Sexual differentiation

Question 1

What do you look at to determine sex?

Answer 1

Gonads
External genitalia
Internal genitalia

Question 2

What are the there areas of the genial ridge (bipotential gonad)?

Answer 2

Pronephros (caudal endforms adrenals)
Mesonephros (centrol region forms the gonas and internal reproductive structures - the Wolffian and Mullerian ducts)
Metanephros (posterior end forms the kidney)

Question 3

What happens in the testis to cause male internal genitalia development?

Answer 3

Sertoli cells are the first cells produced in the testis. They produce AMH (genes involved SF-1 and AMH gene) -> which binds to its receptor and causes Mullerian Duct regression.

Leydig cells produce testosterone (genes: SF-1 and steroid genes) which bind to the androgen receptor and cause Wolffian duct stabilization

Question 4

How do the leydig cells initially produce testosterone to stimulate the development of male genitalia?

Answer 4

Usually they would be stimulated with LH from the pituitary but at this age there is no pituitary. Placental HCG stimulates the leydig cells and promotes the production of testosterone (SF-1 and steroid genes).

At the 2nd and 3rd trimester the pituitary produces H to stimulate the leydig cells.

Testosterone is converted to dehydrotestosterone with 5alpha reductase.

Dehydroteststerone binds to the androgen receptor an stimulates the development of male genitalia.

Question 5

What genes are essential for generating the genital ridge form the intermediate mesoderm?

Answer 5

WT-1 and SF1. If one of these doesn’t form and you don’t get a genital ridge then you are female.

Question 6

What is genes are important to drive the bipotential gonad to develop testis?

Answer 6

SRY (initial gene for determining male gonad development) stimulates -> SOX9 (completes testical development, very low levels in females) -> testis (phenotypically male)

Initial SOX9 transcription by SR-1 (background levels). It is then upregulated by SRY. Then maintained by itself and FGF9 and prostaglandin D2.

Sox9 is self regulated with the help from FGF9. Prostaglandin D2 increases SOX9 in a paracrine manner and recruits more to become sertoli cells. SOX-9 down regulates the expression of the genes involved in the development of an ovary (beta catenin).

It is a cascade that drives maleness.

Question 7

What is genes are important to drive the bipotential gonad to develop ovaries?

Answer 7

FOXL2. Knockout of FOXL2 in adult mice causes the ovaries to develop testicular functions. Suggests antagonism throughout life.

Beta catenin (decreases the expression of SOX9 to drive female development)

Question 8

What does a baby with a uterus mean?

Answer 8

They don’t have a functioning testis because the sertoli cells are the first cell to form -> prevent uterus

Question 9

What is the role of the ovary in sexual differentiation?

Answer 9

Nothing, it just develops for later function.

Question 10

What happens if germs cells don’t make it to the gonads?

Answer 10

The ovaries won’t develop but the testis will develop (structure only, not function)

Question 11

How do the hormones created during development, such as testosterone, reach their target?

Answer 11

By diffusion, there is no circulating blood. This can cause structures to be different on different sides.

Question 12

What does the development of a testis cause?

Answer 12

Male internal and external genialia?

Question 13

When is female internal genitalia retained?

Answer 13

In the absence of AMH (sertoli cells)

Question 14

When are female external genitalia created

Answer 14

In the absence of androgens.

Question 15

What is required to maintain the development of the male genitalia?

Answer 15

Androgens - produced in response to pituitary LH in the 2nd and 3rd trimester

Question 16

What are the male gonads and what are the male internal structures?

Answer 16

These are different .

Gonads = testis

Male internal structures = vas deferens, epididymis, seminal vessels)

Question 17

If a patient has ambiguous genitalia, what info do you need?

Answer 17

Karyotype - XX XY

Pelvic ultrasound for a uterus (determines if there are sertoli cells producing AMH or not.

Question 18

Virilised female: Has a uterus (therefore ovaries) and is XX. What doe it suggest?

Answer 18

Implies prenatal androgen exposure -
Possible causes are
Fetal origion: congenital adrenal hyperplasia
Maternal: ingestion, severe polycystic ovary disease, androgen secreting tumour

Question 19

Undervirilised male: testis, no female internal genitalia, karyotype XY. What is the issue?

Answer 19

Lack of prenatal androgen exposure or inability to respond to testosterone.

Fetal causes: defect of LH receptor mutation on testis- can’t respond to LH or HCG
Steroird biosyntheic defect
Androgen receptor issue

Small normally formed phallus;
Same causes as above but cold but is likely because HCG has been stimulating testosterone production but it was unable to switch to LH induced production because of a pituitary or hypothalamic defect

Question 20

What is SF1 important for?

Answer 20

Regulates the development of the reproductive tract at multiple levels:
Gonadal development, adrenal development, pituitary gonadotroph development

Children with homozygous mutation = A defect in all = no gonads, no adrenals, pituitary LH and FSH don’t work = death.

On gene that works (haplosufficiency) variable phenotype.

Question 21

What does SOX9 do?

Answer 21

Leads to normal male phenotype.
Also important in bone development. If you have a problem with SOX9 then you also have campomelic dysplasia.

XY female with short limbs = SOX9 dysfuncion.

Question 22

What happens in an androgen receptor defect XY?

Answer 22

AMH is produced and causes regression of the female internal genitalia, but the lack of testosterone stimulation prevents the development of the male internal genitalia or male external genitalia.

Will still have puberty because of the conversion to estrogen.