Testosterone (T) regulates a variety of physiologic processes in men. T may exert its regulatory effects directly or via the actions of its metabolites dihydrotestosterone (DHT) and estradiol (E2). T is converted to DHT by the enzyme 5 alpha reductase and to E2 by the aromatase enzyme complex. It is unclear whether T action occurs by the direct effects of T, or whether conversion to one or both active metabolites is required. The proposed studies are designed to clarify the mechanism of T action in men and will focus on two specific areas of T action, pituitary gonadotropin secretion and lipoprotein levels. The first hypothesis to be tested is that the suppressive effects of T on pituitary gonadotropin secretion are partially due to the actions of DHT and E2. We will study men with idiopathic hypothalamic hypogonadism (IHH) who receive pulsatile GnRH infusions. After steady-state blood sampling, they will receive a series of supplemental sex steroid regimens for 4 weeks, using supplemental T plus either an aromatase or 5 alpha reductase inhibitor. T, DHT, and E2 will also be infused continuously for 4 days. Bioactive and immunoactive gonadotropin levels and sex steroid levels will be measured throughout each regimen. To asses any direct effects of either inhibitor on the pituitary, rat hemipituitaries will be incubated in vitro with each inhibitor, and bio- and immunoactive FSH and LH will be measured during 24 hours of GnRH perifusion. The second hypothesis is that the decrease in high-density lipoprotein cholesterol (HDL-C) associated with increases in serum T level is partially due to the actions of DHT and E2. This hypothesis will be tested in 2 human models. The GnRH antagonist Nal-Glu will be used to create rapid, reversible androgen deficiency in normal men. Nal-Glu will be administered for 4 weeks with placebo, with supplemental T and with T plus each inhibitor. Lipoproteins will be measured before, during, and after each regimen. Second, lipoproteins will be measured in the men with IHH. These studies will clarify the contributions of DHT and E2 to T effects on gonadotropin secretion and serum lipids in men and will contribute to current knowledge of normal gonadotropin and lipoprotein physiology. This knowledge may in turn be useful in developing new treatment options for diseases of the male reproductive system and in developing strategies to decrease coronary risk from lipoprotein abnormalities.
