Development of the reproductive system

The development of the reproductive system begins with the formation of undifferentiated gonads and the paired mesonephric and paramesonephric ducts. Further differentiation of the gonads is dependent on the presence or absence of the SRY gene on the Y chromosome, which stimulates differentiation of the testes in male individuals. Testosterone (produced by Leydig cells) drives the differentiation of the mesonephric ducts into male internal sex organs and dihydrotestosterone drives the differentiation of male external genitalia. Mullerian inhibitory factor (MIF), produced by Sertoli cells, suppresses the differentiation of the paramesonephric ducts. In female individuals, the absence of MIF allows differentiation of the paramesonephric ducts into the female internal organs, and estrogen drives the differentiation of female external genitalia. The absence of testosterone prevents the differentiation of the mesonephric ducts in female individuals. The descent of the gonads, which is much more prominent in male individuals, is facilitated by the gubernaculum, which promotes the descent of the testes from their initial retroperitoneal location into the scrotum.

Timeline ^[1]

• Weeks 1–6: No sexual differentiation is apparent (no phenotypical differences).
• Week 6–7: Differentiation of the mesonephric and paramesonephric ducts begins.
• Week 12: Development of the external genitalia is complete.
• Week 20: Phenotypic differentiation is complete.
• Week 33: Descent of the gonads is complete.

Components ^[2][3]

• Chromosomal sex: determined by chromosome count (see “Meiosis”)
  • Female individuals have XX.
  • Male individuals have XY.
  • See “Differences (disorders) of sex development.”
• Gonadal sex: development of the undifferentiated gonads into testes or ovaries
  • Determined primarily by the presence or absence of the SRY gene on the Y chromosome
    • Y chromosome with SRY gene → development of testes
    • Absence of Y chromosome → ovarian development (default)
• Phenotypic sex
  1. Ductal differentiation: development of the embryonic ducts into the internal sex organs
  2. External genitalia differentiation: relies on estradiol and dihydrotestosterone (DHT)

• Description: development of the undifferentiated gonads into testes or ovaries
• Timeline
  • Up to week 6: The male and female gonads are indistinguishable.
  • After week 6: development of testes or ovaries
• Mechanism
  • The Y chromosome contains the SRY gene.
    • The SRY gene encodes testis-determining factor (TDF): transcription factor necessary for testes development.
    • TDF stimulates the proliferation and differentiation of the primitive sex cords into testes.
    • Autosomal SOX9 gene: transcription regulator also involved in testes differentiation that is upregulated by SRY gene
  • Absence of Y chromosome and presence of WNT4 gene; → ovarian development (default)
• Clinical significance
  • Swyer syndrome
  • Turner syndrome
  • SOX9 mutation

References: ^[3]

• Description: development of the embryonic ducts into the internal sex organs
• Timeline: starts in weeks 7–8
• Mechanism
  • Both male and female embryos have mesonephric ducts and paramesonephric ducts.
  • Differentiation relies on the Mullerian inhibitory factor (MIF) and testosterone.
  • Male individuals
    • Mullerian inhibitory factor (Sertoli cells) → degeneration of paramesonephric ducts into appendix testis
    • Testosterone (Leydig cells) → differentiation of mesonephric duct into male internal genitalia (e.g., seminal vesicles, epididymis, ejaculatory duct, ductus deferens), except for the prostate
  • Female individuals
    • Default phenotype
    • Absence of MIF → differentiation of paramesonephric ducts into female internal genitalia (e.g., fallopian tubes, uterus, proximal vagina)
    • Absence of testosterone → degeneration of mesonephric ducts into the Gartner ducts

• Clinical significance
  • See “Differences (disorders) of sex development”.
    • Ovotesticular disorder of sexual development (both ovarian and testicular tissue are present)
    • Persistent Mullerian duct syndrome
    • SOX-9 mutation
    • Mullerian agenesis
  • See “Anomalies of paramesonephric duct fusion” and “Anomalies of the female genital tract”.
    • Incomplete fusion: bicornuate uterus
    • No fusion: uterus didelphys
    • Single paramesonephric duct: unicornuate uterus
    • No paramesonephric ducts development: Mullerian agenesis (or Mayer-Rokitansky-Küster-Hauser syndrome)
      • Vaginal agenesis or hypoplasia with or without uterine agenesis
      • Normal external genitalia
      • Normal functioning ovaries. Outflow obstruction causes primary amenorrhea.

The “default” sex in sexual development is female.

In the testes, Leydig cells Lead to male differentiation, and Sertoli cells Suppress female differentiation.

“SEED” stands for the derivatives of the mesonephric duct in male individuals: Seminal vesicles, Epididymis, Ejaculatory duct, Ductus deferens.

References: ^[2][3][4]

• Description: development of the embryonic ducts into the external genitalia
• Timeline: starts in week 9
• Mechanism: primarily driven by the presence or absence of estradiol and dihydrotestosterone
  • Male: testosterone → dihydrotestosterone (via 5α-reductase) → differentiation of embryonic structures into male external genitalia, bulbourethral glands, and prostate gland
  • Female: estradiol and absence of DHT → differentiation of embryonic structures into female external genitalia

• Clinical significance
  • Androgen insensitivity syndrome
  • 5α-reductase deficiency
  • Aromatase deficiency
  • Congenital adrenal hyperplasia
  • Hypospadias/epispadias
  • 17β-hydroxysteroid dehydrogenase III deficiency

References: ^[2][3][5]

• Description
  • Migration of the testes caudally from their initial retroperitoneal location through the inguinal ring into the scrotum
  • Migration of the ovaries caudally to the pelvic rim
• Timeline: complete by week 33 ^[3]
• Mechanism
  • Descent of the testes
    1. The gubernaculum induces intra-abdominal migration.
    2. Increased intra-abdominal pressure supports the passage of testes through the inguinal canal.
    3. With the regression of the gubernaculum, the migration of the testes to the scrotum is complete.

References: ^[3]