The hypoxic testicle: physiology and pathophysiology

Abstract

Mammalian spermatogenesis is a complex biological process occurring in the seminiferous tubules in the testis. This process represents a delicate balance between cell proliferation, differentiation, and apoptosis. In most mammals, the testicles are kept in the scrotum 2 to 7°C below body core temperature, and the spermatogenic process proceeds with a blood and oxygen supply that is fairly independent of changes in other vascular beds in the body. Despite this apparently well-controlled local environment, pathologies such as varicocele or testicular torsion and environmental exposure to low oxygen (hypoxia) can result in changes in blood flow, nutrients, and oxygen supply along with an increased local temperature that may induce adverse effects on Leydig cell function and spermatogenesis. These conditions may lead to male subfertility or infertility. Our literature analyses and our own results suggest that conditions such as germ cell apoptosis and DNA damage are common features in hypoxia and varicocele and testicular torsion. Furthermore, oxidative damage seems to be present in these conditions during the initiation stages of germ cell damage and apoptosis. Other mechanisms like membrane-bound metalloproteinases and phospholipase A2 activation could also be part of the pathophysiological consequences of testicular hypoxia.

Figure 1

Histological organization of the seminiferous tubules. The figure shows two microscope images of rat testis: (a) low magnification picture of one seminiferous tubule and seminiferous epithelium containing Sertoli and germ cells at different stages of differentiation. Bar 100 μm; (b) a seminiferous tubule section indicating germ cells at different stages of differentiation. Bar 25 μm.

Figure 2

Diagram of molecular and cellular events triggered by hypobaric hypoxia (HH), testicular torsion (TT), and varicocele (Var). This model suggests that HH, TT, and Var have a common mechanism of action at the testicular level by inducing oxidative stress owing to an increase in reactive oxygen and nitrogen species (ROS/RNS) formation and impairment in the oxidative defense mechanisms. Experimental evidence points to heat stress in HH and Var, but this parameter has not been determined in TT. The increase in ROS/RNS is probably owed to mitochondrial dysfunction along with activation of enzymes such as xanthine oxidase (XO) or the inducible nitric oxide synthetase (iNOS). Oxidative stress induces activation of p53, p73, and ASK/p38 MAPK, which stimulate the activation of proapoptotic proteins (e.g., BAX) that in turn will lead to caspase activation and increase in germ cell apoptosis. The induction of proinflammatory cytokines is probably part of the response mechanism to cellular damage.