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.