Hormones, genetic factors, and gender differences in cardiovascular disease.

Abstract

Time for primary review 31 days. On average, women develop heart disease some 10–15 years later than men. This raises the question of whether there is some aspect of ‘femaleness’ which reduces risk, or whether there is some aspect of ‘maleness’ that raises risk. To date, most attention has been focused on the hypothesis that endogenous estrogen is cardioprotective in women [1]. Rising rates of coronary heart disease (CHD) after the menopause, and after oophorectomy, are among the strands of evidence in humans that endogenous estrogen may prevent CHD [2]. However, upon closer examination this evidence is not persuasive, and in fact the evidence is amenable to alternative explanations. During the first 3 decades of adult life, low-density lipoprotein (LDL) cholesterol levels are lower in women than men, and this may contribute to the delayed onset of CHD in women. A more widely held explanation for the later onset of CHD in women is their higher high-density lipoprotein (HDL) cholesterol levels, attributed to higher endogenous estrogen levels in women. However, the difference in HDL cholesterol between women and men is an androgen effect, not an estrogen effect. Up to puberty, young men and women have similar HDL cholesterol levels. At puberty, concurrent with the rise in endogenous testosterone levels, the HDL cholesterol levels in young men decline to the adult level [3,4]. A 20% difference in HDL cholesterol levels predicts at least a 20% difference in CHD rates in the short term, and may predict even larger differences in CHD rates over a lifetime [5]. Thus, the entire gender difference in CHD risk may indeed be due to the lifelong difference in HDL cholesterol levels; however, this difference is a consequence of having the Y chromosome. During fetal development, the Y chromosome directs the formation of … * Tel.: +1-301-435-6669; fax: +1-301-480-5158 rossouwj{at}nih.gov