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.

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.

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.

Upon diagnosis, estrogen and progesterone therapy is typically commenced, promoting the development of female characteristics.

The consequences of streak gonads to a person with Swyer syndrome:

1. Gonads cannot make estrogen, so the breasts will not develop and the uterus will not grow and menstruate until estrogen is administered. This is often given transdermally.

2. Gonads cannot make progesterone, so menstrual periods will not be predictable until progestin is administered, usually as a pill.

3. Gonads cannot produce eggs so conceiving children naturally is not possible. A woman with a uterus and ovaries but without female gamete is able to become pregnant by implantation of another woman's fertilized egg (embryo transfer).

4. Streak gonads with Y chromosome-containing cells have a high likelihood of developing cancer, especially gonadoblastoma. Streak gonads are usually removed within a year or so of diagnosis since the cancer can begin during infancy.

Prognosis in unexplained infertility depends on many factors, but can roughly be estimated by e.g. the

Hunault model, which takes into account female age, duration of infertility/subfertility, infertility/subfertility being primary or secondary, percentage of motile sperm and being referred by a general practitioner or gynecologist.

It has been estimated that POF affects 1% of the female population.

XX gonadal dysgenesis is related to the Swyer syndrome inasmuch as both conditions have the same phenotype and clinical issues; however in Swyer syndrome the karyotype is 46,XY, and thus gonadectomy is recommended.

In Turner syndrome there is a demonstrable abnormality in or absence of one of the sex chromosomes that is the cause of the development of gonadal dysgenesis. In contrast XX gonadal dysgenesis has a normal female chromosome situation.

Another type of XX gonadal dysgenesis is known as 46,XX gonadal dysgenesis epibulbar dermoid, which follows the similar symptoms as the regular syndrome, though it also shows signs of epibulbar dermoid (eye disorder). It has been suggested to be a new type of syndrome.

The consequences to the girl with XX gonadal dysgenesis:

1. Her gonads cannot make estrogen, so her breasts will not develop and her uterus will not grow and menstruate until she is given estrogen. This is often given through the skin now.

2. Her gonads cannot make progesterone, so her menstrual periods will not be predictable until she is given a progestin, still usually as a pill.

3. Her gonads cannot produce eggs so she will not be able to conceive children naturally. A woman with a uterus but no ovaries may be able to become pregnant by implantation of another woman's fertilized egg (embryo transfer).

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).

The cause of POF is usually idiopathic. Some cases of POF are attributed to autoimmune disorders, others to genetic disorders such as Turner syndrome and Fragile X syndrome. An Indian study showed a strong correlation between incidence of POF and certain variants in the inhibin alpha gene. In many cases, the cause cannot be determined. Chemotherapy and radiation treatments for cancer can sometimes cause ovarian failure. In natural menopause, the ovaries usually continue to produce low levels of hormones, but in chemotherapy or radiation-induced POF, the ovaries will often cease all functioning and hormone levels will be similar to those of a woman whose ovaries have been removed. Women who have had a hysterectomy tend to go through menopause several years earlier than average, likely due to decreased blood flow to the ovaries. Family history and ovarian or other pelvic surgery earlier in life are also implicated as risk factors for POF.

There are two basic kinds of premature ovarian failure. Case 1) where there are few to no remaining follicles and case 2) where there are an abundant number of follicles. In the first situation the causes include genetic disorders, autoimmune damage, chemotherapy, radiation to the pelvic region, surgery, endometriosis and infection. In most cases the cause is unknown. In the second case one frequent cause is autoimmune ovarian disease which damages maturing follicles, but leaves the primordial follicles intact. Also, in some women FSH may bind to the FSH receptor site, but be inactive. By lowering the endogenous FSH levels with ethinylestradiol (EE) or with a GnRH-a the receptor sites are free and treatment with exogenous recombinant FSH activates the receptors and normal follicle growth and ovulation can occur. (Since the serum anti-müllerin hormone (AMH) level is correlated with the number of remaining primordial follicles some researchers believe the above two phenotypes can be distinguished by measuring serum AMH levels.)

- Genetic disorders

- Autoimmune diseases

- Tuberculosis of the genital tract

- Smoking

- Radiation and/or chemotherapy

- Ovarian failure following hysterectomy

- Prolonged GnRH (Gonadatrophin Releasing Hormone) therapy

- Enzyme defects

- Resistant ovary

- Induction of multiple ovulation in infertility

Genetic associations include:

Encountered karyotypes include 47XXY, 46XX/46XY, or 46XX/47XXY or XX & XY with SRY Mutations, Mixed Chromosomal abnormalities or hormone deficiency/excess disorders, and various degrees of mosaicism of these and a variety of others. The 3 Primary Karyotypes for True Hermaphroditism are XX with genetic defects (55-70% of cases), XX/XY (20-30% of cases) & XY (5-15% of cases) with the remainder being a variety of other Chromosomal abnormalities and Mosaicisms.

Follicle-stimulating hormone (FSH) insensitivity, or ovarian insensitivity to FSH in females, also referable to as ovarian follicle hypoplasia or granulosa cell hypoplasia in females, is a rare autosomal recessive genetic and endocrine syndrome affecting both females and males, with the former presenting with much greater severity of symptomatology. It is characterized by a resistance or complete insensitivity to the effects of follicle-stimulating hormone (FSH), a gonadotropin which is normally responsible for the stimulation of estrogen production by the ovaries in females and maintenance of fertility in both sexes. The condition manifests itself as hypergonadotropic hypogonadism (decreased or lack of production of sex steroids by the gonads despite high circulating levels of gonadotropins), reduced or absent puberty (lack of development of secondary sexual characteristics, resulting in sexual infantilism if left untreated), amenorrhea (lack of menstruation), and infertility in females, whereas males present merely with varying degrees of infertility and associated symptoms (e.g., decreased sperm production).

A related condition is luteinizing hormone (LH) insensitivity (termed Leydig cell hypoplasia when it occurs in males), which presents with similar symptoms to those of FSH insensitivity but with the symptoms in the respective sexes reversed (i.e., hypogonadism and sexual infantilism in males and merely problems with fertility in females); however, males also present with feminized or ambiguous genitalia (also known as pseudohermaphroditism), whereas ambiguous genitalia does not occur in females with FSH insensitivity. Despite their similar causes, LH insensitivity is considerably more common in comparison to FSH insensitivity.

In the US, up to 25% of infertile couples have unexplained infertility.

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.

There are no documented cases in which both types of gonadal tissue function.

Although fertility is possible in true hermaphrodites, there has yet to be a documented case where both gonadal tissues function, contrary to the misconception that hermaphrodites can impregnate themselves. As of 2010, there have been at least 11 reported cases of fertility in true hermaphrodite humans in the scientific literature, with one case of a person with XY-predominant (96%) mosaic giving birth.

Recently, NR5A1 mutations have been related to human male infertility (MIM 613957). These findings substantially increase the number of NR5A1 mutations reported in humans and show that mutations in NR5A1 can be found in patients with a wide range of phenotypic features, ranging from 46,XY sex reversal with primary adrenal failure to male infertility. For the first time, Bashamboo et al. (2010) conducted a study on the nonobstructive infertile men (a non-Caucasian mixed ancestry n = 315), which resulted in the report of all missense mutations in the NR5A1 gene with 4% frequency. Functional studies of the missense mutations revealed impaired transcriptional activation of NR5A1-responsive target genes. Subsequently, three missense mutations were identified as associated with and most likely the cause of the male infertility, according to computational analyses. The study indicated that the mutation frequency is below 1% (Caucasian German origin, n = 488). In another study the coding sequence of NR5A1 has been analysed in a cohort of 90 well-characterised idiopathic Iranian azoospermic infertile men versus 112 fertile men. Heterozygous NR5A1 mutations were found in 2 of 90 (2.2%) of cases. These two patients harboured missense mutations within the hinge region (p.P97T) and ligand-binding domain (p.E237K) of the NR5A1 protein.

Hormone replacement therapy with estrogen may be used to treat symptoms of hypoestrogenism in females with the condition. There are currently no known treatments for the infertility caused by the condition in either sex.

Treatment of HH is usually with hormone replacement therapy, consisting of androgen and estrogen administration in males and females, respectively.

Identification of 45,X/46,XY karyotype has significant clinical implications due to known effects on growth, hormonal balance, gonadal development and histology. 45,X/46,XY is diagnosed by examining the chromosomes in a blood sample.

The age of diagnosis varies depending on manifestations of disease prompting reason for cytogenetic testing. Many patients are diagnosed prenatally due to fetal factors (increased nuchal fold, or abnormal levels of serum), maternal age or abnormal ultrasounds, while others will be diagnosed postnatal due to external genital malformation. It is not uncommon for patients to be diagnosed later in life due to short stature or delayed puberty, or a combination of both.

45,X/46,XY mosaicism can be detected prenatally through amniocentesis however, it was determined that the proportion of 45,X cells in the amniotic fluid cannot predict any phenotypic outcomes, often making prenatal genetic counselling difficult.

A study of a population of French women from 1670 and 1789 shows that those who married at age 20–24 had 7.0 children on average and 3.7% remained childless. Women who married at age 25–29 years had a mean of 5.7 children and 5.0% remained childless. Women who married at 30–34 years had a mean of 4.0 children and 8.2% remained childless. The average age at last birth in natural fertility populations that have been studied is around 40.

In 1957, a study was done on a large population (American Hutterites) that never used birth control. The investigators measured the relationship between the age of the female partner and fertility. (Infertility rates today are believed to be higher in the general population than for the population in this study from the 1950s.)

This 1957 study found that:

- By age 30, 7% of couples were infertile

- By age 35, 11% of couples were infertile

- By age 40, 33% of couples were infertile

- At age 45, 87% of couples were infertile

Cervical agenesis is estimated to occur in 1 in 80,000 females. It is often associated with deformity of the vagina; one study found that 48% of patients with cervical agenesis had a normal, functional vagina, while the rest of the cases were accompanied by vaginal hypoplasia.

There are a multitude of different etiologies of HH. Congenital causes include the following:

- Chromosomal abnormalities (resulting in gonadal dysgenesis) - Turner's syndrome, Klinefelter's syndrome, Swyer's syndrome, XX gonadal dysgenesis, and mosaicism.

- Defects in the enzymes involved in the gonadal biosynthesis of the sex hormones - 17α-hydroxylase deficiency, 17,20-lyase deficiency, 17β-hydroxysteroid dehydrogenase III deficiency, and lipoid congenital adrenal hyperplasia.

- Gonadotropin resistance (e.g., due to inactivating mutations in the gonadotropin receptors) - Leydig cell hypoplasia (or insensitivity to LH) in males, FSH insensitivity in females, and LH and FSH resistance due to mutations in the "GNAS" gene (termed pseudohypoparathyroidism type 1A).

Acquired causes (due to damage to or dysfunction of the gonads) include ovarian torsion, vanishing/anorchia, orchitis, premature ovarian failure, ovarian resistance syndrome, trauma, surgery, autoimmunity, chemotherapy, radiation, infections (e.g., sexually-transmitted diseases), toxins (e.g., endocrine disruptors), and drugs (e.g., antiandrogens, opioids, alcohol).

The average age of a young woman's first period (menarche) is 12 to 13 (12.5 years in the United States, 12.72 in Canada, 12.9 in the UK) but, in postmenarchal girls, about 80% of the cycles are anovulatory in the first year after menarche, 50% in the third and 10% in the sixth year. A woman's fertility peaks in her early and mid-20s after which it starts to decline. However, the exact estimates of the chances of a woman to conceive after a certain age are not clear, and are subject to debate.

According to the National Institute for Health and Clinical Excellence over 80 out of every 100 women aged under 40 who have regular unprotected sexual intercourse will get pregnant within 1 year of trying. In the second year the percentage rises to over 90%.

According to a 2004 study by Henri Leridon, PhD, an epidemiologist with the French Institute of Health and Medical Research of women trying to get pregnant, without using fertility drugs or in vitro fertilization.

- At age 30

- 75% will have a conception ending in a live birth within one year

- 91% will have a conception ending in a live birth within four years

- At age 35

- 66% will have a conception ending in a live birth within one year

- 84% will have a conception ending in a live birth within four years

- At age 40

- 44% will have a conception ending in a live birth within one year

- 64% will have a conception ending in a live birth within four years

According to a study done on a sample of 782 healthy European couples ages 19–39, fertility starts declining after age 27 and drops at a somewhat greater rate after age 35. The women were divided into four age groups: 19–26, 27–29, 30–34 and 35–39. Statistical analysis showed that the women in the 27–29 age group had significantly less chance on average of becoming pregnant than did the 19- to 26-year-olds. Pregnancy rates did not change notably between the 27–29 age group and the 30–34 age group, but dropped significantly for the 35–39 age group. The age of the male partner had a significant impact on female fertility among the women who had reached their mid-30s, but not among the younger women. However, experts said the new study was too small and there were too many variables which were too difficult to sort out, for a clear conclusion to be drawn. Some experts suggested that the main change in fertility in the older women was the fact that it took them "longer" to conceive, not necessary that they were significantly more unlikely to eventually succeed. David Dunson, a biostatistician at the U.S. National Institute of Environmental Health Sciences, said that: "Although we noted a decline in female fertility in the late 20s, what we found was a decrease in the probability of becoming pregnant per menstrual cycle, not in the probability of eventually achieving a pregnancy."

A French study found no difference between the fertility rate of women under 25 and those ages 26–30, after which fertility started to decrease. Estimating the "fertility of a woman" is quite difficult because of the male factor (quality of sperm). This French study looked at 2,193 women who were using artificial insemination because their husbands were azoospermic. The cumulative success rates after 12 cycles of insemination were 73% for women under age 25, 74% in women ages 26–30, 61% for ages 31–35, and 54% in the over 35 age group. (Note that the study is from 1982; artificial insemination techniques and success rates have evolved greatly since then.)

In Hungary, a study by the (Central Statistics Office) estimated that 7%–12% of Hungarian women younger than 30 were infertile; 13%–22% of women age 35 were infertile; and 24%–46% of women age 40 were infertile.

The below is a table containing estimates of the percentage of women who, if starting to conceive at a certain age, will fail to obtain a live birth. Note that while for the young ages researchers tend to agree, for older ages there is discrepancy.

Poor ovarian reserve is a condition of low fertility characterized by 1): low numbers of remaining oocytes in the ovaries or 2) possibly impaired preantral oocyte development or recruitment. Recent research suggests that premature ovarian aging and premature ovarian failure (aka primary ovarian insufficiency) may represent a continuum of premature ovarian senescence. It is usually accompanied by high FSH (follicle stimulating hormone) levels.

Quality of the eggs (oocytes) may also be impaired as a 1989 study by Scott et al. of 758 in vitro fertilisation (IVF) cycles showed a dramatic decline in implantation rates between high (> 25 mIU/mL) and low day three FSH (<15 mIU/mL) women even though the ages of the women were equivalent between the two groups (mean age 35 years). However, other studies show no association with elevated FSH levels and genetic quality of embryos after adjusting for age. The decline in quality was age related, not FSH related as the younger women with high day three FSH levels had higher live birth rates than the older women with high FSH. There was no significant difference in genetic embryo quality between same aged women regardless of FSH levels. A 2008 study concluded that diminished reserve did not affect the quality of oocytes and any reduction in quality in diminished reserve women was age related. One expert concluded: in young women with poor reserve when eggs are obtained they have near normal rates of implantation and pregnancy rates, but they are at high risk for IVF cancellation; if eggs are obtained, pregnancy rates are typically better than in older woman with normal reserve. However, if the FSH level is extremely elevated these conclusions are likely not applicable.

Although no large studies showing the long term outcomes for women with hyperthecosis exist, a diagnosis of hyperthecosis may suggest an increased risk for metabolic complications of hyperlipidemia and type 2 diabetes . In postmenopausal women, hyperthecosis may also contribute to the pathogenesis of endometrial polyp, endometrial hyperplasia, and endometrioid adenocarcinoma due to the association of hyperestrinism (excess estrins in the body) and hyperthecosis. Treatment for hyperthecosis is based upon each case, but may range from pharmacological interventions to surgical.