Long-term suppression of Leydig cell steroidogenesis prevents Leydig cell aging

Abstract

Male aging is accompanied by reduced testosterone production by the Leydig cells, the testosterone-producing cells of the testis. The mechanism by which this occurs is unknown. Based on the observations that reactive oxygen is capable of damaging components of the steroidogenic pathway and that reactive oxygen is produced during steroidogenesis itself, we hypothesized that long-term suppression of steroidogenesis might inhibit or prevent age-related deficits in Leydig cell testosterone production. To test this, we administered contraceptive doses of testosterone to groups of young (3 months old) and middle-aged (13 months old) Brown Norway rats via Silastic implants to suppress endogenous Leydig cell testosterone production. After 8 months, the implants were removed, which rapidly (days) restores the ability of the previously suppressed Leydig cells to produce testosterone. Two months after removing the implants, when the rats of the two groups were 13 and 23 months of age, respectively, the Leydig cells in both cases were found to produce testosterone at the high levels of young Leydig cells, whereas significantly lower levels were produced by the 23-month-old controls. Thus, by placing the Leydig cells in a state of steroidogenic ''hibernation,'' the reductions in Leydig cell testosterone production that invariably accompany aging did not occur. If hormonal contraception in the human functions the same way, the adverse consequences of reduced testosterone in later life (osteoporosis, reduced muscle mass, reduced libido, mood swings, etc.) might be delayed or prevented.

Expression of a K48R Mutant Ubiquitin Protects Mouse Testis from Cryptorchid Injury and Aging

“…17,42,43 Suppression of steroidogenesis during adulthood protected the aged Leydig cells later in life. 44 According to this hypothesis, Leydig cell steroidogenesis leads to the production of mitochondrial-reactive oxygen species and thereby causes the Leydig cell damage. The protective effects of K48R ubiquitin mutant transgene expression in aged testes can be explained, similar to the cryptorchidism results, through a reactive oxygen species mechanism.…”

Chronic stress induces ageing-associated degeneration in rat Leydig cells

“…45 In fact, long-term suppression of steroidogenesis through the administration of contraceptive doses of testosterone can prevent or delay age-related degeneration in rats in vivo. 46 Additionally, low-dose testosterone treatment can decrease ROS production and subsequent oxidative damage in Leydig cells in vitro. 47 ROS generated both from normal metabolism and in the process of steroidogenesis in Leydig cells, followed by ageassociated degeneration and testicular steroidogenesis inhibition.…”

Aging in male primates: reproductive decline, effects of calorie restriction and future research potential

“…The Brown Norway rat has decreased serum and intratesticular testosterone levels resulting from impaired Leydig cell steroidogenesis with aging (Zirkin and Chen 2000;Syntin et al 2001;Chen et al 2002). A decline in specific intermediary steroids along the steroidogenic pathway within these cells appears to be due to malfunctions of the pathway/enzyme systems rather than a loss of Leydig cell numbers (Chen et al 1996;Chen and Zirkin 1999;Zirkin 2006). Although serum LH levels did not differ, there were measurable changes in the LH pulse and interval (Chen et al 2002).…”