In Western societies men have a greater risk for atherosclerosis than women. This may be related to the fact that men have higher low density lipoprotein (LDL) and lower high density lipoprotein (HDL) levels than women since both of these divergences have been independently associated with an increased likelihood to develop ASVD. It is generally believed that these differences are a reflection of the action of the gonadal steroids but there has been little direct study of the role of endogeneous sex steroids in lipoprotein metabolism. The advent of long-acting gonadotropin releasing hormone analogs which reversibly suppress gonadotropin and thus gonadal steroid secretion when given chronically has now provided a tool with which to manipulate plasma sex steroid hormones and thus observe their effects on lipoprotein metabolism. In order to study the mechanisms for the effects of these hormones, a non-human primate - the baboon will be used. Plasma hormone concentrations will be manipulated by administering the analog alone or with exogenous estrogen and/or testosterone, so as to achieve situations of almost complete suppression, a high testosterone/estradiol ratio, or a low ratio. The effects of these manipulations on the cholesterol and apoprotein moieties of HDL and LDL measured by chemical and radioimmunoassay methods will be tested. Studies of intravascular kinetics of these lipoproteins by radioactive tracer methods, and assays of selected determinants of HDL metabolism, namely hepatic apo A-I mRNA levels and post-heparin hepatic and extrahepatic lipase activities, will performed. A second part of the proposal is aimed at investigating what influence endogenous sex hormones might have on lipoprotein responses to potentially atherogenic influences. Thus the agonist will be used to compare the lipoprotein responses of """"""""average"""""""" and """"""""hyper-responder"""""""" baboons to a dietary fat challenge in the eugonadal and hypogonadal states. A diet rich in animal fats and cholesterol constitutes a potentially harmful environmental influence and the utilization of animals inbred to respond either modestly or exuberantly with respect to their LDL-cholesterol, provides an example of a potentially harmful genetic influence. It will therefore be possible to investigate using sophisticated methodology the influence of the sex steroids on lipoprotein metabolism and the extent to which potentially atherogenic serum lipoprotein responses are modulated by endogenous sex hormones in the male.
