Sexual differentiation and disorders Flashcards
What is sexual determination?
It is the genetic process that is dependent on the switch on the Y chromosome
Chromosomal determination of male or female
What is sexual differentiation?
Is the process by which internal or external genitalia develop as male or female
What are both sexual determination and differentiation and what do they consist of?
Sexual determination and differentiation are contiguous and consist of several stages
What are the levels involved in sex differentiation?
- An early embryo can be said to have a genotypic sex like xx or xy
- In the next level of complexity as the embryo develops, we can say it has a gondal sex, so either testes or ovaries
- Beyond this, we can say a person can have phenotypic sex
- Above this we have the legal sex
- Above all we have gender identity
What does the SRY gene create?
The SRY gene creates the testis
When do ovaries develop?
In the absence of Y chromosome
What cells do the testis form which make important hormones?
- Sertoli cells
- Leydig cells
What hormone do sertoli cells produce?
Sertoli cells produce anti-Mullerian hormone (AMH)
What hormone do leydig cells produce?
Leydig cells make testosterone
Steps involved in 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 on the posterior walls of the low thoracic lumbar region
- Genital ridges become the testes or ovaries
What would the mullerian ducts develop into?
Mullerian duct would develop into the uterus and uterine tubes
What would the wolfian ducts develop into?
Wolfian ducts will develop into the vas deferens and prostate
What are the 3 waves of cells that invade the genital ridge and what do they become in both male and female?
- Primordial germ cells- become sperm (males) or oocytes(female)
- Primitive sex cords- become sertoli cells (male) or granulosa cells (female)
- Mesonephric cells-become blood vessels and leydig cells (male) or theca cells (female)
What are primordial germ cells?
Initially a small cluster of cells in the epithelium of the yolk sac and expands by mitosis at around 3 weeks
Where do primordial germ cells migrate to?
They 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
What are primitive sex cords?
They’re cells from the germinal epithelium that overlies the genital ridge mesenchyme and migrate inwards as columns called the primitive sex cords
What do primitive sex cord do when their is SRY expression?
- Primitive sex cords penetrate the medullary mesenchyme and surround the PGCs to form testis cords
- Eventually they become sertoli cells which express AMH
What do primitive sex cords do when there isn’t SRY expression?
- Sex cords are ill defined and do not penetrate deeply but instead condense in the cortex as small clusters around PGCs
- Eventually become granulosa cells
Where do mesonephric cells originate?
These originate in the mesonephric primordium which are just lateral to the genital ridges
What do mesonephric cells in male act under the influence of and form what?
In males they act under the influence of pre sertoli cells to form:
- Vascular tissue
- Leydig cells
- Basement membrane which contribute to the formation of seminiferous tubules and rete-testis
What do mesonephric cells in females without the influence of SRY form?
They form:
- Vascular tissue
- Theca cells
What are mullerian ducts inhibited in the male by?
Inhibited in the male by AMH
What are wolffian ducts stimulated by?
Stimulated by testosterone
What does lack of stimulation of wolffian ducts mean?
Lack of stimulation by testosterone means regression in female
How does testosterone convert to DHT and where?
Testosterone converted by 5 alpha reductase in the genital skin to DHT
What else binds to testosterone receptor?
DHT also binds to testosterone receptor, but is more potent than testosterone
What does DHT cause and the changes observed?
DHT causes differentiation of the male external genitalia:
- Clitoral are enlarges into penis
- Labia fuse and become ruggated to form scrotum
- Prostate forms
Disorders of sexual differentiation(Gonadal dysgenesis)
- Sexual differentiation is incomplete
- Usually missing SRY in male, or partial or complete deletion of second x in female
Disorders of sexual differentiation(Sex reversal)
-Phenotype doesn’t match genotype
Disorders of sexual differentiation(Intersex)
-Have some component of both tracts or have ambiguous genitalia
What does androgen insensitivity syndrome result in?
- Testes form and make AMH so mullerian ducts regress
- No differentiation of wolffian ducts
- No external male genitalia
Complete AIS
- Appears completely female at birth
- Usually present with primary amenorrhoea
Partial AIS
-Present with varying degrees of penile and scrotal development from ambiguous genitalia to large clitoris
What does a 5 alpha reductase deficiency result in?
- Testosterone is made but not DHT
- Testes form and make AMH so mullerian ducts regress
- Wolffian ducts develop
- No external male genitalia
Why does incidence vary in 5 alpha reductase deficiency?
Incidence varies enormously as it can be autosomal recessive and can depend on inter related marriage
What do we need to assess at puberty with 5 alpha reductase deficiency?
At puberty we need to assess potential high testosterone levels which will occur at adrenarche and puberty may induce virilisation
What is 45XO also known as ?
Also known as turners syndrome
What does XO have a failure of?
- Failure of ovarian function
- Uterus and tubes are present but small
Comment on fertility in turners syndrome
May be fertile and may have mosaicism
What is required in turner’s syndrome?
Hormone support of bones and uterus required
When does congenital adrenal hyperplasia occur?
Happens when a XX female is exposed to high levels of androgens in utero
What makes steroids?
Adrenal glands
What precursor forms progesterone and how?
Cholesterol is the precursor and is imported into the cell and from carbon 21 onwards, these are clipped off forming progesterone
What happens when you clip off an additional 2 carbons from a progesterone with 19 carbons in total?
Forms an androgen
What happens when you clip off 1 additional carbon from an androgen with 18 carbons in total?
Form estrogen now
What happens if 21 hydroxylase enzyme fails?
If 21 hydroxylase enzyme fails, we’re unable to make cortisol
What happens when you can’t make cortisol in a foetus?
You start making more androgens:
- If you make no cortisol, there’s no negative feedback and ACTH increases
- ACTH causes more cholesterol to be taken up
- You then produce more androgens
- So in a baby girl, there would be an increase in testosterone
What does congenital adrenal hyperplasia result in?
- No SRY so no testes and no AMH
- Mullerian ducts remain
- Masculinised external genitalia, but androgen levels are not usually high enough to rescue the wolffian ducts
What is there a possibility of in congenital adrenal hyperplasia?
There may be the possibility of salt wasting due to a lack of aldosterone and this can be lethal
How do we correct the feedback in congenital adrenal hyperplasia?
Need treatment with glucocorticoids to correct feedback
