Lecture 15 - sexual differentiation

Question 1

What is development of genital ridge dependent on?

Answer 1

Nuclear transcription factors

-bind to DNA and alter gene transcription and expression

Question 2

What happens when you lose the gonadal ridge?

Answer 2

No gonads will form = female internal and external genetialia

any defects in the transcription factors can cause you to have female external or internal genetalia

Question 3

Gonadal determination

Answer 3

Bipotential gonad –> ovary (FOXL2)

Bipotential Gonad –> Testis (SRY sex determinig region of Y)

• development of sertoli cells
• stimulates SOX-9 and this leads to formation of testes (in females get repression of this, if this is lost then no gonads form and get female internal and external genetialia)

In a male - SRY stimulates SOX 9 to make FGF9 , however in female the SOX9 will actively repress this

FGF-9 - acts as earliest mitogen - increases no. of pre sertoli cells to push towards testis development

Question 4

Ovarian determination

Answer 4

ovarian follicules only commence differentiation after birth

• unlike testis the ovary does not affect internal genitalia development
• primordial germ cells are involved in development of ovary

Question 5

What happens if dont have SRY or SOX9 or a gene critical in forming testis?

Answer 5

No gonads will form so get female internal and external genetalia

Question 6

Development of internal genitalia

Answer 6

Wolffarian ducts - from internal male genetalia

Mullerian ducts - form as invagnations of wollfarian dcucts, and become the femal intenral genetalia

Determinaiton of internal genitals up to ledig and sertoli cells
Leidig - secretes testosterone and stabilizes wolffarian structures (need high conc of testosterone)
Sertoli cells - through secretion of AMH - inhibits female structures being made

In absence of testis - mullerian structures will remain and not wollfarian

Question 7

What happens if get loss of function of a gene in critical for forming AMH or its receptor in causing a male

Answer 7

• Will get retention of mullerian structures (e.g utereus, fallopian tubes ect.) in an XY male
• Bilateral cryptochidism

Question 8

What will loss of function in a gene that is critical in synthesis of testosoerone have on the action of a male?

Answer 8

Will get absent wolffarian structures

Question 9

Development of external genitalia

Answer 9

• As a fetus have a tubercle, and depends weather you get exposed to dihydrotestosterone or not weather it will develop to a male
• if have lower conc or a insensitivity to androgen will result in partial virilisaiton of external genitalia
• complete resistance - then will have female external genetalia

LH will stimulate leydig cells to produce testosterone

Question 10

Loss of function of gene in synthesis or development of testosterone on male?
-damage to 5-alpha reductase

Answer 10

wil have female external genitalia

5 alpha reductase -will appear female at birth but will start to develop a penis at puberty

Question 11

What tests do you get done if not sure if baby is a boy or a girl?

Answer 11

• Karyotype

- Pelvic ultrasound - tell if have a uterus

Question 12

Virilised (masculinaised) girl

cause

Answer 12

• Have ovaries
• Normal female internal genitalia (uterus)
• Karyotype - XX

-exposed to male hormone before birth (think where has this come from)

• fetal - congongenital adrenal hyperplasia - hard to make cortisol so make lots of male hormone instead
• Maternal - ingestion of male hormones - oral contraceptives, PCOS, andorgen secreting tumours

Question 13

Undervirilised Male

Answer 13

Have testis, no internal female genitalia, karyotype XY
-Implies lack of angrogen or resistant to its effects

• Fetal - LH receptor mutation (usually complete female - no breast development)
• Androgen receptor mutation

Normal formed phallus - hypothalamic - damage lH to make testosterone

Question 14

case 1 - No uterus/ovaries, labial fusion, mild cliteromegaly

Answer 14

• Absent uterus - indicates AMH present
• most likely undervirilised XY infant - functional testicular sertoli cells
• Defect in testosterone synthesis or action

e. g LH receptor defect
- Testosterone synthesis defects, or action defects

ANdrogen receptor is on X chromosome

Question 15

Case 2 - 15 year old girl, pubertal delay

• tanner 2-3 pubic hair , tanner 1 breast development
• genitals normal
• USS confirms small uterus
• Karyotype is XY

Answer 15

• Dont have tesits - MUST BE earlier on in development

- defect has to be high up

Question 16

Mother takes androgen ingesting body bulider also fetal aromatase deficiency

Answer 16

• Virilised female - mother exposed to testosterone early on
• also does somethign similar - , get facial here ect. get aromatased to estrodiol
• WnT4 - in female that turns of maleness - if not enough, then maleness turns on - get testiucalrisaiton , dont have uterus, and high testoerone levels and quite virilised
• ovary havign some testicualr features

17b - will look compelty female will start to devleop a penis in puberty - overocme testicualr barrier, similar to the alpha 5 dehydrgeonease which converts testosterone to DHT - become virilised dramatically