ESE Clinical Practice Guideline on functioning and nonfunctioning pituitary adenomas in pregnancy.

Pregnancies are rare in women with pituitary adenomas, which may relate to hormone excess from secretory subtypes such as prolactinomas or corticotroph adenomas. Decreased fertility may also result from pituitary hormone deficiencies due to compression of the gland by large tumours and/or surgical or radiation treatment of the lesion. Counselling premenopausal women with pituitary adenomas about their chance of conceiving spontaneously or with assisted reproductive technology, and the optimal pre-conception treatment, should start at the time of initial diagnosis. The normal physiological changes during pregnancy need to be considered when interpreting endocrine tests in women with pituitary adenomas. Dose adjustments in hormone substitution therapies may be needed across the trimesters. When medical therapy is used for pituitary hormone excess, consideration should be given to the known efficacy and safety data specific to pregnant women for each therapeutic option. In healthy women, pituitary gland size increases during pregnancy. Since some pituitary adenomas also enlarge during pregnancy, there is a risk of visual impairment, especially in women with macroadenomas or tumours near the optic chiasm. Pituitary apoplexy represents a rare acute complication of adenomas requiring surveillance, with surgical intervention needed in some cases. This guideline describes the choice and timing of diagnostic tests and treatments from the pre-conception stage until after delivery, taking into account adenoma size, location and endocrine activity. In most cases, pregnant women with pituitary adenomas should be managed by a multidisciplinary team in a centre specialised in the treatment of such tumours.

Anabolic effects of oral leucine-rich protein with and without ß-hydroxybutyrate on muscle protein metabolism in a novel clinical model of systemic inflammation-a randomized crossover trial.

BACKGROUND: ß-lactoglobulin (BLG) stimulates muscle protein synthesis and ß-hydroxybutyrate (BHB) inhibits muscle breakdown. Whether combining the 2 can additively attenuate disease-induced muscle loss is unknown. OBJECTIVE: Based on previous observations of anticatabolic effects of protein and ketone bodies during inflammation, and using a novel model combining ongoing systemic inflammation, fasting, and immobilization, we tested whether the anticatabolic muscle response to oral amino acids is altered compared with control conditions, as well as whether coadministration of oral BHB and BLG further improves the muscle anabolic response. Muscle net balance (NBphe) was the primary outcome and intramyocellular signals were assessed. METHODS: In a randomized crossover design, 8 young men underwent either preconditioning with LPS (prestudy day: 1 ng/kg, study day: 0.5 ng/kg) combined with a 36-h fast and bed rest to mimic catabolic inflammatory disease (CAT) or an overnight fast (control [CTR]) prior to isocaloric nutritional interventions on 3 occasions separated by ∼6 wk (range 42 to 83 d). RESULTS: NBphe increased similarly upon all conditions (interaction P = 0.65). From comparable baseline rates, both Rdphe [muscle synthesis, median ratio (95% CI): 0.44 (0.23, 0.86) P = 0.017] and Raphe [muscle breakdown, median ratio (95% CI): 0.46 (0.27, 0.78) P = 0.005] decreased following BHB + BLG compared with BLG. BLG increased Rdphe more under CAT conditions compared with CTR (interaction P = 0.02). CAT increased inflammation, energy expenditure, and lipid oxidation and decreased Rdphe and anabolic signaling [mammalian target of rapamycin (mTOR) and eukaryotic translation initiation factor 4E-binding protein 1 (4EPB1) phosphorylation]. CONCLUSION: In contrast to our initial hypothesis, NBphe increased similarly following BLG during CAT and CTR conditions; CAT however, specifically stimulated the BLG-mediated increase in protein synthesis, whereas BHB coadministration did not affect NBphe, but distinctly dampened the BLG-induced increase in muscle amino acid fluxes thereby liberating circulating amino acids for anabolic actions elsewhere.

What is the efficacy of switching to weekly pegvisomant in acromegaly patients well controlled on combination therapy?

CONTEXT: Although combination therapy of acromegaly with long-acting somatostatin analogs (LA-SSAs) and pegvisomant (PEGV) normalizes insulin-like growth factor-1 (IGF1) levels in the majority of patients, it requires long-term adherence. Switching from combination therapy to monotherapy with weekly PEGV could improve patients' comfort, but the efficacy is unknown. OBJECTIVE: To assess the efficacy of switching to PEGV monotherapy in patients well controlled on combination therapy of LA-SSAs and PEGV. DESIGN: Single-center, open-label observational pilot study. LA-SSA therapy was discontinued at baseline and all patients were switched to PEGV monotherapy for 12 months. If IGF1 levels exceeded 1.0 times upper limit of normal (ULN), PEGV dose was increased by 20 mg weekly. SUBJECTS AND METHODS: The study included 15 subjects (eight males), with a median age of 58 years (range 35-80) on combination therapy of high-dose LA-SSAs and weekly PEGV for >6 months, and IGF1 levels within the normal range. Treatment efficacy was assessed by measuring serum IGF1 levels. RESULTS: After 12 months of weekly PEGV monotherapy, serum IGF1 levels of 73% of the subjects remained controlled. In one patient, LA-SSA had to be restarted due to recurrence of headache. IGF1 levels increased from a baseline level of 0.62 × ULN (range 0.30-0.84) to 0.83 × ULN (0.30-1.75) after 12 months, while the median weekly PEGV dose increased from 60 (30-80) mg to 80 (50-120) mg. CONCLUSION: Our results suggest that switching from combination therapy of LA-SSAs and PEGV to PEGV monotherapy can be a viable treatment option for acromegaly patients without compromising efficacy.

Pegvisomant in combination with long-acting somatostatin analogues in acromegaly: the role of the GH receptor deletion of exon 3.

BACKGROUND: Doses of the GH receptor (GHR) antagonist pegvisomant (PEGV) that normalize insulin-like growth factor 1 (IGF1) levels vary widely among acromegaly patients. Predictors for PEGV response are baseline IGF1 levels, sex, body weight and previous radiotherapy. A GHR polymorphism lacking exon 3 (d3-GHR) is frequent in the general population. The influence of d3-GHR on PEGV responsiveness in acromegaly is unclear. OBJECTIVE: To assess the influence of d3-GHR on IGF1 levels and PEGV responsiveness in acromegaly patients using combined PEGV and long-acting somatostatin receptor ligand (LA-SRIF) treatment. DESIGN: Data were collected at the Rotterdam Pituitary Centre between 2004 and 2013. Patients with elevated IGF1 levels (>1.2 upper limit of normal; n=112) and over 6 months of high-dose LA-SRIF treatment were co-treated with PEGV. GHR genotype was assessed using genomic DNA in 104 patients. RESULTS: D3-GHR was observed in 51 (49.0%) of the patients (7.7% homozygous, 41.3% heterozygous) and was in Hardy-Weinberg equilibrium (P=0.859). Baseline characteristics were similar in d3-GHR and full-length (fl)-GHR genotypes. During PEGV/LA-SRIF treatment IGF1 levels were not different between d3-carriers and non-carriers. Similarly, no difference in PEGV dose required to normalize IGF1 (P=0.337) or PEGV serum levels (P=0.433) was observed between the two groups. However, adenoma size decreased significantly (>20% of largest diameter) in 25.6% of the fl-GHR genotype but only in 7.5% of d3-carriers (P=0.034, OR: 4.6 (CI: 1.1-18.9)). CONCLUSIONS: GHR genotype does not predict the IGF1 normalizing dose of PEGV in acromegaly patients using combination PEGV/LA-SRIF treatment. However, fewer d3-carriers showed significant reductions in adenoma size.

Breast cancer risk in hyperprolactinemia: a population-based cohort study and meta-analysis of the literature.

OBJECTIVE: To enhance the precision of the risk estimate for breast cancer in hyperprolactinemia patients by collecting more data and pooling our results with available data from former studies in a meta-analysis. DESIGN: Population-based cohort study and meta-analysis of the literature. METHODS: Using nationwide registries, we identified all patients with a first-time diagnosis of hyperprolactinemia during 1994-2012 including those with a new breast cancer diagnoses after the start of follow-up. We calculated standardised incidence ratios (SIRs) as a measure of relative risk (RR) using national cancer incidence rates. We performed a meta-analysis, combining data from our study with data in the existing literature. RESULTS: We identified 2457 patients with hyperprolactinemia and 20 breast cancer cases during 19,411 person-years of follow-up, yielding a SIR of 0.99 (95% CI 0.60-1.52). Data from two additional cohort studies were retrieved and analyzed. When the three risk estimates were pooled, the combined RR was 1.04 (95% CI 0.75-1.43). CONCLUSIONS: We found no increased risk of breast cancer among patients with hyperprolactinemia.

Long-term efficacy and safety of pegvisomant in combination with long-acting somatostatin analogs in acromegaly.

BACKGROUND: Treatment for acromegaly patients with long-acting somatotropin release-inhibiting factor (LA-SRIF) often does not result in complete normalization of IGF-1. Addition of pegvisomant (PEGV), a GH receptor antagonist, could improve this; however, the literature has not described long-term follow-up. OBJECTIVE: To assess long-term efficacy and safety of this combined treatment in the largest current single-center cohort of patients, from 2004-2013. DESIGN: Acromegaly patients were treated for at least 6 months with a high-dose LA-SRIF. To patients with persistently elevated IGF-1 levels (>1.2 × upper limit of normal) or poor quality of life, PEGV was added as one weekly injection. RESULTS: The patients (n = 141) were treated with PEGV and LA-SRIFs for a median period of 4.9 years (range, 0.5-9.2). Efficacy, defined as the lowest measured IGF-1 level during treatment, was 97.0%. The median PEGV dose to achieve this efficacy was 80 mg weekly (interquartile range, 60-120 mg). Combination treatment-related adverse events were recorded in 26 subjects (18.4%). Pituitary tumor size increase was observed in one patient. Injection-site reactions were observed in four subjects. In 19 patients (13.5%), transiently elevated liver transaminases of more than three times the upper limit of normal were observed, of which 83% occurred within the first year of combination treatment. Eight patients died, at a mean age of 71 years; none of them were considered treatment-related. CONCLUSIONS: The combination treatment with LA-SRIFs and PEGV was effective in 97% of the patients, it appears to be a safe medical treatment and it reduces the required dose of PEGV.

Sustained AS160 and TBC1D1 phosphorylations in human skeletal muscle 30 min after a single bout of exercise.

BACKGROUND: phosphorylation of AS160 and TBC1D1 plays an important role for GLUT4 mobilization to the cell surface. The phosphorylation of AS160 and TBC1D1 in humans in response to acute exercise is not fully characterized. OBJECTIVE: to study AS160 and TBC1D1 phosphorylation in human skeletal muscle after aerobic exercise followed by a hyperinsulinemic euglycemic clamp. DESIGN: eight healthy men were studied on two occasions: 1) in the resting state and 2) in the hours after a 1-h bout of ergometer cycling. A hyperinsulinemic euglycemic clamp was initiated 240 min after exercise and in a time-matched nonexercised control condition. We obtained muscle biopsies 30 min after exercise and in a time-matched nonexercised control condition (t = 30) and after 30 min of insulin stimulation (t = 270) and investigated site-specific phosphorylation of AS160 and TBC1D1. RESULTS: phosphorylation on AS160 and TBC1D1 was increased 30 min after the exercise bout, whereas phosphorylation of the putative upstream kinases, Akt and AMPK, was unchanged compared with resting control condition. Exercise augmented insulin-stimulated phosphorylation on AS160 at Ser(341) and Ser(704) 270 min after exercise. No additional exercise effects were observed on insulin-stimulated phosphorylation of Thr(642) and Ser(588) on AS160 or Ser(237) and Thr(596) on TBC1D1. CONCLUSIONS: AS160 and TBC1D1 phosphorylations were evident 30 min after exercise without simultaneously increased Akt and AMPK phosphorylation. Unlike TBC1D1, insulin-stimulated site-specific AS160 phosphorylation is modified by prior exercise, but these sites do not include Thr(642) and Ser(588). Together, these data provide new insights into phosphorylation of key regulators of glucose transport in human skeletal muscle.

Growth hormone-induced insulin resistance in human subjects involves reduced pyruvate dehydrogenase activity.

AIM: Insulin resistance induced by growth hormone (GH) is linked to promotion of lipolysis by unknown mechanisms. We hypothesized that suppression of the activity of pyruvate dehydrogenase in the active form (PDHa) underlies GH-induced insulin resistance similar to what is observed during fasting. METHODS: Eight healthy male subjects were studied four times in a randomized, single-blinded parallel design: Control, GH, Fasting (36 h) and GH + Fasting. GH (30 ng × kg(-1) × min(-1)) or saline was infused throughout the metabolic study day. Substrate metabolism and insulin sensitivity were assessed by indirect calorimetry and isotopically determined rates of glucose turnover before and after a hyperinsulinemic euglycemic clamp. PDHa activity, PDH-E1α phosphorylation, PDK4 expression and activation of insulin signalling proteins were assessed in skeletal muscle. RESULTS: Both fasting and GH promoted lipolysis, which was associated with ≈50% reduction in insulin sensitivity compared with the control day. PDHa activity was significantly reduced by GH as well as fasting. This was associated with increased inhibitory PDH-E1α phosphorylation on site 1 (Ser(293)) and 2 (Ser(300)) and up-regulation of PDK4 mRNA, while canonical insulin signalling to glucose transport was unaffected. CONCLUSION: Competition between intermediates of glucose and fatty acids seems to play a causal role in insulin resistance induced by GH in human subjects.

Mortality in Cushing's syndrome: a systematic review and meta-analysis.

CONTEXT: Data on mortality associated with Cushing's disease (CD) and Cushing's syndrome (CS) are scarce. OBJECTIVE: To perform a systematic review and meta-analysis of mortality studies in patients with CD and CS secondary to a benign adrenal adenoma. DATA SOURCES: A search was performed in seven electronic databases. Sixty-six articles were retrieved for analysis and 7 included in the final study. The main outcome measure was standardized mortality ratio (SMR). STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS: Studies reporting SMR for patients diagnosed with CD and/or CS. Outcomes were stratified by subtype of Cushing's syndrome. STUDY APPRAISAL AND SYNTHESIS METHODS: Studies were appraised by two authors and were synthesized using a weighted estimate based on the standard error of the SMR. RESULTS: The weighted mean of SMR for patients with CD was 1.84 (95% confidence interval (CI): 1.28-2.65). CD patients with persistent disease after initial surgery had a SMR of 3.73 (95% CI: 2.31-6.01), whereas mortality of CD patients with initial remission did not differ significantly from the general population (SMR: 1.23 (95% CI: 0.51-2.97)). SMR for patients with a benign adrenal adenoma was 1.90 (95% CI: 0.93-3.91). Age, sex and observation time did not significantly impact mortality. CONCLUSIONS: CD as opposed to CS due to a benign adrenal adenoma is associated with an excess mortality, which is attributed to patients in whom initial surgical cure is not obtained. This underlines the importance of a rigorous and early follow-up of newly operated patients with CD.

Insulin resistance after a 72-h fast is associated with impaired AS160 phosphorylation and accumulation of lipid and glycogen in human skeletal muscle.

During fasting, human skeletal muscle depends on lipid oxidation for its energy substrate metabolism. This is associated with the development of insulin resistance and a subsequent reduction of insulin-stimulated glucose uptake. The underlying mechanisms controlling insulin action on skeletal muscle under these conditions are unresolved. In a randomized design, we investigated eight healthy subjects after a 72-h fast compared with a 10-h overnight fast. Insulin action on skeletal muscle was assessed by a hyperinsulinemic euglycemic clamp and by determining insulin signaling to glucose transport. In addition, substrate oxidation, skeletal muscle lipid content, regulation of glycogen synthesis, and AMPK signaling were assessed. Skeletal muscle insulin sensitivity was reduced profoundly in response to a 72-h fast and substrate oxidation shifted to predominantly lipid oxidation. This was associated with accumulation of both lipid and glycogen in skeletal muscle. Intracellular insulin signaling to glucose transport was impaired by regulation of phosphorylation at specific sites on AS160 but not TBC1D1, both key regulators of glucose uptake. In contrast, fasting did not impact phosphorylation of AMPK or insulin regulation of Akt, both of which are established upstream kinases of AS160. These findings show that insulin resistance in muscles from healthy individuals is associated with suppression of site-specific phosphorylation of AS160, without Akt or AMPK being affected. This impairment of AS160 phosphorylation, in combination with glycogen accumulation and increased intramuscular lipid content, may provide the underlying mechanisms for resistance to insulin in skeletal muscle after a prolonged fast.

Growth hormone (GH)-induced insulin resistance is rapidly reversible: an experimental study in GH-deficient adults.

CONTEXT: It is clinically relevant and of physiological interest to investigate whether GH-induced insulin resistance depends on the timing of GH exposure relative to when insulin sensitivity is assessed. HYPOTHESIS: GH-induced insulin resistance is rapidly reversible. DESIGN AND PARTICIPANTS: Eight male GH-deficient patients underwent a 6-h euglycemic-hyperinsulinemic glucose clamp thrice in a randomized crossover design receiving either no GH (study 0), a 7-h GH infusion (0.2-0.3 mg in total) that terminated 5 h before the clamp (study 1), or a similar GH infusion timed to continue during the first hour of the clamp (study 2). A muscle biopsy was obtained 30 min into the clamp. The patients were compared with eight healthy untreated control subjects (study c). MAIN OUTCOME MEASURES: The glucose infusion rate, indirect calorimetry, and free fatty acid metabolism were assessed. In muscle biopsies, protein phosphorylation of signal transducer and activator of transcription 5, Akt, and Akt substrate 160 (phospho-Akt substrate signal) and gene expression of IGF-I and SOCS1-3 were assessed. RESULTS: Insulin sensitivity differed significantly between the GH-deficiency studies (P = 0.005) with distinct insulin resistance in study 2 and increased insulin sensitivity in study 0 [area under the glucose infusion rate curve (mg/kg · min): 1663 ± 151 (study 0) vs. 1482 ± 166 (study 1) vs. 1123 ± 136 (study 2) vs. 1492 ± 229 (control group)]. Free fatty acid levels and lipid oxidation were elevated in response to GH exposure but became suppressed during the clamp. IGF-I and SOCS3 gene expression was increased in study 2. CONCLUSIONS: Very-low-dose GH exposure evokes acute insulin resistance that subsides after 5 h. This time-dependent reversibility should be considered when assessing the impact of GH on glucose homeostasis.

Time-course effects of physiological free fatty acid surges on insulin sensitivity in humans.

AIM: Physiological elevations of free fatty acids (FFAs) occur in bell-shaped surges lasting some hours, observed nocturnally, during exercise and inflammation. The time-course effects of such FFA surges on insulin sensitivity are unknown. We therefore aimed to define the effects of a graded 4-h FFA elevation intended to mimick physiological excursions. METHODS: Eight lean, healthy men were studied on two occasions: (1) control (saline) and (2) 4 h graded infusion of intralipid (20%)/heparin. Insulin sensitivity was continuously assessed by isotope dilution (3H-glucose) during an 8 h hyperinsulinemic-euglycaemic clamp (0.5 mU kg(-1) min(-1) ). Phosphorylation of Akt and ERK1/2 was measured in muscle biopsies taken at 0 and 120 min. Inflammatory cytokines were assessed with a Luminex Suspension Array System. RESULTS: Infusion of intralipid caused a bell-shaped increase in FFA levels reaching peak levels ~1.9 mmol L(-1) and markedly impairing insulin sensitivity. Impairment of insulin sensitivity was apparent (P>0.05) 120 min after initiation of FFA infusion, significant after 270 min (P < 0.001) and peaked after 360 min. FFA induced insulin resistance prevailed 210 min after cessation of FFA infusion. No effect was observed on Akt and ERK1/2 phosphorylation. CONCLUSIONS: (1) Physiological FFA elevations require at least 120 min to induce insulin resistance, (2) that insulin resistance peaks 360 min after initiation of FFA exposure and (3) ceases 210 min after termination of the FFA infusion. These observations add to our understanding of FFA induced insulin resistance in relation to circadian variations, exercise, generalized inflammation and exposure to stress hormones such as growth hormone.

Impact of GH substitution on exercise capacity and muscle strength in GH-deficient adults: a meta-analysis of blinded, placebo-controlled trials.

BACKGROUND: Several but not all trials suggest that GH replacement in GH-deficient adults improves aerobic exercise capacity, whereas its effect on muscle strength is more dubious. However, a denominator of these studies is a low sample size. OBJECTIVE: We systematically reviewed and analysed all randomized, double-blind, placebo-controlled trials on the effects of GH administration on aerobic exercise capacity and muscle strength in GH-deficient adults. STUDY SELECTION: Fifteen trials were identified from four databases. We conducted an analysis of effects on aerobic exercise capacity, performed on either a treadmill or a bicycle ergometer, muscle strength assessed by a dynamometer, and muscle mass assessed by computerized tomography. RESULTS: The total number of patients included was 306 and the duration of treatment ranged from 3 to 12 months. GH replacement significantly increased aerobic exercise capacity [8.9 ± 0.8%, (P < 0.001)] including VO(2) max [0.17 ± 0.02 l/min (P < 0.001)], as well as muscle volume [7.1 ± 1.6%, (P < 0.001)]. In contrast, muscle strength measured in 113 patients was not significantly increased [3.2 ± 2.2% (P = 0.15)]. CONCLUSION: GH replacement in GH-deficient adults is associated with a significant positive effect on aerobic exercise capacity and muscle mass.

Dose-response effects of free fatty acids on amino acid metabolism and ureagenesis.

AIM: Free fatty acids (FFAs) are important fuels and have vital protein-sparing effects, particularly during conditions of metabolic stress and fasting. However, it is uncertain whether these beneficial effects are evident throughout the physiological range or only occur at very high FFA concentrations. It is also unclear whether secondary alterations in hormone levels and ketogenesis play a role. We therefore aimed at describing dose-response relationships between amino acid metabolism and circulating FFA concentrations at clamped hormone levels. METHODS: Eight healthy men were studied on four occasions (6 h basal, 2 h glucose clamp). Endogenous lipolysis was blocked with acipimox and Intralipid was infused at varying rates (0, 3, 6 or 12 microL kg(-1) min(-1)) to obtain four different levels of circulating FFAs. Endogenous growth hormone, insulin and glucagon secretion was blocked by somatostatin (300 microg h(-1)) and replaced exogenously. 15N-phenylalanine, 2H4-tyrosine and 13C-urea were infused continuously to assess protein turnover and ureagenesis. RESULTS: We obtained four distinct levels of FFA concentrations ranging from 0.03 to 2.1 mmol L(-1) and 3-hydroxybutyrate concentrations from 10 to 360 micromol L(-1). Whole-body phenylalanine turnover and phenylalanine-to-tyrosine degradation decreased with increasing FFA levels as did insulin-stimulated forearm fluxes of phenylalanine. Phenylalanine, tyrosine and urea concentrations also decreased progressively, whereas urea turnover was unperturbed. CONCLUSION: Circulating FFAs decrease amino acid concentrations and inhibit whole-body phenylalanine fluxes and phenylalanine-to-tyrosine conversion. Our data cover FFA concentrations from 0 to 2 mmol L(-1) and indicate that FFAs exert their protein conserving effects in the upper physiological range (>1.5 mmol L(-1)).

Concomitant, specific determination of growth hormone and pegvisomant in human serum.

Growth hormone (GH) and the GH receptor blocker, pegvisomant are usually circulating in high concentration in pegvisomant treated acromegalic patients. This and the close similarity between the peptides make determination of either difficult. In the present methodological study, endogenous GH in serum is initially isolated and determined in a slightly modified commercial immunometric assay, whereafter the now GH free medium allows measurement of pegvisomant. Inter-individual steady state levels of serum pegvisomant vary remarkably in both acromegalic patients and healthy controls, while the intra-individual variations are negligible.

The ghrelin response to exercise before and after growth hormone administration.

CONTEXT: We have previously shown that exercise-induced GH release is not mediated by ghrelin, but it remains to be studied whether the increase in GH may suppress postexercise ghrelin levels. OBJECTIVE: The objective of this study was to characterize systemic ghrelin levels after exercise with and without concomitant GH administration. DESIGN, PARTICIPANTS, AND INTERVENTION: Group A: Twenty-nine elite athletes (age, 18-37 yr) were studied after a maximal exercise test. Group B: In a double blind, placebo-controlled, parallel study, 32 healthy subjects (age, 18-33 yr) were randomized to placebo, GH 0.1 IU/kg per day, or GH 0.2 IU/kg per day for 4 wk. These subjects performed a multistage fitness test to assess maximum oxygen uptake at baseline and after 4 wk. We measured total circulating ghrelin levels before and immediately after exercise and at 15, 30, 60, 90, and 120 min after exercise. RESULTS: Group A: Serum ghrelin levels after exercise decreased significantly (P < 0.01). Group B: Exercise at baseline was associated with a significant lowering of ghrelin levels after exercise (P < 0.0001). In addition, 4 wk of high-dose GH were followed by a further approximately 20% reduction in basal and after exercise serum ghrelin (micrograms per liter): 0.78 (range 0.52-1.17) vs. 0.63 (range 0.50-0.91), P < 0.05. CONCLUSIONS: 1) Ghrelin levels decrease significantly after exercise in elite athletes and healthy subjects. 2) High-dose GH suppresses ghrelin levels. 3) These data support the hypothesis that GH feedback inhibits ghrelin secretion.

Abnormalities of whole body protein turnover, muscle metabolism and levels of metabolic hormones in patients with chronic heart failure.

OBJECTIVE: It is well known that chronic heart failure (CHF) is associated with insulin resistance and cachexia, but little is known about the underlying substrate metabolism. The present study was undertaken to identify disturbances of basal glucose, lipid and protein metabolism. DESIGN: We studied eight nondiabetic patients with CHF (ejection fraction 30 +/- 4%) and eight healthy controls. Protein metabolism (whole body and regional muscle fluxes) and total glucose turnover were isotopically assayed. Substrate oxidation were obtained by indirect calorimetry. The metabolic response to exercise was studied by bicycle ergometry exercise. RESULTS: Our data confirm that CHF patients have a decreased lean body mass. CHF patients are characterised by (i) decreased glucose oxidation [glucose oxidation (mg kg(-1) min(-1)): 1.25 +/- 0.09 (patients) vs. 1.55 +/- 0.09 (controls), P < 0.01] and muscle glucose uptake [a - v diff(glucose) (micromol L(-1)): -10 +/- 25 (patients) vs. 70 +/- 22 (controls), P < 0.01], (ii) elevated levels of free fatty acids (FFA) [FFA (mmol L(-1)): 0.72 +/- 0.05 (patients) vs. 0.48 +/- 0.03 (controls), P < 0.01] and 3-hydroxybutyrate and signs of elevated fat oxidation and muscle fat utilization [a - v diff(FFA) (mmol L(-1)): 0.12 +/- 0.02 (patients) vs. 0.05 +/- 0.01 (controls), P < 0.05] and (iii) elevated protein turnover and protein breakdown [phenylalanine flux (micromol kg(-1) h(-1)): 36.4 +/- 1.5 (patients) vs. 29.6 +/- 1.3 (controls), P < 0.01]. Patients had high circulating levels of noradrenaline, glucagon, and adiponectin, and low levels of ghrelin. We failed to observe any differences in metabolic responses between controls and patients during short-term exercise. CONCLUSIONS: In the basal fasting state patients with CHF are characterized by several metabolic abnormalities which may contribute to CHF pathophysiology and may provide a basis for targeted intervention.

Insulin-like growth factor (IGF) I, -II, and IGF binding protein-3 and risk of ischemic stroke.

BACKGROUND: Low IGF-I levels may be associated with the development of stroke; however, prospective data appear to be unavailable. METHODS: This was a nested case-control study within a Danish follow-up study, including 57,053 men and women. Baseline data included circulating IGF-I, IGF-II, and IGF binding protein (IGFBP)-3 concentrations as well as lifestyle factors and medical history. We identified 254 cases with incident ischemic stroke and 254 gender- and age-matched controls. RESULTS: Participants in the bottom quartiles of IGF-I and IGFBP-3 levels (median concentrations, 72 and 2937 ng/ml, respectively) were at increased risk of ischemic stroke, e.g. adjusted odds ratios (ORs) of 2.06 [95% confidence interval (CI), 1.05-4.03] and 2.29 (95% CI, 1.17-4.49), respectively, when compared with participants in the top quartiles (median concentrations, 125 and 4835 ng/ml, respectively). A negative, although weaker, association was also found for IGF-II (adjusted OR 1.44, 95% CI 0.79-2.64) when comparing the bottom quartile with the top quartile. No substantial associations were seen for IGF-I and IGF-II when also adjusting for IGFBP-3; adjusting IGFBP-3 for IGF-I and -II had only a minor impact on the risk estimates. CONCLUSION: These findings give some support to the hypothesis that the IGF axis is involved in the pathogenesis of ischemic stroke.

Effects of GH replacement therapy in adults on serum levels of leptin and ghrelin: the role of lipolysis.

OBJECTIVE: The regulation and function of systemic ghrelin levels appear to be associated with food intake and energy balance rather than GH. Since GH, in turn, acutely induces lipolysis and insulin resistance in skeletal muscle, we aimed to study the isolated and combined effects of GH, free fatty acids (FFAs) and insulin sensitivity on circulating ghrelin levels in human subjects. DESIGN: Seven GH-deficient patients (aged 37 +/- 4 years (mean +/- s.e.)) were studied on four occasions in a 2 x 2 factorial design with and without GH substitution and with and without administration of acipimox, which lowers FFA levels by inhibition of the hormone-sensitive lipase, in the basal state and during a hyperinsulinemic euglycemic clamp. RESULTS: Serum FFA levels decreased with acipimox administration irrespective of GH status. The GH-induced reduction in insulin sensitivity was countered by acipimox. Fasting ghrelin levels decreased insignificantly during GH administration alone, but were reduced by 33% during co-administration of GH and acipimox (Aci) (in ng/l): 860 +/- 120 (-GH - Aci), 711 +/- 130 (-GH + Aci), 806 +/- 130 (+GH - Aci), 574 +/- 129 (+GH + Aci), P < 0.01. The clamp was associated with a further, moderate lowering of ghrelin. GH and acipimox induced a reciprocal 25% increase in serum leptin levels (microg/l): 11.2 +/- 4.4 (-GH - Aci), 11.7 +/- 4.4 (-GH + Aci), 11.5 +/- 4.4 (+GH - Aci), 13.9 +/- 4.2 (+GH + Aci), P = 0.005. CONCLUSION: Our data suggest that antilipolysis via suppression of the hormone-sensitive lipase in combination with GH administration is associated with significant and reciprocal changes in ghrelin and leptin.

Metabolic consequences of GH deficiency.

Patients with active acromegaly are insulin resistant and glucose intolerant, whereas children with GH deficiency are insulin sensitive and may develop fasting hypoglycemia. Surprisingly, however, hypopituitary adults with unsubstituted GH deficiency tend to be insulin resistant which may worsen during GH substitution. A unifying mechanism explaining insulin resistance in both conditions could be increased flux of free fatty acids (FFA) caused by visceral obesity (untrated GHDA) and enhanced lipid oxidation (GH substitution), respectively. During fasting, which may be considered the natural domain for the metabolic effects of GH, the induction of insulin resistance by GH is associated with enhanced lipid oxidation and protein conservation. In this particular context, insulin resistance appears to constitute a favorable metabolic adaptation. The problem is that GH substitution results in elevated circadian GH levels in non-fasting patients. The best way to address this challenge is to employ evening administration of GH and to tailor the dose. Insulin therapy may cause hypoglycemia, and GH substitution may cause hyperglycemia. Such untoward effects should be minimised by carefully monitoring the individual patient. It is also plausible that the long-term beneficial effects of GH on body composition will balance the insulin antagonistic effects on glucose metabolism.