Sexual differentiation and disorders

Question 1

What is sexual determination?

Answer 1

A genetically controlled process dependent on the ‘switch’ on the Y chromosome - determines if you are male or female

Question 2

What is sexual differentiation?

Answer 2

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

Question 3

What are different levels of sexual differentiation?

Answer 3

• genotypic sex (if the embryo has XX or XY)
• gonadal sex (either ovaries or testes develop)
• phenotypic sex (outward appearance)
• legal sex (what’s written on the passport)
• gender identity (how you feel)

Question 4

Describe how the SRY gene is involved in gonadal development

Answer 4

The SRY is a transcription factor that transcribes itself, along with a transcriptional cascade of events that eventually leads to the development of a testis.

If this gene is absent, ovaries will develop

Question 5

What do Sertoli cells produce?

Answer 5

Anti-Mullerian hormone (AMH)

Question 6

What do Leydig cells produce?

Answer 6

Testosterone

Question 7

Describe gonadal development after fertilisation

Answer 7

After fertilisation, a pair of gonads develop which are bipotential.

Their precursor is derived from common somatic mesenchymal tissue precursors called the genital ridge primordia on the posterior wall of the lower thoracic lumbar region

Question 8

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

Answer 8

1) Primordial Germ Cells (PGCs) - become sperm (male)/oocytes(female)
2) Primitive Sex Cords - become Sertoli cells (male) or Granulosa cells (female)
3) Mesonephric Cells - become blood vessels and Leydig cells (male) or Theca cells (female)

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 hindgut, to the region of the developing kidney and on to the genital ridge - completed by 6 weeks.

Question 10

Describe the formation of the sex cords (sertoli)

Answer 10

1. There is SRY expression
2. The sex chords penetrate the medullary mesenchyme and surround the PGCs to form the testis chords.
3. They eventually become Sertoli cells, which express anti-Mullerian hormone (AMH).

Question 11

Describe the formation of the sex cords (granulosa)

Answer 11

1. There is no SRY expression.
2. The sex chords are ill-defined and do not penetrate deeply, but instead condense in the cortex as small clusters around PGCs.
3. They eventually become Granulosa cells.

Question 12

Describe the role of mesonephric cells in gonadal development

Answer 12

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

In MALES, they act under the influence of pre-Sertoli cells to form:

• vascular tissue
• Leydig cells (synthesise testosterone, don’t express SRY)
• basement membrane - contributing to the formation of seminiferous tubules and rete-testis

In FEMALES, they form:

• vascular tissue
• Theca cells (synthesise androstenedione, which is a substrate for estradiol production by the granulosa)

Question 13

What are the two main structures involved in developing internal reproductive organs?

Answer 13

Mullerian ducts:

• most important in female
• inhibited in males by AMH

Wolffian ducts:

• most important in the male, stimulated by testosterone
• lack of stimulation by testosterone means regression in female

Question 14

Describe the role of 5-a-reductase in external differentiation?

Answer 14

Testosterone is converted to the more potent androgen DHT (dihydrotestosterone) by 5-α-reductase in the genital skin.

DHT also binds to the testosterone receptor and is more potent than testosterone.

DHT causes differentiation of the male external genitalia:

• clitoral area enlarges into the penis
• labia fuse and become ruggated to form the scrotum
• the prostate forms

It is present in both males and females, but because there is no substrate (testosterone) in females, its effects don’t play out.

Question 15

What is gonadal dysgenesis?

Answer 15

Sexual differentiation is incomplete; also used as a general description of the abnormal development of the gonads

Question 16

What is sex reversal?

Answer 16

The phenotype does not match the genotype

Question 17

What is intersex?

Answer 17

Have some components of both tracts/ambiguous genitalia

Question 18

What is androgen insenstivity syndrome?

Answer 18

Testosterone is being made in an XY individual, but has no effect

Question 19

What does AIS result in?

Answer 19

The testes form and make AMH so the Mullarian ducts regress. There is no differentiation of the Wolffian ducts, and thus no external male genitalia, so female external sex characteristics (only exposed to female hormones)

Question 20

What is the difference between complete and partial AIS?

Answer 20

Complete AIS:
- appear completely female at birth, and are assigned the female gender despite being XY

• usually present with primary amenorrhoea, lack of body hair
• would be diagnosed by ultrasound scan and karyotype with male levels of androgens
• would never respond to androgen so they appear and feel female

Partial AIS:
- present with varying degrees of penile and scrotal development, from micropenis to large clitoris

• surgery was universal, but now fortunately considered optional (at least best, delayed)
• decisions made on potential, very difficult for parents

Question 21

What is 5-a-reductase deficiency?

Answer 21

Testosterone is made in an XY individual, but not DHT

Question 22

What does 5-a-reductase deficiency result in?

Answer 22

The testes form and make AMH so the Mullerian ducts regress. The Wolffian ducts then develop, but there is no external male genitalia.

Question 23

Describe 5-a-reductase deficiency

Answer 23

The incidence varies enormously as it is autosomal recessive and can depend on inter-related marriage.

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

At puberty, you need to assess the potential as the high testosterone levels which will occur at adrenarche and puberty may induce virilisation.

Question 24

Describe Turner Syndrome

Answer 24

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 25

What is congenital adrenal hyperplasia?

Answer 25

An XX female is exposed to high levels of androgens in utero

Question 26

What does CAH result in?

Answer 26

No SRY is expressed, so we don’t get any testes or AMH. The Mullerian ducts remain. The individual ends up with masculinised external genitalia, but the androgen levels are not usually high enough to rescue the Wolffian ducts.

Question 27

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

Answer 27

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 28

Describe the effects of CAH

Answer 28

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.