Skip to main content

Advertisement

SpringerLink
Log in

Androgen insensitivity syndrome: a review

  • Short Review
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Purpose

Androgen insensitivity syndrome (AIS) is a disorder characterized by peripheral androgen resistance due to androgen receptor mutations in subjects with 46 XY karyotype. The severity of hormone resistance (complete, partial or mild) determines the wide spectrum of phenotypes.

Methods

We performed a literature review on Pubmed focusing on etiopathogenesis, molecular alterations, and diagnostic-therapeutic management.

Results

AIS is determined by a large variety of X-linked mutations that account for the wide phenotypic spectrum of subjects; it represents one of the most frequent disorders of sexual development (DSD). Clinical suspicion can arise at birth in partial AIS, due to the presence of variable degrees of ambiguity of the external genitalia, and at pubertal age in complete AIS, due to the development of female secondary sex characteristics, primary amenorrhea, and absence of female primary sex characteristics (uterus and ovaries). Laboratory tests showing elevated LH and testosterone levels despite mild or absent virilization may be helpful, but diagnosis can be achieved only after genetic testing (karyotype examination and androgen receptor sequencing). The clinical phenotype and especially the decision on sex assignment of the patient, if the diagnosis is made at birth or in the neonatal period, will guide the following medical, surgical and psychological management.

Conclusions

For the management of AIS, a multidisciplinary team consisting of physicians, surgeons, and psychologists is highly recommended to support the patient and his/her family on gender identity choices and subsequent appropriate therapeutic decisions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Availability of data and material

No data or material to share.

Code availability

No code to share.

References

  1. Hughes IA, Houk C, Ahmed SF, Lee PA, LWPES Consensus Group, ESPE Consensus Group (2006) Consensus statement on management of intersex disorders. Arch Dis Child 91(7):554–563. https://doi.org/10.1136/adc.2006.098319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hughes IA, Davies JD, Bunch TI, Pasterski V, Mastroyannopoulou K, MacDougall J (2012) Androgen insensitivity syndrome. Lancet 380(9851):1419–1428. https://doi.org/10.1016/S0140-6736(12)60071-3

    Article  CAS  PubMed  Google Scholar 

  3. Bertelloni S, Dati E, Baroncelli GI, Hiort O (2011) Hormonal management of complete androgen insensitivity syndrome from adolescence onward. Horm Res Paediatr 76(6):428–433. https://doi.org/10.1159/000334162

    Article  CAS  PubMed  Google Scholar 

  4. Berglund A, Johannsen TH, Stochholm K, Viuff MH, Fedder J, Main KM, Gravholt CH (2016) Incidence, prevalence, diagnostic delay, and clinical presentation of female 46, XY disorders of sex development. J Clin Endocrinol Metab 101(12):4532–4540. https://doi.org/10.1210/jc.2016-2248

    Article  CAS  PubMed  Google Scholar 

  5. Boehmer AL, Brinkmann O, Brüggenwirth H, van Assendelft C, Otten BJ, Verleun-Mooijman MC, Niermeijer MF, Brunner HG, Rouwé CW, Waelkens JJ, Oostdijk W, Kleijer WJ, van der Kwast TH, de Vroede MA, Drop SL (2001) Genotype versus phenotype in families with androgen insensitivity syndrome. J Clin Endocrinol Metab 86(9):4151–4160. https://doi.org/10.1210/jcem.86.9.7825

    Article  CAS  PubMed  Google Scholar 

  6. Quigley CA, De Bellis A, Marschke KB, el-Awady MK, Wilson EM, French FS (1995) Androgen receptor defects: historical, clinical, and molecular perspectives. Endocr Rev 16(3):271–321. https://doi.org/10.1210/edrv-16-3-271

    Article  CAS  PubMed  Google Scholar 

  7. Bhandari RK, Haque MM, Skinner MK (2012) Global genome analysis of the downstream binding targets of testis determining factor SRY and SOX9. PLoS ONE 7(9):e43380. https://doi.org/10.1371/journal.pone.0043380. (Epub 2012 Sep 12)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sekido R, Lovell-Badge R (2008) Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer. Nature 453(7197):930–934. https://doi.org/10.1038/nature06944. (Epub 2008 May 4. Erratum in: Nature. 2008 Dec 11;456(7223):824)

    Article  CAS  PubMed  Google Scholar 

  9. Ostrer H, Huang HY, Masch RJ, Shapiro E (2007) A cellular study of human testis development. Sex Dev 1(5):286–292. https://doi.org/10.1159/000108930

    Article  CAS  PubMed  Google Scholar 

  10. Pellegrino M, Maiorino R, Schonauer S (2010) WNT4 signaling in female gonadal development. Endocr Metab Immune Disord Drug Targets 10(2):168–174. https://doi.org/10.2174/187153010791213074

    Article  CAS  PubMed  Google Scholar 

  11. Nassar GN, Leslie SW (2023) Physiology, Testosterone. 2023 Jan 2. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing

  12. Reyes FI, Boroditsky RS, Winter JS, Faiman C (1974) Studies on human sexual development. II. Fetal and maternal serum gonadotropin and sex steroid concentrations. J Clin Endocrinol Metab 38(4):612–617. https://doi.org/10.1210/jcem-38-4-612

    Article  CAS  PubMed  Google Scholar 

  13. Nagamani M, McDonough PG, Ellegood JO, Mahesh VB (1979) Maternal and amniotic fluid steroids throughout human pregnancy. Am J Obstet Gynecol 134(6):674–680. https://doi.org/10.1016/0002-9378(79)90649-5

    Article  CAS  PubMed  Google Scholar 

  14. Winter JS, Hughes IA, Reyes FI, Faiman C (1976) Pituitary-gonadal relations in infancy: 2. Patterns of serum gonadal steroid concentrations in man from birth to two years of age. J Clin Endocrinol Metab 42(4):679–686. https://doi.org/10.1210/jcem-42-4-679

    Article  CAS  PubMed  Google Scholar 

  15. Kuiri-Hänninen T, Sankilampi U, Dunkel L (2014) Activation of the hypothalamic-pituitary-gonadal axis in infancy: minipuberty. Horm Res Paediatr 82(2):73–80. https://doi.org/10.1159/000362414

    Article  CAS  PubMed  Google Scholar 

  16. Bakker J, Brock O (2010) Early oestrogens in shaping reproductive networks: evidence for a potential organisational role of estradiol in female brain development. J Neuroendocrinol 22(7):728–735. https://doi.org/10.1111/j.1365-2826.2010.02016.x

    Article  CAS  PubMed  Google Scholar 

  17. Arnold AP, Xu J, Grisham W, Chen X, Kim YH, Itoh Y (2004) Minireview: sex chromosomes and brain sexual differentiation. Endocrinology 145(3):1057–1062. https://doi.org/10.1210/en.2003-1491

    Article  CAS  PubMed  Google Scholar 

  18. Masica DN, Money J, Ehrhardt AA (1971) Fetal feminization and female gender identity in the testicular feminizing syndrome of androgen insensitivity. Arch Sex Behav 1(2):131–142. https://doi.org/10.1007/BF01541057

    Article  CAS  PubMed  Google Scholar 

  19. Hines M, Ahmed SF, Hughes IA (2003) Psychological outcomes and gender-related development in complete androgen insensitivity syndrome. Arch Sex Behav 32(2):93–101. https://doi.org/10.1023/a:1022492106974

    Article  PubMed  Google Scholar 

  20. T’Sjoen G, De Cuypere G, Monstrey S, Hoebeke P, Freedman FK, Appari M, Holterhus PM, Van Borsel J, Cools M (2011) Male gender identity in complete androgen insensitivity syndrome. Arch Sex Behav 40(3):635–638. https://doi.org/10.1007/s10508-010-9624-1

    Article  PubMed  Google Scholar 

  21. Brunner F, Fliegner M, Krupp K, Rall K, Brucker S, Richter-Appelt H (2016) Gender role, gender identity and sexual orientation in CAIS (“XY-Women”) compared with subfertile and infertile 46,XX Women. J Sex Res 53(1):109–124. https://doi.org/10.1080/00224499.2014.1002124

    Article  PubMed  Google Scholar 

  22. Savic I, Frisen L, Manzouri A, Nordenstrom A, Lindén Hirschberg A (2017) Role of testosterone and Y chromosome genes for the masculinization of the human brain. Hum Brain Mapp 38(4):1801–1814. https://doi.org/10.1002/hbm.23483

    Article  PubMed  PubMed Central  Google Scholar 

  23. Gottlieb B, Beitel LK, Nadarajah A, Paliouras M, Trifiro M (2012) The androgen receptor gene mutations database: 2012 update. Hum Mutat 33(5):887–894. https://doi.org/10.1002/humu.22046. (Epub 2012 Mar 13)

    Article  CAS  PubMed  Google Scholar 

  24. Zhou D, Xu H, Shen X, Gu R, Chen Y, Chen G, Li P, Shi H, Sun X, Xin A (2022) Complete androgen insensitivity syndrome caused by a novel mutation in the androgen receptor gene and its mechanism. Clin Chim Acta 531:94–99. https://doi.org/10.1016/j.cca.2022.03.021

    Article  CAS  PubMed  Google Scholar 

  25. Chen G, Zhao D, Zhu L, Zhao Y, Zhang J, Wang X, Tian H, Tang D, Shu Q, Qiao S (2022) Novel androgen receptor gene variant containing a frameshift mutation in a patient with complete androgen insensitivity syndrome. Andrologia 54(2):e14292. https://doi.org/10.1111/and.14292

    Article  CAS  PubMed  Google Scholar 

  26. Zhang D, Yao F, Tian T, Deng S, Luo M, Tian Q (2021) Clinical characteristics and molecular genetics of complete androgen insensitivity syndrome patients: a series study of 30 cases from a Chinese tertiary medical center. Fertil Steril 115(5):1270–1279. https://doi.org/10.1016/j.fertnstert.2020.12.008

    Article  CAS  PubMed  Google Scholar 

  27. De Conti L, Baralle M, Buratti E (2013) Exon and intron definition in pre-mRNA splicing. Wiley Interdiscip Rev RNA 4(1):49–60. https://doi.org/10.1002/wrna.1140

    Article  CAS  PubMed  Google Scholar 

  28. Batista RL, Rodrigues AS, Nishi MY, Feitosa ACR, Gomes NLRA, Junior JAF, Domenice S, Costa EMF, de Mendonça BB (2017) Heterozygous nonsense mutation in the androgen receptor gene associated with partial androgen insensitivity syndrome in an individual with 47,XXY Karyotype. Sex Dev 11(2):78–81. https://doi.org/10.1159/000468957

    Article  CAS  PubMed  Google Scholar 

  29. Hornig NC, Holterhus PM (2021) Molecular basis of androgen insensitivity syndromes. Mol Cell Endocrinol 523:111146. https://doi.org/10.1016/j.mce.2020.111146

    Article  CAS  PubMed  Google Scholar 

  30. Hughes IA, Werner R, Bunch T, Hiort O (2012) Androgen insensitivity syndrome. Semin Reprod Med 30(5):432–442. https://doi.org/10.1055/s-0032-1324728

    Article  CAS  PubMed  Google Scholar 

  31. Cools M, Drop SL, Wolffenbuttel KP, Oosterhuis JW, Looijenga LH (2006) Germ cell tumors in the intersex gonad: old paths, new directions, moving frontiers. Endocr Rev 27(5):468–484. https://doi.org/10.1210/er.2006-0005

    Article  CAS  PubMed  Google Scholar 

  32. Bouvattier C, Carel JC, Lecointre C, David A, Sultan C, Bertrand AM, Morel Y, Chaussain JL (2002) Postnatal changes of T, LH, and FSH in 46, XY infants with mutations in the AR gene. J Clin Endocrinol Metab 87(1):29–32. https://doi.org/10.1210/jcem.87.1.7923

    Article  CAS  PubMed  Google Scholar 

  33. Hellmann P, Christiansen P, Johannsen TH, Main KM, Duno M, Juul A (2012) Male patients with partial androgen insensitivity syndrome: a longitudinal follow-up of growth, reproductive hormones and the development of gynaecomastia. Arch Dis Child 97(5):403–409. https://doi.org/10.1136/archdischild-2011-300584

    Article  PubMed  Google Scholar 

  34. Griffin JE, Edwards C, Madden JD, Harrod MJ, Wilson JD (1976) Congenital absence of the vagina. The Mayer-Rokitansky-Kuster-Hauser syndrome. Ann Intern Med 85(2):224–236. https://doi.org/10.7326/0003-4819-85-2-224

    Article  CAS  PubMed  Google Scholar 

  35. Singh S, Ilyayeva S (2022) Androgen Insensitivity Syndrome (2022) In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 31194363.

  36. Savage MO, Chaussain JL, Evain D, Roger M, Canlorbe P, Job JC (1978) Endocrine studies in male pseudohermaphroditism in childhood and adolescence. Clin Endocrinol (Oxf) 8(3):219–231. https://doi.org/10.1111/j.1365-2265.1978.tb01498.x

    Article  CAS  PubMed  Google Scholar 

  37. Han B, Zhu H, Yao H, Ren J, O’Day P, Wang H, Zhu W, Cheng T, Auchus RJ, Qiao J (2022) Differences of adrenal-derived androgens in 5α-reductase deficiency versus androgen insensitivity syndrome. Clin Transl Sci 15(3):658–666. https://doi.org/10.1111/cts.13184

    Article  CAS  PubMed  Google Scholar 

  38. Dahiya S, Singh M, Mandal S, Jain SL, Rathore A, Lal P (2022) Androgen insensitivity syndrome: can cytology help? Cytopathology 33(2):249–252. https://doi.org/10.1111/cyt.13064

    Article  PubMed  Google Scholar 

  39. Hannema SE, Scott IS, Rajpert-De Meyts E, Skakkebaek NE, Coleman N, Hughes IA (2006) Testicular development in the complete androgen insensitivity syndrome. J Pathol 208(4):518–527. https://doi.org/10.1002/path.1890

    Article  CAS  PubMed  Google Scholar 

  40. Birnbaum W, Bertelloni S (2014) Sex hormone replacement in disorders of sex development. Endocr Dev 27:149–159. https://doi.org/10.1159/000363640

    Article  PubMed  Google Scholar 

  41. Birnbaum W, Marshall L, Werner R, Kulle A, Holterhus PM, Rall K, Köhler B, Richter-Unruh A, Hartmann MF, Wudy SA, Auer MK, Lux A, Kropf S, Hiort O (2018) Oestrogen versus androgen in hormone-replacement therapy for complete androgen insensitivity syndrome: a multicentre, randomised, double-dummy, double-blind crossover trial. Lancet Diabetes Endocrinol 6(10):771–780. https://doi.org/10.1016/S2213-8587(18)30197-9

    Article  CAS  PubMed  Google Scholar 

  42. Reddy DS (2004) Testosterone modulation of seizure susceptibility is mediated by neurosteroids 3alpha-androstanediol and 17beta-estradiol. Neuroscience 129(1):195–207. https://doi.org/10.1016/j.neuroscience.2004.08.002

    Article  CAS  PubMed  Google Scholar 

  43. Auer MK, Birnbaum W, Hartmann MF, Holterhus PM, Kulle A, Lux A, Marshall L, Rall K, Richter-Unruh A, Werner R, Wudy SA, Hiort O (2022) Metabolic effects of estradiol versus testosterone in complete androgen insensitivity syndrome. Endocrine 76(3):722–732. https://doi.org/10.1007/s12020-022-03017-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Poujol N, Lobaccaro JM, Chiche L, Lumbroso S, Sultan C (1997) Functional and structural analysis of R607Q and R608K androgen receptor substitutions associated with male breast cancer. Mol Cell Endocrinol 130(1–2):43–51. https://doi.org/10.1016/s0303-7207(97)00072-5

    Article  CAS  PubMed  Google Scholar 

  45. Amies Oelschlager AM, Debiec K (2019) Vaginal dilator therapy: a guide for providers for assessing readiness and supporting patients through the process successfully. J Pediatr Adolesc Gynecol 32(4):354–358. https://doi.org/10.1016/j.jpag.2019.05.002

    Article  PubMed  Google Scholar 

  46. Levin HS (2000) Tumors of the testis in intersex syndromes. Urol Clin North Am 27(3):543–551. https://doi.org/10.1016/s0094-0143(05)70101-4

    Article  CAS  PubMed  Google Scholar 

  47. Rajpert-de Meyts E, Hoei-Hansen CE (2007) From gonocytes to testicular cancer: the role of impaired gonadal development. Ann N Y Acad Sci 1120:168–180. https://doi.org/10.1196/annals.1411.013

    Article  CAS  PubMed  Google Scholar 

  48. Deans R, Creighton SM, Liao LM, Conway GS (2012) Timing of gonadectomy in adult women with complete androgen insensitivity syndrome (CAIS): patient preferences and clinical evidence. Clin Endocrinol (Oxf) 76(6):894–898. https://doi.org/10.1111/j.1365-2265.2012.04330.x

    Article  PubMed  Google Scholar 

  49. Barros BA, Oliveira LR, Surur CRC, Barros-Filho AA, Maciel-Guerra AT, Guerra-Junior G (2021) Complete androgen insensitivity syndrome and risk of gonadal malignancy: systematic review. Ann Pediatr Endocrinol Metab 26(1):19–23. https://doi.org/10.6065/apem.2040170.085

    Article  PubMed  PubMed Central  Google Scholar 

  50. Cheikhelard A, Morel Y, Thibaud E, Lortat-Jacob S, Jaubert F, Polak M, Nihoul-Fekete C (2008) Long-term followup and comparison between genotype and phenotype in 29 cases of complete androgen insensitivity syndrome. J Urol 180(4):1496–1501. https://doi.org/10.1016/j.juro.2008.06.045

    Article  PubMed  Google Scholar 

  51. Coutant R, de Casson FB, Rouleau S, Douay O, Mathieu E, Gatelais F, Bouhours-Nouet N, Voinot C, Audran M, Limal JM (2004) Divergent effect of endogenous and exogenous sex steroids on the insulin-like growth factor I response to growth hormone in short normal adolescents. J Clin Endocrinol Metab 89(12):6185–6192. https://doi.org/10.1210/jc.2004-0814

    Article  CAS  PubMed  Google Scholar 

  52. Perry RJ, Farquharson C, Ahmed SF (2008) The role of sex steroids in controlling pubertal growth. Clin Endocrinol (Oxf) 68(1):4–15. https://doi.org/10.1111/j.1365-2265.2007.02960.x

    Article  CAS  PubMed  Google Scholar 

  53. Ferlin A, Selice R, Carraro U, Foresta C (2013) Testicular function and bone metabolism–beyond testosterone. Nat Rev Endocrinol 9(9):548–554. https://doi.org/10.1038/nrendo.2013.135

    Article  CAS  PubMed  Google Scholar 

  54. Döhnert U, Wünsch L, Hiort O (2017) Gonadectomy in complete androgen insensitivity syndrome: why and when? Sex Dev 11(4):171–174. https://doi.org/10.1159/000478082

    Article  CAS  PubMed  Google Scholar 

  55. Tack LJW, Maris E, Looijenga LHJ, Hannema SE, Audi L, Köhler B, Holterhus PM, Riedl S, Wisniewski A, Flück CE, Davies JH, T’Sjoen G, Lucas-Herald AK, Evliyaoglu O, Krone N, Iotova V, Marginean O, Balsamo A, Verkauskas G, Weintrob N, Ellaithi M, Nordenström A, Verrijn Stuart A, Kluivers KB, Wolffenbuttel KP, Ahmed SF, Cools M (2018) Management of gonads in adults with androgen insensitivity: an international survey. Horm Res Paediatr 90(4):236–246. https://doi.org/10.1159/000493645

    Article  CAS  PubMed  Google Scholar 

  56. Lucas-Herald A, Bertelloni S, Juul A, Bryce J, Jiang J, Rodie M, Sinnott R, Boroujerdi M, Lindhardt Johansen M, Hiort O, Holterhus PM, Cools M, Guaragna-Filho G, Guerra-Junior G, Weintrob N, Hannema S, Drop S, Guran T, Darendeliler F, Nordenstrom A, Hughes IA, Acerini C, Tadokoro-Cuccaro R, Ahmed SF (2016) The long-term outcome of boys with partial androgen insensitivity syndrome and a mutation in the androgen receptor gene. J Clin Endocrinol Metab 101(11):3959–3967. https://doi.org/10.1210/jc.2016-1372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Bouvattier C, Mignot B, Lefèvre H, Morel Y, Bougnères P (2006) Impaired sexual activity in male adults with partial androgen insensitivity. J Clin Endocrinol Metab 91(9):3310–3315. https://doi.org/10.1210/jc.2006-0218

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by MIUR-PRIN2017- 2017S9KTNE_003.

Author information

Author notes

  1. E. D. Paoli and S. Di Chiano contributed equally.

Authors and Affiliations

  1. Laboratory of Seminology‑Sperm Bank “Loredana Gandini”, Department of Experimental Medicine, “Sapienza” University of Rome, Viale del Policlinico 155, 00161, Rome, Italy

    E. Delli Paoli, S. Di Chiano, D. Paoli, A. Lenzi, F. Lombardo & F. Pallotti

  2. Faculty of Medicine and Surgery, University of Enna “Kore”, Contrada Santa Panasia, 94100, Enna, Italy

    F. Pallotti

Authors
  1. E. Delli Paoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Di Chiano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. Paoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Lenzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. F. Lombardo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. F. Pallotti
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

EDP, SDC, FL, FP conceived the present study. EDP, SDC performed literature review and drafted the first version of the manuscript. FP, DP, AL and FL revised the final version. All Authors critically revised subsequent versions of the manuscript and approved the final version.

Corresponding author

Correspondence to F. Pallotti.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

No approval needed.

Research involving human participants and/or animals

No patient/animal was involved in the present research.

Consent to participate

Not applicable.

Consent for publication

All Authors give consent for publication.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Delli Paoli, E., Di Chiano, S., Paoli, D. et al. Androgen insensitivity syndrome: a review. J Endocrinol Invest 46, 2237–2245 (2023). https://doi.org/10.1007/s40618-023-02127-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-023-02127-y

Keywords

Search

Navigation