CORTICOSTEROIDS, STRESS AND LEYDIG CELL FUNCTION

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The increase in adrenal corticosteroid (cortisol or corticosterone) production caused by stress, disease, or therapeutic intervention is accompanied by diminished testosterone production and decreased testicular function. The broad aims of this proposal are to understand how the testicular and adrenal events are linked and to identify the controls that mediate their interaction. Glucocorticoids directly inhibit testosterone production by Leydig cells through a receptor mediated process, whose magnitude is dependent on intracellular active glucocorticoid concentration. The level of active glucocorticoid is determined in part by the level of activity of the glucocorticoid catabolizing enzyme, 11beta- hydroxysteroid dehydrogenase (11beta-HSD) within the Leydig cell. Preliminary studies in this laboratory have shown that inactivation of corticosteroids by 11beta-HSD prevents glucocorticoid-GR interaction in the Leydig cell, and thus provides a mechanism for metabolic control of testosterone production. To understand the underlying bases of the corticosteroid effect, structural and functional changes that occur in the Leydig cell in response to glucocorticoids will be investigated. The effects of glucocorticoids on structural parameters including those that affect cell survival, mitosis, or protein turnover, will be investigated. Effects of glucocorticoids on Leydig cell function will be measured, including protein synthesis as an index of cell viability, activities of testosterone biosynthetic enzymes, and levels of GR, and 11beta-HSD. One end result of glucocorticoid action may be to reduce the number of LH receptors expressed by the Leydig cell. Therefore, GR-mediated effect on LH receptors will be evaluated, to determine if their decrease contributes to diminished testosterone production. Corticosteroids regulate 11beta-HSD and GR in other tissues, and therefore the effects of corticosteroid dependent regulation of these parameters on testosterone biosynthesis in Leydig cells will be investigated. In contrast with adult Leydig cells, immature Leydig cells synthesize low amounts of testosterone, and have no detectable 11beta-HSD. Whether the mechanism of adrenal suppression of testicular function that has been proposed for mature, testosterone secreting Leydig cells applies to immature cells will be studied. In summary, a novel mechanism is proposed in which 11beta-HSD in the Leydig cell controls the magnitude of corticosteroid binding to GR and the resulting inhibition of testosterone production. Explaining how the control of testosterone production by corticosteroid is influenced by the three interacting variables: glucocorticoid receptor, 11beta- hydroxysteroid dehydrogenase, and the level of circulating corticosteroid will contribute to a further understanding of the effects of hypercorticosteroid states on sexual function.