Version May 2024
INTRODUCTION — Loss-of-function mutations of the gene that encodes the androgen receptor (AR) result in androgen insensitivity syndrome (AIS) in 46,XY individuals with functional testes and unhindered testosterone formation. AIS encompasses a clinical continuum of decreased to absent androgen effects, varying from a completely female phenotype to a male phenotype with undervirilization or infertility. In contrast to the variability in phenotypic expression, the conditions have similar endocrine, pathophysiologic, and genetic features [1]. The pathophysiology and clinical features will be reviewed here, while diagnosis and therapy are discussed separately. (See "Diagnosis and treatment of disorders of the androgen receptor".)
PATHOGENESIS
Genetics — The androgen receptor (AR) is a member of the steroid-thyroid-retinoid superfamily of nuclear receptors with a C-terminal region containing hormone-binding and DNA-binding domains and an N-terminal region important in transactivation (figure 1). Specific mutations of the AR gene have been identified in many patients with androgen insensitivity syndromes (AIS). Most mutations today have been localized in the hormone-binding domain and, to a lesser extent, in the DNA-binding domain and the transactivation domain [2]. Mutations in the 5' untranslated region of the AR gene have also been described, which impair AR function by reducing AR protein levels [3].
Androgen action via the AR leads to long-term programming effects by implementing stable functional and structural androgen-dependent traits. These occur during defined androgen-sensitive time windows of individual ontogenesis. Therefore, the AR acts in concert with many other co-factors to induce individual effects within each cell and organ [4], including the brain.
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.
The AR is a transcriptional regulator, and cell-specific transcriptomes have been identified [5]. Furthermore, a distinct class of AR mutation-negative patients with AIS have been described, in whom the AR-responsive target gene apolipoprotein D (APOD) is diminished in genital skin fibroblasts. The exact molecular defect in these patients has not been identified yet [6,7].
Androgen resistance — Recognition that patients with complete androgen insensitivity syndrome (CAIS) have profound resistance to the action of androgen came from studies in which affected women were found to be resistant to the virilizing action of exogenous androgen [8].
This hormone resistance was found to be due to defects in androgen receptor (AR) function as a result of studies of women with CAIS who had no detectable AR binding [9-11], qualitatively abnormal AR binding [12-14], or decreased amounts of qualitatively normal receptor binding [12,15]. Similar findings were described in patients with the less severe phenotypes [15].
Involvement of the AR in these disorders was confirmed when the encoding gene was cloned and specific molecular defects were defined. The AR gene is located on chromosome Xq11-12. X-linkage of the AR gene was established when the human cDNA was cloned from an X-chromosome library [16,17].
CLINICAL FEATURES
Complete androgen insensitivity (CAIS)
●Incidence – The incidence of complete androgen insensitivity syndrome (CAIS) may be as high as 1 in 20,000. In one study, it was the third most frequent cause of primary amenorrhea (after gonadal dysgenesis and congenital absence of the vagina) [18]. CAIS often presents in an adolescent or young adult woman seen for primary amenorrhea and found to have little or no axillary and pubic hair.
●Initial presentation – The clinical presentation may also be at birth or during infancy for inguinal masses (containing testes) or hernias in an otherwise healthy female child. More recently, female newborns have been diagnosed with CAIS when prenatal karyotyping identified a 46,XY karyotype. The labia and clitoris are unambiguous, and the vagina is short and blind ending (table 1).
Other features include normal-appearing testes, an absent uterus, and a 46,XY karyotype. Breast development is that of a typical woman, and overall body habitus is female. Axillary and pubic hair is markedly decreased or absent. Gender identity is mostly female; however, male gender identity has been described, demonstrating that gender identity only partially depends on early endocrine effects [19].
Many patients do not need any surgical procedures. However, a high percentage of patients report dissatisfaction regarding sexual life (dyspareunia and low libido) [20]. Although some patients report satisfactory outcome after vaginoplasty if performed, including normal libido and ability to achieve orgasm [21], women in whom the vagina remains small often experience sexual problems [20] that might be treated by vaginal dilation. (See "Diagnosis and treatment of disorders of the androgen receptor", section on 'Surgery of the urogenital tract'.)
Biochemical features – In the newborn and infant, the laboratory diagnosis is quite difficult. Hormone levels are less suggestive of resistance when patients present in infancy. Luteinizing hormone (LH) and testosterone basal levels may be low, and testosterone only increases after stimulation with exogenous human chorionic gonadotropin [22,23]. (See 'Hormonal profiles' below.)
After puberty, serum testosterone concentrations are in the high-normal to slightly elevated reference range for typical postpubertal boys, and estradiol levels are in the upper typical male reference range [24]. Most affected children are nowadays detected by genetic diagnostics [25]. (See 'Hormonal profiles' below.)
●Gonadal findings – Testes may be located in the abdomen, the inguinal canals, or the labia majora and have the histologic appearance of undescended testes with a normal or increased number of Leydig cells and no spermatogenesis (table 1). The urogenital tract is characterized by absence or near absence of müllerian structures; rarely, uterine remnants are present [26]. Epididymides and vasa deferentia are usually absent, but in one study, the epididymis and vas deferens were identified histologically adjacent to the testes in 10 of 33 affected children (average age six years) [27].
●Risk of tumor development – Germ cell tumors may develop in the cryptorchid testes [28], but the risk of tumor development nowadays is seen as rare [29], and early prophylactic gonadectomy is not recommended at this time. However, there is a risk of increasing tumor formation with age, so that patients should be followed closely and gonadectomy be performed postpubertally on an individualized basis [30,31]. To date, there are no clinical guidelines available on the optimal screening and timing of gonadectomy for patients with gonads in situ [32,33]. Data suggest that miR-371a-3p may be a biomarker for malignant germ cell tumors, but its usefulness for screening of CAIS has not been proven [34]. The development of the cellular compartments of the testis may be altered in CAIS, which also may have an impact on tumor development [35]. (See "Diagnosis and treatment of disorders of the androgen receptor" and "Epidemiology and risk factors for testicular cancer" and "Testicular germ cell neoplasia in situ".)
●Growth pattern – Growth pattern follows that of typical girls, but final height is closer to that of typical boys, suggesting that height is not androgen dependent [36].
Partial androgen insensitivity (PAIS) — Less severe defects in androgen action cause a variety of forms of 46,XY disorders (or differences) of sex development (DSD) that vary from women with mild degrees of virilization to fertile but undervirilized men (table 1). The various phenotypes were originally thought to be separate syndromes, and the recognition that they are due to defects of varying severity in androgen receptor (AR) function came from family studies [37,38]. In one family, three severely affected persons were females, whereas another had perineoscrotal hypospadias and bifid scrotum typical of the male phenotype [39]. In a second family, manifestations varied from male infertility with hypospadias to fertile, undervirilized men [40]. The various clinical phenotypes sometimes cluster within individual families, making it evident that even the same mutation of the AR may facilitate very different cellular effects of androgen action.
Mutations of the coding sequence of the AR are found in only approximately 20 percent of the individuals with the diagnosis of partial androgen insensitivity syndrome (PAIS) and a negative family history [41]. The diagnosis should be reconsidered in these patients, and novel genetic approaches with next-generation sequencing might reveal a different genetic origin of disorders of sex development (DSD) [6,42]. In addition, mutations outside of the coding region of the AR gene should be considered [5]. (See "Diagnosis and treatment of disorders of the androgen receptor", section on 'Genetic testing'.)
Female phenotype with mild virilization — People with this form of PAIS resemble those with CAIS, but they have typical female pattern secondary body hair and partial virilization of the external genitalia at puberty [43]. The external genitalia can exhibit partial fusion of the labioscrotal folds and/or clitoromegaly. As in CAIS, the vagina is short and ends blindly because müllerian structures are absent. The testes are similar to those in CAIS in location and histology, but the wolffian duct derivatives (epididymides, vasa deferentia, seminal vesicles, and ejaculatory ducts, as well as prostate) can be incompletely developed due to prenatal androgen effects.
Predominantly male phenotype — PAIS with predominantly male phenotype is also referred to as mild androgen insensitivity (table 1). These 46,XY children have variable reductions in virilization [37]. The usual phenotype encompasses perineoscrotal hypospadias and a bifid scrotum with intact testes, but the external genitalia can vary from microphallus with a typical penile urethra to complete failure of scrotal fusion and a pseudovagina. (See "Evaluation of the infant with atypical genital appearance (difference of sex development)".)
At the time of puberty, most patients experience marked breast development, which persists, in contrast to pubertal gynecomastia [44]. In adulthood, most humans with PAIS will be infertile due to impaired spermatogenesis. Axillary and pubic hair can be sparse to normal, and chest and facial hair are usually sparse or absent. Patients with PAIS usually do not show increased signs of gender identity ambiguity or instability [45].
In PAIS subjects raised as males, the frequency of sexual dysfunction has been reported to be high in comparison with typical men [46], whereas in a study of adult 46,XY individuals with ambiguous genitalia of various causes, the assessment of satisfaction with sexual function was similar in those raised as males or females, namely 2.5 and 2.7 on a scale with a maximum of 5, respectively [47].
Infertile male syndrome — Some affected 46,XY men in PAIS families present only with infertility, slight undervirilization, and gynecomastia. Subsequently, men with azoospermia or severe oligospermia but without a family history of PAIS were found to have defects in the AR similar to those in men with PAIS [48,49]. This mildest form of PAIS has been termed the infertile male syndrome. The external genitalia and internal urogenital tract are those of typical men. The overall body habitus is male, and facial and body hair growth is usually fully masculine. The testes are usually descended, and testicular histology varies from complete absence of germinal elements to maturation arrest of spermatogenesis (table 1).
Undervirilized fertile male syndrome — Based on the clinical syndromes described above, it was assumed that infertility might be a consistent manifestation of AR disorders. However, rare undervirilized men with PAIS have normal sperm density [50,51]. The external genitalia are those of a typical man, except that the penis may be small. The internal urogenital tract is normal. The testes are descended, sperm density is usually normal, and ejaculate volume is decreased. Some affected men are fertile [50].
The overall body habitus is male with decreased beard and body hair; gynecomastia may be present. Gender orientation is male. The prevalence of this syndrome is unknown because only a few families have been described.
Spinobulbar muscular atrophy — An unanticipated variation of AR gene structure occurs in men with spinobulbar muscular atrophy (Kennedy disease) [52]. This X-linked disorder is characterized by progressive degeneration of anterior motor neurons and is associated with late-onset gynecomastia, defective spermatogenesis, and a hormonal profile consistent with androgen resistance. The AR gene in these men contains an expansion in the number of glutamine repeats in the N-terminal region (figure 1) from the usual 20 glutamines to more than twice that number [53]. In vitro studies of transactivation of a reporter gene by a mutant receptor with the expanded glutamine repeats indicate that receptor function is impaired [54], and the severity of this impairment correlates with the length of expansion of the trinucleotide (CAG) repeat [55]. (See "Diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease", section on 'Spinobulbar muscular atrophy'.)
HORMONAL PROFILES — The hormonal profile is similar in all the syndromes associated with defects of androgen receptor (AR) function, but the endocrine features have been studied most extensively in people with complete androgen insensitivity syndrome (CAIS) [24]. (See 'Complete androgen insensitivity (CAIS)' above.)
Individuals with CAIS with intact gonads have serum testosterone concentrations within or above the reference range for boys/men. However, serum sex hormone-binding globulin (SHBG) concentrations can be increased, reflecting the lack of androgen action [56]. The increased testosterone production is secondary to increases in serum luteinizing hormone (LH) concentrations, which in turn are due to resistance to the feedback effect of androgens on LH secretion at the hypothalamic-pituitary level [24]. Both the frequency and amplitude of pulses of LH secretion are increased [57]. Serum follicle-stimulating hormone (FSH) concentrations are usually normal.
Serum estradiol levels were thought to be higher than normal for boys/men because of aromatization of testosterone. However, later reports suggest that estradiol levels are in the typical male reference range despite the pattern of feminization seen in these women [24]. This is in concordance with our own clinical observations. After gonadectomy, serum gonadotropins increase but may be partially suppressed after starting hormone substitution therapy. (See "Diagnosis and treatment of disorders of the androgen receptor", section on 'Timing of gonadectomy'.)
Production of dihydrotestosterone is decreased in some patients with CAIS, presumably due to the decreased mass of the male urogenital tract tissues, which are major sites of dihydrotestosterone production [58].
In infants with CAIS, basal levels of LH and testosterone may be low during "mini puberty." However, after stimulation with human chorionic gonadotropin, a sharp rise of testosterone is seen. Also, LH rises after gonadotropin-releasing hormone (GnRH) stimulation [23]. Inhibin B and anti-müllerian hormone (AMH) levels are within the age-related reference ranges of boys or even elevated [59,60]. (See "Normal puberty".)
The hormone levels in partial androgen insensitivity syndrome (PAIS) women with mild virilization or PAIS men are similar to those in women with CAIS [37,61]; hormone levels in the infertile male syndrome are less abnormal [48]. In a family with the undervirilized fertile male syndrome, all three men studied had high serum testosterone concentrations, two had high serum estradiol, and all had normal serum LH [50].
GENOTYPE-PHENOTYPE CORRELATIONS — Major deletions or premature termination codons have been found only in people with CAIS. Amino acid substitutions can cause the entire spectrum of phenotypes from infertile men to CAIS. Approximately 80 percent of the amino acid substitutions are in the hormone-binding domain, and many of the remaining 20 percent are in the DNA-binding domain. DNA-binding domain mutations are usually associated with normal androgen binding but defective ability to activate androgen-responsive genes [62]. Understanding how one amino acid substitution leads to a greater impairment in receptor function than another will require knowledge of the crystal structure of the androgen-AR complex. Interestingly, mutations in exon 1 turn out to be more common than originally thought, indicating that this exon needs to be sequenced routinely in a diagnostic setting [63].
The mutations characterized in patients with the infertile male syndrome and the undervirilized fertile male syndrome cause amino acid substitutions mostly in the hormone-binding domain [64,65], although in this patient group mutations have also been described in the N-terminal domain, whose functional properties remain largely unknown [49]. (See 'Infertile male syndrome' above and 'Undervirilized fertile male syndrome' above.)
In some patients with PAIS due to amino acid substitutions in the hormone-binding domain, the hormone resistance can be overcome in part by supraphysiologic doses of androgen [50]. (See "Diagnosis and treatment of disorders of the androgen receptor".)
It is more difficult to understand why, in some families, affected individuals with the same mutation have different phenotypes and how the same mutation can produce different phenotypes in different families [66]. In one study, phenotypic variation was seen in three of nine families with PAIS but in none of the families with CAIS [67]. Variable timing of receptor expression or differences in testosterone synthesis or metabolism could have an impact on the expression of a mutation in a given patient. Alternatively, variations in unidentified proteins, such as other members of the transcription regulatory complex, may alter the activity of the AR. Similarly, differences in the lengths of the polyglutamine and polyglycine repeat sequences in the N-terminal domain of the protein can influence the effect of given mutations [68,69].
Patients with AIS, as well as all patients with DSD, should be registered in the international DSD database.
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
●Pathogenesis – Disorders of androgen action are one common form of 46,XY disorders or differences of sex development (DSD).
Loss-of-function mutations in the androgen receptor (AR) lead to variable loss in virilization or infertility in 46,XY males with testes and normal testosterone formation. (See 'Introduction' above.)
●Clinical presentation – Clinical presentation ranges from phenotypic women with decreased or absent axillary and pubic hair (complete androgen insensitivity syndrome [CAIS]) through individuals with partial androgen insensitivity (PAIS), including women with partial virilization, to phenotypic men with variable defects in virilization to men with isolated infertility. (See 'Clinical features' above.)
In contrast to the variability in phenotypic expression, CAIS and PAIS have similar endocrine, pathophysiologic, and genetic features. (See 'Hormonal profiles' above and 'Genetics' above.)
●Genetics – The AR is coded by a gene on the X-chromosome. Loss-of-function mutations in the coding sequence of the AR can be found in most women with CAIS but only in approximately 20 percent of subjects with PAIS. In some families with PAIS, affected individuals with the same mutation have different phenotypes, and the same mutation can produce different phenotypes in different families. (See 'Pathogenesis' above and 'Genetics' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges James Griffin, MD and Jean Wilson, MD, who contributed to earlier versions of this topic review.
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
