Extremes of Endogenous Testosterone Are Associated With Increased Risk of Incident Coronary Events in Older Women

Abstract

Several lines of evidence suggest that high levels of testosterone are atherogenic in women. The testosterone to estrogen balance in women increases markedly at the time of menopause when central adiposity and the incidence of cardiovascular disease also increase. The view that elevated serum androgen is harmful to the female heart is also supported by the occurrence of hyperandrogenemia, an adverse coronary heart disease (CHD) risk profile, and endothelial dysfunction in young women with polycystic ovarian syndrome. However, there has been no consistent increase in CHD events and mortality in women with polycystic ovarian syndrome. Moreover, recent studies have found that women with atherosclerotic disease have low serum levels of testosterone suggesting that unlike high levels, low levels of this hormone may have beneficial effects on the female heart. This prospective, population-based study evaluated the effects of total testosterone (total T) and bioavailable T (BioT) levels on the risk of incident coronary events among 639 older community-dwelling postmenopausal women. During a median follow-up of 12.3 year, 134 women had an incident CHD event; of these, 45 were nonfatal myocardial infarctions (MIs), 10 were coronary revascularizations, and 79 were fatal MIs. Multivariate regression analysis showed that age-adjusted CHD risk estimates were similar for the four highest total T quintiles relative to the lowest; this suggests a low threshold for incident events with total T. Age-adjusted analyses showed that compared to higher levels, the lowest total T quintile (≤80 pg/mL) was associated with a significant increase in the risk of incident CHD (hazard ratio [HR], 1.62; 95% confidence interval [CI], 1.10―2.39, P = 0.017). With BioT, age-adjusted quintile analyses suggested a U-shaped association for risk of incident CHD (P for quadratic trend <0.001). Both the lowest (low BioT) and the highest (high BioT) quintiles were associated with a significantly increased age-adjusted risk of incident CHD (HR for low BioT: 1. 7 9, with a 95% CI of 1.03-3.16, P = 0.046), and HR for high BioT: 1.96, with a 95% CI of 1.13-3.41, P = 0.022). Adjustment for other variables, including lifestyle characteristics, adiposity, estradiol, and ovarian status had a minimal effect on the results. These findings show that low levels of total T and high levels of BioT are independently associated with higher risk of incident CHD events in community-dwelling postmenopausal women. The data suggest that an optimal range of testosterone may exist for cardiovascular health in older women.