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ORIGINAL RESEARCH |
From the Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan; and the Oregon Health Sciences University, Portland, Oregon.
Address reprint requests to: James Symons, PhD Parke-Davis Pharmaceutical Research 2800 Plymouth Road Ann Arbor, MI 48105 E-mail: james.symons{at}wl.com
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Abstract |
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Methods: Two randomized clinical trials were conducted in which participants recorded information on the daily occurrence of vaginal bleeding or spotting. In study 1, 219 postmenopausal women reporting at least ten hot flushes per week were randomized to placebo or one of four treatment groups (0.2 mg norethindrone acetate/1 µg ethinyl E2, 0.5 mg norethindrone acetate/2.5 µg ethinyl E2, 1 mg norethindrone acetate/5 µg ethinyl E2, or 1 mg norethindrone acetate/10 µg ethinyl E2). In study 2, 266 postmenopausal women reporting at least 56 moderate to severe hot flushes were randomized to placebo or one of three treatment groups (0.5 mg norethindrone acetate/2.5 µg ethinyl E2, 1 mg norethindrone acetate/5 µg ethinyl E2, or 1 mg norethindrone acetate/10 µg ethinyl E2). The total duration of treatment was 16 weeks in study 1 and 12 weeks in study 2. In both studies, subjects reported in daily diaries whether they had either bleeding or spotting.
Results: In study 1, there was a significantly greater relative risk (RR) for bleeding in the group receiving 1 mg norethindrone acetate/10 µg ethinyl E2 at study weeks 4 and 8 (RR = 1.36 and 95% confidence interval [CI] 1.01, 1.83; RR = 1.37 and 95% CI 1.1, 1.72; respectively) compared with placebo, but not at study weeks 12 or 16. The group receiving 1 mg norethindrone acetate/5 µg ethinyl E2 also had a significantly greater risk at weeks 4 and 8 (RR = 1.5 and 95% CI 1.15, 1.96; RR = 1.33 and 95% CI 1.00, 1.77; respectively), whereas the other dose combinations did not differ from placebo. Results from study 2 were similar to those of study 1.
Conclusion: Although there was a greater risk for bleeding and/or spotting at the higher doses of norethindrone acetate and ethinyl E2, this risk declined over time. If compliance with hormone replacement therapy regimens is influenced at least in part by vaginal bleeding, the combined norethindrone acetate/ethinyl E2 regimen investigated in these studies may provide a treatment option.
Hormone replacement therapy (HRT) has been associated with both short- and long-term benefits including the alleviation of hot flushes, night sweats, and insomnia in hypoestrogenemic women.1–7 Hot flush frequency and severity decline as the time from menopause increases, such that long-term use of HRT is not required. However, menopause also results in the loss of the protective effect that estrogen has on maintaining cardiovascular and bone health. Consequently, postmenopausal women are at greater risk for fracture and cardiovascular disease as the time from menopause increases. Long-term use of HRT decreases the risk of osteoporosis and cardiovascular disease.8–15 However, to optimize this benefit, continued long-term use is considered necessary, and HRT compliance has been shown to be poor.16–19
Vaginal bleeding is frequently regarded as one of the major reasons for noncompliance.20–25 Use of continuous combined HRT decreases the frequency and severity of bleeding. However, many women with bleeding episodes continue to terminate treatment with a variety of combined HRT regimens.26–30 Alternative approaches to control these episodes have focused on varying the dose of either the estrogen or the progestin. These approaches have been inconsistent, and the size of the studies has been a major limitation in interpreting the results.
Therefore, as part of the clinical development program for continuous combined administration of norethindrone acetate and ethinyl estradiol (E2), study participants reported the daily occurrence of vaginal bleeding and/or spotting. Norethindrone acetate and ethinyl E2 provide a range of estrogen and progestin doses such that dose-response relations were examined for the effect of vaginal bleeding. Higher doses of the estrogen component of combined HRT were expected to result in increased reports of bleeding and/or spotting when the progestin dose was held constant.
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Materials and Methods |
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In study 1, 219 postmenopausal women between the ages of 41 and 65 years were enrolled at 11 centers. Women who were amenorrheic and within 5 years of natural menopause were eligible for the trial. Menopausal status was confirmed with an FSH level of at least 40 mIU/mL and an E2 concentration no greater than 40 pg/mL. Women were not eligible for the study if they had a history of any chronic disease, current vaginal bleeding, or endometrial hyperplasia, or if HRT was contraindicated. Duration of treatment was 16 weeks.
In study 2, 266 postmenopausal women between 40 and 62 years of age were enrolled at 24 study sites. Subjects were within 5 years of natural or surgical (bilateral oophorectomy) menopause. Menopause was defined as amenorrhea for at least 1 year, or serum FSH of at least 50 mIU/mL and serum E2 of 25 pg/mL or less if amenorrheic for only 6–12 months. Women were not eligible for the study if they were amenorrheic for less than 6 months, if they had a history of any chronic disease, or if HRT was contraindicated. Duration of treatment was 12 weeks.
Both studies were placebo-controlled, double-masked, parallel-group, randomized clinical trials. Each study center obtained approval for the protocol from their institutional review board before initiation of the study. Women who met all of the inclusion criteria and none of the exclusion criteria and provided written informed consent were randomized to one of the treatment groups. Treatment groups for study 1 were placebo and four combinations of norethindrone acetate and ethinyl E2 (0.2/1, 0.5/2.5, 1/5, or 1/10 mg norethindrone acetate/µg ethinyl E2). Treatment groups for study 2 were placebo and three norethindrone acetate/ethinyl E2 combinations (0.5/2.5, 1/5, or 1/10 mg norethindrone acetate/µg ethinyl E2). Subjects were instructed to take one tablet of study medication daily for the duration of the trial.
Subjects in each study kept daily diaries of menopausal symptoms and vaginal bleeding or spotting. Definitions were provided with each diary. Vaginal bleeding was defined as bleeding similar to menstrual flow requiring a regular-size or large sanitary pad or tampon to prevent saturation of underwear. Spotting was defined as bleeding lighter than normal menstrual flow that may stain underwear, but does not require protection to prevent saturation of underwear. For any week during the studies, women were considered amenorrheic if they experienced no bleeding or spotting.
Time points for statistical analyses in study 1 were defined as 4-week intervals for bleeding, spotting, and bleeding and/or spotting. Statistical analyses for each variable were by week (weeks 4, 8, 12, and 16), comparing rates between the placebo group and the active treatment group. An estimate of the relative risk (RR) of an outcome greater than in the placebo group was assessed by the 95% confidence interval (CI) using the Mantel-Haenszel logit estimator, corrected for center-to-center interaction. All women enrolled in this study had a minimum of ten hot flushes during the week before randomization.
The sample size for this study was based on the ability to detect with a power of 95% a clinically significant increase in the number of subjects who experienced a 75% or greater reduction in hot flush frequency compared with placebo. It was expected that 25% of placebo subjects would report 75% or greater reduction in hot flushes. A response rate for active treatment of 65% compared with 25% for placebo treatment was considered clinically significant. Thirty-two evaluable subjects per treatment group would provide 95% power to detect this clinically significant difference with P = .05 using one-sided testing.
Based on the results from study 1, it was decided that descriptive information from study 2 would be assessed, specifically the percentage of subjects who reported bleeding and/or spotting. As in study 1, the sample size was derived from the hypothesized effect on reduction of hot flushes. In study 2, women were required to have at least 56 moderate to severe hot flushes during the week before randomization. The hot-flush entrance criterion resulted in a higher baseline rate of hot flushes in study 2 than in study 1 (Tables 1
and 2).
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Results |
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). Thirty-one subjects did not complete the study, 23 of whom discontinued within the first 8 weeks of treatment. Adverse events were reported as the primary reason (17 of 31) for discontinuation. Ten subjects had adverse events that were considered to be related to medication. These adverse events included headache (three), vaginal bleeding (three), increased insomnia (one), breast tenderness (one), depression (one), and increased appetite (one). There did not appear to be any dose relation associated with withdrawal due to adverse events. Overall, the percentage of subjects with bleeding and/or spotting tended to be greater with increasing doses of norethindrone acetate and ethinyl E2 and to decrease over time within each treatment-dose group.
Percentages of subjects in the placebo group with bleeding ranged from 3% to 5%. In the first 8 weeks of the study, bleeding was as high as 30% in the 1/10 norethindrone acetate/ethinyl E2 group, but decreased rapidly afterward to 5–12% at the end of the study (Figure 1). The RR of bleeding was significantly greater for the 1/10 norethindrone acetate/ethinyl E2 group at week 4 but did not differ from placebo at weeks 12 or 16. Likewise, the 1/5 norethindrone acetate/ethinyl E2 group had a significantly greater RR for bleeding at week 4 but did not differ from placebo for the remainder of the study. The remaining norethindrone acetate and ethinyl E2 dose groups (0.2/1 and 0.5/2.5 mg norethindrone acetate/µg ethinyl E2) essentially did not differ from placebo at any time during the study (Table 3).
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). The same result applies for the combined bleeding and/or spotting variable (Table 3; Figures 2 and 3).
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). Thirty-six women did not complete the 12-week study, 29 of whom discontinued within the first 8 weeks. The treatment completion rate was similar in the 0.5/2.5 and 1/10 norethindrone acetate/ethinyl E2 groups, which had the highest percentages of completers (90% and 89%, respectively). Adverse events were reported most frequently (15 of 36) as the reason for discontinuation. Nine of these women had events considered to be related to treatment or placebo. Events that led to withdrawal included headache (two), breast tenderness (two), superficial thrombophlebitis (one), nervousness (one), vaginal bleeding (one), palpitations (one), and bloating (one). These events were evenly distributed across the treatment and placebo groups.
The descriptive summary of vaginal bleeding and/or spotting in study 2 was very similar to that observed in study 1, and no further statistical analysis was performed. Overall, at all weeks, the incidence of bleeding and/or spotting among subjects treated with norethindrone acetate and ethinyl E2 increased with dose and was greater than the incidence in placebotreated subjects. The highest rates of bleeding and/or spotting occurred in the 1/10 norethindrone acetate/ethinyl E2 subjects at week 4 (33% and 43%, respectively). However, the rate of bleeding and the rate of bleeding and/or spotting among norethindrone acetate and ethinyl E2-treated subjects tended to decrease as the study progressed, such that at week 12, 3–14% of women in the treatment group reported bleeding compared with 2% in the placebo group; 7–26% of women treated with norethindrone acetate and ethinyl E2 reported bleeding and/or spotting compared with 5% in the placebo group. There was good consistency between the studies as exemplified by the bleeding data (Figures 1 and 4).
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Discussion |
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The current studies demonstrate that vaginal bleeding and spotting decrease over a relatively short time in postmenopausal women who receive various dose combinations of norethindrone acetate and ethinyl E2. In women who were treated at the lowest dose (0.5/2.5 mg norethindrone acetate/µg ethinyl E2) shown to be effective in controlling symptoms and preventing osteoporosis,34 there was no significant increase in bleeding, and amenorrhea was maintained throughout the treatment. With the two higher norethindrone acetate and ethinyl E2 dose combinations (1/5 and 1/10 mg norethindrone acetate/µg ethinyl E2), there was an initial increase in bleeding, but after 3 months of treatment, bleeding was indistinguishable from that reported with placebo. Likewise, for the 1/5 norethindrone acetate/ethinyl E2 dose, the percentage of women who were amenorrheic was the same as that in the placebo group at the end of month 3 of the study, whereas more than 70% of subjects in the 1/10 norethindrone acetate/ethinyl E2 group were amenorrheic after 3 months. In addition, although not investigated in these studies, it is possible that women who report frequent bleeding episodes could receive a reduced dose for control of bleeding and continue on therapy for maximum HRT benefit. Indeed, these data suggest exploration of a clinical approach that would include initiating therapy at a lower dose and then increasing to doses known to have maximal benefits (eg, 1/10 norethindrone acetate and ethinyl E2 for maintenance of bone density).
The minimal effective dose of norethindrone acetate and ethinyl E2 has also been reflected in the reported low incidence of hyperplasia or proliferative changes in the endometrium as compared with unopposed ethinyl E2.34 Thus, the protective endometrial effect of norethindrone acetate may be associated with an incidence of vaginal bleeding that does not differ from placebo.
The current studies provide short-term data on the effect of continuous combined norethindrone acetate/ethinyl E2 on vaginal bleeding and spotting. The length of the studies is a limitation. There is an indication that there would be continued control of bleeding episodes, but a longer duration of exposure is needed to confirm this speculation. In addition, by design clinical trials generate homogeneous subject populations, which can limit their generalizability. Thus, additional investigations with less restrictive entry criteria would provide further data regarding risk factors that may be associated with vaginal bleeding and appropriate dose selection and/or dose changes of norethindrone acetate and ethinyl E2.
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Footnotes |
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The FemHRT Study investigators: M. C. Burton, MD, Mark P. Cohen, MD, Richard Hebertson, MD, Leon Speroff, MD, Robert Stillman, MD, Steven C. Voss, MD, Elizabeth L. Evans, MD, William H. Swartz, MD, Herbert Soper, MD, Jon Ruckle, MD, Steven Williams, MD, Simona Scumpia, MD, Edwin Bronsky, MD, Frank Mazzone, MD, Margaret Drehobl, MD, Sherwyn Schwartz, MD, Morton Rosenstein, MD, John Mattox, MD, Stephen F. Gordon, MD, James D. Smith, MD, Helmut Schrott, MD, Troy Williams, MD, Ira Weisberg, MD, Mildred Farmer, MD, Steven Zeig, MD, Louis Cohen, MD, John A. Holmes, MD, Harvey Resnick, MD, Richard E. Hedrick, Jr, MD, John P. Lenihan, MD, Robert B. Jacobson, MD, Ronald Coe, MD, and Robert H. Friedman, MD.
Authors Symons and Kempfert are employees of Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company and hold stock in the company. Author Speroff receives grant support to Oregon Health Sciences University from Parke-Davis.
Received June 15, 1999. Received in revised form February 18, 2000. Accepted March 2, 2000.
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