Effects of hypoxia on testosterone release in rat Leydig cells

Abstract

The aim of this study was to explore the effect and action mechanisms of intermittent hypoxia on the production of testosterone both in vivo and in vitro. Male rats were housed in a hypoxic chamber (12% O(2) + 88% N(2), 1.5 l/ml) 8 h/day for 4 days. Normoxic rats were used as control. In an in vivo experiment, hypoxic and normoxic rats were euthanized and the blood samples collected. In the in vitro experiment, the enzymatically dispersed rat Leydig cells were prepared and challenged with forskolin (an adenylyl cyclase activator, 10(-4) M), 8-Br-cAMP (a membrane-permeable analog of cAMP, 10(-4) M), hCG (0.05 IU), the precursors of the biosynthesis testosterone, including 25-OH-C (10(-5) M), pregnenolone (10(-7) M), progesterone (10(-7) M), 17-OH-progesterone (10(-7) M), and androstendione (10(-7)-10(-5) M), nifedipine (L-type Ca(2+) channel blocker, 10(-6)-10(-4) M), nimodipine (L-type Ca(2+) channel blocker, 10(-5) M), tetrandrine (L-type Ca(2+) channel blocker, 10(-5) M), and NAADP (calcium-signaling messenger causing release of calcium from intracellular stores, 10(-6)-10(-4) M). The concentrations of testosterone in plasma and medium were measured by radioimmunoassay. The level of plasma testosterone in hypoxic rats was higher than that in normoxic rats. Enhanced testosterone production was observed in rat Leydig cells treated with hCG, 8-Br-cAMP, or forskolin in both normoxic and hypoxic conditions. Intermittent hypoxia resulted in a further increase of testosterone production in response to the testosterone precursors. The activity of 17β-hydroxysteroid dehydrogenase was stimulated by the treatment of intermittent hypoxia in vitro. The intermittent hypoxia-induced higher production of testosterone was accompanied with the influx of calcium via L-type calcium channel and the increase of intracellular calcium via the mechanism of calcium mobilization. These results suggested that the intermittent hypoxia stimulated the secretion of testosterone at least in part via stimulatory actions on the activities of adenylyl cyclase, cAMP, L-type calcium channel, and steroidogenic enzymes.

The Hypoxic Testicle: Physiology and Pathophysiology

“…In mice, in vivo application of VEGF to the testis promotes blood capillary formation, but not after the application of antisense oligonucleoties against VEGF [68]. Besides the well-known effects of VEGF as a vascular permeability enhancer and as a mediator of angiogenesis, Hwang et al observed that VEGF produced an increment in the proliferation of Leydig cells and was an acute inducer of testosterone in a dose-dependent manner [69, 70]. Thus, the molecular infrastructure and the signaling mechanisms for sensing and triggering of a physiological response are present in testicular cells and, as will be shown below, can at least partially explain the physiological and pathological changes associated to environmental and local hypoxia in the testis.…”

Testosterone potentiates the hypoxic ventilatory response of adult male rats subjected to neonatal stress

“…The finding that GDX prevented detectable testosterone release points to the testes as the main source of hormone following a hypoxic challenge. As this response was relatively rapid (within 20 min), it would appear that the transduction of the hypoxic signal 'bypassed' the hormonal cascade between the pituitary and the gonads and involved either a more rapid (neural) pathway (Gerendai et al 2005) or a direct effect of hypoxia (Hwang et al 2009).…”

Recent trend in risk assessment of formaldehyde exposures from indoor air

“…In rats, treatment with ascorbic acid prevented the hypobaric hypoxia-induced decrease in epididymal sperm count and increase in testicular and epididymal lipid peroxidation; this suggests that oxidative stress plays a role in these effects (Farias et al 2010). In contrast, hypoxia induced by 12 % oxygen in the air, 8 h/day for 4 days in rats increased the plasma testosterone level and its release forms the Leydig cells (Hwang et al 2009). However, the short-term effects are not considered as they are not relevant for the evaluation of the longer lasting studies described below.…”