Partial androgen insensitivity syndrome (PAIS) is a condition that results in the partial inability of the

cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...

to respond to

androgen An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This in ...

s. 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 Secondary sex characteristics are features that appear during puberty in humans, and at sexual maturity in other animals. These characteristics are particularly evident in the sexually dimorphic phenotypic traits that distinguish the sexes of a ...

puberty Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a girl, the testes in a ...

, 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 The Y chromosome is one of two sex chromosomes (allosomes) in therian mammals, including humans, and many other animals. The other is the X chromosome. Y is normally the sex-determining chromosome in many species, since it is the presence or abs ...

(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. PAIS is one of three types of

androgen insensitivity syndrome Androgen insensitivity syndrome (AIS) is a difference in sex development involving hormonal resistance due to androgen receptor dysfunction. It affects 1 in 20,000 to 64,000 XY ( karyotypically male) births. The condition results in the partial ...

, which is divided into three categories that are differentiated by the degree of genital masculinization:

complete androgen insensitivity syndrome Complete androgen insensitivity syndrome (CAIS) is an AIS condition that results in the complete inability of the cell to respond to androgens. As such, the insensitivity to androgens is only clinically significant when it occurs in individuals ...

(CAIS) is indicated when the external genitalia is that of a typical female,

mild androgen insensitivity syndrome Mild androgen insensitivity syndrome (MAIS) is a condition that results in a mild impairment of the cell's ability to respond to androgens. The degree of impairment is sufficient to impair spermatogenesis and / or the development of secondary sexu ...

(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 Endocrinology (from ''endocrine'' + '' -ology'') is a branch of biology and medicine dealing with the endocrine system, its diseases, and its specific secretions known as hormones. It is also concerned with the integration of developmental events ...

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 Secondary may refer to: Science and nature * Secondary emission, of particles ** Secondary electrons, electrons generated as ionization products * The secondary winding, or the electrical or electronic circuit connected to the secondary winding i ...

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. 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 In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (biology), morphology or physical form and structure, its Developmental biology, developmental proc ...

resulting from androgen insensitivity where the genitalia is partially, but not completely

masculinized Virilization or masculinization is the biological development of adult male characteristics in young males or females. Most of the changes of virilization are produced by androgens. Virilization is most commonly used in three medical and biology ...

. 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 Gynecomastia (also spelled gynaecomastia) is the abnormal non-cancerous enlargement of one or both breasts in males due to the growth of breast tissue as a result of a hormone imbalance between estrogens and androgens. Updated by Brent Wisse ( ...

, decreased

terminal hair, and / or a high pitched voice. The phallic structure ranges from a

penis A penis (plural ''penises'' or ''penes'' () is the primary sexual organ that male animals use to inseminate females (or hermaphrodites) during copulation. Such organs occur in many animals, both vertebrate and invertebrate, but males d ...

with varying degrees of diminished size and

hypospadias Hypospadias is a common variation in fetal development of the penis in which the urethra does not open from its usual location in the head of the penis. It is the second-most common birth abnormality of the male reproductive system, affecting ab ...

to a slightly enlarged

clitoris The clitoris ( or ) is a female sex organ present in mammals, ostriches and a limited number of other animals. In humans, the visible portion – the glans – is at the front junction of the labia minora (inner lips), above the op ...

Wolffian structures The mesonephric duct (also known as the Wolffian duct, archinephric duct, Leydig's duct or nephric duct) is a paired organ that forms during the embryonic development of humans and other mammals and gives rise to male reproductive organs. Stru ...

(the

epididymides The epididymis (; plural: epididymides or ) is a tube that connects a testicle to a vas deferens in the male reproductive system. It is a single, narrow, tightly-coiled tube in adult humans, in length. It serves as an interconnection between t ...

, vasa deferentia, and

seminal vesicles The seminal vesicles (also called vesicular glands, or seminal glands) are a pair of two convoluted tubular glands that lie behind the urinary bladder of some male mammals. They secrete fluid that partly composes the semen. The vesicles are 5� ...

) are typically partially or fully developed. The

prostate The prostate is both an accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found only in some mammals. It differs between species anatomically, chemically, and phys ...

is typically small or impalpable. Müllerian remnants are rare, but have been reported. The

gonads A gonad, sex gland, or reproductive gland is a mixed gland that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, produces sper ...

in individuals with PAIS are

testes A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testoste ...

, regardless of

; 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

Cryptorchidism Cryptorchidism, also known as undescended testis, is the failure of one or both testes to descend into the scrotum. The word is from Greek () 'hidden' and () 'testicle'. It is the most common birth defect of the male genital tract. About 3% of ...

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 Micropenis is an unusually small penis. A common criterion is a dorsal (measured on top) penile length of at least 2.5 standard deviations smaller than the mean human penis size (stretched penile length less than 9.3 cm (3.67 in) in adults ...

chordee Chordee is a condition in which the head of the penis curves downward or upward, at the junction of the head and shaft of the penis. The curvature is usually most obvious during erection, but resistance to straightening is often apparent in the ...

bifid Bifid refers to something that is split or cleft into two parts. It may refer to: * Bifid, a variation in the P wave, R wave, or T wave in an echocardiogram in which a wave which usually has a single peak instead has two separate peaks * Bifid ci ...

scrotum, and / or pseudovaginal perineoscrotal hypospadias.

Impotence Erectile dysfunction (ED), also called impotence, is the type of sexual dysfunction in which the penis fails to become or stay erect during sexual activity. It is the most common sexual problem in men.Cunningham GR, Rosen RC. Overview of mal ...

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 Anejaculation is the pathological inability to ejaculate despite an erection in males, with (''orgasmic'') or without (''anorgasmic'') orgasm. Causes It can depend on one or more of several causes, including: * Sexual inhibition * Pharmacologic ...

appears to occur somewhat independently of impotence; some men are still able to

ejaculate Ejaculation is the discharge of semen (the ''ejaculate''; normally containing sperm) from the male reproductory tract as a result of an orgasm. It is the final stage and natural objective of male sexual stimulation, and an essential componen ...

despite impotence, and others without erectile difficulties cannot. Predominantly female phenotypes include a variable degree of labial fusion and

clitoromegaly Clitoromegaly (or macroclitoris) is an abnormal enlargement of the clitoris that is mostly congenital or acquired, though deliberately induced clitoris enlargement as a form of genital body modification is achieved through various uses of anaboli ...

. 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. Quigley scale for androgen insensitivity syndrome

Quigley scale for androgen insensitivity syndrome

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

, which can be severe. Hypospadias may manifest with a partially formed channel from the urethral opening to the

glans The glans (, plural "glandes" ; from the Latin word for "acorn") is a vascular structure located at the tip of the penis in male mammals or a homologous genital structure of the clitoris in female mammals. Structure The exterior structure ...

. Until recently, it was thought that isolated

was not a manifestation of PAIS. However, in 2010, two cases of PAIS manifesting with isolated micropenis were documented. 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

scrotum The scrotum or scrotal sac is an anatomical male reproductive structure located at the base of the penis that consists of a suspended dual-chambered sac of skin and smooth muscle. It is present in most terrestrial male mammals. The scrotum co ...

. 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 A body orifice is any opening in the body of an animal. External In a typical mammalian body such as the human body, the external body orifices are: * The nostrils, for breathing and the associated sense of smell * The mouth, for eating, brea ...

, but also shows signs of slight

masculinization Virilization or masculinization is the biological development of adult male characteristics in young males or females. Most of the changes of virilization are produced by androgens. Virilization is most commonly used in three medical and biology ...

including mild

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 (

, penile

, and

Comorbidity

All forms of androgen insensitivity are associated with

infertility Infertility is the inability of a person, animal or plant to reproduce by natural means. It is usually not the natural state of a healthy adult, except notably among certain eusocial species (mostly haplodiploid insects). It is the normal st ...

, 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

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 Sexual dysfunction is difficulty experienced by an individual or partners during any stage of normal sexual activity, including physical pleasure, desire, preference, arousal, or orgasm. The World Health Organization defines sexual dysfunction a ...

including

impotence Erectile dysfunction (ED), also called impotence, is the type of sexual dysfunction in which the penis fails to become or stay erect during sexual activity. It is the most common sexual problem in men.Cunningham GR, Rosen RC. Overview of mal ...

and

anejaculation Anejaculation is the pathological inability to ejaculate despite an erection in males, with (''orgasmic'') or without (''anorgasmic'') orgasm. Causes It can depend on one or more of several causes, including: * Sexual inhibition * Pharmacologic ...

. A few AR mutations that cause PAIS are also associated with

and

breast The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues. In females, it serves as the mammary gland, which produces and sec ...

cancers. Vaginal

hypoplasia Hypoplasia (from Ancient Greek ὑπo- ''hypo-'' 'under' + πλάσις ''plasis'' 'formation'; adjective form ''hypoplastic'') is underdevelopment or incomplete development of a tissue or organ. is associated with sexual difficulties including vaginal penetration difficulties and

dyspareunia Dyspareunia ( ) is painful sexual intercourse due to medical or psychological causes. The term ''dyspareunia'' covers both female dyspareunia and male dyspareunia, but many discussions that use the term without further specification concern the ...

. There are indications that individuals with an

intersex Intersex people are individuals born with any of several sex characteristics including chromosome patterns, gonads, or genitals that, according to the Office of the United Nations High Commissioner for Human Rights, "do not fit typical b ...

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 Psychotherapy (also psychological therapy, talk therapy, or talking therapy) is the use of psychological methods, particularly when based on regular personal interaction, to help a person change behavior, increase happiness, and overcome prob ...

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

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 Intersex people are individuals born with any of several sex characteristics including chromosome patterns, gonads, or genitals that, according to the Office of the United Nations High Commissioner for Human Rights, "do not fit typical ...

, as some causes are associated with potentially life-threatening adrenal crises. Determination of

testosterone Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteristi ...

, testosterone precursors and

dihydrotestosterone Dihydrotestosterone (DHT, 5α-dihydrotestosterone, 5α-DHT, androstanolone or stanolone) is an endogenous androgen sex steroid and hormone. The enzyme 5α-reductase catalyzes the formation of DHT from testosterone in certain tissues includi ...

(DHT) at baseline and / or after

human chorionic gonadotropin Human chorionic gonadotropin (hCG) is a hormone for the maternal recognition of pregnancy produced by trophoblast cells that are surrounding a growing embryo (syncytiotrophoblast initially), which eventually forms the placenta after implantatio ...

(hCG) stimulation can be used to exclude such defects in androgen

biosynthesis Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecul ...

. Approximately one half of all 46,XY individuals born with ambiguous genitalia will not receive a definitive diagnosis.

Androgen receptor The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone in ...

(AR) gene

mutations In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...

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 A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells ...

study has long been the

gold standard A gold standard is a monetary system in which the standard economic unit of account is based on a fixed quantity of gold. The gold standard was the basis for the international monetary system from the 1870s to the early 1920s, and from th ...

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 The endocrine system is a messenger system comprising feedback loops of the hormones released by internal glands of an organism directly into the circulatory system, regulating distant target organs. In vertebrates, the hypothalamus is the neur ...

tests is particularly helpful in isolating a diagnosis of PAIS. One such test is the

(hCG) stimulation test. If the gonads are

, there will be an increase in the level of serum testosterone in response to the hCG, regardless of

testicular descent The development of the gonads is part of the prenatal development of the reproductive system and ultimately forms the testes in males and the ovaries in females. The gonads initially develop from the mesothelial layer of the peritoneum. The ovar ...

. The magnitude of the testosterone increase can help differentiate between androgen resistance and gonadal dysgenesis, as does evidence of a

uterus The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The ...

ultrasound Ultrasound is sound waves with frequencies higher than the upper audible limit of human hearing. Ultrasound is not different from "normal" (audible) sound in its physical properties, except that humans cannot hear it. This limit varies ...

examination. Testicular function can also be assessed by measuring serum

anti-Müllerian hormone Anti-Müllerian hormone (AMH), also known as Müllerian-inhibiting hormone (MIH), is a glycoprotein hormone structurally related to inhibin and activin from the transforming growth factor beta superfamily, whose key roles are in growth differen ...

levels, which in turn can further differentiate PAIS from gonadal dysgenesis and bilateral

anorchia Anorchia (also called anorchidism or anorchism) is a disorder of sex development in which a person with XY karyotype, which corresponds to male sex, is born without testes. Within a few weeks of fertilization, the embryo develops rudimentary go ...

. Another useful dynamic test involves measuring the response to exogenous steroids; individuals with AIS show a decreased response in

serum Serum may refer to: * Serum (blood), plasma from which the clotting proteins have been removed **Antiserum, blood serum with specific antibodies for passive immunity * Serous fluid, any clear bodily fluid *Truth serum, a drug that is likely to mak ...

sex hormone binding globulin Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a glycoprotein that binds to androgens and estrogens. When produced by the Sertoli cells in the seminiferous tubules of the testis, it has also been called androgen-bi ...

(SHBG) after a short term administration of anabolic steroids. Two studies indicate that measuring the response in SHBG after the administration of

stanozolol Stanozolol ( abbrev. Stz), sold under many brand names, is an androgen and anabolic steroid (AAS) medication derived from dihydrotestosterone (DHT). It is used to treat hereditary angioedema. It was developed by American pharmaceutical company W ...

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 The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone in ...

protein that result from an AR gene

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...

are not currently available. Areas of management include

sex assignment Sex assignment (sometimes known as gender assignment) is the discernment of an infant's sex at or before birth. A relative, midwife, nurse or physician inspects the external genitalia when the baby is delivered and, in more than 99.95% of b ...

genitoplasty Genitoplasty is plastic surgery to the genitals. Genitoplasties may be reconstructive to repair injuries, and damage arising from cancer treatment, or congenital disorders, endocrine conditions, or they may be cosmetic. __TOC__ Medical uses Geni ...

gonadectomy Castration is any action, surgical, chemical, or otherwise, by which an individual loses use of the testicles: the male gonad. Surgical castration is bilateral orchiectomy (excision of both testicles), while chemical castration uses pharmaceu ...

in relation to

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

risk,

hormone replacement therapy Hormone replacement therapy (HRT), also known as menopausal hormone therapy or postmenopausal hormone therapy, is a form of hormone therapy used to treat symptoms associated with female menopause. These symptoms can include hot flashes, vaginal ...

, and genetic and

. 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

that may be difficult to classify as primarily male or female, and some will be incapable of

virilization Virilization or masculinization is the biological development of adult male characteristics in young males or females. Most of the changes of virilization are produced by androgens. Virilization is most commonly used in three medical and biology ...

. Parents of an affected newborn should seek immediate help at a center with an experienced multidisciplinary team, and should avoid

gender assignment Sex assignment (sometimes known as gender assignment) is the discernment of an infant's sex at or before birth. A relative, midwife, nurse or physician inspects the external genitalia when the baby is delivered and, in more than 99.95% of birt ...

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 A sex organ (or reproductive organ) is any part of an animal or plant that is involved in sexual reproduction. The reproductive organs together constitute the reproductive system. In animals, the testis in the male, and the ovary in the female, a ...

, the extent to which the child can virilize at puberty, surgical options and the postoperative sexual function of the genitalia,

complexity, potential for

fertility Fertility is the capability to produce offspring through reproduction following the onset of sexual maturity. The fertility rate is the average number of children born by a female during her lifetime and is quantified demographically. Ferti ...

, and the projected

gender identity Gender identity is the personal sense of one's own gender. Gender identity can correlate with a person's assigned sex or can differ from it. In most individuals, the various biological determinants of sex are congruent, and consistent with the ...

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 Virilization or masculinization is the biological development of adult male characteristics in young males or females. Most of the changes of virilization are produced by androgens. Virilization is most commonly used in three medical and biology ...

capacity can be assessed by measuring the response to a trial of

exogenous In a variety of contexts, exogeny or exogeneity () is the fact of an action or object originating externally. It contrasts with endogeneity or endogeny, the fact of being influenced within a system. Economics In an economic model, an exogen ...

androgens An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This in ...

; some studies have measured the growth of the

phallus A phallus is a penis (especially when erect), an object that resembles a penis, or a mimetic image of an erect penis. In art history a figure with an erect penis is described as ithyphallic. Any object that symbolically—or, more precise ...

in response to exogenous

, while others have measured the change in

(SHBG) in response to the artificial androgen

to assess androgen sensitivity. Some experts have cautioned that it remains to be proved that a good response to exogenous androgens in

neonates An infant or baby is the very young offspring of human beings. ''Infant'' (from the Latin word ''infans'', meaning 'unable to speak' or 'speechless') is a formal or specialised synonym for the common term ''baby''. The terms may also be used to ...

is a good predictor of androgen response at puberty. If a

in the AR gene is found, it is important to determine whether the mutation is inherited or de novo (i.e. a

somatic mutation A somatic mutation is a change in the DNA sequence of a somatic cell of a multicellular organism with dedicated reproductive cells; that is, any mutation that occurs in a cell other than a gamete, germ cell, or gametocyte. Unlike germline mutatio ...

); a certain amount of the

wild-type The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, "m ...

androgen receptor will be present in cases of somatic mutation, which can induce virilization at puberty. A genital skin

study and a

(hCG) stimulation test may also provide information helpful in the assessment of virilization capacity.

Psychosexual development In Freudian psychology, psychosexual development is a central element of the psychoanalytic sexual drive theory. Freud believed that personality developed through a series of childhood stages in which pleasure seeking energies from the child b ...

is influenced by many factors, including the timing, amount, and type of androgen exposure, receptor functionality, and environment, and is thus difficult to predict.

Gender identity Gender identity is the personal sense of one's own gender. Gender identity can correlate with a person's assigned sex or can differ from it. In most individuals, the various biological determinants of sex are congruent, and consistent with the ...

begins to develop before 3 years of age, although the earliest age at which it can be reliably assessed has yet to be determined. Approximately 25% of individuals with PAIS are dissatisfied with their assigned gender, regardless of being raised as male or female. One study reports that 46,XY individuals born with

and no

are better off being raised male, despite the success of some being raised female. Studies involving the more ambiguous

phenotypic In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological pr ...

forms of PAIS are less decisive.

Homosexuality Homosexuality is Romance (love), romantic attraction, sexual attraction, or Human sexual activity, sexual behavior between members of the same sex or gender. As a sexual orientation, homosexuality is "an enduring pattern of emotional, romant ...

with respect to assigned gender and atypical gender role behavior are known to occur more frequently in individual with PAIS, and may occur with or without

gender dysphoria Gender dysphoria (GD) is the distress a person experiences due to a mismatch between their gender identitytheir personal sense of their own genderand their sex assigned at birth. The diagnostic label gender identity disorder (GID) was used unti ...

; neither should be interpreted as an indication of incorrect

. If an affected child does express feelings of gender dysphoria, the opportunity to explore such feelings with a psychologist experienced in treating

conditions should be accommodated. If feelings of gender dysphoria persist, gender reassignment should be initiated, possibly with the aid of a specialist in the field.

Genitoplasty

Genitoplasty Genitoplasty is plastic surgery to the genitals. Genitoplasties may be reconstructive to repair injuries, and damage arising from cancer treatment, or congenital disorders, endocrine conditions, or they may be cosmetic. __TOC__ Medical uses Geni ...

, unlike gender assignment, can be irreversible, and there is no guarantee that adult gender identity will develop as assigned despite surgical intervention. Some aspects of genitoplasty are still being debated; a variety of different opinions have been presented by professionals, self-help groups, and patients over the last few decades. Points of consideration include what conditions justify genitoplasty, the extent and type of genitoplasty that should be employed, when genitoplasty should be performed, and what the goals of genitoplasty should be. Gender assignment itself does not predicate the need for immediate genitoplasty; in some cases, surgical intervention can be delayed to allow the affected child to reach an age and maturity sufficient to have a role in such decisions. Some studies suggest that early surgeries can still produce satisfactory outcomes, while others suggest it to be unlikely. Even surgeries that are planned as one-stage procedures often require further major surgery. Scarring and tissue loss that result from repeated surgical procedures are of particular concern, due to the presumed negative impact on sexual function. While it is thought that feminizing genitoplasty typically requires fewer surgeries to achieve an acceptable result and results in fewer urologic difficulties, there is no evidence that feminizing surgery results in a better

psychosocial The psychosocial approach looks at individuals in the context of the combined influence that psychological factors and the surrounding social environment have on their physical and mental wellness and their ability to function. This approach is ...

outcome. In one study, individuals with grade 3 PAIS who were raised male rated their body image and sexual function similarly to those who were raised female, even though they were more likely to have genitalia that were abnormal in size and appearance; more than half of the male participants had a stretched penile length that was below 2.5 standard deviations of the mean, while only 6% of female participants presented with a short vagina in adulthood, and participating physicians gave a lower

cosmetic Cosmetic may refer to: *Cosmetics, or make-up, substances to enhance the beauty of the human body, apart from simple cleaning *Cosmetic, an adjective describing beauty, aesthetics, or appearance, especially concerning the human body *Cosmetic, a t ...

rating to the surgical results of the men than the women. Both male and female participants cited the appearance of their genitalia as being the greatest contributing factor to their dissatisfaction with their

body image Body image is a person's thoughts, feelings and perception of the aesthetics or sexual attractiveness of their own body. The concept of body image is used in a number of disciplines, including neuroscience, psychology, medicine, psychiatry, ps ...

. In two larger studies, the common predictor of gender reassignment was stigmatization related to having an

condition. The outcome of masculinizing genitoplasty is dependent on the amount of

erectile tissue Erectile tissue is tissue in the body with numerous vascular spaces, or cavernous tissue, that may become engorged with blood. However, tissue that is devoid of or otherwise lacking erectile tissue (such as the labia minora, the vestibule/vagina and ...

and the extent of

. Procedures include correction of penile curvature and

, reconstruction of the

urethra The urethra (from Greek οὐρήθρα – ''ourḗthrā'') is a tube that connects the urinary bladder to the urinary meatus for the removal of urine from the body of both females and males. In human females and other primates, the urethra ...

correction,

orchidopexy Orchiopexy (or orchidopexy) is a surgery to move and/or permanently fix a testicle into the scrotum. While orchiopexy typically describes the operation to surgically correct an undescended testicle, it is also used to resolve testicular torsion. ...

, and Müllerian remnant removal to prevent infection and pseudo-

incontinence Incontinence or Incontinent may refer to: *Fecal incontinence, the involuntary excretion of bowel contents * Urinary incontinence, the involuntary excretion of urine * Lack of moderation or self-control, especially related to sexual desire - see ...

. Erectile prosthesis may be inserted in cases of successful neophalloplasty in adulthood, although it has a high

morbidity A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...

. Additional surgeries may be required to correct postsurgical complications such as

stenosis A stenosis (from Ancient Greek στενός, "narrow") is an abnormal narrowing in a blood vessel or other tubular organ or structure such as foramina and canals. It is also sometimes called a stricture (as in urethral stricture). ''Stricture'' ...

of the

anastomosis An anastomosis (, plural anastomoses) is a connection or opening between two things (especially cavities or passages) that are normally diverging or branching, such as between blood vessels, leaf veins, or streams. Such a connection may be norm ...

between the native

and the

graft Graft or grafting may refer to: *Graft (politics), a form of political corruption * Graft, Netherlands, a village in the municipality of Graft-De Rijp Science and technology *Graft (surgery), a surgical procedure *Grafting, the joining of plant t ...

, urethral fistulas, and posterior displacement of the balanic meatus. Successful masculinizing genitoplasty performed on individuals with grade 3 PAIS often requires multiple surgeries. If feminizing genitoplasty is performed in infancy, the result will need to be refined at puberty through additional surgery. Procedures include clitoral reduction / recession, labiaplasty, repair of the common urogenital sinus, vaginoplasty, and vaginal dilation through non-surgical pressure methods.

Clitoral The clitoris ( or ) is a female sex organ present in mammals, ostriches and a limited number of other animals. In humans, the visible portion – the glans – is at the front junction of the labia minora (inner lips), above the open ...

reduction / recession surgery carries with it the risk of

necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated diges ...

as well as the risk of impairing the sexual function of the genitalia, and thus should not be performed for less severe

. Clitoral surgery should be focused on function rather than appearance, with care being taken to spare the erectile function and

innervation A nerve is an enclosed, cable-like bundle of nerve fibers (called axons) in the peripheral nervous system. A nerve transmits electrical impulses. It is the basic unit of the peripheral nervous system. A nerve provides a common pathway for the ...

of the clitoris. If PAIS presents with a common urogenital

sinus Sinus may refer to: Anatomy * Sinus (anatomy), a sac or cavity in any organ or tissue ** Paranasal sinuses, air cavities in the cranial bones, especially those near the nose, including: *** Maxillary sinus, is the largest of the paranasal sinuses, ...

, the

American Academy of Pediatrics The American Academy of Pediatrics (AAP) is an American professional association of pediatricians, headquartered in Itasca, Illinois. It maintains its Department of Federal Affairs office in Washington, D.C. Background The Academy was found ...

currently recommends that surgery to separate the

from the

vagina In mammals, the vagina is the elastic, muscular part of the female genital tract. In humans, it extends from the vestibule to the cervix. The outer vaginal opening is normally partly covered by a thin layer of mucosal tissue called the hymen ...

be performed at an early age. As is the case for CAIS, vaginal dilation using pressure dilation methods should be attempted before the surgical creation of a neovagina is considered, and neither should be performed before puberty. Complications of feminizing genitoplasty can include vaginal

, meatal stenosis, vaginourethral

fistula A fistula (plural: fistulas or fistulae ; from Latin ''fistula'', "tube, pipe") in anatomy is an abnormal connection between two hollow spaces (technically, two epithelialized surfaces), such as blood vessels, intestines, or other hollow or ...

, female

urinary tract The urinary system, also known as the urinary tract or renal system, consists of the kidneys, ureters, bladder, and the urethra. The purpose of the urinary system is to eliminate waste from the body, regulate blood volume and blood pressure, c ...

injuries, and recurrent clitoromegaly. Successful feminizing genitoplasty performed on individuals with grade 3 PAIS often requires multiple surgeries, although more surgeries are typically required for successful masculinizing genitoplasty in this population. Many surgical procedures have been developed to create a neovagina, as none of them is ideal. Surgical intervention should be considered only after non-surgical pressure dilation methods have failed to produce a satisfactory result. Neovaginoplasty can be performed using

skin grafts Skin grafting, a type of graft surgery, involves the transplantation of skin. The transplanted tissue is called a skin graft. Surgeons may use skin grafting to treat: * extensive wounding or trauma * burns * areas of extensive skin loss du ...

, a segment of

bowel The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...

ileum The ileum () is the final section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms posterior intestine or distal intestine m ...

peritoneum The peritoneum is the serous membrane forming the lining of the abdominal cavity or coelom in amniotes and some invertebrates, such as annelids. It covers most of the intra-abdominal (or coelomic) organs, and is composed of a layer of mes ...

, ,

buccal mucosa The oral mucosa is the mucous membrane lining the inside of the mouth. It comprises stratified squamous epithelium, termed "oral epithelium", and an underlying connective tissue termed '' lamina propria''. The oral cavity has sometimes been des ...

amnion The amnion is a membrane that closely covers the human and various other embryos when first formed. It fills with amniotic fluid, which causes the amnion to expand and become the amniotic sac that provides a protective environment for the develo ...

, or

dura mater In neuroanatomy, dura mater is a thick membrane made of dense irregular connective tissue that surrounds the brain and spinal cord. It is the outermost of the three layers of membrane called the meninges that protect the central nervous system. ...

. Success of such methods should be determined by sexual function, and not by vaginal length alone, as has been done in the past. Ileal or cecal segments may be problematic because of a shorter

mesentery The mesentery is an organ that attaches the intestines to the posterior abdominal wall in humans and is formed by the double fold of peritoneum. It helps in storing fat and allowing blood vessels, lymphatics, and nerves to supply the intesti ...

, which may produce tension on the neovagina, leading to

. The

sigmoid Sigmoid means resembling the lower-case Greek letter sigma (uppercase Σ, lowercase σ, lowercase in word-final position ς) or the Latin letter S. Specific uses include: * Sigmoid function, a mathematical function * Sigmoid colon, part of the l ...

neovagina is thought to be self-lubricating, without the excess

mucus Mucus ( ) is a slippery aqueous secretion produced by, and covering, mucous membranes. It is typically produced from cells found in mucous glands, although it may also originate from mixed glands, which contain both serous and mucous cells. It ...

production associated with segments of small bowel. Vaginoplasty may create scarring at the

introitus An introitus is an entrance into a canal or hollow organ Organ may refer to: Biology * Organ (biology), a part of an organism Musical instruments * Organ (music), a family of keyboard musical instruments characterized by sustained tone ** Elec ...

(the vaginal opening), requiring additional surgery to correct. Vaginal dilators are required postoperatively to prevent vaginal stenosis from scarring. Other complications include

bladder The urinary bladder, or simply bladder, is a hollow organ in humans and other vertebrates that stores urine from the kidneys before disposal by urination. In humans the bladder is a distensible organ that sits on the pelvic floor. Urine en ...

and bowel injuries. Yearly exams are required, as neovaginoplasty carries a risk of

carcinoma Carcinoma is a malignancy that develops from epithelial cells. Specifically, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that arises from cells originating in the endodermal, mesoderm ...

, although carcinoma of the neovagina is uncommon. Neither neovaginoplasty nor vaginal dilation should be performed before

Gonadectomy

Gonadectomy Castration is any action, surgical, chemical, or otherwise, by which an individual loses use of the testicles: the male gonad. Surgical castration is bilateral orchiectomy (excision of both testicles), while chemical castration uses pharmaceu ...

at time of diagnosis is the current recommendation for PAIS if presenting with

cryptorchidism Cryptorchidism, also known as undescended testis, is the failure of one or both testes to descend into the scrotum. The word is from Greek () 'hidden' and () 'testicle'. It is the most common birth defect of the male genital tract. About 3% of ...

. The risk of

malignancy Malignancy () is the tendency of a medical condition to become progressively worse. Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not s ...

when

are located intrascrotally is unknown; the current recommendation is to

biopsy A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, or an interventional cardiologist. The process involves extraction of sample cells or tissues for examination to determine the presence or extent of a dise ...

the testes at puberty, allowing investigation of at least 30

seminiferous tubules Seminiferous tubules are located within the testes, and are the specific location of meiosis, and the subsequent creation of male gametes, namely spermatozoa. Structure The epithelium of the tubule consists of a type of sustentacular cells known ...

, with diagnosis preferably based on OCT3/4

immunohistochemistry Immunohistochemistry (IHC) is the most common application of immunostaining. It involves the process of selectively identifying antigens (proteins) in cells of a tissue section by exploiting the principle of antibodies binding specifically to ant ...

, followed by regular examinations.

Hormone replacement therapy Hormone replacement therapy (HRT), also known as menopausal hormone therapy or postmenopausal hormone therapy, is a form of hormone therapy used to treat symptoms associated with female menopause. These symptoms can include hot flashes, vaginal ...

is required after gonadectomy, and should be modulated over time to replicate the hormone levels naturally present in the body during the various stages of

. Artificially induced puberty results in the same, normal development of

growth spurt Human height or stature is the distance from the bottom of the feet to the top of the head in a human body, standing erect. It is measured using a stadiometer, in centimetres when using the metric system or SI system, or feet and inches when u ...

, and bone mineral accumulation. Women with PAIS may have a tendency towards bone mineralization deficiency, although this increase is thought to be less than is typically seen in CAIS, and is similarly managed.

Hormonal replacement therapy

Testosterone Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteristi ...

has been used to successfully treat

undervirilization Undervirilization is a medical term describing the state of a male whose body, especially the genitalia, shows evidence of below-normal prenatal (less commonly pubertal) androgen effects. See virilization for a more detailed description of the n ...

in some but not all men with PAIS, despite having supraphysiological levels of testosterone to start with. Treatment options include

transdermal Transdermal is a route of administration wherein active ingredients are delivered across the skin for systemic distribution. Examples include transdermal patches used for medicine delivery. The drug is administered in the form of a patch or ointme ...

gels or patches, oral or injectable

testosterone undecanoate Testosterone undecanoate, sold under the brand names Andriol and Aveed among others, is an androgen and anabolic steroid (AAS) medication that is used mainly in the treatment of low testosterone levels in men, including hormone therapy for tran ...

, other injectable testosterone

esters In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...

, testosterone pellets, or Cheek, buccal testosterone systems. Supraphysiological doses may be required to achieve the desired physiological effect, which may be difficult to achieve using non-injectable testosterone preparations. Exogenous testosterone supplementation in unaffected men can produce various unwanted side effects, including prostatic hypertrophy, polycythemia,

, hair loss, acne, and the suppression of the hypothalamic-pituitary-gonadal axis, resulting in the reduction of gonadotropins (i.e., luteinizing hormone and follicle-stimulating hormone) and spermatogenesis, spermatogenic defect. These effects may not manifest at all in men with AIS, or might only manifest at a much higher concentration of testosterone, depending on the degree of androgen insensitivity. Those undergoing high dose androgen therapy should be monitored for safety and efficacy of treatment, possibly including regular breast exam, breast and Rectal examination, prostate examinations. Some individuals with PAIS have a sufficiently high sperm count to father children; at least one case report has been published that describes fertile men who fit the criteria for grade 2 PAIS (

, penile

, and

). Several publications have indicated that testosterone treatment can correct low sperm counts in men with MAIS. At least one case report has been published that documents the efficacy of treating a low sperm-count with tamoxifen in an individual with PAIS.

Counseling

Depending on

features,

and other sexual problems such as

or Hypoactive sexual desire disorder, sexual aversion may be fairly common among individuals with PAIS, but do not necessarily indicate low libido. Support groups for individuals with PAIS may help affected individuals discuss their concerns more comfortably. Some individuals with PAIS may try to avoid intimate relationships out of fear of rejection; individual therapy may help some to overcome social anxiety, and restore focus to interpersonal relationships instead of solely on sexual function and activity.

Society and culture

Adults with partial androgen insensitivity syndrome include Australian-Maltese advocate Tony Briffa (politician), Tony Briffa, considered to be the world's first openly intersex mayor and public office-bearer. Briffa served as Deputy Mayor of the City of Hobsons Bay, Victoria, between 2009 and 2011, and Mayor between 2011 and 2012. In Intersex in history, history, the Roman sophist and philosopher Favorinus, Favorinus of Arelate has been described as having partial androgen insensitivity syndrome.

Notable people with PAIS

* Tony Briffa (politician), Tony Briffa * Small Luk * Eliana Rubashkyn * Sean Saifa Wall * Sogto Ochirov

Sentencia SU 337/99, Colombia

In Sentencia SU-337/99, of May 12, 1999, the Constitutional Court of Colombia determined that "qualified and persistent" informed consent is required for genital surgeries in children. The Court ruled in the case of XX, an 8-year old with ambiguous genitalia, androgen insensitivity syndrome, androgen insensitivity and XY chromosomes, raised as a girl. Doctors recommended intersex medical interventions, feminizing surgeries, including a

, vaginoplasty and clitoroplasty before puberty, but the hospital would not proceed without the consent of the Colombian Institute of Family Welfare and the Office of the Public Advocate. The mother brought a case against Institute and Office of the Public Advocate, seeking to provide substitute consent. The mother argued that “the capacity to decide, it would be too late and would prevent normal psychological, physical, and social development”. The Court refused the mother's claim. It questioned the urgency of the case, argued by medical teams. Civil rights advocates and a minority of doctors favored deferring treatment due to lack of evidence and the irreversible nature of the proposed interventions. The Court observed that advocates of surgery were more numerous than opponents, alternatives to surgery were not entirely feasible, and surgeries had improved, “making it less likely that sexual sensitivity would be destroyed; and the medical community was improving communication with parents”. The Court determined that a constitutional protection of a right to free development of personality meant that a child's autonomy increases with age, including the development of a gender identity and bodily awareness. It determined that the best interests of the child were protected by allowing the child to determine their own gender identity. The Court determined that genital surgeries should not be conducted on children over the age of five, and that multidisciplinary teams should assess children's needs on a case-by-case basis.

References

External links

* {{DEFAULTSORT:Androgen Insensitivity Syndrome Transcription factor deficiencies Syndromes Intersex variations