Thyroid hormone receptor (TR) is a nuclear receptor that binds T3 (not T4) and acts as a transcription factor. The T3–TR complex upregulates certain genes and downregulates others. Which of the following correctly describes the mechanism of negative feedback of T3 on TSH secretion?

• A T3 enters thyrotroph nuclei, binds TR-beta2 isoform, and the T3–TR complex acts on the negative TRE (nTRE) of the TSH-alpha and TSH-beta subunit promoters to suppress their transcription; T3 also impairs TRH receptor expression on thyrotrophs, reducing TRH sensitivity ✓
• B T3 binds membrane receptors on thyrotrophs to activate Gi, reduce cAMP, and directly prevent TRH-stimulated TSH exocytosis
• C T3 acts only at the hypothalamic level by suppressing TRH gene transcription; it has no direct effect on pituitary thyrotrophs
• D T3 binds albumin on the surface of thyrotrophs, is internalised, and activates a cytoplasmic kinase cascade that phosphorylates and inactivates TRH receptors

Explanation

T3 (the active thyroid hormone) mediates negative feedback predominantly directly at the anterior pituitary. It binds the TR-beta2 isoform (predominant in thyrotrophs) and the occupied receptor acts as a transcriptional repressor at negative TREs in the promoters of both TSH subunit genes (TSH-alpha and TSH-beta), reducing their mRNA and thus TSH synthesis. Additionally, T3 down-regulates TRH receptor expression on thyrotrophs, blunting TRH stimulation. T3 also suppresses TRH gene transcription at the hypothalamic level (reducing TRH), but this is a secondary effect; the pituitary is the primary feedback site. Option B describes a membrane-mediated rapid mechanism which does not reflect the primary transcriptional mechanism.

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

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