A FEW OF THE CAUSES

Caused when an anomaly of adrenal function (21-hydroxylase or 11-hydroxylase deficiency) causes the synthesis and excretion an androgen precursor, initiating virilization of a XX person inutero. Because the virilization originates metabolically, masculinizing effects continue after birth. As in PIA, sex phenotype varies along the same continuum, with the possible added complication of metabolic problems which upset serum sodium balance. The metabolic effects of CAH can be counteracted with cortisone. The scenario for medical intervention for intersex is similar... but CAH people have an increased likelihood of early detection due to metabolic imbalances (Salt Losing Form).

Biologically speaking, the pathway towards a female form seems to be the default for humans, while the path for development of a male fetus is more tortuous, and dependent on many different genes, each of which can be faulty. This means that there is a set of a fairly varied conditions in which a fetus with XY chromosomes develops as a baby girl.

1.Failure of formation of testes due to a variety of reasons (i.e. Swyer syndrome or pure XY gonadal dysgenesis, XO/XY mosaicism, testicular regression syndrome etc.).

2.Underdevelopment of cells in testes due to unresponsiveness to hormones from the pituitary gland (i.e. Leydig cell agenesis or hypoplasia).

3.Enzymatic defects in testosterone biosynthesis (i.e. deficiencies of enzymes 5 alpha reductase, 17 ketosteroid reductase, 17 alpha hydroxylase, 3 beta hydroxysteroid dehydrogenase, 17 beta hydroxysteroid dehydrogenase etc.).

4.Insensitivity of genital tissues to androgens (i.e. AIS).

In AIS/PAIS the cellular metabolism of an XY person is such that the cells do not respond to the effects of androgens. Endocrinological function is normal... but the cells ability to bind androgens, due to compromised receptor site metabolism, causes a partial or complete lack of response to virilization. PAIS produces effects similar to CAH or PIA in a neonate... genital ambiguity. With complete AIS a neonate shows no indication that they are intersexed as the external genitalia are completely phenotypically female. Internal female structures do not develop however because Mullerian Inhibiting Hormone is present and prevents the formation of a female genital tract (oviducts, cervix, uterus, part of the vagina).
Another form of AIS is present in individuals with 5-alpha reductase deficieny. During the formation of the male genital tract from the Wolffian duct portion of the genital anlagen, the target tissues are not repondent to testosterone, another form, hydrotestosterone is required at this stage. The required enzyme, 5-alpha reductase, is missing so these people may be assigned and reared as girls. However, since pubertal genital tissue is sensitive to the effects of testosterone... such a child could experience masculinizing puberty and genital growth - assuming that their gonads have not been removed.

Androgen Insensitivity/Partial Insensitivity Syndrome

Caused by prenatal exposure to exogenous androgens, most commonly progestin. Progestin is a drug which was administered to prevent miscarriage in the 50's and 60's and it is converted to an androgen (virilizing hormone) by the prenatal XX persons metabolism. If the timing is right, the genital anlagen is virilized with effects ranging from enlarged clitoris to the development of a complete phallus and the fusing of the labia. The virilization only occurs prenatally and the endocrinological functionality is unchanged, ie. feminizing puberty occurs due to normally functioning ovaries.
In other words, XX people affected in-utero by virilizing hormones can be born into a continuum of sex phenotype which ranges from "normal female with large clitoris" to "normal male with no testes". It is noteworthy that the use of progestin is not effective in the prevention of miscarriage.

D.E.S. aka Di-ethyl-stilbestrol also made inutero changes to babies, interfering with their development of their sex.

Klinefelters Syndrome

Most men inherit a single X chromosome from their mother, and a single Y chromosome from their father. Men with klinefelter syndrome inherit an extra X chromosomes from either father or mother; their karyotype is 47 XXY. Klinefelter is quite common, occuring in 1/500 to 1/1,000 male births

Klinefelters Syndrome

Those with a Female Mosaic Genotype are at risk for intersexed genitalia.
A female mosaic genotype means that instead of the usual XXY genotype, the genotype can be XXY/XX wherein some of the calls are XXY and some of the cells are XX. Therefore some of the body is XXY and some of the body is genetically female (XX).

The male mosaics XXY/XY are more likely to be male and may even be able to procreate.

Swyer's Syndrome (Complete 46,XY Gonadal Dysgenesis)

If the gonad fails to progress beyond the indifferent stage, it may produce no testosterone Swyer's Syndrome, complete 46 XY gonadal dysgenesis, swyer syndrome, swyers syndrome. Complete XY gonadal dysgenesis usually is diagnosed when a healthy girl of normal stature becomes concerned in her midteens about lack of pubertal development. Eunuchoid skeletal proportions may be found, and the bone age will be delayed Swyer's Syndrome, complete 46 XY gonadal dysgenesis, swyer syndrome, swyers syndrome.

Primary gonadal failure is indicated by elevated levels of serum follicle-stimulating (FSH) and luteinizing hormone (LH) and a low plasma estradiol level. Pelvic ultrasound shows the presence of a small uterus, but the Chromosomal mosaicism is the cause in most cases; however, in the last 8 years, several genes that regulate gonadal differentiation and testis determination have been discovered, and mutations in several of them have been found in association with gonadal dysgenesis.

In 10% to 15% of cases, complete 46,XY gonadal dysgenesis is caused either by a mutation in the SRY gene or by a Yp deletion of the pseudoautosomal junction region in All patients with CYP17 (also called P450 c17 or 17alpha-hydroxylase) deficiency are female regardless of whether they are XX or XY, because there is a complete block in the biosynthesis of androgens and estrogens both prenatally and postnatally.

Adrenal hyperplasia results from impairment of cortisol biosynthesis and a secondary elevation in ACTH secretion. Consequently, the secretion of both desoxycorticosterone and corticosterone is greatly elevated, causing hypertension and hypokalemia. Renin activity and circulating aldosterone are Treatment with dexamethasone reduces ACTH secretion and therefore the levels of desoxycorticosterone and corticosterone, and blood pressure returns to normal. Estrogen is given from age 11 years to 46,XY patients who have no uterus and in combination with cyclical progestogen to 46,XX patients who do have a uterus. Low-dose testosterone is given to induce pubic hair development.

The ovaries of 46,XX patients contain numerous follicles. In one case in which testosterone was provided as an aromatizable substrate, follicular maturation could be induced, but fertilization proved impossible. Numerous mutations in the gene for CYP17 have been demonstrated in patients with deficiency. Several have been expressed in COS cells, and these show that the In this rare disorder, affected XX and XY infants are phenotypic females who lack the ability to secrete any adrenal or gonadal steroids owing to a complete block in cholesterol side-chain cleavage.

Salt loss becomes clinically evident within a week of birth, and severe hypoglycemia may also occur. The lips and genitalia are often deeply pigmented. Because of the apparent absence of cholesterol side-chain cleavage enzyme activity, it was assumed that the defect would reside in the gene encoding P450 scc (CYP11A); however, when this gene was cloned, it was found to be structurally normal in all cases of lipoid adrenal hyperplasia.

Subsequently, mutations were found in the gene encoding the steroidogenic acute regulatory protein (StAR). This protein regulates the transport of cholesterol into the mitochondrion where it can be acted upon by P450 scc (CYP11A).

MRKH stands for Mayer-Rokitansky-Kuster-Hauser Syndrome, named after four men who studied this birth defect. It is a defect wherein a woman is born without a uterus, cervix, and, in many cases, a vagina, and therefore cannot reproduce. The woman is also likely to be missing one kidney

MRKH Syndrome Links

http://ncnc.essortment.com/mayerrokitansky_rknh.htm

http://www.execpc.com/~pdefrain/

http://www.surrogacy.com/online_support/mrkh/

http://www.dmoz.org/Health/Women's_Health/Menstruation/Amenorrhea/MRKH/

7. gonadal tumors: 5 alpha-reductase deficiency
Mullerian dysgenesis
Mullerian duct aphasia
vaginal atresia

Intersexed Links @ Open Directory	Intersexed Resources #1	Intersexed Resources #2
(true hermaphrodite / psuedohermaphrodite)		Those born with female AND male organs.
http://www.isna.org/faq/faq-medical.html
CAH Congenital Adrenal Hyperplasia	AIS Androgen Insensitivity/Partial Insensitivity Syndrome	PIA Progestin-induced androgenization
KS Klinefelters Syndrome	SWS Swyer's syndrome (XY gonadal dysgenesis)	MRKH Mayer-Rokitansky- Kuster-Hauser Syndrome
D.E.S. DES (diethylstilbestrol) is a synthetic estrogen drug that was given to millions of pregnant women primarily from 1938-1971. Use of DES during pregnancy was thought to prevent miscarriage and ensure a healthy pregnancy. DES did not work, and women who took DES and the children they carried are at risk for certain health problems and may need special care. Find out if you were exposed to DES and if you were, tell your doctor. DES Action

A Few of the causes of intersexuality.