SEX STEROID BINDING PROTEIN AND ANDROGEN ACTION

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This proposal will investigate the physiological regulation and actions of sex steroid-binding protein (SBP) in the male. SBP is a B-globulin that exhibits high-affinity binding of testosterone (T), the major circulating androgen. Plasma levels of this protein have been shown to increase markedly after birth in man, monkeys, bats, rabbits, and hamsters, and also during reproductive renewal in seasonal breeders. Current concepts hold that SBP may play an important role in altering the extra- and intracellular distribution, metabolism, and availability of T. Thus, any increases in SBP levels would be expected to influence the action of circulating androgens. Preliminary studies have suggested that both the postnatal and seasonal increases in SBP activity are influenced by the thyroid. To investigate the role of this gland in the regulation of SBP, plasma levels of total and free T3 and T4 will be measured in Djungarian hamsters and correlated with the dramatic increases in SBP levels which occur postnatally in this species. Parallel studies will be conducted in bats during the laboratory-induced seasonal SBP rise. In addition, the dose-response relationship between SBP levels and both L- and D-T4 will be determined in athyrotic males. To investigate the role of SBP in androgen action, two animal models will be employed: 1) the castrated male rat, an animal which lacks an endogenous SBP and thus allows the independent manipulation, by controlled chronic infusions, of both SBP and T; and 2) the male bat, a mammal in which a 30-fold increase in endogenous SBP levels can be induced experimentally. Using the rat model, the effectiveness of pulsative T signals on the prostate, the seminal vesicles, and the hypothalamic/pituitary regulation of LH secretion will be determined under conditions of both high and low levels of exogenously-administered SBP. Using the bat model, the androgenic activation of target tissues by R 1881, a synthetic steroid which binds to androgen receptors in target tissues but not to bat SBP, will be evaluated. Dose-response relationships between this androgen and target response will be established in bats with high and low SBP levels. The results from these in vivo studies, coupled with the extravascular localization of SBP using immunocytochemistry, will provide valuable information on the role of SBP in androgen action at the target tissue level.