3.2.3. Steroids
Several studies have shown that hypoxia results in endocrine dysfunction within the body. Nishimura et al. observed notable reductions in aldosterone and cortisol levels as well as notable increases in IL-6, IL-8, and white blood cell counts following a 75-min period of acute hypoxic exposure at an altitude of 3,500 mm. These findings suggest that acute hypoxia triggers endocrine, inflammatory, and immune responses (Nishimura et al., 2023). Wang et al. found that several important pathways related to testosterone production, including cholesterol metabolism, the PPAR signaling pathway, oxidative stress response, and retinol metabolism, were altered in obese mice exposed to high-altitude hypoxia for 24 days (Wang et al., 2022). Therefore, steroid metabolism is disturbed under hypoxia, and supplementation with exogenous steroids can attenuate the effects of hypoxia on organisms (Shaw et al., 2020; Zhang et al., 2020).
In addition to aldosterone, oestrogens, and androgens, endogenous steroid compounds include cortisol, cholesterol, cortisone, pregnenolone, progesterone, testosterone, and bile acids. CYP3A4 catalyzes the 6b-hydroxylation, dehydroepiandrosterone 7b-/16a-hydroxylation, and estrone 2-hydroxylation of cortisol, cortisone, progesterone, and testosterone. CYP1A2 and CYP3A4 are the major hepatic enzymes responsible for the 2-/4-hydroxylation and 16a-hydroxylation of estrone, respectively. CYP1A1 and CYP1B1 primarily metabolize estrone and estradiol into 2- and 4-catecholestrogens, respectively. CYP11A1, CYP11B1, CYP11B2, CYP17A1, CYP19A1, and CYP21A2 catalyze steroid synthesis. The changes that occur in steroids under hypoxic conditions may be related to CYP. Zhu et al. found that hypoxia leads to low expression of CYP19A1, which converts androgens from the maternal and fetal adrenal glands to estrogens, and that pregnant mice develop pre-eclampsia-like symptoms following reduced or inhibited CYP19A1 expression (Zhu et al., 2021). Myers et al. found that prolonged hypoxia inhibited sheep fetal cortisol synthesis, mainly because the expression of two key steroidogenic enzymes regulating cortisol biosynthesis (CYP17 and CYP11A1) and the adrenocorticotropic hormone receptor was reduced by plateau hypoxia. This may represent an adaptive response to chronic hypoxia to prevent excessive cortisol production, which limits fetal growth and may lead to preterm delivery (Myers et al., 2005). In summary, alterations in CYP activity under hypoxic conditions may affect endocrine system function.