FACTORS INFLUENCING NORMAL AND ABNORMAL GONADAL DIFFERENTIATION

• Genetic Determinants
  • Gonadal differentiation (testis vs. ovary) is determined by genetic information on the X and Y chromosomes.
  • Testis Determination: Presence of Y chromosome genes (e.g., SRY) directs the primitive gonad to develop as a testis, even if extra X chromosomes are present.
  • Ovary Determination: Requires two X chromosomes. Individuals with a single X (45,XO, Turner syndrome) typically develop only rudimentary gonads.
• Chromosomal Abnormalities
  • Meiotic Nondisjunction: Common cause of karyotypic abnormalities in defective gonads.
  • Chromosomal Mosaicism: Different cell lines with varying chromosome makeup. Can arise from mitotic nondisjunction or chromosomal loss post-fertilization.
  • Deletions or Translocations: Rearrangements that disrupt sex-determining genes, leading to severe gonadal abnormalities.
  • Gene Mutations: Specific enzyme errors or defective gonadal structure/hormone secretion due to mutations in sex-determining genes.

STAGES IN GONADAL DIFFERENTIATION

Undifferentiated Stage (Up to ~6 weeks)

• Primitive Gonad: A genital ridge along dorsal mesentery.
• Cortical Region: Cloak of coelomic epithelial cells; potential to form ovarian (cortical) structures.
  • Contains primordial germ cells capable of developing into oogonia or spermatogonia.
• Medullary Region: Mesenchyme with primary sex cords; potential to differentiate into testicular (medullary) tissue.

Testicular Differentiation

• Key Determinants:
  • SRY gene on Y chromosome + SOX9 (autosomal).
  • SRY → upregulates SOX9 → drives testis formation (including antimüllerian hormone [AMH] production by Sertoli precursors).
  • AMH causes müllerian duct regression.
• Primary Sex Cords:
  • Inner portions connect seminiferous tubules to mesonephric (wolffian) duct.
  • Peripheral portions combine with coelomic epithelial ingrowths (containing germ cells) → form seminiferous tubules.
  • Most cortex → tunica albuginea + tunica vaginalis (only cortical remnants in the mature testis).
• Leydig Cells:
  • Appear ~8 weeks, secrete androgens (testosterone) → male external genitalia development.
  • Disappear after birth, reappear at puberty.

Ovarian Differentiation

• Key Determinants:
  • Lack of SRY, SOX9, AMH expression.
  • Likely activation of ovary-inducing genes (e.g., WNT4, NR0B1 [DAX1]) and repression of testis genes (SOX9).
• Cortical Proliferation:
  • Occurs later than testicular differentiation.
  • Secondary sex cords push inward, carrying germ cells to form primordial follicles.
  • Primary sex cords regress to the hilum (forming rete ovarii remnants).
• Proliferation of the cortex ceases at about 6 months.
  • By that time, the outline of follicular structures is set.

DIFFERENTIATION OF GENITAL DUCTS

• Embryonic Duct Systems:
  • Müllerian ducts: Potential to form fallopian tubes, uterus, upper vagina.
  • Mesonephric (Wolffian) ducts: Potential to form vas deferens, seminal vesicles, epididymis.
• Normal Fate:
  • Testis Present: Secretes antimüllerian hormone (AMH) from Sertoli cells → müllerian duct regression. Also produces testosterone from Leydig cells → wolffian duct development into male structures.
  • Ovary or Absent Gonads: Without AMH or testosterone, wolffian ducts regress, and müllerian ducts develop into female internal structures (uterus, tubes, upper vagina).
• Vestigial Remnants:
  • Females: Epoöphoron, paroöphoron, Gartner ducts (wolffian remnants).
  • Males: Appendix testis (müllerian remnant).
• Testis vs. Ovary Genes:
  • Male: SRY → upregulates SOX9 → AMH production.
  • Female: No SRY → no AMH → müllerian ducts persist, wolffian ducts regress.
• Clinical Note:
  • Some individuals with 46,XY gonadal dysgenesis or 46,XX males show that more factors than SRY alone influence gonadal determination (e.g., additional autosomal or X-linked genes).

DIFFERENTIATION OF EXTERNAL GENITALIA

• Undifferentiated Stage (before ~9 weeks)
  • Both sexes have genital tubercle, urethral groove (flanked by urethral folds), and labioscrotal swellings.
  • A urogenital sinus beneath these structures is partitioned from the cloacal opening.
  • The early embryo’s external genitalia can follow male or female pathways.
• Male Development
  • Testosterone from fetal Leydig cells (converted locally to DHT in some tissues) → masculinization.
  • Critical timing: If androgen exposure is adequate before ~12th week, the urethral folds fuse → penile urethra, and the labioscrotal swellings fuse → scrotum.
  • Vagina in male is minimal (prostatic utricle) because müllerian ducts regress.
  • Late or insufficient androgens → incomplete masculinization (various forms of hypospadias, ambiguous genitalia).
• Female Development
  • In absence of significant fetal androgens, the external genitalia develop along intrinsic female lines.
  • Urethral and labioscrotal folds remain unfused → labia minora, labia majora.
  • Genital tubercle → clitoris.
  • By 12 weeks, the vagina has migrated posteriorly, acquiring a separate external opening.
  • No gonadal hormones are needed for typical female differentiation externally; default pathway is female unless overridden by androgens.
• Clinical Correlate
  • Female pseudohermaphroditism: Excess fetal or maternal androgens (e.g., congenital adrenal hyperplasia) → partial masculinization.
  • Male pseudohermaphroditism: Insufficient androgenic effect → under-masculinized external genitalia.