Partial androgen insensitivity syndrome
Encyclopedia
Partial androgen insensitivity syndrome (PAIS) is a condition that results in the partial inability of the cell to respond to androgen
s. The partial unresponsiveness of the cell to the presence of androgenic hormones impairs the masculinization of male genitalia in the developing fetus, as well as the development of male secondary sexual characteristics at puberty
, but does not significantly impair female genital or sexual development. As such, the insensitivity to androgens is only clinically significant when it occurs in genetic males (i.e. individuals with a Y chromosome
, or more specifically, an SRY gene
).
PAIS is one of three types of androgen insensitivity syndrome
, which is divided into three categories that are differentiated by the degree of genital masculinization: complete androgen insensitivity syndrome
(CAIS) is indicated when the external genitalia is that of a normal female, mild androgen insensitivity syndrome
(MAIS) is indicated when the external genitalia is that of a normal 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 .
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
resulting from androgen insensitivity where the genitalia is partially, but not completely masculinized. Genital ambiguities are frequently detected during clinical examination at birth, and consequently, a PAIS diagnosis can be made during infancy as part of a differential diagnostic workup
.
Pubertal undervirilization is common, including gynecomastia
, decreased secondary
terminal hair
, and / or a high pitched voice . The phallic structure ranges from a penis
with varying degrees of diminished size
and hypospadias
to a slightly enlarged clitoris
. Wolffian structures
(the epididymides
, vasa deferentia
, and seminal vesicles) are typically partially or fully developed . The prostate
is typically small or impalpable . Müllerian
remnants are rare, but have been reported .
The gonads in individuals with PAIS are testes, regardless of phenotype
; during the embryonic stage of development
, testes form in an androgen-independent process that occurs due to the influence of the SRY gene
on the Y chromosome
. Cryptorchidism
is common , and carries with it a 50% risk of germ cell malignancy
. If the testes are located intrascrotally
, there may still be significant risk of germ cell malignancy; studies have not yet been published to assess this risk .
Predominantly male phenotypes vary in the degree of genital undermasculinization to include micropenis
, chordee
, bifid
scrotum, and / or pseudovaginal perineoscrotal hypospadias
. Impotence may be fairly common, depending on phenotypic features; in one study of 15 males with PAIS, 80% of those interviewed indicated that they had some degree of impotence . Anejaculation
appears to occur somewhat independently of impotence; some men are still able to ejaculate despite impotence, and others without erectile difficulties cannot . Predominantly female phenotypes include a variable degree of labial fusion
and clitoromegaly
. Ambiguous phenotypic states include a phallic structure that is intermediate between a clitoris and a penis, and a single perineal orifice that connects to both the urethra and the vagina (i.e. urogenital sinus) . At birth, it may not be possible to immediately differentiate the external genitalia of individuals with PAIS as being either male or female , although the majority of individuals with PAIS are raised male .
Given the wide diversity of phenotypes associated with PAIS, the diagnosis is often further specified by assessing genital masculinization . Grades 2 through 5 of the Quigley scale quantify four degrees of increasingly feminized genitalia that correspond to PAIS .
Grade 2, the mildest form of PAIS, presents with a predominantly male phenotype that presents with minor signs of undermasculinized genitalia, such as isolated hypospadias
, which can be severe . Hypospadias may manifest with a partially formed channel from the urethral opening
to the glans
. Until recently, it was thought that isolated micropenis
was not a manifestation of PAIS . However, in 2010, two cases of PAIS manifesting with isolated micropenis were documented .
Grade 3, the most common phenotypic form of PAIS , features a predominantly male phenotype that is more severely undermasculinized, and typically presents with micropenis and pseudovaginal perineoscrotal hypospadias
with bifid
scrotum
.
Grade 4 presents with a gender ambiguous phenotype, including a phallic structure that is intermediate between a clitoris and a penis . The urethra typically opens into a common channel with the vagina (i.e. urogenital sinus) .
Grade 5, the form of PAIS with the greatest degree of androgen insensitivity, presents with a mostly female phenotype, including separate urethral and vaginal orifices
, but also shows signs of slight masculinization including mild clitoromegaly
and / or partial labial fusion
.
Previously, it was erroneously thought that individuals with PAIS were always infertile; at least one case report has been published that describes fertile men that fit the criteria for grade 2 PAIS (micropenis
, penile hypospadias
, and gynecomastia
) .
, though exceptions have been reported for both the mild and partial forms .
PAIS is associated with a 50% risk of germ cell malignancy when the testes are undescended
. If the testes are located intrascrotally
, there may still be significant risk of germ cell malignancy; studies have not yet been published to assess this risk . Some men with PAIS may experience sexual dysfunction
including impotence and anejaculation
. A few AR mutations that cause PAIS are also associated with prostate
and breast
cancers.
Vaginal hypoplasia
, a relatively frequent finding in CAIS and some forms of PAIS , is associated with sexual difficulties including vaginal penetration difficulties and dyspareunia
.
At least one study indicates that individuals with an intersex
condition may be more prone to psychological difficulties, due at least in part to parental attitudes and behaviors , and concludes that preventative long-term psychological counseling
for parents as well as for affected individuals should be initiated at the time of diagnosis.
Lifespan is not thought to be affected by AIS .
to consider for PAIS is particularly large . Prompt diagnosis is particularly urgent when a child is born with ambiguous genitalia, as some causes are associated with potentially life-threatening adrenal crises . Determination of testosterone
, testosterone precursors and dihydrotestosterone
(DHT) at baseline and / or after human chorionic gonadotropin
(hCG) stimulation can be used to exclude such defects in androgen biosynthesis
.
Approximately one half of all 46,XY individuals
born with ambiguous genitalia will not receive a definitive diagnosis . Androgen receptor
(AR) gene mutations cannot be found in 27% to 72% of individuals with PAIS. As a result, genetic analysis
can be used to confirm a diagnosis of PAIS, but it cannot be used to rule out PAIS . Evidence of abnormal androgen binding in a genital skin fibroblast
study has long been the gold standard
for the diagnosis of PAIS , even when an AR mutation is not present . However, some cases of PAIS, including AR-mutant-positive cases , will show normal androgen binding. A family history consistent with X-linked inheritance is more commonly found in AR-mutant-positive cases than AR-mutant-negative cases .
The use of dynamic endocrine tests is particularly helpful in isolating a diagnosis of PAIS . One such test is the human chorionic gonadotropin
(hCG) stimulation test. If the gonads are testes, there will be an increase in the level of serum testosterone in response to the hCG, regardless of testicular descent
. The magnitude of the testosterone increase can help differentiate between androgen resistance and gonadal dysgenesis
, as does evidence of a uterus
on ultrasound
examination . Testicular function can also be assessed by measuring serum anti-Müllerian hormone
levels, which in turn can further differentiate PAIS from gonadal dysgenesis and bilateral anorchia
.
Another useful dynamic test involves measuring the response to exogenous steroids; individuals with AIS show a decreased response in serum
sex hormone binding globulin
(SHBG) after a short term administration of anabolic steroids . Two studies indicate that measuring the response in SHBG after the administration of stanozolol
could help to differentiate individuals with PAIS from those with other causes of ambiguous genitalia, although the response in individuals with predominantly male phenotypes overlaps somewhat with the response in normal males.
; methods to correct a malfunctioning androgen receptor
protein that result from an AR gene mutation
are not currently available. Areas of management include sex assignment
, genitoplasty, gonadectomy in relation to tumor
risk, hormone replacement therapy
, and genetic
and psychological counseling
.
The decision of whether to raise an individual with PAIS as a boy or a girl may not be obvious; grades 3 and 4 in particular present with a phenotype
that may be difficult to classify as primarily male or female, and some will be incapable of virilization at puberty
. Parents of an affected newborn should seek immediate help at a center with an experienced multidisciplinary team, and should avoid gender assignment beforehand . Gender assignment should thereafter be expeditiously decided; current guidelines advise against waiting for the child to decide for his / herself . Key considerations involved in assigning gender include the appearance of the genitalia , the extent to which the child can virilize at puberty , surgical options and the postoperative sexual function
of the genitalia , genitoplasty complexity , potential for fertility
, and the projected gender identity
of the child . The majority of individuals with PAIS are raised male .
Virilization capacity can be assessed by measuring the response to a trial of exogenous
androgens; some studies have measured the growth of the phallus
in response to exogenous testosterone
or dihydrotestosterone
, while others have measured the change in sex hormone binding globulin
(SHBG) in response to the artificial androgen stanozolol
to assess androgen sensitivity . Some experts have cautioned that it remains to be proved that a good response to exogenous androgens in neonates is a good predictor of androgen response at puberty . If a mutation
in the AR
gene is found, it is important to determine if the mutation is inherited
or de novo
(i.e. a somatic mutation); a certain amount of the wild-type androgen receptor will be present in cases of somatic mutation, which can induce virilization at puberty . A genital skin fibroblast
study and a human chorionic gonadotropin
(hCG) stimulation test may also provide information helpful in the assessment of virilization capacity.
Psychosexual development
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
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 micropenis
and no hypospadias
are better off being raised male, despite the success of some being raised female . Studies involving the more ambiguous phenotypic
forms of PAIS are less decisive . Homosexuality
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; neither should be interpreted as an indication of incorrect gender assignment . If an affected child does express feelings of gender dysphoria, the opportunity to explore such feelings with a psychologist experienced in treating intersex
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, 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
outcome . In one study , individuals with grade 3 PAIS that were raised male rated their body image and sexual function similarly to those that were raised female, even though they were more likely to have genitalia that was 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
. In two larger studies , the common predictor of gender reassignment was stigmatization related to having an intersex
condition.
The outcome of masculinizing genitoplasty is dependent on the amount of erectile tissue
and the extent of hypospadias
. Procedures include correction of penile curvature
and chordee
, reconstruction of the urethra
, hypospadias
correction, orchidopexy, and Müllerian remnant removal to prevent infection and pseudo-incontinence
. Erectile prosthesis
may be inserted in cases of successful neophalloplasty in adulthood, although it has a high morbidity . Additional surgeries may be required to correct postsurgical complications such as stenosis
of the anastomosis
between the native urethra
and the graft, 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
reduction / recession surgery carries with it the risk of necrosis
as well as the risk of impairing the sexual function
of the genitalia , and thus should not be performed for less severe clitoromegaly
. 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
, the American Academy of Pediatrics
currently recommends that surgery to separate the urethra
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 stenosis
, meatal
stenosis, vaginourethral fistula
, female hypospadias
, 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 . Surgical intervention should only be considered after non-surgical pressure dilation methods have failed to produce a satisfactory result . Neovaginoplasty can be performed using skin grafts
, a segment of bowel, ileum
, peritoneum
, Interceed, buccal mucosa, amnion
, or dura mater
. Success of such methods should be determined by sexual function
, and not just by vaginal length, as has been done in the past . Ileal
or cecal
segments may be problematic because of a shorter mesentery
, which may produce tension on the neovagina, leading to stenosis
. The 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 introitus
(the vaginal opening), which requires 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 puberty
.
Gonadectomy at time of diagnosis is the current recommendation for PAIS if presenting with cryptorchidism
, due to the high (50%) risk of germ cell malignancy
. The risk of malignancy when testes 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 puberty
. Artificially induced puberty results in the same, normal development of secondary sexual characteristics, growth spurt, 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 .
Testosterone
has been used to successfully treat 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 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
, gynecomastia
, hair loss, acne
, and the suppression of the hypothalamic-pituitary-gonadal axis
, which results in the reduction of gonadotropins (i.e., luteinizing hormone
and follicle-stimulating hormone
) and 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 and 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 that fit the criteria for grade 2 PAIS (micropenis
, penile hypospadias
, and gynecomastia
) . 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 .
Depending on phenotypic
features, impotence and other sexual problems such as anejaculation
or 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 .
Patient groups
Androgen
Androgen, also called androgenic hormone or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors...
s. The partial unresponsiveness of the cell to the presence of androgenic hormones impairs the masculinization of male genitalia in the developing fetus, as well as the development of male secondary sexual characteristics at puberty
Puberty
Puberty is the process of physical changes by which a child's body matures into an adult body capable of reproduction, as initiated by hormonal signals from the brain to the gonads; the ovaries in a girl, the testes in a boy...
, but does not significantly impair female genital or sexual development. As such, the insensitivity to androgens is only clinically significant when it occurs in genetic males (i.e. individuals with a Y chromosome
Y chromosome
The Y chromosome is one of the two sex-determining chromosomes in most mammals, including humans. In mammals, it contains the gene SRY, which triggers testis development if present. The human Y chromosome is composed of about 60 million base pairs...
, or more specifically, an SRY gene
SRY
SRY is a sex-determining gene on the Y chromosome in the therians .This intronless gene encodes a transcription factor that is a member of the SOX gene family of DNA-binding proteins...
).
PAIS is one of three types of androgen insensitivity syndrome
Androgen insensitivity syndrome
Androgen insensitivity syndrome is a condition that results in the partial or complete inability of the cell to respond to androgens. The unresponsiveness of the cell to the presence of androgenic hormones can impair or prevent the masculinization of male genitalia in the developing fetus, as...
, which is divided into three categories that are differentiated by the degree of genital masculinization: complete androgen insensitivity syndrome
Complete androgen insensitivity syndrome
Complete androgen insensitivity syndrome is a condition that results in the complete inability of the cell to respond to androgens. The unresponsiveness of the cell to the presence of androgenic hormones prevents the masculinization of male genitalia in the developing fetus, as well as the...
(CAIS) is indicated when the external genitalia is that of a normal female, mild androgen insensitivity syndrome
Mild androgen insensitivity syndrome
Mild androgen insensitivity syndrome 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 sexual characteristics at puberty in males, but does not...
(MAIS) is indicated when the external genitalia is that of a normal 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 .
Signs and symptoms
A supplemental system of phenotypic grading that uses seven classes instead of the traditional three was proposed by pediatric endocrinologist Charmian A. Quigley et al. in 1995 . The first six grades of the scale, grades 1 through 6, are differentiated by the degree of genital masculinization; grade 1 is indicated when the external genitalia is fully masculinized, grade 6 is indicated when the external genitalia is fully feminized, and grades 2 through 5 quantify four degrees of increasingly feminized genitalia that lie in the interim . Grade 7 is indistinguishable from grade 6 until puberty, and is thereafter differentiated by the presence of secondarySecondary sex characteristic
Secondary sex characteristics are features that distinguish the two sexes of a species, but that are not directly part of the reproductive system. They are believed to be the product of sexual selection for traits which give an individual an advantage over its rivals in courtship and aggressive...
terminal hair
Terminal hair
Terminal hairs are thick, long, and dark, as compared with vellus hair. During puberty, the increase in androgenic hormone levels causes vellus hair to be replaced with terminal hair in certain parts of the human body...
; 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
Karyotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
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
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
resulting from androgen insensitivity where the genitalia is partially, but not completely masculinized. Genital ambiguities are frequently detected during clinical examination at birth, and consequently, a PAIS diagnosis can be made during infancy as part of a differential diagnostic workup
Differential diagnosis
A differential diagnosis is a systematic diagnostic method used to identify the presence of an entity where multiple alternatives are possible , and may also refer to any of the included candidate alternatives A differential diagnosis (sometimes abbreviated DDx, ddx, DD, D/Dx, or ΔΔ) is a...
.
Pubertal undervirilization is common, including gynecomastia
Gynecomastia
Gynecomastia or Gynaecomastia, , is the abnormal development of large mammary glands in males resulting in breast enlargement. The term comes from the Greek γυνή gyné meaning "woman" and μαστός mastós meaning "breast"...
, decreased secondary
Secondary sex characteristic
Secondary sex characteristics are features that distinguish the two sexes of a species, but that are not directly part of the reproductive system. They are believed to be the product of sexual selection for traits which give an individual an advantage over its rivals in courtship and aggressive...
terminal hair
Terminal hair
Terminal hairs are thick, long, and dark, as compared with vellus hair. During puberty, the increase in androgenic hormone levels causes vellus hair to be replaced with terminal hair in certain parts of the human body...
, and / or a high pitched voice . The phallic structure ranges from a penis
Penis
The penis is a biological feature of male animals including both vertebrates and invertebrates...
with varying degrees of diminished size
Micropenis
Micropenis is an unusually small penis. A common criterion is a dorsal erect penile length of at least 2.5 standard deviations smaller than the mean human penis size. The condition is usually recognized shortly after birth...
and hypospadias
Hypospadias
Hypospadias is a birth defect of the urethra in the male that involves an abnormally placed urinary meatus...
to a slightly enlarged clitoris
Clitoris
The clitoris is a sexual organ that is present only in female mammals. In humans, the visible button-like portion is located near the anterior junction of the labia minora, above the opening of the urethra and vagina. Unlike the penis, which is homologous to the clitoris, the clitoris does not...
. Wolffian structures
Wolffian structures
In anatomy, Wolffian structures are male urogenital structures that include the epididymis, vas deferens, and seminal vesicles. They are often referred to in cases of androgen insensitivity syndrome.-See also:...
(the epididymides
Epididymis
The epididymis is part of the male reproductive system and is present in all male amniotes. It is a narrow, tightly-coiled tube connecting the efferent ducts from the rear of each testicle to its vas deferens. A similar, but probably non-homologous, structure is found in cartilaginous...
, vasa deferentia
Vas deferens
The vas deferens , also called ductus deferens, , is part of the male anatomy of many vertebrates; they transport sperm from the epididymis in anticipation of ejaculation....
, and seminal vesicles) are typically partially or fully developed . The prostate
Prostate
The prostate is a compound tubuloalveolar exocrine gland of the male reproductive system in most mammals....
is typically small or impalpable . Müllerian
Müllerian duct
Müllerian ducts are paired ducts of the embryo that run down the lateral sides of the urogenital ridge and terminate at the Müllerian eminence in the primitive urogenital sinus. In the female, they will develop to form the Fallopian tubes, uterus, cervix, and the upper two-third of the vagina; in...
remnants are rare, but have been reported .
The gonads in individuals with PAIS are testes, regardless of phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
; during the embryonic stage of development
Human embryogenesis
Human embryology is the study of human development during the first eight weeks from gametogenesis pre-conception through fertilization up to and including the 8th week after implantation of the zygote in the uterus...
, testes form in an androgen-independent process that occurs due to the influence of the SRY gene
SRY
SRY is a sex-determining gene on the Y chromosome in the therians .This intronless gene encodes a transcription factor that is a member of the SOX gene family of DNA-binding proteins...
on the Y chromosome
Y chromosome
The Y chromosome is one of the two sex-determining chromosomes in most mammals, including humans. In mammals, it contains the gene SRY, which triggers testis development if present. The human Y chromosome is composed of about 60 million base pairs...
. Cryptorchidism
Cryptorchidism
Cryptorchidism is the absence of one or both testes from the scrotum. It is the most common birth defect regarding male genitalia. In unique cases, cryptorchidism can develop later in life, often as late as young adulthood. About 3% of full-term and 30% of premature infant boys are born with at...
is common , and carries with it a 50% risk of germ cell malignancy
Germ cell tumor
A germ cell tumor is a neoplasm derived from germ cells. Germ cell tumors can be cancerous or non-cancerous tumors. Germ cells normally occur inside the gonads...
. If the testes are located intrascrotally
Scrotum
In some male mammals the scrotum is a dual-chambered protuberance of skin and muscle containing the testicles and divided by a septum. It is an extension of the perineum, and is located between the penis and anus. In humans and some other mammals, the base of the scrotum becomes covered with curly...
, 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
Micropenis is an unusually small penis. A common criterion is a dorsal erect penile length of at least 2.5 standard deviations smaller than the mean human penis size. The condition is usually recognized shortly after birth...
, chordee
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 flaccid state as well. In many cases but not all,...
, bifid
Bifid
Bifid refers to something that is split or cleft into two parts. It may refer to:* bifid rib, a congenital abnormality of the human anatomy* bifid penis* bifid cipher, a type of cipher in cryptography...
scrotum, and / or pseudovaginal perineoscrotal hypospadias
Pseudovaginal perineoscrotal hypospadias
Pseudovaginal perineoscrotal hypospadias refers to a configuration of the external genitalia of an infant. In a sense, this configuration is roughly midway between normal male genitalia and normal female genitalia in structure and appearance...
. Impotence may be fairly common, depending on phenotypic features; in one study of 15 males with PAIS, 80% of those interviewed indicated that they had some degree of impotence . Anejaculation
Anejaculation
Anejaculation is the pathological inability to ejaculate in males, with or without orgasm.It can depend on one or more of several causes, including ':*Sexual inhibition*Pharmacological inhibition...
appears to occur somewhat independently of impotence; some men are still able to ejaculate despite impotence, and others without erectile difficulties cannot . Predominantly female phenotypes include a variable degree of labial fusion
Labial fusion
Labial fusion is a medical condition of the female genital anatomy where the labia minora become fused together. It is generally a pediatric condition....
and clitoromegaly
Clitoromegaly
Clitoromegaly is an abnormal enlargement of the clitoris ....
. 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 .
Given the wide diversity of phenotypes associated with PAIS, the diagnosis is often further specified by assessing genital masculinization . Grades 2 through 5 of the Quigley scale quantify four degrees of increasingly feminized genitalia that correspond to PAIS .
Grade 2, the mildest form of PAIS, presents with a predominantly male phenotype that presents with minor signs of undermasculinized genitalia, such as isolated hypospadias
Hypospadias
Hypospadias is a birth defect of the urethra in the male that involves an abnormally placed urinary meatus...
, which can be severe . Hypospadias may manifest with a partially formed channel from the urethral opening
Urethra
In anatomy, the urethra is a tube that connects the urinary bladder to the genitals for the removal of fluids out of the body. In males, the urethra travels through the penis, and carries semen as well as urine...
to the glans
Glans
The glans is a vascular structure located at the tip of the penis in men or a homologous genital structure of the clitoris in women.-Structure:...
. Until recently, it was thought that isolated micropenis
Micropenis
Micropenis is an unusually small penis. A common criterion is a dorsal erect penile length of at least 2.5 standard deviations smaller than the mean human penis size. The condition is usually recognized shortly after birth...
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
Pseudovaginal perineoscrotal hypospadias
Pseudovaginal perineoscrotal hypospadias refers to a configuration of the external genitalia of an infant. In a sense, this configuration is roughly midway between normal male genitalia and normal female genitalia in structure and appearance...
with bifid
Bifid
Bifid refers to something that is split or cleft into two parts. It may refer to:* bifid rib, a congenital abnormality of the human anatomy* bifid penis* bifid cipher, a type of cipher in cryptography...
scrotum
Scrotum
In some male mammals the scrotum is a dual-chambered protuberance of skin and muscle containing the testicles and divided by a septum. It is an extension of the perineum, and is located between the penis and anus. In humans and some other mammals, the base of the scrotum becomes covered with curly...
.
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
Body orifice
-External orifices: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 eyes, for the sense of sight and crying....
, but also shows signs of slight masculinization including mild clitoromegaly
Clitoromegaly
Clitoromegaly is an abnormal enlargement of the clitoris ....
and / or partial labial fusion
Labial fusion
Labial fusion is a medical condition of the female genital anatomy where the labia minora become fused together. It is generally a pediatric condition....
.
Previously, it was erroneously thought that individuals with PAIS were always infertile; at least one case report has been published that describes fertile men that fit the criteria for grade 2 PAIS (micropenis
Micropenis
Micropenis is an unusually small penis. A common criterion is a dorsal erect penile length of at least 2.5 standard deviations smaller than the mean human penis size. The condition is usually recognized shortly after birth...
, penile hypospadias
Hypospadias
Hypospadias is a birth defect of the urethra in the male that involves an abnormally placed urinary meatus...
, and gynecomastia
Gynecomastia
Gynecomastia or Gynaecomastia, , is the abnormal development of large mammary glands in males resulting in breast enlargement. The term comes from the Greek γυνή gyné meaning "woman" and μαστός mastós meaning "breast"...
) .
Comorbidity
All forms of androgen insensitivity are associated with infertilityInfertility
Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...
, 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
Cryptorchidism
Cryptorchidism is the absence of one or both testes from the scrotum. It is the most common birth defect regarding male genitalia. In unique cases, cryptorchidism can develop later in life, often as late as young adulthood. About 3% of full-term and 30% of premature infant boys are born with at...
. If the testes are located intrascrotally
Scrotum
In some male mammals the scrotum is a dual-chambered protuberance of skin and muscle containing the testicles and divided by a septum. It is an extension of the perineum, and is located between the penis and anus. In humans and some other mammals, the base of the scrotum becomes covered with curly...
, 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
Sexual dysfunction or sexual malfunction refers to a difficulty experienced by an individual or a couple during any stage of a normal sexual activity, including desire, arousal or orgasm....
including impotence and anejaculation
Anejaculation
Anejaculation is the pathological inability to ejaculate in males, with or without orgasm.It can depend on one or more of several causes, including ':*Sexual inhibition*Pharmacological inhibition...
. A few AR mutations that cause PAIS are also associated with prostate
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
and breast
Male breast cancer
Male breast cancer is a relatively rare cancer in men that originates from the breast. As it presents a similar pathology as female breast cancer, assessment and treatment relies on experiences and guidelines that have been developed in female patients. The optimal treatment is currently not...
cancers.
Vaginal hypoplasia
Hypoplasia
Hypoplasia is underdevelopment or incomplete development of a tissue or organ. Although the term is not always used precisely, it properly refers to an inadequate or below-normal number of cells. Hypoplasia is similar to aplasia, but less severe. It is technically not the opposite of hyperplasia...
, a relatively frequent finding in CAIS and some forms of PAIS , is associated with sexual difficulties including vaginal penetration difficulties and dyspareunia
Dyspareunia
Dyspareunia is painful sexual intercourse, due to medical or psychological causes. The symptom is reported almost exclusively by women, although the problem can also occur in men. The causes are often reversible, even when long-standing, but self-perpetuating pain is a factor after the original...
.
At least one study indicates that individuals with an intersex
Intersex
Intersex, in humans and other animals, is the presence of intermediate or atypical combinations of physical features that usually distinguish female from male...
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
Psychotherapy is a general term referring to any form of therapeutic interaction or treatment contracted between a trained professional and a client or patient; family, couple or group...
for parents as well as for affected individuals should be initiated at the time of diagnosis.
Lifespan is not thought to be affected by AIS .
Diagnosis
Unfortunately, the number of differentialsDifferential diagnosis
A differential diagnosis is a systematic diagnostic method used to identify the presence of an entity where multiple alternatives are possible , and may also refer to any of the included candidate alternatives A differential diagnosis (sometimes abbreviated DDx, ddx, DD, D/Dx, or ΔΔ) is a...
to consider for PAIS is particularly large . Prompt diagnosis is particularly urgent when a child is born with ambiguous genitalia, as some causes are associated with potentially life-threatening adrenal crises . Determination of testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
, testosterone precursors and dihydrotestosterone
Dihydrotestosterone
Dihydrotestosterone is an androgen or male sex hormone. The enzyme 5α-reductase synthesises DHT in the prostate, testes, hair follicles, and adrenal glands...
(DHT) at baseline and / or after human chorionic gonadotropin
Human chorionic gonadotropin
Human chorionic gonadotropin or human chorionic gonadotrophin is a glycoprotein hormone produced during pregnancy that is made by the developing embryo after conception and later by the syncytiotrophoblast .. Some tumors make this hormone; measured elevated levels when the patient is not...
(hCG) stimulation can be used to exclude such defects in androgen biosynthesis
Biosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
.
Approximately one half of all 46,XY individuals
Karyotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
born with ambiguous genitalia will not receive a definitive diagnosis . Androgen receptor
Androgen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
(AR) gene mutations cannot be found in 27% to 72% of individuals with PAIS. As a result, genetic analysis
Genetic analysis
Genetic analysis can be used generally to describe methods both used in and resulting from the sciences of genetics and molecular biology, or to applications resulting from this research....
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
Fibroblast
A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...
study has long been the gold standard
Gold standard (test)
In medicine and statistics, gold standard test refers to a diagnostic test or benchmark that is the best available under reasonable conditions. It does not have to be necessarily the best possible test for the condition in absolute terms...
for the diagnosis of PAIS , even when an AR mutation is not present . However, some cases of PAIS, including AR-mutant-positive cases , will show normal androgen binding. A family history consistent with X-linked inheritance is more commonly found in AR-mutant-positive cases than AR-mutant-negative cases .
The use of dynamic endocrine tests is particularly helpful in isolating a diagnosis of PAIS . One such test is the human chorionic gonadotropin
Human chorionic gonadotropin
Human chorionic gonadotropin or human chorionic gonadotrophin is a glycoprotein hormone produced during pregnancy that is made by the developing embryo after conception and later by the syncytiotrophoblast .. Some tumors make this hormone; measured elevated levels when the patient is not...
(hCG) stimulation test. If the gonads are testes, there will be an increase in the level of serum testosterone in response to the hCG, regardless of testicular descent
Cryptorchidism
Cryptorchidism is the absence of one or both testes from the scrotum. It is the most common birth defect regarding male genitalia. In unique cases, cryptorchidism can develop later in life, often as late as young adulthood. About 3% of full-term and 30% of premature infant boys are born with at...
. The magnitude of the testosterone increase can help differentiate between androgen resistance and gonadal dysgenesis
Gonadal dysgenesis
Gonadal dysgenesis is a term used to describe multiple reproductive system development disorders. They are conditions of genetic origin. It is characterized by a progressive loss of primordial germ cells on the developing gonads of an embryo....
, as does evidence of a uterus
Uterus
The uterus or womb is a major female hormone-responsive reproductive sex organ of most mammals including humans. One end, the cervix, opens into the vagina, while the other is connected to one or both fallopian tubes, depending on the species...
on ultrasound
Ultrasound
Ultrasound is cyclic sound pressure with a frequency greater than the upper limit of human hearing. Ultrasound is thus not separated from "normal" sound based on differences in physical properties, only the fact that humans cannot hear it. Although this limit varies from person to person, it is...
examination . Testicular function can also be assessed by measuring serum anti-Müllerian hormone
Anti-müllerian hormone
Anti-Müllerian hormone also known as AMH is a protein that, in humans, is encoded by the AMH gene. It inhibits the development of the Müllerian ducts in the male embryo. It has also been called Müllerian inhibiting factor , Müllerian-inhibiting hormone , and Müllerian-inhibiting substance...
levels, which in turn can further differentiate PAIS from gonadal dysgenesis and bilateral anorchia
Anorchia
Anorchia is a medical condition where both testes are absent at birth. Within a few weeks of fertilization, the embryo develops rudimentary sex organs, which are crucial to the development of the reproductive system...
.
Another useful dynamic test involves measuring the response to exogenous steroids; individuals with AIS show a decreased response in serum
Serum
Serum may refer to:*Blood serum, a component of blood which is collected after coagulation.**Antiserum, blood serum with specific antibodies for passive immunity*Serous fluid, any clear bodily fluid*any drug derived from an animal's blood or serous fluid...
sex hormone binding globulin
Sex hormone binding globulin
Sex hormone-binding globulin or sex steroid-binding globulin is a glycoprotein that binds to sex hormones, to be specific, testosterone and estradiol...
(SHBG) after a short term administration of anabolic steroids . Two studies indicate that measuring the response in SHBG after the administration of stanozolol
Stanozolol
Stanozolol, commonly sold under the name Winstrol , Tenabol and Winstrol Depot , was developed by Winthrop Laboratories in 1962...
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 managementSymptomatic treatment
Symptomatic treatment is any medical therapy of a disease that only affects its symptoms, not its cause, i.e., its etiology. It is usually aimed at reducing the signs and symptoms for the comfort and well-being of the patient, but it also may be useful in reducing organic consequences and sequelae...
; methods to correct a malfunctioning androgen receptor
Androgen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
protein that result from an AR gene mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
are not currently available. Areas of management include sex assignment
Sex assignment
Sex assignment refers to the assigning of the biological sex at the birth of a baby. In the majority of births, a relative, midwife, or physician inspects the genitalia when the baby is delivered, sees ordinary male or female genitalia, and declares, "it's a girl" or "it's a boy" without the...
, genitoplasty, gonadectomy in relation to tumor
Germ cell tumor
A germ cell tumor is a neoplasm derived from germ cells. Germ cell tumors can be cancerous or non-cancerous tumors. Germ cells normally occur inside the gonads...
risk, hormone replacement therapy
Hormone replacement therapy (menopause)
Hormone replacement therapy is a system of medical treatment for surgically menopausal, perimenopausal and to a lesser extent postmenopausal women...
, and genetic
Genetic counseling
Genetic counseling or traveling is the process by which patients or relatives, at risk of an inherited disorder, are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning...
and psychological counseling
Psychotherapy
Psychotherapy is a general term referring to any form of therapeutic interaction or treatment contracted between a trained professional and a client or patient; family, couple or group...
.
The decision of whether to raise an individual with PAIS as a boy or a girl may not be obvious; grades 3 and 4 in particular present with a phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
that may be difficult to classify as primarily male or female, and some will be incapable of virilization at puberty
Puberty
Puberty is the process of physical changes by which a child's body matures into an adult body capable of reproduction, as initiated by hormonal signals from the brain to the gonads; the ovaries in a girl, the testes in a boy...
. Parents of an affected newborn should seek immediate help at a center with an experienced multidisciplinary team, and should avoid gender assignment beforehand . Gender assignment should thereafter be expeditiously decided; current guidelines advise against waiting for the child to decide for his / herself . Key considerations involved in assigning gender include the appearance of the genitalia , the extent to which the child can virilize at puberty , surgical options and the postoperative sexual function
Sexual function
Sexual function is a model developed at the Karolinska Institute in Stockholm, Sweden, defining different aspects of the assessment of sexual dysfunction comprises the following components....
of the genitalia , genitoplasty complexity , potential for fertility
Fertility
Fertility is the natural capability of producing offsprings. As a measure, "fertility rate" is the number of children born per couple, person or population. Fertility differs from fecundity, which is defined as the potential for reproduction...
, and the projected gender identity
Gender identity
A gender identity is the way in which an individual self-identifies with a gender category, for example, as being either a man or a woman, or in some cases being neither, which can be distinct from biological sex. Basic gender identity is usually formed by age three and is extremely difficult to...
of the child . The majority of individuals with PAIS are raised male .
Virilization capacity can be assessed by measuring the response to a trial of exogenous
Exogenous
Exogenous refers to an action or object coming from outside a system. It is the opposite of endogenous, something generated from within the system....
androgens; some studies have measured the growth of the phallus
Penis
The penis is a biological feature of male animals including both vertebrates and invertebrates...
in response to exogenous testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
or dihydrotestosterone
Dihydrotestosterone
Dihydrotestosterone is an androgen or male sex hormone. The enzyme 5α-reductase synthesises DHT in the prostate, testes, hair follicles, and adrenal glands...
, while others have measured the change in sex hormone binding globulin
Sex hormone binding globulin
Sex hormone-binding globulin or sex steroid-binding globulin is a glycoprotein that binds to sex hormones, to be specific, testosterone and estradiol...
(SHBG) in response to the artificial androgen stanozolol
Stanozolol
Stanozolol, commonly sold under the name Winstrol , Tenabol and Winstrol Depot , was developed by Winthrop Laboratories in 1962...
to assess androgen sensitivity . Some experts have cautioned that it remains to be proved that a good response to exogenous androgens in neonates is a good predictor of androgen response at puberty . If a mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
in the AR
Androgen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
gene is found, it is important to determine if the mutation is inherited
Heredity
Heredity is the passing of traits to offspring . This is the process by which an offspring cell or organism acquires or becomes predisposed to the characteristics of its parent cell or organism. Through heredity, variations exhibited by individuals can accumulate and cause some species to evolve...
or de novo
De novo
In general usage, de novo is a Latin expression meaning "from the beginning," "afresh," "anew," "beginning again." It is used in:* De novo transcriptome assembly, the method of creating a transcriptome without a reference genome...
(i.e. a somatic mutation); a certain amount of the wild-type androgen receptor will be present in cases of somatic mutation, which can induce virilization at puberty . A genital skin fibroblast
Fibroblast
A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...
study and a human chorionic gonadotropin
Human chorionic gonadotropin
Human chorionic gonadotropin or human chorionic gonadotrophin is a glycoprotein hormone produced during pregnancy that is made by the developing embryo after conception and later by the syncytiotrophoblast .. Some tumors make this hormone; measured elevated levels when the patient is not...
(hCG) stimulation test may also provide information helpful in the assessment of virilization capacity.
Psychosexual development
Psychosexual development
In Freudian psychology, psychosexual development is a central element of the psychoanalytic sexual drive theory, that human beings, from birth, possess an instinctual libido that develops in five stages. Each stage — the oral, the anal, the phallic, the latent, and the genital — is characterized...
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
A gender identity is the way in which an individual self-identifies with a gender category, for example, as being either a man or a woman, or in some cases being neither, which can be distinct from biological sex. Basic gender identity is usually formed by age three and is extremely difficult to...
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
Karyotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
born with micropenis
Micropenis
Micropenis is an unusually small penis. A common criterion is a dorsal erect penile length of at least 2.5 standard deviations smaller than the mean human penis size. The condition is usually recognized shortly after birth...
and no hypospadias
Hypospadias
Hypospadias is a birth defect of the urethra in the male that involves an abnormally placed urinary meatus...
are better off being raised male, despite the success of some being raised female . Studies involving the more ambiguous phenotypic
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
forms of PAIS are less decisive . Homosexuality
Homosexuality
Homosexuality is romantic or sexual attraction or behavior between members of the same sex or gender. As a sexual orientation, homosexuality refers to "an enduring pattern of or disposition to experience sexual, affectional, or romantic attractions" primarily or exclusively to people of the same...
with respect to assigned gender and atypical gender role
Atypical gender role
Gender role is a term used in the social sciences and humanities to denote a set of behavioral norms associated with a given gendered status in a given social group or system...
behavior are known to occur more frequently in individual with PAIS, and may occur with or without gender dysphoria; neither should be interpreted as an indication of incorrect gender assignment . If an affected child does express feelings of gender dysphoria, the opportunity to explore such feelings with a psychologist experienced in treating intersex
Intersex
Intersex, in humans and other animals, is the presence of intermediate or atypical combinations of physical features that usually distinguish female from male...
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, 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
Sexual function
Sexual function is a model developed at the Karolinska Institute in Stockholm, Sweden, defining different aspects of the assessment of sexual dysfunction comprises the following components....
.
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
Psychosocial
For a concept to be psychosocial means it relates to one's psychological development in, and interaction with, a social environment. The individual needs not be fully aware of this relationship with his or her environment. It was first commonly used by psychologist Erik Erikson in his stages of...
outcome . In one study , individuals with grade 3 PAIS that were raised male rated their body image and sexual function similarly to those that were raised female, even though they were more likely to have genitalia that was 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
Beauty
Beauty is a characteristic of a person, animal, place, object, or idea that provides a perceptual experience of pleasure, meaning, or satisfaction. Beauty is studied as part of aesthetics, sociology, social psychology, and culture...
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
Body image refers to a person's perception of the aesthetics and sexual attractiveness of their own body. The phrase body image was first coined by the Austrian neurologist and psychoanalyst Paul Schilder in his masterpiece The Image and Appearance of the Human Body...
. In two larger studies , the common predictor of gender reassignment was stigmatization related to having an intersex
Intersex
Intersex, in humans and other animals, is the presence of intermediate or atypical combinations of physical features that usually distinguish female from male...
condition.
The outcome of masculinizing genitoplasty is dependent on the amount of erectile tissue
Erectile tissue
Erectile tissue is tissue in the body that can become erect, usually by becoming engorged with blood.-Erectile tissue in the clitoris and penis:...
and the extent of hypospadias
Hypospadias
Hypospadias is a birth defect of the urethra in the male that involves an abnormally placed urinary meatus...
. Procedures include correction of penile curvature
Peyronie's disease
Peyronie's Disease Peyronie's Disease Peyronie's Disease (also known as "Induratio penis plastica", or more recently Chronic Inflammation of the Tunica Albuginea (CITA), is a connective tissue disorder involving the growth of fibrous plaques in the soft tissue of the penis affecting up to 10% of men...
and chordee
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 flaccid state as well. In many cases but not all,...
, reconstruction of the urethra
Urethra
In anatomy, the urethra is a tube that connects the urinary bladder to the genitals for the removal of fluids out of the body. In males, the urethra travels through the penis, and carries semen as well as urine...
, hypospadias
Hypospadias
Hypospadias is a birth defect of the urethra in the male that involves an abnormally placed urinary meatus...
correction, orchidopexy, and Müllerian remnant removal to prevent infection and pseudo-incontinence
Incontinence
Incontinence or Incontinent may refer to:*Fecal incontinence, the inability to control one's bowels*Incontinence *Incontinent , a 1981 album by Fad Gadget*Urinary incontinence, the involuntary excretion of urine...
. Erectile prosthesis
Penile prosthesis
A penile prosthesis is a medical device implanted in the penis requiring a surgical procedure. The device is often used for men with organic or treatment-resistant psychogenic impotence who suffer from erectile dysfunction...
may be inserted in cases of successful neophalloplasty in adulthood, although it has a high morbidity . Additional surgeries may be required to correct postsurgical complications such as stenosis
Stenosis
A stenosis is an abnormal narrowing in a blood vessel or other tubular organ or structure.It is also sometimes called a stricture ....
of the anastomosis
Anastomosis
An anastomosis is the reconnection of two streams that previously branched out, such as blood vessels or leaf veins. The term is used in medicine, biology, mycology and geology....
between the native urethra
Urethra
In anatomy, the urethra is a tube that connects the urinary bladder to the genitals for the removal of fluids out of the body. In males, the urethra travels through the penis, and carries semen as well as urine...
and the graft, urethral fistulas, and posterior displacement of the balanic meatus
Urinary meatus
The urinary meatus is an orifice of the urethra. It is the point at which urine and, in males, semen exits the urethra. The meatus features varying degrees of sensitivity to the touch among males and females....
. 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
Clitoris
The clitoris is a sexual organ that is present only in female mammals. In humans, the visible button-like portion is located near the anterior junction of the labia minora, above the opening of the urethra and vagina. Unlike the penis, which is homologous to the clitoris, the clitoris does not...
reduction / recession surgery carries with it the risk of necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
as well as the risk of impairing the sexual function
Sexual function
Sexual function is a model developed at the Karolinska Institute in Stockholm, Sweden, defining different aspects of the assessment of sexual dysfunction comprises the following components....
of the genitalia , and thus should not be performed for less severe clitoromegaly
Clitoromegaly
Clitoromegaly is an abnormal enlargement of the clitoris ....
. 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
Sinus
- Anatomy :In anatomy, where a sinus is a sac or cavity in any organ or tissue:*Sinus , description of the general term*Paranasal sinuses, air cavities in the cranial bones, especially those near the nose, including:...
, the American Academy of Pediatrics
American Academy of Pediatrics
The American Academy of Pediatrics is the major professional association of pediatricians in the United States. The AAP was founded in 1930 by 35 pediatricians to address pediatric healthcare standards. It currently has 60,000 members in primary care and sub-specialist areas...
currently recommends that surgery to separate the urethra
Urethra
In anatomy, the urethra is a tube that connects the urinary bladder to the genitals for the removal of fluids out of the body. In males, the urethra travels through the penis, and carries semen as well as urine...
from the vagina
Vagina
The vagina is a fibromuscular tubular tract leading from the uterus to the exterior of the body in female placental mammals and marsupials, or to the cloaca in female birds, monotremes, and some reptiles. Female insects and other invertebrates also have a vagina, which is the terminal part of the...
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 stenosis
Stenosis
A stenosis is an abnormal narrowing in a blood vessel or other tubular organ or structure.It is also sometimes called a stricture ....
, meatal
Urinary meatus
The urinary meatus is an orifice of the urethra. It is the point at which urine and, in males, semen exits the urethra. The meatus features varying degrees of sensitivity to the touch among males and females....
stenosis, vaginourethral fistula
Fistula
In medicine, a fistula is an abnormal connection or passageway between two epithelium-lined organs or vessels that normally do not connect. It is generally a disease condition, but a fistula may be surgically created for therapeutic reasons.-Locations:Fistulas can develop in various parts of the...
, female hypospadias
Hypospadias
Hypospadias is a birth defect of the urethra in the male that involves an abnormally placed urinary meatus...
, 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 . Surgical intervention should only be considered after non-surgical pressure dilation methods have failed to produce a satisfactory result . Neovaginoplasty can be performed using skin grafts
Skin grafting
Skin grafting is a type of graft surgery involving the transplantation of skin. The transplanted tissue is called a skin graft.Skin grafting is often used to treat:*Extensive wounding or trauma*Burns...
, a segment of bowel, ileum
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 may be used instead of ileum.The ileum follows the duodenum...
, peritoneum
Peritoneum
The peritoneum is the serous membrane that forms the lining of the abdominal cavity or the coelom — it covers most of the intra-abdominal organs — in amniotes and some invertebrates...
, Interceed, buccal mucosa, amnion
Amnion
The amnion is a membrane building the amniotic sac that surrounds and protects an embryo. It is developed in reptiles, birds, and mammals, which are hence called “Amniota”; but not in amphibians and fish , which are consequently termed “Anamniota”. The primary role of this is the protection of the...
, or dura mater
Dura mater
The dura mater , or dura, is the outermost of the three layers of the meninges surrounding the brain and spinal cord. It is derived from Mesoderm. The other two meningeal layers are the pia mater and the arachnoid mater. The dura surrounds the brain and the spinal cord and is responsible for...
. Success of such methods should be determined by sexual function
Sexual function
Sexual function is a model developed at the Karolinska Institute in Stockholm, Sweden, defining different aspects of the assessment of sexual dysfunction comprises the following components....
, and not just by vaginal length, as has been done in the past . Ileal
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 may be used instead of ileum.The ileum follows the duodenum...
or cecal
Cecum
The cecum or caecum is a pouch, connecting the ileum with the ascending colon of the large intestine. It is separated from the ileum by the ileocecal valve or Bauhin's valve, and is considered to be the beginning of the large intestine. It is also separated from the colon by the cecocolic...
segments may be problematic because of a shorter mesentery
Mesentery
In anatomy, the mesentery is the double layer of peritoneum that suspends the jejunum and ileum from the posterior wall of the abdomen. Its meaning, however, is frequently extended to include double layers of peritoneum connecting various components of the abdominal cavity.-Mesentery :The...
, which may produce tension on the neovagina, leading to stenosis
Stenosis
A stenosis is an abnormal narrowing in a blood vessel or other tubular organ or structure.It is also sometimes called a stricture ....
. The sigmoid
Sigmoid colon
The sigmoid colon is the part of the large intestine that is closest to the rectum and anus. It forms a loop that averages about 40 cm...
neovagina is thought to be self-lubricating, without the excess mucus
Mucus
In vertebrates, mucus is a slippery secretion produced by, and covering, mucous membranes. Mucous fluid is typically produced from mucous cells found in mucous glands. Mucous cells secrete products that are rich in glycoproteins and water. Mucous fluid may also originate from mixed glands, which...
production associated with segments of small bowel . Vaginoplasty may create scarring at the introitus
Introitus
The introitus is an entrance that goes into a canal or hollow organ. Introitus is another name for the vaginal orifice.Introitus has also been used for classifying uterine prolapse:*1st degree prolapse: cervix is in the vagina...
(the vaginal opening), which requires additional surgery to correct. Vaginal dilators are required postoperatively to prevent vaginal stenosis from scarring . Other complications include bladder
Bladder
Bladder usually refers to an anatomical hollow organBladder may also refer to:-Biology:* Urinary bladder in humans** Urinary bladder ** Bladder control; see Urinary incontinence** Artificial urinary bladder, in humans...
and bowel injuries . Yearly exams are required as neovaginoplasty carries a risk of carcinoma
Carcinoma
Carcinoma is the medical term for the most common type of cancer occurring in humans. Put simply, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that generally arises from cells originating in the endodermal or ectodermal germ layer during...
, although carcinoma of the neovagina is uncommon . Neither neovaginoplasty nor vaginal dilation should be performed before puberty
Puberty
Puberty is the process of physical changes by which a child's body matures into an adult body capable of reproduction, as initiated by hormonal signals from the brain to the gonads; the ovaries in a girl, the testes in a boy...
.
Gonadectomy at time of diagnosis is the current recommendation for PAIS if presenting with cryptorchidism
Cryptorchidism
Cryptorchidism is the absence of one or both testes from the scrotum. It is the most common birth defect regarding male genitalia. In unique cases, cryptorchidism can develop later in life, often as late as young adulthood. About 3% of full-term and 30% of premature infant boys are born with at...
, due to the high (50%) risk of germ cell malignancy
Germ cell tumor
A germ cell tumor is a neoplasm derived from germ cells. Germ cell tumors can be cancerous or non-cancerous tumors. Germ cells normally occur inside the gonads...
. The risk of malignancy when testes are located intrascrotally
Scrotum
In some male mammals the scrotum is a dual-chambered protuberance of skin and muscle containing the testicles and divided by a septum. It is an extension of the perineum, and is located between the penis and anus. In humans and some other mammals, the base of the scrotum becomes covered with curly...
is unknown; the current recommendation is to biopsy
Biopsy
A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...
the testes at puberty, allowing investigation of at least 30 seminiferous tubules
Seminiferous tubules
Seminiferous tubules are located in the testes, and are the specific location of meiosis, and the subsequent creation of gametes, namely spermatozoa....
, with diagnosis preferably based on OCT3/4 immunohistochemistry
Immunohistochemistry
Immunohistochemistry or IHC refers to the process of detecting antigens in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues. IHC takes its name from the roots "immuno," in reference to antibodies used in the procedure, and...
, followed by regular examinations . Hormone replacement therapy
Hormone replacement therapy
Hormone replacement therapy may refer to:*Hormone replacement therapy *Hormone replacement therapy *Hormone replacement therapy *Androgen replacement therapy -See also:...
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 puberty
Puberty
Puberty is the process of physical changes by which a child's body matures into an adult body capable of reproduction, as initiated by hormonal signals from the brain to the gonads; the ovaries in a girl, the testes in a boy...
. Artificially induced puberty results in the same, normal development of secondary sexual characteristics, growth spurt, 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 .
Testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
has been used to successfully treat undervirilization in some but not all men with PAIS, despite having supraphysiological levels of testosterone to start with . Treatment options include transdermal
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, and transdermal implants used for medical or aesthetic purposes....
gels or patches, oral or injectable testosterone undecanoate
Testosterone undecanoate
Testosterone undecanoate or testosterone undecylate is an ester of testosterone which is used for the treatment of male hypogonadism, and is currently under research for use as a male contraceptive...
, other injectable testosterone esters, testosterone pellets, or buccal
Buccal
Buccal may refer to:* Mouth, a body cavity** Specifically the cheek* Buccal artery...
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
Exogenous
Exogenous refers to an action or object coming from outside a system. It is the opposite of endogenous, something generated from within the system....
testosterone supplementation in unaffected men can produce various unwanted side effects
Side Effects
Side Effects is an anthology of 17 comical short stories written by Woody Allen between 1975 and 1980, all but one of which were previously published in, variously, The New Republic, The New York Times, The New Yorker, and The Kenyon Review. It includes Allen's 1978 O...
, including prostatic hypertrophy, polycythemia
Polycythemia
Polycythemia is a disease state in which the proportion of blood volume that is occupied by red blood cells increases...
, gynecomastia
Gynecomastia
Gynecomastia or Gynaecomastia, , is the abnormal development of large mammary glands in males resulting in breast enlargement. The term comes from the Greek γυνή gyné meaning "woman" and μαστός mastós meaning "breast"...
, hair loss, acne
Acne
Acne is a general term used for acneiform eruptions. It is usually used as a synonym for acne vulgaris, but may also refer to:*Acne aestivalis*Acne conglobata*Acne cosmetica*Acne fulminans*Acne keloidalis nuchae*Acne mechanica...
, and the suppression of the hypothalamic-pituitary-gonadal axis
Hypothalamic-pituitary-gonadal axis
The hypothalamic–pituitary–gonadal axis refers to the effects of the hypothalamus, pituitary gland, and gonads as if these individual endocrine glands were a single entity as a whole...
, which results in the reduction of gonadotropins (i.e., luteinizing hormone
Luteinizing hormone
Luteinizing hormone is a hormone produced by the anterior pituitary gland. In females, an acute rise of LH called the LH surge triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell-stimulating hormone , it stimulates Leydig cell...
and follicle-stimulating hormone
Follicle-stimulating hormone
Follicle-stimulating hormone is a hormone found in humans and other animals. It is synthesized and secreted by gonadotrophs of the anterior pituitary gland. FSH regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and Luteinizing hormone act...
) and spermatogenic
Spermatogenesis
Spermatogenesis is the process by which male primary germ cells undergo division, and produce a number of cells termed spermatogonia, from which the primary spermatocytes are derived. Each primary spermatocyte divides into two secondary spermatocytes, and each secondary spermatocyte into two...
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 and prostate
Rectal examination
A rectal examination or rectal exam is an internal examination of the rectum such as by a physician or other healthcare professional.-Procedure:...
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 that fit the criteria for grade 2 PAIS (micropenis
Micropenis
Micropenis is an unusually small penis. A common criterion is a dorsal erect penile length of at least 2.5 standard deviations smaller than the mean human penis size. The condition is usually recognized shortly after birth...
, penile hypospadias
Hypospadias
Hypospadias is a birth defect of the urethra in the male that involves an abnormally placed urinary meatus...
, and gynecomastia
Gynecomastia
Gynecomastia or Gynaecomastia, , is the abnormal development of large mammary glands in males resulting in breast enlargement. The term comes from the Greek γυνή gyné meaning "woman" and μαστός mastós meaning "breast"...
) . 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
Tamoxifen
Tamoxifen is an antagonist of the estrogen receptor in breast tissue via its active metabolite, hydroxytamoxifen. In other tissues such as the endometrium, it behaves as an agonist, hence tamoxifen may be characterized as a mixed agonist/antagonist...
in an individual with PAIS .
Depending on phenotypic
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
features, impotence and other sexual problems such as anejaculation
Anejaculation
Anejaculation is the pathological inability to ejaculate in males, with or without orgasm.It can depend on one or more of several causes, including ':*Sexual inhibition*Pharmacological inhibition...
or sexual aversion may be fairly common among individuals with PAIS , but do not necessarily indicate low libido
Libido
Libido refers to a person's sex drive or desire for sexual activity. The desire for sex is an aspect of a person's sexuality, but varies enormously from one person to another, and it also varies depending on circumstances at a particular time. A person who has extremely frequent or a suddenly...
. 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
Social anxiety
Social anxiety is anxiety about social situations, interactions with others, and being evaluated or scrutinized by other people...
, and restore focus to interpersonal relationships instead of solely on sexual function
Sexual function
Sexual function is a model developed at the Karolinska Institute in Stockholm, Sweden, defining different aspects of the assessment of sexual dysfunction comprises the following components....
and activity .
External links
InformationPatient groups