A 35-year-old woman presents with weight gain, cold intolerance, and bradycardia. TSH is markedly elevated and free T4 is low. The most physiologically accurate explanation for the elevated TSH is:

• A Increased TRH secretion stimulating thyrotrophs directly
• B Elevated cortisol suppressing pituitary function
• C Direct stimulation of TSH gene expression by low T4 via the TSH receptor
• D Loss of negative feedback of T3/T4 on the anterior pituitary and hypothalamus ✓

Explanation

Thyroid hormones (primarily T3) normally exert negative feedback on both the pituitary thyrotrophs and hypothalamic TRH-secreting neurons, suppressing TSH and TRH synthesis. In primary hypothyroidism, reduced T3/T4 removes this negative feedback, causing both TRH and TSH to rise. The elevated TSH is an appropriate compensatory response attempting to drive the failing thyroid gland. T3 acts via nuclear receptors to suppress the TSH-beta subunit gene directly.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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