Resolution of Hypothyroidism Restores Cold-Induced Thermogenesis in Humans

Background: Hypothyroidism is a frequent endocrine disorder with common symptoms of increased cold sensitivity and unintended weight gain, indicating changes in energy expenditure (EE) and response to cold exposure. Thyroid hormones (TH) play an important role for proper function of brown adipose tissue (BAT) and cold-induced thermogenesis (CIT) in rodents, but the role of hypothyroidism on CIT in humans is uncertain. Methods: This was a prospective observational study. Forty-two patients presenting with subclinical or overt hypothyroidism in whom TH replacement was planned were recruited. Thirty-three patients completed the study. Thermogenesis was measured by indirect calorimetry during warm conditions and after a mild cold stimulus of 90 minutes, both during the hypothyroid state and after at least three months of sufficient TH replacement. CIT was determined as the difference between EE during mildly cold and warm conditions. The primary endpoint was the change of CIT between the hypothyroid and euthyroid state. Results: EE during warm conditions increased from a median of 1330 (interquartile range [IQR] 1251–1433) kcal/24 hours in the hypothyroid state to a median of 1442 (IQR 1294–1579) kcal/24 hours in the euthyroid state (+8.5%; p = 0.0002). EE during mild cold exposure increased from 1399 (IQR 1346–1571) kcal/24 hours to 1610 (IQR 1455–1674) kcal/24 hours (+15%; p < 0.0001). The median CIT was 55 (IQR 1–128) kcal/24 hours at the baseline visit, after restoration of euthyroidism CIT increased by 102% to a median of 111 (IQR 15.5–200) kcal/24 hours (p = 0.011). Serum levels of free thyroxine at the respective visit and mean outdoor temperature during the preceeding 30 days were significantly associated with CIT (p = 0.021 and p = 0.001, respectively). Conclusion: Restoring euthyroidism significantly increases CIT in hypothyroid humans.