Androgen Insensitivity Syndrome Workup

  • Author: Christian A Koch, MD, PhD, FACP, FACE; Chief Editor: Stephen Kemp, MD, PhD   more...
 
Updated: Jul 6, 2010
 

Laboratory Studies

The following studies may be indicated in patients with androgen insensitivity syndrome (AIS).

  • A karyotype is essential to differentiate an undermasculinized male from a masculinized female. Alternatively, the presence of a Y chromosome can be confirmed by fluorescent in situ hybridization (FISH) probes for either the SRY region of the Y chromosome or a subtelomeric Y chromosome probe. These offer a much quicker turnaround time than conventional karyotypes.
  • Levels of testosterone and dihydrotestosterone (DHT) establish the presence of normal steroidogenesis.
    • If the testosterone level is low for age, obtain levels of dehydroepiandrosterone (DHEA), androstenedione, and their precursors, 17-hydroxypregnenolone and 17-hydroxyprogesterone. These levels allow identification of errors in the steroid biosynthetic pathways.
    • An elevated ratio of testosterone to DHT indicates a 5-alpha reductase deficiency, a possible differential for patients with partial androgen insensitivity syndrome but usually not for complete androgen insensitivity syndrome. Low levels of testosterone in the absence of evidence of defective steroidogenesis suggest testicular dysgenesis or Leydig cell aplasia/hypoplasia.
  • Mutation analysis of the androgen receptor gene is now commercially available. It detects upwards of 95% of the mutations for complete androgen insensitivity syndrome and partial androgen insensitivity syndrome. The analysis is performed on DNA obtained from buccal swabs. However, the testing is slow (about 6 wk for results) and expensive (not covered by some insurance companies).
  • For patients with Kennedy disease, an elevated testosterone level can be found in approximately 70% of cases. More than 40 CAG tandem repeats in exon 1 of the AR are diagnostic.[4]
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Imaging Studies

A pelvic ultrasound examination is frequently useful. Identification of any müllerian structures, such as uterus or fallopian tubes, is inconsistent with a diagnosis of complete androgen insensitivity syndrome or partial androgen insensitivity syndrome.

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Histologic Findings

  • Histologic examination of the testes in patients with complete androgen insensitivity syndrome or partial androgen insensitivity syndrome should show fairly normal testicular structure, although the numbers of spermatogonia and/or sperm may be reduced markedly in postpubertal patients.
  • Given current management recommendations (see Treatment), a histologic examination may be impossible to perform until the patient is in late adolescence or early adulthood.
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Contributor Information and Disclosures
Author

Christian A Koch, MD, PhD, FACP, FACE  Professor and Director, Division of Endocrinology, University of Mississippi Medical Center

Christian A Koch, MD, PhD, FACP, FACE is a member of the following medical societies: American Academy of Neurology, American Association of Clinical Endocrinologists, American College of Clinical Endocrinologists, American College of Physicians-American Society of Internal Medicine, American Society for Clinical Pharmacology and Therapeutics, American Society for Dermatologic Surgery, Endocrine Society, and German Diabetes Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Arlan L Rosenbloom, MD  Adjunct Distinguished Service Professor Emeritus of Pediatrics, University of Florida College of Medicine; Fellow of the American Academy of Pediatrics; Fellow of the American College of Epidemiology

Arlan L Rosenbloom, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Epidemiology, American Pediatric Society, Endocrine Society, Florida Pediatric Society, Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Lynne Lipton Levitsky, MD  Chief, Pediatric Endocrine Unit, Massachusetts General Hospital; Associate Professor of Pediatrics, Harvard Medical School

Lynne Lipton Levitsky, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Diabetes Association, American Pediatric Society, Endocrine Society, Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Pfizer Grant/research funds P.I.; Tercica Grant/research funds Other; Eli Lily Grant/research funds PI; NovoNordisk Grant/research funds PI; NovoNordisk Consulting fee Consulting; Onyx Heart Valve Consulting fee Consulting

Merrily P M Poth, MD  Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences

Merrily P M Poth, MD is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, and Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD  Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas for Medical Sciences College of Medicine, Arkansas Children's Hospital

Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, and Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Additional Contributors

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Bruce E Wilson, MD to the development and writing of this article.

References

  1. Ohba K, Hayashida Y, Hakariya H, Ichinose S, Naitou S. [A case of complete androgen insensitivity syndrome]. Hinyokika Kiyo. May 2009;55(5):277-80. [Medline].

  2. Oakes MB, Eyvazzadeh AD, Quint E, Smith YR. Complete androgen insensitivity syndrome--a review. J Pediatr Adolesc Gynecol. Dec 2008;21(6):305-10. [Medline].

  3. Hashmi A, Hanif F, Hanif SM, Abdullah FE, Shamim MS. Complete Androgen Insensitivity Syndrome. J Coll Physicians Surg Pak. Jul 2008;18(7):442-4. [Medline].

  4. [Best Evidence] Dejager S, Bry-Gauillard H, Bruckert E, Eymard B, Salachas F, LeGuern E, et al. A comprehensive endocrine description of Kennedy's disease revealing androgen insensitivity linked to CAG repeat length. J Clin Endocrinol Metab. August 2002;87:3893-3901. [Medline].

  5. Solari A, Groisman B, Bidondo MP, Cinca C, Alba L. [Complete androgen insensitivity syndrome: diagnosis and clinical characteristics]. Arch Argent Pediatr. Jun 2008;106(3):265-8. [Medline].

  6. 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. May 20 2009;[Medline].

  7. Winterborn MH, France NE, Raiti S. Incomplete testicular feminization. Arch Dis Child. Dec 1970;45(244):811-2. [Medline]. [Full Text].

  8. Consortium on the Management of Disorders of Sex Development. Handbook for Parents. ISNA; 2006.

  9. Garrett CC, Kirkman M. Being an XY female: an analysis of accounts from the website of the androgen insensitivity syndrome support group. Health Care Women Int. May 2009;30(5):428-46. [Medline].

  10. [Guideline] Wierman ME, Basson R, Davis SR, et al. Androgen therapy in women: an Endocrine Society Clinical Practice guideline. J Clin Endocrinol Metab. Oct 2006;91(10):3697-710. [Medline]. [Full Text].

  11. [Guideline] Tekgul S, Riedmiller H, Gerharz E, et al. Micropenis. Guidelines on paediatric urology. Mar 2009;[Full Text].

  12. Amrhein JA, Meyer WJ 3rd, Jones HW Jr, Migeon CJ. Androgen insensitivity in man: evidence for genetic heterogeneity. Proc Natl Acad Sci U S A. Mar 1976;73(3):891-4. [Medline]. [Full Text].

  13. Bals-Pratsch M, Schweikert HU, Nieschlag E. Androgen receptor disorder in three brothers with bifid prepenile scrotum and hypospadias. Acta Endocrinol (Copenh). Sep 1990;123(3):271-6. [Medline].

  14. Batch JA, Evans BA, Hughes IA, Patterson MN. Mutations of the androgen receptor gene identified in perineal hypospadias. J Med Genet. Mar 1993;30(3):198-201. [Medline]. [Full Text].

  15. Boczkowski K, Teter J. FAmilial male pseudohermaphroditism. Acta Endocr. 1965;49:497-509.

  16. Bullock LP, Bardin WC. Androgen receptors in testicular feminization. J Clin Endocrinol Metab. Dec 1972;35(6):935-7. [Medline].

  17. Charest NJ, Zhou ZX, Lubahn DB, et al. A frameshift mutation destabilizes androgen receptor messenger RNA in the Tfm mouse. Mol Endocrinol. Apr 1991;5(4):573-81. [Medline].

  18. Cheikhelard A, Morel Y, Thibaud E, Lortat-Jacob S, Jaubert F, Polak M, et al. Long-term followup and comparison between genotype and phenotype in 29 cases of complete androgen insensitivity syndrome. J Urol. Oct 2008;180(4):1496-501. [Medline].

  19. Consortium on the Management of Disorders of Sex Development. Clinical Guidelines for the Management of the Patient with a Disorder of Sex Development. ISNA; 2006.

  20. Dati E, Baroncelli GI, Mora S, Russo G, Baldinotti F, Parrini D. Body composition and metabolic profile in women with complete androgen insensitivity syndrome. Sex Dev. 2009;3(4):188-93. [Medline].

  21. Davies HR, Hughes IA, Savage MO, Quigley CA, Trifiro M, Pinsky L, et al. Androgen insensitivity with mental retardation: a contiguous gene syndrome?. J Med Genet. Feb 1997;34(2):158-60. [Medline]. [Full Text].

  22. Edwards A, Hammond HA, Jin L, et al. Genetic variation at five trimeric and tetrameric tandem repeat loci in four human population groups. Genomics. Feb 1992;12(2):241-53. [Medline].

  23. Eil C. Familial incomplete male pseudohermaphroditism associated with impaired nuclear androgen retention. Studies in cultured skin fibroblasts. J Clin Invest. Apr 1983;71(4):850-8. [Medline]. [Full Text].

  24. Finsterer J. Bulbar and spinal muscular atrophy (Kennedy's disease): a review. Eur J Neurol. May 2009;16(5):556-61. [Medline].

  25. French FS, Baggett B, Van Wyk J. Testicular feminization: clinical, morphological and biochemical studies. J Clin Endocr. 1965;25:661-77.

  26. French FS, Van Wyk JJ, Baggett B, et al. Further evidence of a target organ defect in the syndrome of testicular feminization. J Clin Endocrinol Metab. May 1966;26(5):493-503. [Medline].

  27. Galli-Tsinopoulou A, Hiort O, Schuster T, et al. A novel point mutation in the hormone binding domain of the androgen receptor associated with partial and minimal androgen insensitivity syndrome. J Pediatr Endocrinol Metab. Feb 2003;16(2):149-54. [Medline].

  28. Garrett CC, Kirkman M. Being an XY female: an analysis of accounts from the website of the androgen insensitivity syndrome support group. Health Care Women Int. May 2009;30:428-446. [Medline].

  29. Gaspar ML, Meo T, Bourgarel P, et al. A single base deletion in the Tfm androgen receptor gene creates a short-lived messenger RNA that directs internal translation initiation. Proc Natl Acad Sci U S A. Oct 1 1991;88(19):8606-10. [Medline]. [Full Text].

  30. Gerli M, Migliorini G, Bocchini V, Venti G, Ferrarese R, Donti E, et al. A case of complete testicular feminisation and 47,XXY karyotype. J Med Genet. Dec 1979;16(6):480-3. [Medline]. [Full Text].

  31. German J, Vesell M. Testicular feminization in monozygotic twins with 47 chromosomes (XXY). Ann Genet. 1966;9(1):5-8. [Medline].

  32. Girardin CM, Deal C, Lemyre E, Paquette J, Lumbroso R, Beitel LK. Molecular studies of a patient with complete androgen insensitivity and a 47,XXY karyotype. J Pediatr. Sep 2009;155(3):439-43. [Medline].

  33. Goldstein JL, Wilson JD. Studies on the pathogenesis of the pseudohermaphroditism in the mouse with testicular feminization. J Clin Invest. Jul 1972;51(7):1647-58. [Medline]. [Full Text].

  34. Griffin JE. Testicular feminization associated with a thermolabile androgen receptor in culutred human fibroblasts. J Clin Invest. Dec 1979;64(6):1624-31. [Medline].

  35. Griffin JE, Wilson JD. The syndromes of androgen resistance. N Engl J Med. Jan 24 1980;DA - 19800228(4):198-209. [Medline].

  36. 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. Apr 1988;66(4):754-61. [Medline].

  37. Hughes IA, Evans BA. Complete androgen insensitivity syndrome characterized by increased concentration of a normal androgen receptor in genital skin fibroblasts. J Clin Endocrinol Metab. Aug 1986;63(2):309-15. [Medline].

  38. Imperato-McGinley J, Ip NY, Gautier T, et al. DNA linkage analysis and studies of the androgen receptor gene in a large kindred with complete androgen insensitivity. Am J Med Genet. May 1990;36(1):104-8. [Medline].

  39. Irvine RA, Yu MC, Ross RK, Coetzee GA. The CAG and GGC microsatellites of the androgen receptor gene are in linkage disequilibrium in men with prostate cancer. Cancer Res. May 1 1995;55(9):1937-40. [Medline].

  40. Jagiello G, Atwell JD. Prevalence of testicular feminisatioon. Lancet. 1962;1:329.

  41. Jukier L, Kaufman M, Pinsky L, Peterson RE. Partial androgen resistance associated with secondary 5 alpha-reductase deficiency: identification of a novel qualitative androgen receptor defect and clinical implications. J Clin Endocrinol Metab. Oct 1984;59(4):679-88. [Medline].

  42. Kaufman M, Pinsky L, Baird PA, McGillivray BC. Complete androgen insensitivity with a normal amount of 5 alpha- dihydrotestosterone-binding activity in labium majus skin fibroblasts. Am J Med Genet. 1979;4(4):401-11. [Medline].

  43. Kaufman M, Pinsky L, Bowin A, Au MW. Familial external genital ambiguity due to a transformation defect of androgen-receptor complexes that is expressed with 5 alpha- dihydrotestosterone and the synthetic androgen methyltrienolone. Am J Med Genet. Jul 1984;18(3):493-507. [Medline].

  44. Kaufman M, Pinsky L, Feder-Hollander R. Defective up-regulation of the androgen receptor in human androgen insensitivity. Nature. Oct 29 1981;293(5835):735-7. [Medline].

  45. 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. Aug 1976;58(2):345-50. [Medline].

  46. Keenan BS, Meyer WJ 3d, Hadjian AJ, et al. Syndrome of androgen insensitivity in man: absence of 5 alpha- dihydrotestosterone binding protein in skin fibroblasts. J Clin Endocrinol Metab. Jun 1974;38(6):1143-6. [Medline].

  47. Kovacs WJ, Griffin JE, Weaver DD, Carlson BR, Wilson JD. A mutation that causes lability of the androgen receptor under conditions that normally promote transformation to the DNA-binding state. J Clin Invest. Apr 1984;73(4):1095-104. [Medline]. [Full Text].

  48. Kulshreshtha B, Philibert P, Eunice M, Audran F, Paris F, Khurana ML. Phenotype, hormonal profile and genotype of subjects with partial androgen insensitivity syndrome: report of a family with four adult males and one child with disorder of sexual differentiation. Andrologia. Aug 2009;41(4):257-63. [Medline].

  49. Liao S, Witte D. Autoimmune anti-androgen-receptor antibodies in human serum. Proc Natl Acad Sci U S A. Dec 1985;82(24):8345-8. [Medline].

  50. Lin SY, Ohno S. The binding of androgen receptor to DNA and RNA. Biochim Biophys Acta. Jul 27 1981;654(2):181-6. [Medline].

  51. Long SE, David JS. Testicular feminisation in an Ayrshire cow. Vet Rec. Aug 8 1981;109(6):116-8. [Medline].

  52. Lubs HA, Vilar O, Bergenstal DM. Familial male pseudohermaphroditism with labial testes and partial feminization: endocrine studies and genetic aspects. J Clin Endocr. 1959;19:1110-1120.

  53. Lyon MF, Hawkes SG. X-linked gene for testicular feminization in the mouse. Nature. Sep 19 1970;227(5264):1217-9. [Medline].

  54. 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. Oct 1975;41(4):751-60. [Medline].

  55. Mauvais-Jarvis P, Bercovici JP, Crepy O, Gauthier F. Studies on testosterone metabolism in subjects with testicular feminization syndrome. J Clin Invest. Jan 1970;49(1):31-40. [Medline]. [Full Text].

  56. Meyer WJ 3rd, Migeon BR, Migeon CJ. Locus on human X chromosome for dihydrotestosterone receptor and androgen insensitivity. Proc Natl Acad Sci U S A. Apr 1975;72(4):1469-72. [Medline]. [Full Text].

  57. Muller U, Schneider NR, Marks JF, et al. Maternal meiosis II nondisjunction in a case of 47,XXY testicular feminization. Hum Genet. Feb 1990;84(3):289-92. [Medline].

  58. Northcutt RC, Island DP, Liddle GW. An explanation for the target organ unresponsiveness to testosterone in the testicular feminization syndrome. J Clin Endocrinol Metab. - Liddle GW;29(3):422-5. [Medline].

  59. Oakes MB, Ezvazzadeh AD, Quint E, Smith YR. Complete androgen insensitivity syndrome - a review. J Pediatr Adolesc Gynecol. June 2008;21:305-310. [Medline].

  60. Ohno S. The Y-linked H-Y antigen locus and the X-linked Tfm locus as major regulatory genes of the mammalian sex determining mechanism. J Steroid Biochem. May 1977;8(5):585-92. [Medline].

  61. Ono S. Simplicity of mammalian regulatory systems inferred by single gene determination of sex phenotypes. Nature. Nov 19 1971;234(5325):134-7. [Medline].

  62. Opitz JM, Simpson JL, Sarto GE, et al. Pseudovaginal perineoscrotal hypospadias. Clin Genet. 1972;3(1):1-26. [Medline].

  63. Perez-Palacios G, Ortiz S, Lopez-Amor E, et al. Familial incomplete virilization due to partial end organ insensitivity to androgens. J Clin Endocrinol Metab. Nov 1975;41(5):946-52. [Medline].

  64. Philip J, Trolle D. Familial male hermaphroditism with delayed and partial masculinization. Am J Obstet Gynecol. Dec 15 1965;93(8):1076-83. [Medline].

  65. Pinsky L, Kaufman M, Killinger DW, Burko B, Shatz D, Volpe R. 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. Sep 1984;36(5):965-78. [Medline]. [Full Text].

  66. Pinsky L, Kaufman M, Levitsky LL. Partial androgen resistance due to a distinctive qualitative defect of the androgen receptor. Am J Med Genet. Jun 1987;27(2):459-66. [Medline].

  67. Pinsky L, Kaufman M, Summitt RL. Congenital androgen insensitivity due to a qualitatively abnormal androgen receptor. Am J Med Genet. 1981;10(1):91-9. [Medline].

  68. Purves JT, Miles-Thomas J, Migeon C, Gearhart JP. Complete androgen insensitivity: the role of the surgeon. J Urol. Oct 2008;180(4 Suppl):1716-9. [Medline].

  69. Quigley CA, De Bellis A, Marschke KB, et al. Androgen receptor defects: historical, clinical, and molecular perspectives. Endocrine Reviews. 1995;16:271-321.

  70. Shapiro BH, Levine DC, Adler NT. The testicular feminized rat: a naturally occurring model of androgen independent brain masculinization. Science. Jul 18 1980;209(4454):418-20. [Medline].

  71. Stenchever MA, Jones GK, Jarvis JA. Testicular feminization syndrome. Chromosomal, histologic, and genetic studies in a large kindred. Obstet Gynecol. May 1969;33(5):649-57. [Medline].

  72. Strickland AL, French FS. Absence of response to dihydrotestosterone in the syndrome of testicular feminization. J Clin Endocrinol Metab. Sep 1969;29(9):1284-6. [Medline].

  73. Takeda H, Lasnitzki I, Mizuno T. Change of mosaic pattern by androgens during prostatic bud formation in XTfm/X+ heterozygous female mice. J Endocrinol. Jul 1987;114(1):131-7. [Medline].

  74. Takeda H, Suzuki M, Lasnitzki I, Mizuno T. Visualization of X-chromosome inactivation mosaicism of Tfm gene in XTfm/X+ heterozygous female mice. J Endocrinol. Jul 1987;114(1):125-9. [Medline].

  75. Wilson BE, Reiner WG. Management of intersex: a shifting paradigm. J Clin Ethics. Winter 1998;9(4):360-9. [Medline].

  76. Wilson JD, Carlson BR, Weaver DD, et al. Endocrine and genetic characterization of cousins with male pseudohermaphroditism: evidence that the Lubs phenotype can result from a mutation that alters the structure of the androgen receptor. Clin Genet. Oct 1984;26(4):363-70. [Medline].

 
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Penoscrotal hypospadias is shown. Note the associated ventral chordee and true urethral meatus located at the scrotal level.
 
 
 
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