Benefits and Risks of Postmenopausal Hormone Therapy
Benefits and Risks of Postmenopausal Hormone Therapy
The authors further analyzed results from the Women's Health Initiative randomized trials (1993–2004) of conjugated equine estrogens, with or without medroxyprogesterone acetate, focusing on health benefits versus risks among women who initiated hormone therapy soon after menopause. Data from the Women's Health Initiative observational study (1993–2004) were included in some analyses for additional precision. Results are presented here for incident coronary heart disease, stroke, venous thromboembolism, breast cancer, colorectal cancer, endometrial cancer, or hip fracture; death from other causes; a summary global index; total cancer; and total mortality. Hazard ratios for breast cancer and total cancer were comparatively higher (P < 0.05) among women who initiated hormone therapy soon after menopause, for both regimens. Among these women, use of conjugated equine estrogens appeared to produce elevations in venous thromboembolism and stroke and a reduction in hip fracture. Estrogen plus progestin results among women who initiated use soon after menopause were similar for venous thromboembolism, stroke, and hip fracture but also included evidence of longer-term elevations in breast cancer, total cancer, and the global index. These analyses provide little support for the hypothesis of favorable effects among women who initiate postmenopausal estrogen use soon after menopause, either for coronary heart disease or for health benefits versus risk indices considered.
The Women's Health Initiative (WHI) randomized controlled trials—trials of the use of 0.625 mg/day of conjugated equine estrogens (CEE) among 10,739 posthysterectomy women and CEE plus 2.5 mg/day of medroxyprogesterone acetate (MPA) among 16,608 women with an intact uterus—were designed to examine the effects of hormone therapy on coronary heart disease (CHD) risk and overall health benefits versus risks. The trial design projected a major reduction in CHD risk, based on observational studies, for both regimens. Recruitment into both trials took place during 1993–1998. The CEE/MPA trial was stopped early in 2002, after an average of 5.6 years of follow-up, on the basis of an elevation in breast cancer incidence in conjunction with an unfavorable global index—defined as time to incident CHD, stroke, pulmonary embolism, breast cancer, colorectal cancer, endometrial cancer, or hip fracture or to death from other causes. As a result, the potential use of this regimen for primary disease prevention was much reduced, and interest began to focus on the safety and efficacy of relatively short-term hormone therapy among recently postmenopausal women. This focus intensified after the CEE trial was also stopped early in 2004, after an average of 7.1 years of follow-up, on the basis of an elevation in stroke in conjunction with a limited likelihood of demonstrating a CHD benefit. The global index in the CEE trial, defined as above but without endometrial cancer, differed little between randomization groups, reflecting a balance of health benefits and risks.
Among women who were assigned to active hormone therapy and reported no prior hormone therapy, only 10% in the CEE trial and 17% in the CEE/MPA trial were within 5 years of menopause at randomization. As such, effects of hormone therapy could not be estimated with precision for these important subsets. An additional sizeable group of women had used hormones prior to WHI enrollment and had either stopped hormone use or chosen to undergo a 3-month washout period prior to randomization. Approximately 84% of these women first initiated hormone therapy within 5 years following menopause in both the CEE and CEE/MPA trials. These women contribute information on health effects among women who initiate hormone therapy soon after menopause, particularly concerning benefits and risks some years after first use of hormone therapy.
The WHI observational study, carried out among 93,676 postmenopausal women in the same age range (50–79 years) at enrollment in 1993–1998, is available as an additional source of information on the health effects of these regimens. Women in the observational study were drawn from the same populations as the clinical trial women, and many elements of the protocol were common to the 2 WHI components. These included much baseline questionnaire and interview data, as well as the clinical outcomes ascertained and most aspects of the outcome ascertainment methods.
Results from joint analyses of clinical trial and observational study data have been reported for cardiovascular disease in relation to CEE/MPA and CEE; hazard ratio estimates were in agreement between the clinical trials and the observational study for CHD and venous thromboembolism after allowing for confounding and time since hormone therapy initiation, though there was lesser agreement for stroke. Allowance for duration of hormone therapy use is essential in such analyses, since hormone therapy users in the observational study had often been on the regimen reported at enrollment for several preceding years, and hazard ratios declined with increasing duration of use for both CHD and venous thromboembolism. Similar analyses have been conducted for invasive breast cancer. Hazard ratios were higher in the observational study than in the clinical trials for both CEE and CEE/MPA, even after consideration of confounding and duration of use. This residual discrepancy could be explained, however, by higher breast cancer hazard ratios among women who first used hormone therapy soon after menopause, as compared with those who initiated hormone therapy following a lengthy "gap" time. These analyses, suggesting comparatively unfavorable breast cancer effects among recently postmenopausal women, contrast with corresponding results for CHD and coronary calcification that may suggest more favorable effects among younger, recently postmenopausal women. A "postmenopausal estrogen timing hypothesis," suggesting that estrogens have favorable effects on CHD in recently postmenopausal women but null or harmful effects among older women, has been debated recently, with WHI data being central to both sides of the argument. Of course, evaluation of a broader timing hypothesis involving a range of health effects is needed for decision-making concerning use of hormone therapy and is a major focus of this paper.
We analyzed the effects of CEE and CEE/MPA (particularly longer-term effects), when initiated soon after menopause, on a range of clinical outcomes, including the global index described above, as well as total invasive cancer incidence and total mortality. The analyses used both WHI clinical trial data and combined WHI clinical trial and observational study data.
Abstract and Introduction
Abstract
The authors further analyzed results from the Women's Health Initiative randomized trials (1993–2004) of conjugated equine estrogens, with or without medroxyprogesterone acetate, focusing on health benefits versus risks among women who initiated hormone therapy soon after menopause. Data from the Women's Health Initiative observational study (1993–2004) were included in some analyses for additional precision. Results are presented here for incident coronary heart disease, stroke, venous thromboembolism, breast cancer, colorectal cancer, endometrial cancer, or hip fracture; death from other causes; a summary global index; total cancer; and total mortality. Hazard ratios for breast cancer and total cancer were comparatively higher (P < 0.05) among women who initiated hormone therapy soon after menopause, for both regimens. Among these women, use of conjugated equine estrogens appeared to produce elevations in venous thromboembolism and stroke and a reduction in hip fracture. Estrogen plus progestin results among women who initiated use soon after menopause were similar for venous thromboembolism, stroke, and hip fracture but also included evidence of longer-term elevations in breast cancer, total cancer, and the global index. These analyses provide little support for the hypothesis of favorable effects among women who initiate postmenopausal estrogen use soon after menopause, either for coronary heart disease or for health benefits versus risk indices considered.
Introduction
The Women's Health Initiative (WHI) randomized controlled trials—trials of the use of 0.625 mg/day of conjugated equine estrogens (CEE) among 10,739 posthysterectomy women and CEE plus 2.5 mg/day of medroxyprogesterone acetate (MPA) among 16,608 women with an intact uterus—were designed to examine the effects of hormone therapy on coronary heart disease (CHD) risk and overall health benefits versus risks. The trial design projected a major reduction in CHD risk, based on observational studies, for both regimens. Recruitment into both trials took place during 1993–1998. The CEE/MPA trial was stopped early in 2002, after an average of 5.6 years of follow-up, on the basis of an elevation in breast cancer incidence in conjunction with an unfavorable global index—defined as time to incident CHD, stroke, pulmonary embolism, breast cancer, colorectal cancer, endometrial cancer, or hip fracture or to death from other causes. As a result, the potential use of this regimen for primary disease prevention was much reduced, and interest began to focus on the safety and efficacy of relatively short-term hormone therapy among recently postmenopausal women. This focus intensified after the CEE trial was also stopped early in 2004, after an average of 7.1 years of follow-up, on the basis of an elevation in stroke in conjunction with a limited likelihood of demonstrating a CHD benefit. The global index in the CEE trial, defined as above but without endometrial cancer, differed little between randomization groups, reflecting a balance of health benefits and risks.
Among women who were assigned to active hormone therapy and reported no prior hormone therapy, only 10% in the CEE trial and 17% in the CEE/MPA trial were within 5 years of menopause at randomization. As such, effects of hormone therapy could not be estimated with precision for these important subsets. An additional sizeable group of women had used hormones prior to WHI enrollment and had either stopped hormone use or chosen to undergo a 3-month washout period prior to randomization. Approximately 84% of these women first initiated hormone therapy within 5 years following menopause in both the CEE and CEE/MPA trials. These women contribute information on health effects among women who initiate hormone therapy soon after menopause, particularly concerning benefits and risks some years after first use of hormone therapy.
The WHI observational study, carried out among 93,676 postmenopausal women in the same age range (50–79 years) at enrollment in 1993–1998, is available as an additional source of information on the health effects of these regimens. Women in the observational study were drawn from the same populations as the clinical trial women, and many elements of the protocol were common to the 2 WHI components. These included much baseline questionnaire and interview data, as well as the clinical outcomes ascertained and most aspects of the outcome ascertainment methods.
Results from joint analyses of clinical trial and observational study data have been reported for cardiovascular disease in relation to CEE/MPA and CEE; hazard ratio estimates were in agreement between the clinical trials and the observational study for CHD and venous thromboembolism after allowing for confounding and time since hormone therapy initiation, though there was lesser agreement for stroke. Allowance for duration of hormone therapy use is essential in such analyses, since hormone therapy users in the observational study had often been on the regimen reported at enrollment for several preceding years, and hazard ratios declined with increasing duration of use for both CHD and venous thromboembolism. Similar analyses have been conducted for invasive breast cancer. Hazard ratios were higher in the observational study than in the clinical trials for both CEE and CEE/MPA, even after consideration of confounding and duration of use. This residual discrepancy could be explained, however, by higher breast cancer hazard ratios among women who first used hormone therapy soon after menopause, as compared with those who initiated hormone therapy following a lengthy "gap" time. These analyses, suggesting comparatively unfavorable breast cancer effects among recently postmenopausal women, contrast with corresponding results for CHD and coronary calcification that may suggest more favorable effects among younger, recently postmenopausal women. A "postmenopausal estrogen timing hypothesis," suggesting that estrogens have favorable effects on CHD in recently postmenopausal women but null or harmful effects among older women, has been debated recently, with WHI data being central to both sides of the argument. Of course, evaluation of a broader timing hypothesis involving a range of health effects is needed for decision-making concerning use of hormone therapy and is a major focus of this paper.
We analyzed the effects of CEE and CEE/MPA (particularly longer-term effects), when initiated soon after menopause, on a range of clinical outcomes, including the global index described above, as well as total invasive cancer incidence and total mortality. The analyses used both WHI clinical trial data and combined WHI clinical trial and observational study data.
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