Acute presentation of craniopharyngioma in children and adults in a Danish national cohort.

We aimed to study the occurrence of acute-onset symptoms at initial presentation in a national Danish cohort of patients with childhood- or adult-onset craniopharyngioma, and to investigate potential risk factors for acute presentation. Medical records of 189 consecutive patients (39 children, 150 adults) presenting with craniopharyngioma during the period 1985-2004 were reviewed, and data regarding initial symptoms, neuroimaging results, vision and pituitary function were systematically collected. Acute symptoms preceding hospital admission were noted. Subgroup analyses were based on age, gender and calendar year period. Potential risk factors for acute presentation were analysed through uni- and multivariate analyses. Acute symptoms were reported in 24 (13%) patients. Acute visual symptoms, headache, nausea or vomiting were most frequently reported, and acute symptoms were more frequent among children (28%) than among adults (9%) (P < 0.01). There were no differences according to sex or calendar year period. Hydrocephalus was present in half of childhood cases and one-fifth of adult patients (P < 0.001). Intra-tumour haemorrhage was seen in two cases. Acute symptoms were more frequent among patients with tumours occupying the third ventricle (P < 0.01), radiologic signs of calcification (P < 0.05) or hydrocephalus (P < 0.01). In multivariate analysis, however, only childhood onset (P < 0.05) and calcification (P < 0.05) were independent risk factors for acute presentation. Craniopharyngioma presented with acute symptoms in 13% of patients. Childhood onset and radiologic signs of calcification were independent risk factors for acute presentation. Intra-tumour haemorrhage was rare.

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.

Incidence of craniopharyngioma in Denmark (n = 189) and estimated world incidence of craniopharyngioma in children and adults.

We studied the incidence of craniopharyngioma in Denmark during the period 1985-2004 and estimated worldwide incidence rates (IR) of craniopharyngioma based on a literature review. Craniopharyngioma patients diagnosed during the period 1985-2004 were identified from the Danish National Patient Registry, the Danish Cancer Registry and regional registries. Medical records were reviewed. Danish population data were obtained from Statistics Denmark. European and World population data were obtained from EU and WHO homepages. Prior studies providing data on craniopharyngioma IRs were identified via PubMed and, if appropriate, were included in a weighted analysis estimating overall and children's IRs of craniopharyngioma. IRs are given as new cases per million per year. We identified 189 patients with new verified (162) or probable craniopharyngioma. The overall WHO World-standardised incidence rate was 1.86 (1.60-2.14) for all ages and 2.14 (1.53-2.92) for children (age <15 years). Peak incidence rates were observed in age groups 5-9 and 40-44 years. Fifteen prior studies (including 1,232 craniopharyngioma cases) were identified. Seven and 11 studies, respectively, were eligible for weighted all-ages and childhood population IR analyses, yielding summary IRs of 1.34 (1.24-1.46) (all ages) and 1.44 (1.33-1.56) (children). We have provided a detailed survey of the incidence of craniopharyngioma in Denmark during a recent 20-year period. Overall IR of craniopharyngioma in Denmark was 1.86 (1.60-2.14) as compared to 2.14 (1.53-2.92) among children. Weighted estimates of craniopharyngioma world IRs were 1.34 (1.24-1.46) in all ages and 1.44 (1.33-1.56) among children.

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.

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.

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.

Revisional bariatric surgery.

BACKGROUND: Revisional surgery is required in a significant number of patients because of failure to lose weight, loss of quality of life, weight regain, or complications of the previous procedure. It has traditionally been associated with higher complication rates, and there appears to be no standardized surgical approach to revisional surgery. The aim of the study was to review the revisional procedures performed at St George Private Hospital and analyze the outcomes of the different types of revisional surgery. METHODS: We performed a retrospective review of 75 patients who underwent revisional surgery between December 2003 and October 2007. Demographic, anthropometric, perioperative, and clinical follow-up data were collected, and statistical analyses were performed using SPSS version 14.0. RESULTS: Sixty-six of the 75 patients were female. The mean age at the time of revision was 46.32 (22-68) years. Mean initial weight was 119.08 kg, and body mass index (BMI) was 43.42 kg/m(2). The lowest BMI and excess weight loss (EWL) recorded after primary surgery was 36.9% and 53.5%, respectively. At the time of revision, the mean EWL was 24.79. The EWL at 3 months and 6 months were 41.7% and 47.8%, respectively. Revision was performed laparoscopically in 51 patients and via laparotomy in 24 patients. There was no mortality in the cohort, but there were 17.3% minor and 4.0% major perioperative morbidities. CONCLUSION: Our study suggests that revision can be performed safely. Weight loss is satisfactory, and complications of the previous operations were all reversed. Furthermore, revisions may be done laparoscopically, including those who had previous open procedures.

Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) and Subsequent Central Diabetes Insipidus: A Rare Presentation of Pituitary Apoplexy.

Pituitary apoplexy (PA) is a rare endocrine emergency that occasionally presents with sodium disturbances. Here we present a rare case with a previously healthy 41-year-old female who presented with acute onset headache and nausea without visual impairment or overt pituitary dysfunction. Plasma sodium concentrations declined abruptly during the first two days of admission to a nadir of 111 mmol/l. Urine and blood chemistry were consistent with syndrome of inappropriate antidiuretic hormone secretion (SIADH). Magnetic resonance imaging revealed recent bleeding into a pituitary cystic process. Hyponatremia was successfully corrected with fluid restriction and both visual function and anterior pituitary function remained intact. Subsequently, the patient developed central diabetes insipidus (CDI), which responded well to desmopressin substitution. To our knowledge, this is the first case of PA presenting predominantly with posterior pituitary dysfunction that transitioned from SIADH to permanent CDI.

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.

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.

Detection of growth hormone abuse in sport.

OBJECTIVE: To develop a test for GH abuse in sport. DESIGN: A double blind placebo controlled study of one month's GH administration to 102 healthy non-competing but trained subjects. Blood levels of nine markers of GH action were measured throughout the study and for 56 days after cessation of GH administration. Blood samples were also taken from 813 elite athletes both in and out of competition. RESULTS: GH caused a significant change in the nine measured blood markers. Men were more sensitive to the effects of GH than women. IGF-I and N-terminal extension peptide of procollagen type III were selected to construct formulae which gave optimal discrimination between the GH and placebo groups. Adjustments were made to account for the fall in IGF-I and P-III-P with age and the altered distribution seen in elite athletes. Using a cut-off specificity of 1:10,000 these formulae would allow the detection of up to 86% of men and 60% of women abusing GH at the doses used in this study. CONCLUSIONS: We report a methodology that will allow the detection of GH abuse. This will provide the basis of a robust and enforceable test identifying those who are already cheating and provide a deterrent to those who may be tempted to do so.

Amino acid supplementation is anabolic during the acute phase of endotoxin-induced inflammation: A human randomized crossover trial.

BACKGROUND & AIMS: Inflammation is catabolic and causes muscle loss. It is unknown if amino acid supplementation reverses these effects during the acute phase of inflammation. The aim was to test whether amino acid supplementation counteracts endotoxin-induced catabolism. METHODS: Eight young, healthy, lean males were investigated three times in randomized order: (i) normal conditions (Placebo), (ii) endotoxemia (LPS), and (iii) endotoxemia with amino acid supplementation (LPS + A). Protein kinetics were determined using phenylalanine, tyrosine, and urea tracers. Each study day consisted of a four-hour non-insulin stimulated period and a two-hour hyperinsulinemic euglycemic clamp period. Muscle biopsies were collected once each period. RESULTS: Endotoxin administration created a significant inflammatory response (cytokines, hormones, and vital parameters) without significant differences between LPS and LPS + A. Whole body protein breakdown was elevated during LPS compared with Placebo and LPS + A (p < 0.05). Whole body protein synthesis was higher during LPS + A than both Placebo and LPS (p < 0.003). Furthermore, protein synthesis was higher during LPS than during Placebo (p < 0.02). Net muscle phenylalanine release was markedly decreased during LPS + A (p < 0.004), even though muscle protein synthesis and breakdown rates did not differ significantly between interventions. LPS + A increased mammalian target of rapamycin (mTOR) phosphorylation (p < 0.05) and eukaryotic translation factor 4E-binding protein 1 (4EBP1) phosphorylation (p = 0.007) without activating AMPK or affecting insulin signaling through Akt. During insulin stimulation net muscle phenylalanine release and protein degradation were further reduced. CONCLUSIONS: Amino acid supplementation in the acute phase of inflammation reduces whole body and muscle protein loss, and this effect is associated with activation of mTOR and downstream signaling to protein synthesis through mTORC1, suggesting a therapeutic role for intravenous amino acids in inflammatory states. CLINICAL TRIAL REGISTRY: The Central Denmark Region Ethics Commitee (1-10-71-410-12) www.clinicaltrials.gov (identification number NCT01705782).

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.

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.

Pharmacological antilipolysis restores insulin sensitivity during growth hormone exposure.

Stimulation of lipolysis and the induction of resistance to insulin's actions on glucose metabolism are well-recognized effects of growth hormone (GH). To evaluate whether these two features are causally linked, we studied the impact of pharmacologically induced antilipolysis in seven GH-deficient patients (mean [+/- SE] age 37 +/- 4 years). Each subject was studied under four different conditions: during continuation of GH replacement alone (A), after discontinuation of GH replacement for 2 days (B), after GH replacement and short-term coadministration of acipimox (250 mg, p.o., b.i.d., for 2 days) (C), and after administration of acipimox alone (D). At the end of each study, total and regional substrate metabolisms were assessed in the basal state and after a 3-h hyperinsulinemic/euglycemic clamp. Serum levels of free fatty acids (FFAs) were elevated with GH alone (A) and suppressed with acipimox (C and D). Basal rates of lipid oxidation were highest with GH alone (A), and suppressed by 50% with acipimox (B versus D, P < 0.01; A versus C, P < 0.05). Basal glucose oxidation rates were lowest with GH alone (A) and highest with acipimox (C and D) (P = 0.01). Insulin-stimulated rates of total glucose turnover were significantly lower with GH alone as compared with all other conditions (P = 0.004). Insulin sensitivity as assessed by the M value (rate of glucose infusion) was reduced with GH alone as compared with all other conditions (M value in mg. kg(-1). min(-1): GH alone [A], 2.55 +/- 0.64; discontinuation of GH [B], 4.01 +/- 0.70; GH plus acipimox [C], 3.96 +/- 1.34; acipimox alone [D], 4.96 +/- 0.91; P < 0.01). During pharmacological antilipolysis, GH did not significantly influence insulin sensitivity (C versus D; P = 0.19). From our results, we reached the following conclusions: 1) Our data strongly suggest that the insulin antagonistic actions of GH on glucose metabolism are causally linked to the concomitant activation of lipolysis. 2) In addition, GH may induce residual insulin resistance through non-FFA-dependent mechanisms. 3) The cellular and molecular mechanisms subserving the insulin antagonistic effects of GH remain to be elucidated.

The protein-retaining effects of growth hormone during fasting involve inhibition of muscle-protein breakdown.

The metabolic response to fasting involves a series of hormonal and metabolic adaptations leading to protein conservation. An increase in the serum level of growth hormone (GH) during fasting has been well substantiated. The present study was designed to test the hypothesis that GH may be a principal mediator of protein conservation during fasting and to assess the underlying mechanisms. Eight normal subjects were examined on four occasions: 1) in the basal postabsorptive state (basal), 2) after 40 h of fasting (fast), 3) after 40 h of fasting with somatostatin suppression of GH (fast-GH), and 4) after 40 h of fasting with suppression of GH and exogenous GH replacement (fast+GH). The two somatostatin experiments were identical in terms of hormone replacement (except for GH), meaning that somatostatin, insulin, glucagon and GH were administered for 28 h; during the last 4 h, substrate metabolism was investigated. Compared with the GH administration protocol, IGF-I and free IGF-I decreased 35 and 70%, respectively, during fasting without GH. Urinary urea excretion and serum urea increased when participants fasted without GH (urea excretion: basal 392 +/- 44, fast 440 +/- 32, fast-GH 609 +/- 76, and fast+GH 408 +/- 36 mmol/24 h, P < 0.05; serum urea: basal 4.6 +/- 0.1, fast 6.2 +/- 0.1, fast-GH 7.0 +/- 0.2, and fast+GH 4.3 +/- 0.2 mmol/1, P < 0.01). There was a net release of phenylalanine across the forearm, and the negative phenylalanine balance was higher during fasting with GH suppression (balance: basal 9 +/- 3, fast 15 +/- 6, fast-GH 17 +/- 4, and fast+GH 11 +/- 5 nmol/min, P < 0.05). Muscle-protein breakdown was increased among participants who fasted without GH (phenylalanine rate of appearance: basal 17 +/- 4, fast 26 +/- 9, fast-GH 33 +/- 7, fast+GH 25 +/- 6 nmol/min, P < 0.05). Levels of free fatty acids and oxidation of lipid decreased during fasting without GH (P < 0.01). In summary, we find that suppression of GH during fasting leads to a 50% increase in urea-nitrogen excretion, together with an increased net release and appearance rate of phenylalanine across the forearm. These results demonstrate that GH-possibly by maintenance of circulating concentrations of free IGF-I--is a decisive component of protein conservation during fasting and provide evidence that the underlying mechanism involves a decrease in muscle protein breakdown.

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.

The effect of submaximal exercise on immuno- and bioassayable IGF-I activity in patients with GH-deficiency and healthy subjects.

OBJECTIVE: Growth hormone (GH) increases during exercise, but the response of the insulin-like growth factor (IGF) system has not been as definitive. Therefore, we investigated the effect of the exercise-induced GH response on the circulating IGF-system in GH-deficient (GHD) and intact adults. DESIGN: Eight GHD adults were studied on 2 occasions, with (+GH) and without (-GH) GH administered (0.4 IU) during exercise (45 min of cycle ergometer exercise at the lactate threshold). Eight age-matched controls were only studied on one occasion. Blood samples were drawn at baseline, during and post-exercise. IGFBP-3 proteolysis was measured by an in vitro proteolytic activity assay, IGF-I bioactivity by novel IGF-I kinase receptor activation assay (KIRA) and other hormones by immunoassay. RESULTS: GH administration to GHD adults resulted in a serum GH peak similar to the exercise-stimulated GH response in GH intact controls, but exercise had only a small impact on the IGF system. IGF-I concentration was lower in controls but was only significantly lower than the +GH day. Neither IGF-I nor -II levels changed over time. IGFBP-1 demonstrated a time effect (P<0.01) in all groups, and a time x group interaction (P<0.01) with a rise at 75 min post-exercise, which was greater in the GHD subjects than controls. IGFBP-2 and -3 increased significantly (P<0.01) over time in the GHD subjects, but not in the controls. No change in IGFBP-3 proteolysis or IGF-I bioactivity was found during exercise or recovery in either group. CONCLUSION: Submaximal exercise induced minor changes in IGFBP-1, -2 and -3, without affecting IGFBP-3 proteolysis and IGF-I bioavailability. Thus the metabolic status during submaximal exercise does not require a change in plasma IGF-I bioavailability. Administration of GH to GHD adults does not result in changes in proteolysis or bioavailability.

Lack of effects of hypoglycemia on glucose absorption in healthy men.

OBJECTIVE: To assess the effects of hypoglycemia on glucose absorption by examining the systemic appearance of 3-OMG (a glucose analogue that is transported by the same mechanism as glucose) after oral administration. RESEARCH DESIGN AND METHODS: Six healthy males 22-31 yr of age were studied during a hypoglycemic (50 mg [2.7 mM]/100 ml) and a euglycemic (90 mg [5.0 mM]/100 ml) glucose clamp. At 50 min after exposure to insulin, an oral glucose load containing 20 g of glucose and 4.5 g of 3-OMG dissolved in 300 ml of tap water was administered. Insulin administration was interrupted 30 min after oral glucose administration. RESULTS: Plasma glucose was clamped at 88 +/- 1.3 mg (4.9 +/- 0.1 mM)/100 ml during euglycemia and at 50 +/- 1.9 mg (2.7 +/- 0.1 mM)/100 ml during hypoglycemia. Concentrations of glucagon, growth hormone, cortisol, and epinephrine were significantly elevated during hypoglycemia. After 60 min, circulating 3-OMG concentrations increased to zeniths of 11.4 +/- 0.2 mg (585 +/- 10.0 mM)/100 ml (hypoglycemia) and 11.6 +/- 1.1 mg (585 +/- 56.0 microM)/100 ml (euglycemia; P = 0.95). Absorption of 3-OMG was evident between 15 and 20 min after administrations in both situations. Serum insulin was significantly lower during hypoglycemia compared with the control situation (345 +/- 50 microM [hypoglycemia], 445 +/- 50 microM [euglycemia], P = 0.03). CONCLUSIONS: We conclude that hypoglycemia does not seem to affect intestinal absorption of glucose as judged by systemic appearance of 3-OMG.

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.