Despite the long-term beneficial effects of hormone replacement therapy (HRT) in postmenopausal women, adherence to treatment has been poor.1,2 Women cite the return of menstrual-like cycles and the inconvenience of irregular bleeding as major reasons for stopping treatment.2–4 Continuous-combined HRT regimens, characterized by daily concomitant and continuous administration of an estrogen and a progestogen, are an option for postmenopausal women who wish to avoid the monthly bleeding associated with sequential HRT regimens.5
Although continuous-combined regimens do not cause monthly withdrawal bleeding, unanticipated bleeding episodes can occur during treatment.6,7 These bleeding episodes have been shown to be more prevalent during the initial months of therapy and tend to decrease over time, as most women stop bleeding.6–11 The factors or mechanisms involved in bleeding during continuous-combined therapy are not well understood. There is evidence that bleeding during the initial year of continuous-combined therapy reflects the endometrial adaptation to therapy rather than the presence or development of endometrial abnormalities.12 Although these bleeding episodes are not related to pathology, they could affect women's adherence to therapy. Reduction of the bleeding incidence might therefore constitute an important factor in compliance.
Previous reports have shown that the bleeding associated with oral continuous-combined HRT is related to the doses of both the estrogen and progestogen components.7,8,13 However, less is known about the differential effects on the bleeding profile between clinically equivalent doses of different types of estrogens and progestogens. The bleeding profile associated with the marketed continuous-combined regimens of 0.625 mg of conjugated equine estrogens and low doses of medroxyprogesterone acetate has been described previously,7 but more data are needed on the bleeding profile of continuous-combined formulations with other estrogen and progestogen components.
Norethindrone acetate produces characteristic endometrial morphologic changes and induces more marked atrophy of the endometrium compared with other progestogen derivatives of progesterone.14 At low doses of 0.1, 0.25, and 0.5 mg, and when given in a continuous-combined manner with estradiol (E2) 1 mg, norethindrone acetate can markedly reduce the 12-month incidence of endometrial hyperplasia associated with unopposed E2 1 mg (RJ Kurman, personal communication). Although these combinations appear to provide adequate endometrial protection, the bleeding profile of each dose might differ and thereby influence adherence to treatment. The current study assessed the bleeding profile of continuous-combined formulations of E2 1 mg and low doses of norethindrone acetate in a large prospective study of postmenopausal women.
Materials and Methods
This was a prospective, double-masked, randomized, parallel-groups study with a duration of 12 months (a month was defined as a 28-day period and was equivalent to a cycle) conducted in 40 centers in the United States. The investigators are listed alphabetically as members of The Endometrium Study Group. The study was approved by the institutional review board at each center.
Subjects who volunteered to participate in this study gave written informed consent and were considered eligible if they met the following criteria: healthy women 45 years of age or older with an intact uterus, a minimum of 12 months past menopause, and serum E2 less than or equal to 25 pg/mL. Subjects were ineligible for the study if they met any of the following criteria: treated with estrogen within the past 12 weeks or with estrogen-progestogen combinations within the past 8 weeks; known, suspected, or history of hormone-dependent tumors or cancers; known or suspected endometrial hyperplasia at the study entry biopsy (or, when endometrial biopsy could not be obtained, an endometrial thickness greater than 4 mm by transvaginal ultrasound); abnormal vaginal bleeding of unknown origin; more than 30% above ideal body weight; known deep vein thrombosis, active thrombophlebitis, thromboembolic disorder, cerebrovascular accident, or history of those conditions; myocardial infarction or ischemic heart disease within the past 6 months; systolic blood pressure over 160 mmHg or diastolic blood pressure over 100 mmHg, treated or untreated; presence of any endocrine disorder except controlled thyroid disease; known alcohol or drug abuse; or known smoking habit of one pack or more per day. During the study, subjects were not allowed to use glucocorticoids (except topical preparations), any other estrogen or progestogen products, or any drug known to influence estrogen metabolism.
The randomization code was generated using a block size of eight to ensure equal distribution of the treatment groups across study sites. At each site, subjects were assigned to the lowest available randomization number. Subjects were randomly assigned equally to one of the following four treatment groups: unopposed E2 1 mg, continuous-combined E2 1 mg and norethindrone acetate 0.1 mg, continuous-combined E2 1 mg and norethindrone acetate 0.25 mg, or continuous-combined E2 1 mg and norethindrone 0.5 mg. All study drugs were in tablet form and identical in appearance. The study drugs were manufactured, supplied, and identically packaged by Novo Nordisk A/S, Bagsvaerd, Denmark. The women were instructed to take a single tablet orally, once daily, preferably at bedtime. The duration of treatment was 12 months (cycles of 28 days).
Vaginal bleeding data were assessed based on the daily bleeding information recorded by each woman. Data were recorded through a touch-tone telephone into the Interactive Voice Response System (Covance, Princeton, NJ) at least once per week. This voice response system sent reminder calls to women who failed to report the bleeding data after a 2-week period. Each woman reported the bleeding data for each day as either no bleeding or spotting, bleeding, or spotting. Bleeding was defined as release of uterine blood that required sanitary protection, while spotting was defined as release of uterine blood that did not require sanitary protection.
A bleeding episode was defined as a period of 1 or more consecutive days of bleeding or spotting separated by at least 1 day of no bleeding or spotting. The number of episodes and duration of each episode for a given period were calculated for each treatment group. All months (cycles) were classified into one of the following categories: month with no bleeding, month with bleeding (with or without spotting), or month with spotting only (no bleeding). The bleeding incidence for a specific month was defined as the percentage of women who had at least 1 day of bleeding or spotting during that month.
Women were considered late initiators of bleeding if they reported at least 1 day of bleeding or spotting after having no bleeding or spotting during the initial 6 months of treatment. The distribution of women reporting at least one bleeding or spotting episode during the study was tabulated for early postmenopausal women (1 to 3 years since last menses) and for late postmenopausal women (more than 3 years since last menses) according to treatment group.
For the statistical analyses, pairwise comparisons between treatment groups in the number of women who discontinued from the study and in the number of women who discontinued due to bleeding were analyzed by Fisher exact test using a significance level of .05. Descriptive statistics were used for the rest of the bleeding parameters.
The subject randomization group and demographic characteristics of the population in this study are summarized in Table 1. A total of 1176 postmenopausal women with an intact uterus and a mean age of 56 years were enrolled. The distribution of women according to time since last menses was similar among treatment groups, with approximately one third of the women reporting less than 3 years since last menses, one third reporting 3 to 7 years since last menses, and one third reporting more than 7 years since last menses. The discontinuation rate in the unopposed E2 1 mg group (28%) was significantly (P < .05) higher than discontinuation rates in each of the combination groups (19%, 17%, and 21% for the norethindrone acetate 0.1, 0.25, and 0.5 mg groups, respectively). The main reasons for discontinuation from the study are included in Table 1. The single most common reason for discontinuation was the presence of adverse events related to vaginal bleeding. A significantly (P < .05) lower discontinuation rate due to bleeding was observed in the norethindrone acetate 0.5 mg group (1.7%) compared with the unopposed E2 1 mg group (10.5%) and with the norethindrone acetate 0.1 mg (5.4%) and norethindrone acetate 0.25 mg (4.5%) combination groups.
The Interactive Voice Response System enhanced the women's compliance in recording daily bleeding information. Approximately 97% of all possible bleeding data points were obtained, and bleeding data equivalent to a total of 12,230 months were available for analysis. The overall distribution of months (cycles) with no bleeding, bleeding (with or without spotting), and spotting (without bleeding), as well as the incidence of no bleeding at months 2, 5, 8, and 11, are presented in Table 2. The percentage of months (cycles) with no bleeding decreased over time in the unopposed E2 1 mg group, whereas it increased in all combination groups. The increase was more marked with increasing doses of norethindrone acetate.
As shown in Figure 1, the incidence of bleeding in the participants (with or without spotting) was relatively low in all combination groups throughout the study, including during the initial months of treatment. The incidence of bleeding (with or without spotting) ranged from 24% to 28% during the first 3 months of treatment in the combination groups. After that, the percentage of women who had bleeding (with or without spotting) decreased over time with norethindrone in a dose-dependent manner. At the end of the 12-month treatment period, 75%, 79%, 84%, and 90% of the women reported no bleeding in the unopposed E2 1 mg, norethindrone acetate 0.1, 0.25, and 0.5 mg groups, respectively. The E2-norethindrone 0.5 mg group had the largest decrease in bleeding compared with the other combination groups, with only 10% of the women in that group reporting bleeding (with or without spotting) during the last month of treatment. Of these women, only 3% were actually bleeding whereas the rest were spotting. For the E2-norethindrone acetate 0.5 mg group, spotting only was the most prevalent form of bleeding after 6 months of treatment. The percentage of women bleeding (excluding spotting) at months 3, 6, 9, and 12 is shown in Figure 2.
Approximately 50% of the women in each treatment group did not report any bleeding or spotting during therapy. Among early postmenopausal women (1 to 3 years since last menses), fewer women in the norethindrone acetate 0.5 mg group reported bleeding during the study compared with the other two lower-dose combination groups. For late postmenopausal women (more than 3 years since last menses), differences in bleeding among the three combination groups were less noticeable (Figure 3). Late initiation of bleeding (ie, after 6 months of no bleeding) was approximately 3% in the women in both the norethindrone acetate 0.25 and 0.5 mg combination groups, whereas it was 7% in the norethindrone acetate 0.1 mg group and 16% in the unopposed E2 1 mg group.
The distribution of data for the number and duration of bleeding episodes was skewed (Table 3), because most bleeding episodes were of short duration and some episodes were of extended duration. In women who reported bleeding of any type, the median number of episodes throughout the study was two to three episodes for each 3-month period, irrespective of treatment group. The mean duration of bleeding episodes in the unopposed E2 1 mg group increased over time, but the median duration of 3 days remained unchanged. The median duration of bleeding episodes for the norethindrone acetate 0.1 and 0.25 mg groups was 4 days for the initial 3 months (cycles) and 5 and 4 days, respectively, for the last 3 months; for the norethindrone acetate 0.5 mg group, the median duration was 3 days for the initial 3 months and 2 days for the last 3 months (Table 3).
Continuous-combined HRT formulations of E2 1 mg and low doses of norethindrone acetate ranging from 0.1 to 0.5 mg were associated with a low incidence of vaginal bleeding throughout this 12-month study, including during the initial months of treatment. The data indicate an improvement in bleeding profiles with increasing doses of norethindrone acetate. The results of this study confirm that unwanted bleeding is an important issue for treatment adherence, as it was the most frequently reported reason for study discontinuation. The differences in bleeding incidence between the combination groups appear small but are clinically relevant because the group with the best bleeding profile, the norethindrone acetate 0.5 mg combination group, was associated with the lowest percentage of women discontinuing due to bleeding.
The difference in bleeding profiles observed between women treated with unopposed E2 1 mg and those treated with combinations of E2 1 mg and norethindrone acetate suggests different mechanisms of bleeding for unopposed estrogen and continuous-combined therapy. The incidence of bleeding in the unopposed E2 1 mg group increased over time and could be attributed to the expected increase in endometrial stimulation and the number of endometrial abnormalities associated with unopposed estrogen therapy. The bleeding observed during the initial 3 months of continuous-combined HRT could reflect endometrial adjustment,12 and in this study was independent of the amount of norethindrone acetate. Factors other than the dose of progestogen, such as the dose13 or the endometrial potency of the estrogen component, might be more important for initial bleeding with continuous-combined HRT. After the initial 3 months of treatment, a marked decrease in the incidence of bleeding was observed in the norethindrone acetate combination groups in an apparent dose-dependent manner. This observation is consistent with several other reports that found a higher dose of progestogen reduced the incidence of bleeding.7,8,13
In this study, approximately half of the women who received unopposed E2 1 mg or continuous-combined therapy with estradiol and norethindrone acetate did not have any spotting or bleeding. The proportion of women who had bleeding at least once during therapy appeared to be independent of the presence and dose of progestogen. This finding suggests that the risk of a woman bleeding during HRT might reflect, in part, an individual predisposition to bleed. Further research is needed to identify which factors determine a woman's risk of bleeding during therapy. It has been suggested that the risk of bleeding during continuous-combined HRT decreases with increasing number of years after menopause.7 In the present study, the effect of the norethindrone acetate dose on bleeding appeared to be greater when the last menses occurred less than 3 years before initiation of therapy. In this high-risk group of women close to menopause, treatment with the highest norethindrone acetate dose resulted in the lowest percentage of women who had bleeding for all combination groups. For women whose last menses occurred more than 3 years before initiation of therapy, the norethindrone acetate dose had less effect on bleeding. Our findings support the use of continuous-combined formulations with a relatively higher progestogen dose for women who initiate treatment closer to menopause. For women further beyond menopause or for women at less risk of bleeding, the effect of the norethindrone acetate dose on reducing bleeding might be less relevant.
Late initiation of bleeding is of clinical concern, as it can increase the suspicion of endometrial abnormality. Late initiation was infrequent in the combination groups; when individual cases with late initiation were examined, we found no relationship to the presence of endometrial abnormalities. Most women in the combination groups who reported bleeding during the last 3 months of treatment also reported bleeding during the initial 3 months of therapy.
Our results show that continuous-combined formulations of E2 1 mg with norethindrone acetate 0.1, 0.25, or 0.5 mg are associated with a low incidence of bleeding during the initial 3 months of treatment and beyond. Norethindrone acetate decreases the incidence of bleeding after the initial 3 months of treatment in what appears to be a dose-dependent manner. During continuous-combined HRT with E2 and norethindrone acetate, the proportion of women had no bleeding increased steadily over time, and late initiation of bleeding was infrequent. The effect of higher progestogen dose was most favorable in women who initiated therapy close to menopause. The present study contributes to a better characterization of the bleeding profile associated with continuous-combined HRT.
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