CORTICOSTEROIDS, STRESS AND LEYDIG CELL FUNCTION

肾上腺皮质类固醇（皮质醇或皮质酮）增加 由压力、疾病或治疗干预引起的生产， 伴随着睾丸激素分泌减少和睾丸功能下降 功能本提案的主要目的是了解 睾丸和肾上腺事件是相关的，并确定控制， 调解他们的互动。糖皮质激素直接抑制睾酮 由Leydig细胞通过受体介导的过程产生， 幅度依赖于细胞内活性糖皮质激素 浓度.活性糖皮质激素的水平部分取决于 糖皮质激素分解代谢酶11 β- 羟类固醇脱氢酶（11 β-HSD）。 该实验室的初步研究表明， 皮质类固醇通过11 β-HSD阻止糖皮质激素-GR相互作用 Leydig细胞，从而提供了一种代谢控制机制， 睾丸激素的产生为了理解 皮质类固醇的作用，结构和功能的变化发生在 将研究Leydig细胞对糖皮质激素的反应。的 糖皮质激素对结构参数的影响， 影响细胞存活、有丝分裂或蛋白质周转。 将测量糖皮质激素对间质细胞功能的影响， 包括蛋白质合成作为细胞活力的指标， 睾酮生物合成酶，GR和11 β-HSD水平。一 糖皮质激素作用的最终结果可能是减少LH的数量， Leydig细胞表达的受体。因此，GR介导的对 将评估LH受体，以确定其减少是否有助于 睾丸激素分泌减少皮质类固醇调节11 β-HSD 以及其他组织中的GR，因此皮质类固醇的作用 这些参数对睾酮生物合成的依赖性调节， 将研究Leydig细胞。与成年间质细胞相比， 未成熟的睾丸间质细胞合成少量的睾酮， 可检测的11 β-HSD。肾上腺抑制的机制是否 睾丸功能已经提出成熟，睾丸激素 将研究分泌Leydig细胞适用于未成熟细胞。在 总之，提出了一种新的机制，其中11 β-HSD在Leydig 细胞控制皮质类固醇与GR结合的程度， 导致睾酮产生的抑制。解释如何 皮质类固醇对睾酮产生的控制受 三个相互作用的变量：糖皮质激素受体，11 β- 羟类固醇脱氢酶和循环皮质类固醇水平 将有助于进一步了解 高皮质类固醇状态对性功能的影响。

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.