REPRO: Sexual Differentiation and Disorders

Question 1

What is sexual determination?

Answer 1

It is a genetically controlled process dependant on the ‘switch’ on the Y chromosome. Chromosomal determination tells you if you’re male or female.

Question 2

What is sexual differentiation?

Answer 2

It is the process by which internal and external genitalia develop as male or female.

Question 3

What are the different levels of sexual differentiation, from embryo to adult?

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 gene is a transcription factor that transcribes itself (positive feedback), along with a transcriptional cascade of events that eventually leads to the development of a testis. In the absence of this gene, ovaries develop.
SRY is the triggering event for sexual differentiation.

The testis develops cells that make 2 important hormones:

• SERTOLI cells produce anti-Mullerian hormone (AMH)
• LEYDIG cells make testosterone

Products of the testis influence further gonadal and phenotypic sexual development.

Question 5

Describe gonadal development after fertilisation.

Answer 5

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

Their precursor is derived from common somatic mesenchymal tissue precursors called the genital ridge primordia (3.5 to 4.5 weeks) on the posterior wall of the lower thoracic lumbar region.

Question 6

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

Answer 6

1. Primordial Germ Cells - become sperm (male) or 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 7

Describe primordial germ cell migration.

Answer 7

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 8

Describe the formation of the sex cords (Sertoli/Granulosa).

Answer 8

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

In MALES:

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).

In FEMALES:

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 9

Describe the role of mesonephric cells in gonadal development.

Answer 9

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 10

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

Answer 10

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 11

Describe the role of 5-α-reductase in external differentiation.

Answer 11

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 but 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 12

List some disorders of sexual differentiation.

Answer 12

• gonadal dysgenesis: sexual differentiation is incomplete; also used as a general description of the abnormal development of the gonads
• sex reversal: phenotype not matching the genotype
• intersex: have some components of both tracts, or have ambiguous genitalia

Question 13

What is it called when testosterone is being made in an XY individual, but it has no effect?

What does that result in?

Answer 13

Androgen Insensitivity Syndrome (AIS).

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.

Question 14

What’s the difference between complete and partial AIS?

Answer 14

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 is a clue
• 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 ambiguous genitalia to large clitoris
• surgery was universal, but now fortunately considered optional (at least best, delayed)
• decisions made on potential, very difficult for parents

Question 15

What is it called when testosterone is made in an XY individual, but not DHT?

What does that result in?

Answer 15

5-α-reductase Deficiency.

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

Question 16

Describe 5-α-reductase deficiency.

Answer 16

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 17

Describe Turner Syndrome.

Answer 17

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 18

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

What does that result in?

Answer 18

Congenital Adrenal Hyperplasia (CAH) is the most common cause.

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 19

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

Answer 19

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 20

Describe the effects of Congenital Adrenal Hyperplasia (CAH).

Answer 20

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.