PBK Modeling of Thyroid Hormone Circadian Rhythm: Elucidating Thyroidal and Extrathyroidal Contributions to Thyroid Hormone Chronobiology

Thyroxine (T4) and triiodothyronine (T3), collectively known as thyroid hormones (THs), are regulated by both homeostatic and circadian mechanisms through the hypothalamic-pituitary-thyroid axis. Thyroid-stimulating hormone (TSH) triggers thyroidal secretion of T4 and a small amount of T3. Subsequent conversion of T4 to active T3 in extrathyroidal tissues produces the majority of T3. TSH exhibits a robust circadian pattern, peaking in the early morning hours. T3 generally follows this rhythm, with a slightly delayed phase and a smaller amplitude. In contrast, T4 shows a more dampened rhythm with a seemingly opposite phase to T3 and significant inter-individual variability. Investigating the circadian rhythm of TH is crucial to understanding TH functions. For example, familial longevity is linked to increased basal TSH secretion and a stronger temporal coupling between TSH and free T3, particularly during the nocturnal TSH peak. Clinical studies suggest a direct TSH-T3-shunt pathway exists within the thyroid; however, the true physiological mechanism for thyroid circadian regulation remains unclear, and existing mathematical models have not fully captured these dynamics. To elucidate the mechanism of thyroid hormone circadian regulation, we employed a multi-compartment human physiologically based kinetic (PBK) model we previously published. The model includes Body Blood, Thyroid, Liver, and Rest-of-Body compartments, with explicit descriptions of TH production, distribution, and metabolism, including T4-to-T3 conversion in the extra-thyroidal tissues. In the blood compartments, we model the binding kinetics of the THs to the three thyroid hormone binding proteins (THBPs), thyroxine-binding globulin, transthyretin, and albumin. We utilized control theory, including frequency response analysis using Bode plots, to quantify how the system responds to circadian variations in TSH and other potential circadian signals. We report several novel findings: 1. Neither circadian regulation of thyroidal T4 or T3 production, extrathyroidal or intrathyroidal T4-to-T3 conversion, tissue metabolism, influx/efflux processes, nor THBP dynamics alone can independently reproduce the phase and amplitude ratios observed in human circulating TH profiles. 2. With the TSH-T3-shunt (intrathyroidal T4-to-T3 conversion) in particular, our model indicates that it cannot account for the phase difference between T3 and TSH nor the T3 to T4 amplitude ratio seen in human studies. 3. Human circadian profiles can be recapitulated from a combined regulation of T4-to-T3 conversion in both the thyroid and peripheral tissues. In this scenario, the circadian signal acting on the peripheral conversion leads the TSH action in the thyroidal compartment by approximately 3 hours to achieve the free T3 phase observed in humans. In summary, our model and analysis suggest a novel mechanism underpinning the circadian regulation of thyroid hormone. This research was supported by NIEHS Superfund Research grant P42ES04911 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.