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 * Cellphone, a phone connected to a cellular network * Clandestine cell, a penetration-resistant form of a secret or outlawed organization * Electrochemical cell, a de ...

to respond to

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

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 A secondary sex characteristic is a physical characteristic of an organism that is related to or derived from its sex, but not directly part of its reproductive system. In humans, these characteristics typically start to appear during puberty ...

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 female, the testicles i ...

, 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 in therian mammals and other organisms. Along with the X chromosome, it is part of the XY sex-determination system, in which the Y is the sex-determining chromosome because the presence of the ...

(or more specifically, an

SRY gene Sex-determining region Y protein (SRY), or testis-determining factor (TDF), is a DNA-binding protein (also known as gene-regulatory protein/transcription factor) encoded by the ''SRY'' gene that is responsible for the initiation of male sex ...

). Clinical features include ambiguous genitalia at birth and primary amenhorrhoea with clitoromegaly with inguinal masses. Müllerian structures are not present in the individual. PAIS is one of three types of

androgen insensitivity syndrome Androgen insensitivity syndrome (AIS) is a condition involving the inability to respond to androgens, typically due to androgen receptor dysfunction. It affects 1 in 20,000 to 64,000 XY (karyotype, karyotypically male) births. The condition result ...

, 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 individual ...

(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. PAIS has a similar presentation and is difficult to distinguish from 5α-reductase type 2 deficiency, especially before puberty. 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

terminal hair In humans, terminal hair is a variant of hair that is thick and long such as that growing on the scalp, as compared with vellus hair, colloquially known as peach fuzz, growing elsewhere.Marks, James G; Miller, Jeffery (2006)''Lookingbill and ...

; grade 6 is indicated when secondary terminal hair is present, whereas grade 7 is indicated when it is absent. The

Quigley scale The Quigley scale is a descriptive, visual system of phenotypic grading that defines seven classes between "fully masculinized" and "fully feminized" genitalia. It was proposed by pediatric endocrinologist Charmian A. Quigley et al. in 1995. It is ...

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 (physical form and structure), its developmental processes, its biochemical and physiological propert ...

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 a medical term commonly used in three medical a ...

. 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 non-cancerous enlargement of one or both breasts in men due to the growth of breast tissue as a result of a hormone imbalance between estrogens and androgens. Updated by Brent Wisse (10 Novemb ...

, decreased secondary

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

penis A penis (; : penises or penes) is a sex organ through which male and hermaphrodite animals expel semen during copulation (zoology), copulation, and through which male placental mammals and marsupials also Urination, urinate. The term ''pen ...

with varying degrees of diminished size and

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

to a slightly enlarged

clitoris In amniotes, the clitoris ( or ; : clitorises or clitorides) is a female sex organ. In humans, it is the vulva's most erogenous zone, erogenous area and generally the primary anatomical source of female Human sexuality, sexual pleasure. Th ...

Wolffian structures The mesonephric duct, also known as the Wolffian duct, archinephric duct, Leydig's duct or nephric duct, is a paired organ that develops in the early stages of embryonic development in humans and other mammals. It is an important structure that pl ...

(the

epididymides The epididymis (; : epididymides or ) is an elongated tubular genital organ attached to the posterior side of each one of the two male reproductive glands, the testicles. It is a single, narrow, tightly coiled tube in adult humans, in length; ...

vasa deferentia The vas deferens (: vasa deferentia), ductus deferens (: ductūs deferentes), or sperm duct is part of the male reproductive system of many vertebrates. In mammals, spermatozoa are produced in the seminiferous tubules and flow into the epididyma ...

, and

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

) are typically partially or fully developed. The

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

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 and sex organ 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, ...

in individuals with PAIS are

testes A testicle or testis ( testes) is the gonad in all male bilaterians, including humans, and is homologous to the ovary in females. Its primary functions are the production of sperm and the secretion of androgens, primarily testosterone. The ...

, regardless of

; during the embryonic stage of development, testes form in an androgen-independent process that occurs due to the influence of the

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 . It is the most common birth defect of the male genital tract. About 3% of full-term and 30% of premature infant boy ...

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 A micropenis or microphallus is an unusually small Human penis, penis. A common criterion is a dorsal (measured on top) Human penis size, penile length of at least 2.5 standard deviations smaller than the mean human penis size for age. A micr ...

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

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 ...

scrotum, and/or pseudovaginal perineoscrotal hypospadias.

Impotence Erectile dysfunction (ED), also referred to as impotence, is a form of sexual dysfunction in males characterized by the persistent or recurring inability to achieve or maintain a Human penis, penile erection with sufficient rigidity and durat ...

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 * Pharmacolo ...

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 penis through the urethra. It is the final stage and natural objective of male sexual stimulation, and an essential component of natural concepti ...

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

labial fusion Labial fusion is a medical condition of the vulva where the labia minora become fused together. It is generally a pediatric condition. Presentation Labial fusion is rarely present at birth, but rather acquired later in infancy, since it is caused ...

and

clitoromegaly Clitoromegaly (or macroclitoris) is an abnormal enlargement of the clitoris that is mostly congenital; it is otherwise acquired through deliberately induced clitoral enlargement, a form of body modification, by use of anabolic steroids, in parti ...

. 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 (, : 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 of the g ...

. 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 In most terrestrial mammals, the scrotum (: scrotums or scrota; possibly from Latin ''scortum'', meaning "hide" or "skin") or scrotal sac is a part of the external male genitalia located at the base of the penis. It consists of a sac of skin ...

. 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, drinki ...

, 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 a medical term commonly used in three medical a ...

including mild

and/or partial

. 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 In biology, infertility is the inability of a male and female organism to Sexual reproduction, reproduce. It is usually not the natural state of a healthy organism that has reached sexual maturity, so children who have not undergone puberty, whi ...

, 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 ...

including

impotence Erectile dysfunction (ED), also referred to as impotence, is a form of sexual dysfunction in males characterized by the persistent or recurring inability to achieve or maintain a Human penis, penile erection with sufficient rigidity and durat ...

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 * Pharmacolo ...

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

and

breast The breasts are two prominences located on the upper ventral region of the torso among humans and other primates. Both sexes develop breasts from the same embryology, embryological tissues. The relative size and development of the breasts is ...

cancers. Vaginal

hypoplasia Hypoplasia (; 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 somatic 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 f ...

. There are indications that individuals with an

intersex Intersex people are those 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 binar ...

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 those born with any of several Sexual characteristics, sex characteristics, including chromosome patterns, gonads, or sex organ, genitals that, according to the Office of the United Nations High Commissioner for Human ...

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

testosterone Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...

, testosterone precursors and

dihydrotestosterone Dihydrotestosterone (DHT, 5α-dihydrotestosterone, 5α-DHT, androstanolone or stanolone) is an endogenous androgen sex steroid and hormone primarily involved in the growth and repair of the prostate and the penis, as well as the production o ...

(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 implantat ...

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

biosynthesis Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme-Catalysis, catalyzed processes where chemical substances absorbed as nutrients (or previously converted through biosynthe ...

. 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 th ...

(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, mitosi ...

cannot be found in 27% to 72% of individuals with PAIS. As a result,

genetic analysis Genetic analysis is the overall process of studying and researching in fields of science that involve genetics and molecular biology. There are a number of applications that are developed from this research, and these are also considered parts ...

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 cell (biology), biological cell typically with a spindle shape that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and ...

study has long been the

gold standard A gold standard is a backed currency, monetary system in which the standard economics, 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 ...

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 in an organism comprising feedback loops of hormones that are released by internal glands directly into the circulatory system and that target and regulate distant organs. In vertebrates, the hypotha ...

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 testicles in males and the ovaries in females. The immature ova originate from cells from the dorsal endoderm of the yolk sac. ...

. The magnitude of the testosterone increase can help differentiate between androgen resistance and

gonadal dysgenesis Gonadal dysgenesis is classified as any congenital developmental disorder of the reproductive system characterized by a progressive loss of primordial germ cells on the developing gonads of an embryo. One type of gonadal dysgenesis is the devel ...

, as does evidence of a

uterus The uterus (from Latin ''uterus'', : uteri or uteruses) or womb () is the hollow organ, organ in the reproductive system of most female mammals, including humans, that accommodates the embryonic development, embryonic and prenatal development, f ...

ultrasound Ultrasound is sound with frequency, frequencies greater than 20 Hertz, kilohertz. This frequency is the approximate upper audible hearing range, limit of human hearing in healthy young adults. The physical principles of acoustic waves apply ...

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 Activin and inhibin, inhibin and activin from the transforming growth factor beta superfamily, whose key roles a ...

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

anorchia Gonadal agenesis is a rare condition where an individual lacks both gonads. If the karyotype is 46,XY and the individual otherwise has a male phenotype, it is called anorchia; this occurs in one of 20,000 male births. The corresponding condition ...

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

serum Serum may refer to: Biology and pharmacology *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 Places *Serum, Ind ...

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 is called androgen-binding prot ...

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

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

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 th ...

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, ...

are not currently available. Areas of management include

sex assignment Sex assignment (also known as gender assignment) is the discernment of an infant's sex, typically made at birth based on an examination of the baby's external genitalia by a healthcare provider such as a midwife, nurse, or physician. In the v ...

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 Ge ...

gonadectomy Gonadectomy, the removal of the gonads, may refer to: * Orchiectomy, removal of the testicles * Castration, removal of the use of the testicles, including by chemical means * Oophorectomy Oophorectomy (; from Greek , , 'egg-bearing' and , , 'a ...

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. Effects of menopause can include symptoms such ...

, 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 a medical term commonly used in three medical a ...

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

gender assignment Sex assignment (also known as gender assignment) is the discernment of an infant's sex, typically made at birth based on an examination of the baby's external genitalia by a healthcare provider such as a midwife, nurse, or physician. In the v ...

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, also known as a reproductive organ, is a part of an organism that is involved in sexual reproduction. Sex organs constitute the primary sex characteristics of an organism. Sex organs are responsible for producing and transporting ...

, the extent to which the child can virilize at puberty, surgical options and the postoperative

sexual function Sexual function is how the body reacts in different stages of the sexual response cycle. It is defined as the ability of an individual to react sexually or to experience sexual pleasure. Assessment Relevant aspects of sexual function are describ ...

of the genitalia,

complexity, potential for

fertility Fertility in colloquial terms refers the ability to have offspring. In demographic contexts, fertility refers to the actual production of offspring, rather than the physical capability to reproduce, which is termed fecundity. The fertility rate ...

, 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 in ...

of the child. The majority of individuals with PAIS are raised male, although a large portion are assigned female. 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. Intersex people who have been involuntarily surgically altered at birth often suffer from depression,

anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...

, and

gender dysphoria Gender dysphoria (GD) is the distress a person experiences due to inconsistency between their gender identitytheir personal sense of their own genderand their sex assigned at birth. The term replaced the previous diagnostic label of gender i ...

. The

World Health Organization The World Health Organization (WHO) is a list of specialized agencies of the United Nations, specialized agency of the United Nations which coordinates responses to international public health issues and emergencies. It is headquartered in Gen ...

(WHO) standard of care is to delay surgery until the child is old enough to participate in

informed consent Informed consent is an applied ethics principle that a person must have sufficient information and understanding before making decisions about accepting risk. Pertinent information may include risks and benefits of treatments, alternative treatme ...

, performing intersex genital surgeries on newborn infants is considered a

human rights violation Human rights are universally recognized Morality, moral principles or Social norm, norms that establish standards of human behavior and are often protected by both Municipal law, national and international laws. These rights are considered ...

, including by the WHO.

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 a medical term commonly used in three medical a ...

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 is the opposite of endogeneity or endogeny, the fact of being influenced from within a system. Economics In an economic model, an ...

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

; some studies have measured the growth of the

phallus A phallus (: phalli or phalluses) 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 symbo ...

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 In common terminology, a baby is the very young offspring of adult human beings, while infant (from the Latin word ''infans'', meaning 'baby' or 'child') is a formal or specialised synonym. The terms may also be used to refer to Juvenile (orga ...

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 De novo (Latin, , used in English to mean 'from the beginning', 'anew') may refer to: Science and computers * ''De novo'' mutation, a new germline mutation not inherited from either parent * ''De novo'' protein design, the creation of a protei ...

(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 muta ...

); 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, " ...

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 psychoanalysis, psychosexual development is a central element of the sexual drive theory. According to Freud, personality develops through a series of childhood stages in which pleasure-seeking energies from the child become focused on certa ...

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 in ...

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 (physical form and structure), its developmental processes, its biochemical and physiological propert ...

forms of PAIS are less decisive.

Homosexuality Homosexuality is romantic attraction, sexual attraction, or Human sexual activity, sexual behavior between people of the same sex or gender. As a sexual orientation, homosexuality is "an enduring pattern of emotional, romantic, and/or sexu ...

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

; 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 Ge ...

, 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

. While it is thought that feminizing genitoplasty typically requires fewer surgeries to achieve an acceptable result and results in fewer

urologic Urology (from Greek οὖρον ''ouron'' "urine" and ''-logia'' "study of"), also known as genitourinary surgery, is the branch of medicine that focuses on surgical and medical diseases of the urinary system and the reproductive organs. Org ...

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 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 several disciplines, including neuroscience, psychology, medicine, psychiatry, psycho ...

. In two larger studies, the common predictor of gender reassignment was

stigmatization Stigma, originally referring to the visible marking of people considered inferior, has evolved to mean a negative perception or sense of disapproval that a society places on a group or individual based on certain characteristics such as their ...

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, vestibule, vagina and ...

and the extent of

. Procedures include correction of penile curvature and

, reconstruction of the

urethra The urethra (: urethras or urethrae) is the tube that connects the urinary bladder to the urinary meatus, through which Placentalia, placental mammals Urination, urinate and Ejaculation, ejaculate. The external urethral sphincter is a striated ...

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: * Urinary incontinence, the most commonly occurring type of incontinence, the involuntary excretion of urine *Fecal incontinence Fecal incontinence (FI), or in some forms, encopresis, is a lack of con ...

. 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 adversely affects the structure or function of all or part of an organism and is not immediately due to any external injury. Diseases are often known to be medical conditions that are asso ...

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

stenosis Stenosis () is the abnormal narrowing of 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'' as a term is usually used when narrowing ...

of the

anastomosis An anastomosis (, : 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 normal (su ...

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 ti ...

, urethral

fistulas In anatomy, a fistula (: fistulas or fistulae ; from Latin ''fistula'', "tube, pipe") is an abnormal connection (i.e. tube) joining two hollow spaces (technically, two epithelialized surfaces), such as blood vessels, intestines, or other ho ...

, 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 In amniotes, the clitoris ( or ; : clitorises or clitorides) is a female sex organ. In humans, it is the vulva's most erogenous area and generally the primary anatomical source of female sexual pleasure. The clitoris is a complex structu ...

reduction / recession surgery carries with it the risk of necrosis as well as the risk of impairing the

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 of the clitoris. If PAIS presents with a common urogenital sinus (anatomy), sinus, the American academy of pediatrics, American Academy of Pediatrics currently recommends that surgery to separate the

from the vagina 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

, urinary meatus, meatal stenosis, vaginourethral fistula, female

, urinary tract 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. Invasiveness of surgical procedures#Open surgery, 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 grafting, skin grafts, a segment of bowel, ileum, peritoneum, , buccal mucosa, amnion, or dura mater. Success of such methods should be determined by

, and not by vaginal length alone, as has been done in the past. ileum, Ileal or cecum, cecal segments may be problematic because of a shorter mesentery, which may produce tension on the neovagina, leading to

. The Sigmoid colon, sigmoid neovagina is thought to be self-lubricating, without the excess mucus production associated with segments of small bowel. Vaginoplasty may create scarring at the Vagina#Vaginal opening and hymen, introitus (the vaginal opening), requiring additional surgery to correct. Vaginal dilators are required postoperatively to prevent vaginal stenosis from scarring. Other complications include bladder and bowel injuries. Yearly exams are required, as neovaginoplasty carries a risk of carcinoma, although carcinoma of the neovagina is uncommon. Neither neovaginoplasty nor vaginal dilation should be performed before

Gonadectomy

Gonadectomy at time of diagnosis is the current recommendation for PAIS if presenting with cryptorchidism. The risk of malignancy when

are located intrascrotally is unknown; the current recommendation is to biopsy the testes at puberty, allowing investigation of at least 30 seminiferous tubules, with diagnosis preferably based on OCT3/4 immunohistochemistry, followed by regular examinations. Hormone replacement therapy 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 secondary sexual characteristics, growth spurt, and bone mineralization, 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 (medication), Testosterone has been used to successfully treat Puberty#Physical changes in boys, undervirilization in some but not all men with PAIS, despite having supraphysiological levels of testosterone to start with. Treatment options include transdermal gels or patches, oral or injectable testosterone undecanoate, other injectable testosterone esters, 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

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:Partial Androgen Insensitivity Syndrome Transcription factor deficiencies Syndromes Intersex variations