ENDOCRINES, STRESS, AND HEREDITY ON ATHEROSCLEROSIS 



I! 99 



side effect independent of their direct actions upon 

 atherosclerosis and ischemic disease. It is more likely, 

 however, that emotional upsets induce hormonal and 

 nervous factors which lead to ischemic disease. 



It is thus apparent that any attempt to understand 

 the pathogenesis of the multifaceted process of 

 atherosclerosis requires that many factors be con- 

 sidered. In considering them, the effects of each on 

 lipid metabolism, on the vascular wall, on blood 

 coagulation, and on fibrinolysis have to be studied 

 separately, and after that all the facts must be inte- 

 grated to reconstruct the whole complex process. At 

 present there are many gaps in our knowledge which 

 are difficult to bridge. While the influences of hor- 

 mones and heredity on lipid metabolism and on the 

 vascular wall have been studied to some extent, their 

 influences on blood clotting and fibrinolysis are poorly 

 understood at present, since such studies are still in 

 their infancy. Equally scanty is our knowledge of the 

 effect of emotional factors on atherosclerosis and its 

 sequelae. 



HORMONES 



That hormones influence lipid metabolism and 

 atherosclerosis has long been suspected from clinical 

 findings. Several diseases of endocrine organs show 

 alterations in serum lipid levels and are associated 

 with significant deviations in the incidence and 

 severity of atherosclerosis. Several hormones are also 

 known to affect the morphologic characteristics of the 

 ground substance of the vascular wall and its cell 

 membrane permeability. This would indicate that 

 hormones may influence atherosclerosis either by a 

 direct action on the vascular wall or through their 

 influence on lipid metabolism (synthesis, absorption, 

 transport, storage, excretion, and destruction), or 

 both. The recognition of these factors stimulated 

 extensive research into the mechanism of these 

 actions. Only the action of the following hormones 

 will be considered here: a) thyroid, b) pancreas, c) 

 adrenal and pituitary, and d) sex. The part played 

 by others is too poorly understood and too unimpor- 

 tant to warrant discussion. 



Thyroid 



The effect of thyroid hormone on lipid metabolism, 

 particularly cholesterol metabolism, has been studied 

 extensively in man and in various species of experi- 

 mental animals. Endogenous thyroid hypersecretion, 



as occurs in thyrotoxicosis, and the exogenous 

 administration of the hormone have identical effects 

 and will be discussed together. Different forms of 

 hypothyroidism, whether primary or secondarily 

 induced in man and animals by surgical thyroid- 

 ectomy or by I 131 administration, also show similar 

 effects. The suppression of thyroid hormone secretion 

 by thiourea drugs shows — in rats at least — a greater 

 effect on cholestrol metabolism than that produced 

 by the other methods of inducing hypothyroidism 

 (22, 62). 



Hyperthyroidism decreases serum cholesterol levels 

 in man and animals. Recent tracer studies indicate 

 that thyroid hormone increases synthesis of cholesterol 

 in the liver, particularly of the free cholesterol 

 fraction, and also increases catabolism and fecal 

 excretion of this sterol (cf 22). Boyd (22) found in 

 rats that neither exogenous thyroid hormone nor 

 active thyroid hormone analogues lower normal serum 

 cholesterol levels appreciably; however, if animals are 

 made slightly hypercholesterolemic by dietary means, 

 then these hormone preparations depress the dietary 

 hypercholesterolemia. It has been demonstrated that 

 this action of thyroxin or thyroid hormone is not due 

 to the increase in basal metabolic rate per se, as 

 several thyroxin analogues show the cholesterol 

 depressant action without increase in basal metab- 

 olism (21). Furthermore, in chicks it was shown that 

 dinitrophenol, a drug that increases basal metab- 

 olism, has no effect on serum cholesterol levels 

 (148). Thyroid hormones also reduce /^-lipoprotein 

 concentration and that of certain classes of high 

 density a-lipoproteins (70). 



Hypothyroidism in man and animals produces a 

 decreased synthesis of cholesterol while the biological 

 half-life of serum cholesterol is increased and fecal 

 excretion is reduced (22). The effect of hypothy- 

 roidism on lipoproteins is the direct opposite of the 

 effect of exogenous thyroid hormone administration, 

 i.e., it causes an increase in /3-lipoproteins. 



Pituitary thyroid stimulating hormone is without 

 direct effect on cholesterol metabolism and athero- 

 sclerosis. 



Thyroid hormone also affects the vascular wall. 

 This has long been established in the older literature. 

 Large doses of thyroxin or dessicated thyroid cause 

 damage to the vascular media. They produce necrosis 

 and calcification, similar to the changes produced by 

 catecholamines (10). These are arteriosclerotic 

 changes, not atherosclerosis. Smaller doses of thyroid 

 hormone preparations have been shown to reduce 

 cholesterol-oil-induced hypercholesterolemia and 



