Disorders of Sexual Differentiation

Normal Sexual Differentiation

• Normal Genotypic Development
  • Chromosomal Sex
    • SRY (sex-determining region Y gene)
      • An evolutionarily conserved gene on the Y chromosome of mammals
      • On the short arm of the Y chromosome near the centromere, adjacent to the pseudoautosomal boundary
      • Specifies development of the testis (testis-determining factor); responsible for maleness
      • SRY protein functions:
        • A transcription factor that, by binding and producing bending of the DNA, promotes protein-protein interaction and activates downstream gene expression
          • SRY protein has a characteristic high-mobility group (HMG), DNA-binding domain that can induce significant DNA binding when bound to the regulatory regions of target genes
        • Supporting cells of the developing male urogenital ridge.
          • These cells participate in cord formation and ultimately develop into Sertoli cells.
      • SRY expression leads to induction of SOX (SRY box-related) 9, a subfamily of closely related genes, during gonadal differentiation
  • Additional Genes Involved in Gonadal Determination
    • Duplication of an X-specific gene causes XY sex reversal by expressing a double dose of a region normally subject to X inactivation. This region is designated as the dosage-sensitive sex (DSS) reversal critical region
• Normal Phenotypic Development
  • Gonadal Stage of Differentiation
    • During the first 6 weeks of embryonic development, the gonoads (gonadal ridge, germ cells, internal ducts, and external genitalia) are bipotential in both 46,XY and 46,XX embryos
      • Posterior to the degenerating pronephros (primary kidney), the mesonephric/wolffian duct develops and extends in an anteroposterior direction.
        • The metanephros arises from inductive interactions between the ureteric bud that branches from the caudal wolffian duct and mesenchyme.
      • Soon after formation of the wolffian duct, the paramesonephric/mullerian duct grows rostral to caudal, adjacent lateral the wolffian duct until the duct joins at the urogenital sinus.
    • Under the genetic influences of SRY, the bipotential gonadal ridges differentiate into either ovaries or testes, and germ cells develop into either oocytes or spermatocytes.
      • In the absence of SRY, ovarian organogenesis results.
        • Duplicate copies of at least one X-chromosomal locus are necessary (which presumably explains the dysgenetic ovaries in the 45,XO Turner syndrome patients) for development of the ovary.
      • The precise moment at which this occurs remains unknown.
    • In response to SRY, differentiation of Sertoli cells is noted at 6-7 weeks’ gestation.
    • Germ cells reach a maximum endowment of 20 million cells by 20 weeks’ gestation
  • Male development
    • The initial endocrine function of the fetal testes is the secretion of Anti-Mullerian Hormone (AMH)/Mullerian Inhibiting Substance (MIS) by the Sertoli cells at 7 to 8 weeks’ gestation.
      • AMH/MIS
        • One of the two hormones (androgens being the other) necessary for male sexual differentiation
        • Member of the transforming growth factor-β (TGF-β) family
        • Acts locally and unilaterally to suppress the müllerian ducts
      • Masculinization of the male fetus starts at 7 to 8 weeks of gestation; before the 8th week of gestation the urogenital tract is identical in the two sexes; the first sign of male phenotypic differentiation is degeneration of the müllerian ducts adjacent to the testes
      • By 10 weeks of gestation, degeneration of the müllerian ducts is almost complete and the wolffian ducts have become more prominent
    • Müllerian duct remnants in the male (2):
      1. Appendix testis: a small tissue protrusion at the superior pole of the testicle
      2. Prostatic utricle: the posterior expansion of the prostatic urethra
         • The verumontanum or seminal colliculus is the rounded eminence of the urethral crest within the posterior wall of the mid prostatic urethra. The prostatic utricle opens into it in the midline and the two ejaculatory ducts open just distal to the utricle
         • Present in 10-15% of boys with a proximal hypospadias
           • Most common cause of difficulty in catheterizing the bladder with proximal hypospadias

• • Androgens
    • Leydig cells in the interstitium differentiate at 8-9 weeks
    • Testosterone secretion is detectable at ≈9 weeks’ gestation
      • Initially, androgens are synthesized by the Leydig cells autonomously.
      • Later, synthesis is dependent on placental human chorionic gonadotropin (hCG) secretion.
      • Later in gestation, with declining hCG concentrations, androgen synthesis is dependent on luteinizing hormone (LH) secretion by the fetal pituitary gland.
    • There is a rise in serum and testicular testosterone to a peak concentration at 13 weeks and then a decline
      • The rate-limiting enzyme for fetal testosterone synthesis is 3β-hydroxysteroid dehydrogenase, which is concentrated ≈50x more highly in the fetal testes than in the ovary.
    • Androgens are essential for virilization of (3):
      1. Wolffian duct structures
      2. Urogenital sinus
      3. Genital tubercle
         • Male structures derived from wolffian ducts (5):
           1. Body and tail of epididymis
              • Efferent ductules and head of epididymis are derived from the mesonephric tubules
           2. Vas deferens
           3. Seminal vesicles
              • Distally, the wolffian ducts join the urogenital sinus by about 30 days gestation, where they develop into the seminal vesicles
           4. Ejaculatory duct
           5. Appendix epididymis
         • Male structures derived from urogenital sinus (3):
           1. Prostate
           2. Bulbourethral glands
           3. Prostatic and Penile Urethra§
         • Male structures derived from genital tubercle (1):
           1. Penis
      • Testosterone
        • The major androgen secreted by the testes, enters target tissues by passive diffusion
        • The local source of androgen is important for ipsilateral Wolffian duct development, which does not occur if testosterone is supplied only via the peripheral circulation
          • [Clinical implication: if androgen synthesis is deficient on one side due to testicular dysfunction (e.g. agenesis), the ipsilateral structures derived from the Wollfian duct (see above) may be not develop normally]
      • Dihydrotestosterone (DHT)
        • Testosterone is converted to DHT by intracellular 5α-reductase
          • DHT binds to the androgen receptor with greater affinity and stability than does testosterone.
        • 5α-reductase is found in the prostate, urogenital sinus, and external genitalia
          • In tissues with 5α-reductase at the time of sexual differentiation, DHT is the active androgen
          • The primary enzyme in the prostate is 5α-reductase, type 2. A deletion in the gene coding for this enzyme has been discovered in patients with 5α-reductase deficiency
          • The prostate gland begins to develop during the 10-12th week.
            • Similar to renal and bladder development, prostatic development depends on mesenchymal-epithelial interactions but under the influence of androgens.
            • There is no evidence that AMH/MIS plays a direct role in prostate development
        • At 9-13 weeks of gestation, dihydrotestosterone (DHT) simulates androgen receptors the
          1. Genital tubercle to differentiate into penis
             • Even after the phallus is developed, the term genital tubercle remains, but only as the terminal end of it, which develops into either the glans penis.§
          2. Urethral folds to differentiate into the corpus spongiosum/penile shaft
             • The urogenital sinus extends between the urethral folds and forms the urethral groove, which is lined with endoderm.
          3. Labioscrotal swellings to differentiate into scrotum
          • • Also known as genital swellings or labioscrotal folds§
        • By 12 to 13 weeks’ gestation, the genitalia of the male fetus are completed
        • Under the influence of androgen secreted by the fetal testes, penile growth and testicular descent occur in the third trimester
• Female development
  • Testosterone is not secreted by the ovaries and therefore the Wolffian ducts regress
    • Wolffian duct remnants in the female (2):
      1. Gartner duct
         • Can form cysts near the vaginal introitus and anterolateral vaginal wall
      2. Epoophoron and paroophoron: in the mesentery of the ovary
  • Estrogen synthesis by the ovary is detectable in the female embryo just after 8 weeks of gestation.
    • The rate-limiting enzyme is aromatase, which is higher in the fetal ovary than in the fetal testis.
  • Estrogens are not required for normal female differentiation of the reproductive tract, but they can interfere with male differentiation.
    • Estrogen can block the effect of AMH/MIS on Müllerian ducts
    • Prenatal estrogen treatment of mothers has been associated with male reproductive tract abnormalities
  • Because the ovary does not produce AMH/MIS, the Müllerian ducts are maintained and develop into the female internal reproductive tract (4):
    1. Fallopian tubes
    2. Uterus
    3. Cervix
    4. Proximal 2/3rd of the vagina
       • The distal 1/3rd of the vagina is derived from the urogenital sinus
  • In females and males with abnormalities in testosterone and/or DHT production, 5α-reductase deficiency, or androgen-receptor insufficiency, the primitive perineum does not lengthen and the
    1. Genital tubercle bends inferiorly, passively become the clitoris
    2. Urethral folds passively become the labia minora
    3. Labioscrotal swellings passively become the labia majora
    • The definitive urogenital sinus becomes the vestibule of the vagina
    • 5α-reductase deficiency more likely associated with ambiguous genitalia whereas complete androgen-receptor insufficiency have near-normal female external phenotype

• Gender Identity, Gender Role, and Gender Orientation

• The previously accepted dogma that children are psychosexually neutral at birth and capable of being environmentally oriented (the blue room/pink room theory) has been challenged by those who support the concept of prenatal psychosexual differentiation

UrologySchool.com Summary of Embyrologic Origins of the GU Tract

	Common§	Males	Females
Urogenital sinus	Bladder	Transitional and peripheral zone of prostate§ Prostatic and penile urethra Bulbourethral glands	Distal 1/3 of vagina Urethra
Wollfian duct	Renal collecting tubules and ducts, calyces, infundibulae, pelvis, and ureters§§	Central zone of prostate§ Body and tail of epididymis Vas deferens Seminal vesicles Ejaculatory duct Appendix epididymis	Remnants: Gartner duct Epoopheron or paraoopheron
Mullerian duct		Remnants: Appendix testis Prostatic utricle	Fallopian tubes Uterus Cervix Proximal 2/3rd of the vagina
Mesonephric tubules		Efferent ductules and head of epididymis
Genital tubercle		Penis§	Clitoris
Urethral folds		Corpus spongiosum/penile shaft	Labia minora
Labioscrotal swellings		Scrotum	Labia majora