partial androgen insensitivity syndrome partial androgen insensitivity syndrome partial androgen insensitivity syndrome (pais) is a condition that results in the partial inability of the cell to respond to androgens. it is an x linked recessive condition. the partial unresponsiveness of the cell to the presence of androgenic hormones impairs the masculinization of male genitalia in the developing fetus, as well as the development of male secondary sexual characteristics at puberty, but does not significantly impair female genital or sexual development. as such, the insensitivity to androgens is clinically significant only when it occurs in individuals with a y chromosome (or more specifically, an sry gene). clinical features include ambiguous genitalia at birth and primary amenhorrhoea with clitoromegaly with inguinal masses. mullerian structures are not present in the individual. partial androgen insensitivity syndromeother namespartial androgen resistance syndrome; reifenstein syndromeais results when the function of the androgen receptor (ar) is impaired. the ar protein (pictured) mediates the effects of androgens in the human body.specialtyendocrinology pais is one of three types of androgen insensitivity syndrome, which is divided into three categories that are differentiated by the degree of genital masculinization: complete androgen insensitivity syndrome (cais) is indicated when the external genitalia is that of a typical female, mild androgen insensitivity syndrome (mais) is indicated when the external genitalia is that of a typical male, and partial androgen insensitivity syndrome (pais) is indicated when the external genitalia is partially, but not fully masculinized. androgen insensitivity syndrome is the largest single entity that leads to 46,xy undermasculinization. there are differing opinions on whether treatment is necessary. treatment may include irreversible and far reaching surgical operations such as gonadectomy, as well as hormone replacement therapy, or vaginoplasty if the patient has desire to engage in penetrative sex. signs and symptoms a supplemental system of phenotypic grading that uses seven classes instead of the traditional three was proposed by pediatric endocrinologist charmian a. quigley et al. in 1995. the first six grades of the scale, grades 1 through 6, are differentiated by the degree of genital masculinization; grade 1 is indicated when the external genitalia is fully masculinized, grade 6 is indicated when the external genitalia is fully feminized, and grades 2 through 5 quantify four degrees of increasingly feminized genitalia that lie in the interim. grade 7 is indistinguishable from grade 6 until puberty, and is thereafter differentiated by the presence of secondary terminal hair; grade 6 is indicated when secondary terminal hair is present, whereas grade 7 is indicated when it is absent. the quigley scale can be used in conjunction with the traditional three classes of ais to provide additional information regarding the degree of genital masculinization, and is particularly useful when the diagnosis is pais. left, 19-year-old man with grade 3 pais before initiation of androgen therapy. right, habitus after 3.5 years of androgen treatment. partial androgen insensitivity syndrome is diagnosed when the degree of androgen insensitivity in an individual with a 46,xy karyotype is great enough to partially prevent the masculinization of the genitalia, but is not great enough to completely prevent genital masculinization. this includes any phenotype resulting from androgen insensitivity where the genitalia is partially, but not completely masculinized. genital ambiguities are frequently detected during clinical examination at birth, and consequently, a pais diagnosis can be made during infancy as part of a differential diagnostic workup. pubertal undervirilization is common, including gynecomastia, decreased secondary terminal hair, and / or a high pitched voice. the phallic structure ranges from a penis with varying degrees of diminished size and hypospadias to a slightly enlarged clitoris. wolffian structures (the epididymides, vasa deferentia, and seminal vesicles) are typically partially or fully developed. the prostate is typically small or impalpable. müllerian remnants are rare, but have been reported. the gonads in individuals with pais are testes, regardless of phenotype; during the embryonic stage of development, testes form in an androgen-independent process that occurs due to the influence of the sry gene on the y chromosome. cryptorchidism is common, and carries with it a 50% risk of germ cell malignancy. if the testes are located intrascrotally, there may still be significant risk of germ cell malignancy; studies have not yet been published to assess this risk. predominantly male phenotypes vary in the degree of genital undermasculinization to include micropenis, chordee, bifid scrotum, and / or pseudovaginal perineoscrotal hypospadias. impotence may be fairly common, depending on phenotypic features; in one study of 15 males with pais, 80% of those interviewed indicated that they had some degree of impotence. anejaculation appears to occur somewhat independently of impotence; some men are still able to ejaculate despite impotence, and others without erectile difficulties cannot. predominantly female phenotypes include a variable degree of labial fusion and clitoromegaly. ambiguous phenotypic states include a phallic structure that is intermediate between a clitoris and a penis, and a single perineal orifice that connects to both the urethra and the vagina (i.e. urogenital sinus). at birth, it may not be possible to immediately differentiate the external genitalia of individuals with pais as being either male or female, although the majority of individuals with pais are raised male. schematic representation of the quigley scale. grades 2 through 5 quantify four degrees of increasingly feminized genitalia that correspond to pais. grades 1 and 6/7 correspond to mais and cais, respectively. given the wide diversity of phenotypes associated with pais, the diagnosis is often further specified by assessing genital masculinization. grades 2 through 5 of the quigley scale quantify four degrees of increasingly feminized genitalia that correspond to pais. grade 2, the mildest form of pais, presents with a predominantly male phenotype that presents with minor signs of undermasculinized genitalia, such as isolated hypospadias, which can be severe. hypospadias may manifest with a partially formed channel from the urethral opening to the glans. until recently, it was thought that isolated micropenis was not a manifestation of pais. however, in 2010, two cases of pais manifesting with isolated micropenis were documented. grade 4 pais with bifid scrotum, microphallus-like clitoris, and urethral orifice with terminal sinus urogenitalis grade 3, the most common phenotypic form of pais, features a predominantly male phenotype that is more severely undermasculinized, and typically presents with micropenis and pseudovaginal perineoscrotal hypospadias with bifid scrotum. grade 4 presents with a gender ambiguous phenotype, including a phallic structure that is intermediate between a clitoris and a penis. the urethra typically opens into a common channel with the vagina (i.e. urogenital sinus). grade 5, the form of pais with the greatest degree of androgen insensitivity, presents with a mostly female phenotype, including separate urethral and vaginal orifices, but also shows signs of slight masculinization including mild clitoromegaly and / or partial labial fusion. previously, it was erroneously thought that individuals with pais were always infertile; at least one case report has been published that describes fertile men that fit the criteria for grade 2 pais (micropenis, penile hypospadias, and gynecomastia). comorbidity histopathology of testicular tissue showing immature germ cells and spermatogonia with decreased tubular diameter. scattered groups of leydig cells appearing immature. all forms of androgen insensitivity are associated with infertility, though exceptions have been reported for both the mild and partial forms. pais is associated with a 50% risk of germ cell malignancy when the testes are undescended. if the testes are located intrascrotally, there may still be significant risk of germ cell malignancy; studies have not yet been published to assess this risk. some men with pais may experience sexual dysfunction including impotence and anejaculation. a few ar mutations that cause pais are also associated with prostate and breast cancers. vaginal hypoplasia, a relatively frequent finding in cais and some forms of pais, is associated with sexual difficulties including vaginal penetration difficulties and dyspareunia. there are indications that individuals with an intersex condition may be more prone to psychological difficulties, due at least in part to parental attitudes and behaviors, and concludes that preventative long-term psychological counseling for parents as well as for affected individuals should be initiated at the time of diagnosis. more recent research based on interviews of people with intersex variations indicate a need for more family protection from intervention and more family support. lifespan is not thought to be affected by ais. diagnosis main article: diagnosis of androgen insensitivity syndrome unfortunately, the number of differentials to consider for pais is particularly large. prompt diagnosis is particularly urgent when a child is born with ambiguous genitalia, as some causes are associated with potentially life-threatening adrenal crises. determination of testosterone, testosterone precursors and dihydrotestosterone (dht) at baseline and / or after human chorionic gonadotropin (hcg) stimulation can be used to exclude such defects in androgen biosynthesis. approximately one half of all 46,xy individuals born with ambiguous genitalia will not receive a definitive diagnosis. androgen receptor (ar) gene mutations cannot be found in 27% to 72% of individuals with pais. as a result, genetic analysis can be used to confirm a diagnosis of pais, but it cannot be used to rule out pais. evidence of abnormal androgen binding in a genital skin fibroblast study has long been the gold standard for the diagnosis of pais, even when an ar mutation is not present. however, some cases of pais, including ar-mutant-positive cases, will show normal androgen binding. a family history consistent with x-linked inheritance is more commonly found in ar-mutant-positive cases than ar-mutant-negative cases. the use of dynamic endocrine tests is particularly helpful in isolating a diagnosis of pais. one such test is the human chorionic gonadotropin (hcg) stimulation test. if the gonads are testes, there will be an increase in the level of serum testosterone in response to the hcg, regardless of testicular descent. the magnitude of the testosterone increase can help differentiate between androgen resistance and gonadal dysgenesis, as does evidence of a uterus on ultrasound examination. testicular function can also be assessed by measuring serum anti-müllerian hormone levels, which in turn can further differentiate pais from gonadal dysgenesis and bilateral anorchia. another useful dynamic test involves measuring the response to exogenous steroids; individuals with ais show a decreased response in serum sex hormone binding globulin (shbg) after a short term administration of anabolic steroids. two studies indicate that measuring the response in shbg after the administration of stanozolol could help to differentiate individuals with pais from those with other causes of ambiguous genitalia, although the response in individuals with predominantly male phenotypes overlaps somewhat with the response in normal males. management management of ais is currently limited to symptomatic management; methods to correct a malfunctioning androgen receptor protein that result from an ar gene mutation are not currently available. areas of management include sex assignment, genitoplasty, gonadectomy in relation to tumor risk, hormone replacement therapy, and genetic and psychological counseling. non-consensual interventions are still often performed, although general awareness on the resulting psychological traumatization is rising. sex assignment the decision of whether to raise an individual with pais as a boy or a girl may not be obvious; grades 3 and 4 in particular present with a phenotype that may be difficult to classify as primarily male or female, and some will be incapable of virilization at puberty. parents of an affected newborn should seek immediate help at a center with an experienced multidisciplinary team, and should avoid gender assignment beforehand. older guidelines from 2006 advised against waiting for the child to decide for themselves. according to them, key considerations involved in assigning gender include the appearance of the genitalia, the extent to which the child can virilize at puberty, surgical options and the postoperative sexual function of the genitalia, genitoplasty complexity, potential for fertility, and the projected gender identity of the child. the majority of individuals with pais are raised male. more recently, the interests of intersex people themselves are being taken into consideration by the medical community. some parents have pushed their children with intersex variations to display gender normative roles and behaviours, or to engage in hormonal and surgical interventions to make their bodies appear more aesthetically 'normative'. research based on interviews of people with intersex variations indicate a need for more family protection from intervention and more family support. virilization capacity can be assessed by measuring the response to a trial of exogenous androgens; some studies have measured the growth of the phallus in response to exogenous testosterone