lecture 22: diseases and disorders 1: human sex differentation Flashcards Preview

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Flashcards in lecture 22: diseases and disorders 1: human sex differentation Deck (19):

What are disorders of sexual differentiation (DSD)?

  • discordance between any aspect of sexual phenotype 
    • genetic sex 
    • gonadal sex 
    • phenotypic sex
    • brain sex 


What is discordance of genetic sex?

  • XY females 
  • XX males
  • ~15% of XY females have SRY mutation 
  • ~80% of XX males are SRY positive 
  • XXY Kleinfelters (1:1000) (Downs is 1:1250)
    • frontal baldness absent 
    • tendency to grow fewer chest hairs
    • breast development 
    • female-type pubic hair patter 
    • small testicular size 
    • poor beard growth 
    • narrow shoulders 
    • wide hips
    • long legs 
  • XO Turners (1:2500) 
    • short stature 
    • low hairline
    • characteristic facial features 
    • fold of skin on neck
    • constriction of aorta 
    • shield-shaped thorax 
    • poor breast development 
    • widely spaced nipples 
    • elbow deformity 
    • shortened metacarpal IV 
    • rudimentary ovaries gonadal streak (underdeveloped gonadal structures)
    • small finger nails
    • brown spots (nevi)
    • no menstruation
  • Single X required for normal male development 
  • 2 X chromosomes needed for normal female development 
  • small % of genes escape X-inactivation and X-imprinted genes 
  • SRY gene is right next to the pseudoautosomal region → occasionally gets switched across to X chromosome 


What is the SRY switch gene?

  • single exon gene 
  • high mobility group box (HMG box) 
  • binds to DNA and bends it 
  • structural protein 
  • POORLY conserved (~60% marsupial/human) 
  • expressed in brain and testes


What is the testis determinant?

  • SOX9
  • SRY-like HMG-box containing gene #9
  • mutations throughout the gene
  • HIGHLY conserved between species (more than 90%) 
  • expressed in developing cartilage and testes 
  • autosomal - needed in both male and female 
  • sox9 is necessary and sufficient to drive testicular development in mammals


What is the sox9 promoter?

  • SRY binds to elements in promoter to turn on Sox9
  • can then autoregulate (same DNA binding region) 
  • very hard to switch off once on 


What is discordance of phenotypic sex?

  • external genitalia = most common


What is hypospadias?

  • ectopic placement of urethral opening 
  • most common birth defect 
    • affects 1/125 live males births in Victoria 
  • increased by 50% in past 40 years – and still 1% PA in WA
  • Low T
  • excess E
  • early androgen priming
  • surgical repair 
  • endocrine disruption 


What are disorders of internal reproductive tract?

  • hermaphroditism (v rare) vs pseudohermaphroditism 
  • AMH or AMH-receptor inadequacy 
    • persistent mullerian duct syndryom (PMDS)
    • failure of testicular descent 
  • defects in steroidogenesis or androgen action
    • various phenotypes 
    • congenital adrenal hyperplasia (CAH)
    • androgen insensitivty (CAIS/PAIS) 
    • 5alpha-reductase deficiency (5ARD) 


What is failure of testicular descent?

  • 1:100 boys
  • 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 degrees C cooler 
  • failure of descent (Cryptorchidism)
    • no sperm production 
    • high risk of testicular cancer 


What is persistant mullerian duct syndrome?

  • incidence unknown (rare) 
  • affects genetic males 
  • autosomal recessive; mutations
    • AMH
    • AMHR
  • almost always cryptorchid


What is congenital adrenal hyperplasia?

  • autosomal recessive inheritance 
  • defect in 21-hydroxylase gene (P450c21) 
  • reduced cortisol (therefore increased ACTH) and aldosterone 
  • increased adrenal androgen secretion 
  • affected female foetus is masculinised 
  • but phenotype is intersex 
  • genital surgery → female appearance 


What are examples of genetic females with CAH?


What is complete androgen insensitivity syndrome?

  • complete AIS
  • laboratory 
    • 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 
    • ?effect on gonads and urogenital system?
  • clinical 
    • relatively tall, with normal breast development 
    • absent or sparse body hair 
    • no uterus (therefore no menses) 
    • short vagina 
    • inguinal/abdominal testes
    • partial forms have reduced AR activity or androgen synthesis and intermediate phenotypes 


What is 5alpha-reducatase deficiency?

  • clinical: present as females at birth
  • puberty – masculinization of body, clitoral enlargement, male pattern body hair 
  • Lab: 5AR mutation 


How does gender identity develop?

  • bee (1998) suggests 3 stages:
    • gender identity: 1-3 years 
    • gender stability: 3-4 years 
    • gender constancy: 5-6 years
  • gender identity is distinct from homosexuality (men still identify as men, women as women) 


Can you brothers make you gay?

  • best established influence in sexual orientation research
    • fraternal birth order effect 
  • each additional older brother increases odds of homosexuality by 33%
  • effect restricted to biological older brothers, and not the number of older brothers you grow up with 
  • only true for right-handed homosexual men 
  • confirms sexual orientation before birth 


What is gender dysphoria?

  • beyond homosexuality (men still identify as men; women as women) to cognitive ≠ biological sex
  • cross dressing 
  • transsexuality 
  • gender identity disorder (GID) 
  • hormones and sex reassignment surgery 
  • other gender variant issues 


Who is the genderless child?

  • couple decided not to reveal their baby's gender to the world so they would not be influenced by society's prejudices and preconceptions 
  • only allowed to play with "gender-neutral toys"
  • for the first five years of life alternated between girls' and boys' outfits 
  • mother said that she thought gender stereotyping was "fundamentally stupid" 
  • why would you want to slot people into boxes?



  • DSDs are very common 
  • sex is complex and requires coordination of several systems, genetic and physiological cues 
  • puzzling because it is the most fundamental character 
  • variation in sex in other animals