ENDOCRINES, STRESS, AND HEREDITY ON ATHEROSCLEROSIS 



1203 



conclusion. All these studies would suggest that the 

 adrenal and pituitary glands have a significant 

 influence on lipid metabolism, but the exact mecha- 

 nism of these effects is still poorly understood. They 

 also affect the metabolism of the vascular wall and 

 may, therefore, be intimately related to athero- 

 sclerosis. Whether they have a direct effect on blood 

 coagulation and clot lysis has not yet been explored. 

 Some effects attributable to nervous and emotional 

 factors may actually be related to the release of 

 adrenal hormones under these circumstances. Further 

 studies of these hormones should be conducted. 



Sex Hormones 



Numerous clinical and experimental studies 

 indicate a profound influence of male and female 

 gonadal hormones on lipid and lipoprotein metab- 

 olism and atherosclerosis. Also, it has been reported 

 that these hormones exert a marked influence on 

 ground substance and connective tissue elements as 

 well as a slight, less well understood, effect on the 

 clotting mechanism. The influences of female sex 

 hormones are more pronounced than those of the 

 male hormone, and the effects of the male and female 

 hormones are in general opposite and antagonistic. 



The levels of circulating lipids and lipoproteins in 

 normal males and females of all ages have been 

 extensively studied (6, 96, 135). Up to the age of 20 

 years, total cholesterol and phospholipid levels are 

 similar in the two sexes. Both these lipid fractions rise 

 significantly in men up to the age of 33, and then 

 remain stable up to age 60. In women, on the con- 

 trary, they stay constant up to the age of 32, and 

 from then on a steady rise occurs until 58 years of 

 age. The 1 :3 ratio of free to esterified cholesterol is 

 fairly constant in both sexes at all ages. 



Serum lipoprotein patterns show a distinctly sex- 

 linked difference, as does the cholesterol content in 

 the different lipoprotein fractions. Young women 

 have more a-lipoproteins and a-lipoprotein cho- 

 lesterol than men of all ages, postmenopausal women, 

 or castrated women. Oliver & Boyd (no, 111) 

 studied lipids and lipoproteins during the menstrual 

 cycle and during pregnancy and found a depression of 

 ^-lipoproteins and of the cholesterol phospholipid 

 (C/P) ratio coincident with the peak of estrogen 

 secretion at ovulation. During the third trimester of 

 pregnancy /3-lipoproteins and the C P ratio increase 

 despite large estrogen secretion. These contradictory 

 findings need clarification. 



Sex differences in serum cholesterol levels are also 



observed in animals. Female rats have higher serum 

 cholesterol levels than males (22). Egg-laying hens and 

 pigeons have elevated serum cholesterol levels with 

 very high phospholipid levels and, therefore, signifi- 

 cantly depressed C P ratios. 



The normal lipoprotein pattern of the chick differs 

 from that of man and most mammals in that the main 

 component is a-lipoprotein (151). Furthermore, 

 giving estrogens to the cockerel elevates ^-lipoprotein, 

 instead of a-lipoprotein as in man (151). Incidentally, 

 the effect of diet on lipoprotein levels in chicks is also 

 opposite to that seen in man. 



In man, androgens increase /^-lipoproteins and 

 serum cholesterol. Eunuchs have lower cholesterol 

 and /^-lipoprotein le\-els than normal men (52). 



Estrogen administration to men or postmenopausal 

 women changes the serum lipoprotein pattern to the 

 young female type and this pattern remains as long 

 as therapy is continued, even over several years (151, 

 155). The effect on serum cholesterol is not so uni- 

 form. Several authors described a fall (7, 110), while 

 others found no change (151, 155). However, there is 

 uniform agreement that the phospholipid level 

 rises and therefore that the C/P ratio falls. 



Androgens even in small doses, given to men 

 concomitantly with estrogens, counteract the estro- 

 genic serum lipid effect without counteracting the 

 feminizing effect on the secondary sex characteristics. 

 The latter action represents one instance where the 

 action of the two hormones is not antagonistic, at 

 least in man. 



The mechanism by which the gonadal hormones 

 influence lipid metabolism is not yet entirely clarified. 

 Boyd (22) carried out tracer studies with C 14 -labeled 

 acetate in rats and found that estrogens slightly 

 depress plasma cholesterol synthesis and significantly 

 reduce the biological half-life of cholesterol. Ovariec- 

 tomy in female rats had the opposite effect (22, 44). 



Furman et al. (53) have shown an interrelationship 

 of methyltestosterone and dietary protein intake on 

 serum lipoproteins in men. On a low-protein or 

 protein-free formula diet both a- and ^-lipoproteins 

 were significantly depressed, beyond the depression of 

 the protein-free diet alone. These findings have been 

 confirmed by Olson & Vester (1 15). 



A very definite action of the sex hormones, particu- 

 larly the estrogens, on atherosclerosis has also been 

 established. Data from clinical medicine are sugges- 

 tive, experimental data on animals are indicative. 



Premenopausal women have less gross coronary 

 atherosclerosis than men or castrated women (127, 

 181) and a markedly lower incidence of myocardial 



