Defects in androgen biosynthesis causing 46,XY disorders of sexual development

Seminars in Reproductive Medicine

Volumn 30, Issue 5, 2012, Pages 417-426

  Auchus, Richardj ^a   Miller, Walterl ^b  

^a UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

46 XY DSD; androgen; congenital adrenal hyperplasia; enzyme; steroid; steroidogenesis; testis; testosterone

Indexed keywords

ANDROGEN; CHOLESTEROL; PREGNENOLONE; TESTOSTERONE;

ANDROGEN SYNTHESIS; ARTICLE; DISEASE SEVERITY; GENITAL SYSTEM; HUMAN; P450 OXIDOREDUCTASE DEFICIENCY; PARACRINE SIGNALING; PHENOTYPE; PSYCHOSEXUAL DEVELOPMENT; SEX DIFFERENTIATION DISORDER; SEXUAL DEVELOPMENT; STEROIDOGENESIS;

46, XY DISORDERS OF SEX DEVELOPMENT; ANDROGENS; ANIMALS; FEMALE; FETAL DEVELOPMENT; HUMANS; MALE; MUTATION; TESTIS;

EID: 84866994988     PISSN: 15268004     EISSN: 15264564     Source Type: Journal    
DOI: 10.1055/s-0032-1324726     Document Type: Article

References (92)

1. Jost A. Recherches sur la differenciation sexuelle de l'embryon de lapin. Arch Anat Microsc Morphol Exp: 1947; 36 117 121
2. Jost A., Vigier B., Prépin J., Perchellet J. P. Studies on sex differentiation in mammals. Recent Prog Horm Res: 1973; 29 1 41
3. Miller W. L., Auchus R. J. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev: 2011; 32 1 81 151
4. Wilson J. D., Lasnitzki I. Dihydrotestosterone formation in fetal tissues of the rabbit and rat. Endocrinology: 1971; 89 3 659 668
5. Thigpen A. E., Davis D. L., Milatovich A., et al. Molecular genetics of steroid 5 alpha-reductase 2 deficiency. J Clin Invest: 1992; 90 3 799 809
6. Wilson J. D., Auchus R. J., Leihy M. W., et al. 5α-androstane- 3α,17β-diol is formed in tammar wallaby pouch young testes by a pathway involving 5α-pregnane-3α,17α-diol-20-one as a key intermediate. Endocrinology: 2003; 144 2 575 580
7. Flück C. E., Meyer-Böni M., Pandey A. V., 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 2 201 218
8. Agarwal A. K., Auchus R. J. Minireview: cellular redox state regulates hydroxysteroid dehydrogenase activity and intracellular hormone potency. Endocrinology: 2005; 146 6 2531 2538
9. Miller W. L., Bose H. S. Early steps in steroidogenesis: intracellular cholesterol trafficking. J Lipid Res: 2011; 52 12 2111 2135
10. Miller W. L. Steroidogenic acute regulatory protein (StAR), a novel mitochondrial cholesterol transporter. Biochim Biophys Acta: 2007; 1771 6 663 676
11. Lin D., Sugawara T., Strauss J. F. III., et al. Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis. Science: 1995; 267 5205 1828 1831
12. Bose H. S., Sugawara T., Strauss J. F. III, Miller W. L.; International Congenital Lipoid Adrenal Hyperplasia Consortium. The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. N Engl J Med: 1996; 335 25 1870 1878
13. Bose H. S., Sato S., Aisenberg J., Shalev S. A., Matsuo N., Miller W. L. Mutations in the steroidogenic acute regulatory protein (StAR) in six patients with congenital lipoid adrenal hyperplasia. J Clin Endocrinol Metab: 2000; 85 10 3636 3639
14. Chen X., Baker B. Y., Abduljabbar M. A., Miller W. L. A genetic isolate of congenital lipoid adrenal hyperplasia with atypical clinical findings. J Clin Endocrinol Metab: 2005; 90 2 835 840
15. Kim J. M., Choi J. H., Lee J. H., et al. High allele frequency of the p.Q258X mutation and identification of a novel mis-splicing mutation in the STAR gene in Korean patients with congenital lipoid adrenal hyperplasia. Eur J Endocrinol: 2011; 165 5 771 778
16. Bose H. S., Pescovitz O. H., Miller W. L. Spontaneous feminization in a 46,XX female patient with congenital lipoid adrenal hyperplasia due to a homozygous frameshift mutation in the steroidogenic acute regulatory protein. J Clin Endocrinol Metab: 1997; 82 5 1511 1515
17. Fujieda K., Tajima T., Nakae J., et al. Spontaneous puberty in 46,XX subjects with congenital lipoid adrenal hyperplasia. J Clin Invest: 1997; 99 6 1265 1271
18. Baker B. Y., Lin L., Kim C. J., et al. Nonclassic congenital lipoid adrenal hyperplasia: a new disorder of the steroidogenic acute regulatory protein with very late presentation and normal male genitalia. J Clin Endocrinol Metab: 2006; 91 12 4781 4785
19. Metherell L. A., Naville D., Halaby G., et al. Nonclassic lipoid congenital adrenal hyperplasia masquerading as familial glucocorticoid deficiency. J Clin Endocrinol Metab: 2009; 94 10 3865 3871
20. Khoury K., Barbar E., Ainmelk Y., Ouellet A., Lehoux J. G. Gonadal function, first cases of pregnancy, and child delivery in a woman with lipoid congenital adrenal hyperplasia. J Clin Endocrinol Metab: 2009; 94 4 1333 1337
21. Sertedaki A., Pantos K., Vrettou C., et al. Conception and pregnancy outcome in a patient with 11-bp deletion of the steroidogenic acute regulatory protein gene. Fertil Steril: 2009; 91 3 934 918, e15e18
22. Yang X., Iwamoto K., Wang M., Artwohl J., Mason J. I., 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: 1993; 132 5 1977 1982
23. Hu M. C., Hsu N. C., El Hadj N. B., et al. Steroid deficiency syndromes in mice with targeted disruption of Cyp11a1. Mol Endocrinol: 2002; 16 8 1943 1950
24. Csapo A. I., Pulkkinen M. O. Indispensibility of the human corpus luteum in the maintenance of early pregnancy: Luteectomy evidence. Obstet Gynecol Surv: 1978; 33 2 69 81
25. Csapo A. I., Pulkkinen M. O., Wiest W. G. Effects of luteectomy and progesterone replacement therapy in early pregnant patients. Am J Obstet Gynecol: 1973; 115 6 759 765
26. Tajima T., Fujieda K., Kouda N., Nakae J., Miller W. L. Heterozygous mutation in the cholesterol side chain cleavage enzyme (p450scc) gene in a patient with 46,XY sex reversal and adrenal insufficiency. J Clin Endocrinol Metab: 2001; 86 8 3820 3825
27. Katsumata N., Ohtake M., Hojo T., et al. Compound heterozygous mutations in the cholesterol side-chain cleavage enzyme gene (CYP11A) cause congenital adrenal insufficiency in humans. J Clin Endocrinol Metab: 2002; 87 8 3808 3813
28. Hiort O., Holterhus P. M., Werner R., et al. Homozygous disruption of P450 side-chain cleavage (CYP11A1) is associated with prematurity, complete 46,XY sex reversal, and severe adrenal failure. J Clin Endocrinol Metab: 2005; 90 1 538 541
29. al Kandari H., Katsumata N., Alexander S., Rasoul M. A. Homozygous mutation of P450 side-chain cleavage enzyme gene (CYP11A1) in 46, XY patient with adrenal insufficiency, complete sex reversal, and agenesis of corpus callosum. J Clin Endocrinol Metab: 2006; 91 8 2821 2826
30. Kim C. J., Lin L., Huang N., et al. Severe combined adrenal and gonadal deficiency caused by novel mutations in the cholesterol side chain cleavage enzyme, P450scc. J Clin Endocrinol Metab: 2008; 93 3 696 702
31. Parajes S., Kamrath C., Rose I. T., et al. A novel entity of clinically isolated adrenal insufficiency caused by a partially inactivating mutation of the gene encoding for P450 side chain cleavage enzyme (CYP11A1). J Clin Endocrinol Metab: 2011; 96 11 E1798 E1806
32. 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: 2009; 94 3 936 939
33. Sahakitrungruang T., Tee M. K., Blackett P. R., Miller W. L. Partial defect in the cholesterol side-chain cleavage enzyme P450scc (CYP11A1) resembling nonclassic congenital lipoid adrenal hyperplasia. J Clin Endocrinol Metab: 2011; 96 3 792 798
34. 5 augments the 17,20-lyase activity of human P450c17 without direct electron transfer. J Biol Chem: 1998; 273 6 3158 3165
35. 5 stimulates purified testicular microsomal cytochrome P-450 (C21 side-chain cleavage). Biochem Biophys Res Commun: 1982; 108 2 454 460
36. 5 in the biosynthesis of androgens by human P450c17. Arch Biochem Biophys: 1995; 317 2 343 347
37. 5: endocrinological and mechanistic implications. Biochem J: 1995; 308 Pt 3 901 908
38. Suzuki T., Sasano H., Takeyama J., et al. Developmental changes in steroidogenic enzymes in human postnatal adrenal cortex: immunohistochemical studies. Clin Endocrinol (Oxf): 2000; 53 6 739 747
39. 5 requires residues E48 and E49 to stimulate the 17,20-lyase activity of cytochrome P450c17. Biochemistry: 2006; 45 3 755 762
40. Auchus R. J. The genetics, pathophysiology, and management of human deficiencies of P450c17. Endocrinol Metab Clin North Am: 2001; 30 1 101 119, vii
41. Biglieri E. G., Herron M. A., Brust N. 17-hydroxylation deficiency in man. J Clin Invest: 1966; 45 12 1946 1954
42. Kater C. E., Biglieri E. G. Disorders of steroid 17α-hydroxylase deficiency. Endocrinol Metab Clin North Am: 1994; 23 2 341 357
43. Martin R. M., Lin C. J., Costa E. M., et al. P450c17 deficiency in Brazilian patients: biochemical diagnosis through progesterone levels confirmed by CYP17 genotyping. J Clin Endocrinol Metab: 2003; 88 12 5739 5746
44. Costa-Santos M., Kater C. E., Auchus R. J.; Brazilian Congenital Adrenal Hyperplasia Multicenter Study Group. Two prevalent CYP17 mutations and genotype-phenotype correlations in 24 Brazilian patients with 17α-hydroxylase deficiency. J Clin Endocrinol Metab: 2004; 89 1 49 60
45. Attard G., Reid A. H., Yap T. A., et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol: 2008; 26 28 4563 4571
46. Attard G., Reid A. HM, Auchus R. J., et al. 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: 2012; 97 2 507 516
47. Nakajin S., Shively J. E., Yuan P. M., Hall P. F. Microsomal cytochrome P-450 from neonatal pig testis: two enzymatic activities (17α-hydroxylase and c17,20-lyase) associated with one protein. Biochemistry: 1981; 20 14 4037 4042
48. Zuber M. X., Simpson E. R., Waterman M. R. Expression of bovine 17α-hydroxylase cytochrome P-450 cDNA in nonsteroidogenic (COS 1) cells. Science: 1986; 234 4781 1258 1261
49. Geller D. H., Auchus R. J., Mendonça B. B., Miller W. L. The genetic and functional basis of isolated 17,20-lyase deficiency. Nat Genet: 1997; 17 2 201 205
50. Geller D. H., Auchus R. J., Miller W. L. P450c17 mutations R347H and R358Q selectively disrupt 17,20-lyase activity by disrupting interactions with P450 oxidoreductase and cytochrome b5. Mol Endocrinol: 1999; 13 1 167 175
51. Van Den Akker E. L., Koper J. W., Boehmer A. L., et al. Differential inhibition of 17α-hydroxylase and 17,20-lyase activities by three novel missense CYP17 mutations identified in patients with P450c17 deficiency. J Clin Endocrinol Metab: 2002; 87 12 5714 5721
52. Sherbet D. P., Tiosano D., Kwist K. M., Hochberg Z., Auchus R. J. CYP17 mutation E305G causes isolated 17,20-lyase deficiency by selectively altering substrate binding. J Biol Chem: 2003; 278 49 48563 48569
53. Tiosano D., Knopf C., Koren I., et al. Metabolic evidence for impaired 17α-hydroxylase activity in a kindred bearing the E305G mutation for isolate 17,20-lyase activity. Eur J Endocrinol: 2008; 158 3 385 392
54. Arlt W., Walker E. A., Draper N., et al. Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study. Lancet: 2004; 363 9427 2128 2135
55. Flück C. E., Tajima T., Pandey A. V., et al. Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome. Nat Genet: 2004; 36 3 228 230
56. Huang N., Pandey A. V., Agrawal V., et al. Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis. Am J Hum Genet: 2005; 76 5 729 749
57. Sahakitrungruang T., Huang N., Tee M. K., et al. Clinical, genetic, and enzymatic characterization of P450 oxidoreductase deficiency in four patients. J Clin Endocrinol Metab: 2009; 94 12 4992 5000
58. Hershkovitz E., Parvari R., Wudy S. A., 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 3588
59. Giordano S. J., Kaftory A., Steggles A. W. A splicing mutation in the cytochrome b5 gene from a patient with congenital methemoglobinemia and pseudohermaphrodism. Hum Genet: 1994; 93 5 568 570
60. Kok R. C., Timmerman M. A., Wolffenbuttel K. P., Drop S. L., de Jong F. H. Isolated 17,20-lyase deficiency due to the cytochrome b5 mutation W27X. J Clin Endocrinol Metab: 2010; 95 3 994 999
61. Miller W. L. The syndrome of 17,20 lyase deficiency. J Clin Endocrinol Metab: 2012; 97 1 59 67
62. Bongiovanni A. M. The adrenogenital syndrome with deficiency of 3β-hydroxysteroid dehydrogenase. J Clin Invest: 1962; 41 2086 2092
63. Pang S. The molecular and clinical spectrum of 3beta-hydroxysteroid dehydrogenase deficiency disorder. Trends Endocrinol Metab: 1998; 9 2 82 86
64. 5→4-isomerase. Mol Endocrinol: 1990; 4 12 1850 1855
65. 5→4 isomerase from placenta: expression in nonsteroidogenic cells of a protein that catalyzes the dehydrogenation/isomerization of C21 and C19 steroids. Endocrinology: 1990; 126 5 2493 2498
66. 4- isomerase in human adrenals and gonads. Mol Endocrinol: 1991; 5 8 1147 1157
67. 4 isomerase (3β-HSD) gene: adrenal and gonadal specificity. DNA Cell Biol: 1991; 10 701 711
68. Rhéaume E., Simard J., Morel Y., et al. Congenital adrenal hyperplasia due to point mutations in the type II 3β-hydroxysteroid dehydrogenase gene. Nat Genet: 1992; 1 4 239 245
69. Moisan A. M., Ricketts M. L., Tardy V., et al. New insight into the molecular basis of 3β-hydroxysteroid dehydrogenase deficiency: identification of eight mutations in the HSD3B2 gene eleven patients from seven new families and comparison of the functional properties of twenty-five mutant enzymes. J Clin Endocrinol Metab: 1999; 84 12 4410 4425
70. Cara J. F., Moshang T. Jr, Bongiovanni A. M., Marx B. S. Elevated 17-hydroxyprogesterone and testosterone in a newborn with 3β-hydroxysteroid dehydrogenase deficiency. N Engl J Med: 1985; 313 10 618 621
71. Nordenström A., Forest M. G., Wedell A. A case of 3β-hydroxysteroid dehydrogenase type II (HSD3B2) deficiency picked up by neonatal screening for 21-hydroxylase deficiency: difficulties and delay in etiologic diagnosis. Horm Res: 2007; 68 4 204 208
72. Lutfallah C., Wang W., Mason J. I., et al. Newly proposed hormonal criteria via genotypic proof for type II 3β-hydroxysteroid dehydrogenase deficiency. J Clin Endocrinol Metab: 2002; 87 6 2611 2622
73. Marui S., Castro M., Latronico A. C., et al. Mutations in the type II 3β-hydroxysteroid dehydrogenase (HSD3B2) gene can cause premature pubarche in girls. Clin Endocrinol (Oxf): 2000; 52 1 67 75
74. 5-steroids. Fertil Steril: 2000; 74 3 553 557
75. Carbunaru G., Prasad P., Scoccia B., et al. The hormonal phenotype of Nonclassic 3β-hydroxysteroid dehydrogenase (HSD3B) deficiency in hyperandrogenic females is associated with insulin-resistant polycystic ovary syndrome and is not a variant of inherited HSD3B2 deficiency. J Clin Endocrinol Metab: 2004; 89 2 783 794
76. Mermejo L. M., Elias L. L., Marui S., Moreira A. C., Mendonca B. B., de Castro M. Refining hormonal diagnosis of type II 3β-hydroxysteroid dehydrogenase deficiency in patients with premature pubarche and hirsutism based on HSD3B2 genotyping. J Clin Endocrinol Metab: 2005; 90 3 1287 1293
77. Labrie F., Luu-The V., Lin S. X., Simard J., Labrie C. Role of 17β-hydroxysteroid dehydrogenases in sex steroid formation in peripheral intracrine tissues. Trends Endocrinol Metab: 2000; 11 10 421 427
78. Geissler W. M., Davis D. L., Wu L., et al. Male pseudohermaphroditism caused by mutations of testicular 17β-hydroxysteroid dehydrogenase 3. Nat Genet: 1994; 7 1 34 39
79. Moghrabi N., Hughes I. A., Dunaif A., Andersson S. Deleterious missense mutations and silent polymorphism in the human 17β-hydroxysteroid dehydrogenase 3 gene (HSD17B3). J Clin Endocrinol Metab: 1998; 83 8 2855 2860
80. Boehmer A. L., Brinkmann A. O., Sandkuijl L. A., et al. 17β-hydroxysteroid dehydrogenase-3 deficiency: diagnosis, phenotypic variability, population genetics, and worldwide distribution of ancient and de novo mutations. J Clin Endocrinol Metab: 1999; 84 12 4713 4721
81. Ahmed S. F., Cheng A., Dovey L., et al. Phenotypic features, androgen receptor binding, and mutational analysis in 278 clinical cases reported as androgen insensitivity syndrome. J Clin Endocrinol Metab: 2000; 85 2 658 665
82. Lee Y. S., Kirk J. M., Stanhope R. G., et al. Phenotypic variability in 17β-hydroxysteroid dehydrogenase-3 deficiency and diagnostic pitfalls. Clin Endocrinol (Oxf): 2007; 67 1 20 28
83. Andersson S., Geissler W. M., Wu L., et al. Molecular genetics and pathophysiology of 17β-hydroxysteroid dehydrogenase 3 deficiency. J Clin Endocrinol Metab: 1996; 81 1 130 136
84. McKeever B. M., Hawkins B. K., Geissler W. M., et al. Amino acid substitution of arginine 80 in 17β-hydroxysteroid dehydrogenase type 3 and its effect on NADPH cofactor binding and oxidation/reduction kinetics. Biochim Biophys Acta: 2002; 1601 1 29 37
85. Walter K. N., Kienzle F. B., Frankenschmidt A., et al. Difficulties in diagnosis and treatment of 5α-reductase type 2 deficiency in a newborn with 46,XY DSD. Horm Res Paediatr: 2010; 74 1 67 71
86. Faisal Ahmed S., Iqbal A., Hughes I. A. The testosterone:androstenedione ratio in male undermasculinization. Clin Endocrinol (Oxf): 2000; 53 6 697 702
87. Mendonca B. B., Inacio M., Arnhold I. J., et al. Male pseudohermaphroditism due to 17β-hydroxysteroid dehydrogenase 3 deficiency. Diagnosis, psychological evaluation, and management. Medicine (Baltimore): 2000; 79 5 299 309
88. Chang K. H., Li R., Papari-Zareei M., et al. Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer. Proc Natl Acad Sci U S A: 2011; 108 33 13728 13733
89. 21 steroids are substrates for human cytochrome P450c17. Arch Biochem Biophys: 2003; 418 2 151 160
90. Auchus R. J. The backdoor pathway to dihydrotestosterone. Trends Endocrinol Metab: 2004; 15 9 432 438
91. Homma K., Hasegawa T., Nagai 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 2649
92. Zachmann M., Völlmin J. A., Hamilton W., Prader A. Steroid 17,20-desmolase deficiency: a new cause of male pseudohermaphroditism. Clin Endocrinol (Oxf): 1972; 1 4 369 385