Estrogen and Cardiovascular Disease: Is Timing Everything?

Cardiovascular disease (CVD) is the leading cause of death for both women and men, accounting for 1 in every 3 deaths in the United States (US) [1]. Since the mid-1980s, CVD has killed more women than men each year. In 2011 alone, CVD caused about 10,000 more deaths in women than men [1]. CVD in women is a disease of aging, rarely occurring before the 6th decade of life [2]. It has been proposed that deprivation of ovarian hormones, specifically estrogen, in menopause is causally related to increased CVD risk in aging women [3]. Observational and randomized controlled trials showed differential effects of menopausal hormone therapy (MHT), which included estrogen, on CVD risk: observational studies almost uniformly suggested benefit, while randomized trials showed harm, particularly in elderly women who were many years post-menopausal [4,5]. Multiple hypotheses have been proposed to explain the differences between the unfavorable effects of MHT in randomized studies and the body of observational evidence supporting the beneficial effects of MHT. Prominent among these is the “timing hypothesis” which proposes that MHT started in the perimenopausal or early postmenopausal period is cardioprotective, whereas MHT begun late after menopause increases the risk of CVD [6]. In this review we discuss observational studies and randomized controlled trials of MHT in women and examine the age-dependent effects of estrogen in animal models of acute vascular injury, as well as the effects of estrogen on cellular (macrophage and vascular smooth muscle cell (VSMC)) responses to inflammatory stimuli in vitro. STUDIES OF MENOPAUSAL HORMONES IN WOMEN Observational Studies A meta-analysis of 25 observational studies showed a decreased relative risk of CVD and coronary heart disease (CHD) in postmenopausal women taking MHT compared to those who had never taken hormones (RR=0.70; CI, 0.65-0.75) [7]. The largest and most frequently cited of these, the Nurses’ Health Study (NHS), was a prospective observational study that enrolled 121,700 female nurses 30-55 years of age (Table 1) [8]. The 20 year follow up study of the 70,533 postmenopausal participants (accruing 808,825 person-years of follow up) demonstrated significantly fewer CVD events, non-fatal myocardial infarctions (MIs) or fatal CHD in women on MHT compared to MHT never-users after adjustment for age, body mass index (BMI), weight, diabetes history, hypertension, increased cholesterol, age of menopause, smoking, and family history (RR=0.61; 95% CI 0.52-0.71). Table 1 Studies of Menopausal Hormones The major limitation of the NHS and other observational studies are its non-randomized design [9]. Observational studies are inherently unable to control for selection bias and for confounding differences between treatment groups. Although all of the participants in the NHS were female nurses, there may have been significant differences in unknown or unmeasured variables between the groups due to the non-randomized design of the study. Further studies demonstrated that women who chose to use MHT were more often Caucasian, healthier, wealthier and had more access to healthcare than non-users [10, 11, 12]. To control for these confounding factors, randomized placebo controlled trials were needed to determine the efficacy of MHT as a preventive strategy for CVD.