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Defects of Steroidogenesis A CORE Metadata, citation and similar papers at core.ac.uk Provided by RERO DOC Digital Library J. Endocrinol. Invest. 33: 756-766, 2010 DOI: 10.3275/6869 REVIEW ARTICLE Defects of steroidogenesis A. Biason-Lauber1, M. Boscaro2, F. Mantero3, and G. Balercia2 1University Children’s Hospital, Division of Endocrinology and Diabetology, Zurich, Switzerland; 2Endocrinology, Department of Internal Medicine and Applied Biotechnologies, Umberto I Hospital, School of Medicine, Polytechnic University of Marche, Ancona; 3Endocrinology, Department of Medical and Surgical Sciences, University of Padua, Padua, Italy ABSTRACT. In the biosynthesis of steroid hormones the ferentiation in male and support reproduction. They include neutral lipid cholesterol, a normal constituent of lipid bi- androgens, estrogens, and progestins. A block in the path- layers is transformed via a series of hydroxylation, oxida- way of steroid biosynthesis leads to the lack of hormones tion, and reduction steps into a vast array of biologically downstream and accumulation of the upstream compounds active compounds: mineralocorticoids, glucocorticoids, and that can activate other members of the steroid receptor sex hormones. Glucocorticoids regulate many aspects of family. This review deals with the clinical consequences of metabolism and immune function, whereas mineralocorti- these blocks. coids help maintain blood volume and control renal excre- (J. Endocrinol. Invest. 33: 756-766, 2010) tion of electrolytes. Sex hormones are essential for sex dif- ©2010, Editrice Kurtis Steroid hormones are derivatives of cholesterol that are - glucocorticoids; cortisol is the major representative in synthesized by a variety of tissues, most prominently the humans adrenal gland and gonads, although other tissues, such - mineralocorticoids; aldosterone being most prominent as liver, kidney, placenta, brain, and skin are also quite - androgens such as testosterone active. The cholesterol precursor can be synthesized with- - estrogens, including estradiol and estrone in the cell from acetate, or derive from cholesterol ester - progestogens (also known as progestins) such as pro- stores in intracellular lipid droplets or from uptake of gesterone. cholesterol-containing LDL. Lipoproteins taken up from The biosynthetic pathways for major representatives of plasma are most important when steroidogenic cells are these classes of steroid hormones is depicted in Figure 2. chronically stimulated. Steroid hormones bind to specific intracellular receptors The basic cyclopentanoperhydrophenanthrene ring struc- which upon dimerization interact with the DNA in the nu- ture and carbon numbering system of all steroid hor- cleus. As a result, gene activity is modulated and a hor- mones is depicted in Figure 1, using pregnenolone as an mone-specific response occurs. example. Pregnenolone is an example of what is called a Defects in the receptor or the post-receptor machinery “C-21 steroid” because it has 21 carbons. Similarly, a will lead for the most part to abnormalities of action of steroid such as testosterone is referred to as a “C-19 one specific hormone. Abnormalities of steroid hormone steroid”. production, however, can result in more profound and Biosynthesis of steroid hormones requires a battery of complex effects. A block in the pathway of steroid biosyn- oxidative enzymes located in both mitochondria and en- thesis leads to the lack of hormones downstream and ac- doplasmic reticulum. The rate-limiting step in this pro- cumulation of the upstream compounds that can activate cess is the transport of free cholesterol from the cyto- other members of the steroid receptor family. plasm into mitochondria. Within mitochondria, choles- The consequences of such defects can be schematically terol is converted to pregnenolone by an enzyme in the categorized in 3 groups: inner membrane called cytochrome P450 (see the Ap- pendix) side-chain cleavage (P450scc). Pregnenolone it- self is not a hormone but is the immediate precursor for 21 CH3 the synthesis of all of the steroid hormones. Pregnenolone Typically, endocrinologists classify steroid hormones in- 20 C=O to 5 groups of molecules, based primarily on the recep- 12 18 17 tor to which they bind: 11 16 13 CD 1 19 2 9 14 15 10 8 Key-words: Congenital adrenal hyperplasia (CAH), Cytochrome P450, disorders of sex A B differentiation (DSD), steroidogenic enzymes, steroid hormones, steroidogenesis. Correspondence: A. Biason-Lauber, University Children’s Hospital, Division of En- HO 3 5 7 docrinology and Diabetology, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland. 4 6 E-mail: [email protected] Fig. 1 - Basic cyclopentanoperhydrophenanthrene ring structure Accepted October 26, 2009. and carbon numbering system of all steroid hormones, using First published online February 24, 2010. pregnenolone as example. 756 A. Biason-Lauber, M. Boscaro, F. Mantero, et al. A Cholesterol SCC/StAR 17α-Hydroxylase 17,20-Lyase Pregnenolone 17OH-pregnenolone DHEA POR 3β-HSD POR 3β-HSD α Progesterone 17 -Hydroxylase 17OH-Progesterone 17,20-Lyase Androstenedione POR 21-Hydroxylase 21-Hydroxylase Deoxycorticosterone (DOC) 11-Deoxycortisol 17β-HSD 11β-Hydroxylase 11β-Hydroxylase Corticosterone (B) Cortisol Testosterone Aldo synthase β β (Corticosterone Methyl 11 -HSD1 11 -HSD2 Oxidase I) H6PDH 5α-Reductase Aromatase 18OH Corticosterone Cortisone Aldo synthase (Corticosterone Methyl Dihydrotestosterone Estradiol Oxidase II) (DHT) Aldosterone B Cholesterol CYP11A1/StAR CYP17A1 CYP17A1 Pregnenolone 17OH-pregnenolone DHEA HSD3B2 POR HSD3B2 POR HSD3B2 Progesterone CYP17A1 17OH-Progesterone CYP17A1 Androstenedione POR CYP21A2 CYP21A2 Deoxycorticosterone (DOC) 11-Deoxycortisol HSD17B3 CYP11B1 CYP11B1 Corticosterone (B) Cortisol Testosterone CYP11B2 HSD11B1 HSD11B2 Fig. 2 - Steroidogenic pathway. A: Metabo- H6PD SRD5A2 CYP19 lites in black, P450 enzyme activities in 18OH Corticosterone Cortisone grey, other enzyme families in light grey. CYP11B2 Dihydrotestosterone Estradiol B: metabolites in black, genes in grey. (DHT) SCC: P450 side-chain-cleavage; StAR: Aldosterone steroidogenic acute response protein; POR: P450 oxido reductase; HSD: hydrox- ysteroid dehydrogenase; H6PDH: hexose- Mineralocorticoids Glucocorticoids Sex hormones 6-phosphate dehydrogenase; CYP: cy- (Salt - Water Homeostasis) (Stress response) tochrome P450. 1. defects leading to disorders of sex development (DSD) production of all the 3 types of steroids, causing abnor- (1) and salt-water balance; malities in the salt-water homeostasis and in sexual differ- 2. defects leading to abnormalities of salt-water balance; entiation. That is the case in lipoid adrenal hyperplasia, 3. defects leading to disorders of sex development. where no conversion of cholesterol to any steroid takes Defective genes and clinical consequences of their de- place. This rare cause of CAH is characterized by salt-loss fects are briefly summarized in Table 1. and and 46, XY DSD. In XX subjects internal and external Abnormalities of end-organ action of steroid hormones, genitalia are female, and the syndrome cannot clinically exemplified by the hormone insensitivity syndromes can be separated from congenital adrenal hypoplasia (2). The be grouped in a 4th category. molecular bases of such a defect have been clarified as mutations in the Steroidogenic Acute Response Protein (StAR) (3). Recently, Kim et al. screened nine 46,XY infants DEFECTS LEADING TO ABNORMALITIES OF SEX with adrenal failure and disordered sexual differentiation DEVELOPMENT AND SALT-WATER BALANCE for mutations in the CYP11A1 gene encoding cytochrome The first group of steroid biosynthesis defects include the P450scc and identified 2 patients, both compound het- so-called congenital adrenal hyperplasia (CAH), a collec- erozygotes, bringing the total number of patients with tive name given to a group of disorders characterized by CYP11A1 mutations to 6. Among the 6 patients, the phe- inherited inability of the adrenals to secrete cortisol. The notypic spectrum ranged from severe loss-of-function mu- consequent compensatory rise of ACTH production caus- tations associated with prematurity, complete underan- es hyperplastic growth of the adrenal glands. Blocks of drogenization, and severe, early-onset adrenal failure, to the initial steps of the steroidogenic pathway impair the partial deficiencies found in children born at term with cli- 757 Defects of steroidogenesis toromegaly and later-onset adrenal failure. The authors of tion of DHEA is minimal in childhood, rises 100-fold to lev- this work noted that, in contradistinction to congenital els that exceed the production of cortisol in young adult- lipoid adrenal hyperplasia caused by StAR mutations, hood, and then gradually decreases with advancing age adrenal hyperplasia had not been reported in any of the 6 (6). The mechanisms by which human adrenal C19 steroid patients with P450scc deficiency (4). synthesis is turned on (adrenarche) and turned off (adrenopause) remain unclear. Recent clinical observations P450c17 (17a-hydroxylase/17,20-lyase) suggest a link between premature exaggerated adrenar- The enzyme P450c17 plays an important role in steroid che and the polycystic ovary syndrome (7-10). production. It is essential for the synthesis of cortisol as P450c17 is a single enzyme encoded by a single gene well as the production of sex steroids. P450c17 has two that is expressed in both the adrenals and gonads (11- distinct activities: 17α-hydroxylase activity and 17,20- 13). Like other microsomal P450 enzymes, P450c17
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