Secondary Logo

Journal Logo

Menopausal Symptoms and Treatment-Related Effects of Estrogen and Progestin in the Women's Health Initiative

Barnabei, Vanessa M. MD, PhD; Cochrane, Barbara B. PhD, RN; Aragaki, Aaron K. MS; Nygaard, Ingrid MD; Williams, R Stan MD; McGovern, Peter G. MD; Young, Ronald L. MD; Wells, Ellen C. MD; O'Sullivan, Mary Jo MD; Chen, Bertha MD; Schenken, Robert MD; Johnson, Susan R. MD, MS

doi: 10.1097/01.AOG.0000158120.47542.18
Original Research
Free

OBJECTIVE: To estimate the effects of estrogen plus progestin (E+P) therapy on menopausal symptoms, vaginal bleeding, gynecologic surgery rates, and treatment-related adverse effects in postmenopausal women.

METHODS: Randomized, double-blind, placebo-controlled trial of 16,608 postmenopausal women, ages 50–79 (mean ± standard deviation 63.3 ± 7.1) years, with intact uterus, randomized to one tablet per day containing 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate (n = 8,506) or placebo (n = 8,102), and followed for a mean of 5.6 years. Change in symptoms and treatment-related effects were analyzed at year 1 in all participants. Bleeding and gynecologic surgery rates were analyzed through study close-out.

RESULTS: Baseline symptoms did not differ between the treatment groups. More women assigned to E+P than placebo reported relief of hot flushes (85.7% versus 57.7%, respectively; odds ratio 4.40; 95% confidence interval 3.40–5.71), night sweats (77.6% versus 57.4%; 2.58; 2.04–3.26), vaginal or genital dryness (74.1% versus 54.6%; 2.40; 1.90–3.02), joint pain or stiffness (47.1% versus 38.4%; 1.43; 1.24–1.64), and general aches or pains (49.3% versus 43.7%; 1.25; 1.08–1.44). Women asymptomatic at baseline who were assigned to E+P more often developed breast tenderness (9.3% versus 2.4%, respectively; 4.26; 3.59–5.04), vaginal or genital discharge (4.1% versus 1.0%; 4.47; 3.44–5.81), vaginal or genital irritation (4.2% versus 2.8%; 1.52; 1.27–1.81), and headaches (5.8% versus 4.7%; 1.26; 1.08–1.46) than women on placebo. Estrogen plus progestin treatment prevented the onset of new musculoskeletal symptoms. Vaginal bleeding was reported by 51% of women on E+P and 5% of women on placebo at 6 months; most bleeding was reported as spotting. Gynecologic surgeries (hysterectomy and dilation and curettage) were performed more frequently in women assigned to E+P (3.1% versus 2.5% for hysterectomy, hazard ratio = 1.23, P = .026; 5.4% versus 2.4% for dilation and curettage, hazard ratio = 2.23, P < .001).

CONCLUSION: Estrogen plus progestin relieved some menopausal symptoms, such as vasomotor symptoms and vaginal or genital dryness, but contributed to treatment-related effects, such as bleeding, breast tenderness, and an increased likelihood of gynecologic surgery.

LEVEL OF EVIDENCE: I

This detailed analysis of estrogen plus progestin effects among WHI clinical trial participants showed relief of typical menopausal symptoms but multiple adverse effects.

*For a list of other members of the Women's Health Initiative Investigators, see Appendix.

This study was funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services. The active study drug and placebo were supplied by Wyeth-AyerstResearch Laboratories, Philadelphia, Pennsylvania.

Financial Disclosure Drs. Barnabei and Williams have received honoraria/consulting fees from Wyeth-Ayerst Research Laboratories within the past 3 years.

Address reprint requests to: Vanessa M. Barnabei, md, phd, Department of Obstetrics and Gynecology, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226; e-mail: barnabei@mcw.edu.

Received September 30, 2004. Received in revised form December 21, 2004. Accepted January 5, 2005.

Vasomotor and vaginal symptoms typically attributed to menopause or the menopausal transition occur in approximately 70% of U.S. women and may be severe in up to 20%.1–3 Symptom relief remains the primary indication for hormone therapy, particularly in younger women when symptoms have a significant impact on quality of life.4–6

The Women's Health Initiative (WHI), a large, long-term clinical trial and observational study initiated in 1993, was designed to study major causes of morbidity and mortality in postmenopausal women. The WHI clinical trial includes a trial of hormone therapy (separate trials of estrogen plus progestin and estrogen alone) for the prevention of coronary heart disease and hip fracture,7 plus a dietary trial and a calcium and vitamin D supplementation trial. Interested and eligible women could participate in 1, 2, or all 3 trials. The WHI estrogen plus progestin (E+P) trial intervention was stopped prematurely in July 2002 because the overall health risks of E+P exceeded the benefits8 in otherwise healthy women. In March 2004, the National Institutes of Health also ended early the estrogen-alone trial's intervention phase.9

Although the E+P trial was not designed to address the effects of E+P on the treatment of menopausal symptoms, symptom data were collected on E+P participants across all ages of menopause (50–79 years at baseline). Before the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial10 and the Heart and Estrogen-Progestin Replacement Study (HERS),11 there were limited long-term clinical trial data on treatment-related and menopausal symptoms in older, postmenopausal women. Given the possible increased morbidity of women on E+P, a clear understanding of the impact of hormonal therapy on symptoms is essential. Quality-of-life data from the WHI E+P trial determined that combination therapy did not have a clinically meaningful impact on health-related quality of life.12 However, comprehensive analyses regarding common menopausal complaints, such as hot flushes, and treatment-related symptoms were not presented and could provide an important elaboration of the quality-of-life findings.

The aims of these detailed data analyses from the 16,608 women enrolled in the WHI E+P trial were to better define the relationships among menopausal status, symptoms, and the effects of combined hormone therapy across the spectrum of postmenopausal women and to determine factors that influenced these outcomes. The impact of combined hormone therapy on the rate of selected gynecologic surgery procedures also was assessed.

Back to Top | Article Outline

SUBJECTS AND METHODS

Postmenopausal women between the ages of 50 and 79 years were recruited from 40 clinical centers across the United States to participate in the WHI. The clinical center institutional review boards reviewed and approved the project, and all participants provided written, informed consent. Ten clinical centers that were specifically designated as minority centers were to recruit and randomize 60% of their participants from minority groups to ensure that the racial/ethnic participation in the WHI was proportionate to the U.S. population.13

The WHI E+P trial was designed to evaluate the effects of estrogen plus progestin therapy on specific disease outcomes.7 Women in the E+P trial (n = 16,608) still had a uterus at baseline and were randomly assigned in a 1:1 ratio to either active treatment (0.625 mg/day conjugated equine estrogens plus 2.5 mg/day medroxyprogesterone) or placebo. Details of the E+P trial design, recruitment, screening, randomization, and eligibility criteria are described elsewhere.7,8,13,14 Basically, women were considered postmenopausal if they had no vaginal bleeding for the previous 6 months (12 months for women aged 50–54), had a hysterectomy, or had ever used postmenopausal hormone therapy. Women were excluded if they had medical conditions associated with competing risk, safety concerns, or adherence and retention concerns. Relevant to this analysis is that menopausal symptoms (mild, moderate, or severe) were not an exclusion criterion for the trial except for those participants who were taking hormone therapy at baseline and had severe symptoms after a 3-month washout. Routine follow-up of all E+P trial participants consisted of semiannual contacts to collect self-reported outcome data and assess participant safety, as well as more extensive annual visits to obtain outcome and mammogram report data and carry out physical measurement and gynecologic examinations.

Reports of vaginal bleeding were collected at safety interviews, administered 6 weeks and 6 months after randomization, and semiannually thereafter while participants were still taking study pills. Reports of bleeding and other symptoms (eg, menopausal symptoms or hormonal adverse effects) were followed up by trained clinicians using specific algorithms. The algorithms were predicated on the fact that all participants had a negative endometrial assessment at baseline. Only study gynecologists were unblinded as necessary for the management of bleeding. A general algorithm was followed for the management of bleeding in the E+P trial as follows. Bleeding during the first 6 months that was equal to or lighter than a regular menstrual period was managed without intervention. After the first 6 months, the consulting gynecologist was unblinded for any bleeding. Further management was dependent on severity of bleeding, time since randomization, study arm assignment, and endometrial histology of past biopsy (if any). Bleeding management protocols were designed to ensure that participant safety remained the primary focus. In addition, blinding was preserved to the extent that was ethical and to minimize undue burden in the form of unnecessary work-up or treatment. After the first 6 months of the study, all women in the placebo group with bleeding had endometrial evaluation, either with aspiration biopsy or transvaginal ultrasonography. Women in the active E+P group had endometrial evaluation for heavy bleeding or increasing bleeding of any severity. Biopsy results of atrophy, secretory endometrium, proliferative endometrium, and insufficient tissue were considered negative. Based on histologic findings, women in the active E+P group were managed by using specific protocols for additional estrogen or progestin, with re-evaluation after 6 months. Women in either group were referred to their personal health care providers for follow-up of abnormal findings (complex hyperplasia, hyperplasia with atypia, or cancer). An endometrial echo greater than 5 mm was considered an indication for histologic assessment.

A symptom checklist for WHI included items on menopausal symptoms based on the Postmenopausal Estrogen/Progestin Interventions (PEPI) symptom tool,10 as well as items from other national surveys and clinical trials,15 to capture symptoms commonly associated with hormone use and aging. For this discussion, 15 symptoms were analyzed: hot flushes, night sweats, breast tenderness, vaginal or genital irritation or itching, vaginal or genital dryness, vaginal or genital discharge, headaches or migraines, joint pain or stiffness, general aches or pains, lower back pain, neck pain, bloating or gas, swelling of hands or feet, mood swings, and difficulty concentrating. These symptoms represented those typically associated with menopause in previous research. Participants rated symptom severity on a 4-point scale, from symptom did not occur, to mild (did not interfere with usual activities), moderate (interfered somewhat with usual activities), or severe (so bothersome that usual activities could not be performed). The psychosocial forms containing these symptom items were reviewed for content validity by nationally recognized behavioral and clinical experts and were pretested extensively on age-appropriate women from diverse racial/ethnic groups. These forms were administered to all E+P participants at baseline and year 1 and to an 8.6% subsample of participants (oversampled for minorities) at year 3. This subsampling scheme maximized component- and racial/ethnic–specific information on intermediate effects of the intervention, including blood biomarkers, yet kept costs and clinic burden to a minimum.

Information was collected annually on health changes, hospital admissions, and surgery during the previous year, including gynecologic surgeries. The indication for hysterectomy, based on medical records review, was adjudicated in the majority of cases.

Primary analyses focused on symptom changes in all participants reported from baseline to year 1 in relation to E+P trial randomization assignment and in an 8.6% subsample at year 3. All analyses were based on the intention-to-treat principle using SAS 9.0 (SAS Institute Inc, Cary, NC). The Cochran-Armitage test16 was used to determine changes in prevalence with age for each symptom.

Logistic regression analyses were stratified by prevalence of baseline symptoms (moderate/severe versus symptom did not occur/mild). For each symptom, treatment effect was determined based on the following:

  1. Relief of menopausal symptoms at year 1 among women symptomatic at baseline.
  2. Onset of treatment-related symptoms at year 1 among women asymptomatic at baseline.

We controlled for type I error rates separately for (i) and (ii) by using a Bonferroni corrected α (0.05/15 ∼ 0.003). Because symptoms are not statistically independent, multiple comparison corrections will be conservative.

Logistic regression models were used to examine whether there were subgroups of women for whom E+P had more substantial effects on relief of symptoms or occurrence of treatment-related effects, both adverse and beneficial. Each model included the randomization assignment, a baseline characteristic, and the corresponding interaction term. Baseline characteristics corresponding to these subgroups included age, years-since-menopause, body mass index (BMI), waist-to-hip ratio, prior postmenopausal hormone use, physical activity, smoking, and alcohol use. The type I error rates were controlled separately for the symptomatic and asymptomatic women, where the statistical significance of these interactions (120 symptoms × baseline characteristic combinations) were judged by a Bonferroni-corrected α (0.05/15 × 8 ∼ 0.0004).

For the gynecologic surgery data, Cox proportional hazards models17 were performed after stratification by age and randomization into the low-fat dietary trial. Time to event was defined as the numbers of days from randomization into the WHI trial to the date that the event was reported. Participants who did not self-report a surgery were censored by their last follow-up contact before July 8, 2002. Proportional hazards assumptions were verified by the interaction of time to event and treatment assignment and by inspecting parallelism of estimated survival functions. Nonsignificant, statistically significant interaction terms and parallel log-log survivor functions indicate that hazard functions are proportional.

Back to Top | Article Outline

RESULTS

Overall, 8,506 women were randomly assigned to the estrogen plus progestin group and 8,102 to the placebo group. At baseline, the mean age ± standard deviation (SD) of participants was 63.3 ± 7.1 years. All women had an intact uterus at baseline and were an average of 13.4 years postmenopausal. The women were largely white (83.9%) and well educated (73.8% had some school or college after high school). The mean length of follow-up in the E+P trial was 5.6 years. Detailed baseline characteristics of the E+P trial participants are described elsewhere8,14 and did not differ between the 2 treatment groups.

There were no differences between the 2 treatment groups in any baseline symptom. Menopausal symptoms ranging from mild to severe were reported in all age groups. The prevalence of mild-to-severe hot flushes at baseline was 60.23% for women aged 50–54 years, 44.49% for ages 55–59, 23.37% for ages 60–69, and 11.38% for ages 70–79. The mean number ± SD of moderate or severe symptoms reported by each woman decreased with age, from 1.89 ± 2.31 in the 50–54 year age group to 1.60 ± 2.10, 1.34 ± 1.84, and 1.30 ± 1.77 in age groups 55–59, 60–69, and 70–79, respectively. Baseline symptoms were stratified by age instead of years-since-menopause because we had complete data on participants’ ages; age is strongly correlated with years since menopause (Pearson r = 0.82; computed on continuous versions of both variables).

Rates of moderate-to-severe baseline symptoms for the entire cohort by age group at randomization, along with changing prevalence with age showed that 9 of the 15 symptoms decreased with age. Joint pain or stiffness was the only symptom that increased significantly with age (Table 1).

Table 1

Table 1

The prevalence of all symptoms, particularly vasomotor symptoms (hot flushes and night sweats), varied by ethnicity, with African-American (21.8% for moderate-severe hot flushes) and Hispanic women (19%) 2–3 times more likely to report moderate-to-severe vasomotor symptoms than white (7.9%) and Asian women (6.4%), P < .001.

At the time of the year 1 analysis, among active E+P women who reported moderate-to-severe hot flushes, night sweats, and vaginal or genital dryness at baseline, these symptoms had improved significantly, as had joint pain or stiffness and general aches or pains compared with women on placebo (Table 2). Of symptomatic women 50–54 years old, 82.5% on active treatment and 52.2% on placebo experienced relief of vasomotor symptoms.

Table 2

Table 2

Symptomatic women who were younger (P = .013 for hot flushes, P < .001 for night sweats), thinner (P < .001, P = .01 based on BMI; and P = .15, P < .001 based on waist/hip ratio), and closer to the menopause (P = .04, P < .001) experienced more relief from hot flushes and night sweats, respectively. The effectiveness of E+P on symptom relief did not vary for any other combination of symptom or participant baseline characteristic.

At year 1, the relative risk for breast tenderness and vaginal discharge in the E+P group compared with placebo more than quadrupled, yet only 9.3% and 4.1% of asymptomatic women in the E+P group developed breast tenderness and vaginal or genital discharge, respectively (Table 3). Treatment-related beneficial effects included prevention of vasomotor symptoms and vaginal or genital dryness in previously asymptomatic women. In addition, combined therapy reduced the incidence of new musculoskeletal symptoms, including joint pain or stiffness, general aches or pains, lower back pain, and neck pain.

Table 3

Table 3

In subgroup analyses, younger, asymptomatic women assigned to E+P and those closer to menopause were less likely to develop night sweats at year 1 (P < .001, P < .001, respectively) than those assigned to placebo. Younger women and those closer to menopause also were less likely to develop vaginal or genital discharge and vaginal or genital dryness at year 1 than those assigned to placebo (P < .001, P < .001, respectively). Women who were older (P < .001), further from menopause (P < .001), never/past hormone therapy users (P < .001), and thinner (P < .001) were more likely to develop breast tenderness. Treatment effects did not vary for any other combination of symptoms or baseline characteristics. Missing data ranged from 7.9% to 8.5% per symptom and were handled via complete-case analysis.

Finally, there was a small, although statistically significant (P < .001), difference in weight change from baseline to year 1 (Table 4). A higher proportion of women on combined hormone therapy experienced weight loss than those on placebo. Results hold when stratifying by age.

Table 4

Table 4

Vaginal bleeding was the most frequently reported treatment effect for women in the active treatment group (Fig. 1), occurring in 42.5% and 51.0% of participants in the first 6 weeks and 6 months of the trial, respectively. Thereafter, reports of bleeding declined gradually but never fell below 11.6%. At year 5, 13.0% (544 of 4,184) of women in the E+P group reported bleeding, characterized as mostly spotting in both treatment groups. In the placebo group, 86.6% of women never reported bleeding, while only 33.3% of the active treatment group was amenorrheic throughout the trial. During year 1, 234 women on E+P and 8 women in the placebo group cited vaginal bleeding as one of the reasons for stopping intervention; multiple reasons could be cited by participants. Within the first 12 months of therapy, there were 875 endometrial aspiration procedures and 217 transvaginal ultrasound examinations performed for bleeding, with the majority of these (91.3% and 86.2%, respectively) performed in the E+P group. Complete data on the results of these procedures have been reported previously.18 At 6 months and year 1, women who were older (P < .001, P < .001, respectively), further from menopause (P < .001, P < .001), thinner (P < .001, P < .001) and never/past hormone therapy users (P < .001, P = .009) were more likely to report bleeding. No subgroups were more likely to bleed at year 5 in the active treatment group relative to the placebo group (Bonferroni corrected α = 0.05/8 × 3 = 0.002).

Fig

Fig

Combined hormone therapy led to an increase in the occurrence of common gynecologic surgeries, although the absolute numbers were small. Annualized percentages for hysterectomy were 0.52% for women assigned to E+P (267 of 8,239 women, 3.14%) and 0.43% for placebo (204 of 7,898 women, 2.52%; hazard ratio [HR] 1.23, 95% confidence interval [CI] 1.03–1.48; P = .026). Medical records data on hysterectomies in E+P trial participants during follow-up were collected and evaluated by local clinical center adjudicators. In the adjudicated hysterectomy group (n = 407), the most common indication for the procedure was uterine descensus/prolapse (48.4% overall; 46.9% for the E+P group and 50.3% for the placebo group). Bleeding was the indication for hysterectomy in only 23 women in the E+P group and 8 women in the placebo group. The absolute excess risk of hysterectomy attributable to E+P is 9 events per 10,000 woman-years. Women assigned to E+P were more than twice as likely to undergo a dilation and curettage (D&C) than those assigned to placebo, but information regarding specific indications for this procedure is not available in the database. Annualized percentages for D&C are 0.90% for E+P women (461 of 8,045 women, 5.42%) and 0.41% for placebo (198 of 7,904 women, 2.44%; HR 2.23, CI 1.88–2.63; P < .001). The absolute excess risk of D&C attributable to E+P is 49 events per 10,000 woman-years.

Analyses of symptoms at year 3 on an 8.6% subsample of E+P trial participants (775 women assigned to E+P and 736 assigned to placebo, oversampled for minorities) showed that symptom relief and treatment effects from baseline to year 1 were similar to those seen in the full E+P cohort. By year 3, 83.3% of E+P participants who at baseline were aged 50–59 (n = 576) and had moderate or severe hot flushes were relieved of their symptoms (Table 5). However, 72.3% of placebo participants experienced similar relief. Of women in this same age group who were asymptomatic at baseline, those on E+P were less likely to report vaginal or genital dryness and joint pain or stiffness than women on placebo (Table 6).

Table 5

Table 5

Table 6

Table 6

Back to Top | Article Outline

DISCUSSION

The Women's Health Initiative is the largest, randomized intervention trial of postmenopausal hormone therapy ever conducted. The Estrogen Plus Progestin trial provided us the opportunity to study menopausal symptoms and the effects of hormone therapy on symptoms in women across the spectrum of postmenopausal ages.

Most previous reports of menopausal symptoms have been short-term studies limited to perimenopausal and younger menopausal women who are thought to be most likely to have these symptoms. In the Heart and Estrogen-Progestin Replacement Study (HERS) trial of older postmenopausal women, almost 20% of women aged 70–74 reported frequent or somewhat frequent hot flushes.11 A large, population-based study of symptoms suggested that approximately 50% of women experience vasomotor symptoms at cessation of menses and 20% are symptomatic 4 years postmenopause.19 At baseline, more than 60% of WHI E+P trial participants aged 50–54 and more than 10% of those aged 70–79 still experienced hot flushes, ranging from mild to severe. However, these data might underestimate the prevalence in the general population slightly because women with more severe vasomotor symptoms were excluded from the trial if they were taking hormones at baseline and were unable or unwilling to be randomized to placebo. Estimates from other studies suggest that up to 70% of naturally menopausal women experience vasomotor symptoms, with severe symptoms in 15–20%.2,3 Our data are consistent with these estimates, although they cannot be generalized to women undergoing surgical menopause.

Black and Hispanic women reported a higher prevalence of vasomotor symptoms than white women, and Asian women reported the lowest rates. These data are similar to other reports of ethnic differences in symptom prevalence20 although the reasons for these differences are not known.

At baseline, younger women more frequently reported hot flushes, night sweats, mood swings, and headaches or migraines than older women. Younger women and those closer to menopause also were more likely to have relief of vasomotor symptoms. This suggests that vasomotor symptoms in older women may have causes other than menopausal status and may not respond as well to hormone therapy. Older women more frequently reported joint pain or stiffness. Other pain symptoms, including general aches or pains and low back pain, were very common among all age groups, with remarkable stability across the age distribution. This is somewhat surprising because the prevalence of musculoskeletal symptoms overall would be expected to increase with age. These data suggest that pain symptoms, such as general aches and pains and low back pain, are already well established by midlife. Among women asymptomatic at baseline, there was a prophylactic effect of E+P on these symptoms at years 1 and 3. The beneficial effect of hormone therapy on joint symptoms and other musculoskeletal complaints has long been suspected and women anecdotally have reported improvement, but this has not been well documented in the literature. This benefit of E+P was seen in all age groups of women and persisted at year 3, although the benefit in the subsample was not statistically significant. Hays and colleagues12 reported a benefit in physical functioning and bodily pain in the E+P trial, consistent, in part, with the small, prophylactic effect of E+P on musculoskeletal symptoms seen among asymptomatic women in the current analysis. Smaller studies have demonstrated a beneficial effect of hormone therapy on quality of life in younger menopausal women.21

In WHI E+P trial participants, the rates of vaginal bleeding, a known treatment effect of combined hormone therapy, are similar to those reported in other studies of continuous, combined hormone therapy,22–25 although the range of bleeding reported in these studies is wide. Most prior studies reported short-term bleeding rates only. Our data suggest that bleeding persists in up to 12% of women at 5 or more years of use, which is important information for women considering combined hormone therapy for symptom relief. This is especially true for older women considering hormone therapy, because they were more likely to bleed than women closer to menopause. Most bleeding on combined hormone therapy in the E+P trial was classified as spotting and was associated with benign endometrial changes (ie, normal histology or atrophic/insufficient specimen).

Hysterectomy was slightly more common in women on active E+P, but the indications for the procedure did not differ between the groups. The most common indication, uterine prolapse or descensus, was not increased in women on active intervention.

Estrogen plus progestin improved vasomotor symptoms, vaginal or genital dryness, and all pain symptoms evaluated compared with placebo. In spite of a preponderance of mood swings in younger postmenopausal women, E+P did not have any effect on this symptom, bringing into question a direct relationship between hormonal status and mood. Other studies have shown that mood disorders are more common in symptomatic perimenopausal women, suggesting that some women have a heightened sensitivity to the effects of changing or declining estrogen levels than other women.26 It is not known whether estrogen-alone therapy will have a different effect on mood swings in symptomatic women. The decrease in prevalence of other subjective symptoms, such as difficulty concentrating, could be due to difference in perception of these age groups. In addition, this analysis looked primarily at moderate-to-severe symptoms, which may be more apparent to younger women. Although weight gain has been a concern of women considering hormone therapy, recent data suggest that they are not at greater risk for weight gain.27 The data from this study also confirm that combined hormone therapy has no adverse effect on weight in menopausal women.

Thinner women were more likely to experience relief from vasomotor symptoms, but were more prone to vaginal bleeding and breast tenderness. Older women and those further from menopause also were more likely to report breast tenderness, an anticipated adverse treatment effect of combined hormone therapy. Increases in mammographically defined breast density in response to hormone therapy are greater in women with lower breast density at the time hormone therapy is started.28,29 Although women remote from menopause might be expected to have lower breast density than younger women and be more susceptible to the effects of hormone therapy, a specific association between a change in breast density and breast tenderness has not been established.

Combined hormone therapy decreased the prevalence of vasomotor symptoms associated with menopause, especially in younger women. Estrogen plus progestin also decreased reports of vaginal or genital dryness and joint aches and pains. However, bleeding was common throughout therapy, especially in the first 6 months. Other treatment effects, such as vaginal discharge and irritation and breast tenderness, especially in older women, would limit the overall benefit on quality of life. Our results bridge earlier findings on the effect of E+P on health-related quality of life in this cohort, showing a beneficial effect for younger, symptomatic women only.12 Long-term health benefits of E+P are outweighed by health risks, supporting short-term hormone therapy for the treatment of moderate-to-severe menopausal symptoms, primarily in younger women. According to current prescribing guidelines, combined hormone therapy is indicated only for the treatment of moderate-to-severe vasomotor symptoms associated with menopause30 when the benefits of short-term therapy may outweigh the risks.

Back to Top | Article Outline

REFERENCES

1. Campbell S, Whitehead M. Oestrogen therapy and the menopausal syndrome. Clin Obstet Gynaecol 1977;4:31–47.
2. Bachmann GA. Vasomotor flushes in menopausal women. Am J Obstet Gynecol 1999;180 suppl:S312–6.
3. Fitzpatrick LA, Santen RJ. Hot flashes: the old and the new, what is really true? Mayo Clin Proc 2002;77:1155–8.
4. Daly EA, Gray A, Barlow D, McPherson K, Roche M, Vessey M. Measuring the impact of menopausal symptoms on quality of life. BMJ 1993;307:836–40.
5. Karlberg J, Mattson LA, Wiklund I. A quality of life perspective on who benefits from estradiol replacement therapy. Acta Obstet Gynecol Scand 1995;74:367–72.
6. Freedman MA. Quality of life and the menopause: the role of estrogen. J Womens Health (Larchmt) 2002;11:703–18.
7. Women's Health Initiative Study Group. Design of the Women's Health Initiative clinical trial and observational study. Control Clin Trials 1998;19:61–109.
8. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled clinical trial. JAMA 2002;288:321–33.
9. The 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;291:1701–12.
10. Greendale GA, Reboussin BA, Hogan P, Barnabei VM, Shumaker S, Johnson S, et al. Symptom relief and side effects of postmenopausal hormones: results from the Postmenopausal Estrogen/Progestin Interventions Trial. Obstet Gynecol 1998;92:982–8.
11. Barnabei VM, Grady D, Stovall DW, Cauley JA, Lin F, Stuenkel CA, et al. Menopausal symptoms in older women and the effects of treatment with hormone therapy [published erratum appears in Obstet Gynecol 2003;101:619]. Obstet Gynecol 2002;100:1209–18.
12. Hays J, Ockene JK, Brunner RL, Kotchen JM, Manson JE, Patterson RE, et al. Effects of estrogen plus progestin on health-related quality of life. N Engl J Med 2003;348:1839–54.
13. Hays J, Hunt JR, Hubbell A, Anderson GL, Limacher M, Allen C, et al. The Women's Health Initiative recruitment methods and results. Ann Epidemiol 2003;13 suppl:S18–77.
14. Stefanick ML, Cochrane BB, Hsia J, Barad DH, Liu JH, Johnson SR. The Women's Health Initiative postmenopausal hormone trials: overview and baseline characteristics of participants. Ann Epidemiol 2003;13 suppl:S78–86.
15. Ganz PA, Day R, Ware JE Jr, Redmond C, Fisher B. Base-line quality of life assessment in the National Surgical Adjuvent Breast and Bowel Project Breast Cancer Prevention Trial. J Natl Cancer Inst 1995;87:1372–82.
16. Agresti A. Categorical data analysis. New York (NY): Wiley; 1990.
17. Hosmer DW, Lemeshow S. Applied survival analysis: regression modeling of time to event data. New York (NY): Wiley; 1999.
18. Anderson GL, Judd HL, Kaunitz AM, Barad DH, Beresford SA, Pettinger M, et al. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: The Women's Health Initiative Randomized Trial. JAMA 2003;290:1739–48.
19. McKinlay SM, Brambilla DJ, Posner JG. The normal menopausal transition. Maturitas 1992;14:103–15.
20. Avis NE, Stellato R, Crawford S, Bromberger J, Ganz P, Cain V, et al. Is there a menopausal syndrome? Menopausal status and symptoms across racial/ethnic groups. Soc Sci Med 2001;52:345–56.
21. Derman RJ, Dawood MY, Stone S. Quality of life during sequential hormone replacement therapy: a placebo-controlled study. Int J Fertil Menopausal Stud 1995;40:73–8.
22. Prough SG, Aksel S, Wiebe RH, Shepherd J. Continuous estrogen/progestin therapy in menopause. Am J Obstet Gynecol 1987;157:1449–53.
23. Doren M, Reuther G, Minne HW, Schneider HPG. Superior compliance and efficacy of continuous combined oral estrogen-progestogen replacement therapy in postmenopausal women. Am J Obstet Gynecol 1995;173:1446–51.
24. Lindenfeld EA, Langer RD. Bleeding patterns of the hormone replacement therapies in the Postmenopausal Estrogen and Progestin Interventions Trial. Obstet Gynecol 2002;100:853–63.
25. Udoff L, Langenberg P, Adashi EY. Combined continuous hormone replacement therapy: a critical review. Obstet Gynecol 1995;86:306–16.
26. Joffe H, Hall JE, Soares CN, Hennen J, Reilly CJ, Carlson K, et al. Vasomotor symptoms are associated with depression in perimenopausal women seeking primary care. Menopause 2002;9:392–8.
27. Espeland MA, Stefancik ML, Kritz-Silverstein D, Fineberg SE, Waclawiw MA, James MK, et al. Effect of postmenopausal hormone therapy on body weight and waist and hip girths. J Clin Endocrinol Metabol 1997;82:1549–56.
28. Greendale GA, Reboussin BA, Sie A, Singh HR, Olson LK, Gatewood O, et al. Effects of estrogen and estrogen-progestin on mammographic parenchymal density: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. Ann Intern Med 1999;130:262–9.
29. Laya MB, Gallagher JC, Schreiman JS, Larson EB, Watson P, Weinstein L. Effect of postmenopausal hormonal replacement therapy on mammographic density and parenchymal pattern. Radiology 1995;196:433–7.
30. U.S. Food and Drug Administration. FDA updates hormone therapy information for post menopausal women. Available at: http://www.fda.gov/bbs/topics/NEWS/2004/NEW01022.html. Retrieved February 10, 2005.
Back to Top | Article Outline

APPENDIX

Women's Health Initiative Investigators

Program Office: (National Heart, Lung, and Blood Institute, Bethesda, MD) Barbara Alving, Jacques Rossouw, Linda Pottern, Shari Ludlam, Joan McGowan.

Clinical Coordinating Center: (Fred Hutchinson Cancer Research Center, Seattle, WA) 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, Emily White; (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker, Ronald Prineas, Michelle Naughton; (Medical Research Laboratories, Highland Heights, KY) Evan Stein, Peter Laskarzewski; (University of California at San Francisco, San Francisco, CA) Steven Cummings, Michael Nevitt, Maurice Dockrell; (University of Minnesota, Minneapolis, MN) Lisa Harnack; (McKesson BioServices, Rockville, MD) Frank Cammarata, Steve Lindenfelser; (University of Washington, Seattle, WA) Bruce Psaty, Susan Heckbert.

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

Former Principal Investigators: Baylor College of Medicine, John Foreyt, phd; Emory University, Dallas Hall, md; George Washington University, Valery Miller, md; Kaiser, Oakland, Robert Hiatt, md; Kaiser, 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 (deceased); University of North Carolina, Chapel Hill, David Sheps, md; University of Tennessee, Memphis, William Applegate, md; University of Wisconsin, Catherine Allen, phd (deceased).

© 2005 The American College of Obstetricians and Gynecologists