Androgen Insensitivity Syndrome
Androgen insensitivity syndrome (AIS), formerly known as testicular feminization, is an X-linked recessive condition resulting in a failure of normal masculinization of the external genitalia in chromosomally male individuals. This failure of virilization can be either complete androgen insensitivity syndrome (CAIS) or partial androgen insensitivity syndrome (PAIS), depending on the amount of residual receptor function. 
Both individuals with partial androgen insensitivity syndrome and individuals with complete androgen insensitivity syndrome have 46,XY karyotypes. Individuals with complete androgen insensitivity syndrome have female external genitalia with normal labia, clitoris, and vaginal introitus. [2, 3, 4, 5, 6] The phenotype of individuals with partial androgen insensitivity syndrome may range from mildly virilized female external genitalia (clitorimegaly without other external anomalies) to mildly undervirilized male external genitalia (hypospadias and/or diminished penile size).
See the image of hypospadias below.
In either case, affected individuals have normal testes with normal production of testosterone and normal conversion to dihydrotestosterone (DHT). Because the testes produce normal amounts of müllerian-inhibiting factor (MIF), also known as müllerian-inhibiting substance (MIS) or anti-müllerian hormone/factor (AMH/AMF), affected individuals do not have fallopian tubes, a uterus, or a proximal (upper) vagina.
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. 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.
Medical care for a patient with androgen insensitivity syndrome (AIS) has 2 aspects: hormone replacement therapy (HRT) and psychological support. [5, 7, 8] For individuals with androgen insensitivity syndrome, the standard of care is an orchidectomy to prevent possible malignant degeneration of the testes. 
The basic etiology of androgen insensitivity syndrome is a loss-of-function mutation in the androgen receptor (AR) gene. This AR gene has been localized to the long arm of the X chromosome (ie, Xq11-13). Over 1,000 such mutations have been described, including complete and partial gene deletions, point mutations, and small insertions/deletions. These mutations can cause a variety of functional defects, ranging from a complete loss of receptors on the cell surface because of incomplete protein synthesis to alterations in substrate binding affinity. Altered substrate binding affinity causes a signal transmission loss, despite normal cell surface receptor numbers.
While the genotypes causing complete androgen insensitivity syndrome are fairly consistent in phenotypic presentation, the genotype/phenotype relationships for the mutations causing partial androgen insensitivity syndrome remain unclear. The N-terminal domain encoded by exon 1 of the AR gene contains a substantial number of mutations. Within exon 1, CAG and and GGN repeat regions are polymorphic in length. [10, 11] Molecular phenotyping based on 5 different functional assays matched the clinical phenotype in most cases (70%). 
Loss of AR function means that, despite normal levels of androgen synthesis, the typical postreceptor events that mediate the effects of hormones on tissues do not occur. This results in the phenotype of prenatal undervirilization of external genitalia, absence of pubic and axillary hair, lack of acne, and absence of voice changes at puberty.
In Kennedy disease (spinal and bulbar muscular atrophy [SBMA]), a motor neuron disease caused by a CAG expansion in the AR gene, androgen insensitivity appears later in life, with postpubertal gynecomastia being the most common sign. Muscular weakness (amyotrophic, proximal or distal) usually occurs after the appearance of gynecomastia. Occasional sensory disturbances can occur, as well as reduced fertility. There is an expansion (>40) of a polymorphic CAG tandem-repeat in exon 1 of the androgen receptor. Mild elevation of creatine kinase may exist.  Pituitary glands in patients with Kennedy disease are larger than those in persons without androgen insensitivity. 
The best available data suggest an androgen insensitivity syndrome incidence of approximately 1 case per 20,400 liveborn males. This statistic is based on analysis of a Danish patient registry that included only hospitalized cases; thus, the true incidence of androgen insensitivity syndrome may be higher.  Complete androgen insensitivity syndrome appears more common than partial androgen insensitivity syndrome, although exact figures are unavailable. In the international disorders of sex development registry, of 649 accessible cases, 170 cases had suspected androgen insensitivity syndrome. Of these 170 cases, 19 (11%) had reported anomalies and 9 of these had confirmed androgen receptor mutations. 
All patients with androgen insensitivity syndrome are chromosomally and gonadally male. However, separating the concepts of sex and gender is crucial with these patients. The term sex is usually based on physical attributes, whereas the concept of gender is based on an individual’s self-concept and self-identification, as well as the role an individual assumes in society.
Most patients with complete androgen insensitivity syndrome have a female gender. This may be due, in part, to the patient’s role assignment and upbringing before the diagnosis or to the patient’s choice of female “sex/gender” at diagnosis. The significance of the androgen effect’s absence is increasingly recognized for its influence on the maturing brain (and other systems) in terms of developing adult gender identity. 
Partial androgen insensitivity syndrome is a more complicated problem for gender identity. Just as the genitalia may be highly varied in the degree of virilization, gender identity may be either female or male. At present, no reliable predictors of eventual gender identity have been identified, including genotype or degree of genital virilization at birth.
The medical and psychological prognosis for a woman with androgen insensitivity syndrome is excellent if she has appropriate support and counseling.
Androgen insensitivity syndrome, either complete or partial, has little medical morbidity or mortality. Complete AIS increases the risk of testicular malignancy if the testes are not removed, with risk estimated at 3.6% at 25 years and 33% at 50 years. Prepubertal malignancy in complete AIS is extremely rare. The risk of germ cell tumors (GCT) in partial AIS with untreated undescended testes is significantly greater, with estimates as high as 50%.  Not much documentation on the morbidity or mortality of these tumors specifically in individuals with androgen insensitivity syndrome is available. The tumor is considered cured without need for further therapy if it is removed while still limited to the interior of the testes capsule. The tumor is considered curable in most patients even when undetected at this early state. The use of a magnetic resonance imaging before surgery appears to be helpful in localizing and planning for removal of the gonads for malignancy risk reduction and preventing injury to other structures. 
In contrast to medical morbidity, psychological morbidity is common. Phenotypic females who are discovered to be genetic males may have psychosocial problems. These females require sensitive psychological support. Their psychosocial problems range from identity issues to problems dealing with the gender perceptions of the outside world and the style and sensitivity (or lack thereof) they encounter within the medical system.
Most affected individuals report psychological trauma at diagnosis. Their reactions to the diagnosis frequently are compounded by their interactions with the medical care system, in which they often are treated as oddities and forced to undergo multiple examinations and interviews with students and residents for teaching purposes. Even in nonteaching situations, women with androgen insensitivity syndrome report difficulties identifying offices where physicians and staff are familiar with their condition. Many of these patients have been told that they really are not women but actually are men because of the presence of a Y chromosome and testes. These difficulties and doubts often cause shame and self-doubt, as well as anger and frustration with a medical system they had expected to take care of them. There is far-reaching lack of sexual confidence and sexual satisfaction in individuals with complete androgen insensitivity syndrome.
Educate patients and families about the full nature of androgen insensitivity syndrome. Information for children can be provided in an age-appropriate format, taking care to be as accurate and understandable as possible. As the child matures, education should include information about issues such as vaginal hypoplasia and osteoporosis.
Encourage patient participation in decisions about medical and surgical alternatives. All questions must be answered completely before informed consent can be granted for irreverisble surgery involving reproductive organs. 
Mongan NP, Tadokoro-Cuccaro R, Bunch T, Hughes IA. Androgen insensitivity syndrome. Best Pract Res Clin Endocrinol Metab. 2015 Aug. 29 (4):569-80. [Medline].
Ohba K, Hayashida Y, Hakariya H, Ichinose S, Naitou S. [A case of complete androgen insensitivity syndrome]. Hinyokika Kiyo. 2009 May. 55(5):277-80. [Medline].
Oakes MB, Eyvazzadeh AD, Quint E, Smith YR. Complete androgen insensitivity syndrome–a review. J Pediatr Adolesc Gynecol. 2008 Dec. 21(6):305-10. [Medline].
Hashmi A, Hanif F, Hanif SM, Abdullah FE, Shamim MS. Complete Androgen Insensitivity Syndrome. J Coll Physicians Surg Pak. 2008 Jul. 18(7):442-4. [Medline].
Tordjman KM, Yaron M, Berkovitz A, Botchan A, Sultan C, Lumbroso S. Fertility after high-dose testosterone and intracytoplasmic sperm injection in a patient with androgen insensitivity syndrome with a previously unreported androgen receptor mutation. Andrologia. 2013 Jun 30. [Medline].
Bertelloni S, Dati E, Baroncelli GI, Hiort O. Hormonal management of complete androgen insensitivity syndrome from adolescence onward. Horm Res Paediatr. 2011. 76(6):428-33. [Medline].
Chen MJ, Vu BM, Axelrad M, Dietrich JE, Gargollo P, Gunn S, et al. Androgen Insensitivity Syndrome: Management Considerations from Infancy to Adulthood. Pediatr Endocrinol Rev. 2015 Jun. 12 (4):373-87. [Medline].
Jääskeläinen J. Molecular biology of androgen insensitivity. Mol Cell Endocrinol. 2012 Apr 16. 352(1-2):4-12. [Medline].
Gottlieb B, Beitel LK, Nadarajah A, Paliouras M, Trifiro M. The androgen receptor gene mutations database: 2012 update. Hum Mutat. 2012 May. 33(5):887-94. [Medline].
Elfferich P, van Royen ME, van de Wijngaart DJ, et al. Variable loss of functional activities of androgen receptor mutants in patients with androgen insensitivity syndrome. Sex Dev. 2013. 7(5):223-34. [Medline].
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].
Berglund A, Johannsen TH, Stochholm K, Viuff MH, Fedder J, Main KM, et al. Incidence, Prevalence, Diagnostic Delay, and Clinical Presentation of Female 46,XY Disorders of Sex Development. J Clin Endocrinol Metab. 2016 Dec. 101 (12):4532-4540. [Medline].
Cox K, Bryce J, Jiang J, et al. Novel Associations in Disorders of Sex Development: Findings From the I-DSD Registry. J Clin Endocrinol Metab. 2014 Feb. 99(2):E348-55. [Medline].
[Guideline] Hembree WC, Cohen-Kettenis PT, Gooren L, et al. Endocrine Treatment of Gender-Dysphoric/ Gender-Incongruent Persons: An Endocrine Society* Clinical Practice Guideline. J Clin Endocrinol Metab. November 2017. 102(11):1–35.
Khan S, Mannel L, Koopman CL, Chimpiri R, Hansen KR, Craig LB. The use of MRI in the pre-surgical evaluation of patients with androgen insensitivity syndrome. J Pediatr Adolesc Gynecol. 2014 Feb. 27(1):e17-20. [Medline].
Graziano K, Fallat ME. Using Shared Decision-Making Tools to Improve Care for Patients with Disorders of Sex Development. Adv Pediatr. 2016 Aug. 63 (1):473-80. [Medline].
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. 2009 May. 30(5):428-46. [Medline].
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. 2009 May 20. [Medline].
Topcu V, Ilgin-Ruhi H, Siklar Z, Karabulut HG, Berberoglu M, Hacihamdioglu B, et al. Investigation of androgen receptor gene mutations in a series of 21 patients with 46,XY disorders of sex development. J Pediatr Endocrinol Metab. 2015 Jul 21. [Medline].
Hellmann P, Christiansen P, Johannsen TH, Main KM, Duno M, Juul A. Male patients with partial androgen insensitivity syndrome: a longitudinal follow-up of growth, reproductive hormones and the development of gynaecomastia. Arch Dis Child. 2012 May. 97(5):403-9. [Medline].
Solari A, Groisman B, Bidondo MP, Cinca C, Alba L. [Complete androgen insensitivity syndrome: diagnosis and clinical characteristics]. Arch Argent Pediatr. 2008 Jun. 106(3):265-8. [Medline].
Crouch NS, Michala L, Creighton SM, Conway GS. Androgen-dependent measurements of female genitalia in women with complete androgen insensitivity syndrome. BJOG. 2011 Jan. 118(1):84-7. [Medline].
Wilson JM, Arnhym A, Champeau A, Ebbers M, Coakley F, Baskin L. Complete androgen insensitivity syndrome: an anatomic evaluation and sexual function questionnaire pilot study. J Pediatr Urol. 2011 Aug. 7(4):416-21. [Medline].
De Sousa SM, Kassahn KS, McIntyre LC, Chong CE, Scott HS, Torpy DJ. Case report of whole genome sequencing in the XY female: identification of a novel SRY mutation and revision of a misdiagnosis of androgen insensitivity syndrome. BMC Endocr Disord. 2016 Nov 8. 16 (1):58. [Medline]. [Full Text].
Becker D, Wain LM, Chong YH, Gosai SJ, Henderson NK, Milburn J, et al. Topical dihydrotestosterone to treat micropenis secondary to partial androgen insensitivity syndrome (PAIS) before, during, and after puberty – a case series. J Pediatr Endocrinol Metab. 2015 Aug 15. [Medline].
Schindler M, Fabre C, de Weille J, Carreau S, Mersel M, Bakalara N. Disruption of nongenomic testosterone signaling in a model of spinal and bulbar muscular atrophy. Mol Endocrinol. 2012 Jul. 26(7):1102-16. [Medline].
Patel V, Casey RK, Gomez-Lobo V. Timing of Gonadectomy in Patients with Complete Androgen Insensitivity Syndrome-Current Recommendations and Future Directions. J Pediatr Adolesc Gynecol. 2016 Aug. 29 (4):320-5. [Medline].
King TFJ, Wat WZM, Creighton SM, Conway GS. Bone mineral density in complete androgen insensitivity syndrome and the timing of gonadectomy. Clin Endocrinol (Oxf). 2017 Aug. 87 (2):136-140. [Medline].
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 Jun. 76(6):894-8. [Medline].
Christian A Koch, MD, PhD, FACP, MACE Professor, University of Oldenburg and Dresden, Germany; Past Professor With Tenure, Division of Endocrinology, University of Mississippi Medical Center
Christian A Koch, MD, PhD, FACP, MACE is a member of the following medical societies: American Academy of Neurology, American Association 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, German Diabetes Association
Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Novartis<br/>Received income in an amount equal to or greater than $250 from: Springer Publisher and Elsevier Publisher.
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, Society for Pediatric Research
Disclosure: Nothing to disclose.
Robert P Hoffman, MD Professor and Program Director, Department of Pediatrics, Ohio State University College of Medicine; Pediatric Endocrinologist, Division of Pediatric, Endocrinology, Diabetes, and Metabolism, Nationwide Children’s Hospital
Robert P Hoffman, MD is a member of the following medical societies: American College of Pediatricians, American Diabetes Association, American Pediatric Society, Christian Medical and Dental Associations, Endocrine Society, Midwest Society for Pediatric Research, Pediatric Endocrine Society, Society for Pediatric Research
Disclosure: Nothing to disclose.
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, Pediatric Endocrine Society, Society for Pediatric Research, Florida Chapter of The American Academy of Pediatrics, Florida Pediatric Society, International Society for Pediatric and Adolescent Diabetes
Disclosure: Nothing to disclose.
Bruce E Wilson, MD Associate Professor, Department of Pediatrics and Human Development, Michigan State University College of Human Medicine at East Lansing
Bruce E Wilson is a member of the following medical societies: American Diabetes Association, Association of Clinical Scientists, Lawson-Wilkins Pediatric Endocrine Society, and New York Academy of Sciences
Disclosure: Nothing to disclose.
Androgen Insensitivity Syndrome
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