Normal Sexual Differentiation Flashcards
What is sexual determination?
- Genetically controlled process dependent on the ‘switch’ on the Y chromosome.
- Chromosomal determination of male or female.
What is sexual differentiation?
The process by which internal and external genitalia develop as male or female.
What is the SRY gene?
- Sex determining region
- Only found on the Y chromosome
- Switches on briefly during embryo development to turn the gonad into testis
- Ovaries develop in its absence
Which cells are developed in the testis and what hormones do they produce?
- Sertoli cells -> make anti-Mullarian hormone (AMH)
- Leydig cells -> make testosterone
Where in the testis are Leydig and Sertoli cells found?
- Sertoli cells are found in the seminiferous tubules
- Leydig cells are found adjacent to the seminiferous tubulues
What happens when SRY is activated
- SRY is a DNA binding protein that acts as a transcription factor
- SRY turns off many ovarian genes and turns on testicular genes
- It binds upstream of itself, it’s a transcription factor for itself
- The site of DNA binding is upstream of SOX9 which is also a transcription factor.
- SOX9 can bind its own upstream activation site so its levels remain high even if SRY declines. This is a positive feedback mechanism.
- SOX9 turns off a lot of ovarian genes and turns on many testicular genes
- SOX9 then acts to stimulate the expression of further downstream genes.
- Both SRY and SOX9 are essential for the development of sertoli cells
How does SOX9 achieve its effects?
- Stimulates production of prostaglandin D2 (PGD2) by the pre-sertoli cells. PGD2 acts as a paracrine hormone to stimulate further SOX9 production in these cells. This second positive feedback mechanism serves to re-enforce all precursor cells along the sertoli pathway.
- SOX9 stimulates production of fibroblast growth factor 9 (FGF9). FGF9 acts as a chemotactic factor for cell migration into the developing testis. It also further stimulates the production of SOX9 a third positive feedback mechanism.
- SOX9 stimulates the production of anti-Mullerian hormone (AMH).
- Inhibition of female transcription factors WNT4 and FOXL2
What are the effects of activation of SOX9?
- Positive feedback pathway for itself
- Cause the development of sertoli cells from precursor cells
- Inhibition of WNT4 and FOXL2 (female transcription factors)
- Cell migration into developing testis
- Stimulate the production of AMH
What are gonads after fertilisation?
Bipotential
Where are the gonads derived from?
They are derived from the genital ridge primordia on posterior wall of lower thoracic lumbar region.
What do genital ridge’s become?
Testis or ovaries
What do the Mullerian and Wolffian ducts form?
- Mullerian ducts becomes the uterine tubes and the upper 3rd of the vagina
- Wolffian ducts becomes the vas deferens and the internal genitalia connecting the testis to the urethra
What cells invade the genital ridge?
- Primordial Germ Cells – become Sperm (male) 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).
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 hind gut, to the region of the developing kidney and on to the genital ridge – completed by 6 weeks.
Describe how primitive sex cords invade the genital ridge
- Cells from the germinal epithelium that overlies the genital ridge mesenchyme migrate inwards as columns called the primitive sex cords
How do the primitive sex cords differ in men and women
- In men: they penetrate medullary mesenchyme and surround primordial germ cells to form testis cords (precursors of seminiferous tubules)
- Due to SRY presence
- Eventually become sertoli cells
- In women: No SRY
- Sex cords are ill defined and do not penetrate deeply
- Sex cords condense in the cortex as small clusters around primordial germ cells (all of this is the precursor of an ovarian follicle)
- 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 form?
In males 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) – mainly become this
• Basement membrane – contributing to formation of seminiferous tubules and rete-testis
In females without the influence of SRY they form:
• Vascular tissue
• Theca cells – produce oestrogen but later (not in the embryo)
• In the female no hormone that affects their development
What do primordial germ cells, primitive sex cords and mesonephric cells form in men?
- primordial germ cells: Spermatozoa
- primitive sex cords: Sertoli cells
- mesonephric cells: Leydig cells and blood vessels
What do primordial germ cells, primitive sex cords and mesonephric cells form in women?
- primordial germ cells: Oocytes
- primitive sex cords: Granulosa cells
- mesonephric cells: Theca cells and blood vessels
What causes the Mullerian duct to regress?
AMH (anti-mullerian hormone) made by Sertoli cells
What causes Wolffian duct to regress?
Lack of stimulation by testosterone
What is the hormone that affects male internal sexual differentiation?
Testosterone
What is 5 alpha reductase?
- An enzyme found in the genital skin of both men and women
- converts testosterone into dihydrotestosterone (DHT)
Why doesn’t 5 alpha reductase make DHT in females?
Because they don’t have testosterone
What receptor does DHT bind to?
- Binds to the testosterone receptor
- More potent than testosterone
What does DHT do?
DHT causes differentiation of the male external genitalia:
• Clitoral area enlarges into penis
• Labia fuse and become ruggated to form scrotum
• Prostate forms
How does external differentiation happen?
- Genital tubercle becomes the phallus which becomes the glans penis – happens due to the presence of the DHT
- In women the genital tubercle becomes the clitoris – due to the absence of DHT
What is gender identity?
self-representation or identification as male or female (or neither).
What are gender roles?
expression or portrayal of psychological characteristics that are considered sexually dimorphic within the general population (eg. toy preferences / physical aggression etc).
What is psychosexual neutrality?
the view that gender assignment of a newborn with ambiguous genitalia can be made regardless of the endocrine history.
What is neural bias?
the idea that a tendency for male or female is already present in neonates as a result of prenatal factors such as the hormonal milieu in utero.
