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HANDBOOK OF PHYSIOLOGY 



CIRCULATION II 



infarction (113, 130). After the menopause the 

 incidence of myocardial infarction in women slowly 

 rises to become almost equal to that in men by the 

 eighth decade (110, 113). Furthermore, Marmorston 

 et al. (99) have shown that postmenopausal women 

 with coronary artery disease have lower urinary 

 estrogen levels than healthy women of the same age, 

 and also have lower levels of protein-bound iodine 

 indicating a decreased thyroid function. Bersohn & 

 Oelofse (14) made similar observations in man. Aortic 

 atherosclerosis shows no significant sex difference (43, 

 128, 176). The protection of the female from coronary 

 atherosclerosis is lost in the presence of familial 

 hypercholesterolemia and in diabetes mellitus. 



Cockerels on a high-fat, high-cholesterol (athero- 

 genic) diet are protected against coronary athero- 

 sclerosis when given estrogens (1 19). Also, previously 

 induced atherosclerosis can be completely reversed by 

 the hormone (120). Aortic atherosclerosis is not 

 influenced. Sexually mature, estrogen-secreting hens 

 fed the atherogenic diet develop aortic atherosclerosis 

 but no coronary atherosclerosis (150). Castration of 

 these hens makes them susceptible to coronary lesions 

 (121). Estrogens given to chicks on a normal non- 

 estrogenic diet induce aortic atherosclerosis, but not 

 coronary atherosclerosis (27, 67, 86). These different 

 effects of estrogens on coronary and aortic athero- 

 sclerosis are a good example of the previously stated 

 observation that local anatomic or metabolic factors 

 are of importance in atherogenesis. This makes it 

 imperative for the investigator to study the several 

 vascular beds separately, and not to draw the con- 

 clusion that observations made in one vascular bed 

 necessarily apply to other parts of the arterial tree. 



Freedom from coronary lesions in chickens is 

 accompanied by the previously described char- 

 acteristic serum lipid changes resulting in a normal 

 C V ratio in the presence of hypercholesterolemia. 

 The same effect on lesions and lipids was obtained 

 in rats (108). In male rabbits neither serum lipid 

 changes nor coronary protection can be achieved by 

 estrogen administration (151). Ludden et al. (91) 

 observed that both androgens and estrogens protect 

 intact female rabbits from cholesterol-induced aortic 

 atheroscerosis. Neither hormone was effective in 

 males or in castrated females. 



Another exception to this sex phenomenon is 

 atherosclerosis in a susceptible strain of pigeons 

 (vide infra). Old, egg-laying pigeons show coronary 

 atherosclerosis despite the usual low C/P ratio 

 characteristic for female birds (66, 88-90). 



Androgens in large doses depress diet-induced 



hypercholesterolemia without influencing athero- 

 sclerosis (123). 



Studies in chicks revealed that estrogen protection 

 is preserved even if estrogen administration is com- 

 bined with androgen administration or with ad- 

 ministration of DCA or compound F, or is used after 

 pancreatectomy (149, 154)- The only clear-cut 

 reversal of the estrogen effect was obtained when 

 chicks were made hypothyroid by the administration 

 of thiouracil (122). A slight decrease of estrogen 

 reversal of previously induced lesions was observed 

 when insulin was administered concomitantly with 

 estrogens during the period when the lesions were 

 regressing (154). Recently, 3 we have noted that 

 blocking the reticulo-endothelial system also pre- 

 vented the estrogen effect. 



Estrogens have also been shown to stimulate 

 growth of ground substance, particularly collagen and 

 fibroblasts. They also stimulate the reticuloendothelial 

 system (18, 25). Furthermore, there is some indication 

 that estrogens influence fibrin content and fibrinolytic 

 activity of the blood (11, 56, 57). It has also been 

 reported that intravenous injection of estrogens, 

 particularly conjugated equine estrogens, has a 

 hemostatic effect (58). 



An indication that the local influence of estrogens 

 on the vascular wall may be related to athero- 

 sclerosis was recently obtained in chicks. It was shown 

 that atherosclerotic abdominal aorta and coronary 

 lesions, produced by a high-fat, high-cholesterol, low- 

 protein diet, can ulcerate if large doses of estrogens are 

 given (76). In the chick this was shown to occur as a 

 stage in the healing process of these lesions. This is 

 the first suggestion that estrogens may also influence 

 the vascular wall of the aorta. 



The action of estrogens on lipid metabolism and 

 atherogenesis stimulated several long-term research 

 projects in man using different female sex-hormone 

 preparations in the therapy of patients with proven 

 ischemic heart disease (101, 112, 131, 151, 155). The 

 results show a possible life-prolonging action only 

 when a natural estrogen preparation (conjugated 

 equine estrogens) is being used. It is not known wh\ 

 this difference exists between natural and synthetic 

 compounds. The therapeutic value of this regimen is, 

 however, limited by the accompanying feminizing 

 action of the hormone. Several nonfeminizing estrogen 



3 Pick, R., L. N. Katz, P. J. Johnson, and D. E. Century. The 

 role of the reticulo-endothelial system and estrogens on coro- 

 nary atherogenesis in cholesterol-fed cockerels. Circulation. In 

 press. I October 1962.) 



