Stress hormone and male reproductive function

Abstract

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.

Intrinsic and extrinsic apoptotic pathways are involved in rat testis by cold water immersion-induced acute and chronic stress

“…This may be mediated by non-genomic mechanisms [Dong et al 2004] or genetic mechanisms through the inhibition of genes encoding testosterone biosynthetic enzymes [Payne and Sha 1991], such as 3b-hydroxysteroid dehydrogenase and 17a-hydroxylase/17-20-lyase [Hales and Payne 1989;Orr et al 1994]. Corticosterone also induces Leydig cell apoptosis [Chen et al 2012], resulting in a significant reduction in the secretion of testosterone [Hardy et al 2005] as confirmed by TUNEL. It appears that the number of apoptotic Leydig cells observed were not sufficient to cause a decrease in the level of testosterone after acute stress induction.…”

Chronic stress induces ageing-associated degeneration in rat Leydig cells

“…Similar to the process of Leydig cell ageing, stress inhibits steroidogenic enzyme expression, subsequently decreasing testosterone secretion. 6,7,9 Lipofuscin is an undegradable polymorphous waste material that accumulates in the lysosomal compartment of post-mitotic and slowly dividing cells; importantly, lipofuscin levels progressively increase with age. For this reason, the change in the amount of lipofuscin within the senescenct cells is considered as a marker of cellular ageing.…”

Stress and Cell Death in Testicular Cells

“…In Leydig cells, prolonged exposure to high glucocorticoid concentrations during stress response directly inhibits the transcription of genes encoding enzymes involved in the synthesis of testosterone [60] as 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17α-hydroxylase/17-20 lyase [61][62][63]. In addition, glucocorticoids cause apoptosis in Leydig cells [56], thus contributing to the reduction in testosterone secretion [3] observed during stress. It has been proposed that the activation of apoptosis in these cells may be related to the activation of the Fas system of procaspase 3 with the loss of mitochondrial membrane potential and the increase in the generation of ROS [3].…”

“…In addition, glucocorticoids cause apoptosis in Leydig cells [56], thus contributing to the reduction in testosterone secretion [3] observed during stress. It has been proposed that the activation of apoptosis in these cells may be related to the activation of the Fas system of procaspase 3 with the loss of mitochondrial membrane potential and the increase in the generation of ROS [3]. As mentioned above, the increase in glucocorticoid concentration may be related to the activation of apoptosis in testicular cells through an increase in ROS generation [48].…”

“…This mechanism is regulated via apoptosis through the Fas system activation, which is a paracrine signaling pathway proposed as an important physiological regulator of apoptosis in germ cells [2]. Apoptosis can also be activated by internal stimuli such as: decreased testosterone [3], follicle stimulating hormone (FSH) or by external factors such as stress, which can cause alterations in the spermatogenesis development and affect spermatozoa production [4][5][6].…”