Marked GH secretion after ghrelin alone or combined with GH-releasing hormone (GHRH) in obese patients

OBJECTIVES Ghrelin is a 28-amino-acid peptide, predominantly produced by the stomach. It displays a strong GH-releasing activity mediated by the hypothalamus-pituitary GH secretagogue (GHS)-receptor (GHS-R). There are different studies that suggest the importance of ghrelin in feeding and weight homeostasis. In obesity there is a markedly decreased GH secretion. For both children and adults, the greater the body mass index (BMI), the lower the GH response to provocative stimuli, including the response to GHRH. However, the response to the natural GH secretaogogue ghrelin is unclear at the present time. The aim of the present study was to evaluate the GH response to ghrelin alone or combined with GHRH in a group of obese patients, in order to further understand the deranged GH secretory mechanisms in obesity and to clarify the mechanism of action of ghrelin. PATIENTS AND MEASUREMENTS Six obese female patients (31 +/- 3.4 years) with a BMI of 36.1 +/- 7.7 kg/m(2) were studied. As a control group, six normal nonobese female subjects of similar age and sex were studied. Four tests were performed: placebo, GHRH [1 mug/kg, no more than 100 mug, intravenous (i.v.)], ghrelin (1 mug/kg, no more than 100 mug, i.v.) and GHRH (1 mug/kg, no more than 100 mug, i.v.) plus ghrelin (1 mug/kg, no more than 100 mug, i.v.). Blood samples were taken at appropriate intervals for determination of GH. Statistical analyses were performed by Wilcoxon and by Mann-Whitney tests. RESULTS After GHRH, the median peak GH secretion in obese patients was 2.4 mug/l (range 0.9-8.9 mug/l). Ghrelin-induced GH secretion showed in obese patients a median peak of 24.4 mug/l (range 7.4-85.0 mug/l), significantly greater than the response after GHRH (P < 0.05). After the combined administration of GHRH plus ghrelin in obese patients the median peak GH secretion was 39.9 mug/l (range 19.2-120.0 mug/l), significantly greater than the response after GHRH (P < 0.05) or ghrelin (P < 0.05). GHRH-induced GH secretion in normal control subjects showed a median peak of 25.0 mug/l (range 16.5-33.4 mug/l). Ghrelin-induced GH secretion in normal showed a median peak of 68.5 mug/l (range 22.5-119.5 mug/l), significantly greater than the response after GHRH (P < 0.05). After the combined administration of GHRH plus ghrelin, in normal subjects the median peak GH secretion was 117.8 mug/l (range 77.5-280.1 mug/l), significantly greater than the response after GHRH or ghrelin alone (P < 0.05). When we compare the response of normal and obese patients, after GHRH alone, it was markedly decreased in obese people when compared with normal patients (P < 0.05) with a median GH peak of 25.0 mug/l (range 16.5-33.4 mug/l) and 2.4 mug/l (range 0.9-8.9 mug/l) for normal and obese patients, respectively. When we compare the response of normal and obese patients, after ghrelin alone or GHRH plus ghrelin, it was only blunted in obese subjects when compared with normal subjects with a median GH peak of 68.5 mug/l (range 22.5-119.5 mug/l) and 24.4 mug/l (range 7.4-85 mug/l) for normal and obese subjects, respectively, after ghrelin alone (P < 0.05) and a median GH peak of 117.8 mug/l (range 77.5-280.1 mug/l) and 39.9 mug/l (range 19.2-120.0 mug/l) for normal and obese patients, respectively, after GHRH plus ghrelin (P < 0.05). CONCLUSIONS This study has demonstrated a massive GH response to ghrelin alone or combined with GHRH in obese patients, suggesting that altered ghrelin secretion could play a major role in the blunted GH secretion present in obese patients.