The changes in serum ghrelin levels and their relationship to IGF-I, its binding proteins and leptin in women patients with anorexia nervosa

Ghrelin is recently discovered peptide hormone involved in the regulation of growth hormone secretion as well as in the regulation of food intake and energetic homeostasis. The study was aimed to describe the changes in ghrelin serum levels in patients with anorexia nervosa and its relationship to some other studied parameters. Sixteen women patients with anorexia nervosa and thirteen healthy women of comparable age were examined clinically and blood samples were taken for estimation of serum levels of ghrelin, leptin, soluble leptin receptor, IGF-I, IGFBP-1 and IGFBP-3. Ghrelin serum levels were significantly increased in the group of patients with anorexia nervosa (p < 0,05). In contrary, serum leptin levels were decreased in the group of patients with anorexia nervosa (p < 0,01). Serum ghrelin levels did not correlate with any other of studied parameters with exception of BMI. We can conclude that serum ghrelin levels are increased in patients with anorexia nervosa and their increase fails to significantly stimulate food intake in this group of patients.     

Effects of growth hormone (GH) on ghrelin, leptin, and adiponectin in GH-deficient patients

Ghrelin is a recently discovered gastric peptide that increases appetite, glucose oxidation, and lipogenesis and stimulates the secretion of GH. In contrast to ghrelin, GH promotes lipolysis, glucose production, and insulin secretion. Both ghrelin and GH are suppressed by intake of nutrients, especially glucose. The role of GH in the regulation of ghrelin has not yet been established. We investigated the effect of GH on circulating levels of ghrelin in relation to its effects on glucose, insulin, body composition, and the adipocyte-derived peptides leptin and adiponectin. Thirty-six patients with adult-onset GH deficiency received recombinant human GH for 9 months in a placebo-controlled study. Body composition and fasting serum analytes were assessed at baseline and at the end of the study. The GH treatment was accompanied by increased serum levels of IGF-I, reduced body weight (-2%) and body fat (-27%), and increased serum concentrations of glucose (+10%) and insulin (+48%). Ghrelin levels decreased in 30 of 36 subjects by a mean of -29%, and leptin decreased by a mean of -24%. Adiponectin increased in the women only. The decreases in ghrelin and leptin correlated with changes in fat mass, fat-free mass, and IGF-I. The reductions in ghrelin were predicted independently of the changes in IGF-I and fat mass. It is likely that the reductions in ghrelin and leptin reflect the metabolic effects of GH on lipid mobilization and glucose production. Possibly, a suppression of ghrelin promotes loss of body fat in GH-deficient patients receiving treatment. The observed correlation between the changes in ghrelin and IGF-I may suggest that the GH/IGF-I axis has a negative feedback on ghrelin secretion.     

Serum levels of ghrelin, leptin, IGF-I, IGFBP-3, insulin, thyroid hormones and cortisol in prepubertal children with iron deficiency

The aim of the present study is to investigate possible alterations in ghrelin and other hormone levels related to appetite and somatic growth in children with iron deficiency anemia. Twenty-five patients and 25 healthy controls that were prepubertal and within normal limits regarding height and BMI standard deviation scores were recruited. Ghrelin, leptin, IGF-I, IGFBP-3, insulin, thyroid hormones and cortisol levels were studied. Ghrelin, insulin and IGF-I levels were significantly low in the study group (ghrelin 13.58 +/- 16.32 vs. 35.39 +/- 23.69 ng/ml, p<.001; insulin 3.41 +/- 2.42 vs. 5.67 +/- 1.09 mU/ml, p = .008 and IGF-I 126.94 +/- 92.82 vs. 203 +/- 105.1 ng/ml, p = .015). We concluded that low ghrelin and insulin levels might be causes of the appetite loss in iron deficiency and as a result of appetite loss and undernutrition as well as by direct effects they might be related with growth retardation, which could be also influenced by low IGF-I levels.     

Preliminary evidence that pharmacologic melatonin treatment decreases rat ghrelin levels

Ghrelin is a signal peptide isolated from rat stomach antagonistic to actions of leptin. Ghrelin stimulates the secretion of growth hormone (GH) and increases food intake, body mass, and adiposity in rodents. Photoperiod and melatonin regulate leptin secretion of mammals. The aim of the study was to investigate possible melatonin-ghrelin interactions in weight regulation by studying the effects of continuous pharmacologic melatonin treatment and constant light on plasma ghrelin, leptin, and GH levels in rats. Plasma ghrelin concentrations were significantly reduced by exogenous melatonin. Ghrelin levels correlated negatively with plasma leptin levels in control rats kept in 12 h of light/12 h of dark but not in the melatonin-treated animals. The inverse ghrelin-leptin relationship was also disrupted by constant illumination. The circulating ghrelin and GH levels may not be interrelated in all metabolic situations. The results suggest new interplay between the pineal gland and energy metabolism as well as reenforce the hypothesis that ghrelin is antagonistic to leptin.     

Ghrelin concentrations in healthy children and adolescents

OBJECTIVE: In addition to its regulation by GH releasing hormone (GHRH) and somatostatin, release of GH from the pituitary is modulated by a third factor, ghrelin, which is expressed in high concentration in the stomach and is present in the circulation. Ghrelin has also been shown to cause weight gain by increasing food intake and decreasing fat utilization. Ghrelin is a potential candidate hormone to influence nutrient intake and growth. Its role through normal childhood and adolescence has not been fully defined. DESIGN: Cross-sectional study in 121 healthy children (65 male, 56 female) aged 5-18 years, in whom height, weight, body mass index (BMI), pubertal status and measurements of IGF-I, IGFBP-3, IGFBP-1 and leptin were available. METHODS: Serum ghrelin concentrations have been measured in radioimmunoassay (RIA; Phoenix, AZ, USA) that detects active and inactive human ghrelin. Relationships between ghrelin and anthropometric data and growth factors were assessed by correlation and regression analyses. RESULTS: Ghrelin was detected in all samples, with a median concentration of 162 pg/ml, range 60-493 pg/ml. Prepubertal children had higher ghrelin concentrations than those in puberty [218 pg/ml (n = 42) and 157 pg/ml (n = 79), P < 0.001], with significant negative correlations between ghrelin and age (rs = -0.39, P < 0.001) and pubertal stage (rs = -0.42, P < 0.001). The decrease in ghrelin with advancing pubertal stage/age was more marked in boys than girls. In the whole group, ghrelin was negatively correlated to BMI SD (rs = -0.24, P = 0.006) and to weight SD (rs = -0.24, P = 0.008) but not height sds. Ghrelin was also negatively correlated to IGF-I (rs = -0.48, P < 0.001), IGFBP-3 (rs = -0.32, P < 0.001) and leptin (rs = -0.22, P = 0.02) but not IGF-II. It was positively related to IGFBP-1 (rs = +0.46, P < 0.001). In stepwise multiple regression, 30% of the variability in ghrelin through childhood could be accounted for by log IGF-I (24%) and log IGFBP-1 (6%). CONCLUSIONS: The fall in ghrelin over childhood and with puberty does not suggest that it is a direct growth-promoting hormone. However in view of the negative relationship with IGF-I and the positive relationship with IGFBP-1, this fall in ghrelin could facilitate growth acceleration over puberty.     

Plasma levels of active and total ghrelin in renal failure: A relationship with GH/IGF-I axis

Ghrelin was originally isolated from the rat stomach and significant amounts were found also in the kidney. Present study was designed to examine changes in ghrelin levels in renal failure and their relationship to the GH/IGF-I axis. Fourty patients with mild-to-severe CRF (19 men, 21 women, aged 62.5 +/- 2.2 years, BMI 27.57 +/- 0.73 kg/m(2)) and 34 healthy control subjects (17 men, 17 women, aged 60 +/- 2.6 years, BMI 27.55 +/- 0.79 kg/m(2)) were included in the study. Total ghrelin levels were significantly increased in patients with chronic renal failure (CRF) (p < 0.0001). Total ghrelin in CRF correlated positively with active ghrelin (p < 0.001), GH (p < 0.05), IGF-I (p < 0.05), free IGF-I (p = 0.0001), IGFBP-3 (p < 0.01), IGFBP-2 and -6 (p < 0.05). Active ghrelin in CRF correlated positively with IGF-I (p < 0.001), free-IGF-I (p < 0.005), IGFBP-2 (p < 0.05) and IGFBP-3 (p < 0.05). However, most of the correlation were markedly reduced and the significance disappeared after adjustment for different creatinine levels. Hemodialysis in patients with end stage renal disease (ESRD) resulted in a significant reduction of plasma total and active ghrelin (p < 0.01 and p < 0.001 respectively). In conclusion we demonstrated elevated plasma levels of total ghrelin in CRF, and a reduction of total and active ghrelin after a single course of hemodialysis in ESRD. The elevation of ghrelin levels could be caused by impaired clearance and/or metabolism of ghrelin in the kidney. We did not prove clearly significant relationship between ghrelin serum levels and parameters of GH/IGF-I axis in study subjects.     

Effect of sex hormone administration on circulating ghrelin levels in peripubertal children

BACKGROUND: Ghrelin levels gradually decrease throughout childhood and with advancing pubertal stage. The change during puberty is more pronounced in boys than girls. OBJECTIVE: The objective of the study was to investigate whether the pubertal drop in ghrelin secretion is modified by the increase in sex hormones. PATIENTS AND METHODS: Ghrelin levels were measured in 34 short peripubertal children (17 boys and 17 girls) aged 8-12.5 yr before and after sex hormone priming for GH stimulation testing. RESULTS: In boys, priming with testosterone increased testosterone to pubertal levels (23.7 +/- 7.1 nmol/liter), which in turn induced a marked decrease in ghrelin (from 1615.8 +/- 418.6 to 1390.0 +/- 352.0 pg/ml) and leptin (from 8.0 +/- 4.5 to 5.8 +/- 3.2 ng/ml) and an increase in IGF-I (from 162.7 +/- 52.8 to 291.1 +/- 101.6 ng/ml) (P < 0.001 for all parameters). In girls, priming with estrogen led to a supraphysiological increase in estradiol levels (1313.8 +/- 438.0 pmol/liter), which had no effect on ghrelin, leptin, or IGF-I. There was no correlation between ghrelin levels and levels of sex hormones, leptin, or body mass index in either boys or girls. CONCLUSIONS: A pharmacological increase in sex hormones is associated with a marked decline in circulating levels of ghrelin in boys but not girls. Additional longitudinal studies through puberty are needed to elucidate the physiological interaction between sex hormones and ghrelin.     

Serum ghrelin, IGF-I and IGFBP-3 levels in children with normal variant short stature

This study is planned to investigate the role of ghrelin in normal variant short stature. Serum ghrelin, IGF-I and IGFBP-3 levels were measured in 17 children with constitutional delay of growth, 19 children with familial short stature and 11 age matched healthy children. Mean bone age of the constitutional delay of growth group was lower compared to other groups. Constitutional delay of growth group had lower mean weight compared to the controls. Serum IGF-I values were lower in the constitutional delay of growth group compared to the familial short stature and control groups. IGFBP-3 levels of the groups were similar. Ghrelin levels were higher in the short stature groups compared to the controls. In the multiple regression analyses, weight (beta = -.54, p < 0.0001) and height SDS (beta = -.33, p = 0.01) were the independent determinants of ghrelin. The results of this study, the first one in which ghrelin levels are investigated in normal variant short stature, suggest that ghrelin does not play a role as a cause, but as a consequence in these patients because it is negatively correlated with weight and height standard deviation score. These negative correlations can be attributed to the compensatory response of ghrelin, which deserves further attention in future studies.     

Ghrelin: beyond hunger regulation

Man ingests food to mitigate hunger (mediated by physiological and biochemical signals), satisfy appetite (subjective sensation) and because of psychosocial reasons. Satiation biomarkers (stop feeding) are gastric distention and hormones (CCK, GLP-1) and satiety biomarkers (induce feeding) are food-induced thermogenesis, body temperature, glycaemia and also hormones (insulin, leptin and ghrelin). Oxidative metabolism/body composition, tryptophan/serotonin and proinflammatory cytokines are also implicated on hunger physiology. At the present time, ghrelin is the only known circulating orexigenic with potential on hunger/body weight regulation. It is a neuropeptide (endogenous ligand for the GH secretagogue) recently isolated from the oxyntic mucosa and synthesized mainly in the stomach. Its blood concentration depends on diet, hyperglucemia and adiposity/leptin. It is secreted 1-2 hours preprandially and its concentration decreases drastically during the postprandium. Ghrelin acts on the lateral hypothalamus and theoretically inhibits proinflammatory cytokine secretion and antagonizes leptin. Ghrelin physiologically increases food intake and stimulates adipogenesis, gastrointestinal motility and gastric acid secretion, and has other hormonal and cardiovascular functions. Ghrelin blood concentration is reduced in massive obesity, non-alcoholic steatohepatitis, polycystic ovary syndrome, acromegaly, hypogonadism, ageing, short bowel syndrome and rheumatoid arthritis; and increased in primary or secondary anorexia, starvation, chronic liver disease and celiac disease. Cerebral and peritoneal ghrelin administration (rats) and systemic administration (rats and healthy volunteers, cancer patients or patients on peritoneal dialysis) promotes food consumption and increases adiposity, of utmost importance in the treatment of patients with anorexia.     

Plasma ghrelin levels in healthy elderly volunteers: the levels of acylated ghrelin in elderly females correlate positively with serum IGF-I levels and bowel movement frequency and negatively with systolic blood pressure

Aging is associated with a decrease in growth hormone (GH) secretion, appetite and energy intake. As ghrelin stimulates both GH secretion and appetite, reductions in ghrelin levels may be involved in the reductions in GH secretion and appetite observed in the elderly. However, only preliminary studies have been performed on the role of ghrelin in elderly subjects. In this study, we sought to clarify the physiologic implications of the age-related alterations in ghrelin secretion by determining plasma ghrelin levels and other clinical parameters in healthy elderly subjects. Subjects were > or = 65 years old, corresponding to the SENIEUR protocol, had not had a resection of the upper gastrointestinal tract and had not been treated with hormones. One hundred and five volunteers (49 men and 56 women) were admitted to this study (73.4 +/- 6.3 years old). Plasma levels of acylated ghrelin in elderly female subjects positively correlated with serum IGF-I levels and bowel movement frequency and negatively with systolic blood pressure. In elderly men, desacyl ghrelin levels correlated only weakly with bowel movement frequency. These findings suggest that the plasma levels of the acylated form of ghrelin may influence the age-related alterations in GH/IGF-I regulation, blood pressure and bowel motility. These observational associations warrant further experimental studies to clarify the physiologic significance of these effects.     

Balance in ghrelin and leptin plasma levels in anorexia nervosa patients and constitutionally thin women

Ghrelin, a 28-amino acid octanoylated peptide, has recently been identified in rat stomach as an endogenous ligand for the GH secretagogue receptor. In addition to GH-releasing properties, exogenous ghrelin injections exert orexigenic effects in both rodents and humans. As the endogenous peptide appears directly related to feeding behavior, we assessed its plasma levels in anorexia nervosa (AN) patients before and after renutrition and in constitutionally thin subjects with body mass indexes (BMIs) equivalent to those of AN women but with no abnormal feeding behavior. The relationships between plasma ghrelin levels and other neuroendocrine and nutritional parameters, such as GH, leptin, T3, and cortisol, were also investigated. In AN patients, morning fasting plasma ghrelin levels were doubled compared with levels in controls, constitutionally thin subjects, and AN patients after renutrition. Twenty-four-hour plasma ghrelin, GH, and cortisol levels determined every 4 h were significantly increased, whereas 24-h plasma leptin levels were decreased in AN patients compared with controls and constitutionally thin subjects. Both plasma ghrelin and leptin levels returned to control values in AN patients after renutrition. Constitutionally thin subjects displayed intermediate 24-h plasma ghrelin and leptin levels, significantly different from controls and AN patients, whereas GH and cortisol were not modified. Ghrelin was negatively correlated with BMI, leptin, and T(3) in controls, constitutionally thin subjects, and AN patients, whereas no correlation was found between GH and ghrelin or between cortisol and ghrelin. Ghrelin and BMI or T3 were still correlated after renutrition, suggesting that ghrelin is also a good nutritional indicator. Basal and GHRH-stimulated GH release were significantly increased in AN patients only. In conclusion, ghrelin is increased in AN and constitutionally thin subjects who display very low BMI but different eating behaviors, suggesting that not only is ghrelin dependent on body fat mass, but it is also influenced by nutritional status. Even though endogenous ghrelin is not strictly correlated with basal GH secretion, it may be involved in the magnitude of GHRH-induced GH release in AN patients.     

Impact of Helicobacter pylori infection on ghrelin and various neuroendocrine hormones in plasma

AIM: Ghrelin, an endogenous ligand for growth hormone secretagogue receptor, influences appetite, energy balance, gastric motility and acid secretion. The stomach is the main source of circulating ghrelin. There are inconsistent reports on the influence of Helicobacter pylori (H pylori) infection on circulating ghrelin levels. We sought to elucidate the relationship between ghrelin and various peptides in plasma, with special reference to H pylori. METHODS: Plasma ghrelin levels were measured by radioimmunoassay in 89 subjects who were referred for upper gastrointestinal endoscopy, consisting of 42 H pylori infected and 47 uninfected ones. Plasma gastrin, somatostatin, leptin, insulin-like growth hormone 1 (IGF-1) and chromogranin A concentrations were also measured. Twelve patients were treated with anti- H pylori regimen. RESULTS: Ghrelin circulating levels were greatly decreased in H pylori-positive than negative individuals (194.2±90.2 fmol/mL and 250.4±84,1 respectively, P<0.05), but did not significantly alter following the cure of infection (176.5±79.5 vs 191.3±120.4). There was a significant negative correlation between circulating ghrelin and leptin levels, as well as body mass index, for the whole and uninfected population, but not in H pylori-infected patients. Plasma ghrelin concentrations correlated positively with IGF-1 in H pylori-negative group and negatively with chromogranin A in the infected group. There were no significant correlations among circulating levels of ghrelin, gastrin and somatostatin irrespective of H pylori status. CONCLUSION: H pylori infection influences plasma ghrelin dynamics and its interaction with diverse bioactive peptides involved in energy balance, growth and neuroendocrine function.     

Low plasma ghrelin level in gastrectomized patients is accompanied by enhanced sensitivity to the ghrelin-induced growth hormone release

Ghrelin is a brain-gut peptide with potent GH-releasing activities. It has been suggested that the majority of circulating ghrelin originates from the stomach, with a smaller portion from the small intestine. Gastrectomy (GASTRX) significantly reduces circulating ghrelin concentrations. The implication of decreased circulating ghrelin on the somatotropic axis post GASTRX has not been studied. Therefore, we aimed to investigate the somatotropic axis in 10 gastrectomized patients who underwent total GASTRX for various reasons at least 2 yr ago. At baseline circulating total ghrelin, GH, IGF-I, and IGF binding protein (IGFBP)-3 levels were measured. The GH stimulation test consisted of an insulin-induced hypoglycemia, ghrelin in two iv bolus doses (0.1 and 1 microg/kg), and a GHRH test. GH sensitivity was assessed by an IGF-I generation test. All the tests were performed 2 wk apart. At baseline serum ghrelin levels were reduced by 55% in GASTRX patients, compared with the control group (P < 0.05). IGF-I (P < 0.05) and IGFBP-3 (P < 0.01) levels were also significantly lower than in controls. GH response to the insulin-induced hypoglycemia test in both GASTRX and control subjects was of similar magnitude, whereas circulating plasma ghrelin levels in GASTRX patients were not modified during hypoglycemia. Both doses (0.1 and 1.0 microg/kg) of ghrelin stimulated GH release significantly more in GASTRX than control subjects, respectively (peak mean GH +/- se: 18.2 +/- 5.6 vs. 5.4 +/- 1.3 microg/liter, P < 0.03; and 58.7 +/- 7.5 vs. 35.3 +/- 1.9 microg/liter, P < 0.01). There was no difference in GHRH-induced GH response between GASTRX patients and control subjects (P > 0.05). Concomitantly, increased increments in IGF-I and IGFBP-3 to a single bolus of GH were found (P < 0.03). In conclusion, our data suggest that low circulating ghrelin levels, found in GASTRX patients, are accompanied by enhanced ghrelin sensitivity with respect to GH response. This is associated with increased GH responsiveness. GASTRX is a state of acquired chronic hypoghrelinemia that may require replacement with ghrelin, and it is tempting to speculate that this may affect the GH-IGF-IGFBP axis.     

Circulating and cerebrospinal fluid ghrelin and leptin: potential role in altered body weight in Huntington's disease

OBJECTIVE: In addition to neurological impairment, weight loss is a prominent characteristic of Huntington's disease (HD). Neuropathologically, the disease affects the caudate nucleus and the cerebral cortex, and also the hypothalamus. The recently discovered orexigenic hormone of gastric origin, ghrelin and the adipocyte hormone leptin, are two peripherally produced hormones exerting opposite effects on specific populations of hypothalamic neurons that play a key role in regulating energy intake and energy output. The aim of this study was to investigate the possible involvement of cerebrospinal fluid (CSF) and circulating ghrelin and leptin in the regulation of energy balance in patients with HD. METHODS: Twenty healthy normal-weight subjects undergoing orthopedic surgery, and fifteen patients with genetically verified HD, were enrolled in this study. The unified Huntington's disease rating scale (UHDRS) was used to assess clinical course of the disease. Blood samples for hormonal measurements were obtained by venipuncture and in-parallel CSF samples for leptin/ghrelin determination were obtained by lumbar puncture. RESULTS: Patients with HD had increased concentrations of ghrelin in plasma compared with healthy subjects (4523.7+/-563.9 vs 2781.1+/-306.2 pg/ml, P<0.01). On the other hand, patients with HD had decreased concentrations of leptin in plasma compared with healthy subjects (4.8+/-1.6 vs 10.9+/-2.4 ng/ml, P<0.01). The concentrations of CSF ghrelin and CSF leptin were equivalent to values in healthy subjects. No correlation was found between disease duration--and other clinical features of HD--and plasma or CSF leptin/ghrelin levels. In patients with HD, baseline levels of GH, IGF-I, insulin and glucose did not differ from those in healthy subjects. CONCLUSION: High circulating ghrelin and low leptin levels in patients with HD suggest a state of negative energy balance. Early nutritional support of patients with HD is advocated since patients with HD and higher body mass index at presentation have slower progression of the disease.     

Ghrelin/Leptin-imbalance in patients with primary biliary cirrhosis.

BACKGROUND: The recently discovered peptide hormone ghrelin mainly produced in gastric oxyntic cells may act as a counterpart to leptin in the regulation of food intake and fat utilization. Leptin, involved in the stimulation of proinflammatory cytokines and catabolic energy balance, is elevated in patients with liver cirrhosis. In the present study, we evaluated serum ghrelin and bound leptin levels in patients with primary biliary cirrhosis (PBC) in relation to C-peptide and glucose concentration. METHODS: In 22 female patients with PBC (Child-Pugh stage A) and in 36 female controls we measured serum ghrelin, bound leptin, and C-peptide levels using specific immunoassays. RESULTS: In comparison to controls serum bound leptin levels were significantly higher in patients with PBC ( p < 0.01) whereas serum ghrelin levels were decreased compared to the control group ( p < 0.01). In parallel, C-peptide concentrations were increased ( p < 0.01) with no significant change in circulating glucose levels. CONCLUSION: Our data confirm in PBC patients that serum bound leptin levels are increased and clearly show a parallel decrease in serum ghrelin concentrations acting as a physiological counterpart to leptin. Furthermore, we suggest that these changes are linked to the insulin resistance observed in our patients.     

Estradiol potentiates ghrelin-stimulated pulsatile growth hormone secretion in postmenopausal women

CONTEXT: Ghrelin and an estrogen-rich milieu individually amplify pulsatile GH secretion by increasing the amount of hormone released per burst. However, how these distinct agonists interact in controlling pulsatile GH output is not known. OBJECTIVE: The objective of the study was to test the hypothesis that elevated estradiol (E(2)) concentrations potentiate hypothalamo-pituitary responses to a near-physiological ghrelin stimulus. DESIGN: This was a double-blind, placebo-controlled, prospectively randomized, parallel-cohort study. SETTING: The study was conducted at an academic medical center. SUBJECTS: Twenty-one postmenopausal women participated in the study. INTERVENTIONS: Eleven subjects received placebo (Pl) and 10 others E(2) transdermally in escalating doses over 3 wk to mimic late follicular-phase E(2) concentrations. Saline or a submaximally stimulatory amount of ghrelin (0.3 microg/kg) was infused iv on separate randomly ordered mornings fasting after 17-21 d of Pl or E(2) administration. OUTCOMES: Outcomes included serum concentrations of E(2), ghrelin, GH, IGF-I, IGF binding protein (IGFBP)-1 and IGFBP-3, and the estimated mass and waveform of stimulated GH secretory bursts. RESULTS: Administration of E(2) yielded late follicular-phase E(2) concentrations. Compared with Pl, E(2) did not alter ghrelin concentrations but reduced IGF-I and IGFBP-3 and elevated IGFBP-1 concentrations. Compared with saline, ghrelin infusion amplified pulsatile GH secretion by 7.1-fold (P < 0.01). The effect of E(2) alone was 2.0-fold placebo and that of combined ghrelin/E(2) 10.4-fold (P < 0.01). Ghrelin and E(2) accelerated initial GH release individually but nonadditively by more than 2-fold (P < 0.01). CONCLUSIONS: Estrogen augments ghrelin's near-physiological stimulation of pulsatile GH secretion and mimics ghrelin's acceleration of initial GH release. Thus, we hypothesize that estrogen and a GH secretagogue act via independent as well as convergent mechanisms.     

Growth hormone (GH) secretion in children with Noonan syndrome: frequently abnormal without consequences for growth or response to GH treatment

The role of GH insufficiency in the pathogenesis of short stature in Noonan syndrome is unclear. Cross-sectional study. Seventeen patients with Noonan syndrome (13 boys, 4 girls; aged 4.8-13.3 (mean 9.2) years) and short stature before start of GH treatment. Spontaneous 12-h overnight GH secretion by continuous sampling analysed using Pulsar, plasma IGF-I and IGFBP-3 levels, and 24-h urinary GH excretion were measured at start of GH treatment. A glucagon stimulation test was performed. Height and height velocity were monitored before and after 1 year of GH treatment. IGF-I and IGFBP-3 were remeasured after 1 year of GH treatment. Nine of the 17 children had a mean overnight GH concentration below the lower limit of the normal range. In six of the 17 patients, overnight GH profiles showed high trough GH concentrations. Glucagon stimulation tests were normal in 16 of the 17 patients. Mean IGF-I level was below normal (-0.4 SD). None of the parameters regarding GH secretion obtained from the overnight profile or provocative test was related to height or height velocity, nor to first year response to GH treatment. IGF-I and IGFBP-3 did not correlate with any of the GH secretion data. IGF-I and IGFBP-3 were related to height and height velocity at the start of GH treatment (r = 0.53 (P < 0.01) and r = 0.61 (P < 0.03) respectively). Rises in IGF-I and IGFBP-3 under GH treatment were related to the increment in height velocity (r = 0.70 (P < 0.01) and r = 0.71 (P < 0.02) respectively). Abnormalities in GH secretion are frequent in patients with Noonan syndrome and short stature. These abnormalities were not related to auxology at start of or response to GH treatment. Clinically GH insufficiency is not important in Noonan syndrome and monitoring spontaneous GH secretion is not necessary before the start of GH treatment.     

Ghrelin, a new gastrointestinal endocrine peptide that stimulates insulin secretion: enteric distribution, ontogeny, influence of endocrine, and dietary manipulations.

Ghrelin, an endogenous ligand for the GH secretagogue receptor was characterized recently from extracts of rat stomach. We describe the enteric distribution of ghrelin, ontogeny of stomach ghrelin gene expression, effects of dietary and endocrine manipulations, and vagotomy on stomach ghrelin mRNA and peptide levels and secretion in the rat. Ghrelin expression was examined by Northern blotting. Tissue and plasma ghrelin levels were measured by RIA. A gradient of ghrelin production occurs in the rat gastrointestinal tract with the highest ghrelin expression and peptide levels in the mucosal layer of the stomach-fundus and the lowest levels in the colon. Ghrelin was not detectable in the fetal stomach and increased progressively after birth especially during the second and third postnatal weeks. Plasma ghrelin levels also increased in parallel with stomach ghrelin levels postnatally. Exogenous GH treatment decreased stomach ghrelin expression significantly. A high-fat diet decreased plasma ghrelin levels, whereas a low-protein diet increased plasma ghrelin levels significantly. Intravenous administration of ghrelin stimulates gastrin and insulin secretion. Our findings indicate that ghrelin is an important stomach hormone sensitive to nutritional intake; ghrelin may link enteric nutrition with secretion of GH, insulin, and gastrin.     

Effect of a high-protein diet on ghrelin, growth hormone, and insulin-like growth factor-I and binding proteins 1 and 3 in subjects with type 2 diabetes mellitus

We have developed a diet that over 5 weeks dramatically lowers plasma glucose in people with type 2 diabetes mellitus. This diet consists of 30% carbohydrate, 30% protein, and 40% fat and is referred to as a Low Biologically Available Glucose (LoBAG) diet. The diet also resulted in an approximately 30% increase in fasting insulin-like growth factor-I (IGF-I). Thus, we were interested in determining if the IGF-I elevation was due to an increase in ghrelin and growth hormone (GH) or to a change in IGF-I binding proteins (IGFBPs). Eight men with type 2 diabetes mellitus ingested a control diet (15% protein, 55% carbohydrate, and 30% fat) and a LoBAG₃₀ diet for 5 weeks in a randomized crossover design with a washout period in between. Before and after each 5-week period, subjects had blood drawn for total glycated hemoglobin and, at several time points over 24 hours, for GH, IGF-I, IGFBP-1, IGFBP-3, ghrelin, glucose, and insulin. Fasting and 24-hour glucose concentrations and total glycated hemoglobin were decreased, as expected (all Ps < .05). Fasting IGF-I increased by approximately 30% (P = .05) and remained unchanged throughout 24 hours. Ghrelin, GH, IGFBP-1, IGFBP-3, and insulin were not different between diets. Insulin and IGFBP-1 concentrations were reciprocal, as expected. Insulin-like growth factor-I binding protein 1 decreased as insulin increased to greater than approximately 30 to 40 μU/mL. Ingestion of a LoBAG₃₀ diet by weight-stable subjects with type 2 diabetes mellitus resulted in an increase in total IGF-I without an increase in ghrelin, GH, and IGFBP-3 or a change in IGFBP-1 regulation. The mechanism remains to be determined.