TESTOSTERONE AND ESTROGEN SYNTHESIS

Overview of Steroid Synthesis

• Three coelomic-derived glands—adrenal cortex, ovary, and testis—produce steroids in response to anterior pituitary hormones:
  • Corticotropin (ACTH): Stimulates adrenal cortex.
  • Gonadotropins (LH/FSH): Stimulate gonads (testes/ovaries).
• First Critical Step: Cleaving cholesterol into pregnenolone (C21 steroid precursor) + isocaproaldehyde.
  • Occurs in adrenal cortex, testicular Leydig cells, ovarian theca cells, trophoblast cells (placenta), and certain brain cells.
• Resulting Steroid Families:
  • Androgens: C19 steroids.
  • Estrogens: C18 steroids.

Pathway to Androgens

1. Pregnenolone → 17α-hydroxypregnenolone (17α-hydroxylase/P450c17).
2. 17,20-lyase activity of P450c17 → produces C19 androgens (dehydroepiandrosterone [DHEA], androstenedione).
   • Most adrenal androstenedione depends on DHEA → androstenedione via 3β-HSD.
3. Androstenedione → testosterone via 17β-ketosteroid reductase (17β-HSD3) in adrenal or gonads.

Androgen Production by Gonads

• Testis (Leydig cells): 95% of male testosterone (~7 mg/day) secreted under LH control.
  • Local effect amplified by 5α-reductase type 2 → dihydrotestosterone (DHT) (hair follicles, prostate).
  • In blood, testosterone is bound to sex hormone–binding globulin (SHBG).
  • Liver conjugation → excreted by kidney (water-soluble).
• Adrenal DHEA:
  • Weak androgen → major component of urinary 17-ketosteroids.
  • ~60% of 17-ketosteroids come from adrenal DHEA; normal excretion higher in men (testicular plus adrenal contribution).

Ovarian Androgen and Estrogen Zones

1. Granulosa cells: Main estrogen (e.g., estradiol) formation.
2. Theca cells: More androgen production tendency.
3. Hilar cells: Predominantly androgen formation.
   • Balance of these cells ensures normal femininity; imbalance → androgenicity.
   • Corpus luteum: Major source of progesterone in the ovary.

Conversion to Estrogens

• Testosterone → estradiol, or androstenedione → estrone, by aromatization of the steroid A ring.
  • Estradiol more potent than estrone; estriol is a weak excretory product.
• Estrogen Transport: Bound to SHBG and albumin in blood.
• Estrogen Inactivation:
  • Primarily in liver → estradiol to estrone to estriol, oxidation to inert compounds, or glucuronic acid conjugation.
  • Enterohepatic circulation: Excretion into bile → partial reabsorption.