Development and clinical applications of a mathematical model of the human hypothalamic-pituitary-thyroid axis.

摘要

Thyroid hormone (TH) regulation is a classic example of biological feedback control. Hypothalamic TRH stimulates TSH secretion, which stimulates secretion of thyroid hormones T3 and T4. TH inhibits TSH and TRH, forming two negative feedback loops. We developed a physiology-based mathematical model of the human hypothalamic-pituitary-thyroid axis, quantified with clinical data. We first structured and quantified the TH model components, followed by the brain (TRH and TSH) components. We combined these finished submodels to form a complete closed loop model, which we validated with independent clinical data. We addressed several applications in replacement TH (L-T 4) bioequivalence (equivalence between brands), stability, combined vs. single hormone replacement therapy, circadian rhythms, and thyroid cancer. Bioequivalence: We first tested the current L-T4 FDA bioequivalence standards, finding bioequivalent dose ranges and suggesting an improved baseline correction. We also tested an alternative TSH-based bioequivalence measure, which we found to be more sensitive than the current T4-based measure. Combined therapy: TH replacement typically consists only of T4, as T4 has a longer half-life and most T 3 is made throughout the body by enzymatic T4 → T 3 conversion. We tested whether combined T4+T3 therapy would more effectively treat hypothyroidism, finding standard T 4-only sufficient for most cases. Circadian rhythms: Plasma TSH normally exhibits a daily circadian oscillation, with a nighttime peak and daytime nadir. Decreased TSH circadian rhythms (CR) are observed in both extreme primary and central hypothyroidism, though the causes are not well understood. We examined whether these phenomena might be due to a single cause. We implemented two secretion saturation-based mechanisms for diminished TSH CR in primary hypothyroidism, and found that they yielded decreased CR in both disorders, while the original model did not show decreased CR, supporting our hypothesis. Remnant ablation: After thyroidectomy for thyroid cancer, patients typically undergo TH withdrawal or recombinant human TSH dosing, followed by 131I treatment to ablate remaining thyroid remnants or metastases. We tested alternative T3 and T 4 based withdrawal protocols for rapidity in achieving increased TSH (30-50 mU/L), finding a faster rise using T3-based withdrawal.