Embryology and Congenital Adrenal Hyperplasia Flashcards Preview

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Flashcards in Embryology and Congenital Adrenal Hyperplasia Deck (20)
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Bipotential gonad differentiation into testis or ovary

  • 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


7th week gestational age: males

  • 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


7th week gestational development: females

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


Internal ducts that differentiate in males and females

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


46, XY ductal development

  • 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


46, XX development

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


Development of external genitalia

  • 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


Development of male external genitalia

  • 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


Causes of disorders of sexual differentiation (DSDs)

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


46,XX DSDs

  • 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


46,XY DSDs

  • 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)


Complete Androgen Insensitivity Syndrome (CAIS)

  • 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


CAIS Development

  • 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


21-hydroxylase deficiency

  • 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


11-b-hydroxylase deficiency

  • 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


StAR/Desmolase deficiency

  • <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


3-b-hydroxysteroid dehydrogenase deficiency

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


17-a-hydroxylase / 17,20 lyase deficiency

  • 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


External and internal anatomy of females with 21-hydroxylase deficiency

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


Diagnosis and treatment of 21-hydroxylase deficiency

  • 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