Nurses’ Health Study: Estrogen associated with lower cardiovascular disease risk [Classics Series]

Classics Series, Landmark Trials in Medicine

1. Healthy postmenopausal nurses aged 30-53 years on estrogen therapy had a 44% reduced risk of major coronary disease compared to women not on estrogen.

2. Age-adjusted relative risk of cardiovascular mortality for postmenopausal women on estrogen was 0.72 (CI: 0.55-0.95, p=0.02).

Original date of publication: September 1991

Study Rundown: The impact of exogenous estrogen use on cardiovascular disease risk has been a topic of debate for decades. In the mid-1980s, conflicting results were published from 2 prospective investigations assessing the impact of estrogen use on cardiovascular disease risk. In 1985, initial findings from 4 years of follow-up from the Nurses’ Health Study (NHS), a large prospective observational study of healthy nurses, identified a decreased risk for cardiovascular disease among women on supplemental estrogen therapy. In the same issue of the New England Journal of Medicine, findings from the Framingham Heart study, a large prospective cohort study, demonstrated a 50% increased risk for cardiovascular morbidity among women over 50 years old on estrogen. These contradictory findings led to significant confusion at the time. In the present work, researchers from the Nurses’ Health Study present data from ten years of follow-up comparing risk of major coronary disease among women taking estrogen and those not taking estrogen.

This landmark study demonstrated a reduction in cardiovascular morbidity among postmenopausal women aged 30-63 years on exogenous estrogen. In the early 1990s, the results of this well-designed, large prospective study guided practice such that postmenopausal women were recommended to take estrogen for primary prevention of cardiovascular disease. Since that time, findings of the Women’s Health Initiative (WHI) demonstrated harm with combined estrogen-progestin hormone therapy such that long-term hormone replacement therapy is no longer recommended for primary prevention of cardiovascular morbidity, although a short course of estrogen or estrogen-progestin therapy is still offered to women in the menopausal transition experiencing significant vasomotor symptoms (e.g. hot flashes, night sweats, vaginal dryness) were offered exogenous estrogen therapy. Of note, findings from Nurses’ Health, a prospective observational study of 48 470 healthy postmenopausal nurses aged 30-63 years that assessed the impact of exogenous estrogen, cannot be responsibly compared to the findings of the WHI, a randomized controlled trial assessing the impact of combined estrogen and progesterone in 16,608 healthy postmenopausal women aged 50-79 years. Compared to women in WHI, those in NHS were younger (i.e. closer to the menopausal transition), were not excluded for having their uterus and ovaries removed, were on estrogen only (no progesterone) and had a higher level of medical literacy as practicing nurses.

Strengths included large sample population with low loss to follow-up and a decade-long study period. Limitations included lack of randomization. Women who self-select to take estrogen are likely to engage in other healthy behaviors that may decrease cardiovascular morbidity risk such that selection bias may shift effect estimates away from the null. Further, women in this cohort taking exogenous estrogen were leaner, which might confound findings given the association of cardiovascular morbidity and obesity.

Click here to read the study in NEJM

Relevant reading: Prospective study of postmenopausal estrogen therapy and CHD (NEJM)

Postmenopausal estrogen use, cigarette smoking and cardiovascular mortality in women over 50 (NEJM)

In-Depth [prospective cohort study]: A total of 48 470 healthy postmenopausal nurses aged 30-63 years in the Nurses’ Health Study were followed for 10 years to compare the incidence of cardiovascular disease morbidity and mortality among women taking exogenous estrogen and those not on hormone replacement therapy. As per NHS protocol, every 2 years participants completed follow-up questionnaires. Cardiovascular disease outcomes assessed included nonfatal MI, fatal coronary heart disease, coronary artery bypass graft procedure, stroke and total cardiovascular mortality. Established and potential risk factors were accounted for in multivariate analysis and included smoking, diabetes, hyperlipidemia and hypertension.

Healthy postmenopausal women on estrogen therapy experienced a 44% reduced risk of major coronary disease compared to women not on estrogen (RR=0.56, CI: 0.40-0.80). This risk reduction was similar when analysis was restricted to nonsmokers without diabetes, hypertension, or hyperlipidemia (RR=0.53 CI: 0.31-0.91). Age-adjusted relative risk of cardiovascular mortality was 0.72 (CI: 0.55-0.95, p=0.02). The relative risk for stroke was not significantly different between women taking estrogen and those not taking estrogen (RR=0.97, CI: 0.65-1.45).

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