Influence of sex and sex hormones upon the development of atherosclerosis and upon the lipoproteins of plasma

Abstract Although the extent of lipid deposit in most arteries differs little in men and women, there is some precocity of its development in the coronary arteries of men. Angina pectoris, coronary occlusion, and myocardial infarction rarely occur in women before the age of 40. Arteriosclerotic disease of the vessels of the legs is more common in men. The suceptibility of men and the relative immunity of young women to serious consequences of coronary and peripheral atherosclerosis are not satisfactorily explained by anatomic differences in the sexes. The relative incidence of severe or fatal complications cannot be explained by any demonstrable variation with sex in the concentration of total lipids, cholesterol, or phospholipids. Sex-linked differences in the distribution of lipoproteins can, however, be demonstrated by Cohn fractionation of plasma or by the methods of paper electrophoresis and ultracentrifugation. Young men tend to have in their plasma a greater concentration of beta lipoproteins, a smaller amount of alpha lipoproteins, a higher beta-alpha ratio, and a larger content of S f 10–20 lipoproteins. Action of heparin in clearing alimentary hyperlipemia is less prompt in young men. The number of mast cells in their tissues is less than in young women. None of these distinguishing features of sex are apparent in the aged. Both the incidence of clinical complications and the distinctive differences in the state of lipids in the plasma are less prominent after the time of the menopause. That the chemical differences between young men and women have some relationship to the development of atherosclerosis is indicated by the demonstration that states of relative freedom from the disease are accompanied by lipid patterns like those of young women, and that diseases and conditions which are accompanied by advanced atherosclerosis or are known to be atherogenic have patterns that are exaggerations of those found in young men. Studies of conditions in the domestic fowl have shed some light on the nature of sex-linked differences in the development of atherosclerosis. Spontaneously occurring arterial lesions in the rooster and in the mature egg-laying hen are quite different, although it is doubtful whether either is comparable to human atheroma. Puberty in the hen and the administration of estrogens to the immature or male chick are accompanied by hyperlipemia which in its degree is without counterpart in human physiology. Such gross species' differences have made difficult, the application of knowledge derived from the study of the fowl to the problems of human atherosclerosis. It has been shown in the chick, however, that experimental cholesterol-induced atherosclerosis causes extensive atheromatous lesions of the aorta in both the hen and the rooster. It causes coronary atherosclerosis in the male bird but not in the laying hen. It has been shown also that the administration of estrogen inhibits prophylactically the development of coronary atheroma but does not affect lipid deposit in the aorta. Estrogen also has a therapeutic effect in causing regression of coronary atheroma without modifying the degree of aortic atherosclerosis. These anatomic effects of estrogen are accompanied by modification of the chemical changes consequent to cholesterol feeding, and particularly are responsible for an increase in the concentration of phospholipids and a lowering of cholesterol-phospholipid ratios. They are not reversed in the chick by simultaneous administration of androgen. In man the administration of gonadal hormones is accompanied by profound changes in the distribution of lipids in the plasma. Estrogen transforms the highly abnormal lipid pattern of myocardial infarction to one that is indistinguishable from that of healthy young women. Methyl testosterone exerts an opposite action: it exaggerates the lipid abnormality of survivors of myocardial infarction; it produces patterns similar to those of coronary atherosclerosis in individuals whose plasma has previously shown no lipid abnormalities. Contrary to the experience in the chick, the administration of androgens simultaneously with that of estrogens obliterates the chemical effects of the estrogens. The accumulated clinical and experimental evidence leaves little doubt that sex is a potent factor in the development of atherosclerosis, and that its influence is hormonal and is accompanied by easily recognizable changes in the distribution of lipids in plasma. There is much reason to believe that the development of coronary atherosclerosis and its complications is dependent upon factors not equally operative in other arterial systems.