Disorders of Sexual Differentiation

Question 1

Define 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

Define Sex Reversal

Answer 2

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

Question 3

Define Intersex

Answer 3

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

Question 4

What is Androgen Insensitivity Syndrome (AIS)

Answer 4

In an XY individual, testosterone is made but has no effect – testosterone receptor is not responding.

Testes form and make AMH so mullerian ducts regress.
No differentiation of Wolffian ducts.
No external male genitalia.

Complete AIS (46XY)
• Undescended testes.
• No uterus or fallopian tubes
• External genitalia appear female - abbreviated blind vaginal pouch.
• Usually present with primary amenorrhoea. Lack of body hair is a clue.
• Ultrasound scan and karyotype with male levels of androgens.
• Hormonal puberty may be feminizing without intervention due to aromatization of endogenous androgens to oestrogens. Lacking response to androgen.
• Sex assignment and rearing almost always female.
• Differentiation of gender role and identity usually feminine.
• In adulthood, sexuality often conforms to typical heterosexual female expectations.

Partial AIS (46XY)
•	Spectrum of phenotypes including almost normal female external genitalia through ambiguous genitalia (perineoscrotal hypospadias, microphallus, cryptorchidism).
•	Minor genital deviations go unnoticed or may be surgically repaired.
•	At puberty development of male secondary characteristics may not be very pronounced.  In some cases pubertal gynecomastia (androgen/estrogen ratio) or ambiguous genitalia surgically corrected.  Androgen therapy in some cases.
•	Majority of individuals develop an identity commensurate with their assigned gender - around 20% desire to change gender usually in adolescence or adulthood

Question 5

What is Persistent Mullerian Duct Syndrome

Answer 5

an XY male is unable to make OR respond to AMH in utero

PMDS type I results from mutations of the gene for AMH on chromosome 19.

PMDS type II results from mutations of the gene for AMH receptor (AMH-RII) on chromosome 12.

Both autosomal recessive conditions with expression usually limited to XY offspring

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

Common presentation
• 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.

Treatments
• Surgery (orchiopexy) 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 6

What is 5-α-reductase deficiency

Answer 6

an XY individual – testosterone is made but not DHT

Testes form and make AMH so Mullerian duct regress.
Wolffian ducts develop.
No external male genitalia.

(46XY)
• Testes form, AMH acts, testosterone acts. Internal structures form. External male structures do not fully develop.
• May appear mainly female or may have ambiguous genitalia such as labioscrotal folds or clitoridean penis. The degree of the enzyme block varies and so therefore does the presentation.
• 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 7

What is Turner Syndrome

Answer 7

45 XO
• XO have failure of ovarian function.
• ‘Streak’ ovaries is a form of ovarian dysgenesis - illustrates that we need two X’s for ovarian development.
• Uterus and tubes are present, females may be small or other defects in growth and development. Wide spectrum of phenotypic disorders and severity.
• May be fertile, many have mosaicism. Female gender.
• Hormone support of bones and uterus.

Question 8

What is Congenital adrenal hyperplasia

Answer 8

Imagine baby in womb, on top of those tiny kidneys are tiny adrenal glands and inside them: this enzyme(21-hydroxylase) not working thus progestogens start building up
• decrease in cortisol = decrease in negative feedback = increase in ACTH stimulation = increase in testosterone

ACTH Causes more cholesterol to be taken up thus more progestogens to be made. Therefore 17, 20 lyase starts converting them into testosterone and other androgens (As unable to convert to cortisol and aldosterone).

If the baby is a girl; adrenal gland starts producing testosterone which shouldn’t be happening as they have no y chromosome; they still have an ovary.

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.

• Completeness of the enzyme block varies. May have developed Wolffian structures and ambiguous masculinised external genitalia or hirsutism (hairy) .
• Early studies suggested that XX patients assigned as girls developed female gender identity, but with more masculine childhood behaviour and lower maternal interest as adults.
• Also in CAH need to be aware of possibility of ‘salt-wasting’ due to lack of aldosterone, this can be lethal.

• Treatment with glucocorticoids to correct feedback.