Pathogenesis and clinical manifestations of disorders of androgen action
- Olaf Hiort, MD
Olaf Hiort, MD
- University of Lübeck
- Section Editors
- Peter J Snyder, MD
Peter J Snyder, MD
- Editor-in-Chief — Endocrinology
- Section Editor — Pituitary Disease; Male Reproductive Endocrinology
- Professor of Medicine
- University of Pennsylvania School of Medicine
- Alvin M Matsumoto, MD
Alvin M Matsumoto, MD
- Section Editor — Male Reproductive Endocrinology
- Professor of Medicine
- University of Washington School of Medicine
Loss of function mutations of the gene that encodes the androgen receptor (AR) result in androgen insensitivity syndrome (AIS) in 46,XY individuals with functional testes and unhindered testosterone formation. AIS encompasses a clinical continuum of decreased to absent androgen effects, varying from a completely female phenotype to a male phenotype with undervirilization or infertility. In contrast to the variability in phenotypic expression, the disorders have similar endocrine, pathophysiologic, and genetic features . The pathophysiology will be reviewed here, while diagnosis and therapy are discussed separately. (See "Diagnosis and treatment of disorders of the androgen receptor".)
Recognition that patients with complete androgen insensitivity syndrome (CAIS) have profound resistance to the action of androgen came from studies in which affected women were found to be resistant to the virilizing action of exogenous androgen .
This hormone resistance was found to be due to defects in androgen receptor (AR) function as a result of studies of women with CAIS who had no detectable AR binding [3-5], qualitatively abnormal AR binding [6-8], or decreased amounts of qualitatively normal receptor binding [6,9]. Similar findings were described in patients with the less severe phenotypes .
Involvement of the AR in these disorders was confirmed when the encoding gene was cloned and specific molecular defects were defined. The AR gene is located on chromosome Xq11-12. X-linkage of the AR gene was established when the human cDNA was cloned from an X-chromosome library [10,11].
The AR is a member of the steroid-thyroid-retinoid superfamily of nuclear receptors with a C-terminal region containing hormone-binding and DNA-binding domains and an N-terminal region important in transactivation (figure 1). Specific mutations of the AR gene have been identified in many patients with androgen insensitivity syndromes. Most mutations today have been localized in the hormone-binding domain, and to a lesser extent in the DNA-binding domain and the transactivation domain . Androgen action via the AR leads to long-term programming effects by implementing stable functional and structural androgen-dependent traits. These occur during defined androgen-sensitive time windows of individual ontogenesis. Therefore, the AR acts in concert with many other co-factors to induce individual effects within each cell and organ , including the brain. (See 'Genetics' below.)
- Quigley CA, De Bellis A, Marschke KB, et al. Androgen receptor defects: historical, clinical, and molecular perspectives. Endocr Rev 1995; 16:271.
- Wilkins L. Abnormal sex differentiation: Hermaphroditism and gonadal dysgenesis. In: The Diagnosis and Treatment of Endocrine Disorders in Childhood and Adolescence, Charles C Thomas Pub Ltd, Springfield, IL 1957. p.258.
- Keenan BS, Meyer WJ 3rd, Hadjian AJ, et al. Syndrome of androgen insensitivity in man: absence of 5 alpha-dihydrotestosterone binding protein in skin fibroblasts. J Clin Endocrinol Metab 1974; 38:1143.
- Griffin JE, Punyashthiti K, Wilson JD. Dihydrotestosterone binding by cultured human fibroblasts. Comparison of cells from control subjects and from patients with hereditary male pseudohermaphroditism due to androgen resistance. J Clin Invest 1976; 57:1342.
- Kaufman M, Straisfeld C, Pinsky L. Male pseudohermaphroditism presumably due to target organ unresponsiveness to androgens. Deficient 5alpha-dihydrotestosterone binding in cultured skin fibroblasts. J Clin Invest 1976; 58:345.
- Griffin JE. Testicular feminization associated with a thermolabile androgen receptor in culutred human fibroblasts. J Clin Invest 1979; 64:1624.
- Pinsky L, Kaufman M, Killinger DW, et al. Human minimal androgen insensitivity with normal dihydrotestosterone-binding capacity in cultured genital skin fibroblasts: evidence for an androgen-selective qualitative abnormality of the receptor. Am J Hum Genet 1984; 36:965.
- Brown TR, Maes M, Rothwell SW, Migeon CJ. Human complete androgen insensitivity with normal dihydrotestosterone receptor binding capacity in cultured genital skin fibroblasts: evidence for a qualitative abnormality of the receptor. J Clin Endocrinol Metab 1982; 55:61.
- Griffin JE. Androgen resistance--the clinical and molecular spectrum. N Engl J Med 1992; 326:611.
- Chang CS, Kokontis J, Liao ST. Molecular cloning of human and rat complementary DNA encoding androgen receptors. Science 1988; 240:324.
- Lubahn DB, Joseph DR, Sullivan PM, et al. Cloning of human androgen receptor complementary DNA and localization to the X chromosome. Science 1988; 240:327.
- Werner R, Holterhus PM. Androgen action. Endocr Dev 2014; 27:28.
- Hiort O. The differential role of androgens in early human sex development. BMC Med 2013; 11:152.
- Ross GT. Disorders of the ovary and female reproductive tract. In: Williams Textbook of Endocrinology, Wilson JD, Foster DW (Eds), Saunders, Philadelphia 1985. p.206.
- Ahmed SF, Achermann JC, Arlt W, et al. UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development. Clin Endocrinol (Oxf) 2011; 75:12.
- Bouvattier C, Carel JC, Lecointre C, et al. Postnatal changes of T, LH, and FSH in 46,XY infants with mutations in the AR gene. J Clin Endocrinol Metab 2002; 87:29.
- Doehnert U, Bertelloni S, Werner R, et al. Characteristic features of reproductive hormone profiles in late adolescent and adult females with complete androgen insensitivity syndrome. Sex Dev 2015; 9:69.
- Dodge ST, Finkelston MS, Miyazawa K. Testicular feminization with incomplete Müllerian regression. Fertil Steril 1985; 43:937.
- Hannema SE, Scott IS, Hodapp J, et al. Residual activity of mutant androgen receptors explains wolffian duct development in the complete androgen insensitivity syndrome. J Clin Endocrinol Metab 2004; 89:5815.
- MORRIS JM. The syndrome of testicular feminization in male pseudohermaphrodites. Am J Obstet Gynecol 1953; 65:1192.
- Wünsch L, Holterhus PM, Wessel L, Hiort O. Patients with disorders of sex development (DSD) at risk of gonadal tumour development: management based on laparoscopic biopsy and molecular diagnosis. BJU Int 2012; 110:E958.
- Kaprova-Pleskacova J, Stoop H, Brüggenwirth H, et al. Complete androgen insensitivity syndrome: factors influencing gonadal histology including germ cell pathology. Mod Pathol 2014; 27:721.
- Deans R, Creighton SM, Liao LM, Conway GS. Timing of gonadectomy in adult women with complete androgen insensitivity syndrome (CAIS): patient preferences and clinical evidence. Clin Endocrinol (Oxf) 2012; 76:894.
- Papadimitriou DT, Linglart A, Morel Y, Chaussain JL. Puberty in subjects with complete androgen insensitivity syndrome. Horm Res 2006; 65:126.
- T'Sjoen G, De Cuypere G, Monstrey S, et al. Male gender identity in complete androgen insensitivity syndrome. Arch Sex Behav 2011; 40:635.
- Köhler B, Kleinemeier E, Lux A, et al. Satisfaction with genital surgery and sexual life of adults with XY disorders of sex development: results from the German clinical evaluation study. J Clin Endocrinol Metab 2012; 97:577.
- Wisniewski AB, Migeon CJ, Meyer-Bahlburg HF, et al. Complete androgen insensitivity syndrome: long-term medical, surgical, and psychosexual outcome. J Clin Endocrinol Metab 2000; 85:2664.
- Wilson JD, Harrod MJ, Goldstein JL, et al. Familial incomplete male pseudohermaphroditism, type 1. Evidence for androgen resistance and variable clinical manifestations in a family with the Reifenstein syndrome. N Engl J Med 1974; 290:1097.
- Walker AC, Stack EM, Horsfall WA. Familial male pseudohermaphroditism. Med J Aust 1970; 1:156.
- Gardó S, Papp Z. Clinical variations of testicular intersexuality in a family. J Med Genet 1974; 11:267.
- Chu J, Zhang R, Zhao Z, et al. Male fertility is compatible with an Arg(840)Cys substitution in the AR in a large Chinese family affected with divergent phenotypes of AR insensitivity syndrome. J Clin Endocrinol Metab 2002; 87:347.
- MORRIS JM, MAHESH VB. FURTHER OBSERVATIONS ON THE SYNDROME, "TESTICULAR FEMINIZATION". Am J Obstet Gynecol 1963; 87:731.
- Jürgensen M, Hiort O, Holterhus PM, Thyen U. Gender role behavior in children with XY karyotype and disorders of sex development. Horm Behav 2007; 51:443.
- Bouvattier C, Mignot B, Lefèvre H, et al. Impaired sexual activity in male adults with partial androgen insensitivity. J Clin Endocrinol Metab 2006; 91:3310.
- Migeon CJ, Wisniewski AB, Gearhart JP, et al. Ambiguous genitalia with perineoscrotal hypospadias in 46,XY individuals: long-term medical, surgical, and psychosexual outcome. Pediatrics 2002; 110:e31.
- Aiman J, Griffin JE, Gazak JM, et al. Androgen insensitivity as a cause of infertility in otherwise normal men. N Engl J Med 1979; 300:223.
- Hiort O, Holterhus PM, Horter T, et al. Significance of mutations in the androgen receptor gene in males with idiopathic infertility. J Clin Endocrinol Metab 2000; 85:2810.
- Grino PB, Griffin JE, Cushard WG Jr, Wilson JD. A mutation of the androgen receptor associated with partial androgen resistance, familial gynecomastia, and fertility. J Clin Endocrinol Metab 1988; 66:754.
- Pinsky L, Kaufman M, Killinger DW. Impaired spermatogenesis is not an obligate expression of receptor-defective androgen resistance. Am J Med Genet 1989; 32:100.
- Pinsky L, Beitel LK, Trifiro MA. Spinobulbar muscular atrophy. In: The Metabolic and Molecular Bases of Inherited Disease, 8th, Scriver CR, Beaudet AL, Sly WS, Valle D (Eds), McGraw-Hill, New York 2001. p.4147.
- La Spada AR, Wilson EM, Lubahn DB, et al. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 1991; 352:77.
- Chamberlain NL, Driver ED, Miesfeld RL. The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res 1994; 22:3181.
- Dejager S, Bry-Gauillard H, Bruckert E, et al. A comprehensive endocrine description of Kennedy's disease revealing androgen insensitivity linked to CAG repeat length. J Clin Endocrinol Metab 2002; 87:3893.
- Sinnecker GH, Hiort O, Nitsche EM, et al. 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.
- Boyar RM, Moore RJ, Rosner W, et al. Studies of gonadotropin-gonadal dynamics in patients with androgen insensitivity. J Clin Endocrinol Metab 1978; 47:1116.
- Imperato-McGinley J, Peterson RE, Gautier T, et al. Hormonal evaluation of a large kindred with complete androgen insensitivity: evidence for secondary 5 alpha-reductase deficiency. J Clin Endocrinol Metab 1982; 54:931.
- Kubini K, Zachmann M, Albers N, et al. Basal inhibin B and the testosterone response to human chorionic gonadotropin correlate in prepubertal boys. J Clin Endocrinol Metab 2000; 85:134.
- Rey RA, Belville C, Nihoul-Fékété C, et al. Evaluation of gonadal function in 107 intersex patients by means of serum antimüllerian hormone measurement. J Clin Endocrinol Metab 1999; 84:627.
- Madden JD, Walsh PC, MacDonald PC, Wilson JD. Clinical and endocrinologic characterization of a patients with the syndrome of incomplete testicular feminization. J Clin Endocrinol Metab 1975; 41:751.
- Griffin JE, McPhaul MJ, Russell DW, Wilson JD. The androgen resistance syndromes: steroid 5 alpha-reductase 2 deficiency, testicular feminization, and related disorders. In: The Metabolic and Molecular Bases of Inherited Disease, 8th, Scriver CR, Beaudet AL, Sly WS, Valle D (Eds), McGraw-Hill, New York 2001. p.4117.
- Hiort O, Sinnecker GH, Holterhus PM, et al. Inherited and de novo androgen receptor gene mutations: investigation of single-case families. J Pediatr 1998; 132:939.
- Deeb A, Mason C, Lee YS, Hughes IA. Correlation between genotype, phenotype and sex of rearing in 111 patients with partial androgen insensitivity syndrome. Clin Endocrinol (Oxf) 2005; 63:56.
- Baxter RM, Arboleda VA, Lee H, et al. Exome sequencing for the diagnosis of 46,XY disorders of sex development. J Clin Endocrinol Metab 2015; 100:E333.
- McPhaul MJ, Marcelli M, Zoppi S, et al. 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.
- Philibert P, Audran F, Pienkowski C, et al. Complete androgen insensitivity syndrome is frequently due to premature stop codons in exon 1 of the androgen receptor gene: an international collaborative report of 13 new mutations. Fertil Steril 2010; 94:472.
- Yong EL, Ng SC, Roy AC, et al. Pregnancy after hormonal correction of severe spermatogenic defect due to mutation in androgen receptor gene. Lancet 1994; 344:826.
- Tsukada T, Inoue M, Tachibana S, et al. An androgen receptor mutation causing androgen resistance in undervirilized male syndrome. J Clin Endocrinol Metab 1994; 79:1202.
- Ahmed SF, 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; 85:658.
- Ris-Stalpers C, Verleun-Mooijman MC, de Blaeij TJ, et al. Differential splicing of human androgen receptor pre-mRNA in X-linked Reifenstein syndrome, because of a deletion involving a putative branch site. Am J Hum Genet 1994; 54:609.
- Brüggenwirth HT, Boehmer AL, Ramnarain S, et al. Molecular analysis of the androgen-receptor gene in a family with receptor-positive partial androgen insensitivity: an unusual type of intronic mutation. Am J Hum Genet 1997; 61:1067.
- Adachi M, Takayanagi R, Tomura A, et al. Androgen-insensitivity syndrome as a possible coactivator disease. N Engl J Med 2000; 343:856.
- Holterhus PM, Brüggenwirth HT, Hiort O, et al. Mosaicism due to a somatic mutation of the androgen receptor gene determines phenotype in androgen insensitivity syndrome. J Clin Endocrinol Metab 1997; 82:3584.
- Köhler B, Lumbroso S, Leger J, et al. Androgen insensitivity syndrome: somatic mosaicism of the androgen receptor in seven families and consequences for sex assignment and genetic counseling. J Clin Endocrinol Metab 2005; 90:106.
- McPhaul MJ, Marcelli M, Zoppi S, et al. Mutations in the ligand-binding domain of the androgen receptor gene cluster in two regions of the gene. J Clin Invest 1992; 90:2097.
- Boehmer AL, Brinkmann O, Brüggenwirth H, et al. Genotype versus phenotype in families with androgen insensitivity syndrome. J Clin Endocrinol Metab 2001; 86:4151.
- McPhaul MJ, Marcelli M, Tilley WD, et al. Molecular basis of androgen resistance in a family with a qualitative abnormality of the androgen receptor and responsive to high-dose androgen therapy. J Clin Invest 1991; 87:1413.
- Gao T, Marcelli M, McPhaul MJ. Transcriptional activation and transient expression of the human androgen receptor. J Steroid Biochem Mol Biol 1996; 59:9.
- CLINICAL FEATURES
- Complete androgen insensitivity (CAIS)
- Partial androgen insensitivity (PAIS)
- - Female phenotype with mild virilization
- - Predominantly male phenotype
- - Infertile male syndrome
- - Undervirilized fertile male syndrome
- - Spinobulbar muscular atrophy
- Genotype-phenotype correlations