embryology and CAH Flashcards
key to sexual dimorphism
SRY (sex determining region of Y) which is located on the short arm of the Y chromosome. Presence of Y chromosome independent of number of X chromosomes imparts male development by initiating testicular differentiation
describe development of undifferentiated gonads
At 4-5 weeks: appear as paired genital ridges which form in the posterior abdominal wall medial to mesonephros. They form from proliferation of the epithelium and condensation of underlying mesenchyme
Trx factors in genital ridge
- Wilms tumor related gene (WT-1) - mutations associated with gonadal dysgenesis and Wilms tumor/ nephropathy. 2. NR5A1 aka steroidogenic factor (SF-1)- deletions can cause gonadal dysgenesis, adrenal failure and persistent mullerian structures
Germ cell development
Initially develop in yolk sac then migrate to genital ridge at 6th week. If this does not occur, gonads don’t develop (streak gonads)
development of primitive sex cords
During arrival of of primordial germ cells, the epithelium of the genital ridge proliferates, and epithelial cells penetrate the underlying mesenchyme, forming the primitive sex cords. Indifferent gonad has an inner medulla and outer cortex
Describe gonad differentiation into testes
At 6 weeks- SRY expression. Primitive sex cords form testis or medullary cords. Mesonephric cells migrate into testis. Differentiation of sertoli cells (from surface epithelium) and leydig cells. Tunica albuginea separates testis cords from surface epithelium. Sertoli cells are in the testis cords and leydig cells lie between testis cords (bgin production of testosterone by 8th week)
Trxn factors important for testicular differentiation
- SOX-9: target of SRY. With SF-1 elevates anti-mullerian hormone conc.
Camptomelic dysplasia
deletion/mutation of SOX-9. Results in severe skeletal dysplasia and gonadal dysgenesis in 75% of pts.
Describe gonad differentiation into ovaries plus genes involved
Requires 2 X chromosomes and absent Y, plus migration of germ cells. Cortex develops into ovaries and medullary cords degenerate. Genes involved are DAX1, WNT-4, RSPO1 and FOXL2
List the internal duct structures in male
Wolffian ducts aka mesonephric ducts develop into epididymis, vas deferens and seminal vesicles
Male internal duct differentiation
8 weeks- Testosterone produced by Leydig cells stimulates growth of wolffian structures. Antimullerian hormone produced by Sertoli cells- induces mullerian duct regression
List the internal duct structures in female
Paramesonephric aka mullerian ducts develop into fallopian tuves, midline uterus, upper portion of vagina
Female internal duct differentiation
8 weeks- absence of local testosterone and AMH causes Wolffian duct regression and retention of mullerian duct
Rokitansky syndrome
absent or underdeveloped müllerian structures in a 46,XX female
List the indifferent external genitalia and the structures they develop into
genital tubercle: glans penis or clitoris. urethral folds: penile urethra or labia minora. Labial-scrotal (genital) swellings: scrotum or labia majora
What hormones determine development of male external genitalia
testosterone and DHT- test is converted to DHT by 5 alpha-reductase. DHT has higher affinity for receptor than test. Penile growth and formation of penile urethra is particularly dependent on DHT.
Testosterone production is stimulated by…
In 1st trimester, placental HCG stimulates leydig cells to make testosterone. After 1st trimester, hypothalamic-pituitary-testicular axis required for continued testosterone production
When is male external genitalia formation complete
By 13 weeks- can not be corrected by subsequent androgen exposure
Female androgen exposure in utero results in…
Prior to 13 weeks: urogenital sinus and insertion of urethra into vagina. After 13 weeks can cause clitoromegaly but cannot result in posterior labial fusion or penile urethra
define cryptorchidism
Failure of the testes to reach the scrotal sac. Testes reach the inguinal region by 12 weeks and scrotum by 33 weeks
Prader classification of external genitalia
stage 0 is female. Stage 5 is male. And everything in between
Causes of 46, XX disorder of sex development
Congenital adrenal hyperplasia (most common), SRY translocation, ovotesticular DSD and gestational hyperandrogenism
Causes of 46, XY disorder of sex development
Pure/partial gonadal dysgenesis (SRY mutation, underexpressed SOX9), SF1 or WT1 mutations, duplication of DAX1 or Wnt-4, underexpression of DMRT1 and DMRT2), mixed gonadal dysgenesis (45X/ 46 XY), testicular regression, or Leydig cell dysfunction, defects in steroid metabolism, defects in androgen action
List possible defects in steroidogenesis that can cause 46 XY disorder of sex development
7-dehydrocholesterol reductase deficiency (SLOs), STAR deficiency, 3-β-hydroxysteroid dehydrogenase deficiency, 17α-hydroxylase and 17,20 lyase deficiency, 17b-Hydroxysteroid dehydrogenase deficiency
List possible defects in testosterone metabolism that can cause 46 XY disorder of sex development
5 alpha reductase deficiency- AR disorder. Results in Low DHT which affects development of penis, penile urethra and scrotum
5 alpha reductase deficiency Sx
Males are undervirilized. Testes usually in inguinal canal or labial-scrotal folds. Wollfian ducts differentiated. At puberty, spontaneous virilization occurs. High rate of male gender identity
Complete androgen insensitivity syndrome cause and Sx- gonads, external genitalia, puberty, identity
Mutation in androgen receptor gene. 46 XY, Testes develop intraabdominally or in inguinal canal and androgen is produced by body can not respond to it. Normal female external genitalia with short vagina and absence of Mullerian and Wollfian structures. At puberty, breast develop due to test conversion to estrogen. LIttle/no pubic or axillary hair. female gender identity
layers of adrenal gland and what they produce
Zona Glomerulosa – Mineralocorticoids. Zona Fasciculata – Glucocorticoids. Zona Reticularis - Androgens
What causes congenital adrenal hyperplasia
21-hydroxylase deficiency (most common- AR), 11B-hydroxylase deficiency, STAR deficiency, 3B-hydroxysteroid dehydrogenase deficiency, and 17alpha hydroxylase/ 17,20 lyase deficiency
How does 21-hydroxylase deficiency cause CAH
21-hydroxylase is involved in making aldosterone and cortisol. Since these are not made, the precursors build up and are shuttled to the testosterone pathway producing an excess of testosterone from the adrenal glands
21-hydroxylase deficiency Sx in males and females
males: no genital abnormalities. Females: virilization of external genitalia. Both: hyperpigmentation, hyponatremia/hyperkalemia due to aldosterone deficiency. Mild forms may present later with early pubic hair, axillary hair, penile/clitoral enlargement
21-hydroxylase deficiency diagnosis
Suspected in virilized XX infant, or XY infant with hyponatremia and hyperkalemia. Confirmed by 17-OH progesterone elevation.
21-hydroxylase deficiency treatment
Surgery in females. Hydrocortisone (replace cortisol), florinef (replace mineralocorticoid deficiency). For acute adrenal insufficency- IM or IV solu-cortef
11B-hydroxylase deficiency
11B-hydroxylase is a step in making cortisol and aldosterone. Deficiency results in a build up of 11-deoxycorticoserone and 11-deoxycortisol. Virilization, but no salt wasting b/c 11-deoxycorticosterone has mineralocorticoid activity. HTN is frequent finding (due to salt retention)
StAR protein deficiency
Congenital lipoid hyperplasia. StAR is involved in trasnfer of cholesterol from outer to inner mitochondrial membrane . This results in a deficiency of aldosterone, cortisl and testosterone. Females have normal genitalia, males have female genitalia. Salt wasting. Fatal if not detected early
StAR deficiency imaging
Cholesterol filled adrenal gland is enlarged
3B- hydroxysteroid dehydrogenase deficiency
virilization in girls, undervirilization in boys, salt wasting
17alpha hydroxylase/ 17,20 lyase deficiency
excess aldosterone and deficient cortisol and testosterone. HTn (secondary to increased 11-deoxycorticosterone), hypokalemia. Females born with normal genitalia and present at puberty with failure to develop secondary sex characteristics. Males born undervirilized
5) Categorize adrenal enzymatic blocks as: 1) salt-wasting/salt retaining, and 2) virilizing/undervirilizing
salt wasting: 21 hydroxylase deficiency, StAR deficiency, 3B hydroxysteroid dehydrogenase deficiency, Salt retaining: 11B-hydroxylase deficiency, 17alpha hydroxylase/ 17,20 lyase. Virilizing: 21-hydroxylase def, 11B-hydroxylase def, 3B-hydroxysteroid dehydrogenase (girls only) Undervirilzing: StAr def, 3B-hydroxysteroid dehydrogenase (boys only), 17a- hydroxylase/ 17,20 lyase def (boys only)
