The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders

Overview

Journal Endocr Rev

Publisher Oxford University Press

Specialty Endocrinology

Date 2010 Nov 6

PMID 21051590

Citations 831

Authors

Walter L Miller

Richard J Auchus

Affiliations

Soon will be listed here.

Abstract

Steroidogenesis entails processes by which cholesterol is converted to biologically active steroid hormones. Whereas most endocrine texts discuss adrenal, ovarian, testicular, placental, and other steroidogenic processes in a gland-specific fashion, steroidogenesis is better understood as a single process that is repeated in each gland with cell-type-specific variations on a single theme. Thus, understanding steroidogenesis is rooted in an understanding of the biochemistry of the various steroidogenic enzymes and cofactors and the genes that encode them. The first and rate-limiting step in steroidogenesis is the conversion of cholesterol to pregnenolone by a single enzyme, P450scc (CYP11A1), but this enzymatically complex step is subject to multiple regulatory mechanisms, yielding finely tuned quantitative regulation. Qualitative regulation determining the type of steroid to be produced is mediated by many enzymes and cofactors. Steroidogenic enzymes fall into two groups: cytochrome P450 enzymes and hydroxysteroid dehydrogenases. A cytochrome P450 may be either type 1 (in mitochondria) or type 2 (in endoplasmic reticulum), and a hydroxysteroid dehydrogenase may belong to either the aldo-keto reductase or short-chain dehydrogenase/reductase families. The activities of these enzymes are modulated by posttranslational modifications and by cofactors, especially electron-donating redox partners. The elucidation of the precise roles of these various enzymes and cofactors has been greatly facilitated by identifying the genetic bases of rare disorders of steroidogenesis. Some enzymes not principally involved in steroidogenesis may also catalyze extraglandular steroidogenesis, modulating the phenotype expected to result from some mutations. Understanding steroidogenesis is of fundamental importance to understanding disorders of sexual differentiation, reproduction, fertility, hypertension, obesity, and physiological homeostasis.

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References

Kominami S, Ochi H, Kobayashi Y, Takemori S . Studies on the steroid hydroxylation system in adrenal cortex microsomes. Purification and characterization of cytochrome P-450 specific for steroid C-21 hydroxylation. J Biol Chem. 1980; 255(8):3386-94. View

Storr H, Kind B, Parfitt D, Chapple J, Lorenz M, Koehler K . Deficiency of ferritin heavy-chain nuclear import in triple a syndrome implies nuclear oxidative damage as the primary disease mechanism. Mol Endocrinol. 2009; 23(12):2086-94. PMC: 5419132. DOI: 10.1210/me.2009-0056. View

Zhang L, Yang X, Chang Y, Kappy M, Slover R, Jorgensen V . Studies of 3 beta-hydroxysteroid dehydrogenase genes in infants and children manifesting premature pubarche and increased adrenocorticotropin-stimulated delta 5-steroid levels. J Clin Endocrinol Metab. 1996; 81(11):3961-5. DOI: 10.1210/jcem.81.11.8923844. View

Suzuki T, Sasano H, Takeyama J, Kaneko C, Freije W, Carr B . Developmental changes in steroidogenic enzymes in human postnatal adrenal cortex: immunohistochemical studies. Clin Endocrinol (Oxf). 2001; 53(6):739-47. DOI: 10.1046/j.1365-2265.2000.01144.x. View

Li K, Obeyesekere V, Krozowski Z, Ferrari P . Oxoreductase and dehydrogenase activities of the human and rat 11beta-hydroxysteroid dehydrogenase type 2 enzyme. Endocrinology. 1997; 138(7):2948-52. DOI: 10.1210/endo.138.7.5232. View

Bose H, Sugawara T, Strauss 3rd J, Miller W . The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. N Engl J Med. 1996; 335(25):1870-8. DOI: 10.1056/NEJM199612193352503. View

Ibanez L, Potau N, Virdis R, Zampolli M, Terzi C, Gussinye M . Postpubertal outcome in girls diagnosed of premature pubarche during childhood: increased frequency of functional ovarian hyperandrogenism. J Clin Endocrinol Metab. 1993; 76(6):1599-603. DOI: 10.1210/jcem.76.6.8501168. View

Lin D, Harikrishna J, Moore C, Jones K, Miller W . Missense mutation serine106----proline causes 17 alpha-hydroxylase deficiency. J Biol Chem. 1991; 266(24):15992-8. View

Sherbet D, Tiosano D, Kwist K, Hochberg Z, Auchus R . CYP17 mutation E305G causes isolated 17,20-lyase deficiency by selectively altering substrate binding. J Biol Chem. 2003; 278(49):48563-9. DOI: 10.1074/jbc.M307586200. View

10.

Palermo M, Quinkler M, Stewart P . Apparent mineralocorticoid excess syndrome: an overview. Arq Bras Endocrinol Metabol. 2005; 48(5):687-96. DOI: 10.1590/s0004-27302004000500015. View

11.

Nguyen A, Mapes S, Corbin C, Conley A . Morphological adrenarche in rhesus macaques: development of the zona reticularis is concurrent with fetal zone regression in the early neonatal period. J Endocrinol. 2008; 199(3):367-78. DOI: 10.1677/JOE-08-0337. View

12.

Bujalska I, Draper N, Michailidou Z, Tomlinson J, White P, Chapman K . Hexose-6-phosphate dehydrogenase confers oxo-reductase activity upon 11 beta-hydroxysteroid dehydrogenase type 1. J Mol Endocrinol. 2005; 34(3):675-84. DOI: 10.1677/jme.1.01718. View

13.

Nachtigal M, Hirokawa Y, Flanagan J, Hammer G, Ingraham H . Wilms' tumor 1 and Dax-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression. Cell. 1998; 93(3):445-54. DOI: 10.1016/s0092-8674(00)81172-1. View

14.

Grischuk Y, Rubtsov P, Riepe F, Grotzinger J, Beljelarskaia S, Prassolov V . Four novel missense mutations in the CYP21A2 gene detected in Russian patients suffering from the classical form of congenital adrenal hyperplasia: identification, functional characterization, and structural analysis. J Clin Endocrinol Metab. 2006; 91(12):4976-80. DOI: 10.1210/jc.2006-0777. View

15.

Ratnam K, Ma H, Penning T . The arginine 276 anchor for NADP(H) dictates fluorescence kinetic transients in 3 alpha-hydroxysteroid dehydrogenase, a representative aldo-keto reductase. Biochemistry. 1999; 38(24):7856-64. DOI: 10.1021/bi982838t. View

16.

Mornet E, CRETE P, Kuttenn F, Boue J, White P, BOUE A . Distribution of deletions and seven point mutations on CYP21B genes in three clinical forms of steroid 21-hydroxylase deficiency. Am J Hum Genet. 1991; 48(1):79-88. PMC: 1682755. View

17.

Migeon C, Rosenwaks Z, Lee P, Urban M, Bias W . The attenuated form of congenital adrenal hyperplasia as an allelic form of 21-hydroxylase deficiency. J Clin Endocrinol Metab. 1980; 51(3):647-9. DOI: 10.1210/jcem-51-3-647. View

18.

Bergada I, Del Rey G, Lapunzina P, Bergada C, Fellous M, Copelli S . Familial occurrence of the IMAGe association: additional clinical variants and a proposed mode of inheritance. J Clin Endocrinol Metab. 2005; 90(6):3186-90. DOI: 10.1210/jc.2004-1589. View

19.

OPPENHEIMER E, Linder B, DiMartino-Nardi J . Decreased insulin sensitivity in prepubertal girls with premature adrenarche and acanthosis nigricans. J Clin Endocrinol Metab. 1995; 80(2):614-8. DOI: 10.1210/jcem.80.2.7852529. View

20.

Arakane F, King S, Du Y, Kallen C, Walsh L, Watari H . Phosphorylation of steroidogenic acute regulatory protein (StAR) modulates its steroidogenic activity. J Biol Chem. 1998; 272(51):32656-62. DOI: 10.1074/jbc.272.51.32656. View