The Women’s Health Initiative: Risks outweigh benefits of combination hormone replacement therapy [Classics Series]

1. Combination estrogen and progestin hormone replacement therapy (HRT) is associated with a 29% increased risk of cardiovascular disease, 110% increased risk of venous thromboembolism and 26% increased risk of invasive breast cancer.

2. Over 1 year, 10 000 women taking combination HRT might experience 7 more cardiovascular events, 8 more strokes, 8 more pulmonary emboli, 8 more cases of invasive breast cancer, 6 fewer colorectal cancers and 5 fewer hip fractures.

Original Date of Publication: November 2002

Study Rundown: Whether post-menopausal hormonal replacement therapy (HRT) impacts primary prevention of cardiovascular events, as well as breast and colorectal cancer and fractures, is a topic of great interest in the field of medicine and gynecology. Previous investigations have produced conflicting results, with the majority of studies demonstrating reduced risk of cardiovascular disease with estrogen-only HRT. In 1991, an observational study was published using the Nurse’s Health study cohort that demonstrated a 44% reduced risk (RR: 0.56, CIL 0.40-0.80) of major coronary disease among women on postmenopausal estrogen replacement therapy (see background reading). However, as of the early 1990s, no randomized trials existed to guide practice with regard to the impact of hormone replacement therapy on overall health, including cardiovascular outcomes. The Women’s Health Initiative (WHI) clinical trial was designed to assess the impact of HRT in healthy women on cardiovascular disease, invasive breast cancer, colorectal cancer and fractures. Findings demonstrate an increased risk of cardiovascular disease, venous thromboembolism and invasive breast cancer; increased incidence of invasive breast cancer motivated early termination of the study by the Data Safety and Monitoring Board (DSMB).

This landmark study demonstrated that combined hormonal replacement therapy with both estrogen and progesterone should not be used for primary prevention of cardiovascular morbidity. Strengths included randomized, controlled design, low rate of loss to follow-up (3.5%) and an ethnically diverse, healthy study population. Additionally, rates of actual use were expected to be more comparable to those in the general population. Limitations included presentation of nominal (unadjusted) confidence intervals that did not account for multiple confounders and increased risk for Type I error (incorrect rejection of null hypothesis). The average age in the cohort was 63 years, a full 12 years after the average age of menopause in the United States. As such, the impact of HRT during the menopausal transition, the time when most women seek therapy for bothersome vasomotor symptoms, was not assessed. Lastly, results applied only to the specific combination and dose of HRTs studied herein: 0.625mg conjugated equine estrogen and 2.5mg medroxyprogesterone acetate. Future analysis might oversample women during the menopausal transition and primarily present and discuss multivariate-adjusted confidence intervals.

Click here to read study in JAMA

Relevant Reading: Nurse’s Health study: estrogen therapy and cardiovascular disease

In-Depth [randomized, controlled trial]: A total of 16 608 healthy, postmenopausal women were randomized to receive daily combined estrogen and progestin HRT (0.625mg conjugated equine estrogen and 2.5mg medroxyprogesterone acetate; n=8.506) or placebo (n=8.102). Clinical outcomes were assessed via telephone questionnaires conducted by certified study staff and included cardiovascular disease (cardiovascular death, nonfatal MI, stroke), venous thromboembolic event (deep vein thrombosis, pulmonary embolism), breast cancer, endometrial cancer, colorectal cancer, fractures (hip, vertebral, other osteoporotic) and death due to other causes. The study was prematurely terminated by the DSMB due to evidence for breast cancer harm; average follow-up time was 5.2 years, short of the planned 8.5 year average follow-up.

Women randomized to combination HRT were significantly more likely to experience venous thromboembolic disease (HR:2.11, adjusted CI:1.26-3.55) yet less likely to osteoporotic fracture (HR:0.76, adjusted CI: 0.63-0.92) compared to women randomized to placebo using a multivariate-adjusted model. Using a nominal model, women on combination HRT experienced a 29% increased risk of cardiovascular event (unadjusted/nominal CI:1.02-1.63), a 41% increased risk of stroke (nominal CI: 1.07-1.85) and a 26% increased risk of invasive breast cancer (nominal CI:1.00-1.59). Colorectal cancer risk was reduced by 37% among women on combination HRT (unadjusted CI:0.43-0.92).

More from this author: Cerclage prevents recurrent preterm birth in women with short cervix [Classics Series]. Risks of trial of labor after cesarean delivery (TOLAC) [Classics Series], Vaginal progesterone for sonographic short cervix decreased preterm birth [Classics Series], Progesterone injections reduce recurrent preterm birth [Classics Series], Recurrent pregnancy loss associated with increased cardiovascular morbidity

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