Elevated ghrelin plasma levels in patients with polycystic ovary syndrome.

Polycystic ovary syndrome is a common endocrine disorder in women. It is associated with hirsuitism, obesity, insulin resistance, abnormality in the growth hormone/insulin-like growth factor I (IGF-1) axis and polycystic ovaries. The etiology of PCOS has not been clarified. Ghrelin is an endogenous ligand of the growth hormone secretagogue receptor. It is mainly secreted by stomach cells but has also been shown to be present in hypothalamus, pituitary, pancreas and gonads. Ghrelin is a regulator of energy homeostasis and GH secretion. The influence of ghrelin on insulin secretion and gonadal function is known. Since ghrelin may play an important role in pathophysiology of PCOS, we studied ghrelin levels in a group of 52 women with PCOS and in 16 women in a control group. Plasma levels of insulin, total testosterone, SHBG, LH, and FSH were also measured. In conclusion, PCOS women have higher ghrelin levels than controls. Ghrelin negatively correlates with BMI and insulin levels in PCOS group. A relation between ghrelin and SHBG was observed. Our data suggest that ghrelin could be the possible link in PCOS etiology.     

Simultaneous decrease of plasma obestatin and ghrelin levels after a high-carbohydrate breakfast in healthy women

Ghrelin is a gut peptide produced mainly by stomach, well known to induce appetite stimulatory actions. Obestatin, a recently identified peptide derived from preproghrelin, was initially described to antagonize stimulatory effect of ghrelin on food intake. The postprandial response of obestatin and its relationship with ghrelin in humans remains unknown. We therefore investigated the postprandial response of obestatin and total ghrelin, acyl and desacyl ghrelin and neuropeptide Y (NPY) to a high-carbohydrate breakfast (1 604 kJ) in eight healthy women (age: 24.2+/-0.82 years; BMI 21.6+/-0.61 kg/m(2)). Blood samples were collected before the meal, and 30, 60, 90, 120 and 150 min after the breakfast consumption. Postprandial plasma obestatin concentrations significantly decreased compared with preprandial levels as well as total ghrelin concentrations and reached the lowest values 90 and 120 min after the meal consumption, respectively (p<0.05). Plasma acyl and desacyl ghrelin concentrations decreased after the breakfast and reached lowest values in 30 and 60 min, respectively (p<0.05). Plasma NPY concentrations were lower than preprandial levels 90 and 150 min after consuming breakfast (p<0.05). In conclusion, we demonstrated in healthy young women that plasma obestatin concentrations decrease similarly to ghrelin after a high-carbohydrate breakfast.     

Age-dependent levels of plasma neuropeptides in normal children

Several neuropeptides are secreted in high amounts in pediatric tumors such as neuroblastoma and have been used as markers of residual or recurrent disease. Plasma levels of neuropeptides might be expected to change during development, but have not been determined in normal children. We have obtained fresh plasma from cord blood of six full-term infants and from peripheral blood in 41 healthy children, ages 1 month to 21 years. Levels of six neuropeptides, vasoactive intestinal peptide (VIP), somatostatin, gastrin releasing peptide (GRP), substance P, pancreastatin and neuropeptide Y (NPY) were measured by radioimmunoassay along with insulin-like growth factor-1 (IGF-1) whose plasma levels are known to vary during development. A child with neuroblastoma was treated with the somatostatin analogue, octreotide, and the effect on plasma neuropeptides quantified. Octreotide doses of 2-3 microg/kg daily resulted in a 40-60% decrease in plasma levels of IGF-1, pancreastatin and GRP. These results are the first publication of plasma neuropeptide levels in normal children.     

Enhanced plasma ghrelin levels in rats with streptozotocin-induced diabetes

Human saliva, which contains nitrite, is normally mixed with gastric juice, which contains ascorbic acid (AA). When saliva was mixed with an acidic buffer in the presence of 0.1 mM AA, rapid nitric oxide formation and oxygen uptake were observed. The oxygen uptake was due to the oxidation of nitric oxide, which was formed by AA-dependent reduction of nitrite under acidic conditions, by molecular oxygen. A salivary component SCN⁻ enhanced the nitric oxide formation and oxygen uptake by the AA/nitrite system. The oxygen uptake by the AA/nitrite/SCN⁻ system was also observed in an acidic buffer solution. These results suggest that oxygen is normally taken up in the stomach when saliva and gastric juice are mixed.     

Preeclampsia is associated with a decrease in plasma coenzyme Q10 levels

Preeclampsia is a common ( approximately 7% of all pregnancies) disorder of human pregnancy in which the normal hemodynamic response to pregnancy is compromised. Despite many years of intensive research, the pathogenesis of preeclampsia is still not fully understood. The objective of the present study was to investigate the concentration of coenzyme Q10 in normal pregnancy and preeclampsia. Pregnant women (n = 18), women with preeclampsia (n = 12), and nonpregnant normotensive women (n = 22) were included. Plasma levels of coenzyme Q10 were measured by high-performance liquid chromatography. Plasma coenzyme Q10 levels were significantly higher in normal pregnant women (mean = 1.08, SEM = 0.08 umol/l; p <.005) in comparison to nonpregnant women (mean = 0.86, SEM = 0.16 umol/l) and women with preeclampsia (mean = 0.7, SEM = 0.03 umol/l; p <.0001). These results demonstrated that during preeclampsia there is a significant decrease in plasma levels of coenzyme Q10 compared to normal pregnant women, and compared to those who are not pregnant.     

Sleep enhances nocturnal plasma ghrelin levels in healthy subjects

Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor, has been shown to promote slow-wave sleep (SWS, non-REM sleep stages 3 and 4). Plasma levels of ghrelin are dependent on food intake and increase in sleeping subjects during the early part of the night. It is unknown whether sleep itself affects ghrelin levels or whether circadian networks are involved. Therefore, we studied the effect of sleep deprivation on nocturnal ghrelin secretion. In healthy male volunteers, plasma levels of ghrelin, cortisol, and human growth hormone (hGH) were measured during two experimental sessions of 24 h each: once when the subjects were allowed to sleep between 2300 and 0700 and once when they were kept awake throughout the night. During sleep, ghrelin levels increased during the early part of the night and decreased in the morning. This nocturnal increase was blunted during sleep deprivation, and ghrelin levels increased only slightly until the early morning. Ghrelin secretion during the first hours of sleep correlated positively with peak hGH concentrations. We conclude that the nocturnal increase in ghrelin levels is more likely to be caused by sleep-associated processes than by circadian influences. During the first hours of sleep, ghrelin might promote sleep-associated hGH secretion and contribute to the promotion of SWS.     

Hypopigmentation in the Prader-Willi syndrome.

Cutaneous and ocular pigmentation were evaluated in 29 individuals with the Prader-Willi syndrome (PWS). Criteria for hypopigmentation included the presence of type I or II skin, the lightest skin type in the family by history, and iris translucency on globe transillumination. On the basis of these criteria, 48% of the PWS individuals were hypopigmented. The presence of hypopigmentation correlated with a small interstitial deletion on the proximal long arm of chromosome 15; however, this deletion was also found in individuals who did not meet the full criteria for hypopigmentation. Hairbulb tyrosinase activity and glutathione content, as well as urine cysteinyldopa excretion, were low in PWS individuals with and without hypopigmentation and did not separate these two groups. We conclude that hypopigmentation is found in a significant proportion of individuals with PWS and that the hypopigmentation may be associated with a deletion of the long arm of chromosome 15. The mechanism for the hypopigmentation is unknown.     

Increased plasma ghrelin levels in chronic renal failure are not associated with hemodynamic parameters.

BACKGROUND/AIMS: Hardly anything is known about the effect of renal function on plasma ghrelin levels. Ghrelin is an orexigenic hormone with important hemodynamic effects. We examined differences in plasma ghrelin levels between chronic renal failure (CRF) patients and healthy subjects, and ghrelin's relationship with indices of left ventricular (LV) function. METHODS: Fasting total plasma ghrelin levels were measured in 122 CRF patients (57 on, 65 not on hemodialysis) and 57 control subjects. Indices of LV function were evaluated using echocardiography. RESULTS: Total plasma ghrelin levels were higher in patients with CRF compared to controls, but were not different between patients on and those not on hemodialysis. In a multivariate linear regression model, presence of kidney dysfunction explained 41 % of the variability of ghrelin values. The etiology of renal failure (diabetic nephropathy or not) had no influence on ghrelin levels in the renal patients. Ghrelin levels were not associated with indices of LV systolic function or blood pressure in these patients. CONCLUSION: Fasting plasma ghrelin concentrations are higher in CRF patients regardless of their need for hemodialysis compared to controls. The etiology of renal failure does not have any effect on plasma ghrelin levels. In addition, ghrelin levels are not associated with hemodynamic parameters in patients with CRF.     

Sudden death of a girl with Prader-Willi syndrome

We report on the sudden death of a 3.5-year-old girl with Prader-Willi syndrome (PWS) and 15q11-q13 deletion. She suffered from severe chronic breathing disturbances and recurrent bronchitis. During an episode of acute bronchitis she had a cardiac arrest and died two months later of the sequelae. Brain CT imaging three weeks after the arrest showed bilateral symmetrical haemorrhages in the basal ganglia region. The spatial distribution of the haemorrhages can possibly suggest that the basal ganglia in PWS may be especially susceptible to hypoxemia.     

Behavioral and emotional problems in youngsters with Prader-Willi syndrome.

In this study we document the behavioral/emotional problems of 27 Prader-Willi syndrome (PWS) subjects assessed with the Achenbach Child Behaviour Checklist. Compared with normal subjects of the same age and sex, PW subjects showed significantly more problem behaviour. Of the PWS subjects 87% had total problem scores in the clinical range. No significant difference was found in the proportion of Prader-Willi patients scored in the clinical range on the Internalizing over the Externalizing syndrome. The need for systematic attention towards behavioral/emotional problems when PWS patients enter adolescence is emphasized.     

Acute insulin infusion decreases plasma ghrelin levels in uncomplicated obesity

BACKGROUND: Plasma ghrelin levels have been shown to decrease after insulin infusion in lean subjects. Nevertheless, the mechanism of the suggested inhibitory effect of insulin on ghrelin is still unclear and no data about the effect of acute insulin infusion on plasma ghrelin concentration in obese subjects are available. OBJECTIVE: We sight to evaluate plasma ghrelin concentration during an hyperinsulinemic euglycemic clamp in uncomplicated obese subjects. METHODS: 35 uncomplicated obese subjects, body mass index (BMI) 43.3+/-10.1 kg/m(2), 33 women and 2 men, mean age 34.9+/-10, with a history of excess fat of at least 10 years underwent euglycemic hyperinsulinemic clamp. Blood samples for ghrelin were performed at baseline and steady state of euglycemic insulin clamp. RESULTS: Ghrelin concentrations decreased over time to 10.6+/-15% (range 2-39%) of baseline, from a mean of 205.53+/-93.79 pg/ml to 179.03+/-70.43 pg/ml during the clamp (95% CI, 10.69 to 36.44, P<0.01). In a univariate linear regression analysis baseline plasma ghrelin levels were inversely correlated to BMI (r=-0.564, P=0.04). A linear positive trend between whole body glucose utilization (M(FFMkg) index) and ghrelin reduction during the clamp was found (chi(2) 3.05, p=0.05). CONCLUSIONS: Our data seem to suggest that hyperinsulinemia during a euglycemic clamp is able to suppress plasma ghrelin concentrations in uncomplicated obesity. This effect appears to be positively related to insulin sensitivity.     

Deaths in children with Prader-Willi syndrome. A contribution to the debate about the safety of growth hormone treatment in children with PWS

Irrespective of GH treatment, children with Prader-Willi syndrome (PWS) suffer more frequently and more seriously from respiratory problems than healthy children. The pathogenesis of such respiratory problems in PWS seems to be multifactorial in origin, but mainly related to insufficiency of respiratory muscles and pharyngeal narrowness. Deaths of children with PWS are reported among GH treated as well as untreated children. Our data show that also disturbed body composition plays an important role in fatal outcomes, possibly enhancing the ventilation disorder. For several years, in our recommendations we have pointed out the secondary risks of increasing obesity. In addition, it is recommended for all children with PWS, in particular before institution of GH therapy, to have polysomnography and an otorhinolaryngologic examination performed, and tonsillectomy in the case of enlarged tonsils. Furthermore, upper airway infections should be treated aggressively.     

Auxological and endocrine evolution of 28 children with Prader-Willi syndrome: effect of GH therapy in 14 children

We report on the auxological and endocrine evolution of 28 patients presenting with Prader-Willi syndrome. Half of them received growth hormone (GH) therapy (group 2). The spontaneous auxological evolution was analyzed in the two groups from 2 to 8 years; the mean SDS for height remained stable (-0.6 +/- 0.6) in group 1 and decreased (from -2.0 +/- 0.9 to -2.7 +/- 0.6) in group 2. Magnetic resonance imaging showed marked pituitary hypoplasia in the two groups. In group 2, the mean GH peak after two provocative tests was 3.8 +/- 2.4 microg/l, the mean SDS values for insulin-like growth factor I levels were -2.0 +/- 1.5 (range from -0.5 to -5.0). The mean duration of GH treatment was 3.6 +/- 2.9 (range 1-9.3) years. 14 children completed 1 year of treatment. The two groups had opposite evolutions in Delta SDS for height (-0.8 +/- 0.8 vs. +1.1 +/- 0.8), for growth velocity (-1.9 +/- 2.2 vs. +2.9 +/- 2.7), and for Z score of the body mass index (+0.37 +/- 1.3 vs. -0.14 +/- 0.76; group 1 vs. group 2). This retrospective study shows that, in children with Prader-Willi syndrome and true GH deficiency, long-term GH therapy is effective in increasing growth velocity and in maintaining body mass index.     

Body composition abnormalities in children with Prader-Willi syndrome and long-term effects of growth hormone therapy

Obesity and hypothalamic GH deficiency contribute in different ways to the disturbances of body composition in Prader-Willi syndrome (PWS); while both increase the fat compartment, the reduction of lean tissue mass has been attributed mainly to GH deficiency. Therefore, body composition measured by dual-energy X-ray absorptiometry was prospectively studied in 12 overweight children with PWS and weight for height (WfH) SDS >0 before and during 3.5 years of treatment with hGH (0.037 mg/kg/day) on average. In the long term, there is a net reduction of body fat from 3.1 to 1.2 SD, with a minimum at the end of the second year of treatment. WfH SDS correctly reflects body fat mass and its changes. The initial deficit of lean mass (-1.6 SD) is counteracted by GH only during the first year of therapy (increase to -1.25 SD). But in the long term, GH therapy does not further compensate for this deficit, when lean mass is corrected for its growth-related increase. In conclusion, exogenous GH changes the phenotype of children with PWS: fat mass becomes normal, but, at least in the setting studied, GH is not sufficient to normalize lean tissue mass.     

Psychological profile and behavioural characteristics in 12 patients with Prader-Willi syndrome.

In the present study medical, psychological and behavioural aspects in 12 patients with Prader-Willi syndrome (PWS), aged between 13 months and 28 years are presented. In half of the patients the diagnosis of PWS was made before the age of one year. The contribution of cytogenetic investigations with the detection of a 15q11 deletion in half of the PWS patients is discussed. In the evaluation of the intellectual performances IQ levels were spread between 45 and 95 with a mean IQ of 54. A specific behavioral profile in all patients with characteristic fluctuations with age was observed. Rapid changes in behaviour increased with age and after puberty, mostly related with withholding of food. The present study reinforces the importance of early diagnosis in the PWS with adequate and intelligible information towards the parents. It may prevent the dramatic obesity which leads to severe physical problems and psychological burdens in PWS adolescents and adults.     

Effect of chronic stress on gastric emptying and plasma ghrelin levels in rats

Chronic stress is associated with gastrointestinal functional diseases. Although the pathophysiology seems to be associated with gastrointestinal motility, their mechanisms remain unclear. We investigated gastric emptying and chemical mediators under conditions of continuous stress, which were produced using 8-week-old male Wistar rats kept in a cage filled with water to 2 cm height for 5 days. We examined gastric emptying by the phenol red method and chemical mediators at 4, 8, and 24 h and 3 and 5 days after initiation of stress restraint. Plasma ACTH level was significantly higher in the stress throughout the period of measurement. Continuous stress delayed gastric emptying until 24 h: peak delay was observed at 8 h, whereas gastric emptying was accelerated on days 3 and 5. Plasma noradrenalin level was significantly elevated at every time point until 24 h. Guanethidine pretreatment eliminated the delay in gastric emptying at 8 h. Active ghrelin was significantly increased on days 3 and 5 after peak (at 24 h) plasma total and desacyl ghrelin in the stress group. Number of ghrelin-immunoreactive cells and level of preproghrelin mRNA expression in the gastric body increased in parallel with plasma active ghrelin level. Pretreatment with growth hormone secretagogue receptor antagonist at 5 days partially inhibited the stress-induced acceleration of gastric emptying. Delayed gastric emptying at acute phase of continuous stress was mediated via sympathetic pathway, while acceleration at chronic phase was mediated via increased active ghrelin release from the stomach.