Sexual differentiation and disorders

Question 1

Define sexual differentiation

Answer 1

The process of becoming either a boy or a girl in utiro

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

The two processes are contiguous and consist of several stages.

Question 2

What is sexual determination?

Answer 2

Genetically controlled process dependent on the ‘switch’ on the Y chromosome. Chromosomal determination of male or female. Y = male, absence of Y = female

Question 3

What are the various sexes involved in sex differentiation?

Answer 3

Here we have a 3-day old embryo. This has a genotypic sex; it is either XX or XY.

As the embryo develops it will have a gonadal sex – either have a pair of ovaries or a pair of testes. This is determined by the genotypic sex.

It also has a phenotypic sex (what its shape is, what it looks like, what form it takes) this is congregant with the gonadal sex most of the time.

Then we have a legal sex – marriage laws, football ect. Normally assigned a sex, but now you can change your legal sex if it didn’t fit in with your sexual identity

Gender identity is how the person feels.

Question 4

What gene creates the testes?

Answer 4

SRY gene creates the testis.

Question 5

When does SRY switch on?

When can ovaries form?

Answer 5

Sex determining region Y (SRY) switches on briefly during embryo development (>week 7) to make the gonad into a testis. In its absence an ovary is formed.

Question 6

What do the testes produce and what do they do?

Answer 6

Testis develops cells that make 2 important hormones which are anti-Mullerian hormone (AMH) and testosterone.

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

Question 7

What is the precursor of the pair of bipotential gonads that form after fertilisation?

Answer 7

Their precursor is derived from common somatic mesenchymal tissue precursors called the genital ridge primordia (3½ - 4½ weeks) on posterior wall of lower thoracic lumbar region.

Question 8

In a three week old embryo what can be seen?

Genital ridge, Wolffian duct and Mullerian duct

Answer 8

This is a 3-week old embryo, and the dotted line is the plane shown

The genital ridges will become the ovaries or the testes. At this point the embryos are biopotential, depending on the genes present.

Wolffian duct and Mullerian duct are shown. This forms the internal male genitalia and the Mullerian develops into the female genitalia.

Question 9

What are the cell types that form the gonads from the gential ridge?

Answer 9

The gonads form first – testes or ovaries form in the genital ridges in 3 waves:

Primordial Germ Cells – become Sperm (male) or Oocytes (female).

Primitive Sex Cords – become Sertoli cells (male – cells in the testes) or Granulosa cells (female – cells in the ovarian follicles). Both cells come from the same original cells.

Mesonephric Cells – become blood vessels and Leydig cells (male – androgens) or Theca cells (female). Origen’s are the same.

Question 10

Describe the process of primordial germ cell migration

Answer 10

These cells are diploid at this stage. They are expanding by mitosis.

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 on to the genital ridge – completed by 6 weeks.

Question 11

Describe the process of primitive sex cord (Sertoli/Granulosa) migration

Where do cells in the germinal epithelium migrate to?

Answer 11

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

Question 12

Compare and contrast sertoli and granulosa cells

Answer 12

On table

Question 13

Where are the Mesonephric cells located?

Answer 13

These are lateral to the genital ridges

Question 14

Where do the Mesonephric cells originate from?

Answer 14

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

Question 15

What do Mesonephric cells form in males and females?

Answer 15

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 – these may secrete some androgens or testosterone

Question 16

Summarise what the 3 cell types form in males and females

Answer 16

On table

As the primitive sex cords move inwards, they start on the surface on the genital ridge to find the primordial germ cells. These sex cords form long tubes with the primordial germ cells inside them, foreshadowing what the testes look like.

In females as the granulosa cells invade, they don’t form long tubule like structures they form clusters around the primordial germ cells, foreshadowing the presence of the primordial follicles that will be present in the ovaries.

Question 17

In males and females respectively what do the hormones the gonads produce cause?

What does the W and M ducts form?

Answer 17

The male gonad is making testosterone and AMH. This means in the male the Mullerian duct regresses, because the male is producing AMH, so the Mullerian duct will grow unless AMH is present: which causes it to regress. The Wolffian duct will regress unless there’s testosterone present

In the female there is no testosterone or AMH. So, the Mullerian duct is going to grow because there is no AMH present, and the Wolffian duct is going to regress because there is no testosterone present.

Mullerian ducts:

most important in female

inhibited in the male by AMH

Wolffian ducts:

most important in the male stimulated by testosterone

lack of stimulation by testosterone means regression in female

The wolffian duct will grow into the epididymis, vas deferens (tube from testes), part of prostate

The Mullerian duct will develop into uterine tubes, uterus and part of the vagina due to those chemicals all involved.

Question 18

In a young foetus, we have genitalia that can form a man or women. In this area of the genital skin, there is an enzyme called 5 alpha reductases in males and females.

What does this ennzyme do?

Answer 18

Testosterone is converted in the genital skin to the more potent androgen DHT (dihydrotestosterone) by 5-a-reductase. Dihydrotestosterone is much more potent than testosterone (10 times).

Question 19

What does DHT do?

Answer 19

DHT binds to the testosterone receptor but is more potent than testosterone.

DHT causes differentiation of the male external genitalia:

Clitoral area enlarges into penis
Labia fuse and become ruggated to form scrotum
Prostate forms

In females there is the enzyme, but no testosterone.

Question 20

Give a summary of the undifferentiated gonads

Answer 20

On diagram

Question 21

What are these disorders of sexual differentiation?

Gonadal dysgenesis

Sex reversal

Intersex

Answer 21

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 22

What happens if in an XY individual…

Testosterone is made but has no effect.

What is this called and what does it cause?

Answer 22

Androgen insensitivity syndrome (AIS)

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Question 23

What is the incidence level of AIS?

How do we diagnose AIS?

What occurs in partial AIS?

Answer 23

Complete AIS - incidence 1:20,000

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 - incidence unknown as is probably a spectrum

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 in an XY individual…Testosterone is made but not DHT?

What is it called and what does it cause?

What happens at puberty?

Answer 24

5-α-reductase deficiency

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Need to assess potential as high testosterone level which will occur at adrenarche (first indicators of puberty) and puberty may induce virilisation.

Question 25

What causes Turner syndrome?

Answer 25

Ovary

Yes -no AMH

No – no testosterone

Female

This is called turner syndrome…

Turner syndrome: 1:3000

XO have failure of ovarian function.

‘Streak’ ovaries = ovarian dysgenesis - illustrates that we need 2 X’s for ovarian development. There are som pseudo autosomal regions on the other X – they are expressed which help the other X for normal ovarian development

Uterus and tubes are present but small, other defects in growth and development.

May be fertile…many have mosaicism.

Hormone support of bones and uterus

Question 26

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

Answer 26

Congenital adrenal hyperplasia

Question 27

Describe the steroid synthesis pathway

Answer 27

Cholesterol – it has 3 six sided rings and 1 5 sided rings and a carbon chain on the end. It is the precursor of all the steroids. If we clip the carbon chain – so we only have 21 carbons, then we have a progestogen (lots of them). They have slightly different structures.

If we clip of another 2 carbons, we get the androgens. I.e 19 carbons. You get different types again with these.

If we clip off 1 more carbon atom, then we get 18 and get the oestrogens. You get different types again.

We also have 21 carbon progesterone which are slightly more complex. These are the mineralocorticoids and glucocorticoids. This represents adrenal gland activity. We need 21-Hyrooxylase for this.

Question 28

If we don’t have 21 hydroxylase we cannot produce adrenal hormones, what effect does this have?

Answer 28

Reduced production of cortisol

Question 29

Give an overview of the hypothalamic Pituitary Adrenal Axis

Answer 29

On image

Question 30

What does Corticotropin releasing hormone and Adrenocorticotropic hormone do?

Answer 30

Corticotropin releasing hormone

Stimulates pituitary to secrete ACTH.

Adrenocorticotropic hormone

Stimulates rapid uptake of cholesterol into the adrenal cortex.

Upregulates cholesterol side-chain cleavage enzyme (P450scc). Increases glucocorticoid secretion.

Question 31

What happens if we can’t produce cortisol?

Answer 31

If we can’t produce cortisol progesterone’s increase and get metabolised to androgens, we get a huge build up. So, we now have a female producing lots of androgens

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