Lecture 21: Sexual differentiation Flashcards
The bipotential fetus?
Bipotential gondads at < 6 weeks (same as genital ridge)
bipotential internal genitalia at < 7 weeks
Bipotential external genitalia at < 8 Weeks
The bipotential gonad?
Is the Genital ridge
Arises as paired structures in the intermediate mesoderm and is divided into three from anterior to posterior:
- Pronephros (caudal end forms adrenals)
- Mesonephros (central region forms the gonads and the internal reproductive structures - the wolfian and mullarian ducts)
- Metanephros (posterior end forms the kidneys)
Two inputs to the bipotential gondas and their determination?
From the intermediate mesoderm under transcription factor: WT1 and SF1
and also germ cells from the the yolk sac (Endoderm)
The determination - to an ovary or testis. These two antagonise each other and testes begin first and supress the formation of ovaries. The default mode is female.
Sertoli cells form first in the testes and produce AMH that causes mullerian duct regression (fillopian tube, uterus and upper 1/3 of vagina)
Leydig cells produce testosterone for wolfian duct stabilisation.
Mechanism of gonadal determination?
SRY found soley in sertoli cells - sex determining region of Y stimulates the autosome SOX-9. This then drives the formation of testes - initial SOX-9 transcription is by SF-1 then markedly upregulated by SRY. Finally SOX-9 up-reguates itself via a positive feedback loop and the stimulation of prostacyclin D and FGF9. (these all inhibit ovarian transcription factors)
FOXL2 is the major player involved in ovary formation (+ b catenin that is stimulated by RSP01 is significant as it is inhibited by SOX-9 and vice versa depending on what begins first)
FGF-9 and PGD2 in male determination?
FGF-9 is secreted from Pre-sertoli cells enhancing proliferation of SF-1potitive cells of coelomic epithelium - increased number of precursors of SRY-expressing cells and other gonadal cells.
Thus, FGF9 participates in both sex determination and testis differentiation.
PGD2 increases SOX-9 in a paracrine manner recruiting cells to a sertoli cell lineage.
= CASCADE
Development of external genitalia?
Under the influence of testosterone from leydig cells under hCG control. 5a reductase forms DHT that then causes the major changes. In the 2 and 3rd trimester we need pituitary LH secretion to continue the changes.
Without androgen we form female external genitalia
Ovarian Function and determination?
- Production of steroid hormones
- Generation of mature oocytes capable of being fertiised
The ovaries basically get made and then don’t play a role
Internal genitalia? formation?
These develop from the Wolffian (mesonephric) and Mullerian (paramesonephric) ducts.
Male = Epididymis, vas deferens, seminal vesicles
Female = Fallopian tubes, uterus and upper third of vagina
All determined by the presence of Leydig cells (testosterone stabilises wolffian structures) and sertoli cells (AMH actively causes mullerian regressio) - (essentiall wether or not you have testis)
No heart or blood at this stage so is all paracrine and so can vary between side to side…
Development of external genitalia?
Can result in either normal male or female genitalia. Male results if the genital tubercle is exposed to high concentrations of DHT.
Lower concentrations of androgen or partial insensitivity to androgen results in partial virilisation of the external genitalia.
Absence or complete resistance to androgen results in female external genitalia.
what would happen if you were XY but completly androgen insensitive?
Testis would form under the influece of SRY, SOX-9 and FGF9
AMH is synthesised so no female internal structures but also no male as the testosterone is not detected
External genitalia would be female due to insensitivity
They will undergo female puberty as all testosterone will be aromatised by aromatase in testis and fat into oestrogen. They will have no facial or genital hair and have very good clean skin (all caused by androgens) They will be a little bit taller due to a longer and later puberty but not as tall as a guy as they have female hormones driving the puberty.
Causes of a virilised female?
Present with:
- Ovaries
- Normal female internal genitalia
- Karyotype XX
Implies prenatal androgen exposure
fetal: Congenital adrenal hyperplasia
Maternal: Ingestion, severe PCOS, androgen secreting tumor
Undervirilised male?
Present with:
- Testis
- No female internal genitalia
- Karyotype XY
Implies lack of prenatal androgen exposure or inability to respond to testosterone. Often assosiated with hypospadias
fetal: LH receptor mutation, Androgen receptor mutation
small normally formed phallus: Fetal causes, Hypothalamic/pituitary defect, syndromes (eg. klinefelters)
Causes of XY karyotype but all else female?
Something early on: SRY, SOX-9, WT-1, SF-1
WT1?
Wilm’s tumour 1
- Nuclear transcription factor found in urogenital ridge
- repressor and activating components
- tumour supressor gene in renal tissue
SF1?
steroidogenic factor 1
- released in urogenital ridge at the earliest stages of organogenesis and later in fetal sertoli and adrenal cells
- expressed prior to any steriodogenesis
Several human phenotypes now recognised with haploinsuffiency:
- Sex reversal
- isolated undervirilised boy (chyptochidism)
- Premature ovarian failure
