Received January 11, 2005; Revised May 13, 2005; Accepted May 18, 2005. Author to whom all correspondence and reprint requests should be addressed: Prof. Sven Röjdmark, Karolinska Institute, Department of Medicine, Section of Endocrinology, Stockholm Söder Hospital, 118 83 Stockholm, Sweden. E-mail: sven.rojdmark@sodersjukhuset.se Hunger–Satiety Signals in Patients with Graves’ Thyrotoxicosis Before, During, and After Long-Term Pharmacological Treatment Sven Röjdmark, 1 Jan Calissendorff, 2 Olle Danielsson, 3 and Kerstin Brismar 2 1 Karolinska Institute, Department of Medicine, Section of Endocrinology, Stockholm Söder Hospital, Stockholm; 2 Karolinska Institute, Karolinska University Hospital, Department of Endocrinology and Diabetology, Stockholm; and 3 Karolinska Institute, Karolinska University Hospital, Department of Clinical Chemistry, Stockholm, Sweden Endocrine, vol. 27, no. 1, 55–61, June 2005 0969–711X/05/27:55–61/$30.00 © 2005 by Humana Press Inc. All rights of any nature whatsoever reserved. 55 Patients with Graves’ thyrotoxicosis lose weight despite increased appetite and food intake, thus suggesting a disturbed balance between energy intake and expendi- ture. Underlying mechanisms are not fully elucidated. The objective of this study was to investigate whether hormonal factors, known to affect hunger/satiety, change significantly over time as pharmacological treatment turns hyperthyroidism into euthyroidism. For that pur- pose 11 patients with Graves’ thyrotoxicosis were given thiamazole and l-thyroxine for 18–20 mo. They were investigated on three occasions: Test 1: before pharma- cological therapy; Test 2: during medication; Test 3: a few months after conclusion of the pharmacological treatment. Sixteen healthy subjects were also investi- gated for comparison. The participants were fasted over- night. Blood samples for determination of plasma glu- cose and serum concentrations of free T 3 and T 4 , TSH, albumin, cortisol, insulin, GH, IGF-1, IGFBP-1, leptin, and ghrelin were drawn in the morning from an ante- cubital vein. Laboratory data obtained in test 1 were statistically compared with those in tests 2 and 3. The study showed that the free T 3 level declined from 42.8 ± 4.3 pmol/L in test 1 to 6.0 ± 0.8 pmol/L in test 2 (85 ± 2% decline), and 5.5 ± 0.3 pmol/L in test 3 (86 ± 2% decline). The free T 4 level fell concomitantly from 65.2 ± 4.8 to 16.6 ± 1.7 and 14.4 ± 1.2 pmol/L. The glucose level was significantly higher during hyperthyroid- ism (test 1) than during euthyroidism (tests 2 and 3), whereas cortisol, insulin, GH, IGF-1, and leptin levels were similar. The IGFBP-1 level was initially high (48.8 ± 8.5 μg/L in test 1), but with a relative decline in free T 3 of 85 ± 2% (test 2) the IGFBP-1 level declined by 34 ± 13%, and with a free T 3 decline of 86 ± 2% (test 3) the binding protein fell by 39 ± 29%. This brought about increased IGF-1 bioavailability as reflected by a rising IGF-1/IGFBP-1 ratio from 5.1 ± 1.1 to 13.8 ± 2.9 ( p < 0.01). The ghrelin level was low (2454 ± 304 ng/L) in test 1. It increased to 3127 ± 397 ng/L in test 2 (p < 0.05), and to 3348 ± 279 ng/L in test 3 ( p < 0.01). Con- clusion: Both ghrelin secretion and IGF-1 bioavail- ability are low in patients with untreated thyrotoxicosis, but increase markedly as pharmacotherapy makes them euthyroid. These metabolic changes may be caused by the transition of hyperthyroidism into euthyroidism rather than by the pharmacotherapy per se, since the metabolic changes prevailed also in the posttreatment period. Key Words: Hyperthyroidism; ghrelin; leptin; IGF-1; IGFBP-1. Introduction Weight loss—despite enhanced appetite and increased food intake—characterizes Graves’ thyrotoxicosis (1), and indicates impaired balance between energy intake and energy expenditure. The underlying mechanism is not fully under- stood, but it is well known that not only thyroid hormones, but other hormones as well (2) influence human energy homeostasis and could contribute to the energy imbalance in untreated thyrotoxic patients. Leptin is one such hormone that not only increases energy expenditure (3), but also exerts long-term regulatory influence on food intake (4,5). This regulatory effect is brought about by inhibition of neuropep- tide Y (NPY) (6,7), which under normal conditions stimu- lates appetite and augments intake of food (8). Both cortisol and insulin stimulate leptin secretion (9, 10). Hence, both of them should be of importance for balancing energy intake and expenditure. Ghrelin may also play a role in this context, as this GH secretagogue increases appetite and food intake (11,12) via stimulation of NPY (13). Little is known about how the above-mentioned hor- mones vary over time as long-term pharmacotherapy makes thyrotoxic patients euthyroid. Therefore, the aim of this investigation was not only to study how these hunger–sati- ety signals change during medication, but also to see whether there are additional changes in the posttreatment period.