Regulation of thyroid function

HPT Axis - The Body's Thermostat

• Central Regulation: A classic negative feedback loop maintains thyroid hormone homeostasis, crucial for metabolism, growth, and thermoregulation.

• Mechanism: ↑ T3/T4 levels inhibit TRH and TSH release.
• Pathology: Disruption at any level (primary, secondary, tertiary) leads to hypo/hyperthyroidism.

⭐ In primary hypothyroidism, ↓T3/T4 leads to a compensatory ↑ in both TRH and TSH. The elevated TSH is the most sensitive initial marker.

Thyroid Kitchen - Cooking Up Hormones

HPT Axis Regulation:

• Synthesis Steps:
  • Trapping: Iodide ($I^−$) enters follicular cells via Na+/I− symporter (NIS).
  • Oxidation & Organification: Thyroid peroxidase (TPO) oxidizes $I^−$ to iodine ($I_2$) and adds it to thyroglobulin (TG) tyrosine residues → MIT & DIT.
  • Coupling: TPO couples residues: DIT + DIT → $T_4$; DIT + MIT → $T_3$.
  • Release: TSH stimulates proteolysis of TG, releasing $T_4$ and $T_3$ (ratio ~20:1).
• Peripheral Conversion: $T_4$ is converted to more potent $T_3$ by 5′-deiodinase.

⭐ Wolff-Chaikoff Effect: High levels of iodide acutely inhibit TPO, ↓ hormone synthesis. This transient effect is used to treat thyroid storm.

On the Road - T4's Big Adventure

• Transport: >99% of thyroid hormones are protein-bound in circulation.
  • Thyroxine-binding globulin (TBG): Binds ~70%.
  • Albumin: Binds ~15-20%.
  • Transthyretin (TTR): Binds ~10-15%.
• Activation: Thyroxine (T4) is a prohormone.
  • Converted to triiodothyronine (T3), the more potent form, in peripheral tissues.
  • Enzyme: 5'-deiodinase.
• Inactivation: T4 can also be converted to reverse T3 (rT3), which is metabolically inactive.
• Free Hormone Hypothesis: Only unbound, free hormone (FT4, FT3) is biologically active.

⭐ Estrogen (e.g., in pregnancy or OCP use) ↑ TBG levels, leading to an ↑ in total T4 and T3, but free hormone levels remain normal.

Special Ops - Other Key Regulators

• Central Inhibition: Somatostatin, dopamine, and high-dose glucocorticoids can suppress TSH release from the pituitary, acting as a brake on the HPT axis.
• TBG Levels: Thyroid-binding globulin levels alter total T4/T3, but free hormone levels remain stable in a healthy individual.
  • ↑ TBG: Estrogen (e.g., pregnancy, OCPs) leads to ↑ total T4/T3.
  • ↓ TBG: Androgens, anabolic steroids, and protein-losing states (e.g., nephrotic syndrome).

⭐ Pregnancy elevates TBG, increasing total T4/T3. hCG can also weakly stimulate the TSH receptor.

High‑Yield Points - ⚡ Biggest Takeaways

• TRH from the hypothalamus stimulates TSH release from the anterior pituitary.
• TSH stimulates all steps of thyroid hormone synthesis and release.
• Free T3/T4 exert negative feedback on the hypothalamus and pituitary, with T3 being more potent.
• Most T3 is formed by peripheral conversion of T4 via 5'-deiodinase.
• Wolff-Chaikoff effect: Excess iodide transiently inhibits thyroid peroxidase, decreasing hormone synthesis.
• Jod-Basedow phenomenon: Iodide-induced hyperthyroidism in underlying thyroid disease.