Regulation of Leydig Cell Steroidogenic Function During Aging1

Abstract

This article summarizes a talk on Leydig cell aging presented at the 1999 Annual Meeting of the Society for the Study of Reproduction. In the Brown Norway rat, serum testosterone levels decrease with aging, accompanied by increases in serum FSH. The capacity of Leydig cells to produce testosterone is higher in young than in old rats. Binding studies with hCG revealed reduced receptor number in old vs. young Leydig cells. In response to incubation with LH, cAMP production was found to be reduced in old vs. young Leydig cells, indicating that signal transduction mechanisms in the old cells are affected by aging. Steroidogenic acute regulatory protein and mRNA levels are reduced in old Leydig cells, suggesting that there may be deficits in the transport of cholesterol to the inner mitochondrial membrane of aged cells. The activity of P450 side-chain cleavage enzyme is reduced in old vs. young cells, as are the activities of each of 3beta-hydroxysteroid dehydrogenase, 17alpha-hydroxylase/C17-20 lyase, and 17-ketosteroid reductase. Serum LH levels do not differ between young and old rats, and the administration of LH failed to induce old Leydig cells to produce high (young) testosterone levels, suggesting that the cause of age-related reductions in steroidogenesis is not LH deficits. We hypothesized that reactive oxygen, produced as a by-product of steroidogenesis itself, might be responsible for age-related reductions in testosterone production by the Leydig cells. Consistent with this, long-term suppression of steroidogenesis was found to prevent or delay the reduced steroidogenesis that accompanies Leydig cell aging. A possible explanation of this finding is that long-term suppression of steroidogenesis prevents free radical damage to the cells by suppressing the production of the reactive oxygen species that are a by-product of steroidogenesis itself.

Interbular space characterization in adult capybara (Hydrochoerus hydrochaeris) testis

“…In addition to the already well-known endocrine control through the hypothalamus-hypophysistesticle axis, an elaborated system of intercellular communication is developed in the testicle to assure the perfect functioning of the spermatogenic process (Roser, 2000). Thus, the cells directly or indirectly involved in the production of the male gametes, that is, Sertoli cells, germ cells, Leydig cells, peritubular mioid cells, leukocytes, etc, maintain a paracrinous/autocrine system that modulates this intricate net of cellular interaction, which is fundamental for the perfect functioning of the testicle (Schlatt, 1997;Zirkin and Chen, 2000;Rothschild et al, 2003). The contribution of the Leydig cell for this paracrine communication involves the production of different substances (Lejeune et al, 1997;Roser, 2000;França et al, 2000).…”

Indispensable function for embryogenesis, expression and regulation of the nonspecific form of the 5‐aminolevulinate synthase gene in mouse

“…All the tissues highly expressing ALAS-N mRNA (liver, testis, and Harderian gland) showed lower ALAS-N ⁄ GFP mRNA ratio, suggesting that ALAS-N mRNA stabilization is one of the most important mechanisms by which heme is rapidly supplied in these tissues, whereas the mechanism is less relevant to prompt heme production in the other tissues. Leydig cells are responsible for testosterone production in the testis, in which many CYP450s participate, and testosterone is produced in pulses due to negative feedback of testosterone for luteinizing hormone (LH) secretion (reviewed in Zirkin & Chen 2000). Stabilization ⁄ destabilization of ALAS-N mRNA may contribute to dynamic heme supply for pulsatile production of testosterone.…”

Autophagy in the endocrine glands

“…In the case of aged Leydig cells, decreased autophagy, particularly mitophagy or the selective degradation of damaged mitochondria, leads to a decrease in the clearance of dysfunctional mitochondria and consequently, an accumulation of ROS. As ROS are detrimental to Leydig cell steroidogenesis (Zirkin & Chen 2000, Diemer et al 2003, this accumulation leads to a decrease in testosterone levels, ultimately resulting in conditions such as late-onset hypogonadism (Li et al 2011).…”