EFFECTS OF TSH ON THE THYROID GLAND

Overview: Hypothalamic–Pituitary–Thyroid Regulation

1. Hypothalamic Role
   • Secretes thyrotropin-releasing hormone (TRH), a modified tripeptide (pyroglutamyl-histidyl-proline-amide).
   • TRH increases transcription of TSH α and β subunits.
2. Pituitary Role (Thyrotrophs)
   • Synthesize and secrete thyrotropin (TSH), a glycoprotein hormone.
   • TSH has an α subunit (common to LH, FSH, hCG) and a β subunit (specific to TSH).
   • Thyroid hormones T4 and T3 provide negative feedback by suppressing TRH and TSH subunit transcription.
3. Thyroid Hormones
   • T4 (thyroxine) and T3 (triiodothyronine) are the main output of the thyroid.
   • Serum TSH exhibits an inverse log-linear relationship with serum free T4.
     • Small changes in free T4 can cause large changes in TSH.

TSH: Normal Range and Alterations

• Reference Range: ~0.3–5.0 mIU/L in healthy individuals (lab-dependent).
• Elevations in TSH:
  • Primary hypothyroidism (loss of negative feedback).
  • Secondary hyperthyroidism due to a TSH-secreting pituitary adenoma (rare).
• Decreased TSH: Primary hyperthyroidism (excess T4/T3 suppresses pituitary TSH secretion).

Circadian and Pulsatile Secretion

• TSH rises (surges) nocturnally, preceding sleep onset.

TSH Receptor and Mechanism of Action

1. TSH Receptor
   • A G protein–coupled receptor in thyroid follicular cells.
   • Couples primarily to Gs (cAMP–protein kinase A pathway) and also activates phospholipase C/Ca²⁺ pathways.
2. Downstream Effects
   • Iodine Uptake (via sodium–iodide symporter transcription).
   • Thyroglobulin and Thyroperoxidase gene transcription.
   • Colloid Resorption and Release of T4 and T3.
   • H2O2 Production, iodide efflux, and organification of iodide.
3. Other Ligands
   • Thyroid-Stimulating Immunoglobulins (TSI) in Graves disease → stimulate TSH receptor → hyperthyroidism.
   • Thyroid-Blocking Antibodies in Hashimoto thyroiditis → reduce thyroid function.
   • High LH/hCG Levels (e.g., early pregnancy) can weakly activate the TSH receptor → mild physiologic hyperthyroidism.

Changes in Thyroid Mass and Function with TSH Variations

1. Normal TSH, Intact Axis
   • Normal thyroid mass.
   • Follicular cells: Cuboidal.
   • Euthyroid hormone levels, normal radioactive iodine uptake.
2. Low TSH (Hypothalamic or Pituitary Dysfunction)
   • Secondary Hypothyroidism.
   • Decreased thyroid size (atrophy).
   • Follicular cells: Flattened appearance.
   • Low T4/T3, low radioactive iodine uptake, TSH inappropriately low/normal.
3. Inappropriately Normal or Elevated TSH (TSH-Secreting Adenoma)
   • Excess thyroid growth → goiter (thyroid feels firm on palpation).
   • Follicular cells: Columnar, colloid typically reduced (active hormone synthesis).
   • High T4/T3 levels, often with increased radioactive iodine uptake.

PHYSIOLOGY OF THYROID HORMONES

Iodine Metabolism in Thyroid Hormone Synthesis

1. Iodine Uptake
   • Dietary iodide (I⁻) absorbed via GI tract; taken up by the thyroid (and salivary glands) or excreted in urine.
   • Sodium–Iodide Symporter (NIS) moves iodide into follicular cells (against a gradient).
     • TSH upregulates NIS transcription.
     • Perchlorate (ClO4⁻) and pertechnetate (TcO4⁻) can compete with iodide at NIS.
2. Iodide Transport to Colloid
   • Pendrin (apical transporter) carries iodide into follicular lumen.
   • Iodide is oxidized by thyroid peroxidase (TPO), enabling iodination of tyrosyl residues on thyroglobulin.
   • Antithyroid drugs (e.g., propylthiouracil, methimazole) inhibit TPO.
3. Hormone Formation
   • MIT (monoiodotyrosine) + DIT (diiodotyrosine) → T3.
   • DIT + DIT → T4.
   • Both stored in thyroglobulin (Tg) in the colloid (3–4 T4 molecules per Tg).
4. Release into Circulation
   • TSH stimulates micropinocytosis of colloid → Tg proteolysis in phagolysosomes → release of T4, T3, MIT, DIT.
   • MIT/DIT are deiodinated by Dhal-1; the freed iodide is recycled.
   • Excess iodide inhibits many of these steps (used clinically to manage hyperthyroidism).

T4 and T3 Distribution and Metabolism

1. Proportions
   • ~10:1 ratio of T4:T3 released.
   • Majority of T3 (∼75%) is formed by peripheral 5′-deiodination of T4.
2. Binding in Plasma
   • Mostly bound to thyroxine-binding globulin (TBG), transthyretin, or albumin.
   • TBG has a high affinity for T4, less for T3.
3. Cellular Mechanism of Action
   • T4/T3 enter cells → T3 (active form) binds to thyroid hormone receptors on DNA → regulates gene transcription and influences basal metabolic rate.
   • T3 has ~15-fold higher affinity for the receptor than T4.
4. Inactivation Pathways
   • Inner Ring (5-deiodination) forms reverse T3 (rT3) from T4, or T2 from T3.
   • Conjugation in the liver (e.g., glucuronidation) → excretion in bile, reabsorption in GI tract.

Unique Thyroid Hormone Storage

• The thyroid gland stores large amounts of T4/T3 in colloid (as part of thyroglobulin).
• About 5 mg of T4 can be stored in a 20-g gland.
• Inflammatory damage (e.g., subacute thyroiditis) often leads to a surge of hormones → transient thyrotoxicosis.