Sexual differentiation and disorders Flashcards
What is sexual determination?
A genetically controlled process dependent on the ‘switch’ on the Y chromosome - determines if you are male or female
What is sexual differentiation?
The process by which internal and external genitalia develop as male or female
What are different levels of sexual differentiation?
- genotypic sex (if the embryo has XX or XY)
- gonadal sex (either ovaries or testes develop)
- phenotypic sex (outward appearance)
- legal sex (what’s written on the passport)
- gender identity (how you feel)
Describe how the SRY gene is involved in gonadal development
The SRY is a transcription factor that transcribes itself, along with a transcriptional cascade of events that eventually leads to the development of a testis.
If this gene is absent, ovaries will develop
What do Sertoli cells produce?
Anti-Mullerian hormone (AMH)
What do Leydig cells produce?
Testosterone
Describe gonadal development after fertilisation
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 on the posterior wall of the lower thoracic lumbar region
What are the three waves of cells that invade the genital ridge?
1) Primordial Germ Cells (PGCs) - become sperm (male)/oocytes(female)
2) Primitive Sex Cords - become Sertoli cells (male) or Granulosa cells (female)
3) Mesonephric Cells - become blood vessels and Leydig cells (male) or Theca cells (female)
Describe 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 hindgut, to the region of the developing kidney and on to the genital ridge - completed by 6 weeks.
Describe the formation of the sex cords (sertoli)
- There is SRY expression
- The sex chords penetrate the medullary mesenchyme and surround the PGCs to form the testis chords.
- They eventually become Sertoli cells, which express anti-Mullerian hormone (AMH).
Describe the formation of the sex cords (granulosa)
- There is no SRY expression.
- The sex chords are ill-defined and do not penetrate deeply, but instead condense in the cortex as small clusters around PGCs.
- They eventually become Granulosa cells.
Describe the role of mesonephric cells in gonadal development
These originate in the mesonephric primordium, which is just lateral to the genital ridges.
In MALES, they act under the influence of pre-Sertoli cells to form:
- vascular tissue
- Leydig cells (synthesise testosterone, don’t express SRY)
- basement membrane - contributing to the formation of seminiferous tubules and rete-testis
In FEMALES, they form:
- vascular tissue
- Theca cells (synthesise androstenedione, which is a substrate for estradiol production by the granulosa)
What are the two main structures involved in developing internal reproductive organs?
Mullerian ducts:
- most important in female
- inhibited in males by AMH
Wolffian ducts:
- most important in the male, stimulated by testosterone
- lack of stimulation by testosterone means regression in female
Describe the role of 5-a-reductase in external differentiation?
Testosterone is converted to the more potent androgen DHT (dihydrotestosterone) by 5-α-reductase in the genital skin.
DHT also binds to the testosterone receptor and is more potent than testosterone.
DHT causes differentiation of the male external genitalia:
- clitoral area enlarges into the penis
- labia fuse and become ruggated to form the scrotum
- the prostate forms
It is present in both males and females, but because there is no substrate (testosterone) in females, its effects don’t play out.
What is gonadal dysgenesis?
Sexual differentiation is incomplete; also used as a general description of the abnormal development of the gonads
What is sex reversal?
The phenotype does not match the genotype
What is intersex?
Have some components of both tracts/ambiguous genitalia
What is androgen insenstivity syndrome?
Testosterone is being made in an XY individual, but has no effect
What does AIS result in?
The testes form and make AMH so the Mullarian ducts regress. There is no differentiation of the Wolffian ducts, and thus no external male genitalia, so female external sex characteristics (only exposed to female hormones)
What is the difference between complete and partial AIS?
Complete AIS:
- appear completely female at birth, and are assigned the female gender despite being XY
- usually present with primary amenorrhoea, lack of body hair
- would be diagnosed by ultrasound scan and karyotype with male levels of androgens
- would never respond to androgen so they appear and feel female
Partial AIS:
- present with varying degrees of penile and scrotal development, from micropenis to large clitoris
- surgery was universal, but now fortunately considered optional (at least best, delayed)
- decisions made on potential, very difficult for parents
What is 5-a-reductase deficiency?
Testosterone is made in an XY individual, but not DHT
What does 5-a-reductase deficiency result in?
The testes form and make AMH so the Mullerian ducts regress. The Wolffian ducts then develop, but there is no external male genitalia.
Describe 5-a-reductase deficiency
The incidence varies enormously as it is autosomal recessive and can depend on inter-related marriage.
The individual may appear mainly female, or may have ambiguous genitalia. The degree of the enzyme block varies, and so, therefore, does the presentation.
At puberty, you need to assess the potential as the high testosterone levels which will occur at adrenarche and puberty may induce virilisation.
Describe Turner Syndrome
It is when an individual has the chromosome XO.
They have a failure of ovarian function. They have what are called ‘streak’ ovaries, which are a form of ovarian dysgenesis. It illustrates that we need 2 X’s for proper ovarian development.
The uterus and tubes are present but other, small defects in growth and development may be present. There may be a need for steroid hormone support of the bones and uterus.
What is congenital adrenal hyperplasia?
An XX female is exposed to high levels of androgens in utero
What does CAH result in?
No SRY is expressed, so we don’t get any testes or AMH. The Mullerian ducts remain. The individual ends up with masculinised external genitalia, but the androgen levels are not usually high enough to rescue the Wolffian ducts.
How would an XX female be exposed to high levels of androgens in utero?
There could a failure of the enzyme 21-hydroxylase which converts steroid hormone precursors, to eventually end up as cortisol and aldosterone. This means that there will be a build up of precursors, which will be ushered along to make more androgens.
Also, in the event of the lack of negative feedback from cortisol/aldosterone, more cholesterol will be pushed into steroid genesis for more cortisol/aldosterone, which worsens the situation.
Describe the effects of CAH
The completeness of the enzyme (21-hydroxylase) block varies.
If the enzyme is absent, then children may be wrongly gender assigned at birth, or may have ambiguous genitalia.
There needs to be treatment with glucocorticoids to correct the feedback.
Also, in CAH, we need to be aware of the possibility of ‘salt-washing’ due to the lack of aldosterone; this can be lethal.
