Sexual Differentiation - Anatomy & Physiology

Genetic Sex

• Established at the time of fertilisation.
• The foetus receives its genetic endowment in two equal portions from the male gamete (Spermatozoon) and female gamete (Oocyte).
• The X sex chromosome is larger than the Y sex chromosome.
• Females have XX chromosomes. All oocytes contain one X chromosome, they are the homogametic sex.
• Males have XY chromosomes. Spermatozoa form two distinct populations, one containing X chromosomes and one containing Y chromosomes. They are the heterogametic sex.

• The Y chromosome is required to initiate male development.
• In absence of the Y chromosome, female gonads (Ovaries) will develop.
• The prime male determining gene is SRY (sex determining region of the Y chromosome).

• SRY is a very small piece of DNA that acts as a molecular switch to regulate structural genes and autosomal chromosomes, determining if and when they are to be activated.
• SRY encodes the protein Testes Determining Factor (TDF)
• The presence of SRY alone is sufficient to ensure development of male gonads (Testes).
• Female is the default sex, in absence of SRY female gonads (Ovaries) will develop.

• Subsequent gonadal development is dependent on a normal population of germ cells.
• Normal Oocyte growth requires the activity of both X chromosomes.
• Normal Spermatogenesis requires the activity of no more than one X chromosome.

• Early development of gonads proceeds similarly in both sexes. The gonads are derived from two distinct tissues:
  • Somatic mesenchymal tissue forms the matrix of the gonad
  • Primordial germ cells form the gametes

• Genital ridge forms from somatic mesenchyme.
• Primordial germ cells migrate to the genital ridge.
• At this stage it is not possible to discriminate between male and female gonads.
• Y chromosomal determination of gonadal sex is only visible when primordial germ cell colonisation is complete.

MALE

• Sex cord cells proliferate to form the testes cord. During this period SRY is expressed for the first time within Sertoli cells (SRY is NOT expressed in primordial germ cells).
• Sex cords with a basement membrane become Semniferous Cords which give rise to Semniferous Tubules.
• Within the semniferous cords are two cell populations:
  • Primordial germ cells - Prospermatogonia which give rise to Spermatozoa
  • Mesodermal cord cells which give rise to Sertoli cells
• Between cords, the loose mesenchyme undergoes vascularisation and develops as stromal tissue.
• Within the stromal tissue, cells condense into clusters to form specialized endocrine units - the interstitial Leydig Cells

FEMALE

• At the time the male gonad is undergoing marked changes under the direction of SRY, the female gonad continues to appear indifferent and does not express SRY.
• Small clusters of mesenchyme surround the germ cells to initiate formation of Primary Follicles, characteristic of the Ovary.
• In follicles:
  • Mesenchymal cells give rise to Granulosa cells
  • Germ cells give rise to Oocytes

Foetal sex differentiation

• Endocrine activity of the Ovaries is NOT essential for sex differentiation during foetal life, abnormal ovarian development will have no effect until puberty.
• Testes secrete two essential hormones:
  • Steroidal hormones (mainly C19 androgens) from Leydig cells
  • Mullarian Inhibiting Hormone (MIH) also known as Anti-Mullarian Hormone (AMH) from Sertoli Cells
• In absence of these testicular hormones, female differentiation occurs.
• Thus, sexual differentiation must be actively diverted down the male route, the female route requires no active intervention.

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Internal Genetalia

• Male: Wolffian Duct developes from the Mesonephric Duct
• Female: Mullarian Ducts develop from the Paramesonephric Duct
• This is dependent on appropriate hormonal influence.

MALE

• MIH from Sertoli cells and Androgens from Leydig cells prevent spontaneous development of female internal genetalia.
• Androgens actively maintain Wolffian Ducts, which give rise to male internal genetalia:
  • Epididymis
  • Vas Deferens
  • Vesicular Glands/ Seminal Vesicles
• MIH causes Mullarian Ducts to regress

FEMALE

• Wolffian Ducts spontaneously regress in absence of Androgens.
• Mullarian Ducts persist to give rise to female internal genetalia:
  • Oviducts
  • Uterus
  • Cervix
  • Cranial Vagina
• Normal Ovarian activity is NOT essential for the development of normal female internal genetalia.

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External Genetalia

MALE

• Potential to develop male of female external genetalia. Testosterone is required to develop male external genetalia.
• Androgen secretion from the Testes induces:
  • Urethral folds to fuse to allow enclosure of the urethral tube. This, together with the cells from the genital swelling, forms the shaft of the Penis.
  • Genital swellings fuse in the midline to allow formation of the Scrotum
  • Genital Tubercle expands to give rise to the Glans Penis

FEMALE

• Development is ensured by the absence of Testosterone, it is independent of Ovarian endocrine activity.
• Urethral folds and Genital Swellings remain separate to form the Labia Minora and Majora.
• Genital tubercle forms the Clitoris

• Exposure of the female tract to Androgens will masculinise external genetalia.
• Failure of proper endocrine communication between the gonads, internal and external genitalia can lead to dissociation of gonadal and genital sex.

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Sexual Differentiation of the Brain

MALE

• Testosterone secreted into the blood reaches the brain.
• Converted to Dehydrotestosterone and Oestradiol by Aromatase enzymes in the Hypothalamus.
• Oestradiol masculinises the brain

FEMALE

• Alpha Fetoprotein binds Oestradiol, preventing it from crossing the blood-brain barrier.
• Oestradiol cannot access the Hypothalamus
• Protects female brain from masculising effects of Oestradiol.

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Associated Disorders

Turner's Syndrome

Kleinfelter's Syndrome

Testicular Feminisation

Adrenogenital Syndrome

Intersex

Bovine Freemartinism