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ORIGINAL RESEARCH |
From the Division of Research, Kaiser Permanente Medical Care Program, Oakland, California.
Address reprint requests to: Bruce Ettinger, MD, Division of Research, Kaiser Permanente Medical Care Program, 3505 Broadway, 7th Floor, Oakland, CA 94611-5463; E-mail: bxe{at}dor.kaiser.org.
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ABSTRACT |
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METHODS: We identified 138 women aged 55–75 years who had regularly used HRT at a standard dosage (equivalent to 0.625 mg conjugated estrogen) opposed by cyclic monthly MPA. Each subject’s HRT regimen was changed to 0.3 mg/day esterified estrogens (Estratab; Solvay Pharmaceuticals, Marietta, GA) combined with 14-day courses of MPA, 10 mg/day, every 6 months. Endometrial biopsy was repeated after 1 year of the new regimen. Any vaginal bleeding was reported in each patient’s daily diary. Menopause symptoms were evaluated using the Greene Menopause Symptom Index.
RESULTS: Among 125 women who had biopsy after 1 year of the new regimen, endometrial hyperplasia was found in two (1.6%, 95% confidence interval 0.3%, 6.2%). Of the 125 women, 44% had scheduled bleeding, and 9.4% had unscheduled bleeding. Relative to baseline vasomotor score (range 0–6), an increase of at least 2 U was reported by 20% of subjects at 6 months and by 17% of subjects at 12 months.
CONCLUSION: Most women aged at least 55 years can safely switch their HRT regimen from standard dosage HRT to low-dosage estrogen opposed by MPA at 6-month intervals. Moreover, this new HRT regimen causes little vaginal bleeding while maintaining adequate control of menopausal symptoms.
Low-dosage estrogen (equivalent to half the widely used dosage of 0.625 mg/day conjugated estrogen) has been shown to preserve bone density1–5 and to alleviate menopausal symptoms3,6 in early postmenopausal women and to increase bone density in elderly women.7 On the basis of findings from a large observational study, low-dosage estrogens appear to have similar cardiovascular benefits as standard dosages of estrogens.8 Although a short-term study found that use of unoppposed, low-dosage estrogen produced little endometrial hyperplasia,9 long-term use of this dosage may create a risk of endometrial cancer10; therefore, progestin opposition is necessary to protect the endometrium. However, clinicians have not determined the optimum progestin dosage and schedule to use together with low-dosage estrogen. Low-dosage estrogen use can reasonably be assumed to require less progestin for protecting the endometrium.
In addition to the continuous daily addition of progestin and addition of monthly cyclic progestin, cyclic progestin has been used at less frequent intervals–for example, every 3–6 months.11,12 When added to standard dosage estrogen, the addition of 10 mg of medroxyprogesterone acetate (MPA) every 3 months for 14 days produced a 1.5% rate of hyperplasia (a rate low enough to be interpreted as endometrial protection),11 and long-term use of MPA at 6-month intervals was associated with a low rate of endometrial cancer.12
The goal of the current investigation was to estimate safety and acceptability of using low-dosage estrogen with cyclic addition of progestin (ie, progestin used for 14 days every 6 months). We therefore designed a study to test both the feasibility of switching the hormone replacement therapy (HRT) regimen from standard dosages of estrogen to half the standard dosage while switching from monthly cycles of coprescribed progestin to coprescribed progestin given at 6-month (ie, long-cycle) intervals.
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METHODS |
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. The study protocol was approved by the Kaiser Permanente Medical Care Program Northern California Regional Institutional Review Board, and informed consent was obtained.
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Subjects were given 200 pills of esterified estrogen (Estratab; 0.3 mg, Solvay Pharmaceuticals, Marietta, GA) at the initial and 6-month visits and were instructed to take one pill daily. At the 6-month and 12-month visits, unused pills were returned and counted. Subjects were mailed 14 10-mg MPA pills 10 days before they were due to be taken, and reminder telephone calls ensured adherence to the regimen. At the 6-month and 12-month visits, any unused MPA pills were returned and counted.
Endometrial biopsy done at baseline and after 1 year of follow-up was done on day 8, 9, 10, 11, 12, 13, or 14 of MPA administration. Biopsy results were read by one of two pathologists, who were told only that the women were receiving HRT. Morphology of the biopsied endometrium was designated as 1) atrophy, 2) proliferative, 3) secretory (which could include proliferative morphology with or without predecidual change), and 4) hyper-plastic. Hyperplastic endometrium was further characterized in terms of glandular architecture (ie, complex or simple) and cytologic features (ie, with or without atypia). Metaplastic endometrium was included in this category and was also characterized in terms of glandular architecture and cytology.
Each subject was given a menstrual diary card on which she daily recorded any vaginal bleeding. The diary was kept for 1 month before the study (ie, while following an HRT regimen of estrogen at a standard dosage) and for the entire year of follow-up (ie, while following the new HRT regimen). Vaginal bleeding was quantitated on a scale of 0 to 4 (0 = none, 1 = spotting not requiring sanitary protection, 2 = light bleeding, 3 = moderate bleeding, 4 = heavy bleeding). "Scheduled" bleeding was defined as any bleeding that began after the 7th day of medroxyprogesterone administration and ended within 14 days after it began. "Unscheduled" bleeding was defined as any bleeding that occurred outside this interval. Summary bleeding scores were calculated by applying quantitative assessment of bleeding severity to duration of bleeding (ie, a scheduled period of 1 light, 2 moderate, and 1 heavy day of bleeding would be assigned a summary bleeding score of 12). Subjects also completed questionnaires indicating their overall perception of their menses, including amount of bleeding (ie, light, moderate, or heavy) and cramping (ie, none, mild, moderate, or troublesome). The same menstrual questionnaires were administered at baseline (assessing the previous 12 months) and after 6 months and 12 months of study.
The Greene Menopause Symptom Index14 was used to quantify changes in vasomotor, somatic, and psychologic symptoms during treatment. Symptom changes were evaluated at baseline and at 3 months, 6 months, and 12 months after treatment began. To accurately assess these changes, we carried forward the last-obtained scores for women who dropped out of the study. Severity of each symptom was scored on a 3-point scale (1 = mild, 2 = moderate, 3 = severe); thus, the vasomotor domain (which contained two questions) had a possible range of 0 to 6, the somatic domain (which contained seven questions) had a range of 0 to 21, and the psychologic domain (which contained 11 questions) had a range of 0 to 33.
We calculated confidence intervals of prevalences using an equation developed for use with small samples.15 For nonparametric variables, the paired Wilcoxon signed-rank test was used. All analyses were conducted with SAS software (SAS Institute, Cary, NC).
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RESULTS |
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) indicated that most of these women had considerable exposure to HRT before the study and that they had overall a low incidence of menopausal symptoms. The 5-mg daily dose of MPA was used by about the same number of women who used the 10-mg daily dose of MPA, and mean duration of use was 11.9 days monthly (range 10–16 days). Overall, this group reported relatively low prevalence of heavy menses or troublesome menstrual cramps.
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Table 2 shows results of endometrial biopsy done at baseline and after 1 year. Compared with histology status at baseline, endometrial histology after 1 year tended to be more atrophic. In one woman, simple endometrial hyperplasia developed; this hyperplasia resolved completely after treatment consisting of cessation of estrogen administration and initiation of MPA therapy at a dosage of 10 mg twice daily for 6 weeks. Another woman had complex mucoepidermoid endometrial metaplasia that did not resolve after cessation of estrogen therapy and completion of a 6-week course of MPA and after a 3-month course of MPA. This abnormal histologic pattern persisted during an additional year of follow-up while the patient received no HRT. She declined dilatation and curettage. Considering these two cases, the endometrial hyperplasia rate was 1.6% (95% confidence interval [CI] 0.3%, 6.2%).
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. Whereas nearly all women reported withdrawal bleeding while following the standard dosage HRT regimen, most women following the low-dosage HRT regimen had no bleeding at 6 months (54%) or at 12 months (55%); 44% had no withdrawal bleeding at either time. Among women who had any scheduled bleeding during the study, median duration was 4 days (range 0–12 days) at 6 months and 2 days (range 0–10 days) at 12 months; in contrast, median duration of scheduled bleeding was 4 days (range 0–14 days) while following the standard HRT for the month before the study began. In this same group of women with scheduled bleeding, median bleeding scores were 12 (range 0–34) at 6 months and 10 (range 0–31) at 12 months; these scores were similar to the median reported in the year before the study began (median 12, range 2–31). Troublesome menstrual cramping during the study was reported by 9.9% of subjects (95% CI 5.5%, 16.9%); 4.3% of subjects (95% CI 1.7%, 9.7%) reported having this problem in the year before the study while following a standard dosage HRT regimen.
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On average, the vasomotor, somatic, and psychologic domains of the Greene Menopause Symptom Index14 were low at baseline (each domain score averaged about 10% of the maximum possible domain score) and remained low throughout the study; no domain scores exceeded 20% of the maximum domain score (Figure 3). As expected, worsening of vasomotor symptoms was observed in a few subjects; using a score change of at least 2 points (ie, a third of the maximum possible score) as a cutoff, worsening of symptoms was reported by 15% of subjects (95% CI 9.5%, 22.3%) at 3 months, by 20% of subjects (95% CI 13.6%, 28.3%) at 6 months, and by 17% of subjects (95% CI 11.1%, 25.0%) at 12 months. In contrast, we observed statistically significant improvements in somatic (P < .05) and psychologic (P < .05) scores at each assessment time points during the study. These changes were greatest when assessed at 3 months (when estrogen alone was being taken) and tended to be less when assessed at 6 months (done 1–2 weeks after completion of a 14-day course of MPA added to the estrogen HRT regimen) and at 12 months (done on the 8th–14th day of MPA addition).
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DISCUSSION |
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Reduced frequency and severity of menopausal vasomotor symptoms is dose-related; two-thirds reduction in frequency and severity of hot flushes is usually achieved by use of low-dosage estrogen HRT; 90% reduction is achieved using a standard dosage regimen.6,17 Several low-dosage estrogen formulations have prevented bone loss among early postmenopausal women,1–5 and these products have been approved by the US Food and Drug Administration for this indication. Studies of women aged 65 years and older show that low-dosage estrogen HRT enhances bone mineral density.7 Low-dosage regimens of estrogen HRT have not been shown to reduce risk of hip and other osteoporotic fractures; in an observational study of fractures among postmenopausal women,18 reduced risk was associated with standard dosage estrogen HRT but not with low-dosage estrogen HRT. In a large, observational study,8 women who used low-dosage and standard dosage estrogen HRT had about the same reduction in risk of myocardial infarction relative to nonusers of estrogen, whereas women who used estrogen HRT at dosages higher than standard had less or no reduction in risk of myocardial infarction and a higher risk of stroke.
Women may prefer to switch from standard dosage to low-dosage estrogen HRT to reduce estrogen-related side effects, which appear to be dose-related, such as vaginal bleeding4,19 and breast tenderness.6,9 Despite the 6-month interval between cycles of progestin opposition, we found that women using low-dosage estrogen HRT had little vaginal bleeding. We previously showed that compared with standard dosage estrogen HRT, low-dosage estrogen HRT stimulates by half the growth of endometrial thickness observed sonographically.20 In that study,20 after more than 6 months of using low-dosage estrogen HRT, 85% of women showed endometrial thickness less than 8 mm. Thus, a low incidence of endometrial hyperplasia would be expected among women using unopposed, low-dosage estrogen HRT during such a 6-month interval. In a 2-year study of women who used unopposed, 0.3-mg esterified estrogen, endometrial hyperplasia developed in 1.7% of subjects, a rate not different from that seen in women who received placebo.9 If the rate of endometrial hyperplasia is proportional to the dose of estrogen, then a 7% to 8% annual rate of hyperplasia could be expected in women who received low-dosage estrogen HRT (ie, half the 15% annual rate observed in women who used standard dosage unopposed estrogen HRT). The endometrial hyperplasia rate observed during the year in which a cohort of women received unopposed 0.3 mg daily of conjugated estrogens was about 1% to 2% on the basis of independent readings of two pathologists (James H. Pickar, MD, personal communication, 2000, Wyeth Ayerst Research, Philadelphia, PA). Moreover, a case-control study of the association between estrogen use and endometrial cancer10 indicated that long-term use of unopposed, low-dosage estrogen HRT was associated with a substantial increase in risk and that this increase was similar to that observed among women who used unopposed, standard dosage estrogen HRT. Because endometrial carcinoma attributable to exogenous estrogen can largely be prevented by concomitant administration of progestin, prescription of this regimen is prudent. However, the dosage as well as duration and frequency of progestin administration necessary to offset endometrial stimulation by low-dosage estrogen HRT may be less than that required for standard dosage estrogen HRT. In a 1-year study with continuous combined conjugated estrogens (either 0.45 mg or 0.3 mg) and MPA, 1.5 mg of MPA was sufficient to protect against endometrial hyperplasia (James H. Pickar, MD, personal communication, 2000, Wyeth Ayerst Research).
Using less progestin is a worthwhile goal. Progestin use may cause troublesome, premenstrual-like symptoms,21 doubles incidence of breast tenderness,22 lowers high-density lipoprotein cholesterol levels,23 increases mammographic density,24 and appears to increase risk of breast cancer.25 The 6-month cyclic progestin regimen used in our study exposes a woman to a cumulative dose of 280 mg MPA annually–much less than the 720 mg to 913 mg required when using 5 mg progestin for 12 days per month or 2.5 mg progestin daily. Thus, long-cycle HRT using a low dosage of estrogen can be expected to result in lower incidence of breast abnormality. This possibility deserves further study.
An important strength of our study is that its population of women receiving follow-up endometrial biopsy was large enough for the hyperplasia rate to be precisely defined. We also were able to closely and objectively monitor drug compliance, vaginal bleeding, and symptoms.
Some limitations of our study are worth noting. Outcomes of an unblinded study such as ours are subject to observer bias. However, we took steps to assess outcomes objectively–participants recorded bleeding patterns on daily diary cards returned monthly by mail; bleeding was categorized and quantified according to prior rules; and biopsy specimens were read by pathologists who were not aware of either the schedule or the dosage of HRT being used. In addition, all our subjects had been using estrogen HRT for a considerable time before this study began and therefore probably had a positive experience with this therapy; such positive experience can reasonably be expected to encourage high rates of compliance and represent tolerance to side effects. Moreover, despite long-term use of HRT by women entering our study, endometrial hyperplasia did not develop in these women. For all these reasons, our results cannot be extrapolated to women starting HRT.
Furthermore, our biopsy data represent only a 1-year period and thus leave open the question of long-term safety. However, in most long-term studies3,16 of unopposed or opposed estrogen use, annual rates of hyperplasia observed after the initial year of HRT are similar to rates seen during the initial year. In addition, manufacturing difficulties have halted production of the 0.3-mg esterified estrogen product which we evaluated. However, we suspect that similar levels of safety and tolerability would be observed using other low-dosage estrogen HRT in the 6-month regimen.
What practical recommendations can be made on the basis of our study’s findings? The new regimen would be a good choice for women who are taking standard dosage HRT but who would prefer a lower-dosage regimen, either because of troublesome side effects (eg, bleeding or breast tenderness) or because of safety concerns. The long-cycle regimen might enhance adherence to HRT, especially among women in whom side effects develop when progestin is being taken monthly or daily. Low incidence of bleeding associated with this new regimen could also make long-term continuation of HRT more acceptable.
In conclusion, our study showed that most women aged at least 55 years of age can switch from standard dosage, cyclic monthly HRT to low-dosage, long-cycle HRT without compromising safety or control of menopausal symptoms. The new regimen is a promising alternative to standard HRT for women aged at least 55 years.
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Footnotes |
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The Medical Editing Department, Kaiser Foundation Research Institute, provided editorial assistance.
Supported by a grant from Solvay Pharmaceuticals, Marietta, GA, which markets Estratab. The grant, made to Kaiser Research Foundation, paid for research costs and partial salary support for the authors.
Received November 1, 2000. Received in revised form March 14, 2001. Accepted March 23, 2001.
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REFERENCES |
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2. Weiss SR, Ellman H, Dolker M. A randomized controlled trial of four doses of transdermal estradiol for preventing postmenopausal bone loss. Transdermal Estradiol Investigator Group. Obstet Gynecol 1999;94:330–6.
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23. The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial.JAMA 1995;273:199–208 (published erratum appears in JAMA 1995;274:1676).[Abstract]
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