Androgen insensitivity syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Reddy Kothagadi M.B.B.S[2]

Androgen insensitivity syndrome is due to hormone resistance which may be due to defective androgen receptor (AR) function by either abnormal androgen receptor (AR) binding, decreased receptor binding, or impaired androgen receptor (AR) binding. AIS is an X linked disorder. The development of Androgen insensitivity syndrome is a result of genetic mutations of the androgen receptor (AR) gene located on the chromosome Xq11-12. Associated conditions include primary amenorrhea, infertility and dyspareunia. Androgen receptor (AR) gene defects inhibit the normal development of both internal and external genital structures in 46XY individuals, causing a variety of phenotypes ranging from male infertility to completely normal female external genitalia. Androgen insensitivity syndrome (AIS) represents a spectrum of defects in androgen action and can be subdivided into three broad phenotypes such as complete, partial and mild AIS. A multidisciplinary approach is recommended for clinical management from infancy through to adulthood. Hormone replacement therapy is needed following gonadectomy. Patients who have decided to retain their gonads are considered to be at risk for developing germ cell tumors and for these the sensitive circulating tumor markers may become available soon. Surgical approach to the Androgen insensitivity syndrome involves vaginal dilation or gonadectomy or determination of sex which depend on various factors such as the type of AIS, age, sex and preventive measures to be taken in adolescence and adulthood.

In 1953, the first medical report on AIS was published by J. M. Morris, an american gynecologist. In 1989, the exact location of the human Androgen receptor (AR) gene on Xq11-12 locus was determined and the proof that it is caused by mutations in this gene.

Androgen insensitivity syndrome (AIS) represents a spectrum of defects in androgen action and can be subdivided into three broad phenotypes such as complete, partial and mild AIS.

It is thought that Androgen insensitivity syndrome is caused due to hormone resistance which may be due to defective androgen receptor (AR) function by either abnormal androgen receptor (AR) binding, decreased receptor binding, or impaired androgen receptor (AR) binding. AIS is an X linked disorder. The development of Androgen insensitivity syndrome is a result of genetic mutations of the androgen receptor (AR) gene located on the chromosome Xq11-12. Associated conditions include primary amenorrhea, infertility and dyspareunia.

Androgen insensitivity syndrome is caused due to mutations in the X-linked androgen receptor gene. Androgen receptor (AR) gene defects inhibit the normal development of both internal and external genital structures in 46XY individuals, causing a variety of phenotypes ranging from male infertility to completely normal female external genitalia.

Androgen insensitivity syndrome must be differentiated from other conditions based on the genotype, phenotype and developmental characteristics.

CAIS has a prevalence of 2 per 100,000 to 5 per 100,000. The incidence of complete AIS is about in 5 in 100,000. There is no racial predilection for androgen insensitivity syndrome.

The risk of gonadal germ cell tumor is low during childhood and adolescence but increases in later adulthood. Benign tumors of nongerminomatous germ cell tumor include Sertoli cell adenoma and hamartomas.

The diagnosis of AIS is mostly made post-natally. Studies have shown that the AIS may be identified prenatally by imaging techniques and comparative study such as preimplantation genetic screening, noninvasive prenatal screening and ultrasonography.

If left untreated, androgen insensitivity syndrome may lead to cancers of the male breast, larynx, liver, testes and bladder. Common complications of androgen insensitivity syndrome include Infertility, psychological and social issues, osteoporosis, and cancers. Prognosis is good after orchidectomy at the proper time. For incomplete AIS patients, it depends on the presence and severity of ambiguous genitalia.

The diagnosis of AIS is determined in a 46,XY individual by the undermasculinization of the external genitalia, impaired spermatogenesis and absent or rudimentary müllerian structures. Cases of CAIS are diagnosed during abdominal surgery, delayed menarche and infertility.

Androgen insensitivity syndrome (AIS) is typically characterized by evidence of feminization (i.e., undermasculinization) of the external genitalia at birth, abnormal secondary sexual development in puberty, and infertility in individuals with a 46,XY karyotype.

Laboratory findings which suggest the presence of normal or increased synthesis of testosterone and its normal conversion to dihydrotestosterone, and normal or increased luteinizing hormone (LH) production by the pituitary gland AND/OR by the identification of a hemizygous pathogenic variant.

There are no ECG findings observed in androgen insensitivity syndrome.

There are no X-ray findings associated with androgen insensitivity syndrome.

Pelvic ultrasound helps in determining the presence or absence of uterus and gonads.

Findings of seminoma are observed by FDG PET/CT in androgen insensitivity syndrome. Incidental detection of sertoli-Leydig cell tumor by FDG PET/CT imaging.

MRI may be helpful in the diagnosis of Androgen insensitivity syndrome. MRI may be helpful in localizing the testes, diagnosing malignancy in cryptorchid testes and describing mullerian duct anomalies.

There are no other imaging findings associated with androgen insensitivity syndrome.

There are no other diagnostic studies associated with androgen insensitivity syndrome.

A multidisciplinary approach is recommended for clinical management from infancy through to adulthood. Hormone replacement therapy is needed following gonadectomy. Patients who choose to retain the gonads are at risk of developing germ cell tumors for which sensitive circulating tumor markers may soon become available.

Surgical approach to the Androgen insensitivity syndrome involves vaginal dilation or gonadectomy or determination of sex which depend on various factors such as the type of AIS, age, sex and preventive measures to be taken in adolescence and adulthood.

Currently there are no established methods to prevent androgen insensitivity syndrome (AIS). However, various treatment options may help manage the symptoms of AIS. Genetic counseling is advisable for parents as well as the affected individuals. The use of preimplantation genetic screening, noninvasive prenatal screening and ultrasonography and laparoscopic surgery may help identify, prevent or rectify accordingly. Women with CAIS have decreased bone mineral density, regardless of timing of gonadectomy.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Reddy Kothagadi M.B.B.S[2]

In 1953, the first medical report on Androgen insensitivity syndrome (AIS) was published by J. M. Morris, an American gynecologist. In 1989, the exact location of the human Androgen receptor (AR) gene on Xq11-12 locus was determined and the proof that it is caused by mutations in this gene.

• In 1953, the first medical report on Androgen insensitivity syndrome (AIS) was published by J. M. Morris, an American gynecologist.^{[1][2][3][4][5]}
• Until the late 1950s, Morris’ approach to non-disclosure was consonant with the prevailing medicolegal and ethical climate.^[4]
• In 1988, Minogue and Taraszewski argued that the condition of the patient could not be revealed if the clinician felt that the patient or the patient’s family weren’t in a state to handle the truth about the patient’s condition.^[6][4]
• In 1989, the exact location of the human Androgen receptor (AR) gene on Xq11-12 locus was determined and the proof that it is caused by mutations in this gene.^[7][8][9]
• Until the 1990s, revealing the genotype in CAIS after diagnosis was common. ^[4]
• In 1992, Shah argued that disclosing the genotype is not much relevant to care and as it may be confusing to patient and family.^[4]
• In 1997, Weiner et al expressed his opinion that it was a complex situation whether to tell a patient about her genetic make-up or not as it was questionable topic to deal with. ^[10]

One might fairly call Reifenstein syndrome “even more partial” AIS, but when E.C. Reifenstein described the features of a new syndrome of male “familial hypogonadism” in 1947, it was not known that this condition was due to an abnormal androgen receptor and related to the female conditions of CAIS (complete androgen insensitivity syndrome) or PAIS (partial androgen insensitivity syndrome). Additional familial intersex and hypogonadal conditions described by Lubs, Gilbert, Dreyfus, Rosewater, Walker, and others are now considered variants of the Reifenstein syndrome form of AIS. ^[11]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Reddy Kothagadi M.B.B.S[2]

Androgen insensitivity syndrome (AIS) represents a spectrum of defects in androgen action and can be subdivided into three broad phenotypes into complete androgen insensitivity syndrome (CAIS), mild androgen insensitivity syndrome (MAIS) and partial androgen insensitivity syndrome (PAIS).

• Based on the degree of genital masculinization, androgen insensitivity syndrome is divided into three categories:^[1][2][3][4]

• When the external genitalia is that of a normal female it is classified as complete androgen insensitivity syndrome (CAIS)
• When the external genitalia is that of a normal male it is classified as mild androgen insensitivity syndrome (MAIS)
• When the external genitalia is partially, but not fully masculinized it is classified as partial androgen insensitivity syndrome (PAIS)

• Individuals with both partial androgen insensitivity syndrome (PAIS) and complete androgen insensitivity syndrome (CAIS) have 46 XY karyotypes. ^[1]

Classification of Androgen Insensitivity Syndrome Phenotypes:’ ^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Reddy Kothagadi M.B.B.S[2]

Androgen insensitivity syndrome is due to hormone resistance which may be due to defective androgen receptor (AR) function by either abnormal androgen receptor (AR) binding, decreased receptor binding, or impaired androgen receptor (AR) binding. AIS is an X linked disorder. The development of androgen insensitivity syndrome is a result of genetic mutations of the androgen receptor (AR) gene located on the chromosome Xq11-12. Associated conditions include primary amenorrhea, infertility and dyspareunia.

• Androgen resistance may develop during fetal development and after birth.
• The hormone resistance may be due to defective androgen receptor (AR) function by either abnormal androgen receptor (AR) binding, decreased receptor binding, or impaired androgen receptor (AR) binding. ^[1][2][3]
• A spectrum of phenotypes may be caused due to missense mutations in the androgen receptor (AR) protein. The two important domains of the receptor protein namely DBD and LDB domains are the ones wherein the most frequent missense mutations are found.^[4][5]
• The phenotypic variability impacts and translates the degree to which ligand-binding and receptor functions are disrupted by different substitutions.^[4][6]
• The genetic background has an influence on the resulting phenotype as a result of the same mutation which may lead to different forms of AIS within a family.^[4][7]
• Mutations in the androgen receptor (AR) gene helps as a trusted tool for the diagnosis and molecular subclassification of AIS. The resulting phenotype is affected by the kind of amino acid substitution occurring due to mutation.^[4]
• Information regarding the mutation in the androgen receptor (AR) and its functional consequences helps in determining the genotype-phenotype correlation, to improve and better manage the cases of male pseudohermaphroditism pertaining to surgery of the genitalia, gonadectomy and gender assignment. ^[4]
• The lack of virilization of external genitalia is due to the failure of genital folds to fuse and to form scrotum and penis.
• The agenesis of the fallopian tubes, uterus, cervix and proximal vagina is due to the simultaneous testicular production of mullerian inhibiting factor which regresses the mullerian structures.
• In CAIS (complete androgen insensitivity syndrome), the development of the wolffian duct and the differentiation of male external genitalia do not occur correctly, and the Mullerian ducts regress due to the presence of anti-Mullerian hormone (AMH) produced by the sertoli cells of normally developed gonads. The residual Mullerian structures exist in approximately one third of patients. ^{[8] [9]}
• The female phenotype along with breast development is a result of the peripheral aromatization of testosterone into estrogen.^[10]
• As a result of the defective androgen receptor (AR) due to imperfect feedback mechanism of testosterone at the pituitary and hypothalamus there are elevated levels of serum testosterone, FSH and LH observed.
• Testosterone biosynthetic defects are ruled out by the normal serum 17α hydroxyprogesterone, DHEA and androstenedione levels.^[11]
• Sufficient peripheral conversion of testosterone is indicative of normal estradiol level.

• AIS is an X linked disorder. ^[12]
• A high proportion of De novo mutations arise after the zygote stage which occur at a high rate within the androgen receptor (AR) gene.^[12]
• Spontaneous mutations in the androgen receptor (AR) gene results in androgen insensitivity syndrome even without any family history.^[12]
• The development of androgen insensitivity syndrome is a result of genetic mutations of the androgen receptor (AR) gene located on the chromosome Xq11-12.^[4][12]
• Different mutations in the androgen receptor (AR) gene leads to varied clinical phenotypes.^[13][14]
• There have been more than 800 mutations in the androgen receptor (AR) gene reported in AIS patients. ^[15]

• Primary amenorrhea
• Infertility
• Dyspareunia
• Common testicular tumors seen in the Androgen insensitivity syndrome are: ^[16]

• Germ cell tumors
• Sex cord tumors (seminoma)
• Sertoli cell tumors
• Leydig cell tumors
• Hamartomas

• Complete androgen insensitivity syndrome in a 30 years old woman presenting with primary amenorrhea.^[17]. ^[18]

• 
  Front and side view of the patient by Regragui Souhail et al from The Pan African Medical Journal – ISSN 1937-8688. Pan Afr Med J. 2016;25:199. Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0). ^[17]
• 
  Clinical aspect of the vagina by Regragui Souhail et al from The Pan African Medical Journal – ISSN 1937-8688. Pan Afr Med J. 2016;25:199. Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0). ^[17]
• 
  Intra- abdominal testes – Laparoscopic aspect by Regragui Souhail et al from The Pan African Medical Journal – ISSN 1937-8688. Pan Afr Med J. 2016;25:199. Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0). ^[17]
• 
  The excised testis – Macroscopic aspect by Regragui Souhail et al from The Pan African Medical Journal – ISSN 1937-8688. Pan Afr Med J. 2016;25:199. Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0). ^[17]

• Histopathology of testes shows atrophic seminiferous tubules containing only sertoli cells, associated to a leydig cells hyperplasia.^[18]
• The well-limited nodule presents as a circumscribed structure with a thin capsule consisting of atrophic servolian tubes with a very small interstitial tissue with rare leydig cells. This nodule corresponds to a well differentiated tumor with sertoli-leydig cells. ^[17]
• The gonads on histopathological examination show the following: ^[16]

• Thickened tunica albuginea
• Seminiferous tubules with primary and secondary spermatogonia and sertoli cells
• Intertubular leydig cells were seen along with peritubular fibrosis

• 
  Testes – Atrophy of the seminiferous tubules – Histopathological aspect, HE staining by Regragui Souhail et al from The Pan African Medical Journal – ISSN 1937-8688. Pan Afr Med J. 2016;25:199. Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0). ^[17]
• 
  Testicular parenchyma of lobulated architecture, made of seminiferous tubes of atrophic appearance; these tubes are lined with Sertolia cells, with no obvious signs of spermatogenesis the interstitium is fibrous with rare clusters of Leydig cells by Boutaina Lachiri et al from the Pan African Medical Journal – ISSN 1937-8688. Pan Afr Med J. 2015;20:400. CC BY-NC 3.0, Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/3.0). ^[18]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Reddy Kothagadi M.B.B.S[2]

Androgen insensitivity syndrome is due to mutations in the X-linked androgen receptor gene. Androgen receptor (AR) gene defects inhibit the normal development of both internal and external genital structures in 46XY individuals, causing a variety of phenotypes ranging from male infertility to completely normal female external genitalia.

• Androgen insensitivity syndrome is due to mutations in the X-linked androgen receptor (AR) gene, which encodes for the ligand-activated androgen receptor – a transcription factor.^[1]
• Defects in the androgen receptor (AR) gene prevent the normal development of both internal and external genital structures in 46XY individuals, causing a variety of phenotypes ranging from male infertility to completely normal female external genitalia. ^[2]
• There have been more than 800 mutations in the androgen receptor (AR) gene reported in AIS patients. ^[3]
• AIS phenotype majorly depends on the degree of residual androgen receptor (AR) activity.
• Most severe mutations are generally associated with a CAIS phenotype.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Reddy Kothagadi M.B.B.S[2]

Androgen insensitivity syndrome must be differentiated from other conditions based on the genotype, phenotype and developmental characteristics.

• Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. ^[1]

• Hypospadias

• Undermasculinization of the external genitalia and pubertal undervirilization

• 46,XY infants born small for gestational age

• Deficiency of the 5α-reductase enzyme ^[2]

• Leydig cell agenesis due to LH receptor anomalies:^[2]

• Monosomy 45,X (Turner syndrome) ^[2]

• Klinefelter syndrome
• Mutations in SRY, NR5A1, WT1
• 17,20-lyase deficiency
• 3-Beta-Hydroxysteroid Dehydrogenase Deficiency
• Congenital Adrenal Hyperplasia
• 17 beta-hydroxysteroid dehydrogenase deficiency type 3
• Frasier syndrome
• 17 alpha-hydroxylase deficiency
• p450 oxidoreductase deficiency
• Mutations in the luteinizing hormone receptor
• Smith-Lemli-Opitz syndrome
• Denys-Drash syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Reddy Kothagadi M.B.B.S[2]

CAIS (complete androgen insensitivity syndrome) has a prevalence of 2 to 5 per 100,000. The incidence of complete AIS is about in 5 in 100,000. There is no racial predilection for Androgen insensitivity syndrome.

• CAIS (complete androgen insensitivity syndrome) has a prevalence of 2 to 5 per 100,000 in otherwise healthy phenotypic females who had histologically normal inguinal or abdominal testes.
• PAIS (partial androgen insensitivity syndrome) is usually as common as CAIS.
• MAIS (mild androgen insensitivity syndrome) is much less frequently reported than CAIS and PAIS.

• The incidence of complete AIS is about in 5 in 100,000. The incidence of milder degrees of androgen resistance might be both more common or less common than CAIS. Evidence suggests many cases of unexplained male infertility may be due to the mildest forms of androgen resistance. ^{[1] [2]}
• In Netherlands, the minimal incidence was 1 per 99,000 over a ten-year period.

• Androgen insensitivity syndrome (AIS) is typically characterized by evidence of feminization (i.e., undermasculinization) of the external genitalia at birth, abnormal secondary sexual development in puberty, and infertility in individuals with a 46,XY karyotype. AIS represents a an array of defects in androgen action and can be subdivided into three broad phenotypes: ^[1]

• Those with typical female external genitalia are classified as complete androgen insensitivity syndrome (CAIS)
• Those with predominantly female, predominantly male, or ambiguous external genitalia are classified as partial androgen insensitivity syndrome (PAIS)
• Those with typical male external genitalia are classified as mild androgen insensitivity syndrome (MAIS)

• There is no racial predilection for androgen insensitivity syndrome.

• There have been no studies suggesting the difference in the occurrence of AIS in both developed and developing countries. Except for the establishment of two influential support groups, the AIS Support Group (which has branches in the UK, North America and Australia) and the Intersex Society of North America (ISNA). ^[3]

• There have been no studies suggesting the difference in the occurrence of AIS in both developed and developing countries.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Reddy Kothagadi M.B.B.S[2]

The risk of gonadal germ cell tumor is low during childhood and adolescence but increases in later adulthood. Benign tumors of non-germ-cell origin include sertoli cell adenoma and hamartomas.

• The risk of gonadal germ cell tumor is low during childhood and adolescence but increases in later adulthood.^[1]
• Benign tumors of non-germ-cell origin include Sertoli cell adenoma and hamartomas. ^[2]
• Studies have suggested an increased tumor risk of greater than 30% in late adulthood if gonadectomy is not done and a review of the risk of adult women with complete androgen insensitivity syndrome having a gonadal tumor could not be more specific than 0–22%. Specific analyses in large sample groups suggest a germ cell tumor risk as low as 0·8–2%, especially before puberty. ^[3]
• Evaluation of Relatives at Risk may help identify affected individuals at an early stage. ^[3]
  • It is advisable to evaluate the apparently asymptomatic older and younger siblings of a proband in order to identify as early as possible those who would benefit from institution of treatment and preventive measures.
  • For an apparently asymptomatic older or younger sib who has normal external female genitalia and who has not yet undergone menarche, a karyotype can be done first. For those phenotypic females who have a 46,XY karyotype, molecular genetic testing for the known androgen receptor (AR) variant in the family can be pursued next. If the androgen receptor (AR) variant in the family is not known, androgen binding assays could be considered.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Reddy Kothagadi M.B.B.S[2]

The diagnosis of AIS (androgen insensitivity syndrome) is mostly made post-natally. Studies have shown that the AIS may be identified prenatally by imaging techniques and comparative study such as such as preimplantation genetic screening, noninvasive prenatal screening and ultrasonography. In prepubertal girls with inguinal swellings, screening for CAIS should be considered.

• The diagnosis of AIS (androgen insensitivity syndrome) is mostly made postnatally. But, in a study which diagnosed mid-second trimester fetus with thick nuchal translucency (NT)/nuchal fold (NF) and short limbs was likely to be AIS. Hence, appearance of fetal sex on ultrasound should be compared with genetic sex. ^[1]
• With increased use, discordance among prenatal testing modalities such as preimplantation genetic screening, noninvasive prenatal screening and ultrasonography will become more common requiring expert navigation to identify true pathology.^[2]
• In prepubertal girls with inguinal swellings, screening for CAIS (complete androgen insensitivity syndrome)should be considered. ^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Reddy Kothagadi M.B.B.S[2]

If left untreated, androgen insensitivity syndrome (AIS) may lead to cancers of the male breast, larynx, liver, testes and bladder. Common complications of AIS include Infertility, psychological and social issues, osteoporosis, and cancers. Prognosis is good after orchidectomy at the proper time. For incomplete AIS patients, it depends on the presence and severity of ambiguous genitalia.

• The symptoms of androgen insensitivity syndrome (AIS) usually develop in the fetal developmental stage and start with non-androgenic aspects of male development such as formation of testes, production of testosterone and anti-müllerian hormone (AMH) by the testes which prevents the uterus and upper vagina from forming, and prostate and other internal male genital ducts fail to form because of lack of testosterone action.
• Childhood growth is normal and the karyotypic incongruity remains unsuspected unless an inguinal lump is discovered to be a testis during surgical repair of an inguinal hernia, appendectomy, or other coincidental surgery.
• If left untreated, androgen insensitivity syndrome may lead to cancers of the male breast, larynx, liver, testes and bladder.

• Infertility
• Psychological and social issues
• Osteoporosis: Reduced Bone mineral density (BMD) at the hip and spine is observed in cases with CAIS (complete androgen insensitivity syndrome). No correlation has been observed between the age of gonadectomy and BMD, and also no drop in BMD has been observed in patients followed up after gonadectomy.^[1]
• Some cancers show somatic alterations in Androgen receptor (AR) gene. Such cancers may result in increasing the function rather than decreasing the function as seen in AIS. Some of these include: ^[2]
  • Prostate cancer
  • Male breast cancer
  • Laryngeal cancer
  • Liver cancer
  • Testicular cancer
  • Bladder cancer

In cases of CAIS the prognosis is usually good after orchidectomy done at the proper time. For incomplete androgen insensitivity syndrome patients, it depends on the presence and severity of ambiguous genitalia.

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