A novel minimal mathematical model of the hypothalamus-pituitary-thyroid axis validated for individualized clinical applications

The hypothalamus-pituitary-thyroid (HPT) axis represents a complex, non-linear thyroid hormone system in vertebrates governed by numerous variables. The common modeling approach until now aims at a comprehensive inclusion of all known physiological influences. In contrast, we develop a parsimonious mathematical model that integrates the hypothalamus-pituitary (HP) complex as an endocrinologic unit based on a parameterized negative exponential function between free thyroxine (FT4) as stimulus and thyrotropin (thyroid stimulating hormone, TSH) as response. Model validation with clinical data obtained from geographically different hospitals revealed a goodness-of-fit largely ranging between 90% < R2 < 99%, each HP characteristic curve being uniquely defined for each individual akin to a fingerprint. Specifically, the HP model represents the afferent feedback limb of the HPT axis while the efferent limb is mathematically depicted by TSH input to the thyroid gland which responds by secreting T4 as its chief output. The complete HPT axis thus forms a closed loop system with negative feedback resulting in an equilibrium state or homeostasis under defined conditions illustrated by the intersection of the HP and thyroid response characteristics. In this treatise, we demonstrate how this mathematical approach facilitates homeostatic set points computation for personalized dosing of thyroid medications of patients to individualized euthyroid states.