Hardy Matthew P, Gao Hui-Bao, Dong Qiang, Ge Renshan, Wang Qian, Chai Wei Ran, Feng Xing, Sottas Chantal
Center for Biomedical Research, Population Council, New York, NY 10021, USA.
Cell Tissue Res. 2005 Oct;322(1):147-53. doi: 10.1007/s00441-005-0006-2. Epub 2005 Nov 3.
The Leydig cell is the primary source of testosterone in males. Levels of testosterone in circulation are determined by the steroidogenic capacities of individual Leydig cells and the total numbers of Leydig cells per testis. Stress-induced increases in serum glucocorticoid concentrations inhibit testosterone-biosynthetic enzyme activity, leading to decreased rates of testosterone secretion. It is unclear, however, whether the excessive glucocorticoid stimulation also affects total Leydig cell numbers through induction of apoptosis and thereby contributes to the stress-induced suppression of androgen levels. Exposure of Leydig cells to high concentrations of corticosterone (CORT, the endogenously secreted glucocorticoid in rodents) increases their frequency of apoptosis. Studies of immobilization stress indicate that stress-induced increases in CORT are directly responsible for Leydig cell apoptosis. Access to glucocorticoid receptors in Leydig cells is modulated by oxidative inactivation of glucocorticoid by 11 beta-hydroxysteroid dehydrogenase (11 betaHSD). Under basal levels of glucocorticoid, sufficient levels of glucocorticoid metabolism occur and there is likely to be minimal binding of the glucocorticoid receptor. We have established that Leydig cells express type 1 11 betaHSD, an oxidoreductase, and type 2, a unidirectional oxidase. Generation of redox potential through synthesis of the enzyme cofactor NADPH, a byproduct of glucocorticoid metabolism by 11 betaHSD-1, may potentiate testosterone biosynthesis, as NADPH is the cofactor used by steroidogenic enzymes such as type 3 17beta-hydroxysteroid dehydrogenase. In this scenario, inhibition of steroidogenesis will only occur under stressful conditions when high input amounts of CORT exceed the capacity of oxidative inaction by 11 betaHSD. Changes in autonomic catecholaminergic activity may contribute to suppressed Leydig cell function during stress, and may explain the rapid onset of inhibition. However, recent analysis of glucocorticoid action in Leydig cells indicates the presence of a fast, non-genomic pathway that will merit further investigation.
睾丸间质细胞是男性睾酮的主要来源。循环中睾酮的水平由单个睾丸间质细胞的类固醇生成能力以及每个睾丸中睾丸间质细胞的总数决定。应激诱导血清糖皮质激素浓度升高会抑制睾酮生物合成酶的活性，导致睾酮分泌速率降低。然而，目前尚不清楚过量的糖皮质激素刺激是否也通过诱导细胞凋亡影响睾丸间质细胞的总数，从而导致应激诱导的雄激素水平抑制。将睾丸间质细胞暴露于高浓度的皮质酮（CORT，啮齿动物内源性分泌的糖皮质激素）会增加其凋亡频率。固定应激研究表明，应激诱导的CORT升高直接导致睾丸间质细胞凋亡。11β-羟基类固醇脱氢酶（11βHSD）对糖皮质激素的氧化失活调节了睾丸间质细胞中糖皮质激素受体的可及性。在糖皮质激素的基础水平下，会发生足够水平的糖皮质激素代谢，糖皮质激素受体的结合可能很少。我们已经确定睾丸间质细胞表达1型11βHSD（一种氧化还原酶）和2型（一种单向氧化酶）。11βHSD-1通过合成酶辅因子NADPH（糖皮质激素代谢的副产物）产生氧化还原电位，这可能会增强睾酮的生物合成，因为NADPH是3型17β-羟基类固醇脱氢酶等类固醇生成酶使用的辅因子。在这种情况下，只有在应激条件下，当高输入量的CORT超过11βHSD的氧化失活能力时，才会发生类固醇生成的抑制。自主儿茶酚胺能活性的变化可能导致应激期间睾丸间质细胞功能受到抑制，并可能解释抑制的快速发生。然而，最近对睾丸间质细胞中糖皮质激素作用的分析表明存在一条快速的非基因组途径，值得进一步研究。
