Steiner, Anne Z. MD, MPH1; Xiang, Min MS2; Mack, Wendy J. PhD2,5; Shoupe, Donna MD1; Felix, Juan C. MD1,3; Lobo, Rogerio A. MD6; Hodis, Howard N. MD2,4,5
The transition into menopause is associated with symptoms related to the decline in estrogen production. Vasomotor symptoms, such as hot flushes and sweats, are experienced by 50–80% of postmenopausal women.1 In addition, women complain of vaginitis, pruritus, and dyspareunia associated with vaginal atrophy and commonly seek treatment for these menopausal symptoms.
Estrogen therapy at appropriate doses is effective for ameliorating those symptoms associated with menopause and estrogen deficiency.2 For many years estrogen therapy has been combined with a progestational agent. However, one randomized controlled trial of postmenopausal women showed a possible increase in breast cancer in those women treated with continuous combined conjugated equine estrogen and medroxyprogesterone acetate.3 Estrogen alone has shown a decreased risk of breast cancer that was not statistically significant, with preservation of other benefits of hormone therapy such as reduction of bone fracture risk, reduction of atherosclerotic vascular disease, and reduction of coronary heart disease in postmenopausal women less than 60 years of age.4–8 Other studies have suggested that medroxyprogesterone acetate may be the hormonal agent associated with the increased incidence of breast cancer during combination therapy.9,10 Thus, physicians consider estrogen-only therapies for alleviation of menopausal symptoms and avoidance of the adverse effects associated with continuous combined conjugated equine estrogen plus medroxyprogesterone acetate.
The use of unopposed estrogen is associated with endometrial cancer.11 However, physicians now have a relatively painless method, transvaginal ultrasonography, for screening for precancerous endometrial hyperplasia in postmenopausal women.12 Little is known about the gynecologic outcomes and interventions associated with the use of unopposed estradiol therapy when used with regular transvaginal ultrasound monitoring.
We sought to estimate differences in bleeding patterns, the need for endometrial biopsy, and the development of endometrial hyperplasia in women with uteri randomized to continuous 17β-estradiol or placebo therapy over a 3-year period when monitored annually with transvaginal ultrasonography. In addition, we sought to identify risk factors for bleeding and interventions in women randomized to unopposed estradiol therapy.
MATERIALS AND METHODS
Study participants included 133 healthy postmenopausal women with intact uteri enrolled in the Estrogen in the Prevention of Atherosclerosis Trial (EPAT)6 and 85 postmenopausal women with coronary artery disease and intact uteri enrolled in the Women’s Estrogen-Progestin Lipid-Lowering Hormone Atherosclerosis Regression Trial (WELL-HART).13 The EPAT study was conducted from April 1994 to November 1998, and the WELL-HART study was conducted from June 1995 to October 2000. Patients were recruited for EPAT from advertising in newspapers and newsletters and specific recruitments targeting university employees and health maintenance organization members. Patients with coronary artery disease were recruited for WELL-HART from the angiographic laboratories of five local hospitals. Menopause was confirmed by self-report of cessation of menses for at least 1 year and an estradiol level less than 20 pg/mL. Women were eligible if they were postmenopausal and over 45 years of age. Women were excluded if breast or gynecologic cancer had been diagnosed in the past 5 years or if these cancers were identified during screening or if they had more than five hot flushes per day that interfered with their daily activities. Detailed descriptions of the inclusion and exclusion criteria have been described previously.6,13 Both studies were approved by the University of Southern California Institutional Review Board. Written informed consent was obtained from all participants.
At baseline (before randomization), each woman underwent an endometrial biopsy, Pap test, and transvaginal ultrasound examination. Women were excluded if endometrial hyperplasia was diagnosed on endometrial biopsy or if the endometrial thickness was greater than 5 mm and an endometrial biopsy could not be obtained. Endometrial thickness was measured with a 5-mHz to 7.5-mHz transvaginal probe, measuring the distance between boundaries separating the hyperechoic endometrium from the adjacent inner layer of the myometrium.
Participants in both trials were randomized to either 1 mg of micronized 17β-estradiol daily or placebo for 2 years (EPAT) or 3 years (WELL-HART). Patients in EPAT were randomized within strata defined by categories of low-density lipoprotein cholesterol, duration of previous hormone therapy, and diabetes mellitus.6 Patients in WELL-HART were randomized within strata of diabetes mellitus.13 In both trials, the stratified random treatment group assignments were prepared by the Data Coordinating Center by using a computerized random number generator and blocked randomization. During the trial follow-up, patients were screened annually with a transvaginal ultrasound measurement of the endometrial thickness. If the endometrial thickness was greater than 5 mm, an endometrial biopsy was obtained. The criteria for the diagnosis and classification of endometrial hyperplasia has been described elsewhere.14 Patients were screened annually for breast cancer by breast examination and mammography.
Patients were instructed at randomization to report any uterine bleeding or spotting. All bleeding or spotting complaints were logged in the study event record. With the first report of unscheduled uterine bleeding or spotting that was prolonged, an endometrial biopsy was performed within 2 weeks if a biopsy had not been obtained within the previous 3 months. Bleeding episodes were treated with medroxyprogesterone acetate at the discretion of the study gynecologist, who was blinded to the study randomization.
Simple or complex hyperplasia without atypia was treated with 10 mg medroxyprogesterone acetate daily for 14 days, and the study medication was restarted. Women with hyperplasia with atypia were instructed to stop the study medication and were referred for further evaluation and treatment. After treatment for complex and simple hyperplasia, a repeat endometrial biopsy was performed 3 and 6 months later, respectively, and if found to be normal, the woman was followed as defined by protocol for all study participants. All patients receiving estradiol therapy were given medroxyprogesterone acetate 10 mg for 14 days at study completion.
Only patients with uteri were included in these analyses. A total of 96 patients were from the estradiol group (59 EPAT, 37 WELL-HART); 122 patients were treated with placebo (74 EPAT, 48 WELL-HART). Baseline characteristics were compared between the two treatment groups within each study. Baseline characteristics were also compared between the two trials. To compare baseline characteristics between the two trials, independent sample t tests were used on continuous variables and χ2 tests were used on categorical variables. Kaplan-Meier survival curves were generated to graphically depict the cumulative probability over follow-up of an episode of bleeding, a diagnosis of hyperplasia, and the need for an endometrial biopsy. We tested for treatment group differences in these survival probabilities by a likelihood ratio test in a Cox regression analysis, with adjustment for age, body mass index (BMI), years since menopause, previous hormone use (yes/no), and serum estradiol level at baseline. To consider possible confounding due to study, we also included an indicator variable for study (WELL-HART compared with EPAT). A product interaction term of treatment-by-study further tested if the estradiol-treatment association with endometrial outcomes differed by study. Among affected women in each treatment group, we calculated the median and interquartile range (25 percentile to 75 percentile) of the time to development of endometrial hyperplasia, the number of bleeding episodes, or the time to endometrial biopsy. Medians were compared using a Wilcoxon rank-sum test. We used logistic regression to evaluate whether estradiol treatment and other variables were associated with the likelihood of having vaginal bleeding or an endometrial biopsy. We adjusted for study and also tested interaction terms to determine if associations differed in EPAT compared with WELL-HART. Other independent variables tested for association included age, BMI, years since menopause, previous hormone use (yes/no), and serum estradiol level at baseline. All statistical analyses used SAS 9.1 (SAS Inc, Cary, NC).
For this post hoc cohort analysis of 218 (96 estradiol-treated and 122 placebo-treated) women, we had 80% power to statistically detect (at a two-sided α level of 0.05) treatment-related relative risks on the order of 2.9–10.0 and higher, given the low event rate (on the order of 0–10%) in the placebo group.
Demographic and baseline characteristics for the women included in this analysis are reported in Table 1. Within each trial, all variables were similar between treatment groups. The patients involved in WELL-HART were older than the EPAT patients (P=.005), were more likely to be Hispanic (50.6% in WELL-HART) compared with white (57.1% in EPAT), had higher parity (5.4 versus 3.1, P<.001), and had lower serum estradiol levels at baseline (P<.001).
Compliance with study medications in EPAT was 93% and in WELL-HART 93%. Forty-eight percent of all patients received medroxyprogesterone acetate at least once during the study period (63.5% in the estradiol group, 35.3% in the placebo group, P<.001).
Forty-four percent of women on estradiol and 13.8% of women on placebo developed a thickened endometrium (greater than 5 mm, as measured by transvaginal ultrasonography) at least once during follow-up. Forty-three percent of women on estradiol at 1 year had a thickened endometrium, 23.8% at 2 years, and 14.3% at 3 years.
Hyperplasia developed in nine patients (9.4% of patients, 95% CI 3.6–15.2%) in the combined estradiol groups, compared with none (0% of patients, 95% CI 0–4.5%) in the placebo groups. Eight of the nine cases (88.9%) of hyperplasia were simple without atypia. One woman developed complex hyperplasia with atypia and underwent hysterectomy. Among women who developed hyperplasia, the median time to development of hyperplasia was 1.1 year (interquartile range, 25th–75th percentile [1.0–1.4 years]), with a 2.7% cumulative incidence at 1 year and 10.8% at 2 and 3 years. Some women were diagnosed with hyperplasia after the study conclusion, resulting in a 20% hyperplasia rate after 3 years (Fig. 1, P<.001 between treatment groups, adjusting for study, age, BMI, years since menopause, previous hormone use (yes/no), and serum estradiol level at baseline). No women developed endometrial cancer over the course of the trial.
Among women randomized to estradiol, the cumulative incidence of uterine bleeding was 49% at 1 year of treatment and 67% at 3 years, whereas the cumulative incidence of uterine bleeding was only 11% among placebo patients over 3 years (P<.001) (Fig. 2). Women who did not bleed during the first 2 years did not have any bleeding events. Women on estradiol had on average 2.2 bleeding episodes (median 0, interquartile range 0–3), but those women on estradiol who bled had, on average, 4.7 bleeding episodes (median 3.5, interquartile range 2–7). Among women who bled, the median time from initiation of study medication to onset of bleeding was 0.3 years (interquartile range 0.1–1.6 years) for women on estradiol and 1.9 years (interquartile range 0.05–2.0 years) for women on placebo (P=.03).
Women receiving estradiol were also more likely than women on placebo to have at least one endometrial biopsy (cumulative incidence of 20.5% versus 1.5% at 1 year and 48.2% versus 4.3% at 3 years, P<.001) (Fig. 3). Seven percent of all women had more than one biopsy, while 14.6% of patients on estradiol had more than one biopsy. Among women who had a biopsy, the median time to endometrial biopsy was 1.2 years (interquartile range 0.5–2.1 years) in the estradiol group and 2.0 years (interquartile range 1.9–2.9 years) in the placebo group. The associations of estradiol treatment with time to occurrence of hyperplasia, bleeding, and endometrial biopsy were equally apparent in EPAT and WELL-HART (all statistical tests for interaction were not statistically significant).
With adjustment for potential confounders (study, age, use of previous hormones, BMI, time since menopause, and baseline serum estradiol level), using estradiol significantly increased the odds of biopsy (odds ratio [OR] 18.3, 95% confidence interval [CI] 6.0–55.6) and bleeding (OR 14.1, 95% CI 5.9–33.2). Among all women, age, time since menopause, previous hormone use, and estradiol level did not predict the likelihood of bleeding or the need for endometrial biopsy. Among women on estradiol, obesity (BMI greater than 30 kg/m2) significantly increased the odds of uterine bleeding compared with normal-weight patients (BMI less than 25 kg/m2) (OR 3.7, 95% CI 1.2–11.8). These associations of estradiol treatment and BMI with bleeding did not significantly differ in EPAT compared with WELLHART.
Unopposed estradiol therapy in women with uteri may be necessary in some women to control symptoms associated with menopause. In the setting of regular screening with transvaginal ultrasonography and the use of endometrial biopsy and progestin therapy when indicated, no cases of endometrial cancer were detected over a 3-year period, and precancerous hyperplasia was found in only 9% of participants on unopposed estradiol in this study. Bleeding on this regimen should be anticipated because more than half of participants randomized to estradiol had bleeding, with a median of 3.5 episodes of bleeding among women who did bleed over the study period. Women should also anticipate the possibility of an endometrial biopsy. Obese women on estradiol therapy were at greater risk for bleeding.
The combination of EPAT and WELL-HART results in a large analysis of randomized controlled trial data evaluating the risk of hyperplasia, bleeding, and endometrial biopsies during unopposed oral estradiol therapy with ultrasound monitoring. Ettinger et al15 prescribed for 38 women within 5 years of menopause treatment with unopposed 17β-estradiol in a cyclic regimen with doses ranging from 0.5 to 2 mg for 1 year and sampled the endometrium at 1 year and at episodes of bleeding. The Women’s Estrogen for Stroke Trial (WEST) randomized 369 women to oral estradiol or placebo daily with annual transvaginal ultrasonography or annual treatment with medroxyprogesterone acetate.16
Other trials, including the Postmenopausal Estrogen and Progestin Interventions (PEPI) trial,17 Esterified Estrogens and Methyltestosterone Tablets (ESTRATAB) trial,18 the Women’s Health, Osteoporosis, Progestin, Estrogen (HOPE) trial,19 and Harris et al20 used conjugated or esterified estrogens. During the PEPI trial, 119 women within 10 years of menopause with intact uteri were given 0.625 mg of conjugated equine estrogen daily for up to 3 years. Patients underwent endometrial biopsy annually, with unscheduled bleeding, or in follow-up of earlier hyperplasia. In the ESTRATAB trial, 178 participants were prescribed esterified estrogens in doses ranging from 0.3 mg to 1.25 mg for 2 years and were followed every 6 months with endometrial biopsies. The HOPE trial randomized 797 participants within 4 years of menopause to 0.3–0.625 mg conjugated equine estrogens for 1 year. Women underwent endometrial biopsy at 6 months and after 1 year of treatment.
In EPAT and WELL-HART combined, 9% of patients developed hyperplasia after use of 17β-estradiol therapy for up to 3 years. The majority of hyperplasia was detected during the second year of therapy. This risk of hyperplasia was much lower than the risk found by Ettinger et al (22%), PEPI (62%), ESTRATAB (28%), and WEST (18%), but higher than the study of lower-dosage estrogen, HOPE (3.8%). The PEPI trial also found that the rates of hyperplasia were evenly distributed throughout the trial. These differences may be due to the liberal use of progestins with an episode of bleeding that was at the discretion of the gynecologist in EPAT and WELL-HART.
It is also possible that in EPAT and WELL-HART a number of cases of hyperplasia went undetected in patients with thin endometrium without clinical consequences. Biopsies were not routinely performed during or at the end of the trial. Thus, the biopsy-proven rate of hyperplasia is not known but inferred. In addition, previous epidemiologic studies have shown that the risk of endometrial cancer lingers for many years after cessation of unopposed estradiol. Although we do not know of any endometrial cancers that were subsequently detected among our participants, hyperplasia was noted after cessation of medications. Therefore, close long-term follow-up is needed.
A meta-analysis of 30 observational studies found that duration of use of unopposed estrogen, dosage, and type of estrogen influenced the risk of endometrial cancer.21 Differences in dosing may have contributed to differences in rates of hyperplasia among studies. Women on higher doses of esterified estrogen (1.25 mg) in the ESTRATAB study had a 50% risk of hyperplasia. For those women on lower doses of esterified estrogens, 0.45 mg and 0.3 mg in the HOPE trial, the rates of hyperplasia were 3% or lower. The rate of hyperplasia (8%) in the group on 0.625 mg conjugated equine estrogens in the HOPE trial was similar to ours. The WEST trial, which also used 1 mg of oral estradiol had a much higher hyperplasia rate (17%). However, the women in the WEST trial did not undergo baseline endometrial biopsies. Half of the patients who developed hyperplasia in the estradiol group did so in the first 6 months of therapy. These findings suggest that at least some of the hyperplasia found during the trial preceded or could not be mainly attributed to estradiol use. Differences in hyperplasia rates are less likely to be due to the type of estrogen used. Our hyperplasia rate (9%) using 17β-estradiol was similar to that in the HOPE trial using conjugated equine estrogens.
Amenorrhea was significantly less likely in the estradiol group compared with placebo, with the possibility of amenorrhea decreasing in a linear fashion until 2 years. Our incidence of amenorrhea (50.5% at 1 year and 33% after 2 years) was lower than the percentage of women with amenorrhea in the 0.625 mg esterified estrogen group in the ESTRATAB study (51%)22 and in the 1 mg 17β-estradiol group in the Ettinger et al15 study (70%), but similar to the incidence in the WEST trial (39%). However, due to dropouts, all of these other studies may underestimate the actual probability of bleeding. Among women on estradiol, the median number of episodes of bleeding was much lower in our trial (3.5 episodes during entire enrollment) compared with 2.9–4.0 episodes per 6-month interval for those women on estrogen in the PEPI trial.23 The large number of bleeding episodes in the PEPI trial may be due to either detection bias or bleeding secondary to endometrial biopsy because the mean number of bleeding episodes in the placebo group ranged from 0.03 to 1.8 per 6-month interval.
Our protocol for gynecologic monitoring greatly reduced the number of endometrial biopsies required during unopposed estrogen therapy compared with previous trials. With the use of transvaginal ultrasonography, more than half of the patients treated with estradiol never required an endometrial biopsy during therapy under our gynecologic protocol. All previously mentioned trials required patients to undergo endometrial sampling every 6–12 months. Despite such frequent sampling, unscheduled endometrial biopsies were also common during those studies. In the PEPI trial, 66% of participants on unopposed estrogen underwent unscheduled biopsies.17 However, only 21 unscheduled endometrial biopsies (of 238 patients) were conducted in ESTRATAB.18
This disproportionate number of biopsies in the PEPI trial compared with EPAT and WELL-HART combined or ESTRATAB is due to the study protocols. The EPAT and WELL-HART trials and the ESTRATAB study incorporated the use of transvaginal ultrasonography as a diagnostic modality, either during annual screening (EPAT and WELL-HART) or with bleeding episodes (ESTRATAB trial). Although patients in EPAT and WELL-HART underwent endometrial biopsy with bleeding, it was performed only with the first episode of bleeding and not within 3 months of a previous normal biopsy. Patients enrolled in EPAT and WELL-HART who developed bleeding were also given medroxyprogesterone acetate at the discretion of the study gynecologist.
Women in the PEPI trial had more bleeding episodes that frequently necessitated an endometrial biopsy. Treatment regimens were unmasked with an episode of vaginal bleeding, and the physician made a decision on the need for biopsy based on treatment assignment. This ascertainment bias may have led to more frequent biopsies and detection of hyperplasia in the unopposed estrogen group.
Obesity results in conversion of androgens to estrone via peripheral aromatase.24 Although obesity is a risk factor for endometrial hyperplasia and cancer,25 obesity, along with use of previous hormones, age, and time since menopause, did not predict the need for endometrial biopsy or episodes of bleeding among all users in EPAT and WELL-HART. However, among women on estradiol therapy, obesity did increase the risk of bleeding. Thus, the addition of exogenous 17β-estradiol to endogenous estrone and estradiol most likely resulted in proliferative endometrium and an increased risk of bleeding.
Postmenopausal women will continue to seek treatment for hot flushes and symptoms caused by vaginal atrophy. Physicians consider the use of estrogens, at various doses, for these patients after discussion of the risks and benefits of estrogen therapy. Unopposed estradiol therapy combined with regular ultrasound monitoring with use of occasional progestins with uterine bleeding may be a viable option for the management of menopausal symptoms. Women on 1 mg of daily oral estradiol should anticipate vaginal bleeding and the possibility of endometrial biopsy, especially if they are obese.
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