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Steroid Biochemistry Technological Advances Hiort O, Ahmed SF (eds): Understanding Differences and Disorders of Sex Development (DSD). Endocr Dev. Basel, Karger 2014, vol 27, pp 41–52 (DOI: 10.1159/000363612) Steroid Biochemistry a a b Clemens Kamrath · Stefan A. Wudy · Nils Krone a Division of Pediatric Endocrinology and Diabetology, Laboratory for Translational Hormone Analytics in Pediatric Endocrinology, Steroid Research and Mass Spectrometry Unit, Centre of Child and Adolescent b Medicine, Justus Liebig University, Giessen, Germany; Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK Abstract Accurate analysis of steroid hormones represents an essential part in the evaluation of a patient with disorders or differences in sex development. Analytical methods based on mass spectrometry (MS) have become the state-of-the-art methodology allowing for the most specific qualitative and quan- titative determination of steroid hormones and their metabolites. Liquid chromatography linked with tandem MS (LC-MS/MS) allows for rapid as well as highly specific and sensitive targeted steroid hormone analysis of multiple analytes from a single sample. Urinary steroid profile analysis by gas chromatography (GC)-MS is a non-invasive diagnostic approach and provides qualitative and quan- titative data on the global excretion of steroid hormone metabolites. GC-MS remains the most pow- erful discovery tool for defining inborn errors of steroidogenesis, whereas LC-MS/MS represents a highly sensitive and specific method for targeted steroid hormone analysis. © 2014 S. Karger AG, Basel Steroidogenesis The majority of steroidogenic enzymes are cytochrome P450 (CYP) enzymes catalys- ing redox reactions. These biochemical conversions crucially rely on electron supply via specific electron transfer chains. CYP type 1 enzymes are localised to the mito- chondrion and receive their electrons via adrenodoxin reductase and adrenodoxin. P450 side-chain cleavage enzyme (CYP11A1), 11β-hydroxylase (CYP11B1) and aldo- sterone synthase (CYP11B2) are all CYP type 1 enzymes. In contrast, 17α-hydroxylase (CYP17A1), 21-hydroxylase (CYP21A2) and aromatase (CYP19A1) are CYP type 2 enzymes localised to the endoplasmic reticulum. These microsomal CYP enzymes rely on electron transfer from P450 oxidoreductase (POR) to facilitate the hydroxyl- ation reactions [1]. The acute stimulation of steroidogenesis is mediated at the level of cholesterol im- port into mitochondria, which is facilitated by the steroidogenic acute regulatory Downloaded by: Siriraj Medical Library, Mahidol University 202.28.191.34 - 3/1/2015 6:35:26 PM Cholesterol outer StAR mitochondrial membrane inner Cholesterol ADR/Adx CYP11A1 PAPSS2 POR POR b5 Dehydroepi SULT2A1 Pregnenolone CYP17A1 17OH-Pregnenolone CYP17A1 androsterone DHEA-S Pregnenediol Pregnenetriol DHEA, 16αOH-DHEA HSD3B2 HSD3B2 HSD3B2 Androsterone, Etiocholanolone POR POR b5 POR Progesterone CYP17A1 17OH-Progesterone CYP17A1 Androstenedione CYP19A1 Oestrone POR Pregnanediol POR Pregnanetriol Androsterone CYP21A2 CYP21A2 17OH-Pregnanolone HSD17B Etiocholanolone HSD17B * POR 11-deoxycorticosterone 11-deoxycortisol Testosterone CYP19A1 OESTRADIOL ADR/Adx THDOC, 5αTHDOC ADR/Adx THS Androsterone Oestriol CYP11B2 CYP11B1 21-deoxycortisol SRD5A2 Etiocholanolone Pregnanetriolone Corticosterone CORTISOL DIHYDROTESTOSTERONE THA, THB THF, 5αTHF Androsterone ADR/Adx 5αTHA, 5αTHB H6PDH CYP11B2 HSD11B1 HSD11B2 18OH-corticosterone Cortisone ADR/Adx 18OH-THA THE CYP11B2 ALDOSTERONE THALDO Fig. 1. Steroidogenesis. After the StAR protein-mediated uptake of cholesterol into mitochondria, aldoste- rone, cortisol and androgens are synthesized through the co-ordinated action of a series of steroidogenic enzymes in a zone-specific fashion. The mitochondrial CYP type I enzymes (CYP11A1, CYP11B1, CYP11B2) requiring electron transfer via adrenodoxin reductase (ADR) and adrenodoxin (Adx) are marked (box la- belled ‘ADR/Adx’). The microsomal CYP II enzymes (CYP17A1, CYP21A2, CYP19A1) receive electrons from POR (indicated by circled POR). In addition to POR, the 17,20-lyase reaction catalysed by CYP17A1 also re- quires CYB5 (indicated by circled b5). Urinary steroid hormone metabolites are given in italics below the plasma hormones. The asterisk (*) indicates the 11β-hydroxylation of 17OHP to 21-deoxycortisol in 21OHD. The adrenal conversion of androstenedione to testosterone is catalysed by AKR1C3 (HSD17B5), whereas the testicular conversion is facilitated by HSD17B3. SULT2A1 = Sulfotransferase 2A1; PAPPS2 = 3 -phos- phoadenosine 5 -phosphosulfate synthase 2; DHEA-S = dehydroepiandrosterone sulphate. ′ ′ (StAR) protein [2]. Thereafter, the first step of steroid hormone biosynthesis is the conversion of cholesterol to pregnenolone catalysed by the mitochondrial P450 side- chain cleavage enzyme (P450scc, CYP11A1; fig. 1). The StAR/CYP11A1 system is the quantitative regulator of steroidogenesis, where- as the CYP17A1 enzyme represents the qualitative regulator determining the class of 42 Kamrath · Wudy · Krone Hiort O, Ahmed SF (eds): Understanding Differences and Disorders of Sex Development (DSD). Endocr Dev. Basel, Karger 2014, vol 27, pp 41–52 (DOI: 10.1159/000363612) Downloaded by: Siriraj Medical Library, Mahidol University 202.28.191.34 - 3/1/2015 6:35:26 PM produced steroid hormone. In the zona glomerulosa, absence of CYP17A1 leads to mineralocorticoid synthesis. In contrast, isolated 17α-hydroxylase activity of CYP17A1 results in the synthesis of glucocorticoids in the zona fasciculata. Combined activities of CYP17A1 catalyse both the 17α-hydroxylation and 17,20-lyase reaction of 21-car- bon (C21) steroids to 19-carbon (C19) precursors of sex steroids in the adrenal zona reticularis and gonads. The main pathway to sex steroids facilitated by CYP17A1 is the conversion of 17α-hydroxypregnenolone (17Preg) to dehydroepiandrosterone (DHEA; Δ5 path- way), whereas the conversion of 17α-hydroxyprogesterone (17OHP) to androstene- dione (Δ4 pathway) is hardly relevant under physiological circumstances. The signif- icant predominance of the Δ5 pathway via DHEA in humans is explained by substrate preference of CYP17A1 for 17Preg. The catalytic efficiency of this conversion is about 100-fold higher for the Δ5-steroid 17Preg than for the Δ4-steroid 17OHP. For the 17,20-lyase reaction, CYP17A1 crucially relies on cytochrome b5 (CYB5), which is expressed in the gonads and in the adrenal zona reticularis at the onset of adrenarche [2]. CYB5 acts as an allosteric factor that fosters the interactions of POR with CYP17A1, enhancing 17,20-lyase activity without influencing 17-hydroxylase activity. Another major physiological role of CYB5 is the reduction of methaemoglobin. DHEA is further converted by 3β-hydroxysteroid dehydrogenase (HSD) type 2 (HSD3B2) in the gonads and adrenals to androstenedione. In addition, HSD3B2 is also required for the conversion reactions of pregnenolone to progesterone, and 17Preg to 17OHP. Androstenedione is reduced by 17β-HSD type 3 (HSD17B3) in the testes to testos- terone. In androgen target tissues, testosterone is further converted to dihydrotestos- terone (DHT) by steroid 5α-reductase type 2 (SRD5A2) [2]. It has recently been suggested that 5α-reduction of testosterone is not the only bio- synthetic pathway to produce DHT. In addition, androstanediol can be 3α-oxidated in the target tissues to form DHT via the so-called ‘backdoor pathway’ (fig. 2). In this pathway, androstanediol is hypothesised to derive from sequential 5α- and 3α-reduction of 17OHP to 17α-hydroxyallopregnanolone, followed by its conversion to androsterone by 17,20-lyase activity of CYP17A1, and then its reduction by HSD17B activity (fig. 2) [3]. The physiological relevance of this pathway remains unclear; how- ever, it is likely to play a significant role in the pathophysiology of distinct conditions such as POR deficiency (PORD) or 21-hydroxylase deficiency (21OHD) [4, 5]. Adrenal 21-hydroxylase (CYP21A2) converts 17OHP to 11-deoxycortisol and pro- gesterone to 11-deoxycorticosterone (DOC), both precursors of cortisol and aldoste- rone biosynthesis. The final steps in the synthesis of glucocorticoids and mineralocor- ticoids are catalysed by two closely related mitochondrial enzymes, 11β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2). Steroid 11β-hydroxylase converts 11-deoxycortisol to cortisol and DOC to corticosterone. CYP11B1 is expressed pre- dominantly in the zona fasciculata, and to a lesser extent in the zona reticularis, but not in the zona glomerulosa. Aldosterone synthase is found only in the zona glomer- Steroid Biochemistry 43 Hiort O, Ahmed SF (eds): Understanding Differences and Disorders of Sex Development (DSD). Endocr Dev. Basel, Karger 2014, vol 27, pp 41–52 (DOI: 10.1159/000363612) Downloaded by: Siriraj Medical Library, Mahidol University 202.28.191.34 - 3/1/2015 6:35:26 PM O O O Dehydroepiandrosterone OH Δ5 CYP17A1 POR Testosterone OH HO HO HO CYB5 Pregnenolone 17α-Hydroxy- 3β-HSD2 O pregnenolone (HSD3B2) 3β-HSD2 (HSD3B2) O 4 OH Δ 17β-HSD O CYP17A1 O (AKR1C3) 5α-Reductase 17α-Hydroxy- POR 4-Androstenedione (SRD5A1,2) progesterone CYB5 O Dihydrotestosterone 5α-Reductase OH (SRD5A1,2) O 17α-Hydroxy- OH dihydroprogesterone O 3α-HSD 3α-HSD O Backdoor (HSD17B6) AKR1C2,4 ( ) O OH O 17α-Hydroxy- OH allopregnanolone CYP17A1 POR 17β-HSD CYB5 HO (HSD17B3/AKR1C3) HO HO Androsterone Androstanediol Fig. 2. Pathways to androgen synthesis. Conventional pathways are shown in black, whereas
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