Male pseudohermaphroditism

Male pseudohermaphroditism due to 17-beta-hydroxysteroid dehydrogenase deficiency is a deficiency of 17-beta-hydroxysteroid dehydrogenase isozyme 3 which leads to male pseudohermaphroditism, a condition characterized by incomplete differentiation of male genitalia in 46XY males. It is caused by mutations in the HSD17B3 gene.

Etiology
17-beta-hydroxysteroid dehydrogenase deficiency type 3 (17βHSD3) is a disorder in testosterone biosynthesis. As a consequence of this disorder, normal male sexual differentiation in impaired and hypovirilization occurs (less male sexual characteristics).

Clinical characteristics
17-beta-hydroxysteroid dehydrogenase deficiency-3 is clinically characterized by either ambiguous external genitalia or complete female external genitalia at birth as a consequence of impaired male sexual differentiation in 46,XY individuals. Further investigations on ambiguous genitalia will eventually lead to findings of intersexuality. Severe hypovirilization (absence of male differentiation) can lead to development of female external genitalia. These females (!) are often discovered when there is absence of menarche (first menstruation) and when they begin to virilize during puberty (slowly become more like a man; deepening of the voice, acne, male musculature etc). At careful examination, testis can often be found in the inguinal channel.

Pathophysiology
17-beta-hydroxysteroid dehydrogenase deficiency-3 is biochemically characterized by decreased levels of testosterone and increased levels of androstenedione as a result of the defect in conversion of androstenedione into testosterone. This leads to clinically important higher ratio of androstenedione to testosterone (A'dion/T).-

Genetics
17-beta-hydroxysteroid dehydrogenase deficiency-3 is caused by gene mutations found in the 17BHSD3 gene. 17-beta-hydroxysteroid dehydrogenase deficiency-3 is an autosomal recessive disorder.

Intersexuality is a term used to describe a person whose sex chromosomes, genitalia and/or secondary sex characteristics are determined to be neither exclusively male nor female. A person with intersex may have biological characteristics of both the male and female sexes. Family medical practitioner, research psychologist and popular author Leonard Sax describes intersexuality as conditions in which chromosomal sex is inconsistent with phenotypic sex, or in which the phenotype is not classifiable as either male or female. Applying this ... precise definition, the true prevalence of intersex is seen to be about 0.018%. Applying Sax's approximation to the population of the U.S. yields about 54,000 intersex people.

Language
Research in the late twentieth century has led to a growing medical consensus that diverse intersex physicalities are normal, but relatively rare, forms of human biology. Perhaps the most prominent researcher, Milton Diamond, stresses the importance of care in selection of language related to intersexuality. Foremost, we advocate use of the terms "typical," "usual," or "most frequent" where it is more common to use the term "normal." When possible avoid expressions like maldeveloped or undeveloped, errors of development, defective genitals, abnormal, or mistakes of nature. Emphasize that all of these conditions are biologically understandable while they are statistically uncommon.

Hermaphrodite
The terms hermaphrodite and pseudohermaphrodite, introduced in the 19th century, are now considered problematic. The phrase '"ambiguous genitalia'" refers specifically to genital appearance, but not all intersex conditions result in atypical genital appearance.

Disorders of sex development
The Intersex Society of North America and intersex activists have moved to eliminate the term "intersex" in medical usage, replacing it with "disorders of sex development" (DSD) in order to avoid conflating anatomy with identity. Members of The Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology accepted the term "disorders of sex development" (DSD) in their "Consensus statement on management of intersex disorders" published in the Archives of Disease in Children and in Pediatrics. The term is defined by congenital conditions in which development of chromosomal, gonadal, or anatomical sex is atypical. However, this has been met with criticism from other activists who question a disease/disability model and advocate no legal definition of sexes, no gender assignments, no legal sex on birth certificates, and no official sexual orientation categories.

Alternatives to labeling these as "disorders" have also been suggested, including "Variations of Sex Development"

History
Intersex individuals are treated in different ways by different cultures. In some cultures intersex people were included in larger "third gender" or gender-blending social roles along with other individuals. In most societies, intersexed individuals have been expected to conform to either a male or female gender role.

Whether or not they were socially tolerated or accepted by any particular culture, the existence of intersex people was known to many ancient and pre-modern cultures.

As an example, one of the Sumerian creation legends Enki and Ninmaḫ (more than 4,000 years old) has Ninmah,(a mother-goddess) fashioning mankind out of clay. She boasts that she will determine the fate – good or bad – for all she fashions. Enki, the father god, retorts as follows.

56-61. Enki answered Ninmah: "I will counterbalance whatever fate -- good or bad -- you happen to decide." Ninmah took clay from the top of the abzu [heaven] in her hand and she fashioned from it first a man who could not bend his outstretched weak hands. Enki looked at the man who cannot bend his outstretched weak hands, and decreed his fate: he appointed him as a servant of the king.

... [Three men and one woman with atypical biology are formed and Enki gives each of them various forms of status to ensure respect for their uniqueness] ...

75-78. Sixth, she fashioned one with neither penis nor vagina on its body. Enki looked at the one with neither penis nor vagina on its body and gave it the name Nibru [eunuch(?)], and decreed as its fate to stand before the king.

Since the rise of modern medical science in Western societies, some intersex people with ambiguous external genitalia have had their genitalia surgically modified to resemble either male or female genitals. Ironically since the advancements in surgery have made it possible for intersex conditions to be concealed, many people are not aware of how frequently intersex conditions arise in human beings or that they occur at all. Contemporary social activists, scientists and health practitioners, among others, have begun to revisit the issue and awareness of the existence of physical sexual variation in human beings is returning.

There are increasing calls for recognition of the various degrees of intersex as healthy variations which should not be subject to correction. Some have attacked the common Western practice of performing corrective surgery on the genitals of intersex people as a Western cultural equivalent of female genital cutting. Despite the attacks on the practice, most of the medical profession still supports it, although activism has radically altered medical policies and how intersex patients and their families are treated. Others, typically social conservatives, have claimed that the talk about third sexes represents an ideological agenda to deride gender as a social construct whereas they believe binary gender (i.e. there is only male and female) is a biological imperative.

Depending on the type of intersex condition, corrective surgery may not be necessary for protection of life or health, but purely for aesthetic or social purposes. Unlike other aesthetic surgical procedures performed on infants, such as corrective surgery for a cleft palate, genital surgery may lead to negative consequences for sexual functioning in later life (such as loss of sensation in the genitals, for example, when a clitoris deemed too large/penile is reduced/removed, or feelings of freakishness and unacceptability) which would have been avoided without the surgery; in other cases negative consequences may be avoided with surgery. Opponents maintain that there is no compelling evidence that the presumed social benefits of such "normalizing" surgery outweigh the potential costs. (Similar attitudes are present in some cases of botched infant circumcision, in which the solution might involve intensive medical and parental efforts to reassign the male baby to a female identity, which opponents claim lead to the degrading interpretation that females are essentially castrated males. This view overlooks the embryological origin of the penis/clitoris.) Defenders of the practice argue that it is necessary for individuals to be clearly identified as male or female in order for them to function socially. However, many intersex individuals have resented the medical intervention, and some have been so discontented with their surgically assigned gender as to opt for sexual reassignment surgery later in life.

During the Victorian Period, medical authors introduced the terms "true hermaphrodite" for an individual who has both ovarian and testicular gonadal histology, verified under a microscope, "male pseudo-hermaphrodite" for a person with testicular tissue, but either female or ambiguous sexual anatomy, and "female pseudo-hermaphrodite" for a person with ovarian tissue, but either male or ambiguous sexual anatomy. The writer Anne Fausto-Sterling coined the words herm (for "true hermaphrodite"), merm (for "male pseudo-hermaphrodite"), and ferm (for "female pseudo-hermaphrodite"), and proposed that these be recognized as sexes along with male and female. However, her use was "tongue-in-cheek"; she no longer advocates these terms even as a rhetorical device, and her proposed nomenclature was criticized by Cheryl Chase, in a letter to The Sciences which criticized the traditional standard of medical care as well as Fausto-Sterling's shorter names, and announced the creation of the Intersex Society of North America.

Intersex in popular culture
Beginning as early as 1989, intersex became a topic of interest for broadcast TV and radio in the United States and other countries. Jeffrey Eugenides' novel Middlesex (2002) is narrated by an intersex character who discusses the societal experience of an intersex person. There is also 7 volumes of Japanese manga series I.S._(Aiesu) (published in 2003) which deals about various Intersexuals, how they deal with the issue and how they influence the life of people around them.

Notable intersex people

 * Cheryl Chase (activist), intersex activist
 * Erik Schinegger, alpine skier

Intersex organizations

 * Intersex Society of North America
 * Organisation Intersex International
 * AIS Support Group Australia

Lack in education
In high school, most emphasis is placed upon the most common XX and XY genotypes. Thus, people nowadays may be more likely to look towards the sex chromosomes than, for example, the histology of the gonads. However, according to researcher Eric Villain at the University of California, Los Angeles, "the biology of gender is far more complicated than XX or XY chromosomes". Many different criteria have been proposed, and there is little consensus.

Scope
Sax's strict definition of intersex (above) is most relevant to family practice and psychological research. Other interest groups serve different communities and concerns and so broaden the definition of intersex in these fields.

For instance, the Intersex Society of North America (ISNA) definition also includes androgen insensitivity syndrome (AIS), congenital adrenal hyperplasia (CAH), ambiguous genitalia, and mosaic chromosomes (mosaicism), in addition to sex chromosome aneuplodies, and any deviations from "the Platonic ideal" in the scope of intersex. It is derived from Anne Fausto-Sterling, an academic in gender studies. In other words, it also includes: Note: This inclusion of Kallmann Syndrome as an intersex condition appears to be based on very early descriptions of the most obvious cases of Kallmann Syndrome, some of whom had multiple medical conditions. The majority of males with Kallmann Syndrome in fact do not have micropenis at birth, and not all have undescended testes. Kallmann syndrome is in fact one of many conditions that cause delayed/missing puberty, but which are not listed in this article. It also assumes that Kallmann Syndrome affects only males (again possibly based on very out of date information). Women may also have Kallmann Syndrome, again with delayed puberty. See notes below about Kallmann Syndrome. Most people with Kallmann's do not regard themselves as intersex. Furthermore, if delayed puberty also is included as intersex, then there is a problem in distinguishing normal pre-pubertal children and intersex.
 * hypospadias, the placement of the urinary meatus on underside of the penis or at the base, instead of at the end; and,
 * Kallmann syndrome, a condition in which the pituitary gland does not stimulate to release the hormones required for testicular growth, resulting in undescended testes and a micropenis.

Other conditions whose status as "intersex" are disputed include:
 * Turner syndrome

Note: Again most people with Turner's do not regard themselves as intersex. This is not surprising since the majority of them are born unambiguously female, though a very small percentage with XYXO chromosomes may have ambiguous reproductive organs.


 * Klinefelter syndrome
 * clitoromegaly
 * micropenis

Prevalence
The prevalence of intersex depends on which definition (presented in "Scope" above) is used.

According to the ISNA definition above, 1 percent of live births exhibit some degree of sexual ambiguity, and that between 0.1% and 0.2% of live births are ambiguous enough to become the subject of specialist medical attention, including surgery to disguise their sexual ambiguity.

According to Fausto-Sterling's definition of intersex, on the other hand, 1.7 percent of human births are intersex. She writes, While male and female stand on the extreme ends of a biological continuum, there are many bodies [...] that evidently mix together anatomical components conventionally attributed to both males and females. The implications of my argument for a sexual continuum are profound. If nature really offers us more than two sexes, then it follows that our current notions of masculinity and femininity are cultural conceits. [...] Modern surgical techniques help maintain the two-sex system. Today children who are born "either/or-neither/both" — a fairly common phenomenon — usually disappear from view because doctors "correct" them right away with surgery. However, inspection of the descriptions of specific intersex variations (below) will show that these do not form any "continuum", nor do they change the objective differences between typical male and female forms. The intersex variations each describe a unique type of human physicality.

Ambiguous genitalia
Ambiguous genitalia appear as a large clitoris or small penis and may or may not require surgery.

Because there is variation in all of the processes of the development of the sex organs, a child can be born with a sexual anatomy that is typically female, or feminine in appearance with a larger than average clitoris (clitoral hypertrophy); or typically male, masculine in appearance with a smaller than average penis that is open along the underside. The appearance may be quite ambiguous, describable as female genitals with a very large clitoris and partially fused labia, or as male genitals with a very small penis, completely open along the midline ("hypospadic"), and empty scrotum.

Fertility is variable. The distinctions "male pseudohermaphrodite", "female pseudohermaphrodite" and especially "true hermaphrodite" are vestiges of 19th century thinking that placed "true sex" in the histology (microscopic appearance) of the gonads.

"True hermaphroditism"
With some conditions of intersex, even the chromosomal sex may not be clear. A "true hermaphrodite" is defined as someone with both male gonadal tissue (testes) and female gonadal tissue (ovarian tissue).

In 2004, researchers at UCLA published their studies of a lateral gynandromorphic hermaphroditic bird, which had a testicle on the right and an ovary on the left. Its entire body was split down the middle between male and female, with hormones from both gonads running through the blood.

This extreme example of hermaphroditism is quite rare.

Ovotestes
Although there are no definite reports on any true hermaphroditism in humans, there is, on the other hand, a spectrum of forms of ovotestes. The varieties range, including having two ovotestes or having one ovary and one ovotestis. This is often in the form of streak gonads. Phenotype is not determinable from the ovotestes; in some case the appearance is "fairly typically female," in others it is "fairly typically male," and it may also be "fairly in-between in terms of genital development."

Intersex activist Cheryl Chase (activist) is an example of someone with ovotestes.

Other diagnostic signs
In order to help in classification, other methods than a genitalia inspection can be performed:

For instance, a karyotype display of a tissue sample may determine which of the causes of intersex is prevalent in the case.

Management
Management of intersex can be categorized into one of the following two :
 * 1) Treatments: Restore functionality (or potential functionality)
 * 2) Enhancements: Give the ability to identify with “mainstream” people e.g. breast enlargement surgery

However, there are other categorisation systems of management of intersexed, which falls into neither category.

In any case, the most common procedure is surgery.

Surgery
The exact procedure of the surgery depends on what is the cause of a less common body phenotype in the first place.

If
There is often concern whether surgery should be performed at all.

Traditional approaches to management of Intersexuality has been socially motivated surgery. However, some (Alice Dreger) say that surgical treatment is socially motivated and hence ethically questionable; without evidence doctors regularly assume that intersexed persons can not have a clear identity. This is often taken further with parents of intersexed babies advised that without surgery their child will be stigmatized. Creating such pressures without supporting evidence is either bad science or bad ethics.

The second assumption is that “mainstream” people are always happy and have a clear sense of purpose. One only needs to look within mainstream society to see this is a fiction.

In 20% to 30% of surgical cases to “treat” intersexed babies the result is loss of adult sensations (See Newman 1991, 1992). Given these statistics and the fact that surgery is irreversible it is important to remember this is a material change based on a social framework. In other words, surgery on babies is ignoring the right to autonomy.

In this sense, the treatment is for parental anxiety rather than a treatment or enhancement for the intersexed. Drawing an analogy with a hypothetical homosexuality gene test, comparable treatment would involve the repression all sexuality in anyone who came up positive on such a test.

When
Most modern intersexed advocates argue surgery on intersexed babies should wait until the child can make an informed decision.

Upbringing
It is a hard dilemma for the parents how to bring up an intersex child.

Even if the intersexed children lacks a definite gender, this is not to say that they should be raised without gender.

"Mainstream" sex development
Before discussing the development of intersex, it is necessary to understand the most common pathway of sexual differentiation, where a productive human female has an XX chromosome pair, and a productive male has an XY pair.

During fertilization, the sperm adds either an X (female) or Y (male) chromosome to the X in the ovum. This determines the genetic sex of the embryo. During the first weeks of development, genetic male and female fetuses are "anatomically indistinguishable," with primitive gonads beginning to develop during approximately the sixth week of gestation. The gonads, in a "bipotential state," may develop into either testes (the male gonads) or ovaries (the female gonads) depending on the consequent events. Through the seventh week, male and female fetuses appear identical.

At around eight weeks of gestation, the gonads of an XY embryo differentiate into functional testes, secreting testosterone. Ovarian differentiation, for XX embryos, does not occur until approximately Week 12 of gestation. In normal female differentiation the müllerian duct system develops into the uterus, Fallopian tubes, and inner third of the vagina. In males the müllerian duct-inhibiting hormone MIH causes this duct system to regress. Next, androgens cause the development of the Wolffian duct system, which develops into the vas deferens, seminal vesicles, and ejaculatory ducts. By birth, the typical fetus has been completely "sexed" male or female, the hormones and genital development remaining consistent with the genetic sex.

Less usual chromosomal sex
In addition to the most common XX and XY chromosomal sexes, there are quite a few other possible combinations such as Turner syndrome (XO), Triple X syndrome (XXX), Klinefelter syndrome (XXY), XYY syndrome (XYY), XX male, Swyer syndrome (XY female), and there are many other individuals who do not follow the typical patterns (such as individuals with four or even more sex chromosomes).

Mosaicism and chimerism
A mix can occur, where some of the cells of the body have the common XX or XY, while some have one of the less usual chromosomal contents above. Such a mixture is caused by either mosaicism or chimerism. In mosaicism, the mixture is caused by a mutation in one of the cells of the embryo after fertilization, while chimerism is a fusion of two embryos.

Alternatively, it is simply is a mixture between XX and XY, and doesn't have to involve any less common genotypes in individual cells. This, too, can occur both as a chimerism, or that one sex chromosome has mutated into the other

On the other hand, however, not all cases of mosaicism and chimerism involve intersex.

Incongruence between chromosomal and phenotypic sex
The final body appearance doesn't always correspond with what is dictated by the genes. In other words, there is sometimes an incongruence between genotypic (chromosomal) and phenotypic sex. Although there neither no less common chromosomal sex nor mosaicism/chimerism, but just the most common types (XY or XX), less common phenotypes still appear in such cases. In this sense, the common habit in the 21st century of elevating the role of the sex chromosomes above all other factors when determining gender may be analogous to the older habit of finding "true" sex in the gonads.

This phenomenon complicates the common XY sex-determination system, because it proves that genes don't always definitely determine the sex.

The cause of such an incongruence is mostly congenital adrenal hyperplasia, where the kidney synthesizes vitilizing hormones, even in the absence of testes. Another cause is androgen insensitivity syndrome, where testes are present and functional, but the body doesn't respond properly to them. In either the case of AIS or CAH, testing of the chromosomes can be done to determine the genetic sex of the individual. Both are described below:

Congenital adrenal hyperplasia
The most common cause of sexual ambiguity is congenital adrenal hyperplasia (CAH), an endocrine disorder in which the adrenal glands produce abnormally high levels of virilizing hormones. In genetic females, this leads to an appearance that may be slightly masculinized (large clitoris) to quite masculine.

Cause
CAH is a genetic disorder in which the adrenal glands, while trying to make cortisone, may make an unusually high level of masculinizing hormones. When CAH occurs in an XY embryo, this is not an intersex condition, because it rather enhances the masculine characteristics.

Due to a defect in one of the enzymes that synthesize adrenal hormones, a blockage in one synthetic pathway will occur, causing excessive production of androgenic hormones in a different pathway, virilizing an XX fetus in utero. Genitalia may appear completely masculine, or it may be ambiguous. />

Signs
In genetic females, common signs of CAH include clitoromegaly, labia that resemble a scrotum, and masculine-typical characteristics, including a deep voice and dense body hair.

Other causes of intersex in XXs

 * Progestin-induced virilisation. In this case, the male hormones are caused by use of progestin, a drug that was used in the 1950s and 1960s in order to prevent miscarriage. These individuals normally have internal and external female anatomy, with functional ovaries and will therefore have menstruation. They develop, however, some male secondary characteristics and they frequently have unusually large clitorises. In very advanced cases, such children have initially been identified as boys.


 * In persistent müllerian duct syndrome, the child has XY chromosomes typical of a male. The child has a male body and an internal uterus and fallopian tubes because his body did not produce Müllerian inhibiting factor during fetal development.


 * A similar phenomenon occurs in cases where a cow brings two fraternal twins, one male and one female, to term. Because (unlike humans) such twins share hormones via their placental blood interface with the mother cow, male hormones produced in the body of the fetal bull find their way into the body of the fetal cow and masculinize her brain. The result is a freemartin (unconventional heifer), a cow that will eventually try to mount other cows the way that a bull would.

Androgen insensitivity syndrome
People with AIS have typically male chromosomes (XY), along with typically female appearance and genitalia.

Although people with AIS have a vagina, they lack a uterus, cervix of the uterus, and ovaries, and are thereby infertile. The vagina may be shorter than average; in some cases it is nearly absent. Instead of female internal reproductive organs, a person with AIS has undescended or partially descended testes, of which she may not even be aware.

AIS may be called the genetic male's equivalent of CAH, since AIS affects people with XY genotype, while CAH affects people with XX genotype.

Development of AIS
In androgen insensitivity syndrome, a genetic male with XY chromosomes is otherwise female. The body fails to respond to the testosterone produced by the testes, due to an androgen receptor defect. This defect is mostly inherited, but can also be the cause of spontaneous mutation.

During development, the testes form, but due to the body's insensitivity to the testosterone responsible for the differentiation into Wolffian structures (epididymis, vas deferens, and seminal vesicles) the body differentiates along the female path. In other words, certain hormonal conditions, in this case the body's response to them, must exist for male development to ensue, even if the sex chromosome pattern is 46,XY.

At puberty, a child with AIS develops breasts and a feminine shape. In normal women, both testosterone and estrogen are present, but since the bodies of AIS women do not recognize testosterone, it is converted to estrogen. Testosterone is responsible for the growth of pubic and axillary hair, so many women with AIS have no hair in these areas, or have only sparse hair. Primary amenorrhea (absence of menstruation) is another sign of AIS.

Diagnosis
An AIS female may be unaware of her condition. Symptoms of primary amenorrhea, lack of pubic and axillary hair, and what appears to be a hernia can lead a female with AIS to present these indicators to a doctors, leading to the discovery of AIS.

It is possible to diagnose AIS during the ninth to 12th week of pregnancy, using chorionic villus sampling, and it can be detected by ultrasound and amniocentesis by Week 16, although prenatal diagnosis of AIS is not indicated unless a family history of AIS is known.

Management
Individuals with complete AIS typically identify as female. Nevertheless, surgery and other techniques may be used to make the genital appearance more "typically female."

To lengthen the vagina, a woman with AIS may be instructed by a doctor to apply regular pressure dilation several times a day. Vaginoplasty, the surgical shaping of the vagina, and clitoridectomy, removal of the clitoris, may also be performed.

Complete/Partial androgen insensitivity syndrome
In CAIS, the body reads no "male" hormones. In partial androgen insensitivity syndrome (PAIS), however, the body reads some androgens, so virilization occurs to a certain degree. PAIS results in genitalia that may be ambiguous, due to some, although limited, metabolization of the hormones produced by the testes. Ambiguous genitalia most frequently appear as a large clitoris, known as clitoromegaly, or a small penis, which is called as micropenis or microphallus.

Other causes of intersex in XY

 * 5-alpha-reductase deficiency. In this condition, individuals have testes, as well as vagina and labia, but with a small penis capable of ejaculation instead of a clitoris (this penis, however, appears to be a clitoris at birth). These individuals are normally raised as girls. However, come puberty, their testes will descend, their voice will deepen and they often will develop a male sexual identity. People with this deficiency develop only limited facial hair.

Kallmann syndrome
Kallmann Syndrome is a specific type of hypogonadotropic hypogonadism (HH) in which the distinguishing symptom is anosmia or hyposmia in addition to the HH symptoms of low levels of pituitary hormones LH and FSH.

Kallmann Syndrome is not an intersex condition but does cause pubertal delay in both males and females. Some individuals with Kallmann's may regard themselves as intersex. However, this is possibly because they have other conditions such as PAIS in addition to Kallmann's. Such synchronous conditions is only present in a minority of people with Kallmann's, who mostly have no genital abnormality at birth. Therefore, mostly, there is no inconsistency of sex chromosomes with phenotype and they are therefore not intersex. Having pubertal delay but otherwise usual male or female body and fertility is not intersex.

Complications
Intersex people are in the risk of developing gender identity disorder, feeling significant discomfort or being unable to deal with the condition.

Furthermore, in the cases where nonfunctional testes are present, there is a risk that these develop cancer. Therefore, doctors either remove them by orchidectomy or monitor them carefully. This is the case for instance in androgen insensitivity syndrome.