Approximately 1 in 20,000 individuals with a male appearance have 46,XX testicular disorder.

At puberty, most affected individuals require treatment with the male sex hormone testosterone to induce development of male secondary sex characteristics such as facial hair and deepening of the voice (masculinization). Hormone treatment can also help prevent breast enlargement (gynecomastia). Adults with this disorder are usually shorter than average for males and are unable to have children (infertile).

Sex determination and differentiation is generalized with chromosomal sex during fertilization. At early stages, phenotypic sex does not match chromosomal sex—until later during intrauterine development, sexual maturation is reached. During intrauterine development, females change to male with the testes moving down from a blind vaginal pouch with a developing scrotum, as well as a penis which initially resembled a clitoris. What seems like a female phenotype is altered by increased testosterone levels secretion.

Mutations affecting the androgen receptor (AR) gene may cause either complete or partial androgen insensitivity syndrome. Androgen, a hormone used to describe a group of sex steroid hormones, is responsible for affecting male pseudohermaphroditism. The differentiation of the fetus as male takes place during the sixth or seventh week of gestation. The development is directed by the testicular determining factor: the gene SRY (sex determining region on Y chromosome). Throughout 9th to 13th week, the development of a male genitalia is dependent upon the conversion of testosterone to the more potent androgen by the action of 5α-reductase within the target tissues of the genitalia. A type of internal male pseudohermaphroditism is Persistent Müllerian duct syndrome, which is developed through synthesis of Müllerian-inhibiting factor defects. In such instances, duct derivatives are now in 46XY males—this includes the uterus, fallopian tubes, and upper vagina. These individuals with a hernia sac and bowel loops were found with duct derivatives as well as testes.

A study on a male pseudohermaphrodite kitten showed there was a combination of gastrointestinal and urogenital congenital abnormalities. It was confirmed to have type II atresia ani and rectovaginal fistula that is associated with male pseudohermaphroditism.

The common pathway of sexual differentiation, where a productive human female has an XX chromosome pair, and a productive male has an XY pair, is relevant to the development of intersex conditions.

During fertilization, the sperm adds either an X (female) or a 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, genetically female and genetically male 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, meaning that the genetic sex (XY-male or XX-female) corresponds with the phenotypical sex; that is to say, genetic sex corresponds with internal and external gonads, and external appearance of the genitals.

XX male syndrome is a rare congenital condition where an individual with a female genotype has phenotypically male characteristics that can vary between cases. In 90% of these individuals the syndrome is caused by unequal crossing over between X and Y chromosomes during meiosis in the father, and results in the X chromosome containing the SRY gene, as opposed to the Y chromosome where it is normally found. When the X with the SRY gene combines with a normal X from the mother during fertilization, the result is an XX male. Less common are SRY-negative XX males which can be caused by a mutation in an autosomal or X chromosomal gene. The masculinization of XX males is variable.

This syndrome is diagnosed through various detection methods and occurs in approximately 1:20 000 newborn males, making it less common than Klinefelter syndrome. Treatment is medically unnecessary, although some individuals choose to undergo treatments to make them appear more male or female. It is also called de la Chapelle syndrome, for Albert de la Chapelle, who characterized it in 1972.

According to the UN Office of the High Commissioner for Human Rights:

In biological terms, sex may be determined by a number of factors present at birth, including:

- the number and type of sex chromosomes;

- the type of gonads—ovaries or testicles;

- the sex hormones;

- the internal reproductive anatomy (such as the uterus in females); and

- the external genitalia.

People whose characteristics are not either all typically male or all typically female at birth are intersex.

Some intersex traits are not always visible at birth; some babies may be born with ambiguous genitals, while others may have ambiguous internal organs (testes and ovaries). Others will not become aware that they are intersex unless they receive genetic testing, because it does not manifest in their phenotype.

Surgery is sometimes performed to alter the appearance of the genitals. However many surgeries performed on intersex people lack clear evidence of necessity, can be considered as mutilating, and are widely considered to be human rights violations when performed without the informed consent of the recipient.

Estimates for the incidence of androgen insensitivity syndrome are based on a relatively small population size, thus are known to be imprecise. CAIS is estimated to occur in one of every 20,400 46,XY births. A nationwide survey in the Netherlands based on patients with genetic confirmation of the diagnosis estimates that the minimal incidence of CAIS is one in 99,000. The incidence of PAIS is estimated to be one in 130,000. Due to its subtle presentation, MAIS is not typically investigated except in the case of male infertility, thus its true prevalence is unknown.

Disorders of sex development (DSD), sometimes referred to as disorders of sex differentiation or differences of sex development, are medical conditions involving the reproductive system. More specifically, these terms refer to "congenital conditions in which development of chromosomal, gonadal, or anatomical sex is atypical."

The term has been controversial, and research has shown that affected people experience a negative impact, with the terminology impacting choice and utilization of health care providers. The World Health Organization and many medical journals still reference DSDs as intersex traits or conditions. The Council of Europe, and Inter-American Commission on Human Rights have called for a review of medical classifications that unnecessarily medicalize intersex traits.

Depending on the mutation, a person with a 46,XY karyotype and AIS can have either a male (MAIS) or female (CAIS) phenotype, or may have genitalia that are only partially masculinized (PAIS). The gonads are testes regardless of phenotype due to the influence of the Y chromosome. A 46,XY female, thus, does not have ovaries or a uterus, and can neither contribute an egg towards conception nor gestate a child.

Several case studies of fertile 46,XY males with AIS have been published, although this group is thought to be a minority. Additionally, some infertile males with MAIS have been able to conceive children after increasing their sperm count through the use of supplementary testosterone. A genetic male conceived by a man with AIS would not receive his father's X chromosome, thus would neither inherit nor carry the gene for the syndrome. A genetic female conceived in such a way would receive her father's X chromosome, thus would become a carrier.

The degree to which individuals with XX male syndrome develop the male phenotype is variable, even among SRY-positive individuals. A completely male phenotype usually develops in the presence of the SRY gene but, in some cases, the presence of the SRY gene can result in internal and/or external genitalia ambiguities. Normal XX females undergo X inactivation during which one copy of the X chromosome is silenced. It is thought that X inactivation in XX males may account for the genital ambiguities and incomplete masculinization seen in SRY-positive XX males. The X chromosome with the SRY gene is preferentially chosen to be the active X chromosome 90% of the time, which is why a complete male phenotype is often seen in SRY-positive XX males. In the remaining 10%, X inactivation spreads to include a portion of the SRY gene, resulting in incomplete masculinization.

Masculinization of SRY-negative XX males is dependent upon which genes have mutations and at what point in development these mutations occur.

The 2006 Consensus statement on the management of intersex disorders states that individuals with 17β-hydroxysteroid dehydrogenase III deficiency have an intermediate risk of germ cell malignancy, at 28%, recommending that gonads be monitored. A 2010 review put the risk of germ cell tumors at 17%.

The management of 17β-hydroxysteroid dehydrogenase III deficiency can consist, according to one source, of the elimination of gonads prior to puberty, in turn halting masculinization.

Hewitt and Warne state that, children with 17β-hydroxysteroid dehydrogenase III deficiency who are raised as girls often later identify as male, describing a "well known, spontaneous change of gender identity from female to male" that "occurs after the onset of puberty." A 2005 systematic review of gender role change identified the rate of gender role change as occurring in 39–64% of individuals with 17β-hydroxysteroid dehydrogenase III deficiency raised as girls.

DSDs are medical conditions involving the way the reproductive system develops from infancy (and before birth) through young adulthood. There are several types of DSDs and their effect on the external and internal reproductive organs varies greatly.

A frequently-used social and medical adjective for people with DSDs is "intersex". Parents with DSD children and clinicians involved in DSD treatment usually try to make clear distinctions between biological sex, social gender, and sexual orientation. This helps reduce confusion about the differences between being intersex, being transgender, and being gay/lesbian.

The most common DSD is congenital adrenal hyperplasia (CAH), which results in a person with female (XX) chromosomes having genitals that look somewhat masculine. In mild cases CAH results in a slightly enlarged clitoris, while in more severe cases it can be difficult to decide (just by looking) whether a baby is male or female (this is called having ambiguous genitals). Nevertheless, if they are old enough to know the difference, most children with CAH think of themselves as girls. CAH is caused by a problem with the adrenal glands and is usually treated by taking a daily medication to replace or supplement the missing adrenal hormones. (When this adrenal problem occurs in people with male (XY) chromosomes, the result is over-masculinization and premature puberty).

Another common DSD is androgen insensitivity syndrome (AIS), which means that a person with male (XY) chromosomes does not respond to testosterone in the usual way. This results in a body that to some degree has a feminine appearance. In Complete Androgen Insensitivity Syndrome (CAIS) the result is a totally feminine appearance, including typical female breast development. Consequently, most young women with CAIS are unaware of their condition until the early teen years when they fail to menstruate. In the milder form, called Partial Androgen Insensitivity Syndrome (PAIS), the genitals can vary from mostly female to almost completely male. Some people with PAIS think of themselves as girls/women, others regard themselves as boys/men, and some consider themselves mixed-gender.

One of the more unusual DSDs is 5-alpha-reductase deficiency (5ARD). It is caused by a shortage early in life of an enzyme that activates testosterone. In this condition, a person with male (XY) chromosomes has a body that appears female before puberty. After puberty begins, other testosterone-activating enzymes become available and the body soon takes on a masculine appearance, with the scrotum and penis usually reaching typical or nearly-typical size. If 5ARD is diagnosed at a young age, the child is often raised as a boy (a 1996 Brazilian study suggested that the majority of adults with this condition consider themselves men but this has been questioned in some more recent research).

In addition to CAH, CAIS, PAIS, and 5ARD there are several rarer types of DSDs, and in some cases it is not possible to make a clear diagnosis of the underlying condition.

The penis and clitoris are essentially the same organ (differing only in size, and generically called the phallus). In typical males, the urethra is located at the tip of the penis, while in typical females the urethra is located below the base of the clitoris. When the phallus is of intermediate size, it is possible also to have a urethral opening located along the shaft; this condition is known as hypospadias.

Open-minded parenting, appropriate and conservative medical intervention, and age-appropriate child involvement in the treatment plan contribute greatly to successful outcomes for the entire range of DSDs.

45,X/46,XY mosaicism, also known as X0/XY mosaicism and mixed gonadal dysgenesis, is a rare disorder of sex development in humans associated with sex chromosome aneuploidy and mosaicism of the Y chromosome. This is called a mosaic karyotype because, like tiles in mosaic floors or walls, there is more than one type of cell.

The clinical manifestations are highly variable, ranging from partial virilisation and ambiguous genitalia at birth, to patients with a completely male or female gonads. Most individuals with this karyotype have apparently normal male genitalia, and a minority with female genitalia, with a significant number of individuals showing genital abnormalities or intersex characteristics. A significantly higher than normal number of other developmental abnormalities are also found in individuals with X0/XY mosaicism. Psychomotor development is normal.

In a normal situation, all the cells in an individual will have 46 chromosomes with one being an X and one a Y or with two Xs. However, sometimes during this complicated early copying process (DNA replication and cell division), one chromosome can be lost. In 45,X/46,XY, most or all of the Y chromosome is lost in one of the newly created cells. All the cells then made from this cell will lack the Y chromosome. All the cells created from the cells that have not lost the Y chromosome will be XY. The 46,XY cells will continue to multiply at the same time as the 45,X cells multiply. The embryo, then the fetus and then the baby will have what is called a 45,X/46,XY constitution. This is called a

mosaic karyotype because, like tiles in mosaic floors or walls, there is more than one type of cell.

There are many chromosomal variations that cause the 45,X/46,XY karyotype, including malformation (isodicentricism) of the Y chromosomes, deletions of Y chromosome or translocations of Y chromosome segments. These rearrangements of the Y chromosome can lead to partial expression of the SRY gene which may lead to abnormal genitals and testosterone levels.

Nuclear receptor subfamily 5 group A member 1 (NR5A1), also known as SF1 or Ad4BP (MIM 184757), is located on the long arm of chromosome 9 (9q33.3). The NR5A1 is an orphan nuclear receptor that was first identified following the search for a common regulator of the cytochrome P450 steroid hydroxylase enzyme family. This receptor is a pivotal transcriptional regulator of an array of genes involved in reproduction, steroidogenesis and male sexual differentiation and also plays a crucial role in adrenal gland formation in both sexes. NR5A1 regulates the mullerian inhibitory substance by binding to a conserved upstream regulatory element and directly participates in the process of mammalian sex determination through mullerian duct regression. Targeted disruption of NR5A1 (Ftzf1) in mice results in gonadal and adrenal agenesis, persistence of Mullerian structures and abnormalities of the hypothalamus and pituitary gonadotropes. Heterozygous animals demonstrate a milder phenotype including an impaired adrenal stress response and reduced testicular size. In humans, NR5A1 mutations were first described in patients with 46, XY karyotype and disorders of sex development (DSD), Mullerian structures and primary adrenal failure (MIM 612965). After that, heterozygous NR5A1 mutations were described in seven patients showing 46, XY karyotype and ambiguous genitalia, gonadal dysgenesis, but no adrenal insufficiency. Since then, studies have confirmed that mutations in NR5A1 in patients with 46, XY karyotype cause severe underandrogenisation, but no adrenal insufficiency, establishing dynamic and dosage-dependent actions for NR5A1. Subsequent studies revealed that NR5A1 heterozygous mutations cause primary ovarian insufficiency (MIM 612964).

During embryogenesis, without any external influences for or against, the human reproductive system is intrinsically conditioned to give rise to a female reproductive organisation.

As a result, if a gonad cannot express its sexual identity via its hormones—as in gonadal dysgenesis—then the affected person, no matter whether their chromosomes are XY or XX, will develop external female genitalia. Internal female genitalia, primarily the uterus, may or may not be present depending on the cause of the disorder.

In both sexes, the commencement and progression of puberty require functional gonads that will work in harmony with the hypothalamic and pituitary glands to produce adequate hormones.

For this reason, in gonadal dysgenesis the accompanying hormonal failure also prevents the development of secondary sex characteristics in either sex, resulting in a sexually infantile female appearance and infertility.

Serkal syndrome is an autosomal recessive disorder in XX humans. It is caused by loss of function in WNT4, a protein involved in sex development. The main outcome is female to male sex reversal.

Exposure of spermatozoa to lifestyle, environmental and/or occupational hazards may increase the risk of aneuploidy. Cigarette smoke is a known aneugen (aneuploidy inducing agent). It is associated with increases in aneuploidy ranging from 1.5 to 3.0-fold. Other studies indicate factors such as alcohol consumption, occupational exposure to benzene, and exposure to the insecticides fenvalerate and carbaryl also increase aneuploidy.

The disorder is linked a mutation in the "Wnt4" gene. There is an intraexonic homozygous C to T transition at cDNA position 341. This leads to an alanine to valine residue substitution at amino acid position 114, a location highly conserved in all organisms, including zebrafish and Drosophila. A subsequent influence on mRNA stability leads to protein loss of function. WNT4 usually represses male sex development.

A freemartin or free-martin (sometimes martin heifer) is an infertile female mammal with masculinized behavior and non-functioning ovaries. Genetically the animal is chimeric: Karyotyping of a sample of cells shows XX/XY chromosomes. The animal originates as a female (XX), but acquires the male (XY) component in utero by exchange of some cellular material from a male twin, via vascular connections between placentas: an example of microchimerism. Externally, the animal appears female, but various aspects of female reproductive development are altered due to acquisition of anti-Müllerian hormone from the male twin. Freemartinism is the normal outcome of mixed-sex twins in all cattle species that have been studied, and it also occurs occasionally in other mammals including sheep, goats and pigs.

This condition will occur if there is an absence of both Müllerian inhibiting factor and testosterone. The absence of testosterone will result in regression of the Wolffian ducts; normal male internal reproductive tracts will not develop. The absence of Müllerian inhibiting factor will allow the Müllerian ducts to differentiate into the oviducts and uterus. In sum, this individual will possess female-like internal and external reproductive characteristics, lacking secondary sex characteristics. The genotype may be either 45,XO, 46,XX or 46,XY.

This syndrome, evenly spread in all ethnic groups, has a prevalence of 1-2 subjects per every 1000 males in the general population. 3.1% of infertile males have Klinefelter syndrome. The syndrome is also the main cause of male hypogonadism.

According to 2008 meta-analysis, the prevalence of the syndrome has increased over the past decades; however, this does not appear to be related to increased age of the mother at conception, as no increase was observed in the rates of other trisomies of sex chromosomes (XXX and XYY). The National Institutes of Health; however, state that older mothers might have a slightly increased risk.

There are several forms of gonadal dysgenesis. The term “pure gonadal dysgenesis” (PGD) has been used to describe conditions with normal sets of sex chromosomes (e.g., 46,XX or 46,XY), as opposed to those whose gonadal dysgenesis results from missing all or part of the second sex chromosome. The latter group includes those with Turner syndrome (i.e., 45,X) and its variants, as well as those with mixed gonadal dysgenesis and a mixture of cell lines, some containing a Y chromosome (e.g., 46,XY/45,X).

Thus Swyer syndrome is referred to as PGD, 46,XY, and XX gonadal dysgenesis as PGD, 46,XX. Patients with PGD have a normal karyotype but may have defects of a specific gene on a chromosome.

In 1951, Perrault reported the association of gonadal dysgenesis and deafness, now called Perrault syndrome.