Unraveling the Molecular Basis for Successful Thyroid Hormone Replacement Therapy: The Need for New Thyroid Tissue- and Pathway-Specific Biomarkers

Abstract

Thyroid function is conventionally assessed by measurement of thyroid-stimulating hormone (TSH) and free circulating thyroid hormones, which is in most cases sufficient for correct diagnosis and monitoring of treatment efficiency. However, several conditions exist, in which these parameters may be insufficient or even misleading. For instance, both, a TSH-secreting pituitary adenoma and a mutation of thyroid hormone receptor β present with high levels of TSH and circulating hormones, but the optimal treatment is substantially different. Likewise, changes in thyroid hormone receptor α signaling are not captured by routine assessment of thyroid status, as serum parameters are usually inconspicuous. Therefore, new biomarkers are urgently needed to improve the diagnostic management and monitor treatment efficiency for e. g., replacement therapy in hypothyroidism or thyroid hormone resistance. By comparing animal models to human data, the present minireview summarizes the status of this search for new tissue- and pathway-specific biomarkers of thyroid hormone action.

Improvements in Quality of Life and Thyroid Parameters in Hypothyroid Patients on Ethanol-Free Formula of Liquid Levothyroxine Therapy in Comparison to Tablet LT4 Form: An Observational Study

“…Thyroid hormones, especially T3, stimulate SHBG liver synthesis and improve lipid profiles [40][41][42]. Along with osteocalcin and angiotensin convertase, SHBG and LDL-C levels, are alternative biomarkers through which to assess the supply of thyroid hormones in an organism [3,[43][44][45]. It is worth mentioning that reduced SHBG levels are associated with insulin resistance and obesity due to hyperinsulinemia, which decreases the liver synthesis of SHBG [46].…”

LT4 and Slow Release T3 Combination: Optimum Therapy for Hypothyroidism?

“…However, hormone replacement therapy for various endocrine gland deficiencies faces difficulties due to variations in hormone absorption, serum binding, and transfer, cellular receptors, pe-ripheral conversion, and metabolism. Besides, tissue and pathway-specific biomarkers are not well recognized, and those already known may not be entirely sufficient for a complete understanding of the cellular effects of hormones (38). In the case of LT4 therapy, in addition to the above limitations, some hypothyroid patients receiving LT4 replacement therapy do not feel as well as matched controls (15,22).…”

Seven Years of Active Thyroid Hormone Research in Germany: Thyroid Hormone Action beyond Classical Concepts

“…Besides the classical hormones T3 and T4, the biochemical properties and modes of action of new TH metabolites such as 3-iodothyronamine, thyroacetic acid or 3,5-diiodothyronine [20,21] at membrane receptors have been investigated by the Biebermann group [22,23] and at transient receptor potential channels by Mergler and team [24], in addition to first mouse and cohort analyses, hinting to a potential cardiometabolic relevance [4][5][6]25]. Unravelling the molecular basis of TH action at the level of target cells and tissues is crucial for an individualised TH replacement strategy and hereby comparative studies using rodent and human samples are helpful to identify reliable biomarkers as demonstrated by the groups of Mittag and Brabant [26].…”