1- Sexual Determination And Disorders

Question 1

What is sexual determination?

Answer 1

Genetically controlled process dependent on the switch on the Y chromosome
Chromosomal determination of male and female
Male- XY
Female- XX

Question 2

What is sexual differentiation?

Answer 2

The process by which internal an external genitalia develop as male and female

Question 3

How is gonadal sex determined?

Answer 3

Sex determining region Y (SRY)switches on after week 7 of embryo development
gonad turns into testis
testis develop and produce AMH and testosterone

Question 4

What is the precursor for gonadal development?

Answer 4

The gonadal ridge

Question 5

What are the 3 waves of cells that invade the genital ridge?

Answer 5

Primodal Germ cells - sperm/ oocytes
Primitive sex cords - Sertoli cells (male)/ granulosa cells (female)
Mesonephric Cells - blood vessels and Leydig cells (male) / theca cells (female)

Question 6

What is the process of sexual differentiation?

Answer 6

genotypic sex ( xy/xx)
gonadal sex (ovaries/testis)
phenotypic sex (genitalia)
legal sex
gender identity

Question 7

What are the two ducts present in the embryo before sex determination

Answer 7

Mullerian duct - female
Wolffain duct - male

Question 8

What does the term bipotential mean in relation to the gonads?

Answer 8

They are able to differentiate into either testis or ovaries

Question 9

Describe primordial germ cell migration

Answer 9

An initially small cluster of cells in the epithelium of the yolk sac expands by mitosis at around 3 weeks
They then migrate to the connective tissue of the hind gut, to the region of the developing kidney and in to the genital ridge
This process is completed by 6 weeks

Question 10

Describe the formation of the sex cords

Answer 10

Cells from the germinal epithelium that overlies the genital ridge mesenchyme migrate inwards as columns called the primitive sex cords

Male-
- there’s SRY expression
- penetrate medullary mesenchyme & surround primordial germ cells to form testis cords – precursor of seminiferous tubules.
- eventually become Sertoli cells that express AMH.

Female-
- there’s no SRY expression
- sex cords ill defined and do not penetrate deeply but instead condense in the cortex as small clusters around primordial germ cells – precursor of ovarian follicle
- eventually become granulosa cells

Question 11

Describe the role of mesospheric cells in gonadal development

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

What do primordial cells become in males and in females?

Answer 12

Males: spermatozoa
Females: oocytes

Question 13

What do the primitive sex cords become in males and in females?

Answer 13

Males: Sertoli cells (express SRY and produce AMH)
Females: Granulosa cells

Question 14

What do mesonpheric cells become in males and in females?

Answer 14

Males: Leydig cells (produce androgens- testosterone)
Females: Theca cells

Question 15

What are the 2 main internal ducts that develop into internal reproductive organs?

Answer 15

Mullerian ducts:
- most important in females
- inhibited in the male by AMH

Wolffian ducts:
- most important in males
- stimulated by testosterone
- lack of stimulation by testosterone means regression females

Question 16

How does internal sexual differentiation occur?

Answer 16

Males:
- AMH secreted by Sertoli cells regresses the Mullerian duct
- testosterone secreted by the Leydig cells grows the wolffian duct

Females:
- no AMH so Mullerian duct grows
- no testosterone so wolffian duct regresses
- Mullerian duct develops into uterine tubes, uterus and part of the vagina

Question 17

What is function of 5-alpha reductase in external differentiation?

Answer 17

It converts testosterone in the genital skin to the more potent DHT (dihydrotestosterone)

Question 18

What is the function of DHT?

Answer 18

DHT binds to the testosterone receptor, but is more potent that testosterone
DHT causes differentiation of the male external genitalia:
- Clitoral area enlarges into penis
- Labia fuse and become ruggated to form scrotum
- Prostate forms

Question 19

What is the function of 5- alpha reductase in females?

Answer 19

5- alpha reductase is present but there is no testosterone to be converted to DHT
Therefore no differentiation of external genitalia into male genitals

Question 20

What are the different types of sexual differentiation disorders?

Answer 20

Gonadal dysgenesis:
- Sexual differentiation is incomplete.
- Usually missing SRY in male, or partial or complete deletion of second X in female.
- Also used as a general description of abnormal development of the gonads.

Sex Reversal:
- Phenotype does not match genotype, ie may be male genotypically but externally look like a female.

Intersex:
- Have some components of both tracts or have ambiguous genitalia. Sex of infant difficult to determine.

Question 21

What happens when an XY individual has testosterone but it has no effect?

Answer 21

• gonadal dysgenesis disorder
• it is known as androgen insensitivity syndrome (AIS)

Question 22

What happens in individuals of AIS?

Answer 22

• AIS: androgen insensitivity syndrome
• Testes form and make AMH so Mullerian ducts regress.
• No differentiation of Wolffian ducts
• No external male genitalia

Question 23

What are the differences between partial and complete AIS?

Answer 23

Complete AIS:
- Appear completely female at birth and assigned female gender despite being XY.
- Have undescended testes.

Diagnosis:
- Usually present with primary amenorrhoea. Lack of body hair is a clue.
- Ultrasound scan and karyotype with male levels of androgens.
- Never responded to androgen so appear and often feel female.

Partial AIS:
- Present with varying degrees of penile and scrotal development from ambiguous genitalia to large clitoris.
- Surgery was universal but now fortunately considered optional or at least best delayed. Decisions made on potential. Very difficult for parents.

Question 24

What happens if an XY individual testosterone is made but its not converted into DHT?

Answer 24

• gonadal dysgenesis
• 5- alpha reductase deficiency syndrome

What happens?
- Testes form and make AMH so Mullerian ducts regress.
- Wolffian ducts develop
- No external male genitals

Question 25

Describe 5- alpha reductase deficiency syndrome

Answer 25

Incidence varies enormously as autosomal recessive and can depend on inter-related marriage.

• Testes form, AMH acts, testosterone acts.
• Internal structures form.
• External structures do not develop.

May appear mainly female or may have ambiguous genitalia
The degree of the enzyme block varies and so therefore does the presentation

Question 26

How is 5-alpha reductase definecy diagonised?

Answer 26

Need to assess potential as high testosterone level which will occur at adrenarche and puberty may induce virilisation.

Question 27

What is Turner syndrome?

Answer 27

It is when an individual has the chromosome XO.

They have a failure of ovarian function. They have what are called ‘streak’ ovaries, which are a form of ovarian dysgenesis. It illustrates that we need 2 X’s for proper ovarian development.

The uterus and tubes are present but other, small defects in growth and development may be present. There may be a need for steroid hormone support of the bones and uterus.

Question 28

What happens if XX female is exposed to high levels of androgens in utero?

Answer 28

• gonadal dysgenesis
• congenital adrenal hyperplasia

What happens?
- 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.

Question 29

How would an XX female be exposed to high levels of androgens in utero?

Answer 29

There could a failure of the enzyme 21-hydroxylase which converts steroid hormone precursors, to eventually end up as cortisol and aldosterone. This means that there will be a build up of precursors, which will be ushered along to make more androgens.

Also, in the event of the lack of negative feedback from cortisol/aldosterone, more cholesterol will be pushed into steroid genesis for more cortisol/aldosterone, which worsens the situation.

Question 30

Describe the effects of congenital adrenal hyperplasia (CAH)

Answer 30

The completeness of the enzyme (21-hydroxylase) block varies.

If the enzyme is absent, then children may be wrongly gender assigned at birth, or may have ambiguous genitalia.

There needs to be treatment with glucocorticoids to correct the feedback.

Also, in CAH, we need to be aware of the possibility of ‘salt-washing’ due to the lack of aldosterone; this can be lethal.