What is intersex?

What is intersex?

Intersex often refers to appearance of genitals, but may be used in broader terms of non-binary sexual differentiation such as gender identity or sexual orientation. Several conditions known to be associated with particular variations of sex chromosomes or gene mutations have been named. This article touches on a few of them.

Additional sex chromosomes

Intersex conditions can, but not necessarily do, result from variations in sex chromosome combinations beyond XX and XY. We are not limited to two sex chromosomes, and though having three is more likely than higher numbers, individuals having at least as many as five sex chromosomes have been documented. More than two sex chromosomes may occur in about one in 500 live births and account for a percentage of miscarriages. It is possible for an individual to have two different sets of chromosomes in different body locations, even having been found to have 46 chromosomes in some areas and 47 chromosomes (having a third sex chromosome) in others.

In this section, we’ll be discussing some conditions shown to begin with a naming convention such as “46,XX” or “46,XY”. In this nomenclature, the numeric value (in this case 46) is the number of chromosomes possessed by the individual. 46 is the norm, and these represent the usual 23 pair (22 pair of autosomes and one pair of sex chromosomes). The letters are the sex chromosomes the individual possesses, with XX being a genetic female and XY being a genetic male. A designation such as “47,XXY” is a genetic male who has a second X chromosome, for a total of three sex chromosomes: two Xs and one Y.

When more than one X chromosome is present, only one of them is left fully active in each cell of the body, with the others being about 85% inactivated. The one remaining fully active differs from cell to cell. To visualize this, picture a calico or tortoiseshell cat, whose coloring is sex-linked. In a female tortoiseshell cat, one of her X chromosomes will result in displaying orange coloring, while the other X chromosome results in displaying the black color. The tortoiseshell coloring is a mix of the two being displayed throughout the body, depending on which X is inactivated in each particular cell. (Additional information on X chromosome inactivation is provided in Not a Choice.)

In general, if an individual possesses at least one Y chromosome, they are considered genetically male. That could be XY, XXY, XYY, XXXYY, and more. An individual possessing at least one X and no Y chromosome is considered genetically female. Configurations of more than two sex chromosomes can affect sexual development in the fetus, and result in intersex conditions. Some intersex conditions are evident at birth, while others surface later – possibly at puberty or when trying to become pregnant.

In Klinefelter Syndrome, in which a genetic male possesses a Y and more than one X chromosome (for example 47,XXY or 48,XXXY), the condition may go unnoticed until puberty.

Gene mutations

For reference when locating genes whose mutations are discussed below: Each chromosome includes a shorter arm, designated as “p”, and a longer arm, designated as “q”, when mapping gene locations using cytogenetic bands. The arms are connected at the centromere; the ends of the arms are the telomeres. Regions and bands are numbered sequentially on each arm beginning at the centromere and incrementing the numbers while moving toward the telomere ends.

Mutations to certain genes are known to result in certain intersex conditions. In Swyer Syndrome, also known as gonadal dysgenesis, an XY male appears female at birth, develops with female sex characteristics, but lacks functioning ovaries. They usually are raised as girls, and may be able to give birth with donated eggs or embryos. SRY gene mutations account for about 15% of Swyer Syndrome cases (more on SRY below).

MAP3K1 gene mutations account for up to 18% of Swyer Syndrome cases. MAP3K1 is a protein coding gene located at cytogenetic band 5q11.2, which translates to chromosome 5, long arm, region 1, band 1, sub-band 2. This places it close to the centromere (the point at which the long and short arms of the chromosome are connected). MAP3K1 mutations have been associated with both 46,XY Sex Reversal 6 and 46,XY Partial Gonadal Dysgenesis.

Mutations to DHH and NR5A1 account for a smaller number of cases. DHH is a protein coding gene that has been associated with 46,XY Sex Reversal 7 and 46,XY Gonadal Dysgenesis, Partial, With Minifascicular Neuropathy. It is located at 12q13.12: chromosome 12, long arm, region 1, band 3, sub-band 12.

NR5A1 (Nuclear Receptor Subfamily 5 Group A Member 1) is located on chromosome 9 at 9q33.3: chromosome 9, long arm, region 3, band 3, sub-band 3. It is a protein coding gene whose mutations are associated with both 46,XY Sex Reversal 3 in genetic males (sex reversal; gonadal dysgenesis; failure to develop secondary sex characteristics at puberty; and occasionally clitoral hypertrophy, labial fusion, dysgenetic testes, hypoplasia of the uterus, or ambiguous genitalia) and 46,XX Sex Reversal 4 in genetic females (development of male gonads, micropenis, ambiguous genitalia, clitoral hypertrophy, clitoromegaly, rugated labia majora, ovotestes, short blind-ending vagina, small penis, retractile testes, atrophic testes, dysgenetic testes, or penoscrotal hypospadias, as well as other effects).

These gene mutations generally have multiple effects on development of the fetus, such as adrenal failure or corticoadrenal insufficiency, in addition to their effects on sexual development. For our purpose, the focus is on the aspect of sexual development. Some of the gene mutations affect production of steroidal hormones and therefore sexual development and male-female brain differentiation in the fetus through those hormonal influences.

Fetal development

Genitalia and internal sex organs develop during the first half of fetal development, but not simultaneously. Sexually-differentiating brain structures, including several within the hypothalamus, develop at different times during the second half of fetal development.

An early embryo initially is not sexually differentiated. At about six weeks, a genetically male embryo – that is, one possessing a Y chromosome, and specifically, the SRY gene on the Y chromosome – begins to produce male hormones. These androgens kickstart male development, affecting the internal sex organs, external genitalia, and certain sexually-differentiated structures within the brain.

Absent the androgens, the embryo, regardless of the individual’s sex chromosomes, will continue development with female anatomy and brain patterning. A genetically male fetus that has reduced or absent exposure to male hormones can develop sexually ambiguous or female sex organs, genitals, and/or sexually-differentiated brain structures, depending on when and by how much the androgens are reduced or absent. (Specifics of particular drug and chemical exposure and their effects are not included here, but can be found in Not a Choice.)

If the androgens vary throughout fetal development, a mosaic pattern of sexually mixed or ambiguous development may result. Both male and female genitals, or ambiguous ones may occur. Since they develop at different times, genitals and internal sex organs may not represent the same sex.

Brain structures may tell the individual that they are one sex, while genitals indicate the other. A genetic male or a genetic female who was exposed to male hormones as an embryo may develop appearing to be fully male, but with a BSTc (central nucleus of the bed nucleus of the stria terminalis) insisting they are female or not fully either sex. They may feel like a woman in a man’s body. They may not feel distinctly either male or female. It depends on the degree and timing of male hormone depletion.

A man may develop with male anatomy and feel male, but his SCN (suprachiasmatic nucleus), INAH-3 (interstitial nucleus of the anterior hypothalamus-3), or anterior commissure may tell him he’s attracted to other men, or to both men and women, or to neither.

Similarly, if a genetic female fetus (possessing at least one X sex chromosome and no Y chromosome) is exposed to male hormones or to toxins or other chemicals that mimic male hormones, she may develop with male characteristics in internal sex organs, external genitalia, and/or sexually-differentiated brain structures. Which structures are affected depends on the timing at which male hormones are present. The degree to which male development occurs in each structure depends on the amount of male hormone present as it develops.

Internal sex organs may develop as one sex, and external genitals as the other. Or, they may be a mix of both, or be ambiguous. With fluctuating exposures throughout fetal development, a genetic female may appear as a female physically, but with a BSTc telling her she’s a male, or that she’s uncertain if she feels male or female. She may look and feel female, but with SCN, INAH-3, and/or anterior commissure brain structures telling her she’s physically attracted to other women, to both men and women, or to neither, depending on whether male or female patterning – if either – is stronger. She may develop with male genitals but identify as female. With consistent exposure to androgens or chemicals mimicking them throughout fetal development, she could develop as male both in anatomy and brain structures.

The SRY gene and 46,XX testicular disorder

In this nomenclature, the numeric value (in this case 46) is the number of chromosomes possessed by the individual. 46 is the norm, and these represent the usual 23 pair (22 pair of autosomes and one pair of sex chromosomes). In 46,XX testicular disorder, a genetic female develops with male sexual characteristics. These individuals usually appear male and are raised as male, but usually are infertile. Most cases are associated with either a translocated SRY gene or mutations to other genes.

The SRY gene normally exists only on the Y chromosome. Without going into detail here, it is possible during creation of sperm for an SRY gene to get translocated from the Y to an X chromosome. (Not a Choice explains how this can occur.)

The SRY gene on the Y chromosome usually kickstarts male development in the six-week embryo. If a genetic male embryo lacks the SRY gene, he will tend to develop as a female. If the X chromosome from the father includes a translocated SRY gene, a genetic XX female will tend to develop as a male.

This translocation of the SRY gene and its presence in genetic females causes approximately 80% of these cases, and is known as SRY-positive 46,XX testicular disorder. The other 20% either have been associated with mutations to the SOX3 gene or have not been associated with a genetic cause; these cases are known as SRY-negative 46,XX testicular disorder.

When caused by the translocated SRY gene, male genitalia usually develop. In the non-SRY cases, genitals usually are ambiguous. Generally, testicles usually are small or undescended. Hypospadias may occur, in which the opening of the urethra is located on the underside of the penis. Upon reaching puberty, hormones may be administered to promote a deeper voice, growth of facial hair and other male characteristics, and to prevent development of breasts. This condition may be found in 1 of 20,000 individuals presenting as male.

Numerous gene mutations and their effects have been documented; a couple of them are mentioned here. Mutations of the SOX3 gene may cause male gonads to develop in a genetic female in what is known as a female to male sex reversal. SOX3 is located on the X chromosome at Xq27.1, which is on the long arm of the X chromosome and closer to the end (telomere) than to the middle (centromere): X chromosome, long arm, region 2, band 7, sub-band 1.

SRXY10 gene mutation is associated with 46,XY sex reversal (also known as chromosome 17q24 deletion syndrome), in which a genetic male develops female genitalia, but does not develop secondary sex characteristics at puberty. SRXY10 is located at 17q24, which is on the long arm of chromosome 17, closer to the end than the middle: chromosome 17, long arm, region 2, band 4. The SOX9 gene also is located in band 17q24. Mutations to both SRXY10 and SOX9 are associated with 46,XY Sex Reversal 10.


Additional detail and further information can be found in Not a Choice, which is currently free to read in Kindle Unlimited (as of January 2021).

An excellent resource for conditions related to variations in sex chromosomes is The Association for X and Y Chromosome Variations (AXYS) at

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