Objective: Ghrelin stimulates growth hormone (GH) secretion both in vivo and in vitro. Ghrelin is mainly produced in and released from the stomach but it is probably also produced in the hypothalamic arcuate nucleus. Whether pituitary GH release is under the control of ghrelin from the stomach and/or from the arcuate nucleus is not known. Moreover, no data on the feedback of GH on systemic ghrelin concentrations are available. It has recently been suggested that ghrelin may induce obesity. Design: In this study, we addressed the following two questions: a) are circulating ghrelin levels increased in human GH deficiency (GHD), and b) does GH treatment modify ghrelin levels in human GHD? Methods: The study group consisted of 23 patients with GHD. Eighteen had developed adult-onset GHD and five had developed GHD in their childhood (childhood-onset GHD). Ghrelin was measured with a commercially available radioimmunoassay. All measurements were performed twice, first at baseline, before the start of GH replacement therapy, and then again after one year of therapy. GH doses were adjusted every 3 months, targeting serum total IGF-I levels within the normal gender-and age-related reference values for the healthy population. Maintenance doses were continued once the target serum total IGF-I levels were reached. Results: The sum of skinfolds and body water increased significantly, body fat mass and percentage body fat decreased significantly and body mass index and waist-hip ratio were not significantly changed by one year of GH replacement therapy.Before the start of GH replacement therapy, mean value and range for fasting ghrelin in the studied GHD subjects tended to be lower in comparison with healthy subjects in the control group although the difference did not reach significance (GHD ghrelin mean 67.8 pmol/l, range 37.6-116.3 pmol/l; control mean 83.8 pmol/l, range 35.4 -132 pmol/l; P ¼ 0:11).One year of GH replacement therapy did not modify circulating ghrelin levels (ghrelin before GH therapy: 67.8 pmol/l, range after GH therapy: 65.3 pmol/l,; P ¼ 0:56). Conclusions: We did not observe elevated ghrelin levels in adult GHD subjects and GH replacement therapy did not modify circulating ghrelin levels, despite significant decreases in body fat mass and percentage body fat. It is conceivable that the lack of ghrelin modifications after long-term GH therapy was due to the reduction of adiposity and insulin on one hand, and increased GH secretion on the other. However, it is still possible that systemic ghrelin is involved in the development of obesity, both in normal and GHD subjects.

Introduction: In an animal model of acromegaly (PEPCK-hGH transgenic mice), low systemic levels of ghrelin have been observed compared with normal mice. We hypothesized that systemic circulating ghrelin levels are also decreased in humans with active acromegaly and that the contribution of central ghrelin production to systemic ghrelin levels is minimal. Objectives: The aim of the present study was to investigate, in two subjects with active acromegaly, whether there are differences between systemic ghrelin levels and ghrelin concentrations in the petrosal sinus. Design: We measured systemic and central ghrelin levels in these two acromegalic patients by bilateral simultaneous inferior petrosal sinus sampling. Central and systemic blood samples were drawn before and 1, 5, 10, 15 and 20 min after stimulation with GH-releasing hormone (GHRH). Ghrelin was measured with a commercially available radioimmunoassay. Results: In one acromegalic subject, the baseline systemic and central ghrelin levels were within the same range as in two non-acromegalic obese subjects. No gradient could be observed between central and systemic ghrelin concentrations. Stimulation with GHRH did not change the ghrelin concentrations in this patient. In the other acromegalic subject, the systemic ghrelin levels were also in the same range as in two non-acromegalic obese subjects. However, in this subject, baseline ghrelin concentrations in the right inferior petrosal vein were considerably lower than the systemic ghrelin concentrations, indicating a peripheral over central gradient. Administration of GHRH induced a significant rise in central ghrelin concentrations in the right inferior petrosal vein. Ghrelin levels in the left inferior petrosal vein and systemic ghrelin levels were in the normal range and GHRH stimulation did not change these concentrations. Conclusions: The absence of a central over peripheral ghrelin gradient in these two acromegalics indicated that circulating ghrelin is mainly produced peripherally. Circulating systemic ghrelin levels were not decreased in these two subjects with active acromegaly.