Sex Hormones and Sex Chromosomes Cause Sex Differences in the Development of Cardiovascular Diseases

Abstract

This review summarizes recent evidence concerning hormonal and sex chromosome effects in obesity, atherosclerosis, aneurysms, ischemia/reperfusion injury, and hypertension. Cardiovascular diseases occur and progress differently in the 2 sexes, because biological factors differing between the sexes have sex-specific protective and harmful effects. By comparing the 2 sexes directly, and breaking down sex into its component parts, one can discover sex-biasing protective mechanisms that might be targeted in the clinic. Gonadal hormones, especially estrogens and androgens, have long been found to account for some sex differences in cardiovascular diseases, and molecular mechanisms mediating these effects have recently been elucidated. More recently, the inherent sexual inequalities in effects of sex chromosome genes have also been implicated as contributors in animal models of cardiovascular diseases, especially a deleterious effect of the second X chromosome found in females but not in males. Hormonal and sex chromosome mechanisms interact in the sex-specific control of certain diseases, sometimes by opposing the action of the other.

Keywords: androgen effects; atherosclerosis; coronary artery disease; estrogen effects; gonosomes; heart failure; obesity.

Figure 1

Incidence of cardiovascular disease in men and women as a function of age. Data on the incidence of cardiovascular disease defined as coronary heart disease, heart failure, stroke and intermittent claudication in women (white bars) and men (black bars) from 45 to 94 years of age. Data are derived from the Framingham Heart Study as reported by the National Heart, Lung and Blood Institute and adapted from reference with permission of the publisher.

Figure 2

Two mouse models for measuring sex chromosome effects. A, In the Four Core Genotypes (FCG) model, the testis determining gene (Sry) is removed from Y chromosome to make the “Y^–” chromosome, and an Sry transgene is inserted into chromosome 3. XY^– mice have ovaries and are called XY females (XYF) here. Mice with an Sry transgene have testes and are called males, XXM or XYM. B, The XY* model is useful for figuring out whether a difference between XX and XY is due to effects of the X chromosome or Y chromosome. It compares groups that differ in the number of X chromosomes (female mice with XX or XO and male mice with XY or XXY) or compares mice that differ in the presence/absence of Y chromosome (XO vs. XY and XX vs. XXY), to determine which causes XX vs. XY differences. Adapted from

Figure 3

Summary of effects of gonadal hormones and sex chromosome complement on body weight and adiposity in FCG and XY* mice. A, Male mice (with testes) weigh more than female mice (with ovaries). XX mice also weigh more than XY mice, although the magnitude of effect is less than that due to gonads. Four weeks after gonadectomy (GDX), all four genotypes reach a similar weight. Thereafter XX mice weigh more than XY mice, whether they originally had ovaries or testes. B, In XY* mice, males weigh more than females when gonads are intact, irrespective of sex chromosome complement. After GDX, the effect of gonadal hormones is abolished, and mice with two X chromosomes (XXY, XX) weigh more than mice with one X chromosome (XY, XO).

Figure 4

Cardiovascular disease risk in middle aged men and women as a function of blood pressure. Shown are data from the Framingham Heart Study and adapted from reference with permission of the publisher on estimated ten year rates of cardiovascular disease risk defined as a composite of coronary heart disease, cerebrovascular events, peripheral artery disease, and heart failure in normotensive (systolic blood pressure: 120–129 mm Hg) and pre-hypertensive (systolic blood pressure: 130–139 mm Hg) women (white bar) and men (black bar) 50 to 54 years of age who were non-smokers and did not have diabetes.