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Intracrine Androgen Biosynthesis, Metabolism and Action Revisited Schiffer, Lina; Arlt, Wiebke; Storbeck, Karl-Heinz

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Intracrine Androgen Biosynthesis, Metabolism and Action Revisited Schiffer, Lina; Arlt, Wiebke; Storbeck, Karl-Heinz University of Birmingham Intracrine androgen biosynthesis, metabolism and action revisited Schiffer, Lina; Arlt, Wiebke; Storbeck, Karl-Heinz DOI: 10.1016/j.mce.2017.08.016 License: Creative Commons: Attribution (CC BY) Document Version Publisher's PDF, also known as Version of record Citation for published version (Harvard): Schiffer, L, Arlt, W & Storbeck, K-H 2018, 'Intracrine androgen biosynthesis, metabolism and action revisited', Molecular and Cellular Endocrinology, vol. 465, pp. 4-26. https://doi.org/10.1016/j.mce.2017.08.016 Link to publication on Research at Birmingham portal General rights Unless a licence is specified above, all rights (including copyright and moral rights) in this document are retained by the authors and/or the copyright holders. 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Sep. 2021 Molecular and Cellular Endocrinology 465 (2018) 4e26 Contents lists available at ScienceDirect Molecular and Cellular Endocrinology journal homepage: www.elsevier.com/locate/mce Intracrine androgen biosynthesis, metabolism and action revisited * Lina Schiffer a, Wiebke Arlt a, , Karl-Heinz Storbeck a, b a Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK b Department of Biochemistry, Stellenbosch University, Stellenbosch 7600, South Africa article info abstract Article history: Androgens play an important role in metabolic homeostasis and reproductive health in both men and Received 16 May 2017 women. Androgen signalling is dependent on androgen receptor activation, mostly by testosterone and Received in revised form 5a-dihydrotestosterone. However, the intracellular or intracrine activation of C19 androgen precursors to 28 August 2017 active androgens in peripheral target tissues of androgen action is of equal importance. Intracrine Accepted 28 August 2017 androgen synthesis is often not reflected by circulating androgens but rather by androgen metabolites Available online 1 September 2017 and conjugates. In this review we provide an overview of human C19 steroid biosynthesis including the production of 11-oxygenated androgens, their transport in circulation and uptake into peripheral tissues. Keywords: Androgens We conceptualise the mechanisms of intracrinology and review the intracrine pathways of activation and Intracrinology inactivation in selected human tissues. The contribution of liver and kidney as organs driving androgen Steroid biosynthesis inactivation and renal excretion are also highlighted. Finally, the importance of quantifying androgen Hormone-dependent cancer metabolites and conjugates to assess intracrine androgen production is discussed. Testosterone © 2018 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY 11-oxygenated androgens license (http://creativecommons.org/licenses/by/4.0/). Contents 1. Introduction . ......................... 5 2. De-novo androgen biosynthesis in the adrenal and gonads . ......................... 5 2.1. Adrenal androgen biosynthesis . .. ............................................5 2.2. Ovarian C19 steroid biosynthesis . ............................................8 2.3. Testicular C19 biosynthesis . ............................................8 3. C19 steroids in circulation . ......................... 8 4. C19 steroid metabolism in peripheral target tissues e principles of intracrine androgen activation and inactivation . ............. 10 4.1. Cellular uptake and deconjugation . ...........................................10 4.2. Principles of intracrine androgen steroid metabolism . ............................11 4.3. Enzymes involved in intracrine androgen metabolism . ............................11 5. Pathways of peripheral androgen activation . ........................ 13 5.1. The classical androgen biosynthesis pathway . .......................................13 5.2. The alternate 5a-dione pathway . ...........................................14 5.3. The backdoor pathway . ...........................................14 Abbreviations: 11KA4, 11-keto-androstenedione; 11KDHT, 11-keto-5a-dihydrotestosterone; 11KT, 11-keto-testosterone; 11OHA4, 11b-hydroxy-androstenedione; 11OHDHT, 11b-hydroxy-5a-dihydrotestosterone; 11OHT, 11b-hydroxy-testosterone; 17aHP, 5a-pregnane-17a-ol-3,20-one; 17OHPROG, 17a-hydroxy-progesterone; 3a-adiol, 5a-androstan-3a,17b-diol; 5a-dione, 5a-androstane-3,17-dione; 5-diol, androst-5-ene-3b,17b-diol; A4, androstenedione (androst-4-ene-3,17-dione); AKR, aldo-keto reduc- tase; AR, androgen receptor; AST, androsterone (5a-androstan-3a-ol-17-one); CHOL, cholesterol; CRPC, castration resistant prostate cancer; CYP, cytochrome P450; DHEA, dehydroepiandrosterone (androst-5-ene-3b-ol-17-one); DHEAS, dehydroepiandrosterone sulfate; EpiAST, 5a-androstan-3b-ol-17-one; EpiT, epitestosterone (17a-hydroxy- testosterone, androst-4-ene-17a-ol-3-one); E1, estrone; E1S, estrone sulfate; E2, estradiol; ETIO, etiochonanolone (5b-androstan-3a-ol-17-one); DHT, 5a-dihydrotestosterone (5a-androstan-17b-ol-3-one); HSD, hydroxysteroid dehydrogenase; OATP, organic anion-transporting polypeptide; PAPS, 30-phospho-adenosine-50-phosphosulfate; PCOS, polycystic ovary syndrome; Pdiol, 5a-pregnane-3a,17a-diol-20-one; PORD, cytochrome P450 oxidoreductase deficiency; PREG, pregnenolone; PROG, progesterone; StAR, steroidogenic acute regulatory protein; SHBG, sex hormone-binding globulin; STS, steroid sulfatase; SULT, sulfotransferase; T, testosterone (androst-4-ene-17b-ol-3-one); UGT, uridine diphosphate-glucuronosyl transferase. * Corresponding author. E-mail address: [email protected] (W. Arlt). http://dx.doi.org/10.1016/j.mce.2017.08.016 0303-7207/© 2018 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). L. Schiffer et al. / Molecular and Cellular Endocrinology 465 (2018) 4e26 5 5.4. The 11-oxygenated androgen pathways . ........................14 6. Directionality of biosynthetic steps, phase 1 metabolism and conjugation . ..................... 14 7. Intracrinology in metabolic target tissues . .................................... 14 7.1. Adipose tissue . ........................14 7.2. Skeletal muscle . ........................15 7.3. Liver.........................................................................................................................15 7.3.1. Hepatic phase 1 metabolism . ........................15 7.3.2. Hepatic phase 2 metabolism . ........................16 7.3.3. The liver as a target tissue of androgen action . ........................16 8. Intracrine androgen metabolism in reproductive target tissues . ..................... 16 8.1. Breast and endometrium . ........................16 8.2. Prostate............................................................... .............................. ........................17 8.3. Placenta . ........................17 9. Intracrine androgen metabolism in other tissues . .................................... 18 9.1. Skin ................................................................ ................................ ........................18 9.2. Salivary gland . ........................18 10. Kidney androgen metabolism and renal excretion of androgens . ..................... 18 10.1. The kidney as an androgen-metabolising organ . ........................18 10.2. Renal excretion and analytical considerations . .. ........................19 11. Conclusions . ................................................. 19 Acknowledgments . ........................20 References................................................................. ................................ ........................20 1. Introduction inactivation and excretion are also highlighted. For ease of refer- ence the enzymes discussed in this review are summarised in Androgens (from the greek “andro” meaning male or man) are Table 1 along with the names of the corresponding genes and their traditionally considered male sex steroids responsible for the enzymatic activities. maintenance of male characteristics via the activation of the Androgen Receptor (AR), a ligand-induced nuclear receptor that 2. De-novo androgen biosynthesis in the adrenal and gonads functions as transcription factor after activation. The primary androgen found in men is testosterone (T, androst-4-ene-17b-ol-3- 2.1.
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