Hypothalamic-Pituitary-Thyroid (HPT) Axis

The HPT axis begins with thyrotropin-releasing hormone, a hypothalamic tripeptide that stimulates pituitary thyrotropes to release TSH. TSH acts on the thyroid follicular cell receptor to drive iodide uptake and hormone release, overwhelmingly as thyroxine with less triiodothyronine. Peripheral deiodinases convert T4 to the more active T3 in target tissues, and thyroid hormone feeds back on pituitary and hypothalamus. The relationship between free T4 and TSH is log-linear, so a modest fall in free T4 produces a several-fold rise in TSH.

That amplification is what makes the axis useful. Most circulating T3 is generated peripherally rather than secreted, T4 has a half-life of about a week and T3 roughly a day, and the usual TSH reference interval of about 0.4 to 4 mIU/L sits on a skewed distribution. Because of the long T4 half-life and slow pituitary resetting, TSH takes around six weeks to reach a new steady state after a levothyroxine dose change. TRH stimulation testing became redundant once third-generation TSH assays distinguished suppressed from low-normal values.

TSH is therefore the right first test, but only where its assumptions hold: an intact pituitary and an axis at steady state. In central hypothyroidism TSH can be normal or low while the patient is hypothyroid, and in non-thyroidal illness the whole axis is perturbed, so testing a hospitalised patient often produces results that resolve on their own.

The errors follow from ignoring those assumptions. Repeating TSH two weeks after a dose change and adjusting again chases a value still moving. Treating small movements within the reference interval as findings ignores that an individual's set point is narrower than the population range but assay imprecision is not. And biotin interference reproduces a thyrotoxic pattern, low TSH with high free T4, in a euthyroid person taking a supplement.