Madeleine L. Drent

GLP-1 receptor activation modulates appetite- and reward-related brain areas in humans

Gut-derived hormones, such as GLP-1, have been proposed to relay information to the brain to regulate appetite. GLP-1 receptor agonists, currently used for the treatment of type 2 diabetes (T2DM), improve glycemic control and stimulate satiety, leading to decreases in food intake and body weight. We hypothesized that food intake reduction after GLP-1 receptor activation is mediated through appetite- and reward-related brain areas. Obese T2DM patients and normoglycemic obese and lean individuals (n = 48) were studied in a randomized, crossover, placebo-controlled trial. Using functional MRI, we determined the acute effects of intravenous administration of the GLP-1 receptor agonist exenatide, with or without prior GLP-1 receptor blockade using exendin 9-39, on brain responses to food pictures during a somatostatin pancreatic-pituitary clamp. Obese T2DM patients and normoglycemic obese versus lean subjects showed increased brain responses to food pictures in appetite- and reward-related brain regions (insula and amygdala). Exenatide versus placebo decreased food intake and food-related brain responses in T2DM patients and obese subjects (in insula, amygdala, putamen, and orbitofrontal cortex). These effects were largely blocked by prior GLP-1 receptor blockade using exendin 9-39. Our findings provide novel insights into the mechanisms by which GLP-1 regulates food intake and how GLP-1 receptor agonists cause weight loss.

Efficacy and safety of growth hormone treatment in adults with growth hormone deficiency: a systematic review of studies on morbidity

Due to the positive effects demonstrated in randomized clinical trials on cardiovascular surrogate markers and bone metabolism, a positive effect of growth hormone (GH) treatment on clinically relevant end‐points seems feasible. In this review, we discuss the long‐term efficacy and safety of GH treatment in adult patients with growth hormone deficiency (GHD) with emphasis on morbidity: fatal and nonfatal cardiovascular disease (CVD) and stroke, fractures, fatal and nonfatal malignancies and recurrences, and diabetes mellitus. A positive effect of GH treatment on CVD and fracture risk could be concluded, but study design limitations have to be considered. Stroke and secondary brain tumours remained more prevalent. However, other contributing factors have to be taken into account. Regrowth and recurrences of (peri)pituitary tumours were not increased in patients with GH treatment compared to similar patients without GH treatment. All fatal and nonfatal malignancies were not more prevalent in GH‐treated adults compared to the general population. However, follow‐up time is still relatively short. The studies on diabetes are difficult to interpret, and more evidence is awaited. In clinical practice, a more individualized assessment seems appropriate, taking into consideration the underlying diagnosis of GHD, other treatment regimens, metabolic profile and the additional beneficial effects of GH set against the possible risks. Large and thoroughly conducted observational studies are needed and seem the only feasible way to inform the ongoing debate on health care costs, drug safety and clinical outcomes.

Incidence of Venous Thromboembolism in Patients with Cushing's Syndrome: A Multicenter Cohort Study

CONTEXT Venous thrombosis has frequently been reported in patients with endogenous Cushings syndrome (CS). OBJECTIVE The aim of this study was to evaluate the incidence of venous thromboembolism (VTE) in patients with CS prior to treatment and after surgery. DESIGN AND SETTING We conducted a multicenter cohort study at all university medical centers in The Netherlands. PATIENTS Consecutive patients diagnosed with endogenous CS of benign origin between January 1990 and June 2010 were eligible for inclusion. Patients surgically treated for nonfunctioning pituitary adenoma served as controls for the incidence of postoperative VTE in ACTH-dependent CS. MAIN OUTCOME MEASURES We documented all objectively confirmed VTE during 3 yr prior to, and 3 yr after treatment onset. The incidences of VTE were expressed as incidence rates. RESULTS A total of 473 patients (mean age 42 yr, 363 women) were included (360 ACTH-dependent pituitary CS). The total number of person-years was 2526. Thirty-seven patients experienced VTE during the study period, resulting in an incidence rate of 14.6 [95% confidence interval (CI) 10.3-20.1] per 1000 person-years. The incidence rate for first-ever VTE prior to treatment was 12.9 (95% CI 7.5-12.6) per 1000 person-years (17 events). The risk of postoperative VTE, defined as risk within 3 months after surgery, was 0% for ACTH-independent and 3.4% (95% CI 2.0-5.9) for ACTH-dependent CS (12 events in 350 patients); most events occurred between 1 wk and 2 months after surgery. Compared with the controls, the risk of postoperative VTE in patients undergoing transsphenoidal surgery was significantly greater (P = 0.01). CONCLUSIONS Patients with CS are at high risk of VTE, especially during active disease and after pituitary surgery. Guidelines on thromboprophylaxis are urgently needed.

Does Growth Hormone Replacement Therapy Reduce Mortality in Adults with Growth Hormone Deficiency? Data from the Dutch National Registry of Growth Hormone Treatment in Adults

CONTEXT Adults with GH deficiency (GHD) have a decreased life expectancy. The effect of GH treatment on mortality remains to be established. OBJECTIVE This nationwide cohort study investigates the effect of GH treatment on all-cause and cause-specific mortality and analyzes patient characteristics influencing mortality in GHD adults. DESIGN, SETTING, AND PATIENTS Patients in the Dutch National Registry of Growth Hormone Treatment in Adults were retrospectively monitored (1985-2009) and subdivided into treatment (n = 2229), primary (untreated, n = 109), and secondary control (partly treated, n = 356) groups. MAIN OUTCOME MEASURES Standardized mortality ratios (SMR) were calculated for all-cause, malignancy, and cardiovascular disease (CVD) mortality. Expected mortality was obtained from cause, sex, calendar year, and age-specific death rates from national death and population counts. RESULTS In the treatment group, 95 patients died compared to 74.6 expected [SMR 1.27 (95% confidence interval, 1.04-1.56)]. Mortality was higher in women than in men. After exclusion of high-risk patients, the SMR for CVD mortality remained increased in women. Mortality due to malignancies was not elevated. In the control groups mortality was not different from the background population. Univariate analyses demonstrated sex, GHD onset, age, and underlying diagnosis as influencing factors. CONCLUSIONS GHD men receiving GH treatment have a mortality rate not different from the background population. In women, after exclusion of high-risk patients, mortality was not different from the background population except for CVD. Mortality due to malignancies was not elevated in adults receiving GH treatment. Next to gender, the heterogeneous etiology is of influence on mortality in GHD adults with GH treatment.

The Association of Serum Insulin-Like Growth Factor-I with Mortality, Cardiovascular Disease, and Cancer in the Elderly: A Population-Based Study

CONTEXT Numerous studies have investigated the effect of serum IGF-I concentration on aging and different aging-related diseases, e.g. cardiovascular disease (CVD) and cancer. Decreased as well as increased levels have been reported to be associated with reduced life expectancy in humans. OBJECTIVE This study investigates the association of serum IGF-I concentration with all-cause and cause-specific mortality of community-dwelling older persons and the development of CVD and cancer. DESIGN, SETTING, AND PARTICIPANTS Data were used from the Longitudinal Aging Study Amsterdam (LASA), an ongoing multidisciplinary cohort study in the general Dutch population of older persons (≥65 yr old) where serum IGF-I was measured (n = 1273). The mortality information was ascertained using the International Classification of Diseases, 10th revision, and the presence or absence of CVD and cancer by self-reports with a follow-up of 11.6 yr. MAIN OUTCOME MEASURE We measured all-cause, CVD, and cancer mortality and nonfatal CVD and cancer. RESULTS Fully adjusted Cox proportional hazards models demonstrated an increased risk of all-cause mortality for older persons with IGF-I values in the lowest quintile as compared to the middle quintile [hazard ratio (HR), 1.28; 95% confidence interval (CI), 1.01-1.63]. A more than 2-fold increased risk of CVD mortality was revealed for both low-normal (HR, 2.39; 95% CI, 1.22-4.66) and high-normal (HR, 2.03; 95% CI, 1.02-4.06) IGF-I values. Significant associations of serum IGF-I with nonfatal CVD and fatal and nonfatal cancer were not observed. CONCLUSIONS Results suggest a U-shaped relationship between IGF-I level and mortality, with fatal CVD as the most critical outcome in community-dwelling older persons.

Long-term growth hormone treatment preserves GH-induced memory and mood improvements: a 10-year follow-up study in GH-deficient adult men

Growth hormone (GH) replacement therapy with duration of several years is known to be safe and beneficial in GH-deficient adult patients. However, long-term follow-up data on GH substitution, cognition, and well-being are scarce. The purpose of this study was to investigate whether the benefits of GH replacement in psychological functioning found in previous studies lasting up to 2 years are preserved over a 10-year follow-up period. Twenty-three men (mean age at baseline 28.6 years) with childhood-onset GH deficiency were studied during a 10-year period of GH substitution. Memory tasks, mood questionnaires, and IGF-I values were obtained at baseline and after 0.5, 1, 2, 3, 5, and 10 years of GH substitution. Both mood and memory improved during GH therapy. After 6 months of treatment, anxiety and tension were reduced and vigor had improved. Memory improved after 1 year of substitution. These improvements were maintained during the 10-year follow-up period. Higher intra-subject IGF-I levels were associated with better mood (anxiety, tension, vigor). This study shows that 10 years of GH therapy is beneficial in terms of well-being and cognitive functioning in childhood-onset GH-deficient men. It may be concluded that once the decision to start GH treatment has been taken, this may imply that GH therapy has to be continued for a long period to maintain the psychological improvements and to prevent a relapse.

Effects of Growth Hormone Substitution Therapy on Cognitive Functioning in Growth Hormone Deficient Patients: A Functional MRI Study

Patients with childhood-onset growth hormone (GH) deficiency (GHD) show impairments in mood and cognitive functioning which may resolve following GH substitution. Brain functional magnetic resonance imaging (fMRI) during performance of a memory task was used to assess the cerebral activity of such patients. Thirteen childhood-onset GHD patients (mean age 27.3 ± 6.9 years) were included in a double-blind, placebo-controlled study. The effects of 6 months of GH replacement or placebo therapy were studied using neuropsychological tests and fMRI. One patient was excluded from the study due to noncompliance with the protocol. Six months of GH substitution in these GHD patients resulted in improved memory functioning, both for long-term and working memory. fMRI showed activations during the working memory task in prefrontal, parietal, motor, and occipital cortices, as well as in the right thalamus and anterior cingulate cortex. Decreased activation in the ventrolateral prefrontal cortex was observed after GH treatment as compared with placebo treatment, indicating decreased effort and more efficient recruitment of the neural system involved. It can be concluded that GH treatment for 6 months improved the long-term as well as the working memory in patients with GHD, and this was associated with decreased brain activation in the ventrolateral prefrontal cortex. GH substitution in GHD patients is beneficial for cognitive functioning, the effects of which can be visualized by means of neuroimaging.

Reduced parahippocampal and lateral temporal GABAA-[11C]flumazenil binding in major depression: preliminary results

PurposeMajor depressive disorder (MDD) has been related to both a dysfunctional γ-amino butyric acid (GABA) system and to hyperactivity of the hypothalamic-pituitary-adrenal axis (HPA). Although GABA has been suggested to inhibit HPA axis activity, their relationship has never been studied at the level of the central GABAA-benzodiazepine receptor in depressed patients or in relation to antidepressant treatment.MethodsEleven depressed outpatients were compared, before and after treatment with citalopram, with nine age-matched healthy controls. The subjects were scanned using the positron emission tomography (PET) tracer [11C]flumazenil ([11C]FMZ). Parametric voxel-by-voxel Logan plots were compared with methods based on regions of interest (ROI), to provide volume of distribution (VT) and binding potential (BPND) values. Plasma GABA levels were determined and a dexamethasone-corticotropin releasing hormone (DEX-CRH) test was performed.ResultsIn MDD, parametric voxel-by-voxel Logan plots showed bilateral reduced [11C]FMZ binding in the parahippocampal gyrus and right lateral superior temporal gyrus (p uncorrected ≤0.001). In the temporal area, [11C]FMZ binding showed a strong inverse correlation with HPA axis activity. Plasma GABA did not discriminate MDD from controls, but correlated inversely with [11C]FMZ binding in the right insula. Following treatment with citalopram, voxel-based analysis revealed reduced binding in the right lateral temporal gyrus and dorsolateral prefrontal cortex.ConclusionThe bilateral reduction in limbic parahippocampal and right temporal [11C]FMZ binding found in MDD indicates decreased GABAA-benzodiazepine receptor complex affinity and/or number. The inverse relationship between GABAA binding in the temporal lobe and HPA axis activity, suggests that HPA axis hyperactivity is partly due to reduced GABA-ergic inhibition.

Effects of 10 years of growth hormone (GH) replacement therapy in adult GH-deficient men

Objective  GH‐deficient adults have changes in body composition, bone mineral density (BMD) and lipid profile that can be altered by GH substitution. However, long‐term data on GH substitution (up to 10 years of follow‐up) are limited.

Low accuracy of tumor markers for diagnosing pancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1 patients

CONTEXT The assessment of tumor markers for diagnosing pancreatic neuroendocrine tumors (pNET) in multiple endocrine neoplasia type 1 (MEN1) patients is advised in the current guidelines but has never been validated for this purpose. OBJECTIVE The objective of the study was to assess the diagnostic accuracy of chromogranin A (CgA), pancreatic polypeptide (PP), and glucagon for pNET in MEN1. DESIGN This was a diagnostic study. SETTING The study was conducted at Dutch university medical centers from 2008 to 2011, representing 90% of the total Dutch MEN1 population. PATIENTS AND METHODS Patients for whom data on tumor markers in combination with the reference standard (ie, radiological imaging) were available between 2008 and 2011 were included. The reference standard for the presence of pNET was pathology or detection on magnetic resonance imaging, computed tomography, or endoscopic ultrasound confirmed on subsequent imaging, irrespective of modality at follow-up. MAIN OUTCOME MEASURES The area under the receiver-operating characteristic curve (AUC), positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio, sensitivity, and specificity were calculated for each marker. RESULTS For the analysis of PP, CgA, and glucagon, 73, 81, and 94 patients were available, respectively. The AUC for CgA was 0.48 [95% confidence interval (CI) 0.35-0.61] with a sensitivity 0.33 and a specificity 0.73; the AUC for glucagon was 0.58 (95% CI 0.46-0.70) with a sensitivity 0.43 and a specificity 0.73; and the AUC for PP was 0.64 (95% CI 0.50-0.77) with a sensitivity 0.36 and a specificity 0.74. Age, imaging modality, tumor size, and number did not influence the outcomes. CONCLUSION The diagnostic accuracy of the tumor markers CgA, PP, and glucagon for pNET in MEN1 is low.