Lecture 19: Sexual differentiation Flashcards
What is the process of formation of the bipotential gonad/genital ridge
- IGF-1, WT1 (KTS), SF1 and DAX1 nuclear transcription factors bind and form part of protein complex around DNA, altering gene expression
- Develops the intermediate mesoderm into the genital ridge
- Germ cells from the yolk sac endoderm migrate to the genital ridge- driven by C-kit and Steel (stem cell factor – where they will aggregate
How can genital ridge formation be disrupted and what is the consequence of that for gonad, internal and external genitalia + other organs
Loss of function of a gene for nuclear transcription factors IGFR1, WT1, SF-1, DAX1
Leads to no gonad development, so female internal and external genitalia.
As adrenal, internal genitalia and renal organogenesis occurs from the genital ridge by similar transcription factors, mutations can affect these systems as well.
What is the process of formation of the testes from the bi-potential gonad
- SRY gene (sex) in the pre-sertoli cells is activated before female genes
- Stimulates SOX-9 (autosomal gene) which transcribed product can complete differentiation
- SOX-9 is first transcribed by SF-1 then upregulated by SRY.
- Then SOX-9 upregulates itself via positive feedback loop and stimulation of Prostacyclin d2 and FGF-9
- Altogether they inhibit ovarian transcription factors to produce the testis
How does Prostacyclin D and FGF9 help to upregulate SOX-9
- Prostacyclin D2 increases SOX-9 in a paracrine manner and recruits further cells to a sertoli cell lineage
- FGF-9 is secreted from pre-sertoli cells enhancing the proliferation of SF-1 positive cells of coelomic epithelium resulting in increased number of precursors of SRY expressing cells and other gonadal cells
What is the process of formation of the ovaries from the bi-potential gonad
- Transcription of gene factors like DAX1,
RSPO1, WnT4, B catenin inhibit the transcription of Male gene factors and it is likely this antagonism continues throughout life
Especially FOXL2 - the active driver of ovarian sex
Which gonad determines internal and external genitalia development
The testes not the ovary- in the absence of a testis:
Ovary or No gonad,
The mullerian structures will remain. It will be female internal and external genitalia
What will loss of function in a gene for SF-1, DAX-1 B catenin, WnT4, FOXL2, RSPO1 cause
XX Ovotestes or testicular formation with azoospermia
What germ cell does a primordial germ cell removed early from the genital ridge/ during migration become in an XY, XX. What happens if it isn’t put back
In both sexes PGCs removed will result in oocytes as spermatogenic commitment is determined soon after reaching the genital ridge
PGCs don’t effect testis development if not put back in an XY but in XX if germ cells fail to populate the ovary, it will regress to become stromal tissue
What is Internal genitalia after and before differentiation - for XY and XX
After differentiation
XY: from Wolffian/mesophric ducts -> epididymis, vas deferens, seminal vesicles
XX: Mullerian or paramesonephric ducts form as an invagination of wolffian ducts=> fallopian tubes, uterus and upper 1/3 of vagina
Before differentiation have both ducts
How does the internal genitalia differentiate to male or female
Depends on presence of Leydig and Sertoli cells to differentiate to male (found in the testes- 1 pr duct).
- SF1 and AMH gene help Sertoli cells secrete AMH acting on AMH receptor to actively cause regression of Mullerian structures
- SF1 and Steroid genes help Leydig cells secrete a high local concentration of Testosterone to act on androgen receptor to stabilise the Wolffian ducts
If not leydig/sertoli cells then the wolffian structures naturally regress
In an XY, what will loss of function of just AMH/AMH receptor cause compared to loss of testosterone production/ T2 action
- AMH loss: retention of uterus, fallopian tubes - in addition to wolffian (persistent mullerian duct syndrome). + Bilateral crypto orchidism
- T2 loss: Absent Wolffian structures - epididymis, vas deferens, seminal vesicles but also if AMH is not working then retain female internal genitalia.
Also female external genitalia
What pushes the differentiation of undifferentiated external genitalia to more “male (virilised)” vs “female”
External Female genitalia will develop in the absence of Androgen/ complete androgen insensitivity
If there is some androgen at a low level/excess androgen for a XX or a partial insensitivity to androgen in testis carriers then it will be partial virilisation- small penis or large clitoris
External Male genitalia is due to exposure of genital tubercle to high concentrations of Dihydrotestosterone which is converted from testosterone produced by leydig cells by 5a-reductase
What is the trigger for leydig cells to make testosterone and what gene factors help that
1st trim its placental HCG then it is pituitary LH for rest.
Testosterone helped made by SF-1 and Steroid genes
How is sexual ambiguity assessed at birth
- Karyotype
- Pelvic USS to determine internal female genitalia - as this is large at birth.
If there is a uterus this means sertoli cells are absent - no testis - Check for palpable gonad= almost always testes
What are the possible fetal and maternal causes for over virilisation of an XX external genitalia but everything else XX - review the cases
Prenatal androgen exposure
- Fetal:
congenital adrenal hyperplasia - Maternal
- ingestion of androgens for body building
- severe PCOS
- androgen secreting tumour
