Johnson, Susan R. MD, MS*; Ettinger, Bruce MD†; Macer, Judith L.‡; Ensrud, Kristine E. MD, MPH§; Quan, Judy PhD‡; Grady, Deborah MD, MPH‡
Osteoporotic fractures are a clinically significant cause of morbidity and mortality among postmenopausal women. Hormone therapy (HT)—specifically, conjugated equine estrogens 0.625 mg daily, with or without concomitant progestin—can reduce bone loss1 and reduce risk of hip fracture and other types of clinical fracture.2,3 However, large randomized trials showed that daily estrogen plus progestin increased the risk for coronary events, stroke, pulmonary embolism, breast cancer,2 and dementia.4 These results led most expert groups—including the U.S. Food and Drug Administration,5 the U.S. Preventive Services Task Force,6 and the American College of Obstetrics and Gynecology7—to suggest that HT be prescribed at the lowest effective dose for the shortest possible time. Some adverse effects associated with combination HT are probably related to adding progestin to the estrogen regimen,8 but women with a uterus who are using a standard dose of estrogen need progestin therapy to prevent uterine hyperplasia and cancer.9
We studied ultralow-dose unopposed transdermal estradiol in the hope that this low dose could prevent bone loss, obviate the need for added progestin, and minimize adverse effects associated with estrogen therapy. The Ultralow-dose Transdermal Estrogen Assessment (ULTRA) was a 2-year, double-blind, randomized, placebo-controlled trial of 14 μg of transdermal estradiol per day (one fourth the usual standard dose of 50 μg, given transdermally, or 0.625 mg of conjugated equine estrogens, given orally) in postmenopausal women with a uterus. Previously, this low dose of estradiol effectively prevented bone loss through antiresorptive effects.10 Our research aimed not only to show that 14 μg transdermal estradiol per day effectively prevented osteoporosis but that it is safely used unopposed by progestin. We now report effects of ultralow-dose estradiol on endometrial histology, vaginal bleeding, and vaginal epithelial maturation.
MATERIALS AND METHODS
The design and methods were described previously.10 The ULTRA trial was conducted at 9 clinical centers in the United States. Participants were women, aged 60–80 years, who had a uterus and were at least 5 years beyond menopause. Women were excluded if they had bone density z score below –2.0 at the lumbar spine as measured by dual X-ray absorptiometry, unexplained uterine bleeding, endometrial hyperplasia or endometrial ultrasound image 5 mm or more in double thickness, abnormal mammogram suggesting breast cancer, previous metabolic bone disease, previous use of bone-active medication, hormone use within 3 months before study, or other conditions possibly related to increased adverse effects of estrogen.10 Institutional review boards at each site approved the study protocol. Informed consent was obtained from all study participants.
Participants at each clinical center were assigned to ultralow-dose estradiol or placebo in a 1:1 ratio in randomly permuted blocks of 4 with allocation concealed. Participants, investigators, and outcome assessors were blinded to treatment assignment, and no unblinding occurred during the trial. Treatment consisted of an estradiol patch, 3.25 cm2 in area, or an identical placebo patch. The patch, which released approximately 14 μg of estradiol transdermally per day, was applied to a clean, dry area of the abdomen once weekly.
At baseline, endometrial aspiration biopsy was attempted for all participants; women were excluded if the uterine cavity could not be entered by the biopsy instrument. If the biopsy tissue sample was insufficient for pathology evaluation, transvaginal ultrasonography was performed to measure double endometrial thickness; thickness of 5 mm or more prompted exclusion.10
Participants kept a daily diary to record all episodes of uterine bleeding or spotting. At follow-up visits every 4 months, adherence to treatment was measured by patch counts, bleeding diaries were reviewed, and adverse events were ascertained.
All participants had routine endometrial biopsy using a Pipelle curette (Unimar, Wilton, CT) at each annual follow-up visit. Tissue was placed in formalin and shipped the same day to the central pathology laboratory (Global Medical Services Group, Thousand Oaks, CA). Endometrial samples were evaluated by 2 independent, blinded pathologists with expertise in endometrial histology. If the 2 initial diagnoses did not agree, a third pathologist adjudicated the case. Adjudication was required for 7 (1.7%) of 420 baseline specimens and for 16 (2.3%) of 687 follow-up biopsy specimens.
At follow-up, 3 circumstances dictated whether transvaginal ultrasonography was performed: 1) participant refused to have a biopsy, 2) uterine cavity could not be entered by the biopsy curette, or 3) biopsy tissue sample was insufficient for diagnosis. Transvaginal ultrasonography done under these circumstances conformed to local clinical procedures. In the follow-up phase of the study, we attempted to obtain uterine tissue by repeat biopsy or dilation and curettage if the sonographically measured double thickness of the endometrial wall was 4 mm or more. At the discretion of the principal investigator at each study site, diagnostic uterine evaluation was done when women reported uterine bleeding.
Vaginal smears were not done at baseline but were obtained during pelvic examination from the lateral anterior third of the vaginal wall at 1-year and 2-year follow-up visits. At a blinded central laboratory (Covance Central Laboratory Services, Indianapolis, IN), 200 cells from each smear were categorized as parabasal, intermediate, or superficial. Serum estradiol levels were measured at baseline and annually using a double-antibody sequential radioimmunoassay with a 1.4 pg/mL lower limit of detection (Diagnostics Products Corporation, Los Angeles, CA).
Primary outcome measures of the study were percentage change from baseline in lumbar spine bone density and incidence of endometrial hyperplasia or endometrial cancer at 2-year follow-up. Secondary outcome measures evaluated for this report included incidence of endometrial proliferation, probability of vaginal bleeding and of vaginal bleeding or spotting, and proportion of each of the 3 types of vaginal epithelial cells. Endometrial histology was classified as insufficient for diagnosis or by the categories listed in Table 1. Participants receiving more than 1 histologic diagnosis at follow-up visits were included in the most clinically important category. Vaginal blood flow was classified by participants as either “bleeding” (as heavy or heavier than a normal menstrual period or requiring sanitary pads) or “spotting” (lighter than a normal menstrual period and not requiring sanitary pads). The effect of treatment on vaginal cell maturation was assessed from group differences in mean percentages of parabasal, intermediate, and superficial cells as well as from group differences in the proportion of subjects with superficial vaginal cells. All assessments were based on the last available measurement.
We used exact methods implemented in StatXact 4.0 (Cytel Software Corporation, Cambridge, MA) to obtain 95% confidence intervals (CIs) for prevalence of histologic outcomes in the treatment and control groups and to assess between-group differences in prevalence. For adverse outcomes, the null hypothesis of the inferiority of estradiol was rejected in favor of noninferiority if the upper bound of the 95% CI for the estradiol versus placebo difference in cumulative incidence of the adverse outcome did not exceed a clinically acceptable value. For both endometrial hyperplasia and endometrial proliferation, under the alternative hypothesis that 2-year population cumulative incidence of these endpoints is about 1% in untreated women and that no adverse effect of estradiol exists, estimates using a normal approximation (based on 90% [375/417] of women having a biopsy) give 80% power to reject the null hypothesis that cumulative incidence of either hyperplasia or proliferation was at least 5% higher in the estradiol group. Similarly, under the alternative, noninferiority hypothesis that 2-year population cumulative incidence of spotting or bleeding is 10% in untreated women and that no adverse treatment effect exists, the normal approximation showed that the study would have 80% power to reject the null hypothesis that cumulative incidence was about 10% higher in the estradiol group. Kaplan-Meier curves showing incidence of bleeding and bleeding or spotting were plotted using the freeware package R 1.0 (R Foundation for Statistical Computing, Vienna, Austria).
Mean proportions of parabasal, intermediate, and superficial cells in samples of 200 vaginal epithelial cells were compared across treatment groups using 2 methods. First, numbers of cells in each class were analyzed as a binomial outcome using 200 trials for each participant; this analysis inflates standard errors to reflect unmeasured heterogeneity across participants.11 Second, classification of each of the 200 cells was analyzed as an ordinal outcome using a proportional odds model adapted to repeated measures by means of generalized estimating equations (GEE)12 (Table 3). These models were implemented in SAS 8.2 (SAS Inc, Cary, NC).
Cox proportional hazards models were used to identify independent predictors of vaginal bleeding or spotting, whereas normal logistic models for repeated binary measures13 were used to examine predictors of proliferation seen on endometrial biopsy specimens. These analyses were performed using Stata 8 (Stata Corporation, College Station, TX).
Participants were previously described by treatment group.10 Treatment groups did not differ in demographics or gynecologic history at baseline, but baseline lumbar spine bone mineral density in the treatment group was about 2% lower than in the placebo group. Mean (± standard deviation) age of participants was 67 (± 5) years, 92% were white, mean body mass index was 28 (± 5.3) kg/m2, and mean age at last menstrual period was 50.2 (± 4.6) years. Information about previous estrogen use was not collected.
In the estradiol group, 191 (91.8%) of the women completed follow-up, and 173 (83.2%) continued to receive the study patch for the full 2 years. In the placebo group, 185 (88.5%) completed follow-up, and 161 (77.0%) continued to receive the study patch for the full 2 years. The study patch was discontinued in 10.1% of the estradiol group and in 10.0% of the placebo group because of adverse events. Baseline endometrial biopsy was completed in all but 1 participant, and all tissue samples obtained were normal.
Table 1 shows the consensus histologic diagnosis for endometrial biopsies performed during 2 years of follow-up. Of the 209 women randomized to the ultralow-dose estradiol group, 189 had at least 1 postbaseline biopsy result, as did 177 of the 208 women randomized to the placebo group. The percentage of women with either benign or atrophic endometrium was similar in the estradiol and placebo groups (83.5 versus 86.4%; P = .5). Follow-up biopsy specimens showed proliferative endometrium in 16 (8.5%) of the women in the estradiol group compared with 2 (1.1%) in the placebo group (P = .06). Of the 11 women in the estradiol group who had a biopsy after the biopsy showing proliferation (Fig. 1), none had progressively higher histologic diagnoses, and 9 (82%) reverted to having benign, nonproliferative histology. These results occurred despite the fact that all 11 women continued estradiol therapy. In both cases of proliferation at 12 months in the placebo group, the histology had reverted to benign nonproliferation at 24 months. Women who had vaginal bleeding within 90 days before biopsy were more likely to have proliferation than those without bleeding (odds ratio 9.5, 95% CI 1.1–84, P = .04). Age, number of years since menopause, body mass index, percentage of superficial vaginal cells, and baseline estradiol levels did not predict development of endometrial proliferation, but power for this analysis was limited by the small number of events.
Endometrial hyperplasia developed in a 63-year-old woman in the estradiol group but not in the placebo group. The affected woman had no previous estrogen use and no bleeding or spotting during the study. She had benign baseline endometrial histology with strips of benign surface endometrium. Her 1-year follow-up biopsy results showed atrophic endometrium; 2-year follow-up biopsy results showed focal atypical hyperplasia, no endometrial stroma between the endometrial glands, and no evidence of malignancy. The study drug regimen was stopped, and 10 mg of medroxyprogesterone acetate was given twice daily for 3 months. Follow-up endometrial biopsy results were normal (atrophic endometrium) after the course of medroxyprogesterone and again 6 months later.
Adenosarcoma of the uterus developed in a 67-year-old woman in the estradiol group who had no abnormal gynecologic history and received conjugated equine estrogens for 10 years before being enrolled in the study. At baseline and at 1-year follow-up, endometrial biopsy results showed atrophic endometrium. Vaginal spotting developed during the last month of the study, and results of routine, 2-year follow-up biopsy showed an endocervical polyp with atypical stroma and adenosarcoma with areas of rhabdomyosarcomatous differentiation. The pathology report obtained after subsequent hysterectomy also showed noninvasive uterine adenosarcoma and atrophy of the uterine lining.
The proportion of women who reported vaginal bleeding during the first year of the study was low (5–6%) and was similar in treatment and placebo groups (Fig. 2A). At 2-year follow-up, bleeding was reported by 12.4% of women in the estradiol group and by 8.6% in the placebo group (P = .3). Of the 37 women who reported bleeding, 18 (49%) bled for 1 or 2 days, and 25 (68%) bled for 5 or fewer days. The number of days of bleeding did not differ between subgroups of women receiving treatment (data not shown). More women in the estradiol group (14.6%) than in the placebo group (10.0%) reported either bleeding or spotting during the first year of the study (Fig. 2B), but this difference was not statistically significant (P = .2). During the total 2 years of follow-up, 23.7% of women in the estradiol group and 14.6% in the placebo group reported bleeding or spotting (P = .03). Among women in the estradiol group, 3 clinical variables (younger age [< 65 years], longer interval since menopause [> 15 years], and obesity [body mass index > 28]) plus 1 laboratory value (lower baseline estradiol level [< 5 pg/mL]) were each associated with greater likelihood of spotting or bleeding (Table 2). Among women with none of the 3 clinical variables, no women reported bleeding or spotting, compared with 42% of those with all 3 clinical variables (Fig. 3). Younger age, longer interval since menopause, and obesity also tended to predict vaginal bleeding, but statistical power to demonstrate this association was low because only a small number of women reported bleeding.
Vaginal epithelial cells showed a pattern of greater maturation in the estradiol group than in the placebo group (P < .001; Table 3). In the placebo group, parabasal cells predominated (65%), whereas intermediate cells predominated in the estradiol group (73%). Among women in the estradiol group, 29.2% showed more than 5% superficial cells, whereas only 10.2% of the placebo group had this finding (P < .001). However, the mean number of superficial cells in each group of women was low.
In this study, 2 years of treatment with ultralow-dose unopposed estradiol did not increase the rate of endometrial hyperplasia. Treatment resulted in endometrial proliferation in about 1 in 12 women, but this finding resolved spontaneously in most. The rate of vaginal bleeding of 1 or more days was similar—about 1 in 8—in treatment and placebo groups. Compared with placebo, estradiol treatment was associated with a pattern of greater vaginal cell maturation that was substantially less extensive than typically observed with standard-dose estrogen therapy.
The single case of atypical hyperplasia (0.5%) observed in the estradiol-treated group was identified at a routine endometrial biopsy done at 24-month follow-up. This woman had atrophic endometrium at the routine 12-month assessment and had no bleeding during the trial. Although we cannot determine the cause of hyperplasia in this woman, these features suggest that the hyperplasia may have occurred de novo and not in response to estrogen stimulation. The case of uterine adenosarcoma in the estradiol-treated group was probably not related to estrogen treatment, because the adenosarcoma arose adjacent to an atrophic endometrium. Because uterine sarcoma is rare (approximately 2 cases per 100,000 population per year) and because adenosarcoma represents only 8% of this category of tumors,14 association with estrogen use cannot be directly assessed.
To our knowledge, only one other randomized trial15 evaluated the gynecologic effects of an ultralow dose of estrogen, but that study used long-cycle progestin opposition. In 167 postmenopausal women with a uterus who were randomized to placebo or to 0.25 mg/d of oral micronized 17β estradiol, opposed every 6 months by 14 days of 100 mg of micronized progesterone, one case of hyperplasia occurred in each treatment group during a 3-year period.15
We cannot make direct comparisons, but finding that the annual rate of hyperplasia was less than 1% among women treated with ultralow-dose estradiol suggests that this dose may result in less endometrial stimulation than half-dose unopposed estrogen, defined as the equivalent of 0.3 mg of conjugated equine estrogens. Hyperplasia developed in 1.7% of 59 postmenopausal women with a uterus during their 2-year treatment with 0.3 mg unopposed esterified estrogens,16 whereas women in the same trial who were assigned to receive 0.625 mg of unopposed esterified estrogens had a 28% cumulative 2-year hyperplasia rate. In another trial,17 hyperplasia developed in 3.2% of 63 women treated for 2 years with 0.3 mg of unopposed oral conjugated equine estrogens. That trial showed a clear relation between dose of estrogen and risk of endometrial hyperplasia; by the end of the 2-year study, cumulative incidence of hyperplasia was 0% in women receiving placebo, 3.2% in women receiving 0.3 mg of unopposed conjugated equine estrogens, 14.9% in women receiving 0.45 mg, and 27.3% in women receiving 0.625 mg.17
The rate of hyperplasia in the estradiol group in our study was similar to the rate found in studies of combined estrogen and progestin. For example, during the 3-year Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, hyperplasia was seen in 6 (5.1%) of the women assigned to receive 0.625 mg of conjugated equine estrogens plus monthly cyclic medroxyprogesterone acetate and in 1 (1.0%) of the women assigned to receive conjugated equine estrogens combined with 2.5 mg of medroxyprogesterone acetate daily.18
Proliferative change is an extremely sensitive measure of estrogen’s effect on the endometrium. At some point during the 2-year study, biopsy specimens showed proliferative changes in 16 women in the ultralow-dose estradiol group compared with 2 women in the placebo group. However, the histology in most of these cases reverted to nonproliferation despite continued estradiol treatment. One possible reason for this phenomenon is that continuous exposure to very low doses of estradiol could stimulate endometrial estrogen receptors but that continued exposure may down-regulate these receptors. In addition, our finding of an association between proliferation and vaginal bleeding supports the idea that women who have bleeding while following this regimen should have endometrial evaluation.
Other studies of ultralow-dose estrogen therapy did not report rates of proliferative change, but some reported endometrial thickness as a surrogate measure. In a 12-month trial conducted among 60 postmenopausal women, use of a vaginal ring delivering 7.5 μg of estradiol every 24 hours increased serum estradiol levels only slightly without increased endometrial thickness.19 During a 3-year trial of 0.25 mg oral micronized 17β estradiol daily,15 mean endometrial thickness exceeded 5 mm in about 10% of women receiving placebo and in 12% of women receiving estradiol.
We found only moderate estrogenic effects on the vaginal epithelium (manifested by some shift from parabasal to intermediate cells) and only a 4% difference between placebo and estradiol groups in mean number of superficial cells. Our findings are difficult to compare with those of other studies because our study lacked baseline values and because ages differed between cohorts in our study and other studies. In a study of 71 early postmenopausal women treated with 0.3 mg oral unopposed synthetic conjugated estrogens,20 mean percentages of superficial cells increased from 2% at baseline to 16% at 16 weeks, whereas the percentages of parabasal cells decreased from 23% to 2%. In a 2-year randomized trial in which women received a range of doses of conjugated equine estrogens,21 use of 0.3 mg and 0.45 mg resulted in a median increase of about 10–12% above baseline in vaginal maturation value (superficial cells divided by the sum of parabasal and intermediate cells) compared with an increase of about 20% among women assigned to receive the 0.625-mg dose. Although lack of a relation between vaginal maturation and atrophic vaginal symptoms has been reported,22,23 additional studies are needed to determine whether symptomatic women would benefit from receiving ultralow-dose estradiol.
Vaginal bleeding is a major factor adversely affecting adherence to long-term HT.24 During our study, participants had a low rate of vaginal bleeding despite careful daily monitoring with bleeding diaries, and the treated and placebo groups showed no significant differences in rate of vaginal bleeding. Among postmenopausal women receiving placebo in 2 clinical trials of estrogen therapy,25,26 annual rates of reporting of vaginal bleeding using daily diaries were 7%25 and 12%;26 these rates resembled the 5% annual rate of bleeding reported in our study. We found that women were twice as likely to report vaginal spotting or bleeding than to report bleeding alone and that ultralow-dose estradiol use was associated only with an increase in reported vaginal spotting or bleeding. Although bleeding or spotting was more likely to occur in women treated with ultralow-dose estradiol than in women who received placebo, this difference did not result in greater rates of discontinuing the study medication.
Our study has the advantages of a large randomized trial with excellent follow-up and participant adherence to assigned regimens. In our study, the number of subjects receiving unopposed estrogen who were monitored for endometrial abnormalities exceeds by 2- to 3-fold the largest published studies of endometrial safety of unopposed estrogen regimens.15–18 We can confidently report the rates of proliferation and hyperplasia because almost 90% of the participants in our study had an endometrial biopsy during follow-up. However, we monitored participants for only 2 years, and our cohort was too small for us to exclude the possibility of a change in incidence of endometrial cancer. The risk of endometrial cancer among women taking exogenous unopposed estrogen is duration-dependent.9 Estimates are that many years are required for simple hyperplasia to progress to complex-atypical endometrial hyperplasia and ultimately to adenocarcinoma.27
Can low doses of estrogen be safely used unopposed? Low-dose unopposed estrogen (0.3 mg esterified estrogens or 0.3 mg conjugated equine estrogens) was associated with endometrial hyperplasia in 2–3% of women treated for 2 years.16,21 Although these rates are considerably lower than for standard-dose unopposed estrogen, they are high enough to warrant addition of progestin or careful endometrial monitoring. Use of ultralow-dose transdermal estradiol resulted in 0.5% endometrial hyperplasia among women treated for 2 years—a rate similar to the rate seen among women using standard-dose estrogen combined with progestin.17 However, we lack long-term clinical trial or epidemiologic data regarding the safety of unopposed ultralow-dose estrogen. Our results should be replicated and extended to longer-duration treatment, but current data suggest that women using ultralow-dose transdermal estradiol therapy may not need treatment with progestins or frequent uterine monitoring. Although we did not observe endometrial pathology among women who had bleeding during the study, we recommend that unexpected bleeding among women using ultralow-dose estrogen be evaluated with either biopsy or transvaginal ultrasonography consistent with the standard protocol for evaluating postmenopausal bleeding. Until additional data are available, we recommend also that women be given transvaginal ultrasonography or biopsy for evaluation of the endometrium after 2 years of treatment.
In this study, 2 years of treatment with unopposed ultralow-dose estradiol did not increase rates of endometrial hyperplasia and was associated with little proliferative effect on the endometrium. Vaginal bleeding was uncommon, and its incidence did not differ between active and placebo groups. This new HT option can prevent bone loss by reducing bone turnover.10 Its apparent lack of endometrial stimulation suggests that this HT option should be acceptable as long-term therapy and might be used unopposed by progestin.
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