Disorders of Androgen Biosynthesis

Walter L. Miller

doi:10.1055/s-2002-35385

Seminars in Reproductive Medicine, Table of Contents

Semin Reprod Med 2002; 20(3): 205-216
DOI: 10.1055/s-2002-35385

Disorders of Androgen Biosynthesis

Walter L. Miller

Professor, Department of Pediatrics, The Metabolic Research Unit, and the Center for Reproductive Sciences; and Director, Child Health Research Center, University of California, San Francisco, California

Abstract

ABSTRACT

Disorders of androgen biosynthesis are a relatively rare cause of sexual ambiguity in 46,XY genetic males, but genetic disorders characterized by excessive androgen synthesis are a common cause of virilization in 46,XX genetic females. Understanding of these disorders is relatively simple if one is familiar with the components of the various steroidogenic pathways. The biosynthesis of androgens requires the steroidogenic acute regulatory protein (StAR) and the steroidogenic enzymes P450scc, P450c17, 3βHSDII, 17βHSDIII, and 5α-reductase. Deficiencies have been described in all of these, leading to male pseudohermaphroditism. Other steroidogenic enzymes not involved in androgen biosynthesis, such as P450c21, P450c11β, and P450aro, must also be considered, as mutations in these can result in overproduction of androgens, resulting in female pseudohermaphroditism.

KEYWORDS

Cytochrome P450 - hydroxysteroid dehydrogenase - intersex - steroidogenic acute regulatory protein - steroidogenesis

Full Text

References

REFERENCES

1 Gwynne J T, Strauss III F J. The role of lipoproteins in steroidogenesis and cholesterol metabolism in steroidogenic glands. Endocr Rev . 1982; 3 299-329
2 Strauss III J F, Miller W L. Molecular basis of ovarian steroid synthesis. In: Hillier SG, ed. Ovarian Endocrinology Oxford, UK: Blackwell Scientific 1991: 25-72
3 Anderson R A, Byrum R S, Coates P M, Sando G N. Mutations at the lysosomal acid cholesteryl ester hydrolase gene locus in Wolman disease. Proc Natl Acad Sci U S A . 1994; 91 2718-2722
4 Miller W L. Molecular biology of steroid hormone synthesis. Endocr Rev . 1988; 9 295-318
5 Penning T M. Molecular endocrinology of hydroxysteroid dehydrogenases. Endocr Rev . 1997; 18 281-305
6 Chung B, Matteson K J, Voutilainen R, Mohandas T K, Miller W L. 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 . 1986; 83 8962-8966
7 Yang X, Iwamoto K, Wang M. 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 1977-1982
8 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 3820-3825
9 Lin D, Shi Y, Miller W L. Cloning and sequence of the human adrenodoxin reductase gene. Proc Natl Acad Sci U S A . 1990; 87 8516-8520
10 Chang C-Y, Wu D-A, Lai C-C, Miller W L, Chung B. Cloning and structure of the human adrenodoxin gene. DNA . 1988; 7 609-615
11 Picado-Leonard J, Voutilainen R, Kao L. Human adrenodoxin: cloning of three cDNAs and cycloheximide enhancement in JEG-3 cells. J Biol Chem . 1988; 263 3240-3244
12 Brentano S T, Black S M, Lin D, Miller W L. cAMP post-transcriptionally diminishes the abundance of adrenodoxin reductase mRNA. Proc Natl Acad Sci U S A . 1992; 89 4099-4103
13 Stocco D M, Clark B J. Regulation of the acute production of steroids in steroidogenic cells. Endocr Rev . 1996; 17 221-244
14 Clark B J, Wells J, King S R, Stocco D M. 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 . 1994; 269 28314-28322
15 Lin D, Sugawara T, Strauss III F J. Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis. Science . 1995; 267 1828-1831
16 Papadopoulos V. Peripheral-type benzodiazepine/diazepam binding inhibitor receptor: biological role in steroidogenic cell function. Endocr Rev . 1993; 14 222-240
17 Kirkland R T, Kirkland J L, Johnson C M. Congenital lipoid adrenal hyperplasia in an eight-year-old phenotypic female. J Clin Endocrinol Metab . 1973; 36 488-496
18 Hauffa B P, Miller W L, Grumbach M M, Conte F A, Kaplan S L. Congenital adrenal hyperplasia due to deficient cholesterol side-chain cleavage activity (20,22 desmolase) in a patient treated for 18 years. Clin Endocrinol (Oxf) . 1985; 23 481-493
19 Bose H S, Sugawara T, Strauss III F J, Miller W L. The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. N Engl J Med . 1996; 335 1870-1878
20 Nakae J, Tajima T, Sugawara T. Analysis of the steroidogenic acute regulatory protein (StAR) gene in Japanese patients with congenital lipoid adrenal hyperplasia. Hum Mol Genet . 1997; 6 571-576
21 Voutilainen R, Miller W L. Developmental expression of genes for the steroidogenic enzymes P450scc (20,22 desmolase), P450c17 (17α-hydroxylase/17/20 lyase) and P450c21 (21-hydroxylase) in the human fetus. J Clin Endocrinol Metab . 1986; 63 1145-1150
22 Bose H S, Pescovitz O H, Miller W L. Spontaneous feminization in a 46,XX female patient with congenital lipoid adrenal hyperplasia caused by a homozygous frame-shift mutation in the steroidogenic acute regulatory protein. J Clin Endocrinol Metab . 1997; 82 1511-1515
23 Fujieda K, Tajima T, Nakae J. Spontaneous puberty in 46, XX subjects with congenital lipoid adrenal hyperplasia. J Clin Invest . 1997; 99 1265-1271
24 Caron K, Soo S-C, Wetsel W. 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 . 1997; 94 11540-11545
25 Hasegawa T, Zhao L P, Caron K M. Developmental roles of the steroidogenic acute regulatory protein (StAR) as revealed by StAR knockout mice. Mol Endocrinol . 2000; 14 1462-1471
26 Mellon S H, Deschepper C F. Neurosteroid biosynthesis: genes for adrenal steroidogenic enzymes are expressed in the brain. Brain Res . 1993; 629 283-292
27 Sugawara T, Holt J A, Driscoll D. Human steroidogenic acute regulatory protein (StAR): functional activity in COS-1 cells, tissue-specific expression, and mapping of the structural gene to 8p11.2 and an expressed pseudogene to chromosome 13. Proc Natl Acad Sci U S A . 1995; 92 4778-4782
28 Arakane F, Sugawara T, Nishino H. Steroidogenic acute regulatory protein (StAR) retains activity in the absence of its mitochondrial targeting sequence: Implications for the mechanism of StAR action. Proc Natl Acad Sci U S A . 1996; 93 13731-13736
28a Bose H S, Lingappa V R, Miller W L. Rapid regulation of steroidogenesis by mitochondrial protein import. Nature . 2002; 417 87-91
29 Bose H S, Whittal R M, Baldwin M A, Miller W L. The active form of the steroidogenic acute regulatory protein, StAR, appears to be a molten globule. Proc Natl Acad Sci U S A . 1999; 96 7250-7255
30 Moog-Lutz C, Tomasetto C, Régnier C H. MLN64 exhibits homology with the steroidogenic acute regulatory protein (StAR) and is over-expressed in human breast carcinomas. Int J Cancer . 1997; 71 183-191
31 Bose H S, Whittal R M, Huang M C, Baldwin M A, Miller W L. N-218 MLN64, a protein with StAR-like steroidogenic activity is folded and cleaved similarly to StAR. Biochemistry . 2000; 39 11722-11731
32 Thomas J L, Myers R P, Strickler R C. 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 . 1989; 33 209-217
33 Lorence M C, Murry B A, Trant J M, Mason J I. Human 3β-hydroxysteroid dehydrogenase/Δ⁵→Δ⁴ isomerase from placenta: expression in nonsteroidogenic cells of a protein that catalyzes the dehydrogenation/isomerization of C21 and C19 steroids. Endocrinology . 1990; 126 2493-2498
34 Lee T C, Miller W L, Auchus R J. Medroxyprogesterone acetate and dexamethasone are competitive inhibitors of different human steroidogenic enzymes. J Clin Endocrinol Metab . 1999; 84 2104-2110
35 Morel Y, Mébarke F, Rhéaume E. Structure-function relationships of 3β-hydroxysteroid dehydrogenase: contribution made by the molecular genetics of 3β-hydroxysteroid dehydrogenase deficiency. Steroids . 1997; 62 176-184
36 Moisan A M, Ricketts M L, Tardy V. 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 4410-4425
37 Chang Y T, Zhang L, Alkaddour H S. Absence of molecular defect in the type II 3β-hydroxysteroid dehydrogenase (3β-HSD) gene in premature pubarche children and hirsute female patients with moderately decreased adrenal 3β-HSD activity. Pediatr Res . 1995; 37 820-824
38 Sakkal-Alkaddour H, Zhang L, Yang X. Studies of 3β-hydroxysteroid dehydrogenase genes in infants and children manifesting premature pubarche and increased adrenocorticotropin-stimulated Δ⁵-steroid levels. J Clin Endocrinol Metab . 1996; 81 3961-3965
39 Pang S. The molecular and clinical spectrum of 3β-hydroxysteroid dehydrogenase deficiency disorder. Trends Endocrinol Metab . 1998; 9 82-86
40 Auchus R J, Lee T C, Miller W L. Cytochrome b ₅ augments the 17,20 lyase activity of human P450c17 without direct electron transfer. J Biol Chem . 1998; 273 3158-3165
41 Nakajin S, Shinoda M, Haniu M, Shively J E, Hall P F. C21 steroid side-chain cleavage enzyme from porcine adrenal microsomes: purification and characterization of the 17α-hydroxylase/C_17,20 lyase cytochrome P450. J Biol Chem . 1984; 259 3971-3976
42 Zuber M X, Simpson E R, Waterman M R. Expression of bovine 17α-hydroxylase cytochrome P450 cDNA in non-steroidogenic (COS-1) cells. Science . 1986; 234 1258-1261
43 Matteson K J, Picado-Leonard J, Chung B, Mohandas T K, Miller W L. Assignment of the gene for adrenal P450c17 (17α-hydroxylase/17,20 lyase) to human chromosome 10. J Clin Endocrinol Metab . 1986; 63 789-791
44 Picado-Leonard J, Miller W L. Cloning and sequence of the human gene encoding P450c17 (steroid 17α-hydroxylase/ 17,20 lyase): similarity to the gene for P450c21. DNA . 1987; 6 439-448
45 Zhang L, Rodriguez H, Ohno S, Miller W L. Serine phosphorylation of human P450c17 increases 17,20 lyase activity: implications for adrenarche and for the polycystic ovary syndrome. Proc Natl Acad Sci U S A . 1995; 92 10619-10623
46 Voutilainen R, Tapanainen J, Chung B, Matteson K J, Miller W L. Hormonal regulation of P450scc (20,22 desmolase) and P450c17 (17α-hydroxylase/17,20-lyase) in cultured human granulosa cells. J Clin Endocrinol Metab . 1986; 63 202-207
47 Biglieri E G, Herron M A, Brust N. 17α-hydroxylation deficiency in man. J Clin Endocrinol Metab . 1966; 15 1945-1954
48 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; 17 201-205
49 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 b ₅ . Mol Endocrinol . 1999; 13 167-175
50 Auchus R J, Miller W L. Molecular modeling of human P450c17 (17α-hydroxylase/17,20-lyase): insights into reaction mechanisms and effects of mutations. Mol Endocrinol . 1999; 13 1169-1182
51 Gupta M K, Geller D H, Auchus R J. Pitfalls in characterizing P450c17 mutations associated with isolated 17,20 lyase deficiency. J Clin Endocrinol Metab . 2001; 86 4416-4423
52 Morel Y, Miller W L. Clinical and molecular genetics of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Adv Hum Genet . 1991; 20 1-68
53 White P C, Speiser P W. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev . 2000; 21 245-291
54 Higashi Y, Yoshioka H, Yamane M, Gotoh O, Fujii-Kuriyama Y. Complete nucleotide sequence of two steroid 21-hydroxylase genes tandemly arranged in human chromosome: a pseudogene and genuine gene. Proc Natl Acad Sci U S A . 1986; 83 2841-2845
55 White P C, New M I, Dupont B. Structure of the human steroid 21-hydroxylase genes. Proc Natl Acad Sci U S A . 1986; 83 5111-5115
56 Morel Y, Andre J, Uring-Lambert B. Rearrangements and point mutations of P450c21 genes are distinguished by five restriction endonuclease haplotypes identified by a new probing strategy in 57 families with congenital adrenal hyperplasia. J Clin Invest . 1989; 83 527-536
57 Mellon S H, Miller W L. Extra-adrenal steroid 21-hydroxylation is not mediated by P450c21. J Clin Invest . 1989; 84 1497-1502
58 White P C, Curnow K M, Pascoe L. Disorders of steroid 11β-hydroxylase isozymes. Endocr Rev . 1994; 15 421-438
59 Fardella C E, Miller W L. Molecular biology of mineralocorticoid metabolism. Annu Rev Nutr . 1996; 16 443-470
60 Labrie F, Luu-The V, Lin S X. The key role of 17β-hydroxysteroid dehydrogenases in sex steroid biology. Steroids . 1997; 62 148-158
61 Moghrabi N, Andersson S. 17β-Hydroxysteroid dehydrogenases: physiological roles in health and disease. Trends Endocrinol Metab . 1998; 9 265-270
62 Peltoketo H, Isomaa V, Mäenlavsta O, Vihko R. Complete amino acid sequence of human placental 17β-hydroxysteroid dehydrogenase deduced from cDNA. FEBS Lett . 1988; 239 73-77
63 Tremblay Y, Ringler G E, Morel Y. Regulation of the gene for estrogenic 17-ketosteroid reductase lying on chromosome 17cen→q25. J Biol Chem . 1989; 264 20458-20462
64 Ghosh D, Pleuteu V Z, Zhu D W. Structure of human estrogenic 17β-hydroxysteroid dehydrogenase at 2.2 Å resolution. Structure . 1995; 3 503-513
65 Sawicki M W, Erman M, Puranen T, Vihko P, Ghosh D. Structure of the ternary complex of human 17β-hydroxysteroid dehydrogenase type 1 with 3-hydroxyestra-1,3,5,7-tetraen-17-one (equilin) and NADP+. Proc Natl Acad Sci U S A . 1999; 96 840-845
66 Takeyama J, Sasano H, Suzuki T. 17β-Hydroxysteroid dehydrogenase types 1 and 2 in human placenta: an immunohistochemical study with correlation to placental development. J Clin Endocrinol Metab . 1998; 83 3710-3715
67 Geissler W M, Davis D L, Wu L. Male pseudohermaphroditism caused by mutations of testicular 17β-hydroxysteroid dehydrogenase 3. Nat Genet . 1994; 7 34-39
68 Leenders F, Tesdorpf J G, Markus M. Porcine 80-kDa protein reveals intrinsic 17β-hydroxysteroid dehydrogenase, fatty acyl-CoA-hydratase/dehydrogenase, and sterol transfer activities. J Biol Chem . 1996; 271 5438-5442
69 Dufort I, Rheault P, Huang X F, Soucy P, Luu-The V. Characteristics of a highly labile human type 5 17β-hydroxysteroid dehydrogenase. Endocrinology . 1999; 140 568-574
70 Simpson E R, Mahendroo M S, Means G D. Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocr Rev . 1994; 15 342-355
71 Grumbach M M, Auchus R J. Estrogen: consequences and implications of human mutations in synthesis and action. J Clin Endocrinol Metab . 1999; 84 4677-4694
72 Conte F A, Grumbach M M, Ito Y, Fisher C R, Simpson E R. A syndrome of female pseudohermaphrodism, hypergonadotropic hypogonadism, and multicystic ovaries associated with missense mutations in the gene encoding aromatase (P450arom). J Clin Endocrinol Metab . 1994; 78 1287-1292
73 Thigpen A E, Silver R I, Guileyardo J M. Tissue distribution and ontogeny of steroid 5α-reductase isozyme expression. J Clin Invest . 1993; 92 903-910
74 Wilson J D. The role of androgens in male gender role behavior. Endocr Rev . 1999; 20 726-737
75 Wilson J D, Griffin J E, Russell D W. Steroid 5α-reductase 2 deficiency. Endocr Rev . 1993; 14 577-593