MS) examination. J Clin Psychiatry 1987;48314- 318
PubMed
Lyketsos  CGLopez  OJones  BFitzpatrick  AIBreitner  JDeKosky  S Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the Cardiovascular Health Study. JAMA 2002;2881475- 1483
PubMed Link to Article
Burnam  MAWells  KBLeake  BLandsverk  J Development of a brief screening instrument for detecting depressive disorders. Med Care 1988;26775- 789
PubMed Link to Article
Radloff  LS The CES-D Scale: a self-report depression scale for research in the general population. App Psychol Measurement 1977;1385- 401
Link to Article
Robins  LNHelzer  JECroughan  JRatcliff  KS National Institute of Mental Health Diagnostic Interview Schedule: its history, characteristics, and validity. Arch Gen Psychiatry 1981;38381- 389
PubMed Link to Article
Pocock  SJAssman  SEEnos  LEKasten  LE Subgroup analysis, covariate adjustment and baseline comparisons in clinical trial reporting: current practice and problems. Stat Med 2002;212917- 2930
PubMed Link to Article
SAS Institute, Inc, Statistical Analysis System.  Cary, NC SAS Institute Inc2002-2003;
McHorney  CAWare  JERaczek  AE The MOS 36-Item Short-Form Health Survey (SF-36), II: psychometric and clinical tests of validity in measuring physical and mental health constructs. Med Care 1993;31247- 263
PubMed Link to Article
Cohen  J Statistical Power Analysis for the Behavioral Sciences.  Orlando, Fla Academic Press Inc1988;
Barnabei  VMCochrane  BBAragaki  AK  et al. Women's Health Initiative Investigators, Menopausal symptoms and treatment-related effects of estrogen and progestin in the Women's Health Initiative. Obstet Gynecol 2005;105 ((pt 1)) 1063- 1073
PubMed Link to Article
Haines  CJYim  SFChung  TK  et al.  A prospective, randomized, placebo-controlled study of the dose effect of oral oestradiol on menopausal symptoms, psychological well being, and quality of life in postmenopausal Chinese women. Maturitas 2003;44207- 214
PubMed Link to Article
Polo-Kantola  PErkkola  RHelenius  HIrjala  KPolo  O When does estrogen replacement therapy improve sleep quality? Am J Obstet Gynecol 1998;1781002- 1009
PubMed Link to Article
Kritz-Silverstein  DVon Muhlen  DGGaniats  TGBarrett-Connor  E Hysterectomy status, estrogen use and quality of life in older women: the Rancho Bernardo Study. Qual Life Res 2004;1355- 62
PubMed Link to Article
Cardozo  LLose  GMcClish  DVersi  E A systematic review of the effects of estrogens for symptoms suggestive of overactive bladder. Acta Obstet Gynecol Scand 2004;83892- 897
PubMed Link to Article
 Executive summary. Obstet Gynecol 2004;104 ((suppl)) 1S- 4S
PubMed Link to Article
Schmidt  PJNieman  LDanaceau  MA  et al.  Estrogen replacement in perimenopause-related depression: a preliminary report. Am J Obstet Gynecol 2000;183414- 420
PubMed Link to Article
Ahokas  AAito  MRimon  R Positive treatment effect of estradiol in postpartum psychosis: a pilot study. J Clin Psychiatry 2000;61166- 169
PubMed Link to Article
Krystal  ADEdinger  JWohlgemuth  WMarsh  OR Sleep in peri-menopausal and post-menopausal women. Sleep Med Rev 1998;2243- 253
PubMed Link to Article
Moline  MLBroch  LZak  RGross  V Sleep in women across the life cycle from adulthood through menopause. Sleep Med Rev 2003;7155- 177
PubMed Link to Article

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