Disorders of Sex Development

Sex development starts in utero but progresses with the completion of sexual maturity and reproductive capacity into young adulthood. Three primary components may be classified into the major determinants of sex development: chromosomal sex, gonadal sex (sex determination), and phenotypic type (sex differentiation). Abnormalities at any of these stages can contribute to sex development disorders (DSDs).

Development of sex organs

Sex Development

The X and/or Y chromosome complement (46,XY male; 46,XX female) that is formed at the time of fertilization is described by chromosomal sex. The presence of a regular Y chromosome determines that the formation of the testis can continue even in the presence of multiple X chromosomes (e.g., 47,XXY or 48,XXXY). Loss of X chromosome causes the formation of gonads (45,X or 45,X/46,XY mosaics). Fetuses lacking an X chromosome (45,Y) are not viable.

Testis production is triggered by the expression of the Y chromosome gene (SRY ) encoding the transcription factor of the HMG box. SRY is transiently expressed in cells that are destined to become Sertoli cells and functions as a pivotal transition to determine the lineage of the testis. In chromosomal 46,XY males, mutation of SRY inhibits the development of testis, while translocation of SRY in 46,XX females is necessary to cause the development of testis and a male phenotype. To begin the growth of the testis, other genes are essential. In the emerging male gonad, SOX9 is upregulated by SRY but is inhibited in the female gonad. In a sex-dimorphic way, germ cells also form. Primordial germ cells (PGCs) proliferate and enter meiosis in the developing ovary, while they proliferate in the developing testis and then undergo mitotic arrest.

The structures of the exterior and internal genitals and secondary sex characteristics relate to phenotypic sex. Secretion of anti-müllerian hormone (AMH) from Sertoli cells and testosterone from Leydig testicular cells are needed for the male phenotype. AMH is part of the β-transforming growth factor (TGF) family and serves to induce regression of the Müllerian structures (from 60 to 80 days of gestation) by particular receptors.

Testosterone promotes the production of wolffian structures, including epididymides, vasa deferentia, and seminal vesicles, at ~60–140 days of gestation. Testosterone is the precursor of dihydrotestosterone (DHT), a potent androgen that stimulates the growth of the external genitals (65-100 days, and thereafter), including the penis and scrotum.

In the absence of the gonad, a female phenotype may emerge, but for maturation of the uterus and breast at puberty, estrogen is needed.

Disorders of Chromosomal sex

Differences in sex chromosome number and structure can occur as anomalies of sex growth (e.g., 45,X/46,XY). KS (47,XXY) and TS (45,X) usually do not have genital ambiguity, but are consistent with gonadal dysfunction.

Klinefelter’s Syndrome (47, XXY)

The classic model of Klinefelter Syndrome (47,XXY) develops during gametogenesis after meiotic nondisjunction of sex chromosomes (40 percent during spermatogenesis, 60 percent during oogenesis). Klinefelter’s Syndrome mosaic variants (46,XY/47,XXY) are assumed to originate from chromosomal mitotic non-disjunction within the zygote and occur in at least 10% of people with this disease. There have been records of other chromosomal variants of KS (e.g., 48,XXYY, 48,XXXY), but they are less frequent.

Small testes, infertility, gynecomastia, “eunuchoid” proportions, and inadequate virilization of phenotypic males define Klinefelter’s Syndrome. There is a prevalence of at least 1 in 1000 men, but only 25% of patients are diagnosed. In extreme cases, at the time of puberty, individuals present with small testicles prepubertally or with reduced androgenization and gynecomastia.

Turner’s Syndrome (Gonadal Dysgenesis; 45, X)

Approximately one-half of individuals with Turner’s syndrome have a 45,X karyotype, about 20% have 45,X/46,XX mosaicism, and the remainder have structural abnormalities of the X chromosome such as X fragments, isochromosomes, or rings. The clinical features of Turner’s syndrome result from haploinsufficiency of multiple X chromosomal genes (e.g., short stature homeobox, SHOX). However, imprinted genes also may be affected when the inherited X has different parental origins.

Turner syndrome in phenotypic females is characterized by bilateral streak gonads, primary amenorrhea, short stature, and numerous congenital abnormalities. It affects around 1 in 2500 women and, based on the prevailing health characteristics, is diagnosed at various ages. Prenatally, following chorionic villus screening or amniocentesis for unrelated causes such as old maternal age, a diagnosis of Turner’s syndrome is normally made incidentally. The results from prenatal ultrasound include improved nuchal translucency.

In female neonates or babies with lymphedema, nuchal folds, poor hairline, or left-sided heart abnormalities and in girls with unexplained growth deficiency or pubertal regression, the postnatal diagnosis of Turner syndrome should be regarded.

While there is minimal spontaneous pubertal growth in up to 30 percent of Turner’s syndrome girls (10 percent, 45, X; 30-40 percent, 45, X/46, XX) and ~ 2 percent enter menarche, the vast majority of Turner’s syndrome women develop full ovarian failure.

Mixed Gonadal Dysgenesis (45, X/46, XY)

45,X/46,XY mosaicism usually results from mixed gonadal dysgenesis. The phenotype of this disorder in patients differs considerably. While certain people have a primarily female phenotype with somatic symptoms of Turner’s syndrome, streak gonads, and Müllerian structures, most 45,X/46,XY persons have a male phenotype and testes, and after amniocentesis or during infertility study, the diagnosis is incidentally developed.

A female sex-of-rearing is often assigned (60%) if uterine structures are present, gonads are intraabdominal, and phallic development is poor. In such situations, gonadectomy usually is undertaken to prevent further androgen secretion and prevent development of gonadoblastoma (up to 25%). Individuals raised as males require reconstructive surgery for hypospadias and removal of dysgenetic gonads if the gonads cannot be brought down into the scrotum.

Ovotesticular DSD

Ovotesticular DSD (formerly called actual hermaphroditism) occurs when in one person both an ovary and a testis are located, or when an ovotestis is found. Gonadal asymmetry most commonly happens with a testis on the right and an ovary on the left, for unknown causes. Most individuals with this condition, especially in sub-Saharan Africa, have a 46, XX karyotype. The chimeric karyotype of A 46,XX/46,XY is less common and has a variable phenotype.

Disorders of Gonadal and phenotypic sex

The clinical profiles of patients with gonadal and phenotypic sex abnormalities is subdivided into 46,XY males (46,XY DSD) underandrogenization and 46,XX females excess androgenization (46,XX DSD).

46, XY DSD (Underandrogenized Males)

46,XY fetus underandrogenization (formerly called male pseudohermaphroditism) indicates deficiencies in the manufacture or operation of androgen. It can be caused by testis growth abnormalities, androgen metabolism deficiencies, or testosterone and dihydrotestosterone (DHT) resistance.

In patients with pure (or complete) gonadal dysgenesis, Streak gonads, Müllerian structures (due to insufficient AMH/MIS secretion) and a total absence of androgenization are observed (Swyer syndrome). Serum AMH/MIS is weak, and testosterone’s response to human chorionic gonadotropin (hCG) stimulation is inhibited.

LH receptor (LHCGR) mutations induce Leydig’s cell hypoplasia and androgen deficiency. HCG stimulation of Leydig cells in utero, as well as LH stimulation of Leydig cells late in gestation and during the neonatal phase, is prevented by defects in LH receptor synthesis or operation. Both adrenal and gonadal steroidogenesis is caused by mutations in steroidogenic acute regulatory protein (StAR) and CYP11A1.

Androgen receptor (AR) mutations cause resistance to androgen action (testosterone, DHT) or androgen insensitivity syndrome (AIS). A female phenotype, proper breast growth (due to testosterone aromatization), a short vagina but no uterus (because MIS output is normal), scanty pubic and axillary hair, and a female psychosexual preference are XY persons with full AIS (formerly called testicular feminization syndrome).


  1. Harrisons Endocrinology
  2. Molecular Endocrinology

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