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ORIGINAL RESEARCH

Hormone Replacement Therapy

Effect of Progestin Dose and Time Since Menopause on Endometrial Bleeding

ARCHER, DAVID F. MD; PICKAR, JAMES H. MD

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Hormone replacement therapy (HRT) provides substantial long-term health benefits, such as prevention of osteoporosis and reduction of cardiovascular disease risk, in addition to relief of menopausal vasomotor symptoms and urogenital atrophy.1–5 Studies have also suggested that HRT may improve cognitive function,6,7 prevent or delay the onset of Alzheimer disease,8,9 and reduce rates of colorectal cancer10–12 and mortality.13–16 Despite these potential benefits, compliance with HRT is reportedly low, in large part because of irregular or withdrawal bleeding.17–20 In a recent prospective study, bleeding was the reason most often cited for discontinuation of HRT among women with intact uteri (n = 100).21 An earlier survey of 1330 postmenopausal women receiving transdermal estrogen also found that bleeding was the chief reason for discontinuation, cited by 34% of those stopping treatment.22 Combining conjugated equine estrogens (CEE) with medroxyprogesterone acetate (MPA) in a continuous regimen has been demonstrated to relieve the symptoms of menopause,23 prevent osteoporosis, and improve lipid profiles4,24 while providing an acceptable bleeding profile.23

A large, randomized, double-masked, prospective, multicenter clinical trial was conducted to examine the safety and efficacy of continuous and sequential regimens of CEE plus 2.5 mg or 5.0 mg of MPA daily.23,25,26 The primary end point was the incidence of endometrial hyperplasia at 1 year.26 In our analysis of bleeding data from that trial, we observed that bleeding patterns with different doses of MPA in a continuous combined HRT regimen varied depending on the time since a woman's last menstrual period (LMP).23 The highest rates of amenorrhea were achieved in women who had undergone natural menopause 3 or more years ago. This finding is supported in the study by Archer et al,27 who found that the dose of norethindrone acetate used in a continuous combined HRT regimen with 17β-estradiol had less effect on bleeding in women more than 3 years from their LMP. These findings have important ramifications for compliance with HRT, because an HRT regimen that provides an acceptable bleeding profile for women early in menopause may enhance compliance. Therefore, using data from our original study on bleeding patterns with the two continuous combined therapies only,23 we present a retrospective analysis of bleeding patterns based specifically on time since menopause. We compared bleeding profiles between women who were 3 years or less from their LMP and women more than 3 years from their LMP. This additional knowledge may aid physicians and their patients who are using estrogen plus progestin therapy and are concerned about bleeding frequency.

Materials and Methods

The design and results of the original trial have been reported elsewhere23,25,26 and are reviewed here. Postmenopausal women with intact uteri were enrolled at 99 sites in the United States and Europe. All sites received local institutional approval of the protocol before study initiation. Recruitment numbers among the sites ranged from 1 to 73 patients. Twenty-three sites recruited 25 or more patients each, amounting to 50% of total patients enrolled (1724). Six sites recruited more than 40 patients. The reported bleeding data were similar for the largest recruitment sites compared with the other sites.

Women 45 to 65 years of age were eligible for participation in this study if they had had their last menstrual cycle at least 12 months before entering the study. Their serum screening FSH level had to be above the minimum limit set for postmenopausal women at each laboratory. Women whose reproductive organs were not intact were excluded from the study, as were women with cardiovascular or cerebrovascular disorders; any neoplasia; hypertension; renal or liver disease; endometrial hyperplasia; dysplasia; gallbladder disease; neuroocular disorders; malabsorption disorders; obesity; or a history of alcohol or drug abuse. Women were also excluded if they had used any oral medication containing estrogen or progestin within the 2 weeks before prestudy screening, or within 3 months before prestudy screening for patients who participated in the metabolic study, if they had used an intrauterine device within the past 3 months, or if they smoked more than 15 cigarettes per day.

Conjugated equine estrogens and MPA were supplied to the investigators by Wyeth-Ayerst Laboratories in 28-day-dose packs with double-mask precautions. A computerized, SAS-based (SAS Institute, Inc. Cary, NC) randomization schedule provided by Wyeth-Ayerst was used to generate the randomization table used for treatment group assignment. Medication for each patient was packaged and labeled with the code number to assure randomization. Individual patient randomization envelopes were provided to the investigators so that in the event of an emergency, the appropriate envelope could be opened to identify the drug. At the completion of the study, all envelopes were returned to Wyeth-Ayerst. Informed consent was obtained from all subjects before participation.

Medical monitors and clinical associates from Wyeth-Ayerst Laboratories trained the investigative site personnel in the use of forms and reviewed the protocol with them. During the study, the monitors and associates periodically visited each site to ensure that complete and accurate data were being monitored. Each case report form returned to Wyeth-Ayerst from the sites was thoroughly reviewed, and any missing or contradictory data were clarified by the investigators before entry. Missing data and inconsistencies were identified through a computerized editing procedure. The biostatician, data coordinator, and computer programmer proofread and reviewed the data processing reports to ensure that they were understandable, complete, and reliable.25,26,28

Safety was monitored by performing physical examinations, Papanicolaou smears, and clinical laboratory determinations before treatment and during cycles 6 and 13 of treatment; mammography at the screening examination and during cycle 13; and measurement of vital signs during screening and cycles 3, 6, 9, and 13. The investigators reviewed all laboratory results that were outside the normal range. Any serious or unexpected adverse experience and death from any cause was immediately reported. The goal for total enrollment was 1350 patients; approximately 1750 were recruited, and 1724 patients were enrolled in the estrogen alone and four estrogen-progestin groups. Only the patients in the two estrogen-progestin continuous combined treatment groups are considered in this analysis.

Six hundred seventy-eight patients were randomly assigned to receive oral CEE (0.625 mg/day) in combination with MPA, 2.5 mg/day (n = 340) or 5.0 mg/day (n = 338) in a continuous treatment regimen. Patients were instructed to take one CEE tablet and one MPA capsule at approximately the same time each day. Upon completing one pack, the patient was to start a new pack of medication on the next day with no interruption in treatment. Missed tablets and capsules were to be returned to the investigator at the next visit.

The 1-year treatment was divided into thirteen 28-day cycles. All patients underwent three scheduled endometrial biopsies, one at baseline (before treatment) and two during days 22 to 28 of cycles 6 and 13. If possible, specimens were taken from the anterior and posterior walls of the uterus. Additional unscheduled biopsies could be performed at the physicians' discretion. If a biopsy indicated endometrial hyperplasia, the patient was withdrawn from the study.

Any bleeding or spotting that occurred on the day of the procedure or within 6 days after biopsy was not considered in our analysis of irregular bleeding. Irregular bleeding was evaluated at baseline, cycle 3, cycle 6, and after 1 year. Patients were given daily diary cards on which to record the occurrence of vaginal bleeding or spotting. Bleeding was defined as the release of uterine blood that required sanitary protection. Spotting was defined as the release of uterine blood that did not require sanitary protection. Patients were also asked to record the length of any bleeding episodes. A bleeding episode was defined as a sequence of bleeding days bounded by 1 day of no bleeding.

Bleeding data for all patients who completed 1 year of therapy were analyzed. We excluded patients for whom bleeding data through all 13 cycles were not complete. The number and percentages of women in each treatment group who did not experience bleeding were tabulated after cycle 3, after cycle 6, and at 1 year of treatment. Bleeding profiles were compared between MPA doses and between women who were 3 years or less from their LMP and those who were more than 3 years from their LMP. The Fisher exact probability test was used to compare rates between groups. The chi-square test was used to compare the frequency distribution of the number of days of bleeding between groups. Significance was set at P < .05.

Results

A total of 281 patients in the 2.5 mg/day MPA group and 277 patients in the 5.0 mg/day MPA group (approximately 82% of persons enrolled in each group) completed the study. The demographics of the patients who completed the study are summarized in Table 1. Of those patients who withdrew from the study in either group, 33% discontinued because of adverse reactions, 33% because of other reasons, 18% because of patient request, and 17% because of protocol violation. The demographic characteristics of persons who dropped out did not differ from those of persons who completed 13 cycles of therapy. Bleeding data were completed for 277 and 276 patients, respectively, but because the date of LMP was not available for one woman in each group, data were analyzed for 276 and 275 women. Approximately one third of the women in the two treatment groups were 3 years or less from their LMP at study enrollment (Table 2).

Table 1
Table 1:
Demographic and Baseline Data: Patients Completing Study
Table 2
Table 2:
Number of Patients and Therapeutic Regimen for Which Bleeding Data Were Available for All Treatment Cycles of the 1-Year Study*

The higher dose of MPA and duration of treatment resulted in a lower incidence of endometrial bleeding when all of the women in each treatment group were considered (Table 3). By the end of cycle 3, 68% of patients in the 2.5 mg/day MPA group and 83% of women in the 5.0 mg/day MPA group experienced no bleeding (P < .001). The occurrence of endometrial bleeding continued to decline throughout the study period. After 1 year, 90% of women in the 2.5 mg/day MPA group and 94% of women in the 5.0 mg/day MPA group reported having no bleeding; these differences were not statistically significant (P = .089). The incidence of irregular spotting also decreased over time, concomitant with the decrease in bleeding (data not shown).

Table 3
Table 3:
Frequency of Lack of Bleeding by Treatment Regimen and Treatment Duration: Patients With 13 Cycles of Bleeding Data

Among women 3 years or less from their LMP, the proportion who reported an absence of bleeding after three cycles was greater in the 5.0 mg/day MPA group (72.4%) than the 2.5 mg/day MPA group (59.0%; P < .001). These proportions in the 5.0 mg MPA group compared with the 2.5 mg MPA group were also higher at cycle 6 and after 1 year, although these differences were not statistically significant (Table 3). After 1 year, 88% of these women in the 2.5 mg/day MPA group and 92% of those in the 5.0 mg/day MPA group reported an absence of bleeding.

Among women more than 3 years from their LMP, the proportion of those who reported no bleeding also increased over time and was influenced by MPA dose (Table 3). At cycle 3 and cycle 6, a higher proportion of women in the 5.0 mg/day MPA group than in the 2.5 mg/day MPA group reported no bleeding (P < .001). After 1 year, the proportion of women more than 3 years from their LMP who reported no bleeding was similar in the 2.5 mg/day and 5.0 mg/day MPA groups (90.7% and 94.7%, respectively).

Significantly more women in the 5.0 mg/day MPA group than in the 2.5 mg/day MPA group reported a lack of bleeding at cycle 3, cycle 6, and over the course of the study (Table 3). The difference at 1 year was not significant. In the 5.0 mg/day MPA group, significantly more women more than 3 years from their LMP reported no bleeding at cycle 3 compared with women 3 years or fewer from their LMP. In both groups, lack of bleeding was reported by significantly more women more than 3 years from their LMP compared with women 3 years or fewer from their LMP over the entire course of treatment.

Bleeding patterns were characterized according to the length of bleeding episodes for women 3 years or fewer from their LMP and those more than 3 years from their LMP (Table 4). Bleeding episodes observed during continuous combined HRT were shorter than normal menstrual periods. For women 3 years or fewer from their LMP, there were no differences between treatment groups in the number of days of bleeding reported at any time. Among women more than 3 years from their LMP, fewer days of bleeding were noted in those in the 5.0 mg/day MPA group than in those in the 2.5 mg/day MPA at the end of 1 year (P = .009). Overall, there was a tendency for fewer days in a bleeding episode with the higher dosage of MPA and with greater time since the woman's natural menopause (Table 4).

Table 4
Table 4:
Summary of the Percentage Bleeding and Number of Days for Women With Bleeding Episodes

Two cases of simple hyperplasia (fewer than 1%) were identified in the 2.5 mg/day MPA group, and no cases were reported in the 5.0 mg/day MPA group; this difference was not statistically significant. We also found no difference in the incidence of endometrial hyperplasia between women who were 3 years or fewer from their LMP and those who were more than 3 years from their LMP.

Discussion

To maximize the short- and long-term benefits of HRT, adherence to therapy is necessary. One of the most common reasons that women discontinue HRT is resumption of menstrual bleeding or occurrence of irregular bleeding.17–20 Strategies to eliminate or reduce menstrual or irregular bleeding have been developed.20,29 Initial HRT regimens were cyclic therapies in which a progestin was added to daily estrogen for 10 to 14 days of each month. Continuous combined therapies were later developed to alleviate the recurrence of scheduled bleeding with the cyclic regimens.29 However, continuous combined regimens can result in unscheduled or irregular bleeding that may also influence compliance with therapy.20,29 We analyzed the effects of progestin dose and time since menopause on the incidence of bleeding with two regimens of continuous combined HRT. Our results may aid physicians in tailoring HRT regimens to minimize irregular bleeding and therefore enhance HRT compliance in postmenopausal women.

Overall, at 1 year, women treated with these continuous combined HRT regimens reported relatively little endometrial bleeding. Women who were more than 3 years past their LMP at enrollment and received the 0.625 mg CEE/5.0 mg MPA combination regimen reported the fewest episodes of endometrial bleeding. By the end of the study, 5% or fewer of the women in this group reported bleeding episodes, and the median duration of each episode was limited to 2 days. Among women more than 3 years from their LMP, reported episodes of bleeding did not differ at 1 year between the 0.625 mg CEE/5.0 mg MPA and 0.625 mg CEE/2.5 mg MPA regimens.

Women who were 3 years or fewer from their LMP reported a higher incidence of bleeding while receiving HRT. However, a trend toward improvement in the bleeding profiles among women receiving either regimen was observed over 1 year of therapy. Among women 3 years or fewer from their LMP, at 1 year, 88% of those receiving the 2.5 mg/day MPA regimen reported no episodes of bleeding compared with 92% of those receiving the 5.0 mg/day MPA regimen; this difference was not statistically significant. However, during cycle 3—an important time for patient compliance—the rate of absence of bleeding was significantly higher in the 5.0 mg/day MPA group (72.4%) than in the 2.5 mg/day MPA group (59.0%). This finding may have significant clinical implications for practitioners who wish to minimize irregular bleeding early in therapy in an effort to improve compliance, because a higher incidence of unscheduled bleeding is observed in the first 3 to 4 months of therapy with continuous combined regimens.20 For women who will be less likely to tolerate irregular bleeding, it may be appropriate to initiate therapy with a 0.625 mg CEE/5.0 mg MPA regimen.

It is well established that addition of a progestin to estrogen replacement therapy minimizes the risk of endometrial cancer.26,30–32 Endometrial protection appears to be improved by using continuous combined HRT.33–35 The use of cyclic progestin for fewer than 10 days per month is associated with an increased incidence of endometrial cancer after 5 years of use.33–35 The data on endometrial safety with the continuous combined regimens used in this study have been reported elsewhere.26 Of importance to both patients and physicians, no cases of endometrial hyperplasia occurred among women treated with 0.625 mg CEE/5.0 mg MPA, and fewer than 1% of the women treated with 0.625 mg CEE/2.5 mg MPA developed this condition. The difference between groups was not statistically significant.

It has been suggested that use of a progestin may mitigate the beneficial effect of estrogen on plasma lipoprotein levels. In a prospective study of a subset of patients from our original trial, the 5.0 mg/day continuous MPA group did not exhibit a significant increase in high-density lipoprotein (HDL) cholesterol level at cycle 6 compared with the group that received CEE alone, whereas the 2.5 mg/day continuous MPA group did.25 There were no other significant differences between the two continuous progestin groups in terms of levels of HDL, low-density lipoprotein, or total cholesterol or triglycerides at any other time.

One of the common adverse events reported with use of a progestin is breast pain. In our original trial, the percentage of patients with breast pain (breast or nipple discomfort, pain, soreness, or tenderness) who were receiving combination therapy was significantly higher than that among patients receiving conjugated estrogens alone.26 Although 32% of the patients in the 2.5 MPA group and 36% of the patients in the 5.0 MPA group reported breast pain, only 18% of the patients in both groups withdrew from the study because of adverse events.

Menopause is a change of major physiologic importance in women's lives. An important and growing body of evidence exists suggesting that the decline in estrogen levels that accompanies menopause contributes to numerous disease processes in aging women. The availability of HRT has enabled women to treat estrogen deficiency and improve their overall health status. The impact of HRT is especially notable given the expansion in life expectancy. Women will live 30 of the currently expected 80-year life span in the postmenopausal state—more than one third of their lifetime. To ensure compliance with HRT during these years, regimens must be efficacious yet minimize potential side effects. Relief of menopausal symptoms, the primary reason why women seek treatment with HRT, is immediate and may encourage compliance. Other benefits of therapy, such as biochemical and physiologic changes, may not be readily discerned by the patient. The proposed cardioprotective effects of estrogen on serum lipids and estrogen's beneficial effects on bone, although of immense long-term importance to health and well-being, fall into this category. Long-term data on the beneficial effects of HRT on these variables are expected from the Women's Health Initiative after 2005. Endometrial bleeding, which may be associated with certain HRT regimens, is readily obvious and may be a deterrent to long-term compliance with therapy. Therefore, it is critical to treat patients with a hormone replacement regimen that will provide them with an acceptable bleeding profile.

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