Alterations of Cortisol Metabolism in Human Disorders

Abstract

The interconversion of active and inactive corticosteroids – cortisol and cortisone, respectively, in humans – is modulated by isozymes of 11β-hydroxysteroid dehydrogenase (11-HSD). Studies of this process have provided crucial insights into glucocorticoid effects in a wide variety of tissues. The 11-HSD1 isozyme functions mainly as an oxoreductase (cortisone to cortisol) and is expressed at high levels in the liver and other glucocorticoid target tissues. Because it is required for full physiological effects of cortisol, it has emerged as a drug target for metabolic syndrome and type 2 diabetes. Mutations in the corresponding HSD11B1 gene, or in the H6PD gene encoding hexose-6-phosphate dehydrogenase (which supplies the NADPH required for the oxoreductase activity of 11-HSD1), cause apparent cortisone reductase deficiency, a rare syndrome of adrenocortical hyperactivity and hyperandrogenism. In contrast, the 11-HSD2 isozyme functions as a dehydrogenase (cortisol to cortisone) and is expressed mainly in mineralocorticoid target tissues, where it bars access of cortisol to the mineralocorticoid receptor. Mutations in the HSD11B2 gene encoding 11-HSD2 cause the syndrome of apparent mineralocorticoid excess, a severe form of familial hypertension. The role of this enzyme in the pathogenesis of common forms of low-renin hypertension remains uncertain.

Metabolomics reveals sex-specific metabolic shifts and predicts the duration from positive to negative in non-severe COVID-19 patients during recovery process

“…MG(18:1(9Z)/0:0/0:0) had positive correlations with prothrombin time (PT) and the level of Ca and negative correlations with red cell distribution width (RDW) and white blood cell (WBC), suggesting that a high level of MG(18:1(9Z)/0:0/0:0) may disrupt blood cell homeostasis and cause an adverse effect on COVID-19. Tetrahydrodeoxycortisol (THS) is derived from cortisol metabolism as a regulator of glucocorticoid action in liver and kidney [37] , [38] . For this reason, a negative relationship between THS and alanine aminotransferase (ALT) indicates that glucocorticoid might be an effective drug for improving the liver and kidney functions in COVID-19 patients.…”

Hydroxysteroid 11-Beta Dehydrogenase 1 Overexpression with Copy-Number Gain and Missense Mutations in Primary Gastrointestinal Stromal Tumors

“…Depending on the relative ratio of NADP to NADPH, this enzyme effectively orchestrates the homeostasis of glucocorticoid metabolism [ 15 , 16 ]. During the elevation of reverse cortisone oxo-reductase activity of HSD11B1, the excessive and chronically sustained cortisol might promote adipocyte differentiation and inhibit pre-adipocyte proliferation, hence causing metabolic syndrome and dyslipidemia [ 15 , 16 , 17 ]. In patients with cortisone-reductase deficiency, the mutations in HSD11B1 or hexose-6-phosphate dehydrogenase ( H6PD ) that encodes an enzyme furnishing cofactors for the reaction might abrogate cortisol generation and consequently stimulate adrenal hyperandrogenism mediated by adrenocorticotropic hormone [ 25 , 26 ].…”

“…In a nicotinamide adenine dinucleotide phosphate (NADP)/NADPH ratio-dependent manner, HSD11B1 bidirectionally catalyzes the interconversion between active cortisol and inactive cortisone through its dehydrogenase and oxidoreductase activities, respectively [ 15 , 16 ]. This biochemical mechanism regulates the availability of local glucocorticoid within the hepatic, adipose, and muscular tissues [ 15 , 16 , 17 ].…”

GENETICS IN ENDOCRINOLOGY: Glucocorticoid resistance syndrome

“…As illustrated in Fig. 3, the 11β-HSD2, encoded by HSD11B2 gene, is mostly expressed in epithelial tissues (kidney, colon, , and constitutes a MR-protecting mechanism (51) by catalyzing the interconversion of active cortisol (F) into inactive cortisone (E), which is unable to bind to the MR (52). Interestingly, a low 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) activity was initially reported in one mutated GR patient (37) as revealed by low tetrahydrocortisone (THE)/tetrahydrocortisol (THF) ratio, indicative of an altered renal cortisol metabolism.…”