Thyroid-stimulating hormone pulses finely tune thyroid hormone release and TSH receptor transduction

Detection of circulating thyroid-stimulating hormone (TSH) is a first-line test of thyroid dysfunction, a major health problem (affecting about 5% of the population) that, if untreated, can lead to a significant deterioration of quality of life and adverse effects on multiple organ systems. Human TSH levels display both pulsatile and (non-pulsatile) basal TSH secretion patterns; however, the importance of these in regulating thyroid function and their decoding by the thyroid is unknown. Here, we developed a novel ultra-sensitive ELISA that allows precise detection of TSH secretion patterns with minute resolution in mouse models of health and disease. We characterised the patterns of ultradian TSH pulses in healthy, freely-behaving mice over the day-night cycle. Challenge of the thyroid axis with primary hypothyroidism due to iodine deficiency, a major cause of thyroid dysfunction worldwide, results in alterations of TSH pulsatility. Induction in mouse models of sequential TSH pulses that mimic ultradian TSH profiles in periods of minutes were more efficient than sustained rises in basal TSH levels at increasing both thyroid follicle cAMP levels, as monitored with a genetically-encoded cAMP sensor, and circulating thyroid hormone (TH). Hence this mouse TSH assay provides a powerful tool to decipher how ultradian TSH pulses encode thyroid outcomes, and to uncover hidden parameters in the TSH-TH set-point in health and disease.