Thyroid Hormone Metabolism and Degradation

Most circulating hormone is secreted as the prohormone T4, and its conversion to active T3 or to inactive metabolites occurs largely in peripheral tissues through the removal of iodine atoms by deiodinase enzymes. This peripheral metabolism, together with conjugation and other degradative pathways, determines how much active hormone any given tissue actually experiences.

Definition

Thyroid hormone metabolism is the set of peripheral reactions, chiefly deiodination, that convert T4 into active T3 or inactive metabolites and ultimately degrade and clear the hormones.

Scope

This topic covers the three iodothyronine deiodinases and their roles in activating and inactivating thyroid hormone, the generation of reverse T3 and other iodothyronines, and the conjugation pathways that prepare hormone for excretion. It frames deiodination as the principal mechanism of tissue-specific hormone control. It is a physiological reference and does not address disorders of hormone metabolism.

Core questions

• How is the prohormone T4 converted to active T3?
• How is thyroid hormone signalling terminated by inactivation?
• What distinguishes the three deiodinase enzymes?
• How does deiodination allow tissue-specific control of hormone availability?
• How are spent hormones conjugated and cleared?

Key concepts

• Iodothyronine deiodinases (D1, D2, D3)
• Outer-ring deiodination (activation)
• Inner-ring deiodination (inactivation)
• Reverse T3 (rT3)
• Selenocysteine catalytic site
• Tissue-specific hormone activation
• Sulfation and glucuronidation

Mechanisms

Three selenocysteine-containing deiodinases govern hormone metabolism. Outer-ring (5'-) deiodination by type 1 and type 2 deiodinase removes an iodine from the outer ring of T4 to generate active T3, the form that binds nuclear receptors. Inner-ring (5-) deiodination by type 3 deiodinase, and partly type 1, removes an iodine from the inner ring to produce inactive reverse T3 from T4 or to inactivate T3, terminating the signal. Because the deiodinases are expressed differently across tissues and are themselves regulated, they let individual tissues set their own local T3 concentration largely independently of plasma levels. Conjugation of hormone by sulfation and glucuronidation, mainly in the liver, prepares iodothyronines for biliary and renal excretion.

Clinical relevance

Peripheral deiodination explains why local tissue hormone status can differ from blood levels and why much of the body's active T3 is produced outside the thyroid. This entry describes normal metabolic physiology for reference and does not provide guidance on disorders or therapeutics involving hormone metabolism.

History

The recognition in the 1970s that T4 is largely a prohormone converted to T3 in peripheral tissues shifted attention from glandular secretion to peripheral metabolism. Subsequent identification of the three deiodinases as selenoenzymes, and the mapping of their distinct outer- and inner-ring activities, established deiodination as the central mechanism of local thyroid hormone control.

Key figures

• Antonio C. Bianco
• P. Reed Larsen
• Balazs Gereben
• Domenico Salvatore

Seminal works

• bianco-2002
• gereben-2008

Frequently asked questions

Where is most active T3 produced?

A large share of the body's active T3 is generated outside the thyroid, in peripheral tissues, by deiodinase enzymes that remove an outer-ring iodine atom from the prohormone T4.

What is reverse T3?

Reverse T3 is an inactive metabolite formed when an iodine is removed from the inner ring of T4 instead of the outer ring; producing it is one way the body inactivates hormone rather than activating it.