W4 - Sexual Differentiation and Disorders

Question 1

What is sexual determination?

Answer 1

Genetically controlled process dependant on the ‘switch’ on the Y chromosome.

Question 2

What is sexual differentiation?

Answer 2

Process by which internal and external genitalia develop as male or female.

Genotypic -> Gonadal -> Phenotypic -> Legal -> Gender identity

Question 3

After fertilisation, how are development of the gonads bi-potential?

Answer 3

The genital ridge (precursor of both sexes) in the hindgut, contains the two ducts required for sexual development. Since at this stage the embryo has the potential to be either male or female, it is bi-potential.

Question 4

What is the Mullerian duct?

Answer 4

Develops into female gonads

• woman with yogurt

Question 5

What is the Wolffian duct?

Answer 5

Develops into male gonads

• male wolf

Question 6

1 -What are the 3 waves of cell development within the genital ridge?

Answer 6

1) Primordial Germ Cells - sperm/oocytes
2) Primitive Sex Cords - Sertoli cells/ Granulosa cells
3) Mesonephric Cells - blood vessels and Leydig/Theca cells

Question 7

2- How does the Primordial Germ Cell migration occur?

Answer 7

At 3 weeks - small cluster of cells in epithelium of Yolk sac expands by mitosis.
By 6th week - migrates to connective tissue of hind gut to region of developing kidneys and onto genital ridge.

Question 8

What is Primitive Sex Cords

Answer 8

The Germinal epithelium has cells that overlies genital ridge mesenchyme. It migrates inwards as columns called primitive sex cords.

Question 9

How is Gonadal sex determined in males?

Answer 9

SRY is expressed.
They penetrate the medullary mesenchyme and surround the primordial germ cells to form testis cords - precursors of semineforus tubes.

The Sertoli cells express AMH

Question 10

What happens to the primitive sex cords in females?

Answer 10

No SRY
Sex cords condense in cortex as small clusters around primordial germ cells - the precursor of ovarian follicles.
Granulosa cells are formed.

Question 11

3 - What happens to the Mesonephric cells?

Answer 11

These originate in the mesonephric primordium which are just lateral to the genital ridges.

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)
* Basement membrane – contributing to formation of seminiferous tubules and rete-testis
In females without the influence of SRY they form…
* Vascular tissue
* Theca cells

Question 12

How does male external genitalia form?

Answer 12

Testosterone is converted into a more potent androgen, Dihydrotestosterone (DTH) by 5-a- reductase.
DHT differentiates to male genitals.
- clitoral area enlarges to penis
- labia fuse to become ruggated to form scrotum
- prostate forms

Question 13

What is Gonadal Dysgenesis?

Answer 13

• sexual differentiation is incomplete.
• missing SRY in males
• Partial/complete deletion of second X in females
• General abnormal gonadal development

Question 14

What is sex reversal?

Answer 14

Phenotype doesn’t match genotype.

Question 15

What is intersex?

Answer 15

• Ambiguous genitals
• Patients prefer - Disorder of Sexual Differentiation - DSD

Question 16

What is Androgen Insensitivity Syndrome?

Answer 16

XY - testosterone made, no effect
- Testes form + Male AMH so Mullerian
duct regress.
- No differentiation of wolffian ducts
- feminine / ambiguous external genitalia
* Complete AlS - incidences1:20,000

Appear completely female at birth
despite being Xy - undescended testes.

Diagnosis:
- Amenorrhoea - no periods
- lack of- body hair
- ultra sound scan,
-Karyotype with male levels of androgens
- Never responds to androgen
appear + feel female
* Partial AIS
= incidence unknown -spectrum
- varying degrees of penile + scrotal
development
- Surgery was universal a now optional

Question 17

What is 5-a-reductase deficiency?

Answer 17

XY -> Testosterone is made, not DHT
* Testes form + AMH > Mullerian duct regress
- wolffian duct develops
- feminine / ambiguous external genitallia
Incidence varies -> autosomal recessive
- Testes form, AMH act, testosterone act
- Internal structure form.
- External structures do not develop.
-May appear Mainly female/ ambiguous genitalia.
- Degree of enzyme block varies = does presentation
Puberty: Assess potential as high testosterone levels - occur at adrenarche and puberty may include virilisation.

Question 18

What is Turner Syndrome?

Answer 18

XO ->
* Ovaries
- Mullarian duct, - no AMH
- No wolffian duct
- Externally female
Incidence:1: 3000
- X0 has failure of ovarian function
- (streak’ ovaries, = ovaries dysgenesis -
need 2xs for ovarian development.
- Uterus and tube present, but maybe small.
- May be fertile -> many have mosaicism
Some cells have XX and others XO - severity depends on which stage of development the second X was lost.
Earlier = severe
Explains huge variation.

Question 19

What is Congenital Adrenal Hyperplasia?

Answer 19

XX - exposed to high androgen in utero.

Sex hormones are made from cholesterol. To make mineralocorticoids, you need to convert cholesterol into progestogen. Then process it in smooth ER. It requires 21-Hydrooxylase to convert progestogen to corticoids.

The corticotrophin releasing hormone simulates the pituitary to secrete ACTH.
Adrenocorticotrophic hormone stimulates rapid uptake of cholesterol into adrenal cortex. This increases glucocorticoiid secretions.

The increased production of cortisol maintains a negative feedback loop to inhibit production.
No SRY so no testes and no AMH.
Mullerian ducts remain.
Masculinised external genitalia, but androgen levels not usually high enough to fully rescue Wolffian ducts.

Completeness of the block varies.
If enzyme absent then children may be wrongly gender assigned at birth, or may have ambiguous genitalia.
Also in CAH we need to be aware of possibility of ‘salt-wasting’ due to lack of aldosterone, this can be lethal.
Often require treatment with glucocorticoids to correct feedback.

Question 20

What happens when Adrenal glands can’t make cortisol?

Answer 20

Increase in ACTH increases cholesterol side-chain cleavage enzyme.

Progestegens increasing = metabolised to androgen.

Results:
- No SRY = no testes or AMH
- Mullerian duct remains
- Masculinised external genitalia, but androgen levels not usually high enough to fully rescue Wolfian duct.

Incidence: 1:15,000
- can be misgendered
- CAH - aware of posibility of ‘salt wastage’ due to lack of aldosterone = lethal

Treatment: Glucocorticoid to correct feedback.