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Background The Women's Health Initiative (WHI) and other clinical trials indicate that significant health risks are associated with combination hormone use. Less is known about the effect of hormone therapy on health-related quality of life.
Methods The WHI randomly assigned 16,608 postmenopausal women 50 to 79 years of age (mean, 63) with an intact uterus at base line to estrogen plus progestin (0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate, in 8506 women) or placebo (in 8102 women). 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.
Results Randomization to estrogen plus progestin resulted in no significant effects on general health, vitality, mental health, depressive symptoms, or sexual satisfaction. The use of estrogen plus progestin was associated with a statistically significant but small and not clinically meaningful benefit in terms of sleep disturbance, physical functioning, and bodily pain after one year (the mean benefit in terms of sleep disturbance was 0.4 point on a 20-point scale, in terms of physical functioning 0.8 point on a 100-point scale, and in terms of pain 1.9 points on a 100-point scale). At three years, there were no significant benefits in terms of any quality-of-life outcomes. Among women 50 to 54 years of age with moderate-to-severe vasomotor symptoms at base line, estrogen and progestin improved vasomotor symptoms and resulted in a small benefit in terms of sleep disturbance but no benefit in terms of the other quality-of-life outcomes.
Conclusions In this trial in postmenopausal women, estrogen plus progestin did not have a clinically meaningful effect on health-related quality of life.
These findings have prompted revisions in guidelines for hormone therapy that limit the use of estrogen plus progestin to short-term relief of vasomotor or urogenital symptoms or for the prevention of osteoporosis after careful consideration of alternatives.4,5,6 There is evidence that treatment with estrogen plus progestin produces relief from vasomotor symptoms,7,8 and women report that quality of life is a consideration in their decision to use hormones.9,10 However, results of the few randomized trials that have assessed the effect of hormone replacement on health-related quality of life are inconsistent, particularly when hormones are prescribed specifically for the prevention of disease rather than the relief of symptoms.11 Randomized trials have found a substantial placebo effect, with approximately 25 percent of women in placebo groups reporting improvements in health-related quality of life.12 Hormone use has also been reported to affect depression,13 sexual functioning,14 and cognitive functioning.15 Again, findings are inconsistent, depending on the study design, population, and test instruments.16
In research on health-related quality of life, small differences can be statistically significant yet clinically unimportant, especially in studies using large samples.17 The concept of a minimal clinically meaningful difference, defined as "the smallest effect size that would lead [clinicians] to recommend therapy to their patients,"18 can be applied in the interpretation of results related to health-related quality of life in large, randomized clinical trials. The WHI trial of estrogen plus progestin, a randomized, double-blind, placebo-controlled trial involving 16,608 postmenopausal women, provides an excellent opportunity to assess the relations between the use of estrogen plus progestin and health-related quality of life and other psychosocial measures in postmenopausal women.
Methods
Study Participants
The criteria for eligibility, recruitment procedures, and main study outcomes have been published previously.3,19,20 Briefly, women 50 to 79 years of age with an intact uterus were potentially eligible for this component of the trial. Women were excluded if their last menstrual period occurred less than 6 months before they enrolled in the study (less than 12 months for women 50 to 54 years of age) or if they had medical conditions associated with a life expectancy of less than 3 years, a history of breast cancer or melanoma, other cancers within the previous 10 years (except nonmelanoma skin cancer), a low hematocrit or platelet count, or conditions that would interfere with acceptable adherence to the assigned regimen and retention in the study (e.g., alcoholism or dementia). Potential participants who were using postmenopausal hormones at the initial screening visit were required to undergo a three-month "washout" period before data collection, screening, and enrollment. Women who reported moderate or severe menopausal symptoms during the washout period were discouraged from participating in the study but were not excluded.
Women were seen at a clinic at three screening visits over a period of several months, at which initial consent forms and questionnaires were completed, blood was drawn after a 12-hour fast, standardized physical measurements were taken, and breast and pelvic examinations were performed. Women were required to take lead-in placebo pills for at least four weeks during the screening process so that their compliance with pill taking could be assessed. At randomization, women were assigned to take either a combination of estrogen and progestin (0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate [Prempro, Wyeth]) or a matching placebo pill. Both participating women and members of the clinic staff were unaware of the study-group assignments. Women were seen in the clinics 6 and 12 months after randomization and annually thereafter. Base-line questionnaire items were repeated at the first annual visit for all participants and for a subgroup of 1511 women at the third annual visit. The protocol and all consent forms were approved by the National Institutes of Health and the institutional review boards of all participating institutions.
Assessment of Quality-of-Life–Related Variables
Quality of Life and Functional Status
Quality of life and functional status were assessed with the use of the RAND 36-Item Health Survey (RAND-36).21,22 The RAND-36 contains eight subscales that include general health (5 items), physical functioning (10 items), limitations on usual role-related activities due to physical health problems (4 items), bodily pain (2 items), energy and fatigue (vitality, 4 items), limitations on usual role-related activities due to emotional or mental problems (3 items), social functioning (2 items), and emotional or mental health (5 items). Scores on all eight subscales range from 0 to 100, with higher scores indicating better health or function. In addition, we used a single health-transition question from the RAND-36, asking women to compare their current general health with their general health a year earlier. Although the RAND-3622 contains the same items as the Medical Outcomes Study 36-item Short Form General Health Survey (SF-36),21 it uses a slightly different scoring algorithm for two of the eight subscales.
Depression Score
Depressive symptoms were assessed according to an eight-item scale developed by Burnam and colleagues.23 This scale was developed to screen for depressive disorders (major depression and dysthymia) and is composed of six items from the depression scale of the Center for Epidemiologic Studies (CES-D)24 and two items from the National Institute of Mental Health Diagnostic Interview Schedule.25 Scores range from –8.2 (best) to 4.0 (worst).
Sleep Disturbance
Quality of sleep was assessed by the five-item WHI Insomnia Rating Scale,26 which was developed and validated for use in the WHI. Items in this instrument referred to sleep during the "past four weeks." Four items assessed the problems with the initiation and maintenance of sleep on a five-point response scale ("no, not in past four weeks"; "yes, less than once a week"; "1–2 times a week"; "3 or 4 times a week"; or "5 or more times a week"), and a fifth item assessed the quality of sleep, also using a five-point scale ("very sound or restful," "sound or restful," "average quality," "restless," or "very restless"). Scores range from 0 (worst) to 20 (best).
Sexual Functioning
Sexual functioning was assessed by a single item with a four-point response scale ("very unsatisfied," "a little unsatisfied," "somewhat satisfied," or "very satisfied"). Scores range from 1 (worst) to 4 (best).
Cognitive Functioning
Cognitive functioning was assessed in participants 65 years of age or older by the Modified Mini–Mental State Examination,27 a scale used in the Cardiovascular Health Study.28 This examination consists of 15 parts that contain 46 separately scored items. The functions tested included orientation to time, place, and person; short-term memory; reading; writing; naming; verbal fluency; praxis; and graphomotor skill. The overall score ranges from 0 (worst functioning) to 100 (best functioning).
Menopausal Symptoms
A checklist of symptoms used in previous research7 was modified to assess symptoms associated with menopause, aging, and hormone use. Five items from this checklist, each with four response categories (none, mild, moderate, and severe) were summed to create a menopausal symptom score. Two items assessed the severity of vasomotor symptoms (hot flashes and night sweats), and three assessed emotional and mental symptoms (mood swings, forgetfulness, and difficulty concentrating). The overall score ranges from 0 (best) to 15 (worst).
Statistical Analysis
All primary analyses focused on changes in health-related quality of life from base line to year 1 in relation to study-group assignment. For each measure of health-related quality of life, we fit a linear model to test whether estrogen plus progestin had a significant treatment effect on the change in the score for health-related quality of life. Statistical significance of these 13 treatment effects was judged according to a Bonferroni-corrected alpha value (0.05 ÷ 13, or approximately 0.004). To examine whether a statistically significant effect of estrogen plus progestin was moderated by base-line variables, we fit a series of linear models. Each pair — a base-line variable and the corresponding interaction between that variable and study-group assignment — was added one at a time followed by a test of the interaction, with one degree of freedom. Base-line characteristics included age, body-mass index (the weight in kilograms divided by the square of the height in meters), moderate or severe vasomotor symptoms, menopausal symptoms, sleep disturbance, previous use of hormone therapy, and history of cardiovascular disease. For exploratory purposes, the moderation of the effect of estrogen plus progestin was investigated for nonsignificant main effects. To avoid overly conservative results, tests of significance for the two sets of interaction terms — those related to significant effects and those related to nonsignificant effects — used separate Bonferroni adjustments. We performed similar analyses including women with data available at year 3 (a randomly selected subgroup representing 8.6 percent of the entire study population, in which members of minority groups were oversampled) and including the subgroup of women who were 50 to 59 years of age. A post-hoc analysis was performed including women 50 to 54 years of age who reported moderate-to-severe night sweats or hot flashes at base line. All analyses were based on the intention-to-treat principle and were performed with the use of SAS software, version 8.02.29
To assess the clinical significance of these findings, we determined the effect size and the smallest increment of change. The effect size was defined as
d = (Mestrogen plus progestin – Mplacebo) ÷ Splacebo,
where M is the average difference in a quality-of-life measure, and S the standard deviation of the difference.30 Effect sizes of 0.20 to 0.49 are generally regarded as small, 0.50 to 0.79 as medium, and 0.80 or more as large.31 The smallest increment of change is the smallest benefit or harm to an individual person as measured by a particular instrument. For example, on the physical-limitations scale of the RAND-36, possible scores were 0, 25, 50, 75, and 100, giving a smallest increment of change of 25. The smallest increment of change serves as a reference for use in the translation of the treatment effect in a group into the change that occurs in an individual person.
Results
Study Participants
Overall, 8506 women were randomly assigned to the estrogen-plus-progestin group, and 8102 to the placebo group. The initial design of the WHI allowed women with a uterus to be randomly assigned to estrogen alone, estrogen plus progestin, or placebo. Release of the data from the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial32 showing that estrogen alone enhanced the development of endometrial hyperplasia prompted the WHI to revise this protocol; randomization of women with a uterus was then limited to estrogen plus progestin or placebo. The 331 women randomly assigned to estrogen alone before that change in protocol were unblinded and reassigned to estrogen plus progestin, resulting in the inclusion of 8506 women in the estrogen-plus-progestin group and 8102 in the placebo group.3
There were no significant differences between these groups at base line (Table 1). The mean age was 63.2 years; 84 percent of the women were white, 35 percent had a college education, 26 percent had some previous hormone use, and 12 percent had moderate-to-severe vasomotor symptoms at base line. Base-line scores on the RAND-36 (see Appendix 2) were similar to scores observed in other healthy populations.33
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Effects on Health-Related Quality of Life
When the change in measures of health-related quality of life between base line and year 1 was examined, few differences were observed between the estrogen-plus-progestin group and the placebo group (Table 2). There were small but statistically significant positive effects of estrogen plus progestin, relative to placebo, on physical functioning (P<0.001), bodily pain (P<0.001), and sleep disturbance (P<0.001). For example, the mean benefit in terms of physical functioning was 0.8 point on the 100-point scale. Figure 1 shows the mean differences in the change scores (the change in score from base line to year 1) in the context of the natural variation (SD) of the change scores in the placebo group, as well as the smallest increment of change possible on each scale, all of which reinforces the small size of the statistically significant effects of estrogen plus progestin. The sizes of the effect of estrogen plus progestin on physical functioning, bodily pain, and sleep disturbance were 0.06, 0.09, and 0.11, respectively (with 0.2 generally considered the threshold for even a small effect31).
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Assessments were repeated at year 3 (in 775 women in the estrogen-plus-progestin group and 736 in the placebo group). As is apparent from Table 3, the changes from base line to year 1 in this subgroup were similar to those in the full study population, with small positive effects in women assigned to estrogen plus progestin only for physical functioning (P=0.06), bodily pain (P=0.008), and sleep disturbance (P=0.07). Differences between the groups were not significant at year 3.
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Further analyses were performed to explore whether there were subgroups of women for whom estrogen plus progestin had more substantial effects on health-related quality of life. There were no significant interactions between study-group assignment and the following base-line characteristics: age, race or ethnic group, body-mass index, menopausal symptoms (night sweats or hot flashes, mood swings, forgetfulness, or inability to concentrate), sleep disturbances, previous use of any type of hormone therapy, and history of cardiovascular disease.
Two subgroups are of special interest in this report: the youngest women who were closest to menopause at entry into the trial and were most likely to have menopausal symptoms and the group of women who reported moderate-to-severe vasomotor symptoms (hot flashes or night sweats) at base line and therefore might have had greater improvements in quality of life because of the relief of symptoms by estrogen plus progestin. Limiting the analysis to women who were 50 to 59 years old produced no substantial difference in the findings. We examined the effects of estrogen plus progestin on the relief of symptoms among all women who reported moderate-to-severe vasomotor symptoms at base line (1072 women in the estrogen-plus-progestin group and 974 women in the placebo group). At the one year follow-up, 76.7 percent of the women in the estrogen-plus-progestin group had improvement in the severity of hot flashes, as compared with 51.7 percent of the women in the placebo group (P<0.001); 71.0 percent of the women in the estrogen-plus-progestin group had improvement in the severity of night sweats, as compared with 52.8 percent of the women in the placebo group (P<0.001).
As shown in Table 4, an analysis restricted to women 50 to 54 years of age who reported moderate-to-severe vasomotor symptoms at base line showed positive effects of estrogen plus progestin on sleep disturbance but no statistically significant improvements in any other health-related quality-of-life outcome at the nominal 0.05 level of significance. Thus, despite relief of symptoms by estrogen plus progestin, effects on the health-related quality of life of women 50 to 54 years of age with menopausal symptoms were similar to those observed among all women in the trial.
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The WHI is a large randomized trial of combined hormone treatment in ethnically and geographically diverse postmenopausal women. Estrogen plus progestin had no clinically meaningful benefits on health-related quality of life or other psychosocial outcomes. Assignment to estrogen plus progestin was associated with a small but statistically significant benefit in terms of sleep disturbance, physical functioning, and bodily pain after one year. However, these differences did not represent meaningful effects according to accepted criteria for clinical effectiveness.
There were no significant effects of estrogen plus progestin on general health, limitations (either physical or emotional) on usual role-related activities, vitality, social functioning, mental health, depressive symptoms, or sexual satisfaction. The effect of estrogen plus progestin use did not vary, even among the youngest women closest to menopause or among women who reported hot flashes, night sweats, sleep disturbances, or emotional or mental symptoms at base line.
It has been postulated that positive effects of estrogen plus progestin on health-related quality of life may be masked or delayed during the first year, when some women have bothersome side effects such as bleeding and breast pain. Our results provide no evidence that long-term use of estrogen plus progestin has a more positive effect on health-related quality of life than short-term use. However, it is possible that differences were not significant at three years because of the smaller sample and poorer adherence to assigned therapy.
Sleep disturbance is a common and distressing symptom in postmenopausal women that may be slightly alleviated with the use of estrogen plus progestin. Anecdotal reports suggest that women are motivated to continue long-term use of estrogen plus progestin because they have difficulty sleeping. Our results indicate that, for individual women, the magnitude of the benefit in terms of sleep disturbance was small and would not outweigh the previously discussed risks associated with taking estrogen plus progestin. Although sleep disturbances were reduced, the subgroup of women with sleep disturbances did not benefit more than other women in terms of the effects of estrogen plus progestin on other measures of quality of life.
Analysis of data for the large number of women in the WHI can easily produce statistically significant results even when the differences may not be clinically significant. The calculated effect sizes and graphic representations of the three statistically significant effects on measures of health-related quality of life argue for caution in the interpretation of the significance of these findings. Moreover, in spite of the large number of comparisons made, few differences that were even nominally significant were found.
Previous trials have found few, marginal, and inconsistent effects of postmenopausal hormones on cognitive, emotional, and physical measures of quality of life. In the Heart and Estrogen/Progestin Replacement Study (HERS) comparing estrogen plus progestin with placebo, the effect of estrogen plus progestin on health-related quality of life depended on the presence or absence of menopausal symptoms at entry into the study11 — a pattern that was not observed in the WHI. The PEPI Trial,7 which randomly assigned women to receive placebo, estrogen alone, estrogen with cyclic progestin, or estrogen with daily progestin, showed no significant differences among groups in measures of psychosocial and cognitive functioning.
As others have done in randomized trials of hormone therapy,7,11 we studied postmenopausal women who were willing to be randomly assigned to estrogen plus progestin or placebo. Approximately 20 percent of postmenopausal women seek medical treatment for vasomotor or other menopausal symptoms that affect their quality of life.34 Our data may not be applicable to these women, because women who believed they needed hormone therapy were unlikely to agree to undergo randomization.
A potential limitation of the data on cognitive functioning is that the Modified Mini–Mental State Examination may have been too crude a measure to be responsive to change over a one-year period. Alternatively, the average score on this measure may indicate the presence of a ceiling effect. The WHI Memory Study, an ancillary study of the WHI, was designed specifically to detect cognitive decline and dementia among participants in the hormone trial who were 65 years of age or older. The results of this study should provide a comprehensive evaluation of cognitive changes over the course of the study in this subgroup. Another limitation is the lack of a validated multi-item measure of sexual functioning.
There may be effects of estrogen plus progestin on health-related quality of life that were not measured in the present study. For example, anecdotal reports by women suggest an effect on perceptions of youthfulness and attractiveness, and benefits in terms of skin tone have been attributed to hormone use.35 Clinicians report that many women speak of generalized benefits, as indicated by such statements as "I just feel so much better." There is a sizable placebo effect associated with hormone use11,36 that may contribute to the perceived improvements in health-related quality of life reported by some women. These and other potential effects should be investigated in future research.
Estrogen plus progestin did not have a clinically meaningful effect on any aspect of health-related quality of life assessed in the WHI trial of estrogen plus progestin. The statistically significant effects observed for physical function, bodily pain, and sleep disturbance were small and appeared to be restricted to the first year of use. For most women, these small benefits do not outweigh the risks of heart attack, stroke, blood clots, and breast cancer associated with combined hormone therapy.
Supported by the National Heart, Lung, and Blood Institute, Department of Health and Human Services.
Drs. Shumaker and LaCroix report having served as paid consultants to Pfizer. Dr. Shumaker reports having served as a paid lecturer for Wyeth–Ayerst and Pfizer. Drs. Hays, Brunner, and Shumaker report having received grant support from Wyeth–Ayerst. Dr. Shumaker reports having received grant support from Pfizer. Dr. Brzyski reports having received grant support from Berlex.
Source Information
From the Department of Medicine, Baylor College of Medicine, Houston (J.H.); the Division of Preventive and Behavioral Medicine, University of Massachusetts Medical School, Worcester (J.K.O.); the Women's Health Center, University of Nevada School of Medicine, Reno (R.L.B.); the Division of Epidemiology, Medical College of Wisconsin, Milwaukee (J.M.K.); the Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston (J.E.M.); the Fred Hutchinson Cancer Research Center, Seattle (R.E.P., A.K.A., A.Z.L.); the Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, N.C. (S.A.S.); the Department of Obstetrics and Gynecology, University of Texas Health Science Center, San Antonio (R.G.B.); the Department of Preventive Medicine, State University of New York at Stony Brook, Stony Brook (I.A.G.); and the Epidemiology and Disease Prevention Program, Kaiser Permanente Center for Health Research, Portland, Oreg. (B.G.V.).
This article was published at www.nejm.org on March 17, 2003.
Address reprint requests to Dr. Hays at the Center for Women's Health, Department of Medicine, Baylor College of Medicine, 6535 Fannin St., M.S. A701, Houston, TX 77025, or at jhays{at}bcm.tmc.edu.
References
Appendix 1
The WHI Investigators are as follows: Program Office (National Heart, Lung, and Blood Institute, Bethesda, Md.): J.E. Rossouw, L. Pottern, S. Ludlam, J.A. McGowan, L. Ford. Clinical Coordinating Center: Fred Hutchinson Cancer Research Center, Seattle — R. Prentice, G. Anderson, A. LaCroix, R. Patterson, A. McTiernan, B. Cochrane, J. Hunt, L. Tinker, C. Kooperberg, M. McIntosh, C.Y. Wang, C. Chen, D. Bowen, A. Kristal, J. Stanford, N. Urban, N. Weiss, E. White; Bowman Gray School of Medicine, Winston-Salem, N.C. — S. Shumaker, P. Rautaharju, R. Prineas, M. Naughton; Medical Research Labs, Highland Heights, Ky. — E. Stein, P. Laskarzewski; University of California at San Francisco, San Francisco — S. Cummings, M. Nevitt, M. Dockrell; University of Minnesota, Minneapolis — L. Harnack; McKesson BioServices, Rockville, Md. — F. Cammarata, S. Lindenfelser; University of Washington, Seattle — B. Psaty, S. Heckbert. Clinical Centers: Albert Einstein College of Medicine, Bronx, N.Y. — S. Wassertheil-Smoller, W. Frishman, J. Wylie-Rosett, D. Barad, R. Freeman; Baylor College of Medicine, Houston — J. Hays, R. Young, J. Anderson, S. Lithgow, P. Bray; Brigham and Women's Hospital, Harvard Medical School, Boston — J. Manson, J. Buring, J.M. Gaziano, K. Rexrode, C. Chae; Brown University, Providence, R.I. — A.R. Assaf, R. Carleton (deceased), C. Wheeler, C. Eaton, M. Cyr; Emory University, Atlanta — L. Phillips, M. Pedersen, O. Strickland, M. Huber, V. Porter; Fred Hutchinson Cancer Research Center, Seattle — S.A.A. Beresford, V.M. Taylor, N.F. Woods, M. Henderson, M. Kestin; George Washington University, Washington, D.C. — J. Hsia, N. Gaba, J. Ascensao, S. Laowattana; Harbor–UCLA Research and Education Institute, Torrance, Calif. — R. Chlebowski, R. Detrano, A. Nelson, J. Heiner, J. Marshall; Kaiser Permanente Center for Health Research, Portland, Oreg. — C. Ritenbaugh, B. Valanis, P. Elmer, V. Stevens, N. Karanja; Kaiser Permanente Division of Research, Oakland, Calif. — B. Caan, S. Sidney, G. Bailey, J. Hirata; Medical College of Wisconsin, Milwaukee — J. Morley Kotchen, V. Barnabei, T.A. Kotchen, M.A.C. Gilligan, J. Neuner; MedStar Research Institute–Howard University, Washington, D.C. — B.V. Howard, L. Adams-Campbell, M. Passaro, M. Rainford, T. Agurs-Collins; Northwestern University, Chicago and Evanston, Ill. — L. Van Horn, P. Greenland, J. Khandekar, K. Liu, C. Rosenberg; Rush Presbyterian–St. Luke's Medical Center, Chicago — H. Black, L. Powell, E. Mason; Stanford Center for Research in Disease Prevention, Stanford University, Stanford, Calif. — M.L. Stefanick, M.A. Hlatky, B. Chen, R.S. Stafford, L.C. Giudice; State University of New York at Stony Brook, Stony Brook — D. Lane, I. Granek, W. Lawson, G. San Roman, C. Messina; Ohio State University, Columbus — R. Jackson, R. Harris, D. Frid, W. J. Mysiw, M. Blumenfeld; University of Alabama at Birmingham, Birmingham — C.E. Lewis, A. Oberman, M.N. Fouad, J.M. Shikany, D. Smith West; University of Arizona, Tucson and Phoenix — T. Bassford, J. Mattox, M. Ko, T. Lohman; University at Buffalo, Buffalo, N.Y. — M. Trevisan, J. Wactawski-Wende, S. Graham, J. Chang, E. Smit; University of California at Davis, Sacramento — J. Robbins, S. Yasmeen, K. Lindfors, J. Stern; University of California at Irvine, Orange — A. Hubbell, G. Frank, N. Wong, N. Greep, B. Monk; UCLA, Los Angeles — H. Judd, D. Heber, R. Elashoff; University of California at San Diego, LaJolla and Chula Vista — R.D. Langer, M.H. Criqui, G.T. Talavera, C.F. Garland, R.E. Hanson; University of Cincinnati, Cincinnati — M. Gass, S. Wernke, N. Watts; University of Florida, Gainesville and Jacksonville — M. Limacher, M. Perri, A. Kaunitz, R.S. Williams, Y. Brinson; University of Hawaii, Honolulu — D. Curb, H. Petrovitch, B. Rodriguez, K. Masaki, S. Sharma; University of Iowa, Iowa City and Davenport — R. Wallace, J. Torner, S. Johnson, L. Snetselaar, B. VanVoorhis; University of Massachusetts–Fallon Clinic, Worcester — J. Ockene, M. Rosal, I. Ockene, R. Yood, P. Aronson; University of Medicine and Dentistry of New Jersey, Newark — N. Lasser, N. Hymowitz, V. Lasser, M. Safford, J. Kostis; University of Miami, Miami — M.J. O'Sullivan, L. Parker, R. Estape, D. Fernandez; University of Minnesota, Minneapolis — K.L. Margolis, R.H. Grimm, D.B. Hunninghake, J. LaValleur, K.M. Hall; University of Nevada, Reno — R. Brunner, S. St. Jeor, W. Graettinger, V. Oujevolk; University of North Carolina, Chapel Hill — G. Heiss, P. Haines, D. Ontjes, C. Sueta, E. Wells; University of Pittsburgh, Pittsburgh — L. Kuller, A. Caggiula, J. Cauley, S. Berga, N.C. Milas; University of Tennessee, Memphis — K.C. Johnson, S. Satterfield, R.W. Ke, J. Vile, F. Tylavsky; University of Texas Health Science Center, San Antonio — R. Brzyski, R. Schenken, J. Trabal, M. Rodriguez-Sifuentes, C. Mouton; University of Wisconsin, Madison — C. Allen, D. Laube, P. McBride, J. Mares-Perlman, B. Loevinger; Wake Forest University School of Medicine, Winston-Salem, N.C. — G. Burke, R. Crouse, L. Parsons, M. Vitolins; Wayne State University School of Medicine–Hutzel Hospital, Detroit — S. Hendrix, M. Simon, G. McNeeley, P. Gordon, P. Makela.
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Related Letters:
Effects of Estrogen plus Progestin on Health-Related Quality of Life
Lopes A. A., Latado A., Lopes G. B., Watts N. B.
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N Engl J Med 2004;
350:622, Feb 5, 2004.
Correspondence
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