Extensions, validation, and clinical applications of a feedback control system simulator of the hypothalamo-pituitary-thyroid axis

Background: We upgraded our recent feedback control system (FBCS) simulation model of human thyroid hormone (TH) regulation to include explicit representation of hypothalamic and pituitary dynamics, and updated TH distribution and elimination (D&E) parameters. This new model greatly expands the range of clinical and basic science scenarios explorable by computer simulation. Methods: We quantified the model from pharmacokinetic (PK) and physiological human data and validated it comparatively against several independent clinical data sets. We then explored three contemporary clinical issues with the new model: combined triiodothyronine (T₃)/thyroxine (T₄) versus T₄-only treatment, parenteral levothyroxine (L-T₄) administration, and central hypothyroidism. Results: Combined T₃/T₄ therapy - In thyroidectomized patients, the L-T ₄-only replacement doses needed to normalize plasma T₃ or average tissue T₃ were 145 μg L-T₄/day or 165 μg L-T₄/day, respectively. The combined T₄ + T₃ dosing needed to normalize both plasma and tissue T₃ levels was 105 μg L-T₄ + 9 μg T₃ per day. For all three regimens, simulated mean steady-state plasma thyroid-stimulating hormone (TSH), T ₃, and T₄ was within normal ranges (TSH: 0.5-5 mU/L; T₄: 5-12 μg/dL; T₃: 0.8-1.9 ng/mL). Parenteral T ₄ administration - 800 μg weekly or 400 μg twice weekly normalized average tissue T₃ levels both for subcutaneous (SC) and intramuscular (IM) routes of administration. TSH, T₃, and T ₄ levels were maintained within normal ranges for all four of these dosing schemes (1× vs. 2× weekly, SC vs. IM). Central hypothyroidism - We simulated steady-state plasma T₃, T₄, and TSH concentrations in response to varying degrees of central hypothyroidism, reducing TSH secretion from 50% down to 0.1% of normal. Surprisingly, TSH, T₃, and T₄ plasma concentrations remained within normal ranges for TSH secretion as low as 25% of normal. Conclusions: Combined T ₃/T₄ treatment - Simulated standard L-T₄-only therapy was sufficient to renormalize average tissue T₃ levels and maintain normal TSH, T₃, and T₄ plasma levels, supporting adequacy of standard L-T₄-only treatment. Parenteral T₄ administration - TSH, T₃, and T₄ levels were maintained within normal ranges for all four of these dosing schemes (1× vs. 2× weekly, SC vs. IM), supporting these therapeutic alternatives for patients with compromised L-T₄ gut absorption. Central hypothyroidism - These results highlight how highly nonlinear feedback in the hypothalamic-pituitary- thyroid axis acts to maintain normal hormone levels, even with severely reduced TSH secretion.