Leydig cells contain glucocorticoid receptors and respond to glucocorticoid by decreasing their rate of testosterone production. Serum levels of glucocorticoid are increased during stress caused by a wide variety of conditions, including disease, exercise and psychosocial interaction. Based upon these facts, the applicant and other investigators hypothesize that declines in male reproductive function associated with stress are due in part to the direct inhibition of Leydig cells by glucocorticoid. Therefore, the applicant will test the hypothesis that rapid declines in testosterone occurring within two hours of acute stress are independent of luteinizing hormone and are directly mediated by glucocorticoid acting on Leydig cells. He will also investigate the physiological role of 11beta-hydroxysteroid dehydrogenase (11betaHSD) because this enzyme is abundantly expressed in Leydig cells and metabolizes glucocorticoid.
Three Specific Aims are proposed.
Aim (1) is to test for effects of glucocorticoid mediated by glucocorticoid receptors (GR) in Leydig cells, using both adrenalectomized rats and mice with a Leydig-cell-specific knockout of GR.
Specific Aim (2) will define the consequences of stress for the Leydig cell.
Aim (3) is intended to identify sustained effects of high glucocorticoid concentrations on Leydig cell steroidogenesis after exposure to stress in utero, perinatally or during adulthood. These studies would be the first to establish the extent of direct, GR-mediated glucocorticoid action on Leydig cells during stress. Other stress-induced factors such as nitric oxide and beta-endorphin will be monitored at the testis level because they may affect Leydig cell function independently and/or in addition to glucocorticoid. The hypothesis that 11betaHSD in Leydig cells is a key determinant of stress effects is supported by the fact that 11beta oxidation is the usual mode of 11betaHSD catalysis in Leydig cells from adults. The reverse is true of immature Leydig cells where the 11beta-reductase predominates. The balance of oxidative and reductive catalytic activity displayed by the type 1 isoform of the enzyme in Leydig cells may be adjustable by intracellular conditions, fine-tuning of glucocorticoid effects, affected by stress. Therefore, the applicant will also test for the existence of endogenous inhibitors in the testis that selectively modulate these opposing activities of 11betaHSD. Anticipated results would show that 11betaHSD is a critical intracellular regulator of testosterone production in Leydig cells.
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