Progesterone Within Ovulatory Menstrual Cycles Needed for Cardiovascular Protection: An Evidence-Based Hypothesis

Women experience acute myocardial infarctions (AMI) 10 years later than men – evidence that estrogen is protective is not consistent. Ovulatory disturbances (low progesterone but normal estradiol levels) silently occur in >33% of all cycles. Progesterone-based (cycle-timed serum or saliva) levels or urinary metabolite excretions are necessary to diagnose silent ovulatory disturbances within regular, normal length menstrual cycles. Progesterone acts biphasically in vitro – initial proliferation changes to differentiation. It also suppresses or complements estradiol’s actions. Basic and clinical studies show that progesterone is positively related to endothelial function/blood flow, influences vascular smooth muscle cells and cardiac electrical signals. Several studies in primates document that high fat-fed subordinate females have higher stress, fewer ovulatory cycles and lower progesterone levels but similar cycle lengths as menstruating, dominant females. Subordinate females develop arterial plaque similar to high fat-fed males. In population-based prospective data, women with early pregnancy progesterone deficiency, stress and multiple miscarriages are at five-fold higher AMI risk. Also, early menopausal AMI are associated with significantly more pre-/perimenopausal anovulatory cycles. Given the multi-dimensional positive effects of progesterone on the cardiovascular system (CVS), and persuasive data from primate and human studies associating increased AMI with ovulatory disturbances, this review presents a new CVS protection hypothesis for women – ovulatory cycles with balanced progesterone-estradiol levels decrease women’s risks for AMI. Based on this new theory, it is believed that progesterone as well as estradiol is required during the premenopausal years to prevent women’s early heart disease.