W8L2 Tues Differences in sexual differentiation

Question 1

what is differences in sexual differenciation

Answer 1

• Discordance between any aspect of sexual phenotype
  – Genetic sex
  – Gonadal sex
  – Phenotypic sex
  – Brain sex

Question 2

Discordance of Genetic Sex

Answer 2

§ XY females: ~15 % have SRY mutation (SRY gene for male sex development), others have Sox9 mutation
§ XX males: ~80% are SRY positive (spermatogenesis genes left behind on Y chromosome = infertile)
§ Klinefelter syndrome (XXY): males, tall stature + slightly feminised physique
Ø 1 X must be inactivated but small % genes escape X-inactivation + X-imprinted genes
§ Turner’s syndrome (XO): females missing an X chromosome, short stature + infertile

Question 3

Gonadal Sex: SRY switch gene

Answer 3

§ SRY gene: single point mutations can prevent male development, a single exon gene
Ø High mobility group (HMG) box: binds to DNA + bends it to allow contact with various factors
§ Where most point mutations occur
Ø Poorly conserved gene across mammals, expressed in brain + testes

Question 4

SOX9 – the testis determinant

Answer 4

§ SOX9 gene: autosomal, expressed in developing skeleton, brain, cartilage + testes
Ø Mutations occur throughout gene (SRY-like with HMG-box)
Ø Highly conserved b/w species >90%
Ø Upregulation of SRY → SRY HMG box binds to SOX9 promoter → drives expression of SOX9 → SOX9 HMG box binds to SOX9 promoter → more SOX9 (drives testes formation)

Question 5

Discordance of Phenotypic Sex: hypospadias

Answer 5

§ Hypospadias: ectopic placement of urethral opening affecting 1/125 live male births + ↑50% in past 40 years
Ø Fertilisation issues, abnormal patterning of erectile tissue
Ø Cause: low testosterone, excess oestrogen exposure (BPA)
Ø Formation relies on early androgen priming + phenotype can be surgically repaired

Question 6

Hermaphrodism and psuedohermaphrodism and their cause

Answer 6

§ Hermaphroditism: wolffian duct + Mullerian duct present, very rare
§ Pseudohermaphroditism: some male + female traits in ducts
-Caused by AMH/AMHR inadequency, defect in steroidogenesis or androgen action

Question 7

Defects in steroidogenesis or androgen action

Answer 7

– congenital adrenal hyperplasia (CAH)
– androgen insensitivity (CAIS/PAIS)
– 5α-reductase deficiency (5ARD)

Question 8

AMH/AMH-receptor inadequacy

Answer 8

§ AMH/AMH-receptor inadequacy affects males – prevents Mullerian duct regression = develops into uterus/fallopian tubes/upper part of vagina + male tissues from Wolffian duct
Ø Persistent Mullerian duct syndrome (PMDS): affects XY males, autosomal recessive, mutations in AMH or AMHR, testes almost always undescended (connected to female tissues)

Question 9

Testicular descent

Answer 9

• testes migrate (descend) from abdomen to scrotum via inguinal canal
  – androgens, INSL3 and AMH from testes
  – CGRP from the genitofemoral nerve
• scrotal location  2-3°C cooler
• failure of descent (cryptorchidism)
  – no sperm production
  – high risk of testicular cancer

Question 10

Persistent Müllerian Duct Syndrome

Answer 10

• Incidence unknown (rare)
• Affects genetic males (XY – SRY +ve)
• Autosomal recessive; mutations in
  – AMH
  – AMHR
• Have testes (XY)
• Almost always cryptorchid

Question 11

Congenital adrenal hyperplasia

Answer 11

• Autosomal recessive inheritance ~1:10,000
• Defect in 21-hydroxylase gene (P450c21)
• Reduced cortisol (∴ ↑ ACTH ) and aldosterone
• Increased adrenal androgen secretion
• Affected female foetus is masculinized
• But phenotype is intersex
• Genital surgery → female appearance

Question 12

Complete androgen insensitivity syndrome

Answer 12

Ø Complete androgen insensitivity syndrome (CAIS): XY karyotype, AR gene mutation = unable to sense testosterone, high LH + T (feedback system), no wolffian or Mullerian ducts, short vagina, inguinal/abdominal testes

Question 13

Androgen insensitivity syndrom diagnosis

Answer 13

• XY karyotype (SRY positive)
• AR gene mutation usually detected (allows carrier identification, prenatal diagnosis)
• Adult blood levels: high LH and T, slightly high FSH.
• Oestradiol level higher than normal male, less than adult female

Question 14

5α-reductase deficiency

Answer 14

XY karyotype, 5a-reductase (DHT) insufficient to masculinise prepuberty (female appearance), Present as females at birth
puberty – testes release lots of T = sufficient to masculinise. turn from male to female after puberty

Question 15

Brain sex

Answer 15

§ Gender identity development: gender identity (1-3yrs), gender stability (3-4yrs), gender constancy (5-6yrs)
§ Homosexuality: each additional older brother ↑odds of homosexuality by 33% (for biological brother and right hand)
Ø Mothers develop antibodies to foetal testosterone = affects brain sex patterning
Ø No gay gene – polygenetic trait

Question 16

what is gender dysphoria

Answer 16

brain sex not same as biological sex
Ø Transsexuality, gender identity disorder (GID), sex reassignment surgery, hormones