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DOI: 10.1055/s-2002-35386
Disorders of Androgen Action
Publikationsverlauf
Publikationsdatum:
12. November 2002 (online)
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ABSTRACT
Disorders of androgen action are the main cause of male pseudohermaphroditism and include 5αR deficiency and androgen receptor defects. 5αR deficiency is characterized by female genitalia with some degree of masculinization, clitoromegaly, and severely bifid scrotum corresponding to the so-called pseudovaginal perineoscrotal hypospadias. At the onset of puberty, increased muscle mass, development of pubic hair, and phallic growth are associated with the acquisition of male gender identity. Normal or increased levels of testosterone and an elevated testosterone-to-dihydrotestosterone ratio after human chorionic gonadotropin stimulation testing suggest 5αreductase deficiency, and the diagnosis can be ascertained by identifying the mutation in the 5αR-2 gene. Whatever the patient's age at diagnosis, psychological evaluation with 5αRD is vital. Androgen receptor defects encompass two clinical expressions: the complete and partial androgen insensitivity syndromes. Complete androgen insensitivity syndrome should be suspected at birth in the presence of inguinal hernia in a girl without genital ambiguity. At puberty, the sign of alert is primary amenorrhea with normal female phenotype and harmonious mammary development but no pubic hair growth. Partial androgen insensitivity syndrome covers a wide spectrum of undervirilized phenotypes ranging from clitoromegaly at birth to infertile men. In all cases, complementary investigations should include plasma testosterone and luteinizing hormone as well as androgen-binding capacity in cultured genital skin fibroblasts. Diagnosis is confirmed by identification of the androgen receptor gene mutation. Although patients with complete androgen insensitivity syndrome are raised as females, patients with partial androgen insensitivity syndrome should be managed according to age at diagnosis, response to treatment with exogenous androgens, and the presence of an androgen gene mutation. Gonadectomy in complete androgen insensitivity syndrome should be performed before puberty, and androgen substitution may improve the development of external genitalia in some patients with partial androgen insensitivity syndrome. Psychological follow-up is necesssary.
KEYWORDS
Ambiguous genitalia - 5α-reductase deficiency - androgen insensitivity syndrome
REFERENCES
- 1 Imperato-McGinley J, Guerrero L, Gautier T, Peterson R E. Steroid 5αlpha-reductase deficiency in man: an inherited form of male pseudohermaphroditism. Science . 1974; 186 1213-1216
- 2 Wilson J D, Griffin J E, Russel D W. Steroid 5 alpha-reductase 2 deficiency. Endocr Rev . 1993; 14 577-593
- 3 Imperato-McGinley J, Zhu Y S. Androgens and male physiology: the syndrome of 5 alpha-reductase-2 deficiency (in press). Mol Cell Endocrinol. 2002;
- 4 Russel D W, Wilson J D. Steroid 5 alpha-reductase: two genes/two enzymes. Annu Rev Biochem . 1994; 63 25-61
- 5 Andersson S, Berman D M, Jenkins E P, Russel D W. Deletion of steroid 5αlpha-reductase-2 gene in male pseudohermaphroditism. Nature . 1991; 354 159-161
- 6 Cai L Q, Zhu Y S, Katz M D. 5αlpha-reductase-2 gene mutation in the Dominican Republic. J Clin Endocrinol Metab . 1996; 81 1730-1735
- 7 Mendonca B B, Inacio M, Costa E M. Male pseudohermaphroditism due to steroid 5αlpha-reductase 2 deficiency: diagnosis, psychological evaluation, and management. Medicine (Baltimore) . 1996; 75 64-76
- 8 Sultan C, Lobaccaro J M, Lumbroso S, Poujol N. Disorders of sexual differentiation: recent molecular and clinical advances. In: Kelnar CJH, ed. Bailliere's Clinical Paediatrics London: Baillière Tindall 1996: 221-243
- 9 Prader A. Der genitalbefund beim pseuhermaphroditismus feminus des kongenitalen adrenogenitalen syndroms. Helv Paediatr Acta . 1954; 9 231-248
- 10 Quigley C A, Debellis A, Marschke K B. Androgen receptor defects: historical, clinical, and molecular perspectives. Endocr Rev . 1995; 16 271-321
- 11 Rutgers J L, Scully R E. The androgen insensitivity syndrome (testicular feminization): a clinicopathological study of 43 cases. Int J Gynecol Pathol . 1991; 10 126-144
- 12 Griffin J E. Androgen resistance: the clinical and molecular spectrum. N Engl J Med . 1992; 326 611-618
- 13 McPhaul M J, Marcelli M, Zoppi S, Griffin J E, Wilson J D. Genetic basis of endocrine disease 4. The spectrum of mutations in the androgen receptor gene that causes androgen resistance. J Clin Endocrinol Metab . 1993; 76 17-23
- 14 Batch J A, Evans B A, Hughes I A, Patterson M N. Mutations of the androgen receptor gene identified in perineal hypospadias. J Med Genet . 1993; 30 198-201
- 15 Sinnecker G H, Hiort O, Nitsche E M, Holterhus P M, Kruse K. Functional assessment and clinical classification of androgen sensitivity in patients with mutations of the androgen receptor gene. German Collaborative Intersex Study Group. Eur J Pediatr . 1997; 156 7-14
- 16 Rey R A, Belville C, Nihoul-Fekete C. Evaluation of gonadal function in 107 intersex patients by means of serum antimüllerian hormone measurement. J Clin Endocrinol Metab . 1999; 84 627-631
- 17 Nirdé P, Georget V, Térouanne B. Quantification of androgen receptor messenger RNA from genital skin fibroblasts by reverse transcription-competitive polymerase chain reaction. J Steroid Biochem Mol Biol . 1998; 66 35-43
- 18 Chang C, Kokontis J, Liao S. Molecular cloning of human and rat cDNA encoding androgen receptors. Science . 1988; 240 324-326
- 19 Lubahn D B, Joseph D R, Sar M. The human androgen receptor: complementary deoxyribonucleic acid cloning, sequence analysis and gene expression in prostate. Mol Endocrinol . 1988; 2 1265-1275
- 20 Gottlieb B, Beitel L K, Lumbroso R, Pinsky L, Trifiro M. Update of the androgen receptor gene mutations database. Hum Mutat . 1999; 14 103-114
- 21 Lumbroso S, Lobaccaro J M, Belon C. Molecular prenatal exclusion of Reifenstein syndrome. Eur J Endocrinol . 1994; 130 327-332
- 22 Boehmer A L, Brinkmann A O, Niermeijer M F. Germ-line and somatic mosaicism in the androgen insensitivity syndrome: implications for genetic counseling [letter]. Am J Hum Genet . 1997; 60 1003-1006
- 23 Negro-Vilar A. Selective androgen receptor modulators (SARMs): a novel approach to androgen therapy for the new millennium. J Clin Endocrinol Metab . 1999; 84 3459-3462
- 24 Georget V, Terouanne B, Lumbroso S, Nicolas J C, Sultan C. Trafficking of androgen receptor mutants fused to green fluorescent protein: a new investigation of partial androgen insensitivity syndrome. J Clin Endocrinol Metab . 1998; 83 3597-3603
- 25 Georget V, Nicolas J C, Sultan C. La Green Fluorescent Protein: application à la dynamique intracellulaire des récepteurs stéroïdiens. Med/Sci . 1999; 15 45-55
- 26 Lobaccaro J M, Poujol N, Chiche L. Molecular modeling and in vitro investigations of the human androgen receptor DNA-binding domain: application for the study of two mutations. Mol Cell Endocrinol . 1996; 116 137-147
- 27 Wurtz J M, Bourguet W, Renaud J P. A canonical structure for the ligand-binding domain of nuclear receptors. Nat Struct Biol . 1996; 3 87-94
- 28 Poujol N, Wurtz J M, Tahiri B. Specific recognition of androgens by their nuclear receptor: a structure-function study. J Biol Chem . 2000; 275 24022-24031
- 29 Rodien P, Mebarki F, Mowszowicz I. Different phenotypes in a family with androgen insensitivity caused by the same M780I point mutation in the androgen receptor gene. J Clin Endocrinol Metab . 1996; 81 2994-2998
- 30 Kennedy W R, Alter M, Sung J H. Progressive proximal spinal and bulbar muscular atrophy of late onset: a sex-linked recessive trait. Neurology . 1968; 18 671-680
- 31 La Spada R A, Wilson E M, Lubahn D B, Harding A E, Fischbeck K. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature . 1991; 352 77-79
- 32 Cummings C J, Zoghbi H Y. Fourteen and counting: unraveling trinucleotide repeat diseases. Hum Mol Genet . 2000; 9 909-916
- 33 Paulson H L. Toward an understanding of polyglutamine neurodegeneration. Brain Pathol . 2000; 10 293-299
- 34 Vedscholte J, Ris-Stalpers C, Kuiper G J M G. A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid binding characteristics and response to anti-androgens. Biochem Biophys Res Commun . 1990; 173 534-540
- 35 Newmark J R, Hardy D O, Tonb D C. Androgen receptor gene mutations in human prostate cancer. Proc Natl Acad Sci U S A . 1992; 89 6319-6323
- 36 Sultan C, Terouanne B, Tahiri B. [Androgen-independent prostate carcinoma and androgen-receptor: recent progress in molecular genetics]. Bull Cancer . 1999; 86 618-621
- 37 Wooster R, Mangion J, Eeles R. A germline mutation in the androgen receptor gene in two brothers with breast cancer and Reifenstein syndrome. Nat Genet . 1992; 2 132-134
- 38 Lobaccaro J, Lumbroso S, Belon C. Male breast cancer and androgen receptor gene. Nat Genet . 1993; 5 109-110
- 39 Poujol N, Lobaccaro J M, Chiche L, Lumbroso S, Sultan C. Functional and structural analysis of R607Q and R608K androgen receptor substitutions associated with male breast cancer. Mol Cell Endocrinol . 1997; 130 43-51
- 40 Irvine R A, Yu M C, Ross R K, Coetzee G A. The CAG and GGC microsatellites of the androgen receptor gene are in linkage disequilibrium in men with prostate cancer. Cancer Res . 1995; 55 1937-1940
- 41 Giovannucci E, Stampfer M J, Krithivas K. The CAG repeat within the androgen receptor gene and its relationship to prostate cancer [published erratum appears in Proc Natl Acad Sci U S A 1997;94:8272]. Proc Natl Acad Sci U S A . 1997; 94 3320-3323
- 42 Correa-Cerro L, Wohr G, Haussler J. (CAG)nCAA and GGN repeats in the human androgen receptor gene are not associated with prostate cancer in a French-German population. Eur J Hum Genet . 1999; 7 357-362
- 43 Dowsing A T, Yong E L, Clark M. Linkage between male infertility and trinucleotide repeat expansion in the androgen-receptor gene. Lancet . 1999; 354 640-643
- 44 Tut T G, Ghadessy F J, Trifiro M A, Pinsky L, Yong E L. Long polyglutamine tracts in the androgen receptor are associated with reduced trans-activation, impaired sperm production, and male infertility. J Clin Endocrinol Metab . 1997; 82 3777-3782
- 45 Rebbeck T R, Kantoff P W, Krithivas K. Modification of BRCA1-associated breast cancer risk by the polymorphic androgen-receptor CAG repeat. Am J Hum Genet . 1999; 64 1371-1377
- 46 Vottero A, Stratakis C A, Ghizzoni L. Androgen receptor-mediated hypersensitivity to androgens in women with nonhyperandrogenic hirsutism: skewing of X-chromosome inactivation. J Clin Endocrinol Metab . 1999; 84 1091-1095
- 47 Sawaya M E, Shalita A R. Androgen receptor polymorphisms (CAG repeat lengths) in androgenetic alopecia, hirsutism, and acne. J Cutan Med Surg . 1998; 3 9-15