Disorders of Sexual Differentiation

Question 1

What is gonadal dysgenesis?

Answer 1

• 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.

Question 2

What is sex reversal?

Answer 2

Phenotype does not match genotype, ie may be male genotypically but externally look like a female

Question 3

What is an intersex person?

Answer 3

They have some components of both tracts or have ambiguous genitalia. Sex of infant difficult to determine.

Question 4

What happens if in an XY individual testosterone is made but has no effect?

Answer 4

They have androgen insensitivity syndrome (AIS)

Question 5

What happens in complete androgen insensitivity syndrome?

Answer 5

• Testes form and make AMH so Mullerian ducts regress.
• DHT still made
• Androgen receptor does not detect androgens (testosterone and DHT)
• No differentiation of Wolffian ducts
• Undescended testes.
• No uterus or fallopian tubes
• External genitalia appear female - abbreviated blind vaginal pouch.
• Usually present with primary amenorrhoea (no period). Lack of body hair is a clue.
• Hormonal puberty may be feminizing without intervention due to aromatization of endogenous androgens to estrogens. Lacking response to androgen.

Question 6

What can help detect AIS?

Answer 6

Ultrasound scan and karyotype with male levels of androgens can help detect it.

Question 7

What is partial AIS and why does this happen?

Answer 7

• When the patients genitals appear ambiguous
• Spectrum of phenotypes including almost normal female external genitalia through ambiguous genitalia.
• Minor genital deviations go unnoticed or may be surgically repaired.
• At puberty development of male secondary characteristics may not be very pronounced – testosterone increase at puberty but not enough to fully develop male parts.

Question 8

What happens if XY male is unable to make or respond to AMH in utero?

Answer 8

They have persistent Mullerian duct syndrome.

Question 9

How does Persistent Mullerian duct syndrome (PMDS) happen?

Answer 9

• PMDS type I results from mutations of the gene for AMH on chromosome 19.
• PMDS type II results from mutations of the gene for the AMH receptor (AMH-RII) on chromosome 12.
• Both autosomal recessive conditions with expression usually limited to XY offspring

Question 10

What happens in PMDS?

Answer 10

• Testes form and either fail to make AMH or AMH receptor absent.
• Mullerian ducts remain.
• Differentiation of Wolffian ducts and masculinised external genitalia still happens

Question 11

What is the common presentation of PMDS?

Answer 11

• 60–70% of cases have intra-abdominal Mullerian structures and testes in a position simulating that of the ovaries
• 20–30% have one testis in a hernial sac or scrotum together with Mullerian structures.
• 10% have both testes located in the same hernial sac (transverse testicular ectopia) along with the uterine tubes and/or uterine structures.
• All have increased risk of malignant transformation.

Question 12

What are the treatments for PMDS?

Answer 12

• Surgery to retrieve the testes and position them in the scrotum. If testes cannot be retrieved, testosterone replacement at puberty is an option.
• Removal of uterus dissection of Müllerian tissue away from the vas deferens/epididymis.
• Laparoscopic hysterectomy may prevent the occurrences of neoplastic tissue formation.

Question 13

What happens if in an XY individual testosterone is made but not DHT?

Answer 13

They have 5-α-reductase deficiency

Question 14

What happens in 5-α-reductase deficiency?

Answer 14

• Testes form and make AMH so Mullerian ducts regress.
• Wolffian ducts develop
• No external male genitalia – ambiguous or female genitalia
• Need to assess potential as high testosterone level which will occur at adrenarche and puberty – may induce virilisation.
• Both testosterone and dihydrotestosterone (DHT) are capable of masculinising the brain in non-human primates so some brain masculinisation in utero possible with this condition.

Question 15

What is Turners syndrome?

Answer 15

• When there’s only one X chromosome
• Failure of ovarian function.
• Will have ‘Streak’ ovaries = ovarian dysgenesis - illustrates that we need two X’s for normal ovarian development.
• Uterus and tubes are present, may be small or other defects in growth and development. Wide spectrum of phenotypic disorders and severity.
• They have mosaicism if the X is lost later during development – some patients may still be fertile
• Hormone support of bones and uterus.

Question 16

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

Answer 16

Congenital adrenal hyperplasia

Question 17

What are all steroid hormones made of?

Answer 17

Cholestrol

Question 18

What’s the structure of cholesterol?

Answer 18

Cholesterol has three 6 sided rings, a 5 sided ring and a carbon chain – has 27 carbons in total

Question 19

How is pregnenolone and progesterone made?

Answer 19

• The carbon chain (containing carbons 22-27) is removed
• 17 alpha hydroxylase adds a hydroxyl group on carbon 17 – makes 17 hydroxyprogesterone
• Add oxygen to carbon 3 of pregnenolone – makes progesterone

Question 20

How are androgens made?

Answer 20

• If you take off carbons 21 and 20 off pregnenolone it makes androgens
• the difference between androgens in the placement of the oxygens and hydroxyls

Question 21

How are oestrogens made?

Answer 21

• Aromatase take off a carbon (carbon 19) from androgens to make oestrogens
• there’s types of oestrogens and they’re different due to whether they have hydroxyl groups and how many groups they have

Question 22

What are the different oestrogens?

Answer 22

• Oestrone (1 hydroxyl group)
• oestradiol
• oestratriol

Question 23

What are the sex hormones?

Answer 23

• Progesterogens, androgens and oestrogens

- made in the testis and ovaries

Question 24

Where are the adrenal glands found?

Answer 24

on top of the kidney

Question 25

What do adrenal glands make?

Answer 25

aldosterone and cortisol

Question 26

How are aldosterone and cortisol made?

Answer 26

• 21-hydroxylase is needed for the production of aldosterone and cortisol
• Progesterone made first before making aldosterone – it has 21 carbon atoms
• Cortisol is a glucocorticoid – 21 carbon atoms

Question 27

What does cortisol do normally?

Answer 27

• Gives negative feedback in the hypothalamic pituitary adrenal axis
• Normally Corticotropin releasing hormone is released by hypothalamus which stimulates pituitary to secrete ACTH
• ACTH stimulates rapid uptake of cholesterol into the adrenal cortex and upregulates cholesterol side-chain cleavage enzyme (P450scc).
• ACTH Increases glucocorticoid (cortisol) secretion.
• The cortisol then feeds back to the pituitary and hypothalamus

Question 28

How does congenital adrenal hyperplasia cause its symptoms?

Answer 28

• There’s no negative feedback
• Increased CRH and ACTH levels
• ACTH causes an upregulation of cholesterol side chain cleavage enzyme
• Progesterone levels rise
• They convert into androgens – androgens levels rise
• Build up and release of androgens as aromatase isn’t present in women until puberty either
• Adrenal glands get bigger trying to make cortisol and aldosterone

Question 29

Symptoms of congenital adrenal hyperplasia.

Answer 29

• No SRY so no testes and no AMH.
• Mullerian ducts remain.
• Masculinised external genitalia due to 5-alpha reductase making DHT from the androgens
• Androgen levels not usually high enough to rescue Wolffian ducts.
• Completeness of the enzyme block varies. May have developed Wolffian structures and ambiguous masculinised external genitalia or hirsutism.
• Possibility of ‘salt-wasting’ due to lack of aldosterone, this can be lethal.
• Treatment with glucocorticoids to correct feedback.