Dissociation between plasma adrenocorticotropin and serum cortisol level during the early postoperative period after gastrectomy

We demonstrated the dissociation between plasma adrenocorticotropin (ACTH) and serum cortisol levels during the early recovery period after radical gastrectomy in 9 of 31 patients with gastric adenocarcinoma. Patients with the dissociation between plasma ACTH and serum cortisol levels (DAC) showed a sustained elevation of serum cortisol level on the first or second postoperative day, while the plasma ACTH level returned to its preoperative state. These patients also had more advanced cancers (p < 0.05) and suffered from more postoperative complications (p < 0.05) than those without DAC. In these patients with DAC, serum cortisol and interleukin (IL)-6 levels remained higher on the second postoperative day than in those of the patients without DAC (21.80 +/- 1.57 vs. 13.68 +/- 0.72 microg/dl, p < 0.001, and 74.31 +/- 15.65 vs. 18.75 +/- 3.14 pg/ml, p < 0.001, respectively). On the second postoperative day, serum IL-6 levels showed a significant correlation with serum cortisol levels in all patients (r = 0.511, p < 0.01). These results suggest that the DAC during the early postoperative period after radical gastrectomy is associated with advanced stage of cancer and postoperative complication, and that the increased serum IL-6 level is at least in part responsible for maintaining the elevated serum cortisol.     

Circulating interleukin 6 as a useful marker for predicting postoperative complications.

We examined postoperative serial changes in the levels of serum interleukin 6 (IL-6), serum acute phase reactants (APRs) and plasma neutrophil elastase (NE) in patients with various cancers and reviewed these changes in patients who did, and did not, show postoperative complications. Serum IL-6 level was elevated after surgery, peaking on the first postoperative day. Elevation of serum APRs and plasma NE levels also followed. There was a significant correlation between the serum peak level of IL-6 and those of APRs and NE (P less than 0.01). Moreover, there was a significant difference in the serum IL-6 level in patients with and without complications. The relationship between the serum IL-6 greater than 400 pg/ml and the incidence of postoperative complications was also marked. These results suggest that circulating IL-6 is a clinically useful marker for the earliest detection and prediction of postoperative complications.     

The postoperative stress response and its reflection in cytokine network and leptin plasma levels

The objective of the present report was to clarify the postoperative stress response of some inflammatory markers, namely of proinflammatory cytokines and leptin levels during uncomplicated postoperative periods. The results were compared with the dynamics of these parameters during intraabdominal sepsis. We followed 20 patients after a planned resection of colorectal cancer in stage Ib-IV with uncomplicated healing and 13 obese men after laparoscopic non-adjustable gastric banding. These were compared to 12 patients with proven postoperative sepsis. The control group consisted of 18 healthy men. The observed parameters included serum levels of cytokines, tumor necrosis factor-alpha (TNFalpha), interleukin-1 beta (IL-1 beta), interleukin-1 receptor antagonist (IL-1 ra), IL-6, IL-8, soluble receptor of interleukin-2 (sIL-2R) and leptin. It was found that during the first 24 h after resection there was a significant increase in the serum concentration of IL-6 up to 1125+/-240 ng/l, which declined within the next 48-72 h. Serum concentration of TNFalpha was highest 18-24 h after resection (205+/-22 ng/l) and after banding (184+/-77 ng/l). IL-1 beta had a stable serum concentration without significant elevation. Serum concentration of IL-8 after resection rose to 520+/-200 ng/l after 36-48 h. Maximal cytokine levels after gastric banding were quantitatively lower (IL-6 414+/-240 ng/l, TNFalpha 184+/-77 ng/l) than after resection. We found significant elevation of plasma leptin concentration (32+/-10 ng/ml) 24 h after banding compared with preoperative values (18+/-5 ng/ml, p 0.05). Leptin levels 48 and 72 h after banding rapidly returned to the level before operation. During abdominal surgery leptin shows to be an acute phase reactant. Proinflammatory cytokines can be main regulatory factors of leptin during this period. Significant correlation between leptin and TNFalpha (similarly demonstrated by other authors in models of bacterial inflammation) indicates that TNFalpha can be the crucial regulator of leptin generation in the early postoperative period. On the basis of our results we recommend to observe IL-6 and IL-8 at 24-72 h after the surgery in patients with a high risk of early postoperative septic complications.     

Glucose tolerance and insulin sensitivity following an one-week volleyball competition

The purpose of the study was to compare glucose tolerance and insulin sensitivity between trained (TR) and competition (CP) states, in relation to cortisol and testosterone levels. Sixteen highly trained volleyball players voluntarily participated in this study. The first testing session (TR state) occurred 1 week before the start of national level volleyball CP, and the second testing session (CP state) occurred next morning after the 1-week CP. Fasted serum sample was used for measuring cortisol and testosterone. Subjects were then orally challenged with 75 g of glucose solution for determinations of oral glucose tolerance test (OGTT) and insulin response. Under both fasted and glucose challenged conditions, glucose levels of CP were not different from TR state, whereas insulin levels of CP were significantly elevated above TR (50 min: from 78.8 +/- 8.7 to 96.6 +/- 8.1 microU/ml, P < 0.05; 80 min: from 62.8 +/- 7.0 to 82.0 +/- 7.3; P < 0.05). Muscle creatine kinase (CK) level in blood was significantly increased above TR, suggesting greater muscle damage by CP. Serum leptin level, percent fat mass, and body weight were not different between two states. CP significantly increased serum cortisol level without significantly change in testosterone level. The new finding of the study was that volleyball CP reduced the whole-body insulin sensitivity significantly compared to TR state. The greater level of insulin concentration under CP state appears to be associated with elevated serum cortisol level. Despites the benefit of increased physical activity on metabolic function is widely recognized, physiological stress associated with CP can result in attenuation of systemic insulin sensitivity compared TR state.     

Changes in plasma IL-1beta, TNF-alpha and IL-6 after total hip replacement surgery in general or regional anaesthesia

Different anaesthetic methods influence the neuro-immuno-endocrine biologic responses to surgery and may thus possibly interfere with the postoperative course and development of complications. The neuroendocrine system is closely related to the cytokine network. In this study, the effects of general anaesthesia (n=6) and regional spinal/epidural anaesthesia (n=6) on the cytokine response (IL-1beta, TNFalpha, IL-6) to uncemented total hip replacement surgery were evaluated. The postoperative clinical course was uneventful in every case. In both groups, only very low values of plasma IL-beta were measured perioperatively, whereas plasma IL-6 increased postoperatively with peak values 4 h after surgery. The changes in plasma TNF-alpha were not significant. No significant differences in plasma TNF-alpha or IL-6 were found between patients operated in general or in regional anaesthesia. This suggests minor influence of plasma cytokines on the possible beneficial effects of regional anaesthesia on the clinical course after surgery in low risk patients. There were slightly higher TNF-alpha and IL-6 levels after the operation and significantly lower cortisol levels during the operation in the regional anaesthesia group compared to the general anaesthesia group, giving rise to a significant inverse correlation between peak values of IL-6 and peak values of cortisol. This supports the theory that after surgery the inhibitory effect of cortisol on monocyte cytokine production overrides adrenergic stimulation.     

Acute exercise effect on postabsorptive serum leptin.

We postulated that high circulating cortisol levels during intense exercise would lead to increased serum leptin concentrations. Young, lean men ate a small meal and then exercised on a cycle ergometer for 41 min or rested on a control day. Serum leptin concentration was 10% greater during exercise than in the control condition (P < 0.05). Directly after exercise, serum leptin dropped to approximately 10% less than the control level (P < 0.05) but had recovered to the nonexercised level after approximately 2 h of recovery. Rapid exercise effects on circulating leptin were related to changes in hemoconcentration rather than changes in leptin mass. When serum leptin was normalized to serum protein, leptin increased by 10% in the exercise condition compared with control by the end of recovery (P < 0.05). Although exercise increased serum cortisol concentration threefold, there was no relation between differences in cortisol and exercise vs. control differences in normalized leptin. The increased leptin mass after exercise may have been related to greater plasma glucose concentration during recovery after exercise compared with the control condition.     

Leptin and soluble leptin receptor changes after pulmonary endarterectomy: relations to cortisol and cytokine network

Leptin is a hormone that regulates food intake. During inflammatory status, leptin may contribute to the anorexia and cachexia of infection. Pulmonary endarterectomy was used as a model of non-infectious cytokine network hyperstimulation. Leptin and soluble leptin receptor (SLR) were compared with evolution of cortisol and inflammatory cytokines in twenty-two patients with chronic thromboembolic pulmonary hypertension treated with pulmonary endarterectomy using cardiopulmonary bypass (CBP) and deep hypothermic circulatory arrest (DHCA). Leptin, SLR, cortisol, IL-beta, IL-6, IL-8, and TNFalpha concentrations in arterial blood were measured before/after sternotomy, last DHCA, separation from bypass, 12, 18, 24, 36, and 48 h after sternotomy. Mean duration of CPB was 338.2 min.; mean circulatory arrest time 39.9 min. The initial decline of leptin, SLR, TNFalpha, IL-6, and IL-8 was followed by an increase culminating 6-24 h after sternotomy. Leptin peak levels were detected 24 h after sternotomy (28.0 ng/ml, 21.9-37.6). IL-6 culminated after separation from CPB, IL-8 was highest 12 h after sternotomy. Leptin concentrations correlated with IL-6 (r=0.82), and TNFalpha (r=0.73). Large cardiovascular surgery caused a significant increase in serum leptin, indicating its acute regulation by stress factors. This effect may be secondary to the inflammatory response mediated via cytokine stimulation. Correlation between leptin and IL-6 indicates the role of IL-6 in leptin induction.     

Peripheral leptin administration alters hormone and metabolite levels in the young pig

The present study was conducted to determine if peripheral leptin administration can alter GH secretion or feed intake in young pigs. Six, 6 kg female pigs were fasted overnight and randomly chosen to receive porcine recombinant leptin or saline injections in a crossover design. Three leptin dosages were tested over a 10 day period, 100, 200 or 500 microg/kg body mass (L100, L200 or L500). Leptin was administered in 0.2% bovine serum albumin as a bolus injection into the carotid artery. Blood samples were obtained from the jugular vein over a 24 h period. Leptin delayed feeding in pigs treated with L200 and L500 (P<0.05), while reducing overall intake in pigs treated with L100 (P<0.05). L200 or L500 depressed blood glucose (P<0.05). Plasma insulin levels were elevated by feeding in control animals, while insulin levels were depressed in pigs treated with L200 or L500 (P<0.05). L200 elevated plasma growth hormone (P<0.05) with three peaks apparent at 5, 8, and 13 h post injection. The ability for a single injection of leptin to produce significant changes in hormone and metabolite levels suggests that this peptide has a role in regulation of peripheral metabolism.     

Insensitivity of well-conditioned mature sheep to central administration of a leptin receptor antagonist

Ruminants remain productive during the energy insufficiency of late pregnancy or early lactation by evoking metabolic adaptations sparing available energy and nutrients (e.g. higher metabolic efficiency and induction of insulin resistance). A deficit in central leptin signaling triggers these adaptations in rodents but whether it does in ruminants remains unclear. To address this issue, five mature ewes were implanted with intracerebroventricular (ICV) cannula in the third ventricle. They were used in two experiments with an ovine leptin antagonist (OLA) when well-conditioned (average body condition score of 3.7 on a 5 point scale). The first experiment tested the ability of OLA to antagonize leptin under in vivo conditions. Ewes received continuous ICV infusion of artificial cerebrospinal fluid (aCSF), ovine leptin (4 µg/h) or the combination of ovine leptin (4 µg/h) and its mutant version OLA (40 µg/h) for 48 h. Dry matter intake (DMI) was measured every day and blood samples were collected on the last day of infusion. ICV infusion of leptin reduced DMI by 24% (P<0.05), and this effect was completely abolished by OLA co-infusion. A second experiment tested whether a reduction in endogenous leptin signaling in the brain triggers metabolic adaptations. This involved continuous ICV infusions of aCSF or OLA alone (40 µg/h) for 4 consecutive days. The infusion of OLA did not alter voluntary DMI over the treatment period or on any individual day. OLA did not affect plasma variables indicative of insulin action (glucose, non-esterified fatty acids, insulin and the disposition of plasma glucose during an insulin tolerance test) or plasma cortisol, but tended to reduce plasma triiodothyronine and thyroxine (P<0.07). Overall, these data show that a reduction of central leptin signaling has little impact on insulin action in well-conditioned mature sheep. They also raise the possibility that reduced central leptin signaling plays a role in controlling thyroid hormone production.     

Roles of plasma interleukin-6 and tumor necrosis factor-alpha and FFA and TG in the development of insulin resistance induced by high-fat diet

The role of adipokines in development of insulin resistance still remains controversial. The purpose of the present study was to examine the dynamic changes of fasting plasma levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), free fatty acids (FFA) and insulin in a Sprague-Dawley rat insulin resistant model induced by high-fat diet. Heterotopic deposition of triglycerides (TG) in liver, skeletal muscles and pancreatic islet was also investigated. The fasting plasma level of insulin in rats in the high-fat diet group was significantly higher than that in the normal diet group on day 21 (P<0.01), suggesting that an increased insulin resistance developed in the high-fat diet group. However, no significant difference in the plasma IL-6 level was observed between the two groups (P>0.05), although in both groups, the plasma IL-6 level was significantly higher on day 21 than that of the day 0 (P<0.05). The plasma FFA level in the high-fat diet group began to increase significantly on day 21 (P<0.05), and elevated markedly on day 28, was positively correlated to the fasting plasma insulin level. Histological study revealed a more abundant TG deposition in liver and skeletal muscles (from quadriceps femoris) in the high-fat diet group than in the normal diet group on day 21, and the liver deposition was even higher on day 28. However, no deposition was observed in pancreatic islets. The plasma TNF-alpha level remained unchanged throughout the duration of the experiment. These results indicate that the progression of insulin resistance in high-fat diet rats is closely related to the plasma FFA elevation and the heterotopic deposition of TG in liver and skeletal muscles, but is unrelated to the plasma TNF-alpha and IL-6 levels.     

Lipid and carbohydrate metabolism in mice with a targeted mutation in the IL-6 gene: absence of development of age-related obesity

Obesity-related insulin resistance may be caused by adipokines such as IL-6, which is known to be elevated with the insulin resistance syndrome. A previous study reported that IL-6 knockout mice (IL-6(-/-)) developed maturity onset obesity, with disturbed carbohydrate and lipid metabolism, and increased leptin levels. Because IL-6 is associated with insulin resistance, one might have expected IL-6(-/-) mice to be more insulin sensitive. We examined body weights of growing and older IL-6(-/-) mice and found them to be similar to wild-type (IL-6(+/+)) mice. Dual-energy X-ray absorptiometry analysis at 3 and 14 mo revealed no differences in body composition. There were no differences in fasting blood insulin and glucose or in triglycerides. To further characterize these mice, we fed 11-mo-old IL-6(-/-) and IL-6(+/+) mice a high- (HF)- or low-fat diet for 14 wk, followed by insulin (ITT) and glucose tolerance tests (GTT). An ITT showed insulin resistance in the HF animals but no difference due to genotype. In the GTT, IL-6(-/-) mice demonstrated elevated postinjection glucose levels by 60% compared with IL-6(+/+) but only in the HF group. Although IL-6(-/-) mice gained weight and white adipose tissue (WAT) with the HF diet, they gained less weight than the IL-6(+/+) mice. Total lipoprotein lipase activity in WAT, muscle, and postheparin plasma was unchanged in the IL-6 (-/-) mice compared with IL-6(+/+) mice. There were no differences in plasma leptin or TNF-alpha due to genotype. Plasma adiponectin was approximately 53% higher (71.7 +/- 14.1 microg/ml) in IL-6(-/-) mice than in IL-6(+/+) mice but only in the HF group. Thus these data show that IL-6(-/-) mice do not demonstrate obesity, fasting hyperglycemia, or abnormal lipid metabolism, although HF IL-6(-/-) mice demonstrate elevated glucose after a GTT.     

Effects of inhibition of interleukin-6 signalling on insulin sensitivity and lipoprotein (a) levels in human subjects with rheumatoid diseases

Background

Interleukin-6 (IL-6) is a pro-inflammatory cytokine that has been found to be increased in type 2 diabetic subjects. However, it still remains unclear if these elevated IL-6 levels are co-incidental or if this cytokine is causally related to the development of insulin resistance and type 2 diabetes in humans. Therefore, in the present study we examined insulin sensitivity, serum adipokine levels and lipid parameters in human subjects before and after treatment with the IL-6 receptor antibody Tocilizumab.

Methodology/Principal Findings

11 non-diabetic patients with rheumatoid disease were included in the study. HOMA-IR was calculated and serum levels for leptin, adiponectin, triglycerides, LDL-cholesterol, HDL-cholesterol and lipoprotein (a) (Lp (a)) were measured before as well as one and three months after Tocilizumab treatment. The HOMA index for insulin resistance decreased significantly. While leptin concentrations were not altered by inhibition of IL-6 signalling, adiponectin concentrations significantly increased. Thus the leptin to adiponectin ratio, a novel marker for insulin resistance, exhibited a significant decrease. Serum triglycerides, LDL-cholesterol and HDL-cholesterol tended to be increased whereas Lp (a) levels significantly decreased.

Conclusions/Significance

Inhibition of IL-6 signalling improves insulin sensitivity in humans with immunological disease suggesting that elevated IL-6 levels in type 2 diabetic subjects might be causally involved in the pathogenesis of insulin resistance. Furthermore, our data indicate that inhibition of IL-6 signalling decreases Lp (a) serum levels, which might reduce the cardiovascular risk of human subjects.     

Blood levels of corticosteroid-binding globulin, total cortisol and unbound cortisol in patients undergoing coronary artery bypass grafting surgery with cardiopulmonary bypass

Previous studies have demonstrated a persistent rise in serum cortisol concentrations after cardiac surgery. To further investigate this finding and to evaluate the effect of hemodilution that occurs with the onset of cardiopulmonary bypass (CPB), concentrations of cortisol-binding globulin (CBG), total and unbound cortisol, and packed cell volume (PCV) were studied in 28 patients undergoing coronary artery bypass graft surgery. All patients received a standardized general anesthetic using a balanced technique with sufentanil, isoflurane, and midazolam. Blood was collected preoperatively, intraoperatively during CPB, and postoperatively in the evenings on the day of surgery and on the first and second postoperative day. Cortisol and CBG concentrations were measured by radioimmunoassay and were used to calculate the fraction of unbound cortisol. Serum CBG and cortisol concentrations corrected for hemodilution were significantly higher than non-corrected values. Perioperatively, CBG measurements were significantly intercorrelated. Intraoperatively, total and unbound cortisol concentrations were not significantly increased compared to preoperative values. Postoperatively up to the end of the study period serum concentrations of total and unbound cortisol were significantly increased compared to baseline values. Our results suggest that hemodilution occurs in all patients during cardiac surgery and continues up to the second postoperative day. This may lead to an underestimation of serum cortisol and CBG concentrations in patients undergoing heart surgery with CPB. Intraoperatively, concentrations of total and unbound cortisol were not significantly elevated. The postoperative rise in serum total cortisol concentration was accompanied by an increase in unbound cortisol concentration. The postoperative increase of unbound cortisol concentrations in patients undergoing cardiac surgery with CPB was largely due to an increase in cortisol secretion.     

Serum leptin levels and their response during laparoscopic and open cholecystectomy

We compared serum leptin responses during and after laparoscopic and open cholecystectomy, and assessed their correlation with the responses of inflammatory cytokines. Serum levels of leptin, interleukin-1alpha (IL-1alpha), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were measured by an enzyme-linked immunoassay in 31 patients who underwent laparoscopic cholecystectomy and in 24 patients who underwent open cholecystectomy. Serum samples were obtained preoperatively, at 10 and 30 min after the commencement of surgery, and at 6 and 24 h after the operation. The cumulative responses of leptin, IL-1alpha, IL-6 and TNF-alpha to surgery were calculated and the associations between them were evaluated. Serum leptin levels were significantly increased at 24 h after both procedures. The serum leptin concentration at this time point and the cumulative leptin response were significantly lower after laparoscopic cholecystectomy than after open cholecystectomy. Changes in serum IL-1alpha, TNF-alpha and IL-6 concentrations showed similar kinetics in both groups, with postoperative IL-6 levels being consistently lower in the laparoscopic cholecystectomy group. Cumulative IL-6 and TNF-alpha responses were significantly lower after laparoscopic cholecystectomy than after open cholecystectomy. The cumulative responses of leptin, IL-1alpha and IL-6 correlated significantly with each other. Leptin may be involved in the systemic inflammatory response to surgical injury, and the postoperative leptin elevation and cumulative leptin response are significantly lower after laparoscopic cholecystectomy than after open cholecystectomy.     

Cushing Disease in Children and Adolescents: Twenty Years’ Experience in A Tertiary Care Center in India

ObjectiveTo analyze the clinical presentation, diagnostic evaluation, treatment modalities, and follow-up of pediatric patients with Cushing disease.MethodsIn this retrospective analysis, we reviewed records of children (younger than 20 years) with Cushing disease who had undergone transsphenoidal adenomectomy in a tertiary health care center in India during the period of 1988 to 2008. Endogenous hypercortisolism was identified by a serum cortisol value ≥ 1.8 μg/dL during a low-dose dexamethasone suppression test (LDDST) with or without elevated midnight serum cortisol (≥ 3.2 μg/dL). Corticotropin dependence was defined by a basal plasma corticotropin concentration ≥ 5 pg/mL. Patients with normal pituitary imaging underwent bilateral inferior petrosal sinus sampling (BIPSS). Those with persistent or recurrent disease after surgery were treated with second-line interventions on a case-by-case basis.ResultsTwenty-nine boys and 19 girls were included. Mean age was 14.85 (± 2.5) years. Weight gain (98%), round facies (98%), and growth arrest (83%) were the most common manifestations. LDDST and midnight cortisol had 100% sensitivity for detecting endogenous hypercortisolism, while midnight corticotropin measurement had 100% sensitivity for defining corticotropin dependence. Magnetic resonance imaging and unstimulated BIPSS had 71% and 89% sensitivity, respectively, for diagnosing Cushing disease. Twenty-seven patients (56%) achieved remission after the first transsphenoidal operation with higher remission rates in those with microadenoma (75%). Basal serum cortisol < 5 mg/dL on the fifth postoperative day predicted cure. Eight patients received postoperative radiotherapy, with 4 achieving remission.ConclusionsClinical presentation and diagnostic yield with various tests were similar to those previously reported in the literature. Remission rates were poor after first transsphenoidal operation in patients with macroadenoma and outcome was dismal with a second transsphenoidal operation. Serum cortisol concentration < 5 mg/dL on the fifth postoperative day predicted cure. (Endocr Pract. 2011;17:369-376)     

Cytokine profile in cases with premature elevation of progesterone serum concentrations during ovarian stimulation

The aim of this study was to investigate the concentrations of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), leptin, tumor necrosis factor-alpha, interleukin (IL)-1beta and IL-6, in cycles with a premature rise of serum progesterone. 25 intracytoplasmic sperm injection (ICSI) cycles with (Group 1) and 25 ICSI cycles without a premature progesterone elevation (Group 2) were included. The cut-off value of serum progesterone on the day of human chorionic gonadotropin (hCG) administration was 0.9 ng/ml. The indication for ICSI was male factor infertility exclusively. On the day of hCG injection, serum IL-6, VEGF and bFGF were significantly higher in Group 1 (7.7+/-24.5 pg/ml, 290.2+/-161.4 pg/ml and 15.7+/-8.2 ng/ml respectively) than in Group 2 (1.7+/-0.7 pg/ml, 175.2+/-92.1 pg/ml, and 9+/-1.6 ng/ml respectively). On the day of follicular puncture, serum cytokine concentrations were similar in the two groups. IL-6 intrafollicular concentrations were higher in Group 1 (14.7+/-20.7 pg/ml) than in Group 2 (9+/-9.3 pg/ml, p=0.031). There were no differences regarding the ICSI outcome. Patients with serum progesterone above 0.9 ng/ml, have elevated serum concentrations of IL-6, VEGF, and bFGF, as well as elevated intrafollicular concentrations of IL-6. The outcome of ICSI cycles is not associated with premature elevation of progesterone when the cut-off value is set at 0.9 ng/ml.     

Increased adrenal androgen levels in patients with Prader-Willi syndrome are associated with insulin,IGF-I,and leptin,but not with measures of obesity

BACKGROUND/AIM: Since hyperandrogenism in simple obesity is assumed to arise from hyperinsulinism and/or increased insulin-like growth factor I (IGF-I) or leptin levels, we examined how in patients with Prader-Willi syndrome (PWS), the most frequent form of syndromal obesity, the accelerated adrenarche can be explained despite hypothalamic-pituitary insufficiency with low levels of insulin and IGF-I. METHODS: In 23 children with PWS and a mean age of 5.6 years, height, weight, fat mass, fasting insulin concentration, insulin resistance (by HOMA-R; see text), and leptin and IGF-I levels were determined to test whether they explain the variance of the levels of dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), of androstenedione, and of cortisol before and during 42 months of therapy with growth hormone. RESULTS: The baseline DHEAS, DHEA, and androstenedione concentrations were increased as compared with age-related reference values, whereas the cortisol level was always normal. During growth hormone treatment, the DHEA concentration further rose, and the cortisol level decreased significantly. The insulin and IGF-I concentrations were low before therapy, while fat mass and leptin level were elevated. The hormonal covariates provided alone or together between 24 and 60% of the explanation for the variance of adrenal androgen levels, but the anthropometric variables did not correlate with them. CONCLUSIONS: In children with PWS, elevated androgen levels correlate with hormones that are usually associated with adiposity. However, the lack of direct correlations between disturbed body composition and androgen levels as well as the increased sensitivity to insulin and IGF-I are abnormalities specific to PWS, potentially caused by the underlying hypothalamic defect.     

Similar effects of general and spinal anaesthesia on perioperative stress response in patients undergoing haemorrhoidectomy

Surgery induces release of neuroendocrine hormones (cortisol), cytokines (interleukin-6: IL-6, tumour necrosis factor-alpha: TNF-alpha), acute phase proteins (C-reactive protein: CRP, leptin). We studied the effects of general and spinal anaesthesia on stress response to haemorrhoidectomy. Patients were assigned to general and spinal anaesthesia groups (n = 7). Blood samples were drawn before induction and 24 hours after surgery. Perioperative levels of IL-6, TNF-alpha, CRP, cortisol, and leptin were comparable among the groups. Twenty four hours after surgery, TNF-alpha and cortisol did not change; IL-6 and CRP increased significantly in all patients. Significant increase in leptin levels was found in patients undergoing spinal anaesthesia. Except for the increase in leptin levels, there was no significant difference related to the effects of general and spinal anaesthesia.     

Aspects of central and peripheral regulation of reproduction in mammals

To increase our knowledge concerning the central and peripheral regulation of reproduction in mammals a series of studies were performed. In the first experiment, we found that exogenous leptin altered the activity of the hypothalmo-pituitary-gonadotropic axis in sheep during insufficient feeding. The action of leptin appears to be mediated by changes in GnRH and LH secretion as well as NPY immunoreactivity. The aim of the second experiment was to investigate the role of the adipoinsular axis hormones during pregnancy in rats. The elevated levels of plasma leptin as wells as the increased mRNAs expression of the leptin receptors in placenta indicate the significant role of the hormone in fetal growth and development. On the other hand, a decrease in leptin receptors mRNA content within hypothalamus and pituitary together with unchanged plasma insulin level may suggest that during rat pregnancy leptin resistance was developed in the hypothalamus, pituitary and pancreatic islets. The third experiment was carried out to establish the role of opioids and glucocorticoids in the regulation of the hypothalmo-pituitary-gonadal axis in ewes during natural or synchronized estrous cycle. Prolonged treatment with progesterone resulted in significant changes in plasma levels of Met-enkephalin, cortisol and steroids and altered the expression of proenkephalin mRNA in the hypothalamus, pituitary, ovary and adrenals. Injections of Met-enkephalin or naltrexone (blocker of opioid receptors) modulated the progesterone influence in tested tissues. The data clearly suggest that opioids are involved in the regulation of the estrous cycle at the hypothalamo-pituitary-gonadal/adrenal axes.     

Small weight gain is not associated with development of insulin resistance in healthy, physically active individuals.

We investigated whether weight gain alters insulin sensitivity and leptin levels in physically active individuals. Six (5 males and 1 female; age 26.6+/-1.0 years; BMI 21.5+/-0.9, body fat 17.4+/-2.2%) healthy individuals were enrolled in an overfeeding study (caloric surplus 22.5-26.5 kcal/kg/day) to achieve up to 10% weight gain over 4-6 week period with subsequent weight maintenance over additional 2 weeks. The participants were requested to maintain their previous physical activity which in all of them included 45-60 min training sessions at the gym 2-3 times/week. RESULTS: BMI increased to 23.4+/-0.9 (4.4 kg weight gain; p<0.05) and body fat to 21.0+/-2.8% (p < 0.05) over the period of active weight gain and remained stable over the two week period of weight maintenance; fasting plasma glucose and serum insulin remained unchanged; serum leptin nearly doubled (3.8+/-1.0 vs 6.4+/-1.9 ng/ mL; p < 0.05); insulin sensitivity, when expressed per kg of the total body (11.1+/-1.6 vs 12.4+/-2.1 mg/kg/min; p = NS), and lean body mass (13.4+/-1.9 vs 15.7+/-2.6 mg/kgLBM/min; p = NS), did not decrease after weight gain. On the contrary, insulin action had improved in 5 out of 6 individuals. In conclusion, the data presented in this preliminary report indicate that a small weight gain due to overfeeding in lean, healthy, physically active individuals is associated with rise in circulating leptin levels but not with worsening of insulin action.