Leydig cell aging and the mechanisms of reduced testosterone synthesis

Deleterious Cholesterol Hydroperoxide Trafficking in Steroidogenic Acute Regulatory (StAR) Protein-expressing MA-10 Leydig Cells

“…In summary, our findings are both significant and novel because they describe a previously unrecognized mechanism by which steroid hormone production in the adrenal gland, ovary, and testis may be compromised in physiological states associated with increasing oxidative stress and/or declining antioxidant capacity, important examples being diabetes (61), atherosclerosis (17), and natural aging (16,43). Of added interest, our study provides valuable insights into how the antisteroidogenic effects of ChOOH trafficking might be attenuated by site-selective antioxidants such mitochondrial GPx4 or MitoQ (62).…”

“…An early study (42) showed that rat adrenocortical cells were highly susceptible to oxidative injury and dysfunction, which was attributed to the vigorous Mito electron transport activity required by these cells. These negative effects increased dramatically with animal age in parallel with diminished levels of nonenzymatic and enzymatic antioxidants, including vitamin C, glutathione, glutathione peroxidase-1, and two superoxide dismutases (43). More recent studies with rat primary testicular Leydig cells showed that levels of steroidogenic enzymes declined with advancing animal age along with testosterone output (15, 43).…”

“…Leydig cells, which reside in the testicular interstitium, are reported to be particularly suscepti- ble to oxidative damage in vivo due to their close proximity to reactive oxygen species-producing testicular interstitial macrophages (44). Decreased antioxidant enzyme activities, gene expression, and protein levels, along with lower glutathione, have been reported to play a key role in the diminished ability of Leydig cells from aging rat populations to synthesize testosterone (43,(45)(46)(47). Other work showed that steroidogenic luteal cells in vitro became damaged and dysfunctional when exposed to cumene hydroperoxide or a fatty acid hydroperoxide (48).…”

Cyclic GMP signaling in rat urinary bladder, prostate, and epididymis: tissue-specific changes with aging and in response to Leydig cell depletion

“…Interestingly, bladder strips from castrated rats are more sensitive to NO-induced relaxation and less responsive to PDE5 inhibitors, suggesting that androgen deprivation evokes downregulation of PDE5 activity (Filippi et al 2007). Thus, the age-dependent reduction of bladder PDE5 expression may be a direct local consequence of declined testosterone production by aged Leydig cells (Midzak et al 2009). As reported previously (Paust et al 2002), the old (23-24 months) Wistar rats had about threefold lower (0.76G0.42 ng/ml; nZ67) serum testosterone concentrations than their young (3 months) counterparts (2.49G1.68 ng/ml; nZ56).…”

Hydroxysteroid Dehydrogenases – Localization, Function and Regulation in the Testis

“…In addition, protein and mRNA levels of StAR have been significantly reduced, suggesting deficits in the transport of cholesterol to the inner mitochondrial membrane of aged Leydig cells. Moreover, the activity, protein level, and mRNA level of P450scc, P450c17, 3 -HSD and 17 -HSD have been found markedly reduced in old Leydig cells (Ivell et al, 2003;Luo et al, 1996;Midzak et al, 2009;Zirkin & Chen, 2000). Interestingly, these authors have demonstrated that long-term suppression of steroidogenesis by administration of T prevents or delays the reduced steroidogenesis that accompanies Leydig cell aging due to suppressing the production of the reactive oxygen species that are a by-product of steroidogenesis itself.…”