Diagnosis and treatment of disorders of the androgen receptor

INTRODUCTION — Defects in androgen receptor (AR) function cause a disorder or difference of sex development (DSD) in which 46,XY individuals do not virilize in the typical pattern, despite the presence of bilateral testes and serum testosterone concentrations within or above the usual male reference range [1,2]. The various phenotypes in the condition 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. There may be other forms of androgen insensitivity whose genetic origins are currently mostly unknown. (See "Pathogenesis and clinical features of disorders of androgen action".)

WHEN TO SUSPECT AN ANDROGEN RECEPTOR MUTATION — The possibility of an androgen receptor (AR) mutation 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 atypical genitalia (disorder of sex development [DSD]). (See "Evaluation of the infant with atypical genital appearance (difference of sex development)".)

●Females with inguinal hernias or labial masses. As many as 1 to 2 percent of girls with inguinal hernias may have complete androgen insensitivity syndrome (CAIS) [3,4]. Newborns with a female phenotype can also be diagnosed with CAIS if prenatal karyotyping identified a 46,XY karyotype.

●Females with primary amenorrhea, normal pubertal development, but diminished sexual hair.

●Adolescent girls who become virilized and develop clitoromegaly.

●Adolescent boys who fail to undergo normal male puberty or who have persistent gynecomastia with signs of undervirilization.

●Adult men with undervirilization or with infertility associated with azoospermia or severe oligospermia.

EVALUATION

Biochemical testing — The approach to evaluation depends upon the age of the individual. In infants and children, basal values for gonadotropins and sex steroids are usually not sufficient and stimulation tests are required. In contrast, after puberty, basal hormone values for luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone may easily allow a diagnosis, especially in females with complete androgen insensitivity syndrome (CAIS). Regarding laboratory and genetic diagnosis, a parallel approach may be feasible, especially in the infant with no obvious clinical diagnosis.

●First year of life – During the first year of life, we suggest measuring testosterone, LH, and FSH. In neonates and infants during the first year of life, the usual postnatal increase in gonadotropins and testosterone may not occur in CAIS, but it is usually present in partial androgen insensitivity syndrome (PAIS) [5-7]. Inhibin B or anti-müllerian hormone (AMH) are in the usual reference range or even elevated, suggesting normal testicular Sertoli cell function; however, the postnatal gonadotropin surge is dependent upon normal androgen action.

●Children and adults – The capacity for testosterone synthesis in children with suspected CAIS and PAIS should be assessed by the administration of human chorionic gonadotropin (hCG). Several protocols exist for hCG stimulation, but 1000 to 2000 international units per day for three to five days, or alternatively 5000 international units/m² in a single dose, are administered with measurement of serum androstenedione, testosterone, and dihydrotestosterone (DHT) 72 hours afterwards. In adults, basal hormone measurements are used.

•In normal prepubertal boys, hCG stimulation causes an increase in serum testosterone to above 200 ng/dL (6.9 nmol/L) [8]. The majority of prepubertal children with 46,XY disorder of sex development (DSD), including those with CAIS and PAIS, have normal serum testosterone responses after the administration of hCG [9,10]. Subnormal responses to hCG should be interpreted with caution because responsiveness may vary on repeat testing [11], and responses can be subnormal on occasion in androgen insensitivity [12].

A low serum testosterone concentration in association with a high androstenedione concentration (after hCG stimulation in prepubertal children or basally in an adult) suggests the presence of possible impaired testosterone synthesis due to 17-beta-hydroxysteroid dehydrogenase type 3 deficiency.

•Assessing the ratio of testosterone to DHT in serum can be helpful in distinguishing CAIS and PAIS from 5-alpha-reductase deficiency. In most phenotypic girls/women and boys/men with PAIS, DHT production and the ratio of testosterone to DHT are normal, both basally in postpubertal individuals and after hCG administration prepubertally. In contrast, DHT production is decreased and the plasma ratio of testosterone to DHT is increased in patients with steroid 5-alpha-reductase 2 deficiency. When a testosterone/DHT ratio of 10 was set as a cutoff for diagnosing 5-alpha-reductase deficiency, more than 72 percent of the newborns and infants with a molecularly proven diagnosis had values above the threshold [13].

However, some women with CAIS have secondary 5-alpha-reductase deficiency due to a decreased mass of the urogenital tract tissues in which DHT is normally produced [14]. This secondary 5-alpha-reductase deficiency can lead to elevated ratios of testosterone to DHT in serum.

The laboratory assessment of DHT must be done after organic extraction and/or celite chromatography and a highly sensitive radioimmunoassay, or ideally, with liquid chromatography-tandem mass spectrometry (LC-MS/MS) [15].

●Serum AMH or inhibin B measurements may be used to confirm the presence of normal functioning testes. The AMH and inhibin B levels are within or above the normal male reference range in PAIS or CAIS, relating to the uninhibited Sertoli cell function [16].

●Analysis of steroid profiles in urine may prove valuable in making the diagnosis [17].

Genetic testing — In some cases, biochemical testing is not adequate to make the diagnosis of CAIS or PAIS and appropriate reference ranges are not available [18]. Therefore, molecular genetic studies are needed to make or confirm the diagnosis [19]. The androgen receptor (AR) gene has a coding region of eight exons and is located on chromosome Xq11-12. It encodes a protein of approximately 920 amino acids, which compose the typical three major functional domains of the nuclear receptor superfamily. Over 1000 mutations, as well as some larger structural alterations, have been identified in patients with all forms of androgen insensitivity syndrome, and these mutations can be spread out over the whole coding region.

To detect deletions or duplications of exons or the entire gene, multiplex ligation-dependent probe amplification (MLPA) analysis is now routinely available [20]. While mutational analysis may confirm the diagnosis of androgen insensitivity syndrome, a genotype-phenotype correlation in PAIS does not exist, and therefore, further clinical prognosis is difficult to predict (see 'Genotype-phenotype correlations' below). In a subset of patients with PAIS, de novo post-zygotic mutations may have occurred, resulting in a somatic mosaicism of functioning wild-type and dysfunctional mutated AR [21]. This observation should be considered when doing genetic counseling. Newer diagnostic approaches, such as next-generation and whole-exome and genome sequencing are also now being used [19,22].

DIAGNOSIS

Complete androgen insensitivity syndrome — Complete androgen insensitivity syndrome (CAIS) is mostly due to mutations that cause severe impairment of androgen receptor (AR) function. The diagnosis, which is typically made in an adolescent or young adult woman, is based upon a constellation of clinical and biochemical findings, including:

●Female phenotype with normal breast development

●Primary amenorrhea

●Little or no axillary or pubic hair

●Absent uterus, but testes present

●46,XY karyotype

●Blind vaginal pouch on exam

●Serum testosterone concentrations in the usual adult male range, normal to elevated luteinizing hormone (LH), and inhibin B in the mid-normal male reference range [23]

In CAIS, testes may be located in the abdomen or inguinal region. The site and size of the testes can sometimes be defined by ultrasonography or magnetic resonance imaging (MRI) [24-26].

The AR is coded by a single-copy gene on the X chromosome. The diagnosis of CAIS can be confirmed by sequencing the coding region of this gene. Loss-of-function mutations in the coding sequence of the AR can be found in most women with CAIS. A database that is updated regularly lists the large number of AR mutations reported in subjects with androgen insensitivity [27,28]. Mutations in the 5' untranslated region of the AR gene have also been identified, which are associated with CAIS [29].

The differential diagnosis in a female presenting with primary amenorrhea, absent uterus, and blind vaginal pouch includes müllerian agenesis (also called congenital absence of the vagina or Mayer-Rokitansky-Küster-Hauser syndrome) [24]. However, these women have normal axillary and pubic hair, a 46,XX karyotype, normal ovarian function, and serum androgen and estrogen concentrations in the usual female range. (See "Evaluation and management of primary amenorrhea" and "Congenital uterine anomalies: Clinical manifestations and diagnosis".)

Other considerations include disorders of androgen biosynthesis or Leydig cell dysfunction; however, these 46,XY women lack pubertal development and have hypergonadotropic hypogonadism. 46,XY women with a uterus are considered to have gonadal dysgenesis. (See "Causes of differences of sex development", section on 'Causes of XY differences of sex development'.)

Partial androgen insensitivity syndrome — The diagnosis of partial androgen insensitivity syndrome (PAIS), which is associated with less severe impairments of AR function than CAIS, can be difficult as patients present with a spectrum of reduction in virilization and vary from women with mild degrees of virilization to sometimes fertile but undervirilized men (table 1). In addition to clinical and biochemical features, the diagnosis requires a 46,XY karyotype as well as determination of androstenedione, testosterone, and dihydrotestosterone (DHT) levels (at baseline or after human chorionic gonadotropin [hCG] stimulation) in order to exclude defects in testosterone biosynthesis and 5-alpha-reductase 2 deficiency and Sertoli cell markers as anti-müllerian hormone (AMH) and inhibin B to assess possible genetic defects affecting gonadal development as in partial gonadal dysgenesis [20,30]. (See 'Differential diagnosis' below and "Pathogenesis and clinical features of disorders of androgen action", section on 'Partial androgen insensitivity (PAIS)'.)

The clinical features of PAIS are reviewed in detail separately, but they are summarized here briefly.

●Female phenotype with mild virilization – These women have an overall female phenotype but mild virilization. They have breast development at puberty and predominantly female external genitalia except for posterior labial fusion and/or clitoromegaly. Pubic hair may be sparse (table 1). (See "Pathogenesis and clinical features of disorders of androgen action", section on 'Female phenotype with mild virilization'.)

●Predominantly male phenotype – PAIS with a predominantly male phenotype (table 1) describes 46,XY children with variable defects in virilization, including hypospadias. If AR function is more significantly impaired, there can be complete failure of scrotal fusion, a micropenis with perineoscrotal hypospadias, and a pseudovagina. When AR function is only mildly impaired, men have a male genital phenotype but have gynecomastia, infertility, and a scanty beard and pubic hair. This is also referred to as mild androgen insensitivity. (See "Pathogenesis and clinical features of disorders of androgen action", section on 'Predominantly male phenotype'.)

●Infertile male syndrome – Some affected 46,XY men with PAIS have only infertility, slight undervirilization, and gynecomastia. Most men in this category do not have a positive family history. The diagnosis may be suspected in infertile men with undervirilization or high serum testosterone and/or LH concentrations, although most men with the syndrome have hormone values in the normal male range [31,32]. Thus, this diagnosis should be considered in men with severe idiopathic oligospermia or azoospermia, in whom the multiplication product of basal LH and testosterone values is elevated. However, reference values for multiplication products are not readily available, so most clinicians rely upon finding a high serum testosterone and/or LH concentration only.

The testis histology varies from a maturation arrest of spermatogenesis to germinal cell aplasia [31]. Some of the men have high serum follicle-stimulating hormone (FSH) concentrations and resemble men with azoospermia due to microdeletions of the Y chromosome involving the azoospermia factor genes [33]. (See "Pathogenesis and clinical features of disorders of androgen action", section on 'Infertile male syndrome'.)

●Undervirilized fertile male syndrome – Only a few families have been reported with androgen insensitivity manifested as the undervirilized fertile male syndrome (eg, men with normal fertility but mild undervirilization). The overall body habitus is male with decreased beard and body hair; gynecomastia may be present. The condition might be suspected in an undervirilized man with a normally formed male urethra and gynecomastia, particularly if there is a family history of similarly affected men. Although serum testosterone concentrations were high in the few men reported, it is likely that such a finding may not always be present. Serum LH levels are within the reference range. (See "Pathogenesis and clinical features of disorders of androgen action", section on 'Undervirilized fertile male syndrome'.)

Genotype-phenotype correlations — PAIS disorders can overlap clinically in different families, but variable phenotypes can occur within the same family in individuals with the same gene mutation. While loss-of-function mutations in the AR are found in most, but not all, patients with CAIS, these mutations are identified in only a subset of subjects with PAIS [34].

The diagnosis of PAIS may require gene sequencing and careful pedigree analysis. In general, the more severe the impairment in AR function, the more consistent the phenotype among and between families. In a study of subjects with PAIS and a positive family history, the likelihood of identifying an AR mutation was high [35], while AR mutations were identified in only one-fourth of infants and children with phenotypic and endocrine features suggestive of PAIS but with uninformative family histories [36]. The etiology of the majority of the cases with normal sequences remains unclear. (See 'Differential diagnosis' below.)

Differential diagnosis — At all ages, the major differential diagnosis for PAIS can be extensive [34,37]. A group of patients with androgen insensitivity has been identified that has no evidence of mutations in the AR gene [38]. These patients are characterized by disrupted androgen signaling due to diminished transcriptional induction of the AR target gene apolipoprotein D (APOD). This AR mutation-negative class of androgen insensitivity has to be characterized further to define the molecular origins.

The differential diagnosis and evaluation of the undervirilized 46,XY infant are reviewed in detail separately. (See "Causes of differences of sex development", section on 'Causes of XY differences of sex development'.)

However, major conditions to consider include the following [1,20,39]:

●Mixed gonadal dysgenesis (also termed chromosomal disorder of sex development [DSD]), which is associated with a mosaic 45,X/46,XY karyotype, refers to the presence of a dysgenetic testis on one side and a streak gonad on the other. The presence of a single descended gonad should raise suspicion of this disorder. Müllerian remnants and somatic features of Turner syndrome of variable presentation may be present. (See "Causes of differences of sex development", section on 'Sex chromosome differences of sex development'.)

●46,XY partial gonadal dysgenesis, which is characterized by the presence of müllerian structures but decreased testosterone and AMH and or inhibin B production. The phenotype of partial gonadal dysgenesis can range from genital ambiguity to an undervirilized male. Mutations in a variety of genes, including SRY, FOG2/ZFPM2, NR5A1, DHH, and WNT1 have been identified [19,40]. Because of the phenotypic variability, some patients are diagnosed in infancy with ambiguous genitalia, while others are not diagnosed until puberty when they present with primary amenorrhea or incoherent pubertal development. (See "Causes of primary amenorrhea", section on '46,XY gonadal dysgenesis'.)

●Disorders in androgen synthesis – Defects in testosterone synthesis can be the result of a defect in any of the enzymes in the pathway of testosterone synthesis or a dysfunction of the LH receptor. (See "Causes of differences of sex development", section on 'Conditions affecting androgen synthesis or response'.)

●Steroid 5-alpha-reductase type 2 deficiency. (See "Steroid 5-alpha-reductase 2 deficiency".)

MANAGEMENT — There is no therapy to prevent or reverse the development that occurs during embryogenesis in patients with androgen insensitivity syndromes. Management is therefore initially focused on counseling of families and providing assistance in sex assignment of infants with ambiguous genitalia. Management should then address functional issues, timing of gonadectomy to prevent the increased possible tumor formation in cryptorchid testes, hormone replacement or supplementation at the appropriate time in life, surgery as appropriate for individuals raised as male or female, treatment of gynecomastia in men, and psychological support for the patient and family [41]. (See "Management of the infant with atypical genital appearance (difference of sex development)".)

At this time, in several countries around the world, management of disorders of sex development (DSD), including androgen insensitivity syndrome, are debated vigorously. As a rule, sex assignment may be delayed until a final diagnosis has been reached and a reliable prognosis can be made. Irreversible procedures, particularly surgical corrective surgery, should be performed only after informed consent by the patient. In several countries, surgeries are legally delayed until this consent can be obtained from the older child or adolescent. The diagnostic and management procedures should ideally be performed by a multidisciplinary team in a center with expertise in DSD [41,42].

Three ethical principles that apply to management of DSD have been published by a working group within the German Network DSD/Intersex: to foster the well-being of the child and the future adult, to uphold the rights of children and adolescents to participate in and/or self-determine decisions that affect them now or later, and to respect the family and parent-child relationships [43]. (See 'Psychological support and disclosure' below.)

Sex assignment in the newborn — The choice of sex assignment in neonates with ambiguous genitalia is not always straightforward, and attitudes toward management are changing. One survey suggests that the frequency of male sex assignment has increased in DSD [44]. It is now possible to not assign a legal sex in certain countries including Germany, because of changes in the personal status law. Any decision on sex assignment must consider medical issues as well as local cultural and legal considerations.

In the past, the possibility of future potential fertility was not a consideration in sex assignment. However, development of intracytoplasmic sperm injection for in vitro fertilization using rare spermatozoa obtained by testis biopsy suggests that many men with azoospermia may be potentially fertile [45]. This also favors male sex assignment in 46,XY DSD. (See "Treatments for male infertility".)

Cryptorchid testes — The risk of tumorigenesis is increased in all postpubertal subjects with cryptorchid testes, including subjects with androgen insensitivity. Tumors (germ cell tumors and gonadoblastomas) occur in approximately 1.5 to 2 percent of undescended testes, more often in abdominal than in inguinal testes. Some of these tumors may become malignant [46]. Cryptorchidism is also common in prepubertal boys with partial androgen insensitivity syndrome (PAIS) and should be corrected surgically soon after diagnosis to maintain testicular function and minimize the risk of malignancy. (See "Epidemiology and risk factors for testicular cancer".)

Timing of gonadectomy — Carcinoma in situ of the testis has been described in prepubertal girls with complete androgen insensitivity syndrome (CAIS), but its importance is uncertain [47] (see "Testicular germ cell neoplasia in situ"). Girls with CAIS have a normal pubertal growth spurt and feminize at the time of expected puberty (secondary to aromatization of androgen to estrogen), and testicular tumors do not usually develop until after this time [48,49]. Therefore, gonadectomy in women with delayed until sexual maturation is complete. This approach also respects patient autonomy [50,51]. However, in some situations, the convenience of combining gonadectomy with hernia repair or the need to relieve symptoms of discomfort from labial or inguinal testes may justify removal of the testes before puberty.

In phenotypic women with PAIS, gonadectomy has so far been performed when the diagnosis was made or before the time of expected puberty to prevent the progressive virilization that may occur. However, as current practice requires full informed consent and the assessment of a stable gender identity, pubertal development may be delayed with the use of gonadotropin-releasing hormone (GnRH) agonists if necessary.

Hormone replacement or supplementation — For CAIS and PAIS individuals who are phenotypic females or are raised as female after surgical treatment of ambiguous genitalia, hormone treatment is indicated when gonadectomy is performed after puberty or at the time of expected puberty if gonadectomy was performed prepubertally [52]. Again, this requires consent of the patient, who should be informed about the underlying condition. In girls of pubertal age, low doses of estrogen should be begun to promote feminization and should be gradually increased to full adult doses, similar to induction of puberty protocols. The age and dose of initiation depend upon the child's growth percentile, growth velocity, bone age, target height, and predicted adult height. Adult women can be given full estrogen replacement immediately. The use of testosterone as a hormone supplementation in CAIS, but has demonstrated additional value, especially with regard to sexual functioning [53]. (See "Approach to the patient with delayed puberty", section on 'Estradiol therapy'.)

In patients with PAIS assigned to the male sex, the efficacy and safety of long-term, high-dose androgen therapy given to overcome androgen resistance has not been systematically assessed. One prepubertal boy with PAIS was administered high doses of testosterone, resulting in greater phallic growth than did usual doses [54], and two prepubertal boys were treated successfully with transdermal dihydrotestosterone (DHT) [55,56]. In several adult men with PAIS, administration of high doses (500 mg) of testosterone esters intramuscularly improved masculinization [57]. However, other trials of high-dose therapy have been unsuccessful [58,59]. Use of an aromatase inhibitor or tamoxifen may help prevent the development of gynecomastia, but this has been reported only in a few cases [60,61]. Overall, treatment options have to be personalized, and the outcome is highly variable [62].

Surgery of the urogenital tract — In CAIS and in women with PAIS, vaginal depth may be subnormal but usually can be made adequate with dilator therapy prior to the time when an active sex life is contemplated, and vaginoplasty should be undertaken only in those women who do not have an adequate response to dilator therapy [50,63]. In women with PAIS, vaginoplasties are sometimes appropriate. However, in spite of surgery and dilator therapy, women with CAIS and PAIS are often dissatisfied with their surgical results (vaginal function and clitoral arousal) [64].

In boys with PAIS, appropriate hypospadias repair might be undertaken as early as is feasible.

Gynecomastia in men with PAIS — The breast enlargement in men with partial androgen insensitivity syndrome (PAIS), including patients with the predominantly male phenotype, some with the infertile male syndrome, and most undervirilized fertile males, is similar to other types of gynecomastia. It is the result both of increased local estrogen production and of androgen resistance (see "Epidemiology, pathophysiology, and causes of gynecomastia"). Mastectomy is appropriate if the gynecomastia is disfiguring or disturbing to the individual. The frequency of carcinoma of the breast may be increased in men with PAIS [65], probably due to the effects of prolonged estrogen stimulation of the breast rather than to direct effects of the mutant androgen receptor (AR). In two siblings with PAIS and gynecomastia, two months of tamoxifen therapy was beneficial with no adverse effects [61]. (See "Management of gynecomastia".)

Psychological support and disclosure — Current practice guidelines suggest that families be educated about the condition as soon as the diagnosis is made and that patients be informed gradually but completely about their diagnosis, with appropriate education provided in an age-appropriate fashion [41-43,66-68]. Such disclosure prevents the unfortunate consequences of a patient learning the diagnosis inadvertently.

International support groups have been established for individuals with androgen insensitivity:

In the United States and South America:

AIS-DSD Support Group for Women and Families

PO Box 2148

Duncan, OK 73534-2148

E-mail: [email protected]

In Germany:

XY-Frauen Selbsthilfegruppe

In Europe:

European Reference Network for Rare Endocrine Conditions (Endo-ERN)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Differences of sex development".)

SUMMARY AND RECOMMENDATIONS

●Complete androgen insensitivity syndrome (CAIS) is characterized by an external female phenotype in a 46,XY individual with absent or sparse genital hair, absent uterus, serum testosterone concentrations that are higher than or within the usual male range, and the ability to synthesize testosterone and Sertoli cell markers, such as inhibin B and anti-müllerian hormone (AMH; prepubertal subjects). (See 'Complete androgen insensitivity syndrome' above.)

●Partial androgen insensitivity syndrome (PAIS) is characterized by a variable phenotype from phenotypic women with mild virilization to phenotypic men with undervirilization and gynecomastia or infertility. The differences in these various phenotypes are due to variable degrees of loss of function of the androgen receptor (AR). (See 'Complete androgen insensitivity syndrome' above.)

●The differential diagnosis for CAIS is müllerian agenesis in adults, and for PAIS, the differential diagnoses are mixed or partial gonadal dysgenesis, defects in testosterone synthesis, and steroid 5-alpha-reductase 2 deficiency. (See 'Complete androgen insensitivity syndrome' above and 'Differential diagnosis' above.)

●The capacity for testosterone synthesis in infants and children with suspected CAIS and PAIS should be assessed by the administration of human chorionic gonadotropin (hCG) 1000 to 2000 international units per day for three to five days (or alternatively 5000 international units/m² in a single dose), with measurement of serum androstenedione, testosterone, and dihydrotestosterone (DHT). Adults are evaluated with basal hormone samples. (See 'Evaluation' above.)

In normal prepubertal boys and in those with CAIS and PAIS, hCG stimulation causes an increase in serum testosterone to above 200 ng/dL (6.9 nmol/L). The majority of individuals with CAIS and PAIS have normal serum testosterone responses after the administration of hCG. Elevation of androstenedione or of the ratio of testosterone to DHT may help identify impaired testosterone synthesis due to 17-beta-hydroxysteroid dehydrogenase type 3 deficiency and steroid 5-alpha-reductase 2 deficiency, respectively. The AMH and inhibin B levels should be within the normal male reference range in patients with CAIS or PAIS. (See 'Evaluation' above.)

●The DNA for the AR gene should be sequenced in subjects suspected to have CAIS or PAIS based on consistent clinical features and hormonal studies, although the probability of finding a mutation is low in PAIS subjects with negative family histories. Due to the availability of novel next-generation sequencing technology, parallel approaches of genetic testing and laboratory investigations are proposed. (See 'Genetic testing' above.)

●Parents of newborns, infants, and children with CAIS or PAIS should be provided educational resources and support services. Any child, adolescent, or adult patient should receive age-appropriate information about the condition as well as psychological support. (See 'Psychological support and disclosure' above.)

●In women with CAIS or PAIS, we suggest administration of estrogen at the time of expected puberty, if gonadectomy was performed in childhood, or as soon as gonadectomy is performed after puberty (Grade 2B). However, testosterone therapy may have advantages in patients with proved CAIS. (See 'Hormone replacement or supplementation' above.)

●We suggest that gonadectomy be delayed until after the pubertal growth spurt and feminization in most subjects with CAIS (Grade 2C). Gonadectomy might be recommended in phenotypic women at the time of diagnosis of PAIS to prevent further virilization. Gonadotropin-releasing hormone (GnRH) agonists might prevent undesired virilization if time is needed for counseling and decision-making. (See 'Hormone replacement or supplementation' above.)

●We suggest surgical correction of cryptorchidism in boys with PAIS soon after diagnosis to maintain testicular function and minimize the risk of malignancy (Grade 2B). (See 'Cryptorchid testes' above.)

●In CAIS and in women with PAIS, vaginal depth may be subnormal but usually can be made adequate with dilator therapy when sexual activity is contemplated, and vaginoplasty should be undertaken only in those women who do not have an adequate response to dilator therapy. (See 'Surgery of the urogenital tract' above.)

●In males with PAIS, hypospadias repair might be undertaken at a younger age and mastectomy is appropriate for disfiguring persistent gynecomastia. (See 'Surgery of the urogenital tract' above and 'Gynecomastia in men with PAIS' above.)