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

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

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.

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

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.

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.

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.