Metabolism of adrenal steroids
- William J Kovacs, MD
William J Kovacs, MD
- Professor of Medicine
- Penn State College of Medicine
The actions of glucocorticoids can be terminated by conversion of these steroids to biologically inactive forms. The processes by which these steroids are inactivated involve a number of enzymes and tissues. The importance of alterations in the metabolic degradation of adrenal steroids in human physiology and disease states is becoming increasingly clear and will be reviewed here.
Adrenal steroid biosynthesis is reviewed separately. (See "Adrenal steroid biosynthesis".)
Hepatic — The major site of cortisol metabolism is the liver. There cortisol is reduced, oxidized, or hydroxylated, and the products of these reactions are made water soluble by conjugation with sulfate or glucuronic acid to facilitate their excretion in urine (figure 1). Gas chromatography with mass spectrometry (GC/MS) has provided quantitative data on the urinary excretion of each of these cortisol metabolites, allowing identification of a number of inherited and acquired disorders characterized by abnormal glucocorticoid dynamics .
Reduction — Cortisol is inactivated mainly by reductive disruption of its 3-keto, delta-4 double bond structure. Reduction reactions can also result in “regeneration” of cortisol from its inactive metabolite, cortisone.
●Reduction of the keto group, with formation of a 3-hydroxyl group, is carried out by 3-alpha-hydroxysteroid dehydrogenase.
●Reduction of the cortisol A ring double bond, which results in an asymmetric carbon atom at position 5, is carried out by 5-alpha-reductase (of which there are two isoforms expressed in liver) and 5 beta-reductase.
- Shackleton CH. Mass spectrometry in the diagnosis of steroid-related disorders and in hypertension research. J Steroid Biochem Mol Biol 1993; 45:127.
- Jenkins EP, Hsieh CL, Milatovich A, et al. Characterization and chromosomal mapping of a human steroid 5 alpha-reductase gene and pseudogene and mapping of the mouse homologue. Genomics 1991; 11:1102.
- Thigpen AE, Russell DW. Four-amino acid segment in steroid 5 alpha-reductase 1 confers sensitivity to finasteride, a competitive inhibitor. J Biol Chem 1992; 267:8577.
- Thigpen AE, Silver RI, Guileyardo JM, et al. Tissue distribution and ontogeny of steroid 5 alpha-reductase isozyme expression. J Clin Invest 1993; 92:903.
- Wake DJ, Strand M, Rask E, et al. Intra-adipose sex steroid metabolism and body fat distribution in idiopathic human obesity. Clin Endocrinol (Oxf) 2007; 66:440.
- Charbonneau A, Luu-The V. Assignment of steroid 5beta-reductase (SRD5B1) and its pseudogene (SRD5BP1) to human chromosome bands 7q32-->q33 and 1q23-->q25, respectively, by in situ hybridization. Cytogenet Cell Genet 1999; 84:105.
- Jez JM, Flynn TG, Penning TM. A nomenclature system for the aldo-keto reductase superfamily. Adv Exp Med Biol 1997; 414:579.
- Kondo KH, Kai MH, Setoguchi Y, et al. Cloning and expression of cDNA of human delta 4-3-oxosteroid 5 beta-reductase and substrate specificity of the expressed enzyme. Eur J Biochem 1994; 219:357.
- Palermo M, Marazzi MG, Hughes BA, et al. Human Delta4-3-oxosteroid 5beta-reductase (AKR1D1) deficiency and steroid metabolism. Steroids 2008; 73:417.
- Napolitano A, Voice MW, Edwards CR, et al. 11Beta-hydroxysteroid dehydrogenase 1 in adipocytes: expression is differentiation-dependent and hormonally regulated. J Steroid Biochem Mol Biol 1998; 64:251.
- Pagé N, Warriar N, Govindan MV. 11 beta-hydroxysteroid dehydrogenase activity in human lung cells and transcription regulation by glucocorticoids. Am J Physiol 1994; 267:L464.
- Cooper MS, Stewart PM. 11Beta-hydroxysteroid dehydrogenase type 1 and its role in the hypothalamus-pituitary-adrenal axis, metabolic syndrome, and inflammation. J Clin Endocrinol Metab 2009; 94:4645.
- Bujalska IJ, Draper N, Michailidou Z, et al. Hexose-6-phosphate dehydrogenase confers oxo-reductase activity upon 11 beta-hydroxysteroid dehydrogenase type 1. J Mol Endocrinol 2005; 34:675.
- SANDBERG AA, CHANG E, SLAUNWHITE WR Jr. The conversion of 4-C14-cortisol to C14-17-ketosteroids. J Clin Endocrinol Metab 1957; 17:437.
- Shackleton CH, Neres MS, Hughes BA, et al. 17-Hydroxylase/C17,20-lyase (CYP17) is not the enzyme responsible for side-chain cleavage of cortisol and its metabolites. Steroids 2008; 73:652.
- Voccia E, Saenger P, Peterson RE, et al. 6 beta-Hydroxycortisol excretion in hypercortisolemic states. J Clin Endocrinol Metab 1979; 48:467.
- Gibson GG, Plant NJ, Swales KE, et al. Receptor-dependent transcriptional activation of cytochrome P4503A genes: induction mechanisms, species differences and interindividual variation in man. Xenobiotica 2002; 32:165.
- Siest G, Antoine B, Fournel S, et al. The glucuronosyltransferases: what progress can pharmacologists expect from molecular biology and cellular enzymology? Biochem Pharmacol 1987; 36:983.
- Falany CN, Green MD, Tephly TR. The enzymatic mechanism of glucuronidation catalyzed by two purified rat liver steroid UDP-glucuronosyltransferases. J Biol Chem 1987; 262:1218.
- Falany CN, Green MD, Swain E, Tephly TR. Substrate specificity and characterization of rat liver p-nitrophenol, 3 alpha-hydroxysteroid and 17 beta-hydroxysteroid UDP-glucuronosyltransferases. Biochem J 1986; 238:65.
- Strott CA. Steroid sulfotransferases. Endocr Rev 1996; 17:670.
- Jin Y, Duan L, Lee SH, et al. Human cytosolic hydroxysteroid dehydrogenases of the aldo-ketoreductase superfamily catalyze reduction of conjugated steroids: implications for phase I and phase II steroid hormone metabolism. J Biol Chem 2009; 284:10013.
- PETERSON RE. The influence of the thyroid on adrenal cortical function. J Clin Invest 1958; 37:736.
- McGUIRE JS Jr, TOMKINS GM. The effects of thyroxin administration on the enzymic reduction of delta 4-3-ketosteroids. J Biol Chem 1959; 234:791.
- Finken MJ, Andrews RC, Andrew R, Walker BR. Cortisol metabolism in healthy young adults: sexual dimorphism in activities of A-ring reductases, but not 11beta-hydroxysteroid dehydrogenases. J Clin Endocrinol Metab 1999; 84:3316.
- Peterson RE. Metabolism of adrenal cortical steroids. In: The Human Adrenal Cortex, Christy NP (Ed), Harper and Row, New York 1971. p.87.
- Voice MW, Seckl JR, Edwards CR, Chapman KE. 11 beta-hydroxysteroid dehydrogenase type 1 expression in 2S FAZA hepatoma cells is hormonally regulated: a model system for the study of hepatic glucocorticoid metabolism. Biochem J 1996; 317 ( Pt 2):621.
- Tomlinson JW, Finney J, Gay C, et al. Impaired glucose tolerance and insulin resistance are associated with increased adipose 11beta-hydroxysteroid dehydrogenase type 1 expression and elevated hepatic 5alpha-reductase activity. Diabetes 2008; 57:2652.
- Tomlinson JW, Finney J, Hughes BA, et al. Reduced glucocorticoid production rate, decreased 5alpha-reductase activity, and adipose tissue insulin sensitization after weight loss. Diabetes 2008; 57:1536.
- WEST CD, BROWN H, SIMONS EL, et al. Adrenocortical function and cortisol metabolism in old age. J Clin Endocrinol Metab 1961; 21:1197.
- Stewart PM, Shackleton CH, Beastall GH, Edwards CR. 5 alpha-reductase activity in polycystic ovary syndrome. Lancet 1990; 335:431.
- PETERSON RE. Adrenocortical steroid metabolism and adrenal cortical function in liver disease. J Clin Invest 1960; 39:320.
- Westerbacka J, Yki-Järvinen H, Vehkavaara S, et al. Body fat distribution and cortisol metabolism in healthy men: enhanced 5beta-reductase and lower cortisol/cortisone metabolite ratios in men with fatty liver. J Clin Endocrinol Metab 2003; 88:4924.
- Ahmed A, Rabbitt E, Brady T, et al. A switch in hepatic cortisol metabolism across the spectrum of non alcoholic fatty liver disease. PLoS One 2012; 7:e29531.
- Boonen E, Vervenne H, Meersseman P, et al. Reduced cortisol metabolism during critical illness. N Engl J Med 2013; 368:1477.
- MIGEON CJ, GREEN OC, ECKERT JP. STUDY OF ADRENOCORTICAL FUNCTION IN OBESITY. Metabolism 1963; 12:718.
- Andrew R, Phillips DI, Walker BR. Obesity and gender influence cortisol secretion and metabolism in man. J Clin Endocrinol Metab 1998; 83:1806.
- Stimson RH, Johnstone AM, Homer NZ, et al. Dietary macronutrient content alters cortisol metabolism independently of body weight changes in obese men. J Clin Endocrinol Metab 2007; 92:4480.
- WERK EE Jr, MACGEE J, SHOLITON LJ. EFFECT OF DIPHENYLHYDANTOIN ON CORTISOL METABOLISM IN MAN. J Clin Invest 1964; 43:1824.
- BURSTEIN S, KLAIBER EL. PHENOBARBITAL-INDUCED INCREASE IN 6-BETA-HYDROXYCORTISOL EXCRETION: CLUE TO ITS SIGNIFICANCE IN HUMAN URINE. J Clin Endocrinol Metab 1965; 25:293.
- Edwards OM, Courtenay-Evans RJ, Galley JM, et al. Changes in cortisol metabolism following rifampicin therapy. Lancet 1974; 2:548.
- Baciewicz AM, Self TH, Bekemeyer WB. Update on rifampin drug interactions. Arch Intern Med 1987; 147:565.
- Kyriazopoulou V, Parparousi O, Vagenakis AG. Rifampicin-induced adrenal crisis in addisonian patients receiving corticosteroid replacement therapy. J Clin Endocrinol Metab 1984; 59:1204.
- Yamada S, Iwai K. Letter: Induction of hepatic cortisol-6-hydroxylase by rifampicin. Lancet 1976; 2:366.
- Sirgo MA, Rocci ML Jr, Ferguson RK, et al. Effects of cimetidine and ranitidine on the conversion of prednisone to prednisolone. Clin Pharmacol Ther 1985; 37:534.
- Peden NR, Rewhorn I, Champion MC, et al. Cortisol and dexamethasone elimination during treatment with cimetidine. Br J Clin Pharmacol 1984; 18:101.
- Dimaraki EV, Jaffe CA. Troglitazone induces CYP3A4 activity leading to falsely abnormal dexamethasone suppression test. J Clin Endocrinol Metab 2003; 88:3113.
- Whitworth JA, Stewart PM, Burt D, et al. The kidney is the major site of cortisone production in man. Clin Endocrinol (Oxf) 1989; 31:355.
- Albiston AL, Obeyesekere VR, Smith RE, Krozowski ZS. Cloning and tissue distribution of the human 11 beta-hydroxysteroid dehydrogenase type 2 enzyme. Mol Cell Endocrinol 1994; 105:R11.
- Agarwal AK, Rogerson FM, Mune T, White PC. Gene structure and chromosomal localization of the human HSD11K gene encoding the kidney (type 2) isozyme of 11 beta-hydroxysteroid dehydrogenase. Genomics 1995; 29:195.
- Edwards CR, Stewart PM, Burt D, et al. Localisation of 11 beta-hydroxysteroid dehydrogenase--tissue specific protector of the mineralocorticoid receptor. Lancet 1988; 2:986.
- Funder JW, Pearce PT, Smith R, Smith AI. Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated. Science 1988; 242:583.
- Arriza JL, Weinberger C, Cerelli G, et al. Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor. Science 1987; 237:268.
- Seckl JR, Walker BR. Minireview: 11beta-hydroxysteroid dehydrogenase type 1- a tissue-specific amplifier of glucocorticoid action. Endocrinology 2001; 142:1371.
- Masuzaki H, Paterson J, Shinyama H, et al. A transgenic model of visceral obesity and the metabolic syndrome. Science 2001; 294:2166.
- Seckl JR, Walker BR. 11beta-hydroxysteroid dehydrogenase type 1 as a modulator of glucocorticoid action: from metabolism to memory. Trends Endocrinol Metab 2004; 15:418.
- Basu R, Basu A, Grudzien M, et al. Liver is the site of splanchnic cortisol production in obese nondiabetic humans. Diabetes 2009; 58:39.
- Stimson RH, Andersson J, Andrew R, et al. Cortisol release from adipose tissue by 11beta-hydroxysteroid dehydrogenase type 1 in humans. Diabetes 2009; 58:46.
- Stewart PM, Tomlinson JW. Selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 for patients with metabolic syndrome: is the target liver, fat, or both? Diabetes 2009; 58:14.
- Simonyte K, Olsson T, Näslund I, et al. Weight loss after gastric bypass surgery in women is followed by a metabolically favorable decrease in 11beta-hydroxysteroid dehydrogenase 1 expression in subcutaneous adipose tissue. J Clin Endocrinol Metab 2010; 95:3527.
- Nuotio-Antar AM, Hasty AH, Kovacs WJ. Quantitation and cellular localization of 11beta-HSD1 expression in murine thymus. J Steroid Biochem Mol Biol 2006; 99:93.
- Thieringer R, Le Grand CB, Carbin L, et al. 11 Beta-hydroxysteroid dehydrogenase type 1 is induced in human monocytes upon differentiation to macrophages. J Immunol 2001; 167:30.
- Zhang TY, Ding X, Daynes RA. The expression of 11 beta-hydroxysteroid dehydrogenase type I by lymphocytes provides a novel means for intracrine regulation of glucocorticoid activities. J Immunol 2005; 174:879.
- Albert C, Barbier O, Vallée M, et al. Distribution of uridine diphosphate-glucuronosyltransferase (UGT) expression and activity in cynomolgus monkey tissues: evidence for differential expression of steroid-conjugating UGT enzymes in steroid target tissues. Endocrinology 2000; 141:2472.
- Melby JC. Intermediary metabolism of aldosterone. In: Handbook of Experimental Pharmacology, Page IH, Bumpus FN (Eds), Springer-Verlag, New York 1973. Vol 37, p.298.
- KELLY WG, BANDI L, LIEBERMAN S. ISOLATION AND CHARACTERIZATION OF HUMAN URINARY METABOLITES OF ALDOSTERONE. V. DIHYDROALDOSTERONE AND 21-DEOXYTETRAHYDROALDOSTERONE. Biochemistry 1963; 2:1249.
- KELLY WG, BANDI L, LIEBERMAN S. ISOLATION AND CHARACTERIZATION OF HUMAN URINARY METABOLITES OF ALDOSTERONE. IV. THE SYNTHESIS AND STEREOCHEMISTRY OF TWO BICYCLIC ACETAL METABOLITES. Biochemistry 1963; 2:1243.
- ULICK S, LARAGH JH, LIEBERMAN S. The isolation of a urinary metabolite of aldosterone and its use to measure the rate of secretion of aldosterone by the adrenal cortex of man. Trans Assoc Am Physicians 1958; 71:225.
- AXELRAD BJ, CATES JE, JOHNSON BB, LUETSCHER JA Jr. Aldosterone in urine of normal man and of patients with oedema; its increased recovery after hydrolysis with acid and with beta-glucuronidase. Br Med J 1955; 1:196.
- COPPAGE WS Jr, ISLAND DP, COONER AE, LIDDLE GW. The metabolism of aldosterone in normal subjects and in patients with hepatic cirrhosis. J Clin Invest 1962; 41:1672.
- Bledsoe T, Liddle GW, Riondel A, et al. Comparative fates of intravenously and orally administered aldosterone: evidence for extrahepatic formation of acid-hydrolyzable conjugate in man. J Clin Invest 1966; 45:264.
- TAIT JF, LITTLE B, TAIT SA, et al. SPLANCHNIC EXTRACTION AND CLEARANCE OF ALDOSTERONE IN SUBJECTS WITH MINIMAL AND MARKED CARDIAC DYSFUNCTION. J Clin Endocrinol Metab 1965; 25:219.
- Knights KM, Bowalgaha K, Miners JO. Spironolactone and canrenone inhibit UGT2B7-catalyzed human liver and kidney microsomal aldosterone 18beta-glucuronidation: a potential drug interaction. Drug Metab Dispos 2010; 38:1011.
- BAULIEU EE, CORPECHOT C, DRAY F, et al. AN ADRENAL-SECRETED "ANDROGEN": DEHYDROISOANDROSTERONE SULFATE. ITS METABOLISM AND A TENTATIVE GENERALIZATION ON THE METABOLISM OF OTHER STEROID CONJUGATES IN MAN. Recent Prog Horm Res 1965; 21:411.
- GLUCOCORTICOID METABOLISM
- - Reduction
- - Oxidation
- - Hydroxylation
- - Conjugation
- - Alterations in hepatic metabolism of cortisol
- Age and disease
- Obesity and nutrition
- ALDOSTERONE METABOLISM
- Alterations in aldosterone metabolism
- ADRENAL ANDROGEN METABOLISM