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Adrenal Androgens and Androgen Precursors—Definition, Synthesis, Regulation and Physiologic Actions

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Abstract

The human adrenal produces more 19 carbon (C19) steroids, by mass, than either glucocorticoids or mineralocorticoids. However, the mechanisms regulating adrenal C19 steroid biosynthesis continue to represent one of the most intriguing mysteries of endocrine physiology. This review will discuss the C19 steroids synthesized by the human adrenal and the features within the adrenal that allow production of these steroids. Finally, we consider the effects of these steroids in normal physiology and disorders of adrenal C19 steroid excess. © 2014 American Physiological Society. Compr Physiol 4:1369‐1381, 2014.

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Figure 1. Figure 1. Adrenal C19 steroid biosynthetic pathways. The steroid secreted from the human adrenal at the highest levels have larger font. The more abundant steroids are graphically overemphasized. Abbreviations: DHEA, dehydroepiandrosterone; DHEAS, DHEA sulfate; StAR, steroidogenic acute regulatory protein; CYP11A1, cytochrome P450 cholesterol side‐chain cleavage; HSD3B2, 3β‐hydroxysteroid dehydrogenase type 2; CYB5A, cytochrome b5; AKR1C3, 17β‐hydroxysteroid dehydrogenase type 5; SULT2A1, steroid sulfotransferase type 2A1, CYP11B1, 11β‐hydroxylase.
Figure 2. Figure 2. Adrenal steroidogenic enzymes and associated proteins that impact C19 steroid production with their human adrenal zonal expression pattern. Abbreviations: ZG, zona glomerulosa; ZF, zona fasciculata; ZR, zona reticularis; CYP11A1, cytochrome P450 cholesterol side‐chain cleavage; CYP17, 17α‐hydroxylase/17,20‐lyase; CYB5, cytochrome b5; SULT2A1, steroid sulfotransferase type 2A1; AKR1C3, 17β‐hydroxysteroid dehydrogenase type 3; HSD3B2, 3β‐hydroxysteroid dehydrogenase type 2.
Figure 3. Figure 3. Adrenal‐derived C19 steroids act as precursors for the production of more potent androgens in peripheral tissues, including hair follicles, genital skin, and prostate. The classical pathway for bioactive androgen synthesis, as well as a proposed alternative pathway using 11β‐hydroxyandrostenedione (11OHA) is shown. Abbreviations: A4, androstenedione; T, testosterone; DHT, dihydrotestosterone; 11OHT, 11β‐hydroxytestosterone;11OHDHT, 11β‐hydroxyDHT; STS, sulfatase; HSD3B, 3β‐hydroxysteroid dehydrogenases; HSD17, 17β‐hydroxysteroid dehydrogenases; SRD5A, 5α‐reductase type A.
Figure 4. Figure 4. Pathways of steroid hormone synthesis in 21‐hydroxylase deficiency. Abbreviations: A4, androstenedione; T, testosterone; DHT, dihydrotestosterone; 11OHA, 11β‐hydroxyandrostenedione; 11OHT, 11β‐hydroxytestosterone; SRDA1/2, 5α‐reductase types 1 or 2; AKR1C2/4, 3α‐hydroxysteroid dehydrogenases types 2 or 4; CYP17A1, 17α‐hydroxylase/17,20‐lyase; HSD17B3/6, 17β‐hydroxysteroid dehydrogenase types 3 or 6; AKR1C3, 17β‐hydroxysteroid dehydrogenase types 5.


Figure 1. Adrenal C19 steroid biosynthetic pathways. The steroid secreted from the human adrenal at the highest levels have larger font. The more abundant steroids are graphically overemphasized. Abbreviations: DHEA, dehydroepiandrosterone; DHEAS, DHEA sulfate; StAR, steroidogenic acute regulatory protein; CYP11A1, cytochrome P450 cholesterol side‐chain cleavage; HSD3B2, 3β‐hydroxysteroid dehydrogenase type 2; CYB5A, cytochrome b5; AKR1C3, 17β‐hydroxysteroid dehydrogenase type 5; SULT2A1, steroid sulfotransferase type 2A1, CYP11B1, 11β‐hydroxylase.


Figure 2. Adrenal steroidogenic enzymes and associated proteins that impact C19 steroid production with their human adrenal zonal expression pattern. Abbreviations: ZG, zona glomerulosa; ZF, zona fasciculata; ZR, zona reticularis; CYP11A1, cytochrome P450 cholesterol side‐chain cleavage; CYP17, 17α‐hydroxylase/17,20‐lyase; CYB5, cytochrome b5; SULT2A1, steroid sulfotransferase type 2A1; AKR1C3, 17β‐hydroxysteroid dehydrogenase type 3; HSD3B2, 3β‐hydroxysteroid dehydrogenase type 2.


Figure 3. Adrenal‐derived C19 steroids act as precursors for the production of more potent androgens in peripheral tissues, including hair follicles, genital skin, and prostate. The classical pathway for bioactive androgen synthesis, as well as a proposed alternative pathway using 11β‐hydroxyandrostenedione (11OHA) is shown. Abbreviations: A4, androstenedione; T, testosterone; DHT, dihydrotestosterone; 11OHT, 11β‐hydroxytestosterone;11OHDHT, 11β‐hydroxyDHT; STS, sulfatase; HSD3B, 3β‐hydroxysteroid dehydrogenases; HSD17, 17β‐hydroxysteroid dehydrogenases; SRD5A, 5α‐reductase type A.


Figure 4. Pathways of steroid hormone synthesis in 21‐hydroxylase deficiency. Abbreviations: A4, androstenedione; T, testosterone; DHT, dihydrotestosterone; 11OHA, 11β‐hydroxyandrostenedione; 11OHT, 11β‐hydroxytestosterone; SRDA1/2, 5α‐reductase types 1 or 2; AKR1C2/4, 3α‐hydroxysteroid dehydrogenases types 2 or 4; CYP17A1, 17α‐hydroxylase/17,20‐lyase; HSD17B3/6, 17β‐hydroxysteroid dehydrogenase types 3 or 6; AKR1C3, 17β‐hydroxysteroid dehydrogenase types 5.
References
 1. Abraham GE . Ovarian and adrenal contribution to peripheral androgens during the menstrual cycle. J Clin Endocrinol Metab 39: 340‐346, 1974.
 2. Akin L , Kurtoglu S , Kendirici M , Akin MA . Familial glucocorticoid deficiency type 2: A case report. J Clin Res Pediatr Endocrinol 2: 122‐125, 2010.
 3. Anderson DC . The adrenal androgen‐stimulating hormone does not exist. Lancet 2: 454‐456, 1980.
 4. Anuka E , Gal M , Stocco DM , Orly J . Expression and roles of steroidogenic acute regulatory (StAR) protein in ‘non‐classical’, extra‐adrenal and extra‐gonadal cells and tissues. Mol Cell Endocrinol 371: 47‐61, 2013.
 5. Artemenko IP , Zhao D , Hales DB , Hales KH , Jefcoate CR . Mitochondrial processing of newly synthesized steroidogenic acute regulatory protein (StAR), but not total StAR, mediates cholesterol transfer to cytochrome P450 side chain cleavage enzyme in adrenal cells. J Biol Chem 276: 46583‐46596, 2001.
 6. Attard G , Reid AH , Auchus RJ , Hughes BA , Cassidy AM , Thompson E , Oommen NB , Folkerd E , Dowsett M , Arlt W , de Bono JS . Clinical and biochemical consequences of CYP17A1 inhibition with abiraterone given with and without exogenous glucocorticoids in castrate men with advanced prostate cancer. J Clin Endocrinol Metab 97: 507‐516, 2012.
 7. Aubert ML , Grumbach MM , Kaplan SL . Heterologous radioimmunoassay for plasma human prolactin (hPRL); values in normal subjects, puberty, pregnancy and in pituitary disorders. Acta Endocrinol 77: 460‐476, 1974.
 8. Auchus RJ . The genetics, pathophysiology, and management of human deficiencies of P450c17. Endocrinol Metab Clin North Am 30: 101‐119, 2001.
 9. Auchus RJ . The backdoor pathway to dihydrotestosterone. Trends Endocrinol Metab 15: 432‐438, 2004.
 10. Auchus RJ , Lee TC , Miller WL . Cytochrome b5 augments the 17,20 lyase activity of human P450c17 without direct electron transfer. J Biol Chem 273: 3158‐3165, 1998.
 11. Auchus RJ , Rainey WE . Adrenarche ‐ physiology, biochemistry and human disease. Clin Endocrinol 60: 288‐296, 2004.
 12. Azziz R . Diagnosing the diagnosis: Why we must standardize the defining features of polycystic ovary syndrome. Ann Clin Biochem 45: 3‐5, 2008.
 13. Azziz R WK , Reyna R , Key TJ , Knochenhauer ES , Yildiz BO . The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab 89: 2745‐2749, 2004.
 14. Bergh C , Carlsson B , Olsson JH , Selleskog U , Hillensjo T . Regulation of androgen production in cultured human thecal cells by insulin‐like growth factor I and insulin. Fertil Steril 59: 323‐331, 1993.
 15. Biglieri EG , Herron MA , and Brust N . 17α‐hydroxylation deficiency in man. J Clin Invest 15: 1945‐1954, 1966.
 16. Black SM , Harikrishna JA , Szklarz GD , Miller WL . The mitochondrial environment is required for activity of the cholesterol side‐chain cleavage enzyme, cytochrome P450scc. Proc Natl Acad Sci U S A 91: 7247‐7251, 1994.
 17. Bloem LM , Storbeck KH , Schloms L , Swart AC . 11beta‐hydroxyandrostenedione returns to the steroid arena: Biosynthesis, metabolism and function. Molecules 18: 13228‐13244, 2013.
 18. Bolte E , Wiqvist N , Diczfalusy E . Metabolism of dehydroepiandrosterone and dehydroepiandrosterone sulphate by the human foetus at midpregnancy. Acta Endocrinol 52: 583‐597, 1966.
 19. Bongiovanni AM . The adrenogenital syndrome with deficiency of 3 beta‐hydroxysteroid dehydrogenase. J Clin Invest 41: 2086‐2092, 1962.
 20. Bose HS , Sugawara T , Strauss JF , III, Miller WL . The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. N Engl J Med 335: 1870‐1878, 1996.
 21. Bose HS , Whittal RM , Huang MC , Baldwin MA , Miller WL . N‐218 MLN64, a protein with StAR‐like steroidogenic activity, is folded and cleaved similarly to StAR. Biochemistry 39: 11722‐11731, 2000.
 22. Brunelli VL , Chiumello G , David M , Forest MG . Adrenarche does not occur in treated patients with congenital adrenal hyperplasia resulting from 21‐hydroxylase deficiency. Clin Endocrinol 42: 461‐466, 1995.
 23. Byrne GC , Perry YS , Winter JS . Kinetic analysis of adrenal 3 beta‐hydroxysteroid dehydrogenase activity during human development. J Clin Endocrinol Metab 60: 934‐939, 1985.
 24. Byrne GC , Perry YS , Winter JS . Steroid inhibitory effects upon human adrenal 3 beta‐hydroxysteroid dehydrogenase activity. J Clin Endocrinol Metab 62: 413‐418, 1986.
 25. Campbell B . Adrenarche in comparative perspective. Am J Hum Biol 23: 44‐52, 2011.
 26. Carmina E . Ovarian and adrenal hyperandrogenism. Ann N Y Acad Sci 1092: 130‐137, 2006.
 27. Carmina E , Azziz R . Diagnosis, phenotype, and prevalence of polycystic ovary syndrome. Fertil Steril 86 Suppl 1: S7‐S8, 2006.
 28. Caron K , Soo S‐C , Wetsel W , Stocco D , Clark B , Parker K . Targeted disruption of the mouse gene encoding steroidogenic acute regulatory protein provides insights into congenital lipoid adrenal hyperplasia. Proc Natl Acad Sci U S A 94: 11540‐11545, 1997.
 29. Catteau‐Jonard S , Dewailly D . Pathophysiology of polycystic ovary syndrome: The role of hyperandrogenism. Front Horm Res 40: 22‐27, 2013.
 30. Chung B , Matteson KJ , Voutilainen R , Mohandas TK , Miller WL . Human cholesterol side‐chain cleavage enzyme, P450scc: cDNA cloning, assignment of the gene to chromosome 15, and expression in the placenta. Proc Natl Acad Sci U S A 83: 8962‐8966, 1986.
 31. Chung BC , Picado‐Leonard J , Haniu M , Bienkowski M , Hall PF , Shively JE , Miller WL . Cytochrome P450c17 (steroid 17α‐hydroxylase/17,20 lyase): Cloning of human adrenal and testis cDNAs indicates the same gene is expressed in both tissues. Proc Natl Acad Sci U S A 84: 407‐411, 1987.
 32. Clark BJ , Wells J , King SR , Stocco DM . The purification, cloning and expression of a novel luteinizing hormone‐induced mitochondrial protein in MA‐10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR). J Biol Chem 269: 28314‐28322, 1994.
 33. Conley AJ , Bird IM . The role of cytochrome P450 17 alpha‐hydroxylase and 3 beta‐hydroxysteroid dehydrogenase in the integration of gonadal and adrenal steroidogenesis via the delta 5 and delta 4 pathways of steroidogenesis in mammals. Biol Reprod 56: 789‐799, 1997.
 34. Conley AJ , Pattison JC , Bird IM . Variations in adrenal androgen production among (nonhuman) primates. Semin Reprod Med 22: 311‐326, 2004.
 35. Costa‐Santos M , Kater CE , Auchus RJ . Two prevalent CYP17 mutations and genotype‐phenotype correlations in 24 brazilian patients with 17‐hydroxylase deficiency. J Clin Endocrinol Metab 89: 49‐60, 2004.
 36. Cutler GB, Jr. , Glenn M , Bush M , Hodgen GD , Graham CE , Loriaux DL . Adrenarche: A survey of rodents, domestic animals, and primates. Endocrinology 103: 2112‐2118, 1978.
 37. de Bono JS , Logothetis CJ , Molina A , Fizazi K , North S , Chu L , Chi KN , Jones RJ , Goodman OB , Saad F , Staffurth JN , Mainwaring P , Harland S , Flaig TW , Hutson TE , Cheng T , Patterson H , Hainsworth JD , Ryan CJ , Sternberg CN , Ellard SL , Fléchon A , Saleh M , Scholz M , Efstathiou E , Zivi A , Bianchini D , Loriot Y , Chieffo N , Kheoh T , Haqq CM , Scher HI , Investigators C‐A‐ . Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 364: 1995‐2005, 2011.
 38. de Peretti E , Forest MG . Unconjugated dehydroepiandrosterone plasma levels in normal subjects from birth to adolescence in human: The use of a sensitive radioimmunoassay. J Clin Endocrinol Metab 43: 982‐991, 1976.
 39. Deyashiki Y , Ogasawara A , Nakayama T , Nakanishi M , Miyabe Y , Sato K , Hara A . Molecular cloning of two human liver 3 alpha‐hydroxysteroid/dihydrodiol dehydrogenase isoenzymes that are identical with chlordecone reductase and bile‐acid binder. Biochem J 299 (Pt 2): 545‐552, 1994.
 40. Dhom G . The prepuberal and puberal growth of the adrenal (Adrenarche). Beitr Pathol 150: 357‐377, 1973.
 41. Dickerman Z , Grant DR , Faiman C , Winter JS . Intraadrenal steroid concentrations in man: Zonal differences and developmental changes. J Clin Endocrinol Metab 59: 1031‐1036, 1984.
 42. Doberne Y , Levine LS , New MI . Elevated urinary testosterone and androstanediol in precocious adrenarche. Pediatr Res 9: 794‐797, 1975.
 43. Du X , Rosenfield RL , Qin K . KLF15 Is a transcriptional regulator of the human 17beta‐hydroxysteroid dehydrogenase type 5 gene. A potential link between regulation of testosterone production and fat stores in women. J Clin Endocrinol Metab 94: 2594‐2601, 2009.
 44. Ducharme JR , Forest MG , De Peretti E , Sempe M , Collu R , Bertrand J . Plasma adrenal and gonadal sex steroids in human pubertal development. J Clin Endocrinol Metab 42: 468‐476, 1976.
 45. Dufort I , Rheault P , Huang XF , Soucy P , Luu‐The V . Characteristics of a highly labile human type 5 17beta‐hydroxysteroid dehydrogenase. Endocrinology 140: 568‐574, 1999.
 46. Endoh A , Kristiansen SB , Casson PR , Buster JE , Hornsby PJ . The zona reticularis is the site of biosynthesis of dehydroepiandrosterone and dehydroepiandrosterone sulfate in the adult human adrenal cortex resulting from its low expression of 3 beta‐hydroxysteroid dehydrogenase. J Clin Endocrinol Metab 81: 3558‐3565, 1996.
 47. Falany CN . Enzymology of human cytosolic sulfotransferases. FASEB J 11: 206‐216, 1997.
 48. Fardella CE , Zhang LH , Mahachoklertwattana P , Lin D , Miller WL . Deletion of amino acids Asp487‐Ser488‐Phe489 in human cytochrome P450c17 causes severe 17 alpha‐hydroxylase deficiency. J Clin Endocrinol Metab 77: 489‐493, 1993.
 49. Fluck CE , Miller WL , Auchus RJ . The 17, 20‐lyase activity of cytochrome p450c17 from human fetal testis favors the delta5 steroidogenic pathway. J Clin Endocrinol Metab 88: 3762‐3766, 2003.
 50. Frandsen VA , Stakemann G . The site of production of oestrogenic hormones in human pregnancy. 3. Further observations on the hormone excretion in pregnancy with anencephalic foetus. Acta Endocrinol 47: 265‐276, 1964.
 51. Gassner HL , Toppari J , Quinteiro Gonzalez S , Miller WL . Near‐miss apparent SIDS from adrenal crisis. J Pediatr 145: 178‐183, 2004.
 52. Geissler WM , Davis DL , Wu L , Bradshaw KD , Patel S , Mendonca BB , Elliston KO , Wilson JD , Russell DW , Andersson S . Male pseudohermaphroditism caused by mutations of testicular 17 beta‐hydroxysteroid dehydrogenase 3. Nat Genet 7: 34‐39, 1994.
 53. Gell JS , Atkins B , Margraf L , Mason JI , Sasano H , Rainey WE , Carr BR . Adrenarche is associated with decreased 3 beta‐hydroxysteroid dehydrogenase expression in the adrenal reticularis. Endocr Res 22: 723‐728, 1996.
 54. Gell JS , Carr BR , Sasano H , Atkins B , Margraf L , Mason JI , Rainey WE . Adrenarche results from development of a 3beta‐hydroxysteroid dehydrogenase‐deficient adrenal reticularis. J Clin Endocrinol Metab 83: 3695‐3701, 1998.
 55. Geller DH , Auchus RJ , Miller WL . P450c17 mutations R347H and R358Q selectively disrupt 17,20‐lyase activity by disrupting interactions with P450 oxidoreductase and cytochrome b5. Mol Endocrinol 13: 167‐175, 1999.
 56. Genazzani AR , Facchinetti F , Petraglia F , Pintor C , Bagnoli F , Puggioni R , Corda R . Correlations between plasma levels of opioid peptides and adrenal androgens in prepuberty and puberty. J Steroid Biochem 19: 891‐895, 1983.
 57. Genazzani AR , Facchinetti F , Pintor C , Puggioni R , Parrini D , Petraglia F , Bagnoli F , Corda R . Proopiocortin‐related peptide plasma levels throughout prepuberty and puberty. J Clin Endocrinol Metab 57: 56‐61, 1983.
 58. Goodarzi MO , Azziz R . Diagnosis, epidemiology, and genetics of the polycystic ovary syndrome. Best Pract Res Clin Endocrinol Metab 20: 193‐205, 2006.
 59. Granot Z , Geiss‐Friedlander R , Melamed‐Book N , Eimerl S , Timberg R , Weiss AM , Hales KH , Hales DB , Stocco DM , Orly J . Proteolysis of normal and mutated steroidogenic acute regulatory proteins in the mitochondria: The fate of unwanted proteins. Mol Endocrinol 17: 2461‐2476, 2003.
 60. Griffin JE . Androgen resistance–the clinical and molecular spectrum. N Engl J Med 326: 611‐618, 1992.
 61. Guercio G , Rivarola MA , Chaler E , Maceiras M , Belgorosky A . Relationship between the GH/IGF‐I axis, insulin sensitivity, and adrenal androgens in normal prepubertal and pubertal boys. J Clin Endocrinol Metab 87: 1162‐1169, 2002.
 62. Hauffa BP , Miller WL , Grumbach MM , Conte FA , Kaplan SL . Congenital adrenal hyperplasia due to deficient cholesterol side‐chain cleavage activity (20, 22‐desmolase) in a patient treated for 18 years. Clin Endocrinol 23: 481‐493, 1985.
 63. Herman‐Giddens ME , Slora EJ , Wasserman RC , Bourdony CJ , Bhapkar MV , Koch GG , Hasemeier CM . Secondary sexual characteristics and menses in young girls seen in office practice: A study from the Pediatric Research in Office Settings network. Pediatrics 99: 505‐512, 1997.
 64. Hochberg Z . Juvenility in the context of life history theory. Arch Dis Child 93: 534‐539, 2008.
 65. Hochberg Z . Evo‐Devo of child growth III: Premature juvenility as an evolutionary trade‐off. Horm Res Paediatr 73: 430‐437, 2010.
 66. Hu MC , Hsu NC , El Hadj NB , Pai CI , Chu HP , Wang CK , Chung BC . Steroid deficiency syndromes in mice with targeted disruption of Cyp11a1. Mol Endocrinol 16: 1943‐1950, 2002.
 67. Hui XG , Akahira J , Suzuki T , Nio M , Nakamura Y , Suzuki H , Rainey WE , Sasano H . Development of the human adrenal zona reticularis: Morphometric and immunohistochemical studies from birth to adolescence. J Endocrinol 203: 241‐252, 2009.
 68. Ibanez L , Dimartino‐Nardi J , Potau N , Saenger P . Premature adrenarche–normal variant or forerunner of adult disease? Endocr Rev 21: 671‐696, 2000.
 69. Imai T , Globerman H , Gertner JM , Kagawa N , Waterman MR . Expression and purification of functional human 17 alpha‐hydroxylase/17,20‐lyase (P450c17) in Escherichia coli. Use of this system for study of a novel form of combined 17 alpha‐hydroxylase/17,20‐lyase deficiency. J Biol Chem 268: 19681‐19689, 1993.
 70. Imai T , Yanase T , Waterman MR , Simpson ER , Pratt JJ . Canadian Mennonites and individuals residing in the Friesland region of The Netherlands share the same molecular basis of 17 alpha‐hydroxylase deficiency. Hum Genet 89: 95‐96, 1992.
 71. Imperato‐McGinley J , Guerrero L , Gautier T , Peterson RE . Steroid 5alpha‐reductase deficiency in man: An inherited form of male pseudohermaphroditism. Science 186: 1213‐1215, 1974.
 72. Jakobsson J , Palonek E , Lorentzon M , Ohlsson C , Rane A , Ekstrom L . A novel polymorphism in the 17beta‐hydroxysteroid dehydrogenase type 5 (aldo‐keto reductase 1C3) gene is associated with lower serum testosterone levels in caucasian men. Pharmacogenomics J 7: 282‐289, 2007.
 73. John ME , John MC , Boggaram V , Simpson ER , Waterman MR . Transcriptional regulation of steroid hydroxylase genes by corticotropin. Proc Natl Acad Sci U S A 83: 4715‐4719, 1986.
 74. Kagimoto M , Winter JS , Kagimoto K , Simpson ER , Waterman MR . Structural characterization of normal and mutant human steroid 17 alpha‐hydroxylase genes: Molecular basis of one example of combined 17 alpha‐hydroxylase/17,20 lyase deficiency. Mol Endocrinol 2: 564‐570, 1988.
 75. Kamrath C , Hochberg Z , Hartmann MF , Remer T , Wudy SA . Increased activation of the alternative “backdoor” pathway in patients with 21‐hydroxylase deficiency: Evidence from urinary steroid hormone analysis. J Clin Endocrinol Metab 97: E367‐E375, 2012.
 76. Kaplowitz P , Soldin SJ . Steroid profiles in serum by liquid chromatography‐tandem mass spectrometry in infants with genital hair. J Pediatr Endocrinol Metab 20: 597‐605, 2007.
 77. Katagiri M , Kagawa N , Waterman MR . The role of cytochrome b5 in the biosynthesis of androgens by human P450c17. Arch Biochem Biophys 317: 343‐347, 1995.
 78. Kaufman FR , Stanczyk FZ , Matteri RK , Gentzschein E , Delgado C , Lobo RA . Dehydroepiandrosterone and dehydroepiandrosterone sulfate metabolism in human genital skin. Fertil Steril 54: 251‐254, 1990.
 79. Keeney DS , Jenkins CM , Waterman MR . Developmentally regulated expression of adrenal 17 alpha‐hydroxylase cytochrome P450 in the mouse embryo. Endocrinology 136: 4872‐4879, 1995.
 80. Kenny FM , Preeyasombat C , Migeon CJ . Cortisol production rate. II. Normal infants, children, and adults. Pediatrics 37: 34‐42, 1966.
 81. Khanna M , Qin KN , Klisak I , Belkin S , Sparkes RS , Cheng KC . Localization of multiple human dihydrodiol dehydrogenase (DDH1 and DDH2) and chlordecone reductase (CHDR) genes in chromosome 10 by the polymerase chain reaction and fluorescence in situ hybridization. Genomics 25: 588‐590, 1995.
 82. Kirkland RT , Kirkland JL , Johnson CM , Horning MG , Librik L , Clayton GW . Congenital lipoid adrenal hyperplasia in an eight‐year‐old phenotypic female. J Clin Endocrinol Metab 36: 488‐496, 1973.
 83. Kirschner MA , Bardin CW . Androgen production and metabolism in normal and virilized women. Metabolism 21: 667‐688, 1972.
 84. Koritz SB , Kumar AM . On the mechanism of action of the adrenocorticotrophic hormone. The stimulation of the activity of enzymes involved in pregnenolone synthesis. J Biol Chem 245: 152‐159, 1970.
 85. Korth‐Schutz S , Levine LS , New MI . Dehydroepiandrosterone sulfate (DS) levels, a rapid test for abnormal adrenal androgen secretion. J Clin Endocrinol Metab 42: 1005‐1013, 1976.
 86. Kristiansen SB , Endoh A , Casson PR , Buster JE , Hornsby PJ . Induction of steroidogenic enzyme genes by insulin and IGF‐I in cultured adult human adrenocortical cells. Steroids 62: 258‐265, 1997.
 87. Kumagai J , Hofland J , Erkens‐Schulze S , Dits NF , Steenbergen J , Jenster G , Homma Y , de Jong FH , van Weerden WM . Intratumoral conversion of adrenal androgen precursors drives androgen receptor‐activated cell growth in prostate cancer more potently than de novo steroidogenesis. Prostate 73: 1636‐1650, 2013.
 88. l'Allemand D , Penhoat A , Lebrethon MC , Ardevol R , Baehr V , Oelkers W , Saez JM . Insulin‐like growth factors enhance steroidogenic enzyme and corticotropin receptor messenger ribonucleic acid levels and corticotropin steroidogenic responsiveness in cultured human adrenocortical cells. J Clin Endocrinol Metab 81: 3892‐3897, 1996.
 89. Labrie F , Simard J , Luu‐The V , Belanger A , Pelletier G . Structure, function and tissue‐specific gene expression of 3beta‐hydroxysteroid dehydrogenase/5‐ene‐4‐ene isomerase enzymes in classical and peripheral intracrine steroidogenic tissues. J Steroid Biochem Mol Biol 43: 805‐826, 1992.
 90. Lachance Y , Luu‐The V , Labrie C , Simard J , Dumont M , de Launoit Y , Guerin S , Leblanc G , Labrie F . Characterization of human 3 beta‐hydroxysteroid dehydrogenase/delta 5‐delta 4‐isomerase gene and its expression in mammalian cells. J Biol Chem 265: 20469‐20475, 1990.
 91. Lachance Y , Luu‐The V , Verreault H , Dumont M , Rheaume E , Leblanc G , Labrie F . Structure of the human type II 3 beta‐hydroxysteroid dehydrogenase/delta 5‐delta 4 isomerase (3 beta‐HSD) gene: Adrenal and gonadal specificity. DNA Cell Biol 10: 701‐711, 1991.
 92. Lam CW , Arlt W , Chan CK , Honour JW , Lin CJ , Tong SF , Choy KW , Miller WL . Mutation of proline 409 to arginine in the meander region of cytochrome p450c17 causes severe 17 alpha‐hydroxylase deficiency. Mol Genet Metab 72: 254‐259, 2001.
 93. Lebrethon MC , Jaillard C , Naville D , Begeot M , Saez JM . Effects of transforming growth factor‐beta 1 on human adrenocortical fasciculata‐reticularis cell differentiated functions. J Clin Endocrinol Metab 79: 1033‐1039, 1994.
 94. Lee‐Robichaud P , Wright JN , Akhtar ME , Akhtar M . Modulation of the activity of human 17α‐hydroxylase‐17,20‐lyase (CYP17) by cytochrome b5: Endocrinological and mechanistic implications. Biochem J 308: 901‐908, 1995.
 95. Lee TC , Miller WL , Auchus RJ . Medroxyprogesterone acetate and dexamethasone are competitive inhibitors of different human steroidogenic enzymes. J Clin Endocrinol Metab 84: 2104‐2110, 1999.
 96. Legro RS , Arslanian SA , Ehrmann DA , Hoeger KM , Murad MH , Pasquali R , Welt CK . Diagnosis and treatment of polycystic ovary syndrome: An endocrine society clinical practice guideline. J Clin Endocrinol Metab 98: 4565‐4592, 2013.
 97. Likitmaskul S , Cowell CT , Donaghue K , Kreutzmann DJ , Howard NJ , Blades B , Silink M . ‘Exaggerated adrenarche’ in children presenting with premature adrenarche. Clin Endocrinol 42: 265‐272, 1995.
 98. Lin D , Sugawara T , Strauss JF, III , Clark BJ , Stocco DM , Saenger P , Rogol A , Miller WL . Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis. Science 267: 1828‐1831, 1995.
 99. Lin HK , Jez JM , Schlegel BP , Peehl DM , Pachter JA , Penning TM . Expression and characterization of recombinant type 2 3 alpha‐hydroxysteroid dehydrogenase (HSD) from human prostate: Demonstration of bifunctional 3 alpha/17 beta‐HSD activity and cellular distribution. Mol Endocrinol 11: 1971‐1984, 1997.
 100. Lorence MC , Murry BA , Trant JM , Mason JI . Human 3 beta‐hydroxysteroid dehydrogenase/delta 5—‐4isomerase from placenta: Expression in nonsteroidogenic cells of a protein that catalyzes the dehydrogenation/isomerization of C21 and C19 steroids. Endocrinology 126: 2493‐2498, 1990.
 101. Luu‐The V . Assessment of steroidogenesis and steroidogenic enzyme functions. J Steroid Biochem Mol Biol 137: 176‐182, 2013.
 102. Luu The V , Lachance Y , Labrie C , Leblanc G , Thomas JL , Strickler RC , Labrie F . Full length cDNA structure and deduced amino acid sequence of human 3 beta‐hydroxy‐5‐ene steroid dehydrogenase. Mol Endocrinol 3: 1310‐1312, 1989.
 103. Mahesh VB , Greenblatt RB , Aydar CK , Roy S , Puebla RA , Ellegood JO . Urinary steroid excretion patterns in hirsutism. I. Use of adrenal and ovarian suppression tests in the study of hirsutism. J Clin Endocrinol Metab 24: 1283‐1292, 1964.
 104. Mapes S , Corbin CJ , Tarantal A , Conley A . The primate adrenal zona reticularis is defined by expression of cytochrome b5, 17alpha‐hydroxylase/17,20‐lyase cytochrome P450 (P450c17) and NADPH‐cytochrome P450 reductase (reductase) but not 3beta‐hydroxysteroid dehydrogenase/delta5‐4 isomerase (3beta‐HSD). J Clin Endocrinol Metab 84: 3382‐3385, 1999.
 105. Matocha M , Waterman MR . Synthesis and processing of mitochondrial steroid hydroxylases. In vivo maturation of the precursor of cytochrome P450scc, cytochrome P450 and adrenodoxin. J Biol Chem 260: 2259‐2265, 1985.
 106. McCartin S , Russell AJ , Fisher RA , Wallace AM , Arnhold IJ , Mason JI , Varley J , Mendonca BB , Sutcliffe RG . Phenotypic variability and origins of mutations in the gene encoding 3beta‐hydroxysteroid dehydrogenase type II. J Mol Endocrinol 24: 75‐82, 2000.
 107. Mellon SH , Shively JE , Miller WL . Human proopiomelanocortin‐(79‐96), a proposed androgen stimulatory hormone, does not affect steroidogenesis in cultured human fetal adrenal cells. J Clin Endocrinol Metab 72: 19‐22, 1991.
 108. Merke DP , Chrousos GP , Eisenhofer G , Weise M , Keil MF , Rogol AD , Van Wyk JJ , Bornstein SR . Adrenomedullary dysplasia and hypofunction in patients with classic 21‐hydroxylase deficiency. N Engl J Med 343: 1362‐1368, 2000.
 109. Miller WL , Auchus RJ . The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev 32: 81‐151, 2011.
 110. Moisan AM , Ricketts ML , Tardy V , Desrochers M , Mebarki F , Chaussain JL , Cabrol S , Raux‐Demay MC , Forest MG , Sippell WG , Peter M , Morel Y , Simard J . New insight into the molecular basis of 3b‐hydroxysteroid dehydrogenase deficiency: Identification of eight mutations in the HSD3B2 gene in eleven patients from seven new families and comparison of the functional properties of twenty‐five mutant enzymes. J Clin Endocrinol Metab 84: 4410‐4425, 1999.
 111. Moran C AR . The role of the adrenal cortex in polycystic ovary syndrome. Obstet Gynecol Clin North Am 28: 63‐75, 2001.
 112. Moran C , Reyna R , Boots LS , Azziz R . Adrenocortical hyperresponsiveness to corticotropin in polycystic ovary syndrome patients with adrenal androgen excess. Fertil Steril 81: 126‐131, 2004.
 113. Morel Y , Mebarki F , Rheaume E , Sanchez R , Forest MG , Simard J . Structure‐function relationships of 3 beta‐hydroxysteroid dehydrogenase: Contribution made by the molecular genetics of 3 beta‐hydroxysteroid dehydrogenase deficiency. Steroids 62: 176‐184, 1997.
 114. Nahum R , Thong KJ , Hillier SG . Metabolic regulation of androgen production by human thecal cells in vitro. Hum Reprod 10: 75‐81, 1995.
 115. Nakamura Y , Gang HX , Suzuki T , Sasano H , Rainey WE . Adrenal changes associated with adrenarche. Rev Endocr Metab Disord 10: 19‐26, 2009.
 116. Nakamura Y , Hornsby PJ , Casson P , Morimoto R , Satoh F , Xing Y , Kennedy MR , Sasano H , Rainey WE . Type 5 17beta‐hydroxysteroid dehydrogenase (AKR1C3) contributes to testosterone production in the adrenal reticularis. J Clin Endocrinol Metab 94: 2192‐2198, 2009.
 117. Nelson DR , Kamataki T , Waxman DJ , Guengerich FP , Estabrook RW , Feyereisen R , Gonzalez FJ , Coon MJ , Gunsalus IC , Gotoh O , Okuda K , Nebert DW . The P450 superfamily: Update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. DNA Cell Biol 12: 1‐51, 1993.
 118. Nestler JE , Jakubowicz DJ , de Vargas AF , Brik C , Quintero N , Medina F . Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. J Clin Endocrinol Metab 83: 2001‐2005, 1998.
 119. Noordam C , Dhir V , McNelis JC , Schlereth F , Hanley NA , Krone N , Smeitink JA , Smeets R , Sweep FC , Claahsen‐van der Grinten HL , Arlt W . Inactivating PAPSS2 mutations in a patient with premature pubarche. N Engl J Med 360: 2310‐2318, 2009.
 120. Nowell S , Falany CN . Pharmacogenetics of human cytosolic sulfotransferases. Oncogene 25: 1673‐1678, 2006.
 121. O'Connell Y , McKenna TJ , Cunningham SK . beta‐Lipotropin‐stimulated adrenal steroid production. Steroids 61: 332‐336, 1996.
 122. Onoda M , Hall PF . Cytochrome b5 stimulates purified testicular microsomal cytochrome P450 (C21 side‐chain cleavage). Biochem Biophys Res Commun 108: 454‐460, 1982.
 123. Orentreich N , Brind JL , Rizer RL , Vogelman JH . Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab 59: 551‐555, 1984.
 124. Otterness DM , Her C , Aksoy S , Kimura S , Wieben ED , Weinshilboum RM . Human dehydroepiandrosterone sulfotransferase gene: Molecular cloning and structural characterization. DNA Cell Biol 14: 331‐341, 1995.
 125. Pang S . Congenital adrenal hyperplasia owing to 3 beta‐hydroxysteroid dehydrogenase deficiency. Endocrinol Metab Clin North Am 30: 81‐99, vi‐vii, 2001.
 126. Parker CR, Jr. , Bruneteau DW , Greenblatt RB , Mahesh VB . Peripheral, ovarian, and adrenal vein steroids in hirsute women: Acute effects of human chorionic gonadotropin and adrenocorticotrophic hormone. Fertil Steril 26: 877‐888, 1975.
 127. Parker L , Lifrak E , Shivley J , Lee T , Kaplan B , Walker P , Calaycay J , Florsheim W , Soon‐Shiong B . Human adrenal gland cortical androgen‐stimulating hormone (CASH) is identical with a portion of the joining peptide of pituitary pro‐opiomelanocortin (POMC). In: 71st Annual Meet of The Endocrine Society 1989.
 128. Parker LN. Adrenal Androgens in Clinical Medicine. Academic Press, Inc., 1989, p. 615.
 129. Parker LN , Sack J , Fisher DA , Odell WD . The adrenarche: Prolactin, gonadotropins, adrenal androgens, and cortisol. J Clin Endocrinol Metab 46: 396‐401, 1978.
 130. Pelletier G . Expression of steroidogenic enzymes and sex‐steroid receptors in human prostate. Best Pract Res Clin Endocrinol Metab 22: 223‐228, 2008.
 131. Penhoat A , Rainey WE , Viard I , Saez JM . Regulation of adrenal cell‐differentiated functions by growth factors. Horm Res 42: 39‐43, 1994.
 132. Penhoat A , Sanchez P , Jaillard C , Langlois D , Begeot M , Saez JM . Human proopiomelanocortin‐(79‐96), a proposed cortical androgen‐stimulating hormone, does not affect steroidogenesis in cultured human adult adrenal cells. J Clin Endocrinol Metab 72: 23‐26, 1991.
 133. Penning TM , Burczynski ME , Jez JM , Hung CF , Lin HK , Ma H , Moore M , Palackal N , Ratnam K . Human 3alpha‐hydroxysteroid dehydrogenase isoforms (AKR1C1‐AKR1C4) of the aldo‐keto reductase superfamily: Functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones. Biochem J 351: 67‐77, 2000.
 134. Qin K , Ehrmann DA , Cox N , Refetoff S , Rosenfield RL . Identification of a functional polymorphism of the human type 5 17beta‐hydroxysteroid dehydrogenase gene associated with polycystic ovary syndrome. J Clin Endocrinol Metab 91: 270‐276, 2006.
 135. Rainey WE , Carr BR , Sasano H , Suzuki T , Mason JI . Dissecting human adrenal androgen production. Trends Endocrinol Metab 13: 234‐239, 2002.
 136. Rainey WE , Rehman KS , Carr BR . The human fetal adrenal: Making adrenal androgens for placental estrogens. Semin Reprod Med 22: 327‐336, 2004.
 137. Rege J , Nakamura Y , Satoh F , Morimoto R , Kennedy MR , Layman LC , Honma S , Sasano H , Rainey WE . Liquid chromatography‐tandem mass spectrometry analysis of human adrenal vein 19‐carbon steroids before and after ACTH stimulation. J Clin Endocrinol Metab 98: 1182‐1188, 2013.
 138. Reiter EO , Fuldauer VG , Root AW . Secretion of the adrenal androgen, dehydroepiandrosterone sulfate, during normal infancy, childhood, and adolescence, in sick infants, and in children with endocrinologic abnormalities. J Pediatr 90: 766‐770, 1977.
 139. Rezvani I , Garibaldi LR , Digeorge AM , Artman HG . Disproportionate suppression of dehydroepiandrosterone sulfate (DHEAS) in treated patients with congenital adrenal hyperplasia due to 21‐hydroxylase deficiency. Pediatr Res 17: 131‐134, 1983.
 140. Rheaume E , Lachance Y , Zhao HF , Breton N , Dumont M , de Launoit Y , Trudel C , Luu‐The V , Simard J , Labrie F . Structure and expression of a new complementary DNA encoding the almost exclusive 3 beta‐hydroxysteroid dehydrogenase/delta 5‐delta 4‐isomerase in human adrenals and gonads. Mol Endocrinol 5: 1147‐1157, 1991.
 141. Rheaume E , Simard J , Morel Y , Mebarki F , Zachmann M , Forest MG , New MI , Labrie F . Congenital adrenal hyperplasia due to point mutations in the type II 3 beta‐hydroxysteroid dehydrogenase gene. Nat Genet 1: 239‐245, 1992.
 142. Rich BH , Rosenfield RL , Lucky AW , Helke JC , Otto P . Adrenarche: Changing adrenal response to adrenocorticotropin. J Clin Endocrinol Metab 52: 1129‐1136, 1981.
 143. Rosenfield RL . Hirsutism and the variable response of the pilosebaceous unit to androgen. J Investig Dermatol Symp Proc 10: 205‐208, 2005.
 144. Rosenfield RL , Grossman BJ , Ozoa N . Plasma 17‐ketosteroids and testosterone in prepubertal children before and after ACTH administration. J Clin Endocrinol Metab 33: 249‐253, 1971.
 145. Rosenfield RL , Lucky AW . Acne, hirsutism, and alopecia in adolescent girls. Clinical expressions of androgen excess. Endocrinol Metab Clin North Am 22: 507‐532, 1993.
 146. Rosenfield RL , Rich BH , Lucky AW . Adrenarche as a cause of benign pseudopuberty in boys. J Pediatr 101: 1005‐1009, 1982.
 147. Rubtsov P , Karmanov M , Sverdlova P , Spirin P , Tiulpakov A . A novel homozygous mutation in CYP11A1 gene is associated with late‐onset adrenal insufficiency and hypospadias in a 46,XY patient. J Clin Endocrinol Metab 94: 936‐939, 2009.
 148. Ryan CJ , Smith MR , de Bono JS , Molina A , Logothetis CJ , de Souza P , Fizazi K , Mainwaring P , Piulats JM , Ng S , Carles J , Mulders PF , Basch E , Small EJ , Saad F , Schrijvers D , Van Poppel H , Mukherjee SD , Suttmann H , Gerritsen WR , Flaig TW , George DJ , Yu EY , Efstathiou E , Pantuck A , Winquist E , Higano CS , Taplin ME , Park Y , Kheoh T , Griffin T , Scher HI , Rathkopf DE , Investigators C‐A‐ . Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 368: 138‐148, 2013.
 149. Sahakitrungruang T , Tee MK , Blackett PR , Miller WL . Partial defect in the cholesterol side‐chain cleavage enzyme P450scc (CYP11A1) resembling nonclassic congenital lipoid adrenal hyperplasia. J Clin Endocrinol Metab 96: 792‐798, 2011.
 150. Sandison AT . A form of lipoidosis of the adrenal cortex in an infant. Arch Dis Child 30: 538‐541, 1955.
 151. Shikita M , Hall PF . The stoichiometry of the conversion of cholesterol and hydroxycholesterols to pregnenolone (3beta‐hydroxypregn‐5‐en‐20‐one) catalysed by adrenal cytochrome P‐450. Proc Natl Acad Sci U S A 71: 1441‐1445, 1974.
 152. Shimizu K , Hayano M , Gut M , Dorfman RI . The transformation of 20α‐hydroxcholesterol to isocaproic acid and C21 steroids. J Biol Chem 236: 695‐699, 1961.
 153. Siiteri PK , MacDonald PC . The utilization of circulating dehydroisoandrosterone sulfate for estrogen synthesis during human pregnancy. Steroids 2: 713‐730, 1963.
 154. Simard J , Durocher F , Mebarki F , Turgeon C , Sanchez R , Labrie Y , Couet J , Trudel C , Rheaume E , Morel Y , Luu‐The V , Labrie F . Molecular biology and genetics of the 3 beta‐hydroxysteroid dehydrogenase/delta5‐delta4 isomerase gene family. J Endocrinol 150 Suppl: S189‐S207, 1996.
 155. Simard J , Ricketts ML , Gingras S , Soucy P , Feltus FA , Melner MH . Molecular biology of the 3beta‐hydroxysteroid dehydrogenase/delta5‐delta4 isomerase gene family. Endoc Rev 26: 525‐582, 2005.
 156. Simpson ER , Mason JI , John ME , Zuber MX , Rodgers RJ , Waterman MR . Regulation of the biosynthesis of steroidogenic enzymes. J Steroid Biochem 27: 801‐805, 1987.
 157. Sirianni R , Rehman KS , Carr BR , Parker CR, Jr. , Rainey WE . Corticotropin‐releasing hormone directly stimulates cortisol and the cortisol biosynthetic pathway in human fetal adrenal cells. J Clin Endocrinol Metab 90: 279‐285, 2005.
 158. Smail PJ , Faiman C , Hobson WC , Fuller GB , Winter JSD . Further studies on adrenarche in nonhuman primates. Endocrinology 111: 844‐848, 1982.
 159. Smith CP , Dunger DB , Williams AJ , Taylor AM , Perry LA , Gale EA , Preece MA , Savage MO . Relationship between insulin, insulin‐like growth factor I, and dehydroepiandrosterone sulfate concentrations during childhood, puberty, and adult life. J Clin Endocrinol Metab 68: 932‐937, 1989.
 160. Sparkes RS , Klisak I , Miller WL . Regional mapping of genes encoding human steroidogenic enzymes: P450scc to 15q23‐q24, adrenodoxin to 11q22; adrenodoxin reductase to 17q24‐q25; and P450c17 to 10q24‐q25. DNA Cell Biol 10: 359‐365, 1991.
 161. Speiser PW , White PC . Congenital adrenal hyperplasia. N Engl J Med 349: 776‐788, 2003.
 162. Stahl NL TC , Beauchamps G , Greenblatt RB . Serum testosterone levels in hirsute women: A comparison of adrenal, ovarian and peripheral vein values. Obstet Gynecol 41: 650‐654, 1973.
 163. Stahl NL TC , Greenblatt RB . Ovarian, adrenal, and peripheral testosterone levels in the polycystic ovary syndrome. Am J Obstet Gynecol 117: 194‐200, 1973.
 164. Stocco DM , Clark BJ . Regulation of the acute production of steroids in steroidogenic cells. Endoc Rev 17: 221‐244, 1996.
 165. Storbeck KH , Bloem LM , Africander D , Schloms L , Swart P , Swart AC . 11beta‐Hydroxydihydrotestosterone and 11‐ketodihydrotestosterone, novel C19 steroids with androgenic activity: A putative role in castration resistant prostate cancer? Mol Cell Endocrinol 377: 135‐146, 2013.
 166. Strott CA . Sulfonation and molecular action. Endoc Rev 23: 703‐732, 2002.
 167. Sugawara T , Holt JA , Driscoll D , Strauss JF, III , Lin D , Miller WL , Patterson D , Clancy KP , Hart IM , Clark BJ , et al. Human steroidogenic acute regulatory protein: Functional activity in COS‐1 cells, tissue‐specific expression, and mapping of the structural gene to 8p11.2 and a pseudogene to chromosome 13. Proc Natl Acad Sci U S A 92: 4778‐4782, 1995.
 168. Suzuki T , Sasano H , Takeyama J , Kaneko C , Freije WA , Carr BR , Rainey WE . Developmental changes in steroidogenic enzymes in human postnatal adrenal cortex: Immunohistochemical studies. Clin Endocrinol 53: 739‐747, 2000.
 169. Talbot NB , Butler AM , Maclachlan EA . The effect of testosterone and allied compounds on the mineral, nitrogen, and carbohydrate metabolism of a girl with Addison's Disease. J Clin Invest 22: 583‐593, 1943.
 170. Thomas JL , Myers RP , Strickler RC . Human placental 3b‐hydroxy‐5‐ene‐steroid dehydrogenase and steroid 5/4‐ene‐isomerase: Purification from mitochondria and kinetic profiles, biophysical characterization of the purified mitochondrial and microsomal enzymes. J Steroid Biochem 33: 209‐217, 1989.
 171. Topor LS , Asai M , Dunn J , Majzoub JA . Cortisol stimulates secretion of dehydroepiandrosterone in human adrenocortical cells through inhibition of 3betaHSD2. J Clin Endocrinol Metab 96: E31‐E39, 2011.
 172. Toscano V , Balducci R , Adamo MV , Mangiantini A , Cives C , Boscherini B . Changes in steroid pattern following acute and chronic adrenocorticotropin administration in premature adrenarche. J Steroid Biochem 32: 321‐326, 1989.
 173. Trivax B , Azziz R . Diagnosis of polycystic ovary syndrome. Clin Obstet Gynecol 50: 168‐177, 2007.
 174. Tsujishita Y , Hurley JH . Structure and lipid transport mechanism of a StAR‐related domain. Nat Struct Biol 7: 408‐414, 2000.
 175. Tzingounis VA AM , Natrajan PK , Greenblatt RB . The significance of adrenal and ovarian catheterization in patients with polycystic ovary syndrome. Int J Gynaecol Obstet 17: 78‐82, 1978.
 176. Vickery LE . Molecular recognition and electron transfer in mitochondrial steroid hydroxylase systems. Steroids 62: 124‐127, 1997.
 177. Voutilainen R , Perheentupa J , Apter D . Benign premature adrenarche: Clinical features and serum steroid levels. Acta Paediatr Scand 72: 707‐711, 1983.
 178. Wajchenberg BL AS , Okada H , Czeresnia CE , Peixoto S , Lima SS , Goldman J . Determination of the source(s) of androgen overproduction in hirsutism associated with polycystic ovary syndrome by simultaneous adrenal and ovarian venous catheterization. Comparison with the dexamethasone suppression test. J Clin Endocrinol Metab 63: 1204‐1210, 1986.
 179. Watari H , Arakane F , Moog‐Lutz C , Kallen CB , Tomasetto C , Gerton GL , Rio MC , Baker ME , Strauss JF, 3rd . MLN64 contains a domain with homology to the steroidogenic acute regulatory protein (StAR) that stimulates steroidogenesis. Proc Natl Acad Sci U S A 94: 8462‐8467, 1997.
 180. Weber A , Clark AJ , Perry LA , Honour JW , Savage MO . Diminished adrenal androgen secretion in familial glucocorticoid deficiency implicates a significant role for ACTH in the induction of adrenarche. Clin Endocrinol 46: 431‐437, 1997.
 181. Weinshilboum RM , Otterness DM , Aksoy IA , Wood TC , Her C , Raftogianis RB . Sulfation and sulfotransferases 1: Sulfotransferase molecular biology: cDNAs and genes. FASEB J 11: 3‐14, 1997.
 182. Wilson JD , Auchus RJ , Leihy MW , Guryev OL , Estabrook RW , Osborn SM , Shaw G , Renfree MB . 5alpha‐androstane‐3alpha,17beta‐diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha‐pregnane‐3alpha,17alpha‐diol‐20‐one as a key intermediate. Endocrinology 144: 575‐580, 2003.
 183. Yanase T , Simpson ER , Waterman MR . 17 alpha‐hydroxylase/17,20‐lyase deficiency: From clinical investigation to molecular definition. Endoc Rev 12: 91‐108, 1991.
 184. Yang X , Iwamoto K , Wang M , Artwohl J , Mason JI , Pang S . Inherited congenital adrenal hyperplasia in the rabbit is caused by a deletion in the gene encoding cytochrome P450 cholesterol side‐chain cleavage enzyme. Endocrinology 132: 1977‐1982, 1993.
 185. Yasukochi Y , Masters BS . Some properties of a detergent‐solubilized NADPH‐cytochrome c(cytochrome P‐450) reductase purified by bio‐specific affinity chromatography. J Biol Chem 251: 5337‐5344, 1976.
 186. Yildiz BO , Azziz R . The adrenal and polycystic ovary syndrome. Rev Endocr Metab Disord 8: 331‐342, 2007.
 187. Zuber MX , John ME , Okamura T , Simpson ER , Waterman MR . Bovine adrenocortical cytochrome P‐450(17 alpha). Regulation of gene expression by ACTH and elucidation of primary sequence. J Biol Chem 261: 2475‐2482, 1986.
 188. Zuber MX , Simpson ER , Waterman MR . Expression of bovine 17α‐hydroxylase cytochrome P450 cDNA in non‐steroidogenic (COS‐1) cells. Science 234: 1258‐1261, 1986.

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Adina Turcu, Joshua M. Smith, Richard Auchus, William E. Rainey. Adrenal Androgens and Androgen Precursors—Definition, Synthesis, Regulation and Physiologic Actions. Compr Physiol 2014, 4: 1369-1381. doi: 10.1002/cphy.c140006