Embryology of Reproductive System

Question 1

How long does the indifferent stage last?

Answer 1

5-7 wks

Question 2

Genital Ridges

2 Sets of Ducts

PGCs

External Genitalia

Answer 2

• Genital ridges - on medial side of mesonephros (early kidney) and become gonads

1- Mesonephric ducts (“wollfian”) –> male internal ducts (empties into cloaca)

2- Paramesonephric ducts (“mullerian”) –> female internal ducts (empties into cloaca)

• Primordial germ cells (later diff into gamete precursor cells) - originate in yolk sac –> up gut –> developing gonads
• External genitalia develops from urogenital sinus of the cloaca (endoderm) and the mesoderm around it

Question 3

What are the first male cells? What do they do?

Answer 3

• 1st unique cells = sertoli cells (require expression of SRY gene)
• Lead to formation of testis cords around primordial germ cells
• Produce growth factors and chemotactic factors
• Produce anti-Mullerian hormone
• Produce desert hedgehog (regulates Leydig cels and peritubular myoid cell development)

Question 4

Role of Leydig Cells

Answer 4

• Produce androgens and insulin-like growth factors (including ILG3 for descent of testis)
• Responsible for testis cord elongation

Question 5

Male Duct Development

Answer 5

• Testosterone from Leydig cells–> mesonephric duct growth –> seminal vesicles, vas deferens, epididymis, etc
• Anti-Mullerian hormone from Sertoli cells–> disappearance of paramesonephric duct (apoptosis)

Question 6

What are the major players in initiation of female development?

Answer 6

• Retinoic acid of mesonephros stimulates meiosis of primordial germ cells
• Granulosa cells surround primordial germ cells to arrest primordial germ cells (prophase meiosis I) AND produce aromatase for estrogen production

Question 7

Female Duct Development

Answer 7

• Lack of SRY –> mesonephric ducts degenerate spontaneously and paramesoephric ducts remain and become oviducts, uterus, cervix and upper vagina
• 2 ducts must fuse

Question 8

Descent of Gonads in Males v Females

Answer 8

• As mesonephric tubules degenerate, ligaments form
  
  • Cranial ligament (top)
  • Caudal ligament (bottom)
• Males - cranial ligament disappears and caudal ligament expands to become gubernaculum –> testis move down posterior pelvic wall, over pelvic rim and into inguinal canal and scrotum
  
  • Uses insulin-like growth factor 3 and androgens
  • **Failure = cryptorchidism
• Females - more lateral movement of oviducts and ovaries
  
  • Cranial ligaments become suspensory ligaments
  • Caudal ligaments become round ligament

Question 9

Male External Genitalia Development

Answer 9

• Testosterone in this region –> dihydrotestosterone (DHT) by 5-alpha reductase–> promotes development of male external genitalia
• Genital tubercle expands –> glans
• Genital folds elongate bringing sinus w/ it and closing off at end to form shaft of penis/ urethra within
• Genital swellings –> scrotum

Question 10

Female External Genitalia Development

Answer 10

• Lack of DHT –> female external genitalia
  
  • Genital tubercle –> clitoris
  • Genital swellings –> labia majora
  • Genital folds –> labia minora

Question 11

Male Specific Genes

Answer 11

• SRY boosts Sox9 gene –> early differentiation and proliferation of Sertoli cells –> testis development
• SRY mutation –> loss of function XY sex reversal w/ streak gonads; translocation of SRY to X chromosome in XX leads to sex reversal
• Sox9 mutation –> XY male to female sex reversal; also cartilage abnormalities
• SRY also boosts fgf9/fgfr2 growth factors in males (expressed in females but not boosted b/c no SRY)

Question 12

Female Specific Genes

Answer 12

• Foxl2 –> development of granulosa cells
  
  • Mutation –> pre-mature ovarian failure
• Rspo1 and Wnt4 –> stabilize beta-catenins which act to influence transcription for granulosa cell development
• R-spondin 1 mutation –> loss of function sex reversal in XX - ovotestes; gain of function sex reversal in XY - gonadal dysgenesis
• Wnt 4 mutation –> loss of function XX female to male partial sex reversal; gain of function sexual ambiguity in XY

Question 13

Streak Gonad

Answer 13

small and fibrotic gonads that lack typical germ cell or support cell morphology b/c primordial germ cells do not reach genital ridge, are abnormal or degenerate (Turner Syndrome)

Question 14

Hypospadia

Answer 14

dec closure of urethra b/c genital folds do not close properly (linked to synthetic estrogen use and change in HOX patterns)

Question 15

Bicornate Uterus

Answer 15

• failure of fusion of paramesonephric ducts; from excess exposure to estrogen and Hox gene mutations

Question 16

Mayer-Rokitansky-Kuster-Hauser Syndrome

Answer 16

• partial or complete absence of uterus, cervix, upper vagina; do not form or are incomplete; all paramesonephric duct derivatives

Question 17

CAH

Answer 17

XX - ovaries, female ducts, masculine external genitalia

XY - testes, normal ducts, normal external genitalia

abnormal bone growth in both

Question 18

Androgen Insensivity

Answer 18

XY

testes

mullerian duct degenerates but wolffian duct not masculinized

female ducts

“testicular feminization”

Abnormal androgen receptors

Question 19

5 Alpha Reductase Def

Answer 19

(no DHT)

XY

testes

normal ducts

female external genitalia

“testicular feminization”

Question 20

Persistent Mullerian Duct Syndrome

Answer 20

(loss of anti-mullerian hormone or receptor function)

XY

testes

uterus and oviducts as well as masculinized wollfian ducts

male external genitalia

testis descent may be blocked by female ducts

Question 21

Genes for Both Bipotential Gonad and Later Stages

Answer 21

• SF1 - promotes differentiation of bipotential gonad and adrenals; regulates steroid and anti-Mullerian hormone production
  
  • Mutation –> gonadal dysgenesis, ovary insufficiency and adrenal abnormalities
• WT1 (wilms tumor) - differentiation of bipotential gonad and kidney; later regulates anti-Mullerian hormone production
  
  • Mutation –> gonadal dysgenesis, renal abnormalities, prone to renal tumors