Objective: Ghrelin promotes a positive energy balance, e.g. by increasing food intake. Stimulation of the activity of the hypothalamus-pituitary-thyroid (HPT) axis promotes a negative energy balance, e.g. by increasing energy expenditure. We therefore hypothesized that ghrelin suppresses the HPT axis in humans, counteracting its energy-saving effect. Design and methods: In this single-blind, randomized, cross-over study, we determined secretion patterns of free triiodothyronine (fT 3 ), free thyroxine (fT 4 ), TSH, and thyroid-binding globulin (TBG) between 2000 and 0700 h in 20 healthy adults (10 males and 10 females, 25.3G2.7 years) receiving 50 mg ghrelin or placebo at 2200, 2300, 0000, and 0100 h. Results: FT 4 plasma levels were significantly higher after ghrelin administration than after placebo administration from 0000 h until 0620 h except for the time points at 0100, 0520, and 0600 h. TSH plasma levels were significantly lower from 0200 until the end of the study at 0700 h except for the time points at 0540, 0600, and 0620 h. The relative increase of fT 4 (area under the curve (AUC) 0130-0700 h (ng/dl!min): placebo: 1.31G0.03; ghrelin: 1.39G0.03; PZ0.001) was much weaker than the relative decrease of TSH (AUC 0130-0700 h (mIU/ml!min): placebo: 1.74G0.12; ghrelin: 1.32G0.12; PZ0.007). FT 3 and TBG were not affected. Conclusions: This is the first study to report that ghrelin affects the HPT axis in humans. The early fT 4 increase was possibly induced by direct ghrelin action on the thyroid where ghrelin receptors have been identified. The TSH decrease might have been caused by ghrelin-mediated inhibition at hypothalamic level by feedback inhibition through fT 4 , or both.