sexual differentiation Flashcards
Sexual determination
Genetically controlled process dependent on the ‘switch’ on the Y chromosome. Chromosomal determination of male or female.
Sexual differentiation
The process by which internal and external genitalia develop as male or female.
Gonadal sex
SRY gene creates the testis.
Sex determining region Y (SRY) switches on briefly during embryo development (>week 7) to make the gonad into a testis. In its absence an ovary is formed.
Testis develops cells that make 2 important hormones which are anti-Mullerian hormone (AMH) and testosterone
Products of the testis influence further gonadal and phenotypic sexual development.
Gonadal development
After fertilisation a pair of gonads develop which are bipotential.
Their precursor is derived from common somatic mesenchymal tissue precursors called the genital ridge primordia (3½ - 4½ weeks) on posterior wall of lower thoracic lumbar region.
Genital ridge 3 waves of cells
- Primordial germ cells
- Primitive sex cords
- Mesonepheric cells
Primordial germ cells
Become Sperm (male) or Oocytes (female).
Primitive sex cords
Become Sertoli cells (male) or Granulosa cells (female).
Mesonepheric cells
Become blood vessels and Leydig cells (male) or Theca cells (female).
- Primordial Germ cell migration
An initially small cluster of cells in the epithelium of the yolk sac expands by mitosis at around 3 weeks.
They then migrate to the connective tissue of the hind gut, to the region of the developing kidney and on to the genital ridge – completed by 6 weeks.
- Primitive sex cords (Sertoli/Granulosa)
Cells from the germinal epithelium that overlies the genital ridge mesenchyme migrate inwards as columns called the primitive sex cords.
SRY
Expressed in males - Penetrate medullary mesenchyme & surround primordial germ cells to form testis cords – precursor of seminiferous tubules.
Eventually become Sertoli Cells which express AMH.
SRY and females
There is no SRY
Sex cords ill-defined and do not penetrate deeply but instead condense in the cortex as small clusters around primordial germ cells – the precursor of ovarian follicle
Eventually, become Granulosa cells
Male mesonephric cells
They act under the influence of pre-sertoli cells (which themselves express SRY) to form…
• Vascular tissue
• Leydig cells (synthesize testosterone, do not express SRY)
• Basement membrane – contributing to formation of seminiferous tubules and rete-testis
Female mesonephric cells
In females without the influence of SRY they form…
• Vascular tissue
• Theca cells
Mullerian ducts
- most important in female
* inhibited in the male by AMH
Wolffian ducts
- most important in the male stimulated by testosterone
* lack of stimulation by testosterone means regression in female
5-α-reductase & External Differentiation
Testosterone is converted in the genital skin to the more potent androgen DHT (dihydrotestosterone) by 5-a-reductase.
DHT binds to the testosterone receptor, but is more potent than testosterone.
DHT causes differentiation of the male external genitalia:
• Clitoral area enlarges into penis
• Labia fuse and become ruggated to form scrotum
• Prostate forms
Gonadal dysenesis
Sexual differentiation is incomplete. Usually missing SRY in male, or partial or complete deletion of second X in female. Also used as a general description of abnormal development of the gonads.
Sex reversal
Phenotype does not match genotype, ie may be male genotypically but externally look like a female.
Intersex
Have some components of both tracts or have ambiguous genitalia. Sex of infant difficult to determine.
DSD
Disorder of sexual differentiation
AIS
Androgen insensitivity syndrome
Appear completely female at birth and assigned female gender despite being XY.
Have undescended testes.
Diagnosis for AIS=
Usually present with primary amenorrhoea. Lack of body hair is a clue.
Ultrasound scan and karyotype with male levels of androgens.
Never responded to androgen so appear and often feel female.
Partial AIS
incidence unknown as is probably a spectrum
Present with varying degrees of penile and scrotal development from ambiguous genitalia to large clitoris.
Surgery was universal but now fortunately considered optional or at least best delayed. Decisions made on potential. Very difficult for parents.
5-a-reductase deficiency
Incidence varies enormously as autosomal recessive and can depend on inter-related marriage.
Testes form, AMH acts, testosterone acts.
Internal structures form.
External structures do not develop.
May appear mainly female or may have ambiguous genitalia
The degree of the enzyme block varies and so therefore does the presentation.
What happens at puberty with 5-a-reductase deficiency?
Need to assess potential as high testosterone level which will occur at adrenarche and puberty may induce virilisation.
Turner syndrome
- Turner syndrome: 1:3000
- XO have failure of ovarian function.
- ‘Streak’ ovaries = ovarian dysgenesis - illustrates that we need 2 X’s for ovarian development.
- Uterus and tubes are present but small, other defects in growth and development.
- May be fertile…many have mosaicism.
- Hormone support of bones and uterus
What happens if XX female is exposed to high levels of androgens in utero?
Congenital adrenal hyperplasia
Hypothalamic pituitary adrenal axis
Corticotropin releasing hormone
Stimulates pituitary to secrete ACTH
Adrenocorticotropic hormone
Stimulates rapid uptake of cholesterol into the adrenal cortex.
Upregulates cholesterol side-chain cleavage enzyme (P450scc). Increases glucocorticoid secretion.
Congenital adrenal hyperplasia (CAH)
Congenital adrenal hyperplasia: 1:15,000
Completeness of the block varies.
If enzyme absent then children may be wrongly gender assigned at birth, or may have ambiguous genitalia.
Also in CAH we need to be aware of possibility of ‘salt-wasting’ due to lack of aldosterone, this can be lethal.
Often require treatment with glucocorticoids to correct feedback.