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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 2 853-857
Copyright © 2003 by The Endocrine Society

Hyperthyroidism Is Associated with Suppressed Circulating Ghrelin Levels

Anne Lene Dalkjær Riis, Troels Krarup Hansen, Niels Møller, Jørgen Weeke and Jens Otto Lunde Jørgensen

Medical Department M (Endocrinology and Diabetes), Aarhus University Hospital (A.L.D.R., T.K.H., J.W., J.O.L.J.), and Institute of Experimental Clinical Research (N.M.), Aarhus University, 8000 Aarhus, Denmark

Address all correspondence and requests for reprints to: Dr. Anne Lene Riis, Medical Department M, Aarhus University Hospital, 8000 Arhus, Denmark. E-mail: anne.lene.riis{at}iekf.au.dk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Ghrelin stimulates GH secretion as well as appetite and food intake. To explore whether ghrelin is involved in the regulation of appetite and body weight in hyperthyroidism, circulating ghrelin levels were measured in nine hyperthyroid patients before and after medical treatment and compared with those in eight healthy control subjects. All participants were studied in the postabsorptive state and during a 3-h euglycemic hyperinsulinemic clamp. Before treatment the patients had 3- to 5-fold elevations of T3, and during treatment the patients gained 5 kg of body weight. Ghrelin levels were decreased in hyperthyroidism both in the fasting state (hyperthyroid, 1080 ± 195 pg/ml; euthyroid, 1480 ± 215 pg/ml; P = 0.03) and during clamp (hyperthyroid, 833 ± 150 pg/ml; euthyroid, 1210 ± 180 pg/m; P = 0.02). After treatment, ghrelin levels did not differ from those in control subjects. In all three study groups the clamp significantly reduced ghrelin levels compared with fasting levels. In conclusion, ghrelin levels are reduced in hyperthyroidism and become normalized by medical antithyroid treatment. Hyperinsulinemia suppresses ghrelin regardless of thyroid status. Ghrelin is not a primary stimulator of appetite and food intake in hyperthyroidism, and the mechanisms underlying the suppressive effect of hyperthyroidism on ghrelin secretion remain unclear.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
WEIGHT LOSS IN hyperthyroidism and weight gain after restoration of euthyroidism are hallmarks of the natural history of Graves’ disease. Hyperthyroid patients have increased appetite and food intake with a craving for carbohydrate-rich food, but the physiological mechanisms underlying this behavior are unclear (1, 2). Ghrelin is a recently discovered peptide hormone secreted by gastric endocrine cells (3) that stimulates GH secretion and is involved in the regulation of energy balance causing increased food intake, decreased fat oxidation, and weight gain (4). In human studies exogenous ghrelin stimulates appetite and food intake (5), whereas circulating ghrelin levels are reversibly decreased in obesity (6, 7, 8) and increased in anorexia nervosa (9, 10) and in the cachexia associated with chronic heart failure (11). The close association between ghrelin, food intake, and energy balance makes it potentially relevant to assay this new hormone during conditions of altered thyroid function. We therefore found it of relevance to measure circulating basal and insulin-stimulated concentrations of ghrelin in hyperthyroid patients before and after medical treatment as well as in healthy control subjects.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Participants

Nine hyperthyroid women, aged 26–49 yr, with newly diagnosed Graves’ disease were consecutively recruited and studied before and after 2–3 months of medical treatment with methimazole. All patients exhibited TSH receptor antibodies (>2 IU/liter). The patients were compared with a control group of eight age-matched healthy lean women. All participants provided written informed consent after receiving oral and written information concerning the study. All procedures took place at the Clinical Research Center at the Medical Department M, Aarhus University Hospital, and were performed in accordance with the Declaration of Helsinki II. The Arhus County ethical scientific committee previously approved the protocol.

Methods and study design

The participants were admitted to the Clinical Research Center the evening before the study. The investigations were carried out in the morning after a 12-h overnight fast. One iv catheter was placed in an antecubital vein for infusions, and another catheter was placed in a superficial vein draining a hand, which was heated in a box with an air temperature of 65 C to arterialize the blood. In each experiment the participants were studied in the postabsorptive basal state for 3 h and thereafter during a 3-h hyperinsulinemic euglycemic clamp. Hyperinsulinemia was induced by a continuous iv infusion of regular human insulin (0.6 mU/kg·min; Actrapid, Novo, Denmark), and euglycemia was maintained by a variable iv infusion of 20% glucose adjusted to clamp the arterialized blood glucose concentration at 5 mmol/liter. Every 5–10 min plasma glucose was sampled and immediately measured in duplicate on an autoanalyzer (Beckman, Palo Alto, CA) by the glucose oxidase method. Data on intermediary lipid metabolism and insulin sensitivity from this study have been published previously (12).

Human serum ghrelin was measured with a commercially available RIA (Phoenix Pharmaceuticals, Inc., Belmont, CA) that uses 125I-labeled bioactive ghrelin as a tracer and polyclonal antibody raised in rabbits against the C-terminal end of human octanoylated ghrelin and measures total circulating ghrelin concentrations. The coefficient of variation for the assay was 3.9%. Thyroid hormones (total T3 and total T4) and TSH were measured by immunofluorescent methods (Immulite, Diagnostic Products, Los Angeles, CA). Free thyroid hormones (T4 and T3) were measured by RIA (13, 14). We used a two-site immunoassay ELISA (15) to measure serum insulin. A double monoclonal immunofluorometric assay (Delfia, Wallac, Inc., Turku, Finland) was used to measure serum GH, whereas plasma glucagon (16), IGF-I (17), and serum C peptide (Immunoclear, Stillwater, MN) were measured by RIA. Serum free fatty acids (FFA) were determined by a colorimetric method (Wako Chemicals, Neuss, Germany). Blood samples were deproteinized with perchloric acid for determination of glycerol and 3-hydroxybutyrate by an automated fluorometric method (18). Indirect calorimetry (Deltatrac, Datex Instrumentarium, Inc., Helsinki, Finland) was performed in both study periods to assess the respiratory quotient (RQ) and total energy expenditure (EE). RQ is the ratio of the volume of CO2 produced to the volume of O2 consumed. Anthropometrical measurements and whole body DEXA scanning (QDR 1000/2000/W scanner, Hologic, Inc., Waltham, MA) were performed in the patients before and after medical antithyroid therapy.

Statistical methods

We tested the data for normal distribution by P-P plots, Q-Q plots, histograms, and Kolmogorov-Smirnov test using SPSS for Windows 10.0 (SPSS, Inc., Chicago, IL). Data are given as the mean ± SEM. Two-tailed t tests for paired or unpaired data were used for comparison of data between groups, and P < 0.05 was considered statistically significant. Pearson’s product-moment correlation with two-tailed probability values was used to measure the strength of association between the variables. Multiple linear regression and forward stepwise analysis were used to determine the strongest predictors of ghrelin levels among total T3, free T3, total T4, and free T4 and EE per kilogram of lean body mass (LBM; dependent variable).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Body composition, energy metabolism, and thyroid function

The patients and control subjects were of comparable age and height (Table 1Go). Both before and after treatment the patients tended to have lower body weight (P = 0.28 after treatment) than the control subjects. The patients gained an average of 5 kg of body weight during treatment, and the dual energy x-ray absortiometry scans indicated that this was attributable to proportional increments in fat and LBM, albeit only the increase in fat mass was statistically significant. In the hyperthyroid state the patients had a 3- to 5-fold elevation of total and free T3, compared with posttreatment, when T3 decreased to normal levels. At admission the patients were clinically hyperthyroid, with tachycardia (resting heart rate, 100 vs. 68 beats/min after treatment) and increased total EE [52 vs. 38 (kcal/24 h)/kg LBM after treatment].


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  		Table 1. Anthropometric measurements, thyroid hormones, and fasting EE in patients with Graves’ disease before (hyperthyroid) and after (euthyroid) medical treatment and in healthy control subjects

 
Hormones and metabolites

Postabsorptive state. In hyperthyroid patients fasting ghrelin levels were significantly reduced to 79 ± 8% of the ghrelin levels in the euthyroid state (Table 2Go and Fig. 1Go). The ghrelin levels of the hyperthyroid patients were also significantly lower than those of the healthy control subjects, whereas after treatment their ghrelin levels did not differ from those of the healthy controls. Fasting levels of glucose, insulin, C peptide, glucagon, leptin, GH, and IGF-I did not differ with thyroid state. As for the metabolites of lipid metabolism: glycerol levels were elevated during hyperthyroidism, and the concentrations of FFA (P = 0.07) as well as 3-hydroxybutyrate (P = 0.06) tended to be elevated. Analogously, the RQ was decreased in the hyperthyroid state, indicating elevated lipid oxidation (Tables 1Go and 2Go).


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  		Table 2. Fasting levels of circulating hormones and metabolites in patients with Graves’ disease before (hyperthyroid) and after (euthyroid) medical treatment and in healthy control subjects

 


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  		Figure 1. Ghrelin in the postabsoptive state (fasting) and during euglycemic hyperinsulinemic clamp (clamp) in hyperthyroid patients before (Ht.) and after treatment (Eut.) and in healthy control subjects (Ctr.). *, P < 0.005 when comparing fasting and clamp subjects within groups.

 
Glucose clamp. During the euglycemic hyperinsulinemic clamp ghrelin levels of the hyperthyroid patients were significantly reduced to 71 ± 7% compared with those in the euthyroid state (Table 2Go and Fig. 1Go). The ghrelin levels of the hyperthyroid patients were also significantly lower than those of the healthy control subjects. After antithyroid therapy, serum ghrelin concentrations increased to a level no longer different from that in the control group. In the hyperthyroid state circulating levels of lipid intermediates were inadequately suppressed during insulin stimulation, and RQ was decreased accordingly (data not shown). Treatment of the hyperthyroid patients was associated with normalization of these parameters.

In all three study groups, the concentrations of circulating ghrelin decreased significantly during the hyperinsulinemic euglycemic clamp compared with fasting concentrations (Fig. 1Go). The relative clamp-induced suppression in ghrelin levels was more pronounced in the hyperthyroid state (19 ± 6% vs. 16 ± 5%; P = 0.02), whereas a 15 ± 3% suppression was recorded in the healthy control group (P = NS compared with either hyperthyroid or euthyroid patients).

Correlations and regression analysis

In hyperthyroid patients and healthy controls, ghrelin levels were negatively correlated with free and total thyroid hormone levels and EE per kilogram of LBM both in the fasting state and during the clamp [Fig. 2Go; total T3: fasting, r = -0.60; P = 0.01; clamp, r = -0.69; P = 0.003; free T3: fasting, r = -0.64; P = 0.006; clamp, r = -0.71; P = 0.001; free T4: fasting, r = -0.51; P = 0.04; clamp, r = -0.58; P = 0.01; total T4: fasting, r = -0.73; P = 0.001; clamp, r = -0.76; P = 0.001; EE per kilogram of LBM: fasting, r = -0.50; P = 0.04; clamp, r = -0.53; P = 0.03]. Ghrelin was not correlated with LBM, fat mass, body mass index, age, RQ, FFA, glycerol, leptin, GH, or fasting insulin. Multiple linear regression and forward stepwise analysis revealed total T4 levels to be the most important and negative predictor of both fasting ghrelin levels and clamp ghrelin levels.



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  		Figure 2. Correlation between free T3 and ghrelin in hyperthyroid patients and healthy control subjects during euglycemic, hyperinsulinemic clamp.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present study demonstrates that hyperthyroidism is associated with reduced ghrelin levels, which become normalized after 2 months of antithyroid therapy. Furthermore, we observed a significant suppression of ghrelin during the clamp independently of thyroid status. These human data extend and support the very recent reports of decreased ghrelin levels in hyperthyroid rats and increased ghrelin levels in hypothyroid rats (19). As expected, hyperthyroidism in the present study was associated with a reduction in the amount of both lean and fat tissue mass. Food intake was not measured, but hyperphagia is a well described feature of hyperthyroidism (1, 2). Notably, the evidence that ghrelin stimulates food intake in humans stems from the observations that ghrelin appears to increase acutely immediately before a meal (10, 20), and that ghrelin administration stimulates food intake (5). These data were obtained in normal weight, healthy adults, which contrast with the observations that obesity is associated with low ghrelin levels (6). Moreover, ghrelin levels are increased in obese subjects after weight loss (7, 8) as well as in patients with anorexia nervosa (9, 10), bulimia nervosa (21), and after a 12-h fast (22). Together, these findings could suggest that a condition characterized by weight loss and hyperphagia, such as hyperthyroidism, would be associated with elevated ghrelin levels. It appears that the increased food intake in hyperthyroidism is regulated through other pathways, which, in turn, may feedback inhibit gastric ghrelin release. The mechanisms subserving the aberrant eating behavior in hyperthyroidism are poorly characterized, but increased activity of the sympathetic nervous system and reduced availability of tryptophan for brain serotonin synthesis have been suggested as putative mediators (1).

In rodents, ghrelin injections led to an increase in RQ without any change in energy expenditure or locomotor activity, reflecting increased utilization of carbohydrates and decreased utilization of fat (4). This was speculated to be related to reduced sympathetic nervous system activity, and the ghrelin-induced metabolic changes led to an efficient metabolic state, resulting in increased body weight and fat mass. Thyrotoxicosis is a catabolic condition with increased sympathetic nerve system activity (23), resulting in increased thermogenesis (24) and overall energy expenditure. In this context the changes in ghrelin with thyroid state, as observed in our study, could reflect the transition to a more energy-efficient metabolic state, leading to a positive energy balance and weight gain.

In observational studies an inverse correlation between circulating levels of ghrelin and insulin has been reported (20, 25), and administration of natural ghrelin lowers insulin levels in healthy human subjects (26). By contrast, ghrelin has been shown to stimulate insulin secretion in rodents (27, 28). Acute suppression of ghrelin is seen after ingestion of a mixed meal as well as during an oral glucose load (10, 20, 29, 30). Reduced ghrelin levels during a euglycemic hyperinsulinemic glucose clamp have quite recently been reported (31) in a group of average overweight subjects, and our study confirms these results in lean women regardless of thyroid status. In that respect our results contrast with the observations by Caixàs et al. (29) showing that ghrelin is not suppressed by a sc insulin injection and continuous iv glucose administration. This latter group suggested that the presence of nutrients in the stomach is the mechanism by which ghrelin levels are suppressed. At present it is not possible to distinguish to what degree insulin and glucose each contribute to the suppression of ghrelin.

As ghrelin levels fluctuate with preprandial surges and postprandial trough levels, the physiological relevance of measuring single fasting and clamp levels could be questioned. It has, however, been reported that the morning fasting trough value at 0060 h as well as a postprandial trough value after breakfast correlate closely with 24-h area under the curve values (20). Nevertheless, knowledge about the diurnal ghrelin pattern in patients with thyroid disease would be of great relevance. Further, the effect, if any, of isolated ß-blockade on ghrelin levels in human subjects in general and hyperthyroid patients in particular would be relevant to investigate.

Based only on single measurements of GH and IGF-I, no differences in GH status were recorded when comparing the patients before and after antithyroid therapy. In hyperthyroid patients, 4-fold increased 24-h levels of GH have previously been observed (32), and a negative feedback control of GH on ghrelin secretion has been proposed (33, 34), whereas others found no evidence of such a mechanism (35). Although our design did not allow a thorough evaluation of GH secretion, it appears that the pronounced differences in ghrelin levels were not associated with major changes in GH secretion.

The distinct suppressed ghrelin levels in hyperthyroidism cannot be explained by any of the mechanisms known to affect circulating ghrelin negatively, such as elevated body mass index and energy surplus (6, 7, 21), insulin (31), GH (33, 34), and somatostatin (36); therefore, it seems plausible that an excess of thyroid hormone in itself regulates ghrelin. Weight loss (37), anorexia nervosa (38), cachexia (39), and chronic heart disease (40) are all conditions associated with low T3 levels and elevated ghrelin levels.

In summary, hyperthyroidism is associated with decreased levels of circulating serum ghrelin, and this feature is normalized after treatment. This indicates that circulating ghrelin is not the mediator of the hyperphagia associated with hyperthyroidism, and that thyroid hormone regulates circulating ghrelin levels. It is also shown that a euglycemic hyperinsulinemic clamp reduces circulating ghrelin levels compared with fasting levels independently of thyroid status.


   Acknowledgments
 
The technical assistance of Lone Svendsen and Iben Christensen is highly appreciated.


   Footnotes
 
This work was supported by grants from The Danish Health Research Council (Grant 9600822; Aarhus University-Novo Nordisk Center for Research in Growth and Regeneration), the World Anti Doping Agency, the Aarhus University Research Fund, and The Musikforlæggerne Agnes and Knut Mørks Fund.

Abbreviations: EE, Energy expenditure; FFA, free fatty acids; LBM, lean body mass; RQ, respiratory quotient.

Received August 16, 2002.

Accepted November 18, 2002.


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 Subjects and Methods
 Results
 Discussion
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