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Smoking acutely increases plasma ghrelin concentrations.

To the Editor:

Smoking and smoking cessation are associated with weight changes (1), and many smokers give weight gain as a primary reason for not trying to quit smoking (2). A relationship has been reported between smoking and plasma concentrations of ghrelin, a 28-amino acid growth hormone-releasing peptide secreted mainly by the stomach (3-5). Our primary aim was to determine whether smoking has an acute effect on plasma ghrelin concentrations.

We enrolled 36 healthy volunteers, 28 men [mean (SD) age, 28.4 (7.5) years] and 8 women [30.4 (9.8) years]; 26 volunteers were smokers and 10 were nonsmokers. The study was approved by the Ethics Committee of our institution, and informed, written consent was obtained from each participant. None of the individuals had a history of gastric surgery or any serious health problems. Smoking history and body mass index (BMI) were determined for all participants. Blood samples were collected after overnight fasting, and plasma was frozen in aliquots at -80[degrees]C immediately after centrifugation (1600g for 15 min at 4[degrees]C).

We measured ghrelin with an enzyme immunoassay (Phoenix Pharmaceuticals). The intraassay CV was <5%, the intraassay CV was <14%, and the lower detection limit was 0.1 [micro]g/L. The participants smoked 1 filtered cigarette containing 0.8 mg of nicotine under highly regulated conditions. Every 15 s, a puff lasting 5 s was taken, and the whole cigarette had to be smoked within 5 min. Plasma ghrelin concentrations were determined at 0,2,5,15, and 60 min after the initiation of smoking.

We used the Student t-test to compare the mean values for the studied groups. Significance between groups was set at P = 0.05. The mean (SD) plasma concentrations for baseline and at 2,5,15, and 60 min are shown in Fig. 1. We observed significant increases (P <0.001) from baseline at 2,5, and 15 min after smoking. A separate analysis revealed that increases occurred in both smokers and nonsmokers. In general, peak values were observed at 2 min (Fig. 1). Baseline mean values for smokers did not differ significantly from those for nonsmokers. We observed no significant difference in mean (SD) BMI between men [25.8 (2.5) kg/[m.sup.2]] and women [23.4 (5.1) kg/ [m.sup.2]; P = 0.73] or between smokers [25.8 (3.2) kg/[m.sup.2]] and nonsmokers [23.7 (3.3) kg/[m.sup.2]; P = 0.1].

This study demonstrates the acute effect of cigarette smoking on plasma concentrations of the novel orexigenic hormone ghrelin. The most interesting finding of this study was the unexpected increase in ghrelin concentrations shortly after smoking. The effect of smoking 1 cigarette continued for at least 15 min and was independent of the BMI of each individual. The most intense increase was noted 2 min after smoking initiation. Given the known anorexic action of smoking (6), a decrease in ghrelin concentrations might be expected as an acute effect of smoking. Alcohol has also exhibited an unexpected acute inhibitory effect on ghrelin secretion in healthy individuals, despite its strong orexigenic influence in humans (7).


We speculate that this acute increase of ghrelin during smoking is related to adverse effects on gastric mucosa, gastric motility, mucosal blood flow, and concentrations of free radicals (8). Enhancement of ghrelin secretion could also be an indirect influence mediated by other factors, including growth hormone (nicotine increases the growth hormone concentration) (9), leptin (inverse correlation with ghrelin concentrations) (10), and vagal nerve stimulation (smoking affects vagal nerve activity) (11). Our finding that smoking is more likely to produce an acute release of intracellular ghrelin into the circulation rather than a time- or dose-dependent stomach secretion is partially in agreement with the hypothesis of investigators (4,5) that circulating ghrelin concentrations are related to the time elapsed after smoking. Rather than being definitive, however, our observations may also lead to hypotheses for future research.

In conclusion, the findings of this study provide evidence that smoking affects hormones that influence the appetite, specifically ghrelin. Further studies are warranted to clarify the effect of smoking on various gut hormones to explain the weight disturbances associated with smoking cessation.

We have no financial relationship with any commercial entity that has an interest in the subject of this letter. We are grateful to George Zacharis, MD, for valuable assistance in enrolling healthy volunteers for our project.


(1.) Cryer PE, Haymond MW, Santiago JV, Shah SD. Norepinephrine and epinephrine release and adrenergic mediation of smoking-associated hemodynamic and metabolic events. N Engl J Med 1976;295:573-7.

(2.) Filozof C, Fernandez Pinilla MC, Fernandez-Cruz A. Smoking cessation and weight gain. Obes Rev 2004;5:95-103.

(3.) Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999;402:656-60.

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(5.) Langenberg C, Bergstrom J, Laughlin GA, Barrett-Connor E. Ghrelin and the metabolic syndrome in older adults. J Clin Endocrinol Metab 2005;90:6448-53.

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(7.) CalissendorffJ, Danielsson 0, Brismar K, Rojdmark S. Inhibitory effect of alcohol on ghrelin secretion in normal man. Eur J Endocrinol 2005;152:743-7.

(8.) Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 2002;346:162330.

(9.) Wilkins JN, Carlson HE, Van Vunakis H, Hill MA, Gritz E, Jarvik ME. Nicotine from cigarette smoking increases circulating levels of cortisol, growth hormone, and prolactin in male chronic smokers. Psychopharmacology 1982;78: 305-8.

(10.) Chan JL, Bullen J, Lee JH, Yiannakouris N, Mantzoros CS. Ghrelin levels are not regulated by recombinant leptin administration and/or three days of fasting in healthy subjects. J Clin Endocrinol Metab 2004;89:335-43.

(11.) Niedermaier ON, Smith ML, Beightol LA, Zukowska-Grojec Z, Goldstein DS, Eckberg DL. Influence of cigarette smoking on human autonomic function. Circulation 1993;88:562-71.

Demosthenes Bouros [1] * Argyris Tzouvelekis [1] Stavros Anevlavis [1] Michael Doris [1] Stavros Tryfon [2] Marios Froudarakis [1] Vasiliki Zournatzi [1] Asterios Kukuvitis [3]

[1] Department of Pneumonology University Hospital of Alexandroupolis Alexandroupolis, Thrace, Greece

[2] Department of Pneumonology General Hospital G. Papanikolaou Thessaloniki, Greece

[3] Department of Endocrinology Medical School University of Thrace and University Hospital of Alexandroupolis Alexandroupolis, Greece

* Address correspondence to this author at: Department of Pneumonology, University Hospital of Alexandroupolis, 68100, Alexandroupolis, Thrace, Greece. Fax 30-25510-76106; e-mail

DOI: 10.1373/clinchem.2005.065243
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Title Annotation:Letters
Author:Bouros, Demosthenes; Tzouvelekis, Argyris; Anevlavis, Stavros; Doris, Michael; Tryfon, Stavros; Frou
Publication:Clinical Chemistry
Article Type:Letter to the editor
Date:Apr 1, 2006
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