The Challenges and Complexities of Thyroid Hormone Replacement

Shayri M. Kansagra, BS; Christopher R. McCudden, PhD; Monte S. Willis, MD, PhD


Lab Med. 2010;41(6):229-348. 

In This Article

Thyroid Hormone Receptor-independent Signaling in the Brain

Thyroid hormones have been shown to exert numerous biological effects in the brain independent of THRs. For example, thyroid hormones can influence brain function by interacting with the p85 regulatory subunit of phosphoinositide 3-kinase (PI3K) in the cytosol (Figure 4).[68] Interaction between T3 with PI3Ks in endothelial cells is central to responses to middle cerebral artery occlusion (ie, activation of the Akt-pathway and rapid induction of nitric oxide synthesis, which results in a reduction in infarct size).[69]

Thyroxine is also capable of thyroid receptor-independent bioactivity, where T4 binds to membrane receptors formed by αVβ3 integrin. This complex stimulates the mitogen-activated protein kinase (MAPK) pathway, resulting in phosphorylation of downstream transcription factors and associated changes in gene expression (Figure 4).[70] Thyroxine and reverse T3 (rT3, but not T3) also stimulate actin polymerization in cultured astrocytes and cerebellar granule cells to promote neuronal growth.[71,72] In animal models, actin polymerization has been linked to regulation of growth hormone, where hypothyroid rats had fewer somatotrophs.

It is also known that thyroid hormones regulate mitochondria directly and indirectly. Mitochondria contain thyroid binding elements, which allow the thyroid hormones to regulate oxidative phosphorylation directly. Through additional complex and poorly understood signaling pathways, thyroid hormones also regulate ATP levels by promoting mitochondriogenesis, uncoupling protein synthesis, and inducing proton leak.[73] While these processes can occur systemically, both body temperature and energy regulation have direct implications for brain function.

Besides the well-known thyroid hormones T4 and T3, there are also biologically significant hormone derivatives that were recently discovered. Thyronamine and 3-iodothyronamine (decarboxylated thyroid hormone derivatives) may also play a role in brain function or development.[74] The complexity of T3 and T4 signaling pathways at the molecular level is just beginning to be delineated. Emerging evidence about thyroid signaling strongly suggests the existence of independent signaling pathways for T3 and T4. It may take some time to completely delineate the molecular signaling pathways for T3 and T4, but this information may allow us to understand the mechanisms underlying the controversy between T3/T4 combination and monotherapy and provide a basis for the development of future therapeutic approaches.