Diagnosis and treatment of disorders of the androgen receptor
- 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
- Mitchell E Geffner, MD
Mitchell E Geffner, MD
- Section Editor — Pediatric Endocrinology
- Professor of Pediatrics
- Keck School of Medicine, University of Southern California
Defects in androgen receptor (AR) function cause a disorder of sex development (DSD) in which 46,XY individuals do not virilize normally, despite the presence of bilateral testes and serum testosterone concentrations within or above the normal male range . The various phenotypes in the disorder are mostly due to varying degrees of impairment in AR function. Since the AR is encoded by a gene on the X chromosome, all AR mutations are inherited in an X-linked recessive fashion. (See "Pathogenesis and clinical manifestations of disorders of androgen action".)
The possibility of an androgen receptor (AR) disorder causing resistance to the action of androgen should be considered in the following clinical situations:
●Males and females of all ages, including newborns, who have ambiguous genitalia (see "Evaluation of the infant with atypical genitalia (disorder of sex development)")
●Girls with inguinal hernias or labial masses
●Women with primary amenorrhea
- Hughes IA, Houk C, Ahmed SF, et al. Consensus statement on management of intersex disorders. Arch Dis Child 2006; 91:554.
- German J, Simpson JL, Morillo-Cucci G, et al. Testicular feminisation and inguinal hernia. Lancet 1973; 1:891.
- Sarpel U, Palmer SK, Dolgin SE. The incidence of complete androgen insensitivity in girls with inguinal hernias and assessment of screening by vaginal length measurement. J Pediatr Surg 2005; 40:133.
- Griffin JE, Edwards C, Madden JD, et al. Congenital absence of the vagina. The Mayer-Rokitansky-Kuster-Hauser syndrome. Ann Intern Med 1976; 85:224.
- Hales ED, Rosser SB. Computed tomography of testicular feminization. J Comput Assist Tomogr 1984; 8:772.
- Tanaka YO, Mesaki N, Kurosaki Y, et al. Testicular feminization: role of MRI in diagnosing this rare male pseudohermaphroditism. J Comput Assist Tomogr 1998; 22:884.
- Gottlieb B, Beitel LK, Nadarajah A, et al. The androgen receptor gene mutations database: 2012 update. Hum Mutat 2012; 33:887.
- http://androgenb.mcgill.ca/ (Accessed on August 12, 2014).
- Hornig NC, de Beaufort C, Denzer F, et al. A Recurrent Germline Mutation in the 5'UTR of the Androgen Receptor Causes Complete Androgen Insensitivity by Activating Aberrant uORF Translation. PLoS One 2016; 11:e0154158.
- Hornig NC, Ukat M, Schweikert HU, et al. Identification of an AR Mutation-Negative Class of Androgen Insensitivity by Determining Endogenous AR Activity. J Clin Endocrinol Metab 2016; 101:4468.
- Hughes IA, Werner R, Bunch T, Hiort O. Androgen insensitivity syndrome. Semin Reprod Med 2012; 30:432.
- Aiman J, Griffin JE. The frequency of androgen receptor deficiency in infertile men. J Clin Endocrinol Metab 1982; 54:725.
- 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.
- Pryor JL, Kent-First M, Muallem A, et al. Microdeletions in the Y chromosome of infertile men. N Engl J Med 1997; 336:534.
- Hughes IA, Davies JD, Bunch TI, et al. Androgen insensitivity syndrome. Lancet 2012; 380:1419.
- Melo KF, Mendonca BB, Billerbeck AE, et al. Clinical, hormonal, behavioral, and genetic characteristics of androgen insensitivity syndrome in a Brazilian cohort: five novel mutations in the androgen receptor gene. J Clin Endocrinol Metab 2003; 88:3241.
- 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.
- Mendonca BB, Domenice S, Arnhold IJ, Costa EM. 46,XY disorders of sex development (DSD). Clin Endocrinol (Oxf) 2009; 70:173.
- Griffin JE, Wilson JD. Disorders of sexual differentiation. In: Campbell's Urology, Walsh PC, Retik AB, Stamey TA, Vaughan ED Jr (Eds), Saunders, Philadelphia 1992. p.1509.
- Bastian C, Muller JB, Lortat-Jacob S, et al. Genetic mutations and somatic anomalies in association with 46,XY gonadal dysgenesis. Fertil Steril 2015; 103:1297.
- 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.
- Nagel RA, Lippe BM, Griffin JE. Androgen resistance in the neonate: use of hormones of hypothalamic-pituitary-gonadal axis for diagnosis. J Pediatr 1986; 109:486.
- Lee PA, Brown TR, LaTorre HA. Diagnosis of the partial androgen insensitivity syndrome during infancy. JAMA 1986; 255:2207.
- Walsh PC, Curry N, Mills RC, Siiteri PK. Plasma androgen responce to hCG stimulation in prepubertal boys with hypospadias and cryptorchidism. J Clin Endocrinol Metab 1976; 42:52.
- Savage MO, Chaussain JL, Evain D, et al. Endocrine studies in male pseudohermaphroditism in childhood and adolescence. Clin Endocrinol (Oxf) 1978; 8:219.
- Campo S, Moteagudo C, Nicolau G, et al. Testicular function in prepubertal male pseudohermaphroditism. Clin Endocrinol (Oxf) 1981; 14:11.
- Allen TD, Griffin JE. Endocrine studies in patients with advanced hypospadias. J Urol 1984; 131:310.
- Ahmed SF, Cheng A, Hughes IA. Assessment of the gonadotrophin-gonadal axis in androgen insensitivity syndrome. Arch Dis Child 1999; 80:324.
- Maimoun L, Philibert P, Cammas B, et al. Phenotypical, biological, and molecular heterogeneity of 5α-reductase deficiency: an extensive international experience of 55 patients. J Clin Endocrinol Metab 2011; 96:296.
- 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.
- Kulle AE, Riepe FG, Melchior D, et al. A novel ultrapressure liquid chromatography tandem mass spectrometry method for the simultaneous determination of androstenedione, testosterone, and dihydrotestosterone in pediatric blood samples: age- and sex-specific reference data. J Clin Endocrinol Metab 2010; 95:2399.
- Hellmann P, Christiansen P, Johannsen TH, et al. Male patients with partial androgen insensitivity syndrome: a longitudinal follow-up of growth, reproductive hormones and the development of gynaecomastia. Arch Dis Child 2012; 97:403.
- Chan AO, Shek CC. Urinary steroid profiling in the diagnosis of congenital adrenal hyperplasia and disorders of sex development: experience of a urinary steroid referral centre in Hong Kong. Clin Biochem 2013; 46:327.
- Holterhus PM, Wiebel J, Sinnecker GH, et al. Clinical and molecular spectrum of somatic mosaicism in androgen insensitivity syndrome. Pediatr Res 1999; 46:684.
- Eggers S, Sadedin S, van den Bergen JA, et al. Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort. Genome Biol 2016; 17:243.
- Hiort O, Birnbaum W, Marshall L, et al. Management of disorders of sex development. Nat Rev Endocrinol 2014; 10:520.
- Wiesemann C, Ude-Koeller S, Sinnecker GH, Thyen U. Ethical principles and recommendations for the medical management of differences of sex development (DSD)/intersex in children and adolescents. Eur J Pediatr 2010; 169:671.
- Kolesinska Z, Ahmed SF, Niedziela M, et al. Changes over time in sex assignment for disorders of sex development. Pediatrics 2014; 134:e710.
- Schlegel PN, Girardi SK. Clinical review 87: In vitro fertilization for male factor infertility. J Clin Endocrinol Metab 1997; 82:709.
- Levin HS. Tumors of the testis in intersex syndromes. Urol Clin North Am 2000; 27:543.
- Cassio A, Cacciari E, D'Errico A, et al. Incidence of intratubular germ cell neoplasia in androgen insensitivity syndrome. Acta Endocrinol (Copenh) 1990; 123:416.
- Hurt WG, Bodurtha JN, McCall JB, Ali MM. Seminoma in pubertal patient with androgen insensitivity syndrome. Am J Obstet Gynecol 1989; 161:530.
- Purves JT, Miles-Thomas J, Migeon C, Gearhart JP. Complete androgen insensitivity: the role of the surgeon. J Urol 2008; 180:1716.
- Cheikhelard A, Morel Y, Thibaud E, et al. Long-term followup and comparison between genotype and phenotype in 29 cases of complete androgen insensitivity syndrome. J Urol 2008; 180:1496.
- Jorgensen PB, Kjartansdóttir KR, Fedder J. Care of women with XY karyotype: a clinical practice guideline. Fertil Steril 2010; 94:105.
- Grino PB, Isidro-Gutierrez RF, Griffin JE, Wilson JD. Androgen resistance associated with a qualitative abnormality of the androgen receptor and responsive to high dose androgen therapy. J Clin Endocrinol Metab 1989; 68:578.
- Ong YC, Wong HB, Adaikan G, Yong EL. Directed pharmacological therapy of ambiguous genitalia due to an androgen receptor gene mutation. Lancet 1999; 354:1444.
- Foresta C, Bettella A, Ferlin A, et al. Response to local dihydrotestosterone treatment in a patient with partial androgen-insensitivity syndrome due to a novel mutation in the androgen receptor gene. Am J Med Genet 2002; 107:259.
- Price P, Wass JA, Griffin JE, et al. High dose androgen therapy in male pseudohermaphroditism due to 5 alpha-reductase deficiency and disorders of the androgen receptor. J Clin Invest 1984; 74:1496.
- 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.
- Leonard JM, Bremner WJ, Capell PT, et al. Male hypogonadism; Klinefelter and Reifenstein syndrome. In: Genetic forms of hypogonadism. Birth defects: Original Article Series Vol II, Vergama D (Ed), Stratton, New York 1975. p.17.
- Warne GL, Grover S, Zajac JD. Hormonal therapies for individuals with intersex conditions: protocol for use. Treat Endocrinol 2005; 4:19.
- Saito R, Yamamoto Y, Goto M, et al. Tamoxifen treatment for pubertal gynecomastia in two siblings with partial androgen insensitivity syndrome. Horm Res Paediatr 2014; 81:211.
- Lucas-Herald A, Bertelloni S, Juul A, et al. The Long-Term Outcome of Boys With Partial Androgen Insensitivity Syndrome and a Mutation in the Androgen Receptor Gene. J Clin Endocrinol Metab 2016; 101:3959.
- Ismail-Pratt IS, Bikoo M, Liao LM, et al. Normalization of the vagina by dilator treatment alone in Complete Androgen Insensitivity Syndrome and Mayer-Rokitansky-Kuster-Hauser Syndrome. Hum Reprod 2007; 22:2020.
- 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.
- Wooster R, Mangion J, Eeles R, et al. A germline mutation in the androgen receptor gene in two brothers with breast cancer and Reifenstein syndrome. Nat Genet 1992; 2:132.
- Goodall J. Helping a child to understand her own testicular feminisation. Lancet 1991; 337:33.
- Minogue BP, Taraszewski R, Elias S, Annas GJ. The whole truth and nothing but the truth? Hastings Cent Rep 1988; 18:34.
- 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.
- Complete androgen insensitivity syndrome
- Partial androgen insensitivity syndrome
- - Genotype-phenotype correlations
- - Differential diagnosis
- - Genetic testing
- Gender assignment in the newborn
- Cryptorchid testes
- Timing of gonadectomy
- Hormone replacement or supplementation
- Surgery of the urogenital tract
- Gynecomastia in men with PAIS
- Psychological support and disclosure
- SUMMARY AND RECOMMENDATIONS