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Testicular Steroidogenesis

Living reference work entry
Part of the Endocrinology book series (ENDOCR)

Abstract

Testosterone is the major androgen in circulation in male humans, produced primarily in the Leydig cells of the testis. Biosynthesis of testosterone from cholesterol occurs via a series of enzymatic reactions. Testosterone may be further metabolized into a more potent androgen, dihydrotestosterone. In recent years an alternate pathway of dihydrotestosterone biosynthesis without using testosterone as a precursor has emerged. Majority of classically studied effects of androgens are thought to be mediated via nuclear receptor-dependent long-term transcriptional effects, but there also exist membrane receptor-based effects of androgens which are being uncovered from recent studies that may explain rapid effects of androgens in many cases. In this chapter we are describing the biosynthesis, mechanism of action, and therapeutic effects of testosterone and related androgens.

Keywords

Androgens Anabolic steroids Androgen receptor Testosterone CYP17A1 SRD5A1 Dihydrotestosterone 

Notes

Acknowledgments

This work has been supported by the Swiss National Science Foundation grant 320030-146127.

References

  1. Auchus RJ. The backdoor pathway to dihydrotestosterone. Trends Endoscrinol Metab. 2004;15:432–8.CrossRefGoogle Scholar
  2. Biason-Lauber A, Miller WL, et al. Of marsupials and men: "backdoor" dihydrotestosterone synthesis in male sexual differentiation. Mol Cell Endocrinol. 2013;371(1–2):124–32.CrossRefPubMedGoogle Scholar
  3. Bongiovanni AM. The adrenogenital syndrome with deficiency of 3 beta-hydroxysteroid dehydrogenase. J Clin Invest. 1962;41:2086–92.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Bose HS, Sugawara T, et al. The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. N Engl J Med. 1996;335(25):1870–8.CrossRefPubMedGoogle Scholar
  5. Burckhardt MA, Udhane S, et al. Human 3beta-hydroxysteroid-dehydrogenase deficiency seems to affect fertility but may not harbor a tumor risk: lesson from an experiment of nature. Eur J Endocrinol. 2015;173(5):K1–K12.CrossRefPubMedGoogle Scholar
  6. Burkhard FZ, Parween S, et al. P450 oxidoreductase deficiency: analysis of mutations and polymorphisms. J Steroid Biochem Mol Biol. 2017;165(Pt A):38–50.CrossRefPubMedGoogle Scholar
  7. Camats N, Pandey AV, et al. Ten novel mutations in the NR5A1 gene cause disordered sex development in 46,XY and ovarian insufficiency in 46,XX individuals. J Clin Endocrinol Metab. 2012;97(7):E1294–306.CrossRefPubMedGoogle Scholar
  8. de Castro AL, Cavalari FC, et al. Epitestosterone and testosterone have similar nonclassical actions on membrane of Sertoli cells in whole seminiferous tubules. Horm Metab Res. 2013;45(01):15–21.PubMedGoogle Scholar
  9. Cavalari FC, de Castro AL, et al. Non-classic androgen actions in JSertoli cell membrane in whole seminiferous tubules: effects of nandrolone decanoate and catechin. Steroids. 2012;77(1–2):118–25.CrossRefPubMedGoogle Scholar
  10. Chang KH, Li R, et al. Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer. Proc Natl Acad Sci USA. 2011;108(33):13728–33.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Choi MH, Skipper PL, et al. Characterization of testosterone 11β-hydroxylation catalyzed by human liver microsomal cytochromes p450. Drug Metab Dispos. 2005;33(6):714–8.CrossRefPubMedGoogle Scholar
  12. Davey RA, Grossmann M. Androgen receptor structure, function and biology: from bench to bedside. Clin Biochem Rev. 2016;37(1):3–15.PubMedPubMedCentralGoogle Scholar
  13. Dhayat NA, Frey AC, et al. Estimation of reference curves for the urinary steroid metabolome in the first year of life in healthy children: tracing the complexity of human postnatal steroidogenesis. J Steroid Biochem Mol Biol. 2015;154:226–36.CrossRefPubMedGoogle Scholar
  14. Dhayat NA, Dick B, et al. Androgen biosynthesis during minipuberty favors the backdoor pathway over the classic pathway: insights into enzyme activities and steroid fluxes in healthy infants during the first year of life from the urinary steroid metabolome. J Steroid Biochem Mol Biol. 2017;165:312–322.Google Scholar
  15. Duggal R, Liu Y, et al. Evidence that cytochrome b5 acts as a redox donor in CYP17A1 mediated androgen synthesis. Biochem Biophys Res Commun. 2016;477(2):202–8.CrossRefPubMedGoogle Scholar
  16. Faisal Ahmed S, Iqbal A, et al. The testosterone:androstenedione ratio in male undermasculinization. Clin Endocrinol. 2000;53(6):697–702.CrossRefGoogle Scholar
  17. Fassnacht M, Schlenz N, et al. Beyond adrenal and ovarian androgen generation: increased peripheral 5 alpha-reductase activity in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2003;88(6):2760–6.CrossRefPubMedGoogle Scholar
  18. Fevold HR, Lorence MC, et al. Rat P450(17 alpha) from testis: characterization of a full-length cDNA encoding a unique steroid hydroxylase capable of catalyzing both delta 4- and delta 5-steroid-17,20-lyase reactions. Mol Endocrinol. 1989;3(6):968–75.CrossRefPubMedGoogle Scholar
  19. Flück CE, Pandey AV. Impact on CYP19A1 activity by mutations in NADPH cytochrome P450 oxidoreductase. J Steroid Biochem Mol Biol. 2017;165(Pt A):64–70.CrossRefPubMedGoogle Scholar
  20. Flück CE, Miller WL, et al. The 17, 20-lyase activity of cytochrome P450c17 from human fetal testis favors the Δ5 steroidogenic pathway. J Clin Endocrinol Metab. 2003;88(8):3762–6.CrossRefPubMedGoogle Scholar
  21. Flück CE, Tajima T, et al. Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome. Nat Genet. 2004;36(3):228–30.CrossRefPubMedGoogle Scholar
  22. Flück CE, Meyer-Boni M, et al. Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation. Am J Hum Genet. 2011;89:201–18.CrossRefPubMedPubMedCentralGoogle Scholar
  23. Flück CE, Pandey AV, et al. Characterization of novel StAR (steroidogenic acute regulatory protein) mutations causing non-classic lipoid adrenal hyperplasia. PLoS One. 2011;6(5):e20178.CrossRefPubMedPubMedCentralGoogle Scholar
  24. Foradori CD, Weiser MJ, et al. Non-genomic actions of androgens. Front Neuroendocrinol. 2008;29(2):169–81.CrossRefPubMedGoogle Scholar
  25. Fukami M, Homma K, et al. Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development. Dev Dyn. 2013;242(4):320–9.CrossRefPubMedGoogle Scholar
  26. Govindan MV. Specific region in hormone binding domain is essential for hormone binding and trans-activation by human androgen receptor. Mol Endocrinol. 1990;4(3):417–27.CrossRefPubMedGoogle Scholar
  27. Hatzoglou A, Kampa M, et al. Membrane androgen receptor activation induces apoptotic regression of human prostate cancer cells in vitro and in vivo. J Clin Endocrinol Metab. 2005;90(2):893–903.CrossRefPubMedGoogle Scholar
  28. Hershkovitz E, Parvari R, et al. Homozygous mutation G539R in the gene for P450 oxidoreductase in a family previously diagnosed as having 17,20-lyase deficiency. J Clin Endocrinol Metab. 2008;93(9):3584–8.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Homma K, Hasegawa T, et al. Urine steroid hormone profile analysis in cytochrome P450 oxidoreductase deficiency: implication for the backdoor pathway to dihydrotestosterone. J Clin Endocrinol Metab. 2006;91(7):2643–9.CrossRefPubMedGoogle Scholar
  30. Idkowiak J, Randell T, et al. A missense mutation in the human cytochrome b5 gene causes 46,XY disorder of sex development due to true isolated 17,20 lyase deficiency. J Clin Endocrinol Metab. 2012;97(3):E465–75.CrossRefPubMedGoogle Scholar
  31. Ishii Y, Nurrochmad A, et al. Modulation of UDP-glucuronosyltransferase activity by endogenous compounds. Drug Metab Pharmacokinet. 2010;25(2):134–48.CrossRefPubMedGoogle Scholar
  32. Ishii Y, Koba H, et al. Alteration of the function of the UDP-glucuronosyltransferase 1A subfamily by cytochrome P450 3A4: different susceptibility for UGT isoforms and UGT1A1/7 variants. Drug Metab Dispos. 2014;42(2):229–38.CrossRefPubMedGoogle Scholar
  33. Kamrath C, Hochberg Z, et al. Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis. J Clin Endocrinol Metab. 2012;97(3):E367–75.CrossRefPubMedGoogle Scholar
  34. Ko E, Choi H, et al. Testosterone stimulates Duox1 activity through GPRC6A in skin keratinocytes. J Biol Chem. 2014;289(42):28835–45.CrossRefPubMedPubMedCentralGoogle Scholar
  35. Kuiri-Hanninen T, Sankilampi U, et al. Activation of the hypothalamic-pituitary-gonadal axis in infancy: minipuberty. Hormone research in paediatrics. 2014;82(2):73–80.CrossRefPubMedGoogle Scholar
  36. Lieberherr M, Grosse B. Androgens increase intracellular calcium concentration and inositol 1,4,5-trisphosphate and diacylglycerol formation via a pertussis toxin-sensitive G-protein. J Biol Chem. 1994;269(10):7217–23.PubMedGoogle Scholar
  37. Loss ES, Jacobsen M, et al. Testosterone modulates K+ATP channels in Sertoli cell membrane via the PLC-PIP2 pathway. Horm Metab Res. 2004;36(08):519–25.CrossRefPubMedGoogle Scholar
  38. Lourenco D, Brauner R, et al. Loss-of-function mutation in GATA4 causes anomalies of human testicular development. Proc Natl Acad Sci USA. 2011;108(4):1597–602.CrossRefPubMedPubMedCentralGoogle Scholar
  39. Marti N, Galvan JA, et al. Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome. Mol Cell Endocrinol. 2016;441:116–23.CrossRefPubMedGoogle Scholar
  40. Matsumoto T, Sakari M, et al. The androgen receptor in health and disease. Annu Rev Physiol. 2013;75(1):201–24.CrossRefPubMedGoogle Scholar
  41. Miller WL. The syndrome of 17,20 lyase deficiency. J Clin Endocrinol Metab. 2012;97(1):59–67.CrossRefPubMedGoogle Scholar
  42. Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev. 2011;32(1):81–151.CrossRefPubMedGoogle Scholar
  43. Miller WL, Flück CE. Adrenal cortex and its disorders. In: Sperling MA, editor. Pediatric endocrinology. Philadelphia: Saunders; 2014.Google Scholar
  44. Neunzig J, Sánchez-Guijo A, et al. A steroidogenic pathway for sulfonated steroids: the metabolism of pregnenolone sulfate. J Steroid Biochem Mol Biol. 2014;144(Part B):324–33.CrossRefPubMedGoogle Scholar
  45. Nicolo C, Flück CE, et al. Restoration of mutant cytochrome P450 reductase activity by external flavin. Mol Cell Endocrinol. 2010;321(2):245–52.CrossRefPubMedGoogle Scholar
  46. Pandey AV, Flück CE. NADPH P450 oxidoreductase: structure, function, and pathology of diseases. Pharmacol Ther. 2013;138(2):229–54.CrossRefPubMedGoogle Scholar
  47. Pandey AV, Sproll P. Pharmacogenomics of human P450 oxidoreductase. Front Pharmacol. 2014;5:103.CrossRefPubMedPubMedCentralGoogle Scholar
  48. Pandey AV, Kempna P, et al. Modulation of human CYP19A1 activity by mutant NADPH P450 oxidoreductase. Mol Endocrinol. 2007;21(10):2579–95.CrossRefPubMedGoogle Scholar
  49. Papakonstanti EA, Kampa M, et al. A rapid, nongenomic, signaling pathway regulates the actin reorganization induced by activation of membrane testosterone receptors. Mol Endocrinol. 2003;17(5):870–81.CrossRefPubMedGoogle Scholar
  50. Parween S, Roucher-Boulez F, et al. P450 oxidoreductase deficiency: loss of activity caused by protein instability from a novel L374H mutation. J Clin Endocrinol Metab. 2016;101(12):4789–98.CrossRefPubMedGoogle Scholar
  51. Peterson RE, Imperato-McGinley J, et al. Male pseudohermaphroditism due to multiple defects in steroid-biosynthetic microsomal mixed-function oxidases. A new variant of congenital adrenal hyperplasia. N Engl J Med. 1985;313(19):1182–91.CrossRefPubMedGoogle Scholar
  52. Pi M, Parrill AL, et al. GPRC6A mediates the non-genomic effects of steroids. J Biol Chem. 2010;285(51):39953–64.CrossRefPubMedPubMedCentralGoogle Scholar
  53. Prader A, Gurtner HP. The syndrome of male pseudohermaphrodism in congenital adrenocortical hyperplasia without overproduction of androgens (adrenal male pseudohermaphrodism). Helv Paediatr Acta. 1955;10(4):397–412.PubMedGoogle Scholar
  54. Simoncini T, Genazzani A. Non-genomic actions of sex steroid hormones. Eur J Endocrinol. 2003;148(3):281–92.CrossRefPubMedGoogle Scholar
  55. Strott CA. Steroid sulfotransferases. Endocr Rev. 1996;17(6):670–97.CrossRefPubMedGoogle Scholar
  56. Suntharalingham JP, Buonocore F, et al. DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human disease. Best Pract Res Clin Endocrinol Metab. 2015;29(4):607–19.CrossRefPubMedPubMedCentralGoogle Scholar
  57. Swart AC, Storbeck KH. 11beta-Hydroxyandrostenedione: downstream metabolism by 11betaHSD, 17betaHSD and SRD5A produces novel substrates in familiar pathways. Mol Cell Endocrinol. 2015;408:114–23.CrossRefPubMedGoogle Scholar
  58. Ueda T, Mawji NR, et al. Ligand-independent activation of the androgen receptor by Interleukin-6 and the role of steroid receptor coactivator-1 in prostate cancer cells. J Biol Chem. 2002;277(41):38087–94.CrossRefPubMedGoogle Scholar
  59. Walker WH. Non-classical actions of testosterone and spermatogenesis. Philos Trans R Soc B: Biol Sci. 2010;365(1546):1557–69.CrossRefGoogle Scholar
  60. Wang C, Liu Y, et al. G protein-coupled receptors: extranuclear mediators for the non-genomic actions of steroids. Int J Mol Sci. 2014;15(9):15412.CrossRefPubMedPubMedCentralGoogle Scholar
  61. van de Wijngaart DJ, Dubbink HJ, et al. Androgen receptor coregulators: recruitment via the coactivator binding groove. Mol Cell Endocrinol. 2012;352(1–2):57–69.CrossRefPubMedGoogle Scholar
  62. Zachmann M. Prismatic cases: 17,20-desmolase (17,20-lyase) deficiency. J Clin Endocrinol Metab. 1996;81(2):457–9.PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Pediatric Endocrinology and Diabetology Department of Pediatrics, Bern University Hospital, and Department of Clinical ResearchUniversity of BernBernSwitzerland

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