Embryology and Congenital Adrenal Hyperplasia

Question 1

Bipotential gonad differentiation into testis or ovary

Answer 1

• Most individuals are 46XX (female) or 46XY (female)
• Default state is female
  
  • Key to differentiation is Y chromosome **(SRY region) **–> testes-determining factor
• 5th week gestational age
  
  • Genital ridges (undifferentiated gonads) overlay mesonephric ducts (primordial kidney)
• 6th week gestational age
  
  • Primordial germ cells migrate from yolk sac –> genital ridges
    
    • Failure of migration –> streak gonads
    • Primitive sex cords continue to proliferate
• 7th week gestational age
  
  • Gonads undifferentiated and bipotential
• 8th week gestational age
  
  • Leydig cells start to secrete testosterone

Question 2

7th week gestational age: males

Answer 2

• SRY expression begins –> differentiation
• Sertoli cells make Anti-Mullerian Factor (AMF) –> Mullerian duct regression
• Spermatic cord development followed by seminiferous tubules & Leydig cell formation
• Medullary cords mature into testis cords

Question 3

7th week gestational development: females

Answer 3

• In absence of Y chromosome and SRY gene
  
  • Gonads develop into ovaries
• DAX-1 and WNT-1 cause ovary differentiation
• Medullary cords degenerate

Question 4

Internal ducts that differentiate in males and females

Answer 4

• Female
  
  • Mullerian/paramesonephric ducts
• Male
  
  • Wolffian/mesonephric ducts

Question 5

46, XY ductal development

Answer 5

• After testicular differentiation, fetal testes produce 2 substances critical for male development
  
  • Anti-Mullerian hormone (AMH)
    
    • Promotes regression of Mullerian structures
    • Produced by Sertoli cells
    • If not expressed before 8th week of gestation, no Mullerian regression will take place
  • Testosterone
    
    • Promotes development of Wolffian structures (male internal genitalia)
    • Produced by Leydig cells
    • In absence of high concentrations of T, Wolffian structures regress
• Wolffian structures become:
  
  • seminal vesicle, ejaculatory duct, epididymis, ductus deferens

Question 6

46, XX development

Answer 6

• In absence of testes –> no AMH, no testosterone production
• Mullerian structures develop into:
  
  • Paired Fallopian tubes
  • Midline uterus
  • Upper 1/3 of vagina

Question 7

Development of external genitalia

Answer 7

• Develop from sexually indifferent structures:
  
  • Genital tubercle –> precursor of penis or clitoris
  • Labial-scrotal folds –> precursor of scrotum or labia majora
  • Urethral folds –> precursor of penile urethra or labia minora

Question 8

Development of male external genitalia

Answer 8

• Dependent on testosterone and DHT
• Testosterone (5a-reductase) –> DHT
• DHT essential for penile growth & development of penile urethra
• Development complete by 13 weeks
  
  • Any defects occurring prior to 13 weeks cannot be corrected by subsequent androgen exposure

Question 9

Causes of disorders of sexual differentiation (DSDs)

Answer 9

• Occur as result of alterations in 3 main processes:
  
  • Gonadal differentiation
  • Steroidogenesis
  • Androgen action

Question 10

46,XX DSDs

Answer 10

• Most commonly manifests as congenital adrenal hyperplasia
  
  • Secondary to 21-hydroxylase deficiency –> directs steroidogenesis down androgen production path
  • Girls typically present with genital ambiguity, but normal ovaries and uterus
• Translocation of SRY gene to X chromosome
  
  • Causes virilization or sex reversal in XX fetus
  • True hermaphrodite is 46,XX with both ovarian and testicular tissue (ovotestis) and ambiguous genitalia

Question 11

46,XY DSDs

Answer 11

• Can result from abnormal testicular development and differentiation (gonadal dysgenesis)
• Complete 46,XY dysgenesis results in:
  
  • Normal female external genitalia
  • Normal female internal genitalia (lack of AMH, T)
  • Streak gonads
• Partial 46,XY dysgenesis –> incomplete testis determination –> ambiguous genitalia with varying degrees of virilization
• Can also result from disorders of steroidogenesis
• Complete androgen insensitivity syndrome (CAIS)

Question 12

Complete Androgen Insensitivity Syndrome (CAIS)

Answer 12

• Form of pseudo-hermaphroditism
  
  • “Testicular feminization”
• Caused by mutations in androgen receptor gene
• X-linked trait, little to no androgen-mediated effects
• Affected XY individuals have normal female external genitalia with short vagina, absence of Mullerian structures (AMH from testes), lack of Wolffian structures (lack of testosterone-driven effects)
• Presents with increased testosterone, estrogen, and LH

Question 13

CAIS Development

Answer 13

• XY - like normal male development
• Testes develop - like normal male development
• Androgen produced, but body cannot respond - abnormal
• Wolffian ducts regress - like normal female development
• AMH produced - like normal male development
• Mullerian ducts do not develop - like normal male development
• External genitalia are female - like normal female development
• Feminizing puberty without menses - abnormal

Question 14

21-hydroxylase deficiency

Answer 14

• 95% of adrenal enzyme deficiencies
• Salt-wasting or retaining?
  
  • Salt wasting –> hyponatremia, hyperkalemia, hypotension, hypoglycemia
• Virilizing or undervirilizing?
  
  • Virilizing –> everything gets pushed through androgen pathway

Question 15

11-b-hydroxylase deficiency

Answer 15

• 5% of adrenal enzyme defiencies
• Salt-wasting or retaining?
  
  • Salt-retaining –> 11-deoxycortisone is potent mineralocorticoid –> hypertension
• Virilizing or undervirilizing?
  
  • Virilizing –> overstimulation of zona reticularis by ACTH

Question 16

StAR/Desmolase deficiency

Answer 16

• <1% of adrenal enzyme deficiencies
• Salt-wasting or retaining?
  
  • Salt-wasting –> can’t make pregnenolone or any of the hormones in pathway
• Virilizing or under-virilizing?
  
  • Undervirilizing –> can’t make pregnenolone or any of the hormones in pathway

Question 17

3-b-hydroxysteroid dehydrogenase deficiency

Answer 17

• Salt-wasting or retaining?
  
  • Salt wasting –> underactive aldosterone pathway
• Virilizing or under-virilizing?
  
  • Males: undervirilization –> not enough T
  • Females: overvirilization –> increased DHEA

Question 18

17-a-hydroxylase / 17,20 lyase deficiency

Answer 18

• Salt wasting or retaining?
  
  • Salt retaining –> overactive aldosterone pathway
• Virilizing or under-virilizing?
  
  • Males: undervirilized –> decrease in T production
  • Females: normal external genitalia but decreased pubertal estrogen –> no secondary sex characteristics

Question 19

External and internal anatomy of females with 21-hydroxylase deficiency

Answer 19

• External anatomy:
  
  • Virilization of external genitalia in females
• Internal anatomy:
  
  • Unaffected - absence of testes means no local testosterone or AMH is produced

Question 20

Diagnosis and treatment of 21-hydroxylase deficiency

Answer 20

• Diagnosis made on newborn screen: measuring 17-hydroxyprogesterone levels
• False positives possible in stressed, premature, and low birth weight infants
• Treatment includes:
  
  • Surgical repair for females
  • Hydrocortisone to replace glucocorticoids
  • Florinef to replace mineralocorticoids
  • More drugs in times of stress or acute adrenal insufficiency