Annual rhythms of thyroid hormone signaling: Environmental influences on thyroid function and disease implications

Hormones within the hypothalamic-pituitary-thyroid (HPT) axis play a central role in acclimatization, dynamically responding to nutritional, thermal, and photoperiodic cues to coordinate metabolic, thermoregulatory, and reproductive functions. Abundant food elevates thyroid hormone (TH), driving energy storage and foraging behaviors, while scarcity reduces TH levels, inducing energy-saving states like hypometabolism or hibernation, in which TH-leptin crosstalk is important. Cold exposure upregulates TH to enhance mitochondrial thermogenesis, with TH acting as a pivotal mediator in the coordination between the hypothalamic thermoregulatory center and peripheral organs. The photoperiodic response converges evolutionarily on the TSH-DIO2-T3 axis, modulating seasonal GnRH release for seasonal reproductive activity. Humans display an annual rhythm of HPT-axis hormones, characterized by winter TSH elevation with TH variability, which affects thyroid dysfunction diagnosis and necessitates seasonally adjusted therapies. Extreme natural environmental stressors and modern environmental changes can profoundly disrupt this acclimatization to decompensate into a pathophysiological state. Meanwhile, thyroid diseases like hypo- and hyperthyroidism show seasonal patterns of disease onset and exacerbation, indicating that the environment impacts disease progression. Thus, cross-species analysis of seasonal dynamics of TH signaling can enhance our understanding of environmental impacts on thyroid function and inform therapeutic strategies aligned with endogenous annual rhythms to optimize the management of thyroid disorders.