Intersex Variations

The external genitalia are the bits we have on the outside of our body. The way the external genitalia develops when we are in the womb depends mostly on how much androgens our body’s are exposed to and receive. Because of this, external genitalia has a spectrum of appearances. From typically female, to typically male, and everything in between, such as ambiguous genitalia (genitalia that is not clearly male nor female) and genital ambiguity.

The internal genitalia are the bits we have on the inside of our body. The internal genitalia include organs such as the prostate and uterus. Internal genitalia can develop in different ways depending on what kind of gonads / reproductive organs we have and the hormones our bodies are exposed to and receive when we are in the womb.

Gonads are testes, ovaries, ovotestes, and streak/dysgenic gonads. Ovotestes contain both testicular (testicle) and ovarian (ovary) tissue. Streak/dysgenic gonads are gonads that are very underdeveloped, and may possess undifferentiated gonadal tissue. These organs (gonads) are what usually produce most of the body’s sex hormones. Gonads can also produce gametes (reproductive material), such as sperm or eggs.

Our sex chromosomes carry genetic material that help inform the way our bodies develop when we are in the womb. The sex chromosomes include the X chromosome and the Y chromosome. Some people have two X chromosomes (46, XX), others have one X chromosome and one Y chromosome (46, XY). Some people may have an extra sex chromosome (47, XXY) or lack the second sex chromosome (45, X). Some people have one chromosomal makeup in some cells (E.g. 47, XXY) and another chromosomal makeup in other cells (E.g. 46, XX). This is called chromosomal mosaicism. We write out the example chromosomal pattern like so: 47, XXY/46, XX.

Genes essentially tell our body how to develop and function. There are multiple genes on the sex chromosomes and the autosomes (any chromosome that isn’t a sex chromosome) that can affect the way our bodies develop.

Hormones are like little messengers. They tell the body how to develop, and stimulate growth. Sex hormones tell our external genitalia how to develop when we are in the womb, and tell our bodies what secondary sex traits to develop during puberty. Enzymes help convert hormones into other hormones.

Secondary sex characteristics are the traits that we can develop during puberty. This can include physical changes such the development of pubic and armpit hair, male patterned body and facial hair, voice deepening, adam’s apple growth, breast development, changes to body shape, bone growth (such as increases in height), changes to the external genitalia, and many more!

Other names:
Testicular Feminization Syndrome (TFS), Androgen Resistance Syndrome, AR Deficiency, DHTR Deficiency, etc.

Overview:
Androgen insensitivity syndrome describes an array of phenotypes resulting from a variable insensitivity to androgens. Let’s break that down! Androgen receptors (AR) basically translate the message that androgenic hormones are trying to send to the cells. Androgens encourage the virilization of the external genitalia in the womb, differentiation of the male internal genitalia, and encourage male pubertal development. People with AIS have androgen receptors that cannot fully process androgens, or have a lack of androgen receptors. This receptor insensitivity is often due to mutations to the AR genes (can be sporadic or X-linked recessive). This means that in those with 46, XY sex chromosomes, the androgens (messages) that are produced from the testes are not received by the body. Depending on the functionality/amount of androgen receptors, bodies with AIS can develop in many different ways.

CAIS:
Complete AIS describes a full or nearly full lack of receptor sensitivity. Those with CAIS usually have 46,XY sex chromosomes, two testes, typical female external genitalia, a lack of/rudimentary male internal genitalia, and absent mullerian structures due to testicular AMH production. During puberty those with CAIS only develop female secondary sex traits due to aromatization of androgens into estrogens.

PAIS:
Partial AIS describes partial, but variable, receptor sensitivity. Those with PAIS usually have 46,XY sex chromosomes, two testes, variable external genitalia (sometimes predominantly male or female, sometimes ambiguous). In PAIS the development of the male internal genitalia is also variable, and mullerian structures are typically absent. Those PAIS may have female, absent/reduced, or predominantly male pubertal development.

MAIS:
Mild AIS describes a slight lack of receptor sensitivity. Those with MAIS generally have 46, XY sex chromosomes, two testes, typical male external genitalia, and developed male internal genitalia. During puberty those with MAIS may have less or absent male secondary sex development, and may develop certain female secondary sex traits such as breast tissue.

Overview:
5ARD is defined by a reduced/absent presence or function of an enzyme called 5-alpha-reductase type 2 (5AR), usually caused by mutations to the SRD5A2 gene. The 5AR enzyme facilitates the conversion of the hormone testosterone into dihydrotestosterone (DHT). DHT is what influences the development/virilization of the male external genitalia and the development of the prostate within the womb.

Primary sex characteristics:
Individuals with 46,XY sex chromosomes and 5ARD typically have two testes, and male internal genitalia (may be underdeveloped due to lack of DHT). The appearance of the external genitalia is variable, often the external genitalia appears female leaning or ambiguous. Other times the external genitalia is predominantly male with certain differences, such as forms of hypospadias or micropenis.

Secondary sex characteristics:
Testicular function is typical in 5ARD, so there is a higher production of androgens, such as testosterone, that facilitate the development of typical male secondary sex characteristics. Those with 5ARD may have less male patterned body and facial hair, as DHT plays a big role in androgenic hair growth. DHT also plays a role in the growth of the external genitalia and prostate during puberty, thus in those with 5ARD genital growth may be reduced. Those with 5ARD typically do not produce much estrogens, so there is generally no female secondary sex development.

Overview:
46, XY Congenital Adrenal Hyperplasia (abbreviated to XY CAH) encapsulates multiple differences to the way the body’s endocrine organs, specifically the testes and adrenal glands, process and produce hormones and enzymes. There are multiple variations under the umbrella of XY CAH, these variations generally have similar sex characteristics but result from different genetic mutations and enzyme deficiencies.

Primary sex characteristics:
Those with XY CAH have 46, XY sex chromosomes, two testes, typical or underdeveloped male internal genitalia, and variable external genitalia. Sometimes people with XY CAH will have female/predominantly female external genitalia, sometimes the external genitalia will be ambiguous, and sometimes the genitalia will be predominantly male.

Secondary sex characteristics:
Due to the unusual conversion of other hormones into testosterone, those with XY CAH can have variable secondary sex development. Some people with XY CAH have relatively typical male puberties, some have a partial absence of male puberty, and others have a complete absence of pubertal development. Those with XY CAH typically do not produce much estrogens, so there is generally no/minimal female secondary sex development.

Other aspects of XY CAH:
Some people with XY CAH may experience something called salt-wasting, or adrenal crises. This is when the body does not produce enough salt to sustain itself. It is crucial that those who experience adrenal crises are given the appropriate corticosteroids, as an adrenal crisis can have a significant impact on health and well being, and can be life threatening.

XY CAH variations:
Variations classified as XY CAH include:

17 alpha hydroxylase deficiency, 17,20 lyase deficiency, Combined 17 alpha hydroxylase/17,20-lyase deficiency, 3 beta HSD deficiency, POR deficiency, StAR deficiency, and Cytochrome b5 deficiency.

Overview:
Aromatase Excess Syndrome (AES or AEXS) is an intersex variation defined primarily by its increased activity/production of the enzyme aromatase generally due to mutations of the CYP19A1 gene. Enzymes are catalysts, which mean that they can induce change in the chemical structure of certain hormones to convert them into other hormones. The enzyme aromatase converts the androgens androstenedione and testosterone into estrogens. When there is an excess of the enzyme aromatase, there is a subsequent excess of estrogens.

Primary sex characteristics:
The excess production of estrogens in AEXS usually does not affect the development of the primary sex characteristics in utero. So those with aromatase excess syndrome and 46, XY sex chromosomes generally have two testes, typical male internal genitalia, and typical male external genitalia. There are exceptions however, where the conversion of androgens to estrogens results in less testosterone being converted into DHT. This can produce differences to the external genitalia such as mild hypospadias or micropenis.

Secondary sex characteristics:
The presence of more estrogens can induce female secondary sex development come puberty, such as the development of breast tissue. Higher estrogen activity also influences the development of the bone and the skeleton, producing an advanced bone age and a shorter stature come adulthood. Most people with AEXS have typical male secondary sex development. However sometimes androgens are converted to estrogens in very high quantities, this can produce lower androgens and subsequently result in a lack of male pubertal changes.

Overview:
17-beta-HSD3 deficiency is defined by a reduced/absent presence or function of an enzyme called 17-beta-HSD3, usually caused by mutations to the HSD17B3 gene. The 17-beta-HSD3 enzyme facilitates the conversion of the hormone androstenedione into testosterone. Testosterone is what converts into another hormone DHT, which is what influences the development/virilization of the male external genitalia.

Primary sex characteristics:
Individuals with 46,XY sex chromosomes and 17-beta-HSD3 deficiency typically have two testes, and male internal genitalia (may be underdeveloped). The appearance of the external genitalia is variable, often the external genitalia appears female leaning or ambiguous. Other times the external genitalia is predominantly male with certain differences, such as forms of hypospadias or micropenis.

Secondary sex characteristics:
Due to the unusual conversion of other hormones into testosterone, those with 17-beta-HSD3 can have variable secondary sex development. Some people with 17-beta-HSD3 have relatively typical male puberties, some have a partial absence of male puberty, and others have a complete absence of pubertal development. Those with 17-beta-HSD3 typically do not produce much estrogens, so there is generally no/minimal female secondary sex development.

Overview:
Kallmann syndrome is a variation defined by both a lack of sense of smell, as well as a lack of sex hormone production as a result of a deficit in gonadotropin releasing hormone (GnRH). The hypothalamus produces GnRH, which stimulates the pituitary gland to produce the hormones LH and FSH. These hormones are what signal the testes to produce androgens (such as testosterone), in those with Kallmann syndrome, androgen production is significantly reduced. The differences to the function of the hypothalamus and olfactory bulbs (Which is what causes an absent/reduced sense of smell) can result from many different genetic mutations, some affected genes may include ANOS1, CHD7, FGF8, FGFR1, and PROK2. Additionally, Kallmann syndrome is often inherited / familial.

Primary sex characteristics:
Those with 46, XY sex chromosomes and Kallmann syndrome have two testes, male internal genitalia, and male external genitalia (often including micropenis, and sometimes hypospadias). The testes are often atypically small, and may be undescended (not in the scrotum).

Secondary sex characteristics:
During adolescence, those with Kallmann syndrome often have an absent or incomplete development of male secondary sex traits. This includes absent or reduced growth of the testes and external genitalia. Typically, there is not much estrogen production from the testes or other endocrine organs, so typically there is an absence of female pubertal changes. However, breast tissue may develop due to the ratio of androgens to estrogens.

Overview:
Partial gonadal dysgenesis (abbreviated to PGD) is defined by the symmetrical partial dysgenesis of the testes. Partial gonadal dysgenesis shares many similarities with mixed gonadal dysgenesis, and in certain instances accurate identification of PGD can be difficult. Defining features of PGD include the presence of solely testicular tissue, and dysgenesis of the testes tends to be more symmetrical than MGD.

Primary sex characteristics:
Those with partial gonadal dysgenesis have variable primary sex characteristics. Usually those with PGD have 46, XY or 46, XY/45, X sex chromosomes, two dysgenic testes, variable internal genitalia, and variable external genitalia. The development of the external genitalia is primarily dependent on the testes ability to produce androgens in utero. Internal genital development in PGD is often dependent on the ability to produce androgens and AMH in utero.

Secondary sex characteristics:
Depending on the degree of testicular dysgenesis and testicular production of androgens, people with PGD can have variable secondary sex development. Typically those with more extensive gonadal dysgenesis do not produce very many androgens, and thus may not develop male secondary sex characteristics. People with PGD and minimal gonadal dysgenesis may have a typical male puberty. Usually those with PGD do not produce very much estrogens, and thus do not develop female secondary sex traits.

Overview:
Leydig cell hypoplasia (LCH) is defined by the underdevelopment or absence of specific cells in the testicles called leydig cells due to LHCGR gene mutations. These cells are what produce most of the body’s androgens, such as testosterone. Androgens are what influence the development of the male external genitalia in utero, and promote male pubertal changes in adolescence. Those with LCH have 46, XY sex chromosomes and testes, but due to the underdevelopment of their leydig cells, may have external genitalia that appears ambiguous, female, or male with genital ambiguity.

Primary sex characteristics:
Those with LCH have 46, XY sex chromosomes, two small testes, absent female internal genitlaia, variable male internal genitalia, and variable external genitalia. The sertoli cells in the testes are typical, so the higher amounts of AMH (the hormone produced by the sertoli cells that regresses mullerian/uterine structures) produce an absence of female internal genitalia. Depending on the degree of underdevelopment of the leydig cells, the male internal genitalia can be completely absent or underdeveloped. Likewise with the development of the external genitalia, with complete forms of LCH having female external genitalia, and partial forms having ambiguous or atypical male external genitalia.

Secondary sex characteristics:
In complete forms of LCH, the testes produce very minimal amounts of sex hormones (both androgens, like testosterone, and estrogens). Thus there is usually an absence of both male and female pubertal development. In partial forms of LCH, testicular androgen production is variable, and there may be some male pubertal development.

Overview:
Persistent mullerian duct syndrome (PMDS) is an intersex variation usually defined by the presence of mullerian structures (such as the uterus) in those with 46, XY sex chromosomes, two testes, and male external genitalia. The presence of mullerian structures in PMDS is usually as a result of reduced production or reception of a hormone called anti-mullerian-hormone (AMH). AMH contributes to the regression of these structures in the womb. Mutations to certain genes that regulate the production or reception of this hormone, such as mutations to the AMH and AMHR2 gene often is the underlying cause of PMDS. Although in certain individuals, the variation is not always pinpointed to a specific genetic mutation.

Primary sex characteristics:
Those with PMDS have 46, XY sex chromosomes, two testes, male internal and external genitalia, as well as mullerian structures such as the uterus, cervix and/or upper vagina. Occasionally, those with PMDS may have predominantly male genitalia with genital ambiguity, and/or genital differences such as hypospadias or micropenis.

Secondary sex characteristics:
Testicular androgen production is usually not impaired, so higher amounts of androgens will be produced and male secondary sex traits will develop. Those with PMDS usually do not produce much estrogens, so female secondary sex traits do not develop. Despite this, due to the presence of uterine structures, those with PMDS may experience menstrual bleeding, typically via the urethra.

Other forms and similar variations:
In some instances, other variations such as mixed gonadal dysgenesis, partial gonadal dysgenesis, XX/XY chimerism, and ovotesticular DSD, can bear similarities in sex characteristics to PMDS, and may be identified as PMDS.

Overview:
46, XX testicular difference of sex development (XX TDSD) is defined by the presence of two testes in those who have 46, XX sex chromosomes. Despite the common belief that the development of the testes is dependent only on the Y chromosome, various genes can influence the development of the gonads. Some people with XX TDSD possess the SRY gene, which triggers testicular development. Others may have mutations to other gonad-determining genes, such as the SOX9 and SF1 genes that in these instances, result in the development of testes.

Primary sex characteristics:
Those with XX TDSD typically have 46, XX sex chromosomes, two testes, male internal genitalia, and male, male with ambiguity, or ambiguous external genitalia. The testes may be undescended, often the testes will be also smaller than usual (hypoplastic) or dysgenic.

Secondary sex characteristics:
The testes typically produce higher amounts of androgens, so there will usually be some male pubertal changes. Depending on the functionality of the testes, there may be less androgen production, and thus a varying lack of male secondary sex traits. Sometimes those with XX TDSD will experience the development of breast tissue, this is usually due to lower androgen production producing a ratio of androgens to estrogens that promotes this development.

Overview:
Cloacal and bladder exstrophy syndromes are defined by an exstrophic bladder (and bowel in cloacal exstrophy). Essentially, the bladder and bowel develop outside of the abdominal wall, and are externally exposed. In cloacal and bladder exstrophy, the development of the external genitalia is often disrupted, certain external genital organs may appear split (bifid), the urethra may open at the pubis, and the penis may be concealed and upturned. This can result in the external genitalia being difficult to identify as clearly male or female.

Primary sex characteristics:
Those with 46, XY cloacal or bladder exstrophy usually have 46, XY sex chromosomes, two testes, male internal genitalia, and male external genitalia with aforementioned genital differences. In some people, the testes are also undescended.

Secondary sex characteristics:
Those with 46, XY cloacal and bladder exstrophy typically have functional testes that produce higher amounts of androgens, thus a full male puberty will occur. There is also minimal production of estrogens, so there will be an absence of female secondary sex development.

Overview:
Klinefelter syndrome (KS) is defined by the presence of 47, XXY sex chromosomes, alongside phenotypic markers commonly associated with the karyotype. Some people with KS have something called chromosomal mosaicism. This means that some of their body’s cells contain a 47, XXY chromosomal makeup, and other cells contain another chromosomal makeup, often 46, XY. The presence or absence of chromosomal mosaicism in Klinefelter syndrome is one aspect of the variability we see in the Klinefelter phenotype.

Primary sex characteristics:
Those with Klinefelter syndrome generally have 47, XXY or 47, XXY/46, XY sex chromosomes, two testes, male internal genitalia, and male external genitalia. In Klinefelter syndrome, the testes are often small, and may have progressive dysgenesis. Those with Klinefelter syndrome may have certain differences to the genitalia, such as hypospadias or micropenis due to lessened androgen production within the womb, or micropenis as a result of less androgens during adolescence.

Secondary sex characteristics:
The testes in KS have variable functionality, and can produce variable amounts of androgens. Thus the secondary sex development in KS can range from a complete absence of male secondary sex development, to a typical male puberty. Most commonly however, those with KS will have a delayed or incomplete male puberty. Those with KS may have some breast development and widening of the hips. This is generally due to lower androgen production producing an atypical ratio of estrogens to androgens, or peripheral aromatization of testosterone to estrogens.

Other aspects of KS:
As you may know, a tall stature is a common hallmark of Klinefelter syndrome. There are two main contributing factors to the tall stature we see in KS. One factor being that lower androgens during puberty can cause a delayed closure of the growth plates, causing height to increase for longer than typical. The second, more prominent factor being the presence of 3 sex chromosomes carrying the SHOX gene. This gene helps to promote the maturation and longitudinal growth (lengthening) of young bone, predominantly in the limbs. In people with KS, the extra dosage of the SHOX gene produces a taller stature, regardless of the amount of androgens the individual produces.

Overview:
46, XY prenatal diethylstilbestrol (DES) exposure describes differences to the external genitalia that can occur as the result of a 46, XY embryo early in gestation being exposed to a synthetic estrogenic medication called “diethylstilbestrol”. This medication can disrupt the development of the external genitalia, thus some individuals have ambiguous genitalia, or male genitalia with ambiguity. Prescription of DES during pregnancy stopped in 1971, due to the carcinogenic effects the medication had on some of those who had been exposed to it in utero.

Primary sex characteristics:
Those with 46, XY prenatal (DES) exposure have 46, XY sex chromosomes, two testes (may be underdeveloped), male internal genitalia, and ambiguous or atypical male external genitalia (e.g. hypospadias and micropenis).

Secondary sex characteristics:
Those with this variation often have functional testes that produce higher amounts of androgens, thus a full male puberty will occur. Some people have some degree of testicular underdevelopment, and thus may produce less testosterone come puberty. This can result in a partial absence of male secondary sex traits. There is also minimal production of estrogens, so there will be an absence of female secondary sex development.

Overview:
46, XX gonadal dysgenesis is defined by the presence of ovarian dysgenesis and 46, XX sex chromosomes. XX gonadal dysgenesis can have multiple genetic causes, usually it is caused by genetic mutation to a gene that promotes ovarian development (such as the BMP15 gene), and can be sporadic or familial. XX gonadal dysgenesis can be partial (ovaries are partially functional) or complete (two streak ovaries, very minimal/no function).

Primary sex characteristics:
Those with 46, XX gonadal dysgenesis typically have 46, XX sex chromosomes, two streak ovaries (complete) or two dysgenic ovaries / and ovary and a streak (partial), female internal genitalia (may be underdeveloped), and female external genitalia.

Secondary sex characteristics:
Due to absent function from the streak ovaries in complete forms of XX gonadal dysgenesis, minimal estrogens are produced, and there is typically an absence of female secondary sex development as well as menstrual periods. In partial forms, ovarian function and estrogen production is lessened, puberty is often delayed and/or incomplete, menstrual periods may or may not occur. Those with XX gonadal dysgenesis do not produce very much androgens, so male secondary sex development is absent.

Overview:
Kallmann syndrome is a variation defined by both a lack of sense of smell, as well as a lack of sex hormone production as a result of a deficit in gonadotropin releasing hormone (GnRH). The hypothalamus produces GnRH, which stimulates the pituitary gland to produce the hormones LH and FSH. These hormones are what signal the ovaries to produce estrogen and progesterone, in those with Kallmann syndrome, estrogen and progesterone production is significantly reduced. The differences to the function of the hypothalamus and olfactory bulbs (Which is what causes an absent/reduced sense of smell) can result from many different genetic mutations, some affected genes may include ANOS1, CHD7, FGF8, FGFR1, and PROK2. Additionally, Kallmann syndrome is often inherited / familial.

Primary sex characteristics:
Those with 46, XX sex chromosomes and Kallmann syndrome have two ovaries, female internal genitalia, and female external genitalia.

Secondary sex characteristics:
During adolescence, those with Kallmann syndrome often have an absent or incomplete development of female secondary sex traits. This often includes underdevelopment of the uterus and ovaries during puberty. Typically, there is not much androgen production from the ovaries or other endocrine organs, so typically there is an absence of male pubertal changes.

Overview:
46, XX congenital adrenal hyperplasia (XX CAH) encapsulates multiple differences to the way the body’s endocrine organs, specifically the adrenal glands, process and produce hormones and enzymes. There are a couple of different variations of XX CAH, generally a shared characteristic of these variations is that the adrenal glands produce higher amounts of androgens (such as testosterone). Despite this shared characteristic, these variations of XX CAH derive from different genetic mutations and enzyme deficiencies.

Primary sex characteristics:
Those with XX CAH have 46, XX sex chromosomes, two ovaries, female internal genitalia, and variable external genitalia. Those with classical forms of XX CAH (higher androgens produced by adrenal glands in utero) can have external genitalia that ranges from predominantly female with genital ambiguity, to ambiguous genitalia, to male external genitalia. Those with non-classical forms of XX CAH do not produce very many androgens in utero, thus they are born with typical female external genitalia.

Secondary sex characteristics:
Those with virilizing XX CAH variations (classical and non-classical) often have an early onset of secondary sex development, such as male patterned body hair and bone growth due to higher adrenal production of androgens. Those with XX CAH typically also experience female secondary sex development due to typical ovarian function and thus higher estrogen production. The production of higher androgens and estrogens also influences the development of the bone and the skeleton, producing an advanced bone age and a shorter stature come adulthood.

Other aspects of XX CAH:
Some people with XX CAH may experience something called salt-wasting, or adrenal crises. This is when the body does not produce enough salt to sustain itself. It is crucial that those who experience adrenal crises are given the appropriate corticosteroids, as an adrenal crisis can have a significant impact on health and well being, and can be life threatening.

XX CAH variations:

Virilizing variations classified as XX CAH include:
21 hydroxylase deficiency, 11 beta hydroxylase, 3 beta HSD deficiency, and POR deficiency.

Non-virilizing variations of XX CAH that cause sex hormone deficit include:
17 alpha hydroxylase deficiency, 17,20 lyase deficiency, Combined 17 alpha hydroxylase/17,20-lyase deficiency, StAR deficiency.

Overview:
Aromatase deficiency syndrome (ADS) is an intersex variation defined primarily by its decreased production of the enzyme aromatase generally due to mutations of the CYP19A1 gene. Enzymes are catalysts, which mean that they can induce change in the chemical structure of certain hormones to convert them into other hormones. The enzyme aromatase converts the androgens androstenedione and testosterone into estrogens. When there is a deficit of the enzyme aromatase, there is a subsequent deficit of estrogens and and higher androgens that remain unconverted to estrogens.

Primary sex characteristics:
Those with 46, XX sex chromosomes and ADS have two ovaries (may be hypoplastic or cystic), female internal genitalia, and usually ambiguous external genitalia. External genitalia may also be predominantly female or predominantly male.

Secondary sex characteristics:
Due to the unusual conversion of estrogens in ADS, estrogens are typically very low, and there is often an absence of female secondary sex development as well as menstrual periods. Due to the excess of unconverted androgens, those with ADS may develop male secondary sex traits such as male patterned body and facial hair, some deepening of the voice, and often cystic. Due to the low estrogens, the growth plates close very late, thus those with ADS often have a tall adult stature.

Overview:
Progestin induced virilization describes differences to the external genitalia that can occur as the result of a 46, XX embryo early in gestation being exposed to progestin medications. The structure of many progestins is similar to that of androgenic hormones, thus exposure to progestins in utero can virilize the external genitalia. Those with 46, XX sex chromosomes who are exposed to progestins in utero may have ambiguous genitalia, or female genitalia with genital ambiguity.

Primary sex characteristics:
Those with progestin induced virilization have 46, XX sex chromosomes, two ovaries, female internal genitalia, and ambiguous or female genitalia with genital ambiguity.

Secondary sex characteristics:
Since the ovaries in people with progestin induced virilization function typically, in adolescence those with progestin induced virilization will experience a full female puberty. Neither the ovaries nor other endocrine organs produce very much androgens, so there will be no male secondary sex development.

Overview:
Cloacal and bladder exstrophy syndromes are defined by an exstrophic bladder (and bowel in cloacal exstrophy). Essentially, the bladder and bowel develop outside of the abdominal wall, and are externally exposed. In cloacal and bladder exstrophy, the development of the external genitalia is often disrupted, certain external genital organs such as the clitoris may be split (bifid), the urethral tract may be exposed, and the vagina may be short, smaller than typical, or in some instances duplicated or absent. At birth, the genitalia may be difficult to identify as male or female due to these genital differences, and obstruction from the exposed organs.

Primary sex characteristics:
Those with 46, XX cloacal and bladder exstrophy usually have 46, XX sex chromosomes, two ovaries, female internal genitalia, and female external genitalia with aforementioned differences. Cloacal or bladder exstrophy may also present alongside differences to the formation of the uterus, such as duplication or septation.

Secondary sex characteristics:
Due to the ovaries producing higher amounts of estrogens and progesterone, there is usually a full female puberty. Those with XX cloacal and bladder exstrophy do not produce very much androgens, and thus male secondary sex development is absent.

Overview:
Turner syndrome (abbreviated to TS) is primarily defined by the complete or partial absence of the second sex chromosome, alongside the sex characteristics and other physical characteristics often associated with the chromosomal difference.

Primary sex characteristics:
Those with turner syndrome can have 45, X sex chromosomes, partial deletion of the second sex chromosome via mosaicism (e.g. 45, X/46, XX, 45, X/47, XXX, sometimes 45, X/46, XY), and structural differences to the second sex chromosome (e.g. 46, XX with an absence of part of the second X chromosome). Those with turner syndrome have ovaries with varying degrees of dysgenesis. Some have two streak or dysgenic ovaries, others may have hypoplastic ovaries. There is female internal genitalia (may be underdeveloped), and female external genitalia.

Secondary sex characteristics:
Secondary sex characteristics are variable in turner syndrome. In those with two streak gonads, minimal estrogens are produced, and there is typically an absence of female secondary sex development as well as menstrual periods. When the ovaries have a lesser degree of dysgenesis or hypoplasia, ovarian function and estrogen production is lessened, puberty may be delayed and/or incomplete, and menstrual periods may or may not occur. In most presentations of turner syndrome there is not very much androgen production, so male secondary sex development is absent.

Other physical differences associated with TS:
Turner syndrome often presents with other notable physical features. These can include, but are not limited to; short stature, webbed neck, broad or “barrel shaped” chest with widely spaced nipples, certain ear and hearing issues, cardiological (heart), and renal (kidney) malformations.

Association with mixed gonadal dysgenesis:
Some people with mixed gonadal dysgenesis (MGD) and 45, X/46, XY sex chromosomes or 46, XY sex chromosomes with structural differences to the Y chromosome may also have certain physical characteristics associated with turner syndrome despite having different sex characteristics. Some of those with MGD may also be diagnosed with TS as a result of similarities in physical traits and the partial absence of the second sex chromosome.

Overview:
MRKH is defined by the complete or near complete absence of mullerian structures in those who have 46, XX sex chromosomes and two ovaries. MRKH can occur as a result of mutations to a couple of different genes that influence mullerian development, such as LHX1, TBX6, RBM8A, etc. Some of these genetic mutations are inherited, and some are sporadic.

Primary sex characteristics:
Those who have MRKH usually have 46, XX sex chromosomes, two ovaries, typical female external genitalia, and a variable lack of mullerian structures. Some people with MRKH have a complete lack of mullerian structures, which means they do not have a uterus, cervix, or upper vagina, and may or may not have fallopian tubes. Others may have rudimentary mullerian remnants, such as small uterine cavities or the presence of a cervix without a uterus. An absent or atypically small vaginal canal (vaginal agenesis/hypoplasia) can also occur in some people with MRKH.

Secondary sex characteristics:
Due to the ovaries producing higher amounts of estrogens and progesterone, there is female pubertal development. In most people with MRKH, there is a lack of menstruation (periods) during puberty. Occasionally however, people with mullerian remnants may experience menstrual bleeding if they have uterine remnants. Those with MRKH usually do not produce much androgens, so there is no male pubertal development.

Other forms and similar reproductive variations:
MRKH also has multiple forms or types that may have additional anatomical differences. MRKH type 2 describes those with the MRKH phenotype and anatomical differences to other organ systems. Those with MRKH type 2 may have MURCS syndrome, which is usually characterized by kidney, urinary, and skeletal anomalies.

WNT4 genetic mutations can result in MRKH as well as differences to the way the ovaries synthesize hormones. This can result in higher androgens, and some male secondary sex development (such as male pattern facial or body hair).

Other mullerian anomalies that are sometimes classified as MRKH or are similar may include; mullerian hypoplasia, unicornuate uterus, isolated vaginal agenesis.

Overview:
Estrogen insensitivity syndrome (EIS) is defined by absent reception of estrogenic hormones produced by the body. Let’s break that down! The estrogen receptors (ER) basically translates the message that estrogenic hormones are trying to send to the cells. Estrogens encourage female pubertal development. People with EIS have estrogen receptors that cannot process estrogens, this receptor insensitivity is often due to mutations to the ER-alpha gene. This means that in those with 46, XX sex chromosomes, the estrogens (messages) that are produced from the ovaries are not received by the body.

Primary sex characteristics:
Those with 46, XX estrogen insensitivity syndrome have 46, XX sex chromosomes, two ovaries, female internal genitalia (underdeveloped following puberty), and female external genitalia.

Secondary sex characteristics:
The ovaries in those with EIS produce estrogens, but due to a lack of estrogen reception, there is a complete absence of female secondary sex development and menstruation. Due to the absence of estrogen reception during puberty, the uterus typically remains infantile sized, and the ovaries are unable to ovulate, resulting in cystic ovaries. Due to the presence of adrenal androgens, those with EIS usually develop pubic and axillary hair.

Overview:
46, XX gonadal dysgenesis is defined by the presence of ovarian dysgenesis and 46, XX sex chromosomes. XX gonadal dysgenesis can have multiple genetic causes, usually it is caused by genetic mutation to a gene that promotes ovarian development (such as the BMP15 gene), and can be sporadic or familial. XX gonadal dysgenesis can be partial (ovaries are partially functional) or complete (two streak ovaries, very minimal/no function).

Primary sex characteristics:
Those with 46, XX gonadal dysgenesis typically have 46, XX sex chromosomes, two streak ovaries (complete) or two dysgenic ovaries / and ovary and a streak (partial), female internal genitalia (may be underdeveloped), and female external genitalia.

Secondary sex characteristics:
Due to absent function from the streak ovaries in complete forms of XX gonadal dysgenesis, minimal estrogens are produced, and there is typically an absence of female secondary sex development as well as menstrual periods. In partial forms, ovarian function and estrogen production is lessened, puberty is often delayed and/or incomplete, menstrual periods may or may not occur. Those with XX gonadal dysgenesis do not produce very much androgens, so male secondary sex development is absent.

Overview:
Partial gonadal dysgenesis (abbreviated to PGD) is defined by the symmetrical partial dysgenesis of the testes. Partial gonadal dysgenesis shares many similarities with mixed gonadal dysgenesis, and in certain instances accurate identification of PGD can be difficult. Defining features of PGD include the presence of solely testicular tissue, and dysgenesis of the testes tends to be more symmetrical than MGD.

Primary sex characteristics:
Those with partial gonadal dysgenesis have variable primary sex characteristics. Usually those with PGD have 46, XY or 46, XY/45, X sex chromosomes, two dysgenic testes, variable internal genitalia, and variable external genitalia. The development of the external genitalia is primarily dependent on the testes ability to produce androgens in utero. Internal genital development in PGD is often dependent on the ability to produce androgens and AMH in utero.

Secondary sex characteristics:
Depending on the degree of testicular dysgenesis and testicular production of androgens, people with PGD can have variable secondary sex development. Typically those with more extensive gonadal dysgenesis do not produce very many androgens, and thus may not develop male secondary sex characteristics. People with PGD and minimal gonadal dysgenesis may have a typical male puberty. Usually those with PGD do not produce very much estrogens, and thus do not develop female secondary sex traits. While uncommon, occasionally those with PGD and mullerian structures may experience menstrual bleeding.

Overview:
46, XY complete gonadal dysgenesis (XY CGD) is defined by complete dysgenesis of the gonads in those with 46, XY sex chromosomes. XY CGD can be caused by many different genetic mutations that are involved in the development of the gonads. The SRY gene on the Y chromosome may be absent or inactive, XY CGD due to this genetic difference is often called Swyer syndrome. Other mutations that can result in XY CGD include mutations to the WT1 gene on the chromosome 11, XY CGD caused by WT1 gene mutations is often called Fraiser syndrome.

Primary sex characteristics:
Those with 46, XY complete gonadal dysgenesis, have 46, XY sex chromosomes, two streak gonads, female internal genitalia (underdeveloped), and female external genitalia.

Secondary sex characteristics:
Due to absent function from the streak gonads in complete forms of XY CGD, minimal estrogens and androgens are produced, and there is typically an absence of both female and male secondary sex development, as well as an absence of menstrual periods.

Overview:
Some forms of mixed gonadal dysgenesis (abbreviated to MGD) can be defined by asymmetrical dysgenesis of the gonads. MGD is a variation with variable phenotypes, but one defining feature of MGD is the presence of a typical or dysgenic testis or ovotestis alongside a streak/dysgenic gonad.

Primary sex characteristics:
Those with mixed gonadal dysgenesis often have 45, X/46, XY sex chromosomes, but other chromosomal patterns are also possible! 46, XX/46, XY mosaicism, 45, X/47, XXY mosaicism, 46, XY with partial Y deletion/mutation, and some other chromosomal makeups can cause MGD. In those with MGD and a typical or dysgenic testis or ovotestis, the other gonad is often a streak gonad (streak ovary, testis, or ovotestis) or a dysgenic ovotestis or ovary. The internal genitalia is variable, though those with MGD often have uterine remnants or a uterus. There may also be male internal genitalia, such as a prostate and seminal vesicles. External genitalia is variable, from typically male, to ambiguous, to female with genital ambiguity.

Secondary sex characteristics:
The degree of secondary sex development is primarily dependent on the amount of androgens the testicular tissue produces. Puberty can be typically male, or there can be a partial/full lack of secondary sex development. Usually in this phenotype of MGD, there is not much estrogen production, if there is any female secondary sex development, it is typically isolated to breast growth. Menstrual bleeding can occur in those with uterine structures/a uterus.

Overview:
Turner syndrome (abbreviated to TS) is primarily defined by the complete or partial absence of the second sex chromosome, alongside the sex characteristics and other physical characteristics often associated with the chromosomal difference.

Primary sex characteristics:
Those with turner syndrome can have 45, X sex chromosomes, partial deletion of the second sex chromosome via mosaicism (e.g. 45, X/46, XX, 45, X/47, XXX, sometimes 45, X/46, XY), and structural differences to the second sex chromosome (e.g. 46, XX with an absence of part of the second X chromosome). Those with turner syndrome have ovaries with varying degrees of dysgenesis. Some have two streak or dysgenic ovaries, others may have hypoplastic ovaries. There is female internal genitalia (may be underdeveloped), and female external genitalia.

Secondary sex characteristics:
Secondary sex characteristics are variable in turner syndrome. In those with two streak gonads, minimal estrogens are produced, and there is typically an absence of female secondary sex development as well as menstrual periods. When the ovaries have a lesser degree of dysgenesis or hypoplasia, ovarian function and estrogen production is lessened, puberty may be delayed and/or incomplete, and menstrual periods may or may not occur. In most forms of turner syndrome there is not very much androgen production, so male secondary sex development is absent. Occasionally, there may be some amount of thin excess body hair due to the ratio of adrenal androgens to ovarian estrogens.

Other physical differences associated with TS:
Turner syndrome often presents with other notable physical features. These can include, but are not limited to; short stature, webbed neck, broad or “barrel shaped” chest with widely spaced nipples, certain ear and hearing issues, cardiological (heart), and renal (kidney) malformations.

Association with mixed gonadal dysgenesis:
Some people with mixed gonadal dysgenesis (MGD) and 45, X/46, XY sex chromosomes or 46, XY sex chromosomes with partial Y chromosome deletion may also have certain physical characteristics associated with turner syndrome despite having different sex characteristics. Some of those with MGD may also be diagnosed with TS as a result of similarities in physical traits and the partial absence of the second sex chromosome.

Other names:
Testicular Regression Syndrome, TRS, XY gonadal agenesis, XY agonadism, Vanishing Testis Syndrome

Overview:
46, XY anorchia can be defined by the complete absence of both testicles (and any gonadal tissue) in those who otherwise have male primary sex characteristics. Anorchia is sometimes pinpointed to a particular genetic cause, as in some instances it seems to be heritable/familial. Aside from genetic causes, anorchia is often caused by physical trauma to the testicles around the 10th-14th week of gestation, resulting in the testicles completely regressing.

Primary sex characteristics:
Those with anorchia have 46, XY sex chromosomes, no gonads, male internal genitalia (may be partially undeveloped), and male to ambiguous external genitalia. The appearance of the external genitalia is dependent on when in gestation the testicles regress. The earlier the testes regress, the less exposure the genitalia has to the androgens the testes produce. Thus causing a spectrum of presentations, including genital differences and genital ambiguity.

Secondary sex characteristics:
Due to the absence of any gonadal tissue, those with anorchia will not produce much androgens or estrogens at all. Aside from possibly developing pubic or axillary hair due to androgen production from the adrenal glands, those with anorchia will not experience any natural pubertal development.

Other forms:
XY gonadal agenesis/agonadism usually describes the absence of any gonadal tissue alongside female leaning external genitalia. The testes regress earlier in gestation, generally 8 weeks or under. Subsequently there is a complete absence of internal genitalia, and female external genitalia (w/ or w/o genital ambiguity).

Overview:
Leydig Cell Hypoplasia (LCH) is defined by the underdevelopment or absence of specific cells in the testicles called leydig cells due to LHCGR gene mutations. These cells are what produce most of the body’s androgens, such as testosterone. Androgens are what influence the development of the male external genitalia in utero, and promote male pubertal changes in adolescence. Those with LCH have 46, XY sex chromosomes and testes, but due to the underdevelopment of their leydig cells, may have external genitalia that appears ambiguous, female, or male with genital ambiguity.

Primary sex characteristics:
Those with LCH have 46, XY sex chromosomes, two testes, absent female internal genitalia, variable male internal genitalia, and variable external genitalia. The sertoli cells in the testes are typical, so the higher amounts of AMH (the hormone produced by the sertoli cells that regresses mullerian/uterine structures) produce an absence of female internal genitalia. Depending on the degree of underdevelopment of the leydig cells, the male internal genitalia can be completely absent or underdeveloped. Likewise with the development of the external genitalia, with complete forms of LCH having female external genitalia, and partial forms having ambiguous or atypical male external genitalia.

Secondary sex characteristics:
In complete forms of LCH, the testes produce very minimal amounts of sex hormones (both androgens, like testosterone, and estrogens). Thus there is usually an absence of both male and female pubertal development. In partial forms of LCH, testicular androgen production is variable, and there may be some male pubertal development.

Overview:
46, XX agonadism is defined by the complete absence of both ovaries (and any gonadal tissue) in those who have 46, XX sex chromosomes. The exact cause of 46, XX agonadism is not well defined, however the presence of agonadism can be familial. Those with 46, XX agonadism tend to have additional anatomical differences to other organ systems, such as kidney, urinary, skeletal, heart, and lung anomalies.

Primary sex characteristics:
Those with 46, XX agonadism have 46, XX sex chromosomes, complete absence of ovarian/ gonadal tissue, absent female internal genitalia, and typical female external genitalia.

Secondary sex characteristics:
Due to the absence of any gonadal tissue, those with 46, XX agonadism will not produce much androgens or estrogens at all. Aside from possibly developing pubic or axillary hair due to androgen production from the adrenal glands, those with 46, XX agonadism will not experience any natural pubertal development.

Some forms of mixed gonadal dysgenesis (abbreviated to MGD) can be defined by asymmetrical dysgenesis of the gonads. MGD is a variation with variable phenotypes, but one defining feature of MGD is the presence of a typical/dysgenic testis / ovotestis and a streak/dysgenic gonad.

Primary sex characteristics:
Those with mixed gonadal dysgenesis often have 45, X/46, XY sex chromosomes, but other chromosomal patterns are also possible! 46, XX/46, XY mosaicism, 45, X/47, XXY mosaicism, 46, XY with partial Y deletion/mutation, and some other chromosomal makeups can cause MGD. In those with MGD and a typical or dysgenic testis or ovotestis, the other gonad is often a streak gonad (streak ovary, testis, or ovotestis) or a dysgenic ovotestis or ovary. The internal genitalia is variable, though those with MGD often have uterine remnants or a uterus. There may also be male internal genitalia, such as a prostate and seminal vesicles. External genitalia is variable, from typically male, to ambiguous, to female with genital ambiguity.

Here is a visual example of how the internal genitalia and gonads can form in MGD:

Secondary sex characteristics:
The degree of secondary sex development is primarily dependent on the amount of androgens the testicular tissue produces. Puberty can be typically male, or there can be a partial/full lack of secondary sex development. Usually in this phenotype of MGD, there is not much estrogen production, if there is any female secondary sex development, it is typically isolated to breast growth. Menstrual bleeding can occur in those with uterine structures/a uterus.

Overview:
46, XX/46, XY chimerism is usually defined by the fusion of two fraternal twin zygotes (fertilized eggs) into a single embryo. These zygotes have two different sex chromosome makeups, with one zygote being 46, XX, and the other zygote being 46, XY. Due to this, those with XX/XY chimerism can have a variety of gonadal tissue compositions, including the presence of both testicular and ovarian tissue.

Primary sex characteristics:
Those with XX/XY chimerism have 46, XX/46, XY sex chromosomes, variable gonads, variable internal genitalia, and variable external genitalia. Suffice to say that XX/XY chimerism has a lot of variability! Gonadal tissue varies, from predominantly testicular tissue (e.g. one testis and one ovotestis) to relatively equal amounts of testicular and ovarian tissue (e.g. two ovotestes), to predominantly ovarian tissue (e.g. one ovary and one ovotestis). The presence of more than 2 gonads can occur in some instances (e.g. two testes and one ovary). As for internal genitalia, mullerian remnants or a uterus may be present. Those with more testicular tissue often also possess a prostate and seminal vesicles. External genital appearance can range from typical male external genitalia, to ambiguous genitalia, to typical female external genitalia.

Secondary sex characteristics:
The development of secondary sex characteristics is dependent on how much testicular and ovarian tissue there is within the body, as well as its functionality. Those who have predominantly functional ovarian tissue often experience a full female puberty. Those who have predominantly functional testicular tissue often experience a full male puberty. Some people with XX/XY chimerism produce higher amounts of both androgens and estrogens, producing a mixture of secondary sex traits. Menstrual bleeding may occur when there is the presence of mullerian structures / a uterus.

Overview:
Ovotesticular DSD is usually defined by the presence of both testicular (testicle) and ovarian (ovary) tissue in the body. OTDSD has a wide array of phenotypic presentations, and some may overlap with other variations, such as mixed gonadal dysgenesis. The defining difference between the classification of MGD and OTDSD being the presence of gonadal dysgenesis. Typically, most of the gonadal tissue in OTDSD is non-dysgenic. Ovotesticular DSD does not have a singular root cause, rather many differences to the chromosomes and/or the genes can result in somebody having OTDSD. Genetic differences such as: chromosomal mosaicism (e.g. 46, XX/XY or 46, XX/XXY), 46, XX w/ SF1 mutations, 46, XY with SRY mutation, 46, XX/XY chimerism, and many more can result in OTDSD.

Primary sex characteristics:
Those with OTDSD can have a range of primary sex characteristics. As stated, sex chromosome makeup is variable, common chromosomal makeups may include: 46, XX, 46, XX/46, XY mosaicism OR chimerism, 46, XX / 47, XXY mosaicism, 46, XY, 45, X0 / XY mosaicism, etc. The gonads are also variable, some people with OTDSD have one testis or ovary and one ovotestis, some have two ovotestes, others may have one testis and one ovary. Occasionally, more than 2 gonads are present (e.g. two testes and one ovary). Those with OTDSD tend to have mullerian remnants or a uterus. Those with more testicular tissue often also possess a prostate. The external genital formation is dependent on the gonads and their degree of functionality. External genital appearance can range from typical male external genitalia, to ambiguous genitalia, to typical female external genitalia.

Here is a visual example of how the internal genitalia and gonads can form in OTDSD:

Secondary sex characteristics:
The development of secondary sex characteristics is dependent on how much testicular and ovarian tissue there is within the body, as well as its functionality. Those who have predominantly functional ovarian tissue often experience a full female puberty. Those who have predominantly functional testicular tissue often experience a full male puberty. Some people with OTDSD produce higher amounts of both androgens and estrogens, producing a mixture of secondary sex traits. Others may not produce much androgens or estrogens, producing a lack of secondary sex traits.  Regardless of other secondary sex traits, menstrual bleeding is common in those with mullerian structures and higher hormone production.