Signal Amplification in the <scp>HPT</scp> Axis—Evidence for Its Existence, Location, Significance, and Molecular Mechanisms

Thyroid hormones (THs) are under negative feedback regulation via the hypothalamic-pituitary-thyroid (HPT) axis. How this axis operates to keep the circulating THs within a narrow physiological range is not well understood quantitatively. Led by the design principle of robust homeostatic feedback control, here we review and synthesize the literature under a unifying theme of signal amplification in the HPT axis, providing evidence for its existence, location, functional significance, and potential molecular mechanisms. Drawing on human studies of the circulating TSH-T4 relationship, we assert that a signal amplifier exists in the brain, where the TH feedback signal is amplified to inhibit TRH and TSH. With mathematical models we illustrate that placing the signal amplifier of the HPT feedback loop in the brain, not in the thyroid, provides an evolutionary advantage, which minimizes the disruption of operating TH levels by possible perturbations. We review the molecular neuroendocrine literature to reveal how signal amplification (ultrasensitivity) is likely achieved mechanically in the hypothalamus and anterior pituitary. We identify multiple signaling pathways in the TRH neurons, β2-tanycytes, and thyrotropes that mediate the feedback action of THs, including transcriptional and posttranslational regulations of the synthesis, maturation, degradation, and release of TRH and TSH. Collectively, these multistep regulations amplify T3 signal, providing a high feedback loop gain for robust TH homeostatic control. The nature's design principle revealed here enhances our cross-scale understanding of the systems biology of the HPT axis as a dynamical control system, which can promote precision thyroid medicine and risk assessment of thyroid-disrupting chemicals.