Project: Research project

Project Details


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.
Effective start/end date12/31/8912/31/89


  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute


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