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The thyroid gland produces thyroxine (T4) and triiodothyronine (T3), iodine-containing hormones that increase metabolic rate, heat production, and growth. T4 is the major circulating form and serves as a prohormone; it is converted peripherally to the more active T3 through deiodinase enzymes. T3 acts on nuclear thyroid hormone receptors to increase expression of metabolic enzymes, uncoupling proteins (especially UCP1 in brown adipose tissue), and Na-K-ATPase, thereby increasing oxygen consumption and heat production (thermogenesis). Thyroid hormone secretion is controlled by TSH from the anterior pituitary, which is itself controlled by TRH from the hypothalamus, forming a negative feedback loop: elevated T3/T4 inhibits TSH and TRH release, maintaining euthyroid (normal thyroid) state.
Measure thyroid hormones (free T4, T3) and TSH in normal subjects and in hyper/hypothyroidism. Measure metabolic rate using indirect calorimetry and correlate with thyroid hormone levels. Understand how thyroid disease affects growth, energy expenditure, and thermogenesis.
T4 itself is not highly metabolically active; T3 (produced by peripheral conversion of T4) is the active form. Reverse T3 (rT3) is produced during fasting and illness and is not metabolically active.
From your study of the endocrine system and hormone signaling mechanisms, you know that hormones are chemical messengers and that their effects depend on receptor binding and intracellular signaling cascades. Thyroid hormones are unusual among hormones because they act on nearly every cell in the body, functioning less like targeted signals and more like a metabolic thermostat that sets the pace of cellular activity.
The thyroid gland produces two iodine-containing hormones: thyroxine (T4), which has four iodine atoms, and triiodothyronine (T3), which has three. About 90% of thyroid output is T4, but T4 is relatively inactive — it is a prohormone whose main purpose is to circulate in the blood (bound to carrier proteins like thyroxine-binding globulin) and serve as a reservoir. The real action happens peripherally, where deiodinase enzymes in target tissues strip one iodine from T4 to produce T3. Type 1 and type 2 deiodinases generate active T3, while type 3 deiodinase converts T4 to reverse T3 (rT3), an inactive metabolite. This peripheral conversion system gives tissues local control over thyroid hormone activation — the brain, for example, uses type 2 deiodinase to maintain stable T3 levels even when circulating T4 fluctuates.
Once generated, T3 enters the cell nucleus and binds to thyroid hormone receptors (TRs), which are transcription factors that sit on DNA response elements. T3 binding activates transcription of genes encoding metabolic enzymes, the Na-K-ATPase (which consumes a large fraction of cellular ATP), mitochondrial proteins, and uncoupling proteins like UCP1 in brown adipose tissue. UCP1 dissipates the mitochondrial proton gradient as heat rather than ATP — this is the molecular basis of non-shivering thermogenesis. The net effect of T3 action is increased oxygen consumption, increased ATP turnover, and increased heat production across virtually all tissues. This is why hypothyroid patients feel cold, fatigued, and gain weight, while hyperthyroid patients feel hot, anxious, and lose weight despite eating more.
Thyroid hormone secretion is governed by the hypothalamic-pituitary-thyroid (HPT) axis, a classic negative feedback loop. The hypothalamus secretes thyrotropin-releasing hormone (TRH), which stimulates the anterior pituitary to release thyroid-stimulating hormone (TSH). TSH binds to receptors on thyroid follicular cells, stimulating iodine uptake, thyroglobulin synthesis, and hormone release. When circulating T3 and T4 rise above the set point, they inhibit both TRH and TSH secretion, reducing thyroid output. This feedback is so reliable that TSH is the single best screening test for thyroid dysfunction: an elevated TSH with low free T4 indicates primary hypothyroidism, while a suppressed TSH with high free T4 indicates hyperthyroidism. The axis also adapts to physiological states — during illness or starvation, decreased T4-to-T3 conversion and increased rT3 production lower metabolic rate, conserving energy in what is called euthyroid sick syndrome (or non-thyroidal illness syndrome).