Introduction to Secondary Sex Determination in Mammals

• Secondary sex determination in mammals is the process of developing the female and male phenotypes in response to hormones secreted by the ovaries and testes.
• It has two major phases:
  • the first occurs during embryonic development
  • the second occurs at puberty.

Hormonal Regulation of the Sexual Phenotype

• The hormones and paracrine signals produced by the gonads coordinate the development of the secondary sexual organs, which include:
  • the internal and external genitalia
  • the reproductive ducts
  • the accessory glands.

Female Phenotype

• In females, the ovaries secrete:
  • estrogen, which induces the differentiation of the Müllerian ducts into the uterus, cervix, oviducts, and upper vagina.
  • inhibin, which suppresses follicle-stimulating hormone (FSH) secretion from the anterior pituitary gland.
• The external genitalia of females develop from:
  • the genital tubercle, which becomes the clitoris
  • the labioscrotal folds, which become the labia majora.
• The urogenital sinus, which is derived from the endoderm of the cloaca, forms:
  • the lower vagina
  • Skene’s glands, which produce secretions similar to those of the prostate
  • bladder
  • urethra.
• The Wolffian ducts are the primordial male reproductive ducts that develop from the intermediate mesoderm. They require testosterone to persist, and thus they atrophy in females.

Male Phenotype

• In males, the testes secrete two factors that are essential for masculinization:
  • anti-Müllerian hormone (AMH), which causes the degeneration of the Müllerian ducts by inducing apoptosis in their epithelium and breaking down their basal lamina.
  • testosterone, which stimulates the differentiation of the Wolffian ducts into the epididymis, vas deferens, and seminal vesicle.
• Testosterone also promotes the development of male external genitalia, but not directly. It is converted to dihydrotestosterone (DHT), a more potent androgen, by an enzyme called 5α-ketosteroid reductase 2 in certain tissues. DHT causes:
  • the genital tubercle to develop into the penis
  • the labioscrotal folds to develop into the scrotum.
• The urogenital sinus forms:
  • the prostate gland, which secretes fluid that nourishes and protects sperm
  • Cowper’s glands, which secrete mucus that lubricates and neutralizes urine in the urethra
  • urethra.
• The mechanism by which testosterone and DHT masculinize the genital tubercle involves their interaction with the Wnt pathway, which is a signaling pathway that regulates cell proliferation, differentiation, migration, and polarity.
  • The Wnt pathway activates male development in the genital tubercle by downregulating Wnt inhibitors such as Dickkopf, which are expressed in the urogenital swellings.

Genetic Analysis of Secondary Sex Determination

• The correlation between chromosomal sex (XX or XY) and anatomical sex (female or male) is not always perfect. There are cases where individuals have intersex conditions, which are phenotypes in which male and female traits are seen in the same individual.

Pseudohermaphroditism

• Pseudohermaphroditism is characterized by having one type of gonad but secondary sex characteristics that differ from what would be expected from the gonadal sex.

Male Pseudohermaphroditism

• Male pseudohermaphroditism can be caused by mutations in the gene encoding the androgen receptor or by mutations affecting testosterone synthesis.
• An example of male pseudohermaphroditism is androgen insensitivity syndrome (AIS), which is caused by mutations in the gene encoding the androgen receptor. Individuals with AIS are chromosomally male (XY) and have testes that produce testosterone and AMH, but they cannot respond to testosterone or DHT. Therefore, they develop female external genitalia and are raised as girls. However, they have no uterus or oviducts because of AMH, and they have internal testes in the abdomen.

Female Pseudohermaphroditism

• Female pseudohermaphroditism can be caused by overproduction of androgens in the ovary or adrenal gland.
• An example of female pseudohermaphroditism is congenital adrenal hyperplasia (CAH), which is caused by mutations in the gene encoding an enzyme that metabolizes cortisol steroids in the adrenal gland. Individuals with CAH are chromosomally female (XX) and have ovaries, but they overproduce androgens that can bind to the androgen receptor. Therefore, they develop male external genitalia and are raised as boys. However, they have a uterus and oviducts because of the absence of AMH.

True Hermaphroditism

• True hermaphroditism is characterized by having both ovarian and testicular tissue in the same individual. This can result from chromosomal abnormalities such as 46,XX/46,XY mosaicism or 46,XX with SRY translocation.

Summary

• Secondary sex determination in mammals is regulated by the hormones and paracrine signals produced by the gonads, which coordinate the development of the secondary sexual organs.
• This process is usually consistent with the chromosomal sex, but there are exceptions due to genetic or hormonal variations that can create different phenotypes.