Acromegaly management in the Nordic countries: A Delphi consensus survey.

OBJECTIVE: Acromegaly is associated with increased morbidity and mortality if left untreated. The therapeutic options include surgery, medical treatment, and radiotherapy. Several guidelines and recommendations on treatment algorithms and follow-up exist. However, not all recommendations are strictly evidence-based. To evaluate consensus on the treatment and follow-up of patients with acromegaly in the Nordic countries. METHODS: A Delphi process was used to map the landscape of acromegaly management in Denmark, Sweden, Norway, Finland, and Iceland. An expert panel developed 37 statements on the treatment and follow-up of patients with acromegaly. Dedicated endocrinologists (n = 47) from the Nordic countries were invited to rate their extent of agreement with the statements, using a Likert-type scale (1-7). Consensus was defined as ≥80% of panelists rating their agreement as ≥5 or ≤3 on the Likert-type scale. RESULTS: Consensus was reached in 41% (15/37) of the statements. Panelists agreed that pituitary surgery remains first line treatment. There was general agreement to recommend first-generation somatostatin analog (SSA) treatment after failed surgery and to consider repeat surgery. In addition, there was agreement to recommend combination therapy with first-generation SSA and pegvisomant as second- or third-line treatment. In more than 50% of the statements, consensus was not achieved. Considerable disagreement existed regarding pegvisomant monotherapy, and treatment with pasireotide and dopamine agonists. CONCLUSION: This consensus exploration study on the management of patients with acromegaly in the Nordic countries revealed a relatively large degree of disagreement among experts, which mirrors the complexity of the disease and the shortage of evidence-based data.

Diabetes mellitus in patients with acromegaly: pathophysiology, clinical challenges and management.

Acromegaly is a rare endocrine disease caused by hypersecretion of growth hormone, most commonly arising due to a pituitary adenoma. Diabetes mellitus is a common complication of acromegaly, occurring in approximately one-third of patients. The risk of diabetes mellitus in acromegaly is driven by increased exposure to growth hormone, which directly attenuates insulin signalling and stimulates lipolysis, leading to decreased glucose uptake in peripheral tissues. Acromegaly is a unique human model, where insulin resistance occurs independently of obesity and is paradoxically associated with a lean phenotype and reduced body adipose tissue mass. Diabetes mellitus in patients with acromegaly is associated with an increased risk of cardiovascular morbidity and mortality. Therefore, preventive measures and optimized treatment of diabetes mellitus are essential in these patients. However, specific recommendations for the management of diabetes mellitus secondary to acromegaly are lacking due to limited research on this subject. This Review explores the underlying mechanisms for diabetes mellitus in acromegaly and its effect on morbidity and mortality. We also discuss treatment modalities for diabetes mellitus that are suited for patients with acromegaly. Improved understanding of these issues will lead to better management of acromegaly and its associated metabolic complications.

Changes in acromegaly comorbidities, treatment, and outcome over three decades: a nationwide cohort study.

Objective: To study the time-dependent changes in disease features of Danish patients with acromegaly, including treatment modalities, biochemical outcome, and comorbidities, with a particular focus on cancer and mortality. Methods: Pertinent acromegaly-related variables were collected from 739 patients diagnosed since 1990. Data are presented across three decades (1990-1999, 2000-2009, and 2010-2021) based on the year of diagnosis or treatment initiation. Results: Adenoma size and insulin-like growth factor I (IGF-I) levels at diagnosis did not differ significantly between study periods. The risk of being diagnosed with diabetes, heart disease, sleep apnea, joint disease, and osteoporosis increased from the 1990s to the later decades, while the mortality risk declined to nearly half. The risk of cancer did not significantly change. Treatment changed toward the use of more medical therapy, and fewer patients underwent repeat surgeries or pituitary irradiation. A statistically significant increase in the proportion of patients achieving IGF-I normalization within 3-5 years was observed over time (69%, 83%, and 88%). The proportion of patients with three or more deficient pituitary hormones decreased significantly over time. Conclusion: Modern medical treatment regimens of acromegaly as well as increased awareness and improved diagnostics for its comorbidities have led to better disease control, fewer patients with severe hypopituitarism, and declining mortality in the Danish cohort of acromegaly patients. The risk of cancer did not increase over the study period.

The changing landscape of acromegaly - an epidemiological perspective.

Acromegaly is a rare disease and thus challenging to accurately quantify epidemiologically. In this comprehensive literature review, we compare different approaches to studying acromegaly from an epidemiological perspective and describe the temporal evolution of the disease pertaining to epidemiological variables, clinical presentation and mortality. We present updated epidemiological data from the population-based Danish cohort of patients with acromegaly (AcroDEN), along with meta-analyses of existing estimates from around the world.Based on this, we conclude that the incidence, prevalence and age at acromegaly diagnosis are all steadily increasing, but with considerable variation between studies. An increased number of incidental cases may contribute to the increase in incidence and age at diagnosis, respectively. The clinical features at presentation are trending toward a milder disease phenotype at diagnosis, and advances in therapeutic options have reduced the mortality of patients with acromegaly to a level similar to that of the general population. Moreover, the underlying cause of death has shifted from cardiovascular to malignant neoplastic diseases.

The Socioeconomic Consequences of Cushing's Syndrome: A Nationwide Cohort Study.

CONTEXT: The long-term somatic and psychiatric consequences of Cushing's syndrome are well-described, but the socioeconomic consequences are largely unknown. OBJECTIVE: We studied employment status, educational level, risk of depression, and other socioeconomic outcomes of Cushing's syndrome in the years before diagnosis and after surgery. DESIGN: Nationwide register-based cohort study. METHODS: We used a validated algorithm to identify 424 patients operated for adrenal (n = 199) or pituitary Cushing's syndrome (n = 225) in Denmark from January 1, 1986 to December 31, 2017. We obtained socioeconomic registry data from 10 years before diagnosis (year -10) to 10 years after surgery (year +10) and included a sex- and age-matched reference population. We identified prognostic factors for returning to work using modified Poisson regression. RESULTS: Compared to the reference population, the patients' employment was permanently reduced from year -6 [relative risk (RR) 0.92, 95% CI 0.84-0.99] to year +10 (RR 0.66, 95% CI 0.57-0.76). Sick leave (RR 2.15, 95% CI 1.40-3.32) and disability pension (RR 2.60, 95% CI 2.06-3.27) were still elevated in year +10. Annual income, education, parenthood, relationship status, and risk of depression were also negatively impacted, but parenthood and relationship status normalized after surgery. Among patients, negative predictors of full-time employment after surgery included female sex, low education, comorbidity, and depression. CONCLUSION: Cushing's syndrome negatively affects a wide spectrum of socioeconomic variables many years before diagnosis of which only some normalize after treatment. The data underpin the importance of early diagnosis and continuous follow-up of Cushing's syndrome and, not least, the pervasive health threats of glucocorticoid excess.

Safety of growth hormone replacement in survivors of cancer and intracranial and pituitary tumours: a consensus statement.

Growth hormone (GH) has been used for over 35 years, and its safety and efficacy has been studied extensively. Experimental studies showing the permissive role of GH/insulin-like growth factor 1 (IGF-I) in carcinogenesis have raised concerns regarding the safety of GH replacement in children and adults who have received treatment for cancer and those with intracranial and pituitary tumours. A consensus statement was produced to guide decision-making on GH replacement in children and adult survivors of cancer, in those treated for intracranial and pituitary tumours and in patients with increased cancer risk. With the support of the European Society of Endocrinology, the Growth Hormone Research Society convened a Workshop, where 55 international key opinion leaders representing 10 professional societies were invited to participate. This consensus statement utilized: (1) a critical review paper produced before the Workshop, (2) five plenary talks, (3) evidence-based comments from four breakout groups, and (4) discussions during report-back sessions. Current evidence reviewed from the proceedings from the Workshop does not support an association between GH replacement and primary tumour or cancer recurrence. The effect of GH replacement on secondary neoplasia risk is minor compared to host- and tumour treatment-related factors. There is no evidence for an association between GH replacement and increased mortality from cancer amongst GH-deficient childhood cancer survivors. Patients with pituitary tumour or craniopharyngioma remnants receiving GH replacement do not need to be treated or monitored differently than those not receiving GH. GH replacement might be considered in GH-deficient adult cancer survivors in remission after careful individual risk/benefit analysis. In children with cancer predisposition syndromes, GH treatment is generally contraindicated but may be considered cautiously in select patients.

ß-Lactoglobulin Is Insulinotropic Compared with Casein and Whey Protein Ingestion during Catabolic Conditions in Men in a Double-Blinded Randomized Crossover Trial.

BACKGROUND: Muscle loss during acute infectious disease is mainly triggered by inflammation, immobilization, and malnutrition. OBJECTIVE: The objective was to compare muscle protein kinetics and metabolism following ingestion of the dairy protein supplements ß-lactoglobulin (BLG), casein (CAS), and whey (WHE) during controlled catabolic conditions. METHODS: We used a randomized crossover design (registered at clinicaltrials.gov as NCT03319550) to investigate 9 healthy male participants [age: 20-40 y; BMI (in kg/m2) 20-30] who were randomly assigned servings of BLG, CAS, or WHE (0.6 g protein/kg, one-third as bolus and two-thirds as sip every 20 min) on 3 separate occasions separated by ∼6-8 wk. The participants received an infusion of lipopolysaccharide (1 ng/kg) combined with 36 h of fasting and bed rest before each study day, mimicking a clinical catabolic condition. The forearm model and isotopic tracer techniques were used to quantify muscle protein kinetics. Muscle biopsy specimens were obtained and intramyocellular signaling investigated using Western blot. RESULTS: BLG, CAS, and WHE improved the net balance of phenylalanine (NBphe) from baseline with ∼75% (P < 0.001) with no difference between interventions (primary outcome, P < 0.05). No difference in rates of appearance and disappearance of phenylalanine or in intramyocellular signaling activation was found between interventions (secondary outcomes). The incremental AUC for serum insulin was 62% higher following BLG compared with CAS (P < 0.001) and 30% higher compared with WHE (P = 0.002), as well as 25% higher in WHE compared with CAS (P = 0.006). Following BLG consumption, plasma concentrations of glucose-dependent insulinotropic peptide (GIP) increased 70% compared with CAS (P = 0.001) and increased 34% compared with WHE (P = 0.06). No significant difference was found between WHE and CAS (P = 0.12). CONCLUSION: BLG, WHE, and CAS have similar effects on muscle in young male participants during catabolic conditions. BLG showed specific, possibly GIP-dependent, insulinotropic properties, which may have future clinical implications.

A multidimensional cohort study of late toxicity after intensity modulated radiotherapy for sinonasal cancer.

PURPOSE: To evaluate the occurrence of late toxicity after curatively intended intensity modulated radiotherapy (IMRT) for sinonasal cancer and assess dose-response associations. METHODS: Patients treated with IMRT in 2008-2016 were included. Cross sectional examinations of toxicity from the optic pathway, the brain, the pituitary gland and the nose were performed along with quality of life - (QoL) and dose-response analyses. RESULTS: Twenty-seven patients were enrolled; median age was 67 years (range 47-83). Five patients (19%) had radiation-related ocular toxicity. The risk of visual acuity impairment increased with increasing dose (grade 2 odds ration (OR) 1.12, p = 0.01; grade 3 OR 1.14, p = 0.02) and dose constraint violations (grade 2, OR = 21, p < 0.01; grade 3, OR = 41, p < 0.01). Six patients (22%) exhibited evidence of radiation-related hypopituitarism, but no dose-response association was detected. Seventeen patients (63%) had impaired olfactory function. The risk of olfactory impairment increased with higher stage (OR = 3.32, p = 0.03). Three patients (11%) had structural abnormalities in irradiated areas of the brain, and impaired cognitive function was present in 17 patients (63%). Cognitive, physical, role functioning as well as fatigue and insomnia were affected the most in QOL analyses. Fifteen patients (56%) had grade 2 radiation-related impairment in at least one organ. Grade 3 toxicity was only present in patients with toxicities in >3 organs and in patients initially treated for T4 tumours. Three patients (11%) had radiation-related impaired function in all examined OARs. CONCLUSION: Late toxicity after radiotherapy was substantial in all examined organs, with dose-response associations between visual acuity impairment and the optic nerve. The results have led to changed praxis for follow-up examinations in Denmark.

Ghrelin Does Not Directly Stimulate Secretion of Glucagon-like Peptide-1.

CONTEXT: The gastrointestinal hormone ghrelin stimulates growth hormone secretion and appetite, but recent studies indicate that ghrelin also stimulates the secretion of the appetite-inhibiting and insulinotropic hormone glucagon-like peptide-1 (GLP-1). OBJECTIVE: To investigate the putative effect of ghrelin on GLP-1 secretion in vivo and in vitro. SUBJECTS AND METHODS: A randomized placebo-controlled crossover study was performed in eight hypopituitary subjects. Ghrelin or saline was infused intravenously (1 pmol/min × kg) after collection of baseline sample (0 min), and blood was subsequently collected at time 30, 60, 90, and 120 minutes. Mouse small intestine was perfused (n = 6) and GLP-1 output from perfused mouse small intestine was investigated in response to vascular ghrelin administration in the presence and absence of a simultaneous luminal glucose stimulus. Ghrelin receptor expression was quantified in human (n = 11) and mouse L-cells (n = 3) by RNA sequencing and RT-qPCR, respectively. RESULTS: Ghrelin did not affect GLP-1 secretion in humans (area under the curve [AUC; 0-120 min]: ghrelin infusion = 1.37 ± 0.05 min × nmol vs. saline infusion = 1.40 ± 0.06 min × nmol [P = 0.63]), but induced peripheral insulin resistance. Likewise, ghrelin did not stimulate GLP-1 secretion from the perfused mouse small intestine model (mean outputs during baseline/ghrelin infusion = 19.3 ± 1.6/25.5 ± 2.0 fmol/min, n = 6, P = 0.16), whereas glucose-dependent insulinotropic polypeptide administration, used as a positive control, doubled GLP-1 secretion (P < 0.001). Intraluminal glucose increased GLP-1 secretion by 4-fold (P < 0.001), which was not potentiated by ghrelin. Finally, gene expression of the ghrelin receptor was undetectable in mouse L-cells and marginal in human L-cells. CONCLUSIONS: Ghrelin does not interact directly with the L-cell and does not directly affect GLP-1 secretion.

Prevalence of lifestyle characteristics in glucocorticoid users and non-users: a Danish population-based cross-sectional study.

OBJECTIVES: Lifestyle may affect observed associations between glucocorticoid use and adverse events. This study aimed to investigate whether lifestyle differ according to use of systemic glucocorticoids. DESIGN: Population-based cross-sectional study. SETTING: The Central Denmark Region. PARTICIPANTS: 30 245 adults (≥25 years of age) who participated in a questionnaire-based public health survey in 2010. OUTCOME MEASURES: Systemic glucocorticoid use was categorised as never use, current use (prescription redemption ≤90 days before completing the questionnaire), recent use (prescription redemption 91-365 days before completing the questionnaire), former use (prescription redemption >365 days before completing the questionnaire) and according to cumulative dose expressed in prednisolone equivalents (<100, 100-499, 500-999, 1000-1999, 2000-4999, ≥5000 mg). We computed the prevalence of lifestyle factors (body mass index, smoking, alcohol intake, physical activity and dietary habits) according to glucocorticoid use. We then estimated age-adjusted prevalence ratios (aPRs) and 95% CIs, comparing the categories of glucocorticoid users versus never users. All analyses were stratified by sex. RESULTS: Of the 30 245 participants (53% women, median age 53 years), 563 (1.9%) were current users, 885 (2.9%) were recent users, 3054 (10%) were former users and 25 743 (85%) were never users. Ever users of glucocorticoids had a slightly higher prevalence of obesity than never users (18% vs 14%, aPR=1.4, 95% CI 1.2 to 1.5 in women and 17% vs 15%, aPR=1.2, 95% CI 1.1 to 1.4 in men). In women, ever users of glucocorticoids had a slightly lower prevalence of high-risk alcohol consumption compared with never users (17% vs 20%, aPR=0.8, 95% CI 0.7 to 1.0). Smoking, diet and physical activity did not differ substantially according to use of glucocorticoids. CONCLUSION: Our study provides a framework for quantifying potential uncontrolled confounding by lifestyle factors in studies of systemic glucocorticoids.

Fifteen-year nationwide trends in systemic glucocorticoid drug use in Denmark.

OBJECTIVE: Glucocorticoid treatment of inflammatory disorders is associated with significant adverse effects related to glucocorticoid excess as well as adrenal insufficiency. This necessitates awareness of its use. We therefore investigated trends in systemic glucocorticoid use as well as morbidity and comedications among users. DESIGN: Cross-sectional drug utilisation study. METHODS: We conducted a population-based study of 926,314 users of systemic glucocorticoids (oral and injectable formulations) from 1999 to 2014 using Danish nationwide registries. We computed annual prevalence and incidence of systemic glucocorticoid use and prevalence of comedications and morbidity. Further, we assessed the annual amount of disease-modifying drug use. RESULTS: Of the 926,314 users of systemic glucocorticoids, 54% were female and median age at first-time use was 55 years. The annual prevalence was ≈ 3%, while the incidence was ≈ 1.4/100 person years (p-y). Both figures remained constant from 1999 to 2014. In the elderly, the annual prevalence was 6.7-7.7% (60-79 years of age) and 9.7-11% (≥80 years of age). Incidence increased among persons aged ≥80 years from 3.0/100 p-y in 1999 to 3.6/100 p-y in 2014. Concomitantly, the annual amount of for example methotrexate, azathioprine and tumour necrosis factor (TNF)-alpha agents increased and new biological agents emerged. The most frequent comedications were antibiotics (49%), cardiovascular drugs (38%) and NSAIDs (37%). CONCLUSIONS: Our findings confirm a widespread use of systemic glucocorticoids, especially in the elderly, which prevails despite increased use of disease-modifying drugs. The continuously prevalent use of glucocorticoid use constitutes a challenge for the endocrine community.

Acute intravenous acyl ghrelin infusion induces thirst but does not affect sodium excretion: two randomized, double-blind, placebo-controlled crossover studies in hypopituitary patients.

OBJECTIVE: Acyl ghrelin, which is the endogenous ligand for the growth hormone secretagogue receptor, potently stimulates pituitary growth hormone release, and to some degree adrenocorticotropic hormone and prolactin. Ghrelin is also orexigenic and has recently been shown to stimulate renal sodium absorption in rodent models. Increased thirst sensation has been observed as a side effect of acyl ghrelin administration in some human studies. The objective of this clinical trial was to investigate the direct effects of acyl ghrelin on thirst sensation and sodium excretion in hypopituitary patients. DESIGN: Hypopituitary patients on stable replacement with hydrocortisone and growth hormone were investigated in two double-blind and placebo-controlled crossover studies. The patients received a 5-h intravenous infusion of acyl ghrelin (5 pmol/kg/min in the first study and 1 pmol/kg/min in the second study). Thirst sensation was measured on a Visual Analog Scale (VAS). In the second study plasma osmolality, vasopressin, copeptin, water intake, diuresis and urinary excretion of sodium and creatinine were measured. RESULTS: In the initial study, acyl ghrelin (5 pmol/kg/min) increased thirst sensation (time × treatment analysis of variance for the effect of acyl ghrelin infusion P = 0.003). In the second study acyl ghrelin (1 pmol/kg/min) also increased thirst (P = 0.04) but did not affect urinary excretion of either sodium or water. CONCLUSIONS: We demonstrate that acyl ghrelin infusion increases thirst sensation, without affecting sodium excretion or diuresis in human subjects.

Acipimox Acutely Increases GLP-1 Concentrations in Overweight Subjects and Hypopituitary Patients.

CONTEXT: Glucagon-like peptide-1 (GLP-1) is an incretin hormone used therapeutically in type 2 diabetes and obesity. The interplay between ambient free fatty acids (FFAs) and GLP-1 remains unclear. Acipimox suppresses adipose tissue lipolysis via activation of the PUMA-G (also known as HCA2 and GPR109a) receptor. OBJECTIVE: To investigate whether lowering of serum FFA level with acipimox affects GLP-1 secretion. DESIGN: Two randomized crossover studies were performed in human subjects. Rat intestine was perfused intra-arterially and intraluminally, and l-cells were incubated with acipimox. PARTICIPANTS: The participants were healthy overweight subjects and hypopituitary adult patients. INTERVENTIONS: The overweight participants received acipimox 250 mg 60 minutes before an oral glucose test. The hypopituitary patients received acipimox 250 mg 12, 9, and 2 hours before and during the metabolic study day, when they were studied in the basal state and during a hyperinsulinemic euglycemic clamp. RESULTS: Acipimox suppressed FFA but did not affect insulin in the clinical trials. In overweight subjects, the GLP-1 increase after the oral glucose tolerance test (area under the curve) was more than doubled [4119 ± 607 pmol/L × min (Acipimox) vs 1973 ± 375 pmol/L × min (control), P = 0.004]. In hypopituitary patients, acipimox improved insulin sensitivity (4.7 ± 0.8 mg glucose/kg/min (Acipimox) vs 3.1 ± 0.5 mg glucose/kg/min (control), P = 0.005], and GLP-1 concentrations increased ~40%. An inverse correlation between FFA and GLP-1 concentrations existed in both trials. In rat intestine, acipimox did not affect GLP-1 secretion, and l-cells did not consistently express the putative receptor for acipimox. CONCLUSIONS: Acipimox treatment increases systemic GLP-1 levels in both obese subjects and hypopituitary patients. Our in vitro data indicate that the underlying mechanisms are indirect.

Hypercortisolism in Newly Diagnosed Type 2 Diabetes: A Prospective Study of 384 Newly Diagnosed Patients.

Cross-sectional studies in small and selected populations report a high prevalence of hypercortisolism in patients with type 2 diabetes (T2D), which could have therapeutic implications, if confirmed. We therefore estimated the prevalence of hypercortisolism in a large and unselected cohort of recently diagnosed T2D patients. Consecutive patients with recently diagnosed T2D first underwent an overnight dexamethasone (1 mg) suppression test (OD). Patients not suppressing serum cortisol ≤50 nmol/l proceeded with a 48-h low dose dexamethasone suppression test (LDDST) and 24-h urinary free cortisol collection (UFC). Patients with elevated cortisol levels according to LDDST and/or UFC underwent imaging guided by plasma ACTH levels, and assessment of bone mineral density. A total of 384 T2D patients (232male/152 females) with a mean age of 60±10 years were included. Eighty-five (22%) patients suppressed incompletely to OD of whom 20 (5%) failed to suppress after LDDST and/or had elevated UFC (=hypercortisolism). Patients with hypercortisolism did not differ as regards age, BMI, HbA1c, T-score or blood pressure, but a higher proportion of them received antihypertensive treatment (100% vs. 64%, p=0.001). Imaging revealed adrenal adenoma(s) in 9 cases and a pituitary macroadenoma in 1 case. We found a 5% prevalence of hypercortisolism in unselected, recently diagnosed T2D, which was not associated with a persuasive cushingoid phenotype. The clinical implications are therefore uncertain.

[Acromegaly].

Acromegaly is a rare and disabling disease with a plethora of symptoms and signs attributed to sustained elevations and actions of growth hormone and insulin-like growth factor 1. Acromegaly is characterised by excessive somatic growth and multiple comorbidities in addition to occasional compression of the optic nerve and hypopituitarism due to the underlying adenoma. The course of the disease is insidious, and a diagnostic delay of 5-10 years is typical, and this pre-diagnostic period is also associated with increased morbidity. Effective treatment is available, once the diagnosis is established.

Hyper- and hypothyroidism and gastrointestinal cancer risk: a Danish nationwide cohort study.

OBJECTIVE: The association between thyroid dysfunction and gastrointestinal cancer is unclear. DESIGN: We conducted a nationwide population-based cohort study to examine this potential association. METHODS: We used Danish medical registries to assemble a nationwide population-based cohort of patients diagnosed with hyperthyroid or hypothyroid disease from 1978 through 2013. We computed standardized incidence ratios (SIRs) with corresponding 95% confidence intervals (CI) as measures of the relative risk of each cancer, comparing patients with thyroid dysfunction with that expected in the general population. RESULTS: We included 163,972 patients, of which 92,783 had hyperthyroidism and 71,189 had hypothyroidism. In general, we found an increased risk of all gastrointestinal cancers within the first year after thyroid disease diagnosis. After more than five years of follow-up, patients with hyperthyroidism had a slightly increased risk of pancreatic and gallbladder and biliary tract cancer. Patients with hypothyroidism had a slightly increased risk of stomach, anal, liver, gallbladder and biliary tract, and pancreatic cancer after more than five years of follow-up, but the observed numbers of cancers were in general similar to the expected. CONCLUSIONS: The increased risks of all gastrointestinal cancers in the first year following hyper- or hypothyroidism diagnosis are likely due to detection bias. After more than five years of follow-up, there does not seem to be a consistent causal association between thyroid disease and gastrointestinal cancer.

Cancer Incidence in Patients With Acromegaly: A Cohort Study and Meta-Analysis of the Literature.

Context: Acromegaly has been associated with increased risk of cancer morbidity and mortality, but research findings remain conflicting and population-based data are scarce. We therefore examined whether patients with acromegaly are at higher risk of cancer. Design: A nationwide cohort study (1978 to 2010) including 529 acromegaly cases was performed. Incident cancer diagnoses and mortality were compared with national rates estimating standardized incidence ratios (SIRs). A meta-analysis of cancer SIRs from 23 studies (including the present one) was performed. Results: The cohort study identified 81 cases of cancer after exclusion of cases diagnosed within the first year [SIR 1.1; 95% confidence interval (CI), 0.9 to 1.4]. SIRs were 1.4 (95% CI, 0.7 to 2.6) for colorectal cancer, 1.1 (95% CI, 0.5 to 2.1) for breast cancer, and 1.4 (95% CI, 0.6 to 2.6) for prostate cancer. Whereas overall mortality was elevated in acromegaly (SIR 1.3; 95% CI, 1.1 to 1.6), cancer-specific mortality was not. The meta-analysis yielded an SIR of overall cancer of 1.5 (95% CI, 1.2 to 1.8). SIRs were elevated for colorectal cancer, 2.6 (95% CI, 1.7 to 4.0); thyroid cancer, 9.2 (95% CI, 4.2 to 19.9); breast cancer, 1.6 (1.1 to 2.3); gastric cancer, 2.0 (95% CI, 1.4 to 2.9); and urinary tract cancer, 1.5 (95% CI, 1.0 to 2.3). In general, cancer SIR was higher in single-center studies and in studies with <10 cancer cases. Conclusions: Cancer incidence rates were slightly elevated in patients with acromegaly in our study, and this finding was supported by the meta-analysis of 23 studies, although it also suggested the presence of selection bias in some earlier studies.

Effects of Prednisolone on Serum and Tissue Fluid IGF-I Receptor Activation and Post-Receptor Signaling in Humans.

Context: Short-term glucocorticoid exposure increases serum insulinlike growth factor I (IGF-I) concentrations but antagonizes IGF-I tissue signaling. The underlying mechanisms remain unknown. Objective: To identify at which levels glucocorticoid inhibits IGF-I signaling. Design and Methods: Nineteen healthy males received prednisolone (37.5 mg/d) and placebo for 5 days in a randomized, double-blinded, placebo-controlled crossover study. Serum was collected on days 1, 3, and 5, and abdominal skin suction blister fluid (SBF; ~interstitial fluid) was taken on day 5 (n = 9) together with muscle biopsy specimens (n = 19). The ability of serum and SBF to activate the IGF-I receptor (IGF-IR) (bioactive IGF) and its downstream signaling proteins was assessed using IGF-IR-transfected cells. Results: Prednisolone increased IGF-I concentrations and bioactive IGF in serum (P ≤ 0.001) but not in SBF, which, compared with serum, contained less bioactive IGF (~28%) after prednisolone (P < 0.05). This observation was unexplained by SBF concentrations of IGFs and IGF-binding proteins (IGFBPs) 1 to 4. However, following prednisolone treatment, SBF contained less IGFBP-4 fragments (P < 0.05) generated by pregnancy-associated plasma protein A (PAPP-A). Concomitantly, prednisolone increased SBF levels of stanniocalcin 2 (STC2) (P = 0.02) compared with serum. STC2 blocks PAPP-A from cleaving IGFBP-4. Finally, prednisolone suppressed post-IGF-IR signaling pathways at the level of insulin receptor substrate 1 (P < 0.05) but did not change skeletal muscle IGF-IR, IGF-I, or STC2 messenger RNA. Conclusion: Prednisolone increased IGF-I concentrations and IGF bioactivity in serum but not in tissue fluid. The latter may relate to a STC2-mediated inhibition of PAPP-A in tissue fluids. Furthermore, prednisolone induced post-IGF-IR resistance. Thus, glucocorticoid may exert distinct, compartment-specific effects on IGF action.

Development of ACRODAT®, a new software medical device to assess disease activity in patients with acromegaly.

PURPOSE: Despite availability of multimodal treatment options for acromegaly, achievement of long-term disease control is suboptimal in a significant number of patients. Furthermore, disease control as defined by biochemical normalization may not always show concordance with disease-related symptoms or patient's perceived quality of life. We developed and validated a tool to measure disease activity in acromegaly to support decision-making in clinical practice. METHODS: An international expert panel (n = 10) convened to define the most critical indicators of disease activity. Patient scenarios were constructed based on these chosen parameters. Subsequently, a panel of 21 renowned endocrinologists at pituitary centers (Europe and Canada) categorized each scenario as stable, mild, or significant disease activity in an online validation study. RESULTS: From expert opinion, five parameters emerged as the best overall indicators to evaluate disease activity: insulin-like growth factor I (IGF-I) level, tumor status, presence of comorbidities (cardiovascular disease, diabetes, sleep apnea), symptoms, and health-related quality of life. In the validation study, IGF-I and tumor status became the predominant parameters selected for classification of patients with moderate or severe disease activity. If IGF-I level was ≤1.2x upper limit of normal and tumor size not significantly increased, the remaining three parameters contributed to the decision in a compensatory manner. CONCLUSION: The validation study underlined IGF-I and tumor status for routine clinical decision-making, whereas patient-oriented outcome measures received less medical attention. An Acromegaly Disease Activity Tool (ACRODAT) is in development that might assist clinicians towards a more holistic approach to patient management in acromegaly.

Short-term acipimox treatment is associated with decreased cardiac parasympathetic modulation.

AIMS: The nicotinic acid analogue acipimox is an antilipolytic agent, which acutely inhibits lipolysis and suppresses systemic levels of free fatty acids (FFA) and improves insulin sensitivity in obese patients. These effects of acipimox are transient due to a counter-regulatory increase in growth hormone levels that reverse the antilipolytic effect of acipimox. Hypopituitary patients constitute a viable model to study the growth hormone-independent effects of acipimox and the impact of isolated changes in FFA concentrations and insulin sensitivity on parasympathetic nervous activity. The aim of the present study was to investigate if pharmacological antilipolysis with acipimox acutely affects autonomic tone. METHODS: We studied heart rate variability as a measure of autonomic tone in eight hypopituitary men with and without acipimox treatment. The standard deviation of normal-to-normal intervals, root mean square of successive differences and high frequency were measured as heart rate variability parameters. The patients were studied in the basal and insulin-stimulated state with clamped plasma glucose on two occasions in a randomized, double-blind and placebo-controlled crossover study. RESULTS: Plasma glucose (4.7 vs. 4.9 mmol l-1 , P = 0.02) and serum FFA (0.05 vs. 0.41 mmol l-1 , P < 0.001) were significantly decreased during acipimox treatment. Acipimox had an inhibitory effect on standard deviation of normal-to-normal intervals (41.3 vs. 45.3 ms, P = 0.01), root mean square of successive differences (23.2 vs. 11 ms, P = 0.03) and high frequency (3.79 vs 3.60 ln (ms2 ), P = 0.02) and these effects were reversed during clamping. CONCLUSIONS: Short-term inhibition of lipolysis by acipimox treatment lowered circulating FFA levels, improved insulin sensitivity, and was accompanied by reduced parasympathetic tone. The effect of acipimox on the parasympathetic modulation was reversed by hyperinsulinaemia.