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ORIGINAL RESEARCH |
From the Departments of Psychiatry and Family and Preventive Medicine, University of California, San Diego, San Diego, California.
Address reprint requests to: Etta A. Lindenfeld, MD, MPH, 8950 Villa La Jolla Drive, Suite 2232, La Jolla, CA 92037; E-mail: etlinden{at}ucsd.edu.
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ABSTRACT |
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 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: A total of 875 women in the Postmenopausal Estrogen and Progestin Interventions Trial took either placebo, conjugated equine estrogen 0.625 mg, conjugated equine estrogen 0.625 mg plus medroxyprogesterone acetate 2.5 mg in a continuous fashion, or conjugated equine estrogen 0.625 mg daily plus either cyclical medroxyprogesterone acetate 10 mg or cyclical micronized progesterone 200 mg/day for 12 days per month. Bleeding days, amounts, and episodes were recorded in diaries and aggregated by 6-month intervals for 3 years for the 596 participants with a uterus. Any bleeding for women on continuous regimens, or more than 6 episodes of bleeding per 6-month period for cyclical regimens, was considered excess.
RESULTS: Conjugated equine estrogen plus micronized progesterone cyclical was associated with fewer excess episodes of bleeding than conjugated equine estrogen plus medroxyprogesterone acetate continuous in the first 6 months. Quantities of bleeding for conjugated equine estrogen plus micronized progesterone cyclical were less than for conjugated equine estrogen plus medroxyprogesterone acetate cyclical through 30 months and for the number of bleeding days through study end. The 3-year cumulative quantities, days, and episodes of bleeding were significantly lower for conjugated equine estrogen plus micronized progesterone cyclical than for conjugated equine estrogen plus medroxyprogesterone acetate cyclical. Placebo treated women had scant bleeding and conjugated equine estrogen had modest amounts relative to the combination therapies.
CONCLUSION: The bleeding measures for conjugated equine estrogen plus micronized progesterone cyclical showed consistent advantages over those for cyclical conjugated equine estrogen plus medroxyprogesterone acetate in terms of quantity, length, and episodes of bleeding. In the first 6 months, conjugated equine estrogen plus micronized progesterone cyclical had fewer excess bleeding episodes than continuous conjugated equine estrogen plus medroxy-progesterone acetate.
Continuation rates for women prescribed hormone replacement therapy (HRT) are poor, despite the clinical belief that HRT would benefit them. These poor continuation rates are generally attributed to unacceptable side effects and cancer fears. In a study of about 29,000 women aged 40–59 years who received new HRT prescriptions, 54% were no longer on treatment at the end of 1 year.1
Women often report that bleeding was the most important single reason for discontinuing HRT. Among about 200 women with a uterus given a prescription for HRT at a health maintenance organization, 25% discontinued cyclical therapy, and 21% discontinued continuous therapy after 1 year. During the first 6 months of therapy, irregular bleeding occurred in 37% of women on cyclical therapy and 34% of those on continuous therapy. Among the quitters, 31% of cyclical users and 20% of continuous users identified irregular bleeding as the reason for quitting.2 A similar effect of bleeding on HRT compliance was found in an 18-month study of a randomly selected population of about 2400 women 45–55 years old. Interviews revealed that 20% of women had discontinued therapy, and 22% of those cited bleeding as a cause for discontinuation.3
Even lower continuation rates were seen in a Kaiser Permanente study of new users. In that study, only 50% of those prescribed cyclical HRT remained on therapy at 1 year, and only 24% continued at 3 years. Compliance with continuous therapy was worse at 41% after 1 year and 19% after 3 years.4 Of those who quit, 47% of those on continuous therapy and 81% of those on cyclical therapy cited monthly or irregular bleeding as a reason for quitting.2 Variation in discontinuation rates between studies may be attributable to differences in established factors that predispose women to stop HRT. Factors identified in other studies include having a uterus, being older, being non-Caucasian, having less education, concerns about or existence of osteoporosis among younger women,5–7 and possibly pre-existing negative attitudes toward cyclical bleeding.8,9
Prior studies of bleeding patterns and HRT have focused on differing dosage levels10 and the relationship between bleeding, endometrial thickness measured by transvaginal ultrasound, and histopathology.11 There is some evidence that bleeding patterns differ by the compounds used in HRT regimens. In a comparison of continuous regimens consisting of conjugated equine estrogen plus medroxyprogesterone acetate versus 17-ß-estradiol and norethindrone acetate, the conjugated equine estrogen plus medroxyprogesterone acetate regimen had fewer bleeding days and a shortened time to amenorrhea.12
The Postmenopausal Estrogen and Progestin Interventions Trial evaluated three regimens of combined HRT and a regimen with unopposed estrogen. Bleeding data were collected at clinic visits every 6 months, providing an opportunity to compare bleeding patterns over an extended time, including differences between medroxyprogesterone acetate and micronized progesterone, both widely used progestogens in the United States.
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MATERIALS AND METHODS |
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There was a run-in period of 4–12 weeks to test each participant’s ability to be at least 80% medication compliant, to be void of bleeding or spotting, and for lack of serious adverse events. After randomization, medication compliance was assessed at each 6-month return clinic visit by participant interview, pill counts, and diary review. Participants who took at least 80% of their study medication in a specific 6-month interval were considered compliant for that interval. Bleeding data were recorded for women meeting this definition of compliance for the interval just concluded. Parameters recorded included the number of days with bleeding and the quantity of bleeding (as the number of pads used). If a woman was noncompliant during the prior 6-month interval, the bleeding parameters were recorded as missing.
For women assigned to placebo, unopposed conjugated equine estrogen, or continuous conjugated equine estrogen plus medroxyprogesterone acetate, any bleeding or spotting was considered excess bleeding because regular bleeding was not expected in these groups. For women on one of the cyclical regimens, an episode of bleeding or spotting was defined as bleeding or spotting for 1–10 days. Participants reporting more than 10 days of bleeding or more than six episodes in 6 months were considered to have excess bleeding. Six-month groupings and study-long cumulative values for bleeding quantities, length of bleeding episodes, number of episodes, and the number of excess episodes were examined by treatment group. Because in preliminary work conjugated equine estrogen plus micronized progesterone cyclical had bleeding rates intermediate between the continuous and cyclic treatments, it was used as the comparison group in several analyses. Because bleeding may represent pathology, the relationship between histology and bleeding by treatment was explored.
SPSS for Windows 6.1 (SPSS Inc., Chicago, IL) was used for all statistical analyses. Mean values were calculated for each 6-month interval and for the entire study period for continuous variables, including days of bleeding and bleeding quantity. When cumulative means were calculated, the calculation used a weighting factor for the number of intervals contributed by each woman (maximum of six in which she was compliant). Factors tested for effects on bleeding included clinic site, age, body mass index, waist–hip ratio, years since last menstrual period, education (categorized as less than or equal to high school, less than or equal to college, and postgraduate studies), income (<$35,000, $35,000–75,000, and >$75,000), and use of nonsteroidal antiinflammatory medication. Analysis of variance models were used to adjust the only significant modifiers, age and income, for importance while testing differences between treatments for the continuous bleeding variables, using cyclical conjugated equine estrogen plus micronized progesterone as the reference for contrasts. Where variances were unequal for some group contrasts, confirmatory tests for statistical significance were performed using nonparametric methods. Because results were equivalent using both methods, parametric values are shown for consistency and ease of interpretation.
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RESULTS |
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shows the baseline characteristics for each of the five treatment groups. There were no statistically significant differences between the groups for any of the characteristics, indicating that randomization was effective for these parameters. The cohort has been described in detail elsewhere.13,15 Briefly, these were healthy women with a mean age of 56 years, who were for the most part married, averaging a little more than 5 years since their last menstrual period, employed, and with high levels of education. About half of these women with a uterus had taken HRT prior to the study for an average duration of about 2 years.
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shows the number of women compliant on study drug during each 6-month study interval. The numbers of women randomized to unopposed conjugated equine estrogen who remained compliant declined steeply owing to protocol-mandated withdrawal following development of endometrial hyperplasia. This has been described in detail.16 Drop-out rates were much lower in all other treatment groups and, after excluding the unopposed estrogen group, there were no important differences in these fractions between the regimens.
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. Women on placebo generally had the fewest mean episodes of excess bleeding, ranging from 1 to 3 for each 6-month treatment interval among the small numbers of women affected. Considering the active treatments, cyclical conjugated equine estrogen plus micronized progesterone had the lowest mean number of excess bleeding episodes, ranging between 1.0 and 1.5 in any 6-month interval and occurring in 2–9 cases. Cyclical conjugated equine estrogen plus medroxyprogesterone acetate was next, with 1.2–1.7 mean excess bleeding episodes among 6–18 cases. Unopposed conjugated equine estrogen had between 2.9 and 4.0 mean episodes among 21–44 cases. The greatest number of episodes occurred in the continuous conjugated equine estrogen plus medroxyprogesterone acetate group, with means ranging between 3.5 and 5.3 among 37–71 cases. The total numbers of excess bleeding episodes were virtually identical for placebo and conjugated equine estrogen plus cyclical micronized progesterone. These fractions were about half as great as for the next best treatment, cyclical conjugated equine estrogen plus medroxyprogesterone acetate.
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. The cumulative quantity of bleeding was lowest in women assigned to placebo, followed by those assigned to unopposed estrogen. Levels for women on continuous conjugated equine estrogen plus medroxyprogesterone acetate were the next highest, and the two cyclical regimens had the greatest cumulative quantity of bleeding. Cumulative bleeding measures in the unopposed estrogen group were lower than the combination therapies, despite the high rates of hyperplasia that developed. Women taking continuous conjugated equine estrogen plus medroxyprogesterone acetate had some bleeding on an average of 99 days, about 9% of the treatment time. Of the two cyclical treatments, conjugated equine estrogen plus micronized progesterone had lower cumulative bleeding for each measure than conjugated equine estrogen plus medroxyprogesterone acetate; 23% fewer pads used (P = .03), 23% fewer bleeding days (P = .004), and 12% fewer bleeding episodes (P = .005). Table 4 shows the cumulative absolute value for each variable, and the disparities between treatments for the bleeding measures are readily seen. Interestingly, the cumulative mean length of bleeding in days was not significantly different for continuous medroxyprogesterone acetate compared with cyclical micronized progesterone.
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). Using cyclical conjugated equine estrogen plus micronized progesterone as the reference group, most contrasts between treatments were significant. As would be expected in women who were on average 5 years postmenopausal, bleeding in the placebo group was scant. The quantity of bleeding in women who took unopposed conjugated equine estrogen was low relative to the combination therapies; however, those results are conservative because of the high rate of protocol-mandated withdrawal due to endometrial hyperplasia. Although each group started with equal numbers, only 53 women from the unopposed conjugated equine estrogen group remained on treatment at their 36-month visit, compared with an average of 95 women in the other treatment groups.
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, mirror the significant differences of bleeding amounts. In the first 6 months, there were fewer days of bleeding with cyclical conjugated equine estrogen plus micronized progesterone than with continuous conjugated equine estrogen plus medroxyprogesterone acetate. For the entire 36-month study period, the mean number of days with bleeding for unopposed conjugated equine estrogen and continuous conjugated equine estrogen plus medroxyprogesterone acetate was similar, but these results must be seen in the context of the excess loss to treatment in the unopposed conjugated equine estrogen arm. Contrasts adjusted for modifiers and multiple comparisons using conjugated equine estrogen plus cyclical micronized progesterone as the reference group showed that the mean length of bleeding was significantly shorter for placebo and unopposed conjugated equine estrogen, continuous conjugated equine estrogen plus medroxyprogesterone acetate, and significantly greater for cyclical conjugated equine estrogen plus medroxyprogesterone acetate.
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. The divergent effects for continuous conjugated equine estrogen plus medroxyprogesterone acetate at initiation compared with later intervals is demonstrated, as are the consistently lower levels of bleeding days for cyclical conjugated equine estrogen plus micronized progesterone compared with cyclical conjugated equine estrogen plus medroxyprogesterone acetate over time.
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DISCUSSION |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Women who took cyclical conjugated equine estrogen plus medroxyprogesterone acetate experienced the greatest cumulative number of days with bleeding, the greatest quantity of bleeding, and more episodes of bleeding than any of the other hormone regimens. Both the number of days and quantity of bleeding were significantly lower with cyclical conjugated equine estrogen plus micronized progesterone than with conjugated equine estrogen plus medroxyprogesterone acetate in all treatment intervals, except for quantity at the 36-month visit. That micronized progesterone was consistently superior in bleeding burden to medroxyprogesterone acetate in this study is notable in light of another study that showed medroxyprogesterone acetate was associated with less bleeding than norethindrone acetate.12 This suggests that micronized progesterone would be associated with less bleeding than norethindrone as well. Interestingly, the average number of days with bleeding over the entire 3-year study period for continuous conjugated equine estrogen plus medroxyprogesterone acetate (13.8 per 6 months) and conjugated equine estrogen plus micronized progesterone (20.9 per 6 months) were only marginally different (P = .052).
Continuation rates on assigned treatment in clinical trials exceed those in typical patients because of the positive attributes of the research population, which, as in the Postmenopausal Estrogen and Progestin Interventions Trial, is additionally screened for compliant behavior as a condition of eligibility. Clinical trial participants also have the benefit of compliance counseling by trial staff, and their performance is influenced by the extra commitment volunteers make to address a research question. Accordingly, the continuation rates demonstrated here are probably optimistic for all active treatments. Outside of a clinical trial, the degree of bleeding would likely impact continuation, as has been shown in a number of other studies.18–20
In a follow-up study of HRT continuation rates among former Postmenopausal Estrogen and Progestin Interventions Trial participants, one third of women assigned to combined hormone therapy were no longer taking it when surveyed an average of 19 months after study completion.5 This is about double the discontinuation of 15%–18% for combined therapies during the 36 months of the Postmenopausal Estrogen and Progestin Interventions Trial17; however, participants on conjugated equine estrogen plus micronized progesterone were unable to continue on that regimen because the formulation of micronized progesterone tested in the Postmenopausal Estrogen and Progestin Interventions Trial did not have U.S. Food and Drug Administration approval when the trial ended. Therefore, treatment comparisons of post-study continuation rates are not valid for that arm.
Protocol-mandated discontinuation of study treatment for women assigned to unopposed conjugated equine estrogen who developed endometrial hyperplasia created a systematic bias for bleeding women in this treatment group to be noncompliant. This is an issue that cannot be overcome in any long-duration study, owing to ethical concerns. Accordingly, the rates of bleeding found for unopposed estrogen in the present study are probably conservative.
Although it is generally reported that bleeding resolves over time, excess bleeding persisted for women in all treatment groups in the Postmenopausal Estrogen and Progestin Interventions Trial. In fact, there was a small but uniform increase in the percent of women bleeding at visit month 30, for reasons unknown. This study may be more likely than others to demonstrate excess bleeding with long-term use because of the stringent definition of compliance that we applied and the high rates of compliance in this cohort. Those factors insured that noncompliant women, who may be less likely to bleed because they have less exposure to treatment, were excluded.
The Postmenopausal Estrogen and Progestin Interventions Trial did not evaluate a continuous regimen with micronized progesterone, and the U.S. Food and Drug Administration presently approves only cyclical micronized progesterone. We are unaware of other reports describing bleeding patterns with continuous micronized progesterone and any oral estrogen. A study evaluating micronized progesterone 100 mg for 25 days per month with transdermal estrogen in more than 100 women reported that 81% developed amenorrhea over a 6-month period.21 The marginal differences in bleeding measures between cyclical micronized progesterone and continuous medroxyprogesterone acetate regimens in this study, especially in the first 6 months, suggest that a continuous regimen with micronized progesterone could be associated with less bleeding than continuous medroxyprogesterone acetate.
Differences in progestogens may be clinically important, with regard to both the likelihood that women will remain on treatment and metabolic effects. Micronized progesterone is chemically identical to endogenous progesterone; this should minimize its adverse effects compared with other progestogens. Indeed, the Postmenopausal Estrogen and Progestin Interventions Trial and other studies have demonstrated that medroxyprogesterone acetate significantly attenuates estrogen-associated benefits on lipids and carbohydrate metabolism18,22 and estrogen-associated protection against vasospasm,23,24 whereas progesterone does not. The present analysis shows that micronized progesterone also offers advantages with regard to tolerability because cyclical conjugated equine estrogen plus micronized progesterone generates less bleeding than continuous conjugated equine estrogen plus medroxyprogesterone acetate in the first 6 months, and than cyclical conjugated equine estrogen plus medroxyprogesterone acetate for 3 years.
To promote HRT compliance in a clinical setting, the North American Menopause Society consensus opinion on achieving long-term continuance of menopausal estrogen replacement therapy/HRT encourages patient involvement in decision making, discussing patient preferences, and providing educational information.25 The practicalities of clinical practice limit the time and frequency of contact with patients, so that minimizing undesirable side effects, in addition to these cognitive strategies, is key to patient comfort with HRT. The current study shows that of the continuous and cyclical regimens with a progestogen, conjugated equine estrogen plus micronized progesterone was associated with the fewest days of bleeding during the first 6 months, a key time for women’s decisions on continuing HRT. Of the two cyclical regimens, women on conjugated equine estrogen plus micronized progesterone had fewer days of bleeding and a lower quantity of bleeding than women on conjugated equine estrogen plus medroxyprogesterone acetate. Utilization of this knowledge of the differences in bleeding rates offers the clinician a logical rationale for a hormone prescription choice, and that may promote to compliance.
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Footnotes |
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Received February 5, 2002. Received in revised form May 8, 2002. Accepted May 16, 2002.
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REFERENCES |
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