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ORIGINAL RESEARCH |
From the Medical College of Wisconsin, Milwaukee, Wisconsin; University of California, San Francisco, San Francisco, California; Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia; University of Pittsburgh, Pittsburgh, Pennsylvania; University of California, San Diego, San Diego, California; Stanford University, Palo Alto, California; and Wyeth-Ayerst Research, Philadelphia, Pennsylvania.
Address reprint requests to: Vanessa M. Barnabei, MD, PhD, Medical College of Wisconsin, Department of Obstetrics and Gynecology, 9200 West Wisconsin Avenue, Milwaukee, WI 53226; E-mail: barnabei{at}mcw.edu.
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ABSTRACT |
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 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: We used data from the Heart and Estrogen/Progestin Replacement Study, a blinded, clinical trial among 2763 women with documented coronary disease and a uterus who were randomized to receive either conjugated estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 mg in one tablet or placebo. Participants were queried at baseline and annually regarding menopausal symptoms. Breast symptoms were self-reported, and uterine bleeding was recorded on a daily diary.
RESULTS: Symptoms associated with menopause were relatively common among Heart and Estrogen/Progestin Replacement Study participants, whose average age was 67 years and who averaged 18 years since menopause. At baseline, 16% of women reported frequent hot flashes, 26% vaginal dryness, 10% genital irritation, 55% trouble sleeping, and 53% early awakening. Women assigned to hormone therapy reported less frequent hot flashes, vaginal dryness, and trouble sleeping compared with women assigned to placebo, but more frequent vaginal discharge, genital irritation, uterine bleeding, and breast symptoms. The reporting of breast symptoms among women in the hormone group decreased from 40% at 1 year to 13% by the 4th year. Uterine bleeding was reported by 31% and spotting by an additional 33% of women in the hormone group during the 1st year of treatment; by the 4th year, these proportions had fallen to 11% and 20%, respectively.
CONCLUSION: Symptoms typically attributed to menopause are common in elderly women. Postmenopausal hormone therapy reduces hot flashes, trouble sleeping, and vaginal dryness, but at standard doses in elderly women is associated with vaginal discharge, genital irritation, uterine bleeding, and breast symptoms.
Hot flashes, insomnia, and other symptoms attributed to menopause are common in climacteric women and can be effectively treated with estrogens.1 In some women, menopausal symptoms persist for many years after the cessation of menses, but the frequency and severity of such symptoms in older women have not been well documented. There is little evidence regarding the efficacy or side effects of postmenopausal hormone therapy for treatment of symptoms when started many years after the menopause.
The Heart and Estrogen/Progestin Replacement Study2 was a large, randomized, double-blind, placebo-controlled study of combined hormone therapy for the secondary prevention of heart disease in older postmenopausal women. We used data from 2763 women enrolled in this trial to determine the frequency and severity of menopausal symptoms at baseline and the effect of treatment with hormone therapy on symptoms and side effects.
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MATERIALS AND METHODS |
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Participants were randomly assigned by computer-generated random numbers to take one tablet daily of continuous-combined hormone therapy consisting of conjugated estrogens 0.625 mg plus medroxyprogesterone acetate 2.5 mg (hormone therapy) or placebo in an identical tablet. Randomization was stratified by clinical center and performed in variable blocks of 4–6.
Data were collected at baseline on demographic characteristics, reproductive health history, exercise, smoking and alcohol consumption, quality of life measures, and medication use. Height, weight, and waist and hip circumference were measured, and body mass index was calculated. Participants reported history of prior headache. Breast symptoms were not ascertained at baseline, and women with uterine bleeding were excluded. Participants were queried regarding menopausal symptoms using a 6-point Likert scale (none, little, some, a good bit, most, all of the time) that asked about symptoms occurring during the week prior to completing the questionnaire. Women who reported symptoms some or a good bit of the time were classified as having somewhat frequent symptoms and those who reported symptoms most or all of the time were classified as having very frequent symptoms.
During follow-up, physical examination and the menopausal symptom questionnaire were repeated annually. Women who reported breast pain (pain, discomfort, aching, throbbing, soreness, tenderness, heaviness, tingling, burning, or sensitivity) or breast swelling (swelling, enlargement, or fullness) were considered to have breast symptoms. Bleeding was recorded daily on a bleeding diary as none, spotting (no pad used), or bleeding (pad used). Although participants were weighed at each annual visit, symptomatic weight gain was based on self-report.
Participants, investigators, and staff at the 20 Heart and Estrogen/Progestin Replacement Study centers who ascertained the main cardiovascular outcomes were blinded to study drug assignment throughout the study. To avoid unblinding of these individuals, breast discomfort and uterine bleeding were reported directly to gynecology staff at each center who were located separately from the main trial staff and did not discuss breast or bleeding complaints with them. If necessary, and after obtaining permission from the Heart and Estrogen/Progestin Replacement Study Coordinating Center at the University of California, San Francisco, the gynecologist at each center was permitted to open a sealed envelope containing treatment assignment; this occurred for 34 women (30 in the hormone therapy group and four in the placebo group).
Adherence was defined as an average pill count of at least 80% of assigned study medication at each annual visit.
Baseline characteristics of both the placebo and treatment groups are reported as percents or means (± standard deviation) and compared at baseline using the 
2 or t test as appropriate. We evaluated the effect of treatment assignment on the proportion of women in each group reporting very frequent or somewhat frequent symptoms and side effects using unadjusted intention-to-treat proportional odds models at each annual visit.
We defined improvement in symptoms as a change from very frequent symptoms at baseline to either somewhat frequent or no symptoms at 1 year of treatment or a change from somewhat frequent symptoms at baseline to no symptoms at 1 year. The proportion of women in each group who improved by the first annual visit was also compared using unadjusted intention-to-treat proportional odds models.
Symptom relief was analyzed only for participants reporting one or more symptoms at baseline and, conversely, side effects only among those who were initially symptom free. To determine if baseline characteristics predicted either relief of symptoms or side effects related to use of hormone therapy, we used unadjusted proportional odds models to test for interaction between the variables in Table 1
and treatment assignment.
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RESULTS |
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).
Symptoms typically associated with menopause were relatively common among the Heart and Estrogen/Progestin Replacement Study participants. At baseline, 16% of the 2763 women reported that they had somewhat frequent or very frequent hot flashes, 26% reported vaginal dryness, 10% genital irritation, 55% trouble sleeping, and 53% early awakening (Table 2). There were no differences in menopausal symptoms at baseline between the treatment groups, except that women assigned to hormone therapy were more likely to report pelvic cramps than women assigned to placebo (very frequent or somewhat frequent pelvic cramps in the hormone group = 5.3% compared with 3.3% in the placebo group, P = .01) (Table 3). Breast tenderness was not queried at baseline, and women with uterine bleeding were excluded.
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We evaluated the effect of hormone therapy on symptoms and side effects by comparing the proportion of women in the treatment groups who reported somewhat to very frequent symptoms at the first annual visit. After 1 year of therapy, women assigned to hormone therapy were less likely to report hot flashes, vaginal dryness, and trouble sleeping compared with women assigned to placebo, but they were more likely to report vaginal discharge, genital irritation, and pelvic cramps (Table 3). These differences persisted after adjustment for the baseline difference between the treatment groups in proportion with pelvic cramps. Among women without pelvic cramps at baseline, those who reported any bleeding or spotting in the 1st year were more likely to report somewhat frequent or frequent pelvic cramps at year 1 (relative risk 2.6; 95% confidence interval 1.8, 3.7; P < .001). Most differences between the treatment groups that were evident after year 1 persisted; however, by 4 years of treatment, the proportion of women reporting pelvic cramps and vaginal dryness no longer differed between the treatment groups. By 4 years of treatment, women in the hormone group were more likely to report nausea or vomiting and headaches than women in the placebo group. No differences were noted between the treatment groups in the proportion of women who reported early awakening, weight gain, or swelling of the hands or feet. Among women assigned to hormone therapy, the proportion reporting breast symptoms decreased from 40% at 1 year to 13% by the 4th year (Figure 1). Uterine bleeding was reported by 31% of women in the hormone group and spotting by an additional 33% during the 1st year of treatment; by the 4th year, these proportions had fallen to 11% and 20%, respectively. Differences between the groups in proportion bleeding were statistically different at each year of the trial (P < .001). At year 1, data were available for 1293 women in the hormone group and 1315 in the placebo group, with 81% and 92% compliance, respectively. At year 4, these numbers were 860 and 904, with 71% and 82% compliance. There were no changes in the statistical significance of the results when only adherent women were included in the analysis.
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). Among women with trouble sleeping at baseline (632 in the hormone group and 628 in the placebo group), 39% of women in the hormone group and 33% in the placebo group reported improvement by 1 year (P = .02); among those with vaginal or genital dryness at baseline (352 in the hormone group and 357 in the placebo group), 61% and 47% were improved at 1 year (P < .001).
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). Breast symptoms were more likely to occur among women in the hormone group with lower body mass index (P = .02), longer duration of menopause (P = .03), and higher parity (P = .002) (Figure 3). Bleeding associated with hormone use was more likely to occur among women who exercised three or more times per week compared with those who exercised less (P = .04) (Figure 4).
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DISCUSSION |
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At baseline, the 2763 women who participated in the Heart and Estrogen/Progestin Replacement Study reported a relatively high prevalence of symptoms generally associated with menopause: 16% reported frequent hot flashes, 26% vaginal dryness, 10% genital irritation, 55% trouble sleeping, and 53% early awakening. Although vasomotor symptoms are clearly associated with menopause,6,7 symptoms such as trouble sleeping and early awakening may be due to multiple other causes. Treatment with hormone therapy resulted in improvement in trouble sleeping, suggesting that estrogen deficiency is at least partly responsible for this symptom in women. There was no improvement in early awakening with hormone treatment, suggesting that this symptom may not be related to estrogen status.
Hot flashes are very common in perimenopausal and younger postmenopausal women. Among perimenopausal women, 60%–75% report hot flashes.4–7 In the Postmenopausal Estrogen/Progestin Interventions Trial,8 in which the average age of participants was 56.1 years, 46% reported hot flashes. These data suggest that although the prevalence decreases markedly with age, hot flashes are still a common complaint among women one or more decade after the menopause.
Urogenital symptoms, including vaginal dryness and discharge, genital irritation, and pelvic cramps, were also common among the Heart and Estrogen/Progestin Replacement Study participants. The high incidence of incontinence in the Heart and Estrogen/Progestin Replacement Study participants has been reported previously.9 A European study of the prevalence of urogenital atrophic changes found that these symptoms had a significant impact on the daily life of 30% of women and were an irritating problem in another 22%.10
Weight gain is a frequent complaint in postmenopausal women. For example, in the Postmenopausal Estrogen/Progestin Interventions Trial, 32% reported weight gain.8 In the Heart and Estrogen/Progestin Replacement Study participants, who had a mean body mass index of 28 ± 5 at baseline, 28% reported self-perceived weight gain at the first annual visit, but only 16% had actually gained more than 5 pounds, based on the difference in measured weight at baseline and 1 year. There was no difference between the hormone and placebo groups in self-reported weight gain.
Compared with placebo, women treated with hormone therapy were less likely to report hot flashes, vaginal dryness, and trouble sleeping during the trial. By 1 year of treatment, improvement in these symptoms among women treated with hormones was especially marked for hot flashes. Younger women and women closer to menopause appeared to be more likely to have relief of hot flashes related to hormone use. Caution should be used in interpreting these results, however, because we performed multiple analyses to identify predictors of benefit. Many clinical trials among perimenopausal and younger postmenopausal women have shown that hormone therapy relieves hot flashes.4–7,11 To our knowledge, however, this is the first report to document the effect of hormone therapy on hot flashes in older postmenopausal women. Other studies also have documented a beneficial effect of postmenopausal estrogen therapy on sleep quality. One randomized, prospective study found that improvement in vasomotor symptoms was the most predictive factor for improved sleep quality,12 suggesting that one mechanism by which hormone therapy improves sleep quality is relief of vasomotor instability.
Women assigned to hormone therapy were more likely to develop somewhat or very frequent vaginal discharge, genital irritation, uterine bleeding, and breast symptoms than those assigned to placebo. Why hormone therapy might result in genital irritation in older women is not entirely clear, but the symptom may be due to increased activity of the vaginal and cervical epithelium, resulting in vaginal discharge that causes genital irritation. Although a higher proportion of hormone-treated women reported pelvic cramps at 1 year, pelvic cramps were more common among women assigned to hormone therapy at baseline, and there was no difference between the treatment groups in later years of treatment. Thus, it is not clear that hormone therapy is associated with pelvic cramps in older women.
Uterine bleeding was a common and expected side effect of hormone therapy. The frequency of reported bleeding or spotting was similar to that reported by many other studies of postmenopausal hormone replacement therapy.13,14 Continuous combined hormone therapy as used in the Heart and Estrogen/Progestin Replacement Study is known to cause uterine bleeding or spotting among 20%–80% of perimenopausal women during the first 6–12 months of treatment, with a more than 40%–50% incidence of amenorrhea at the end of 12 months of therapy.13–15 In the Postmenopausal Estrogen/Progestin Interventions Trial, 20%–30% of women continued to have bleeding or spotting at 36 months of therapy (personal communication, C. LeGault, 1998). In the Heart and Estrogen/Progestin Replacement Study, bleeding or spotting occurred in almost 66% of women in the 1st year of treatment, and 20% continued to report bleeding or spotting after 4 years of treatment. To some extent, the high prevalence of this symptom might be due to very careful reporting using a daily diary; this theory is supported by the relatively high prevalence of reported bleeding or spotting in the placebo group (6%–16%). Bleeding rates in the Heart and Estrogen/Progestin Replacement Study may not be generalizable to other groups of older women, because potential Heart and Estrogen/Progestin Replacement Study participants were excluded if they had a history of abnormal bleeding, hyperplasia on baseline biopsy, or endometrial thickness greater than 5 mm. Bleeding due to hormone therapy was not significantly more likely among overweight women or those remote from menopause but was more likely to occur among women who reported at baseline that they exercised three or more times per week. The mechanism whereby exercise might increase risk for hormonerelated bleeding is not clear, and this finding may have occurred by chance, because we conducted multiple analyses of potential predictors of side effects.
Breast symptoms were the most common side effect in women assigned to hormone therapy. By the first annual visit, breast symptoms had been reported by 40% of women assigned to hormone therapy, compared with 9% assigned to placebo (P < .001). Breast symptoms became less prevalent with time but were still reported by 13% of women in the hormone group at the fourth annual visit. Because all women assigned to hormone therapy in the Heart and Estrogen/Progestin Replacement Study took a combination of estrogen plus progestin, we cannot compare the effects on the breast of unopposed estrogen with combination therapy. In the Postmenopausal Estrogen/Progestin Interventions Trial,8 breast tenderness was associated with estrogen plus progestin therapy (either medroxyprogesterone acetate or micronized progesterone) but not with unopposed estrogen therapy. As in the Heart and Estrogen/Progestin Replacement Study, breast symptoms associated with combination hormone therapy in the Postmenopausal Estrogen/Progestin Interventions Trial persisted well beyond the 1st year of use and declined gradually over time.
Women in the Heart and Estrogen/Progestin Replacement Study who had lower body mass index, longer duration since menopause, and higher parity were more likely to develop hormone-related breast symptoms. Women with lower body mass index may have lower endogenous estrogen levels at baseline and experience a greater stimulatory effect from exogenous hormone treatment. Greater increases in mammographic breast density are seen in women with lower density at the time they begin therapy,16,17 and a similar effect might be expected in women remote from menopause, who tend to have a lower breast density than younger postmenopausal women; however, there is little evidence linking increases in breast density with breast symptoms. It is not clear why increased parity would lead to more hormone-induced breast tenderness. Older women beginning hormone therapy, particularly those remote from menopause with low body mass index, should be counseled that breast symptoms are a likely side effect of estrogen plus progestin therapy at the doses used in this study.
Symptoms that did not differ between the groups during the study include early awakening, self-perceived weight gain, and swelling of hands and feet. In the Heart and Estrogen/Progestin Replacement Study, hormone therapy was not associated with headaches during the 1st year, but a higher proportion of hormone-treated women reported headache by 4 years of treatment. Headaches have been reported to occur more frequently in women taking hormone replacement therapy, but data have been inconsistent. In the Postmenopausal Estrogen/Progestin Interventions Trial,8 headache occurred more frequently in women assigned to unopposed estrogen who reported no headache at baseline and less frequently in women who reported headache at baseline; these differences were not seen in the estrogen plus progestin groups. Nausea or vomiting also were reported more frequently in women in the hormone group at the 4th year of treatment, although we would have expected this effect to be more prominent early on in the study if it were due to a direct effect of the hormones on the gastrointestinal tract.
Hormone replacement therapy improved menopausal symptoms, but side effects, particularly bleeding and breast tenderness, were common. The occurrence of bleeding and breast tenderness decreased gradually over time. It is not clear that the initiation of hormone therapy at standard doses provides a net symptom benefit in elderly women. Depending on the indication for starting hormone therapy, lower doses may be advisable to start and increased as tolerated until the desired dose is attained.
Symptoms typically attributed to menopause are common in elderly women. Postmenopausal hormone therapy reduces hot flashes, trouble sleeping, and vaginal dryness, but at standard doses in elderly women is associated with vaginal discharge, genital irritation, uterine bleeding, and breast symptoms. Counseling prior to institution of hormone therapy in elderly postmenopausal women should include a discussion of symptom relief and side effects as well as the medical risks and benefits of therapy.
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Footnotes |
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Received December 11, 2001. Received in revised form May 3, 2002. Accepted June 6, 2002.
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REFERENCES |
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2. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605–13.
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