Hormone Therapy Use and Risk of Chronic Disease in the Nurses' Health Study: A Comparative Analysis With the Women's Health Initiative

Abstract

Observational studies and randomized controlled trials of menopausal hormone therapy (HT) and chronic disease risk appear to have divergent results for cardiovascular disease. However, differences may be related to a modifying effect of age, time since menopause, and HT formulation. In the Nurses' Health Study (NHS) (enrolling during 1980-1994 and following participants until 2002), we investigated associations between the use of oral conjugated equine estrogens (CEE) (0.625 mg/day) plus medroxyprogesterone acetate (MPA) (<10 mg/day) or oral CEE alone and cardiovascular disease, cancer, all-cause mortality, and other major endpoints among postmenopausal women, aged 50-79 years at HT initiation. Among women aged 50-59 years at HT initiation, associations of CEE alone or CEE+MPA with most clinical outcomes were highly concordant between NHS and Women's Health Initiative (WHI). However, for myocardial infarction, results for CEE+MPA were in the direction of risk elevation in WHI and in the direction of risk reduction in NHS. When examined according to years since menopause onset (<10 years) rather than age group, results were nonsignificant and concordant for both studies. Because few women in the NHS initiated HT after age 60 years, we did not examine associations in this group. Discrepancies between NHS and WHI could largely be attributed to differences in the age structure of the populations and age at HT initiation.

Keywords: Nurses’ Health Study; Women's Health Initiative; cardiovascular disease; chronic disease; epidemiologic methods; hormone therapy; randomized controlled trials.

Figure 1.

Association between hormone therapy use (oral conjugated equine estrogens (CEE) (0.625 mg/day)) and health outcomes among postmenopausal women who underwent a hysterectomy, in the Nurses’ Health Study (1980–2002) (diamonds) and in the intervention phase of the Women's Health Initiative (WHI) (squares) CEE-alone trial (1) among participants aged 50–79 years (A) and aged 50–59 years (B) at entry into analysis. All NHS models adjusted for age, calendar time, smoking status, alcohol intake, physical activity, body mass index, aspirin use of at least 1 day/month, history of high blood pressure, history of hypercholesterolemia, history of type 2 diabetes mellitus (all models except diabetes as an outcome), age at menopause, parental history of early myocardial infarction (MI), parental history of cancer, duration of CEE use, and duration of CEE plus medroxyprogesterone acetate (MPA) use. Breast cancer models additionally adjusted for height, parity, age at first birth, body mass index at age 18, history of benign breast disease, and mammogram in the previous cycle. Results for total MI, colorectal cancer, cancer deaths, and all-cause mortality are not reported for the age group 50–79 years because a significant interaction by age was reported in the intervention phase of the WHI (1). Hip fracture results are shown only for the 50–79 years group because there were fewer than 5 cases in the WHI in the 50–59 years group (1). CI, confidence interval; HR, hazard ratio.

Figure 2.

Association between hormone therapy use (oral conjugated equine estrogens (CEE) (0.625 mg/day) plus medroxyprogesterone acetate (MPA) (<10 mg/day)) and health outcomes among postmenopausal women with an intact uterus, in the Nurses’ Health Study (1980–2002) (squares) and in the intervention phase of the Women's Health Initiative (WHI) (diamonds) CEE+MPA trials (1) among participants aged 50–79 years (A) and 50–59 years (B) at entry into analysis. All NHS models adjusted for age, calendar time, smoking status, alcohol intake, body mass index, aspirin use of at least 1 day/month, history of high blood pressure, history of hypercholesterolemia, history of type 2 diabetes mellitus (all models except diabetes as an outcome), age at menopause, parental history of early myocardial infarction (MI), parental history of cancer, duration of CEE use, and duration of CEE+MPA use. Breast cancer models additionally adjusted for height, parity, age at first birth, body mass index at age 18, history of benign breast disease, and mammogram in the previous cycle. Hip fracture results are shown only for the 50–79 years group because there were fewer than 5 cases in the WHI in the 50–59 years group (1). CI, confidence interval; HR, hazard ratio.

Figure 3.

Association between hormone therapy (HT) use and total myocardial infarction among postmenopausal women, aged 50–79 years at entry into analysis and less than 10 years since onset of menopause, in the Nurses’ Health Study (1980–2002) (diamonds) and in the intervention phase of the Women's Health Initiative (squares) HT trials (1). All NHS outcomes were adjusted for age, calendar time, smoking status, alcohol intake, body mass index, aspirin use of at least 1 day/month, history of high blood pressure, history of hypercholesterolemia, history of type 2 diabetes mellitus, age at menopause, parental history of early myocardial infarction, parental history of cancer, duration of oral conjugated equine estrogens (CEE) use, and duration of CEE plus medroxyprogesterone acetate (MPA) use. CI, confidence interval; HR, hazard ratio.