GIP receptor antagonism eliminates paradoxical growth hormone secretion in some patients with acromegaly.

CONTEXT: About 30% of patients with active acromegaly experience paradoxically increased growth hormone (GH) secretion during the diagnostic oral glucose tolerance test (OGTT). Endogenous glucose-dependent insulinotropic polypeptide (GIP) is implicated in this paradoxical secretion. OBJECTIVE: We used the GIP receptor (GIPR) antagonist GIP(3-30)NH2 to test the hypothesis that GIP mediates this paradoxical response when GIPR is abundantly expressed in somatotropinomas. DESIGN, PATIENTS, SETTING, INTERVENTIONS: 25 treatment-naïve patients with acromegaly were enrolled. Each patient underwent one OGTT during simultaneous placebo infusion and one OGTT during a GIP(3-30)NH2 infusion. Blood samples were drawn at baseline and regularly after infusions to measure GH. We assessed pituitary adenoma size by magnetic resonance imaging and GIPR expression by immunohistochemistry on resected somatotropinomas. For mechanistic confirmation, we applied in vitro and ex vivo approaches. MAIN OUTCOME MEASURE: The effect of GIP(3-30)NH2 on paradoxical GH secretion during OGTT as a measure of GIP involvement. RESULTS: In four of seven patients with paradoxical GH secretion, GIP(3-30)NH2 infusion completely abolished the paradoxical response (P = 0.0003). Somatotrophs were available from three of four of these patients, all showing abundant GIPR expression. Adenoma size did not differ between patients with and without paradoxical GH secretion. CONCLUSIONS: Of 25 patients with acromegaly, seven had paradoxical GH secretion during OGTT, and pharmaceutical GIPR blockade abolished this secretion in four. Corresponding somatotroph adenomas abundantly expressed GIPR, suggesting a therapeutic target in this subpopulation of patients. In vitro and ex vivo analyses confirmed the role of GIP and the effects of the antagonist.

Key Device Attributes for Injectable Somatostatin Receptor Ligand Therapy in Acromegaly and Neuroendocrine Tumours.

INTRODUCTION: People living with acromegaly and neuroendocrine tumours (NETs) may be treated with injectable somatostatin receptor ligands (SRLs), administered by either a caregiver or as self-injection via a proprietary or generic device. Injection device attributes that contribute to ease of use and storage, minimise preparation requirements, and reduce injection pain are associated with improved adherence and more favourable therapeutic outcomes. The aim of this study was to assess current opinion surrounding favourable SRL device attributes for people living with acromegaly and NETs as well as that of their caregivers. METHODS: Participants (healthcare professionals [HCPs] and patients/non-HCP caregivers) from 11 countries were invited to answer survey questions related to their demographic, experience, and preferences as they relate to the real-world use of injectable SRL devices. Questions were developed based on review of available literature and meetings with a Scientific Committee. RESULTS: Device attributes preferred by the patient/non-HCP caregiver group (n = 211) included confidence that the correct drug amount is delivered (76%), quick administration with minimal pain/discomfort (68%), and device safety (needle-safety and low risk of contamination; 53%). Device attributes preferred by HCPs (n = 52) were quick administration with minimal pain/discomfort (69%), correct use is easy to learn, confidence in handling the device (63%), and confidence that the correct drug amount is delivered (62%). CONCLUSION: The results identified key features of injection devices for SRL therapy which merit consideration for optimal management and underscore the importance of patient partnership in treatment decisions.

Gene expression profiling of subcutaneous adipose tissue reveals new biomarkers in acromegaly.

CONTEXT: Active acromegaly is characterized by lipolysis-induced insulin resistance, which suggests adipose tissue (AT) as a primary driver of metabolic aberrations. OBJECTIVE: To study the gene expression landscape in AT in patients with acromegaly before and after disease control in order to understand the changes and to identify disease-specific biomarkers. METHODS: RNA sequencing was performed on paired subcutaneous adipose tissue (SAT) biopsies from six patients with acromegaly at time of diagnosis and after curative surgery. Clustering and pathway analyses were performed in order to identify disease activity-dependent genes. In a larger patient cohort (n = 23), the corresponding proteins were measured in serum by immunoassay. Correlations between growth hormone (GH), insulin-like growth factor I (IGF-I), visceral AT (VAT), SAT, total AT, and serum proteins were analyzed. RESULTS: 743 genes were significantly differentially expressed (P-adjusted < .05) in SAT before and after disease control. The patients clustered according to disease activity. Pathways related to inflammation, cell adhesion and extracellular matrix, GH and insulin signaling, and fatty acid oxidation were differentially expressed.Serum levels of HTRA1, METRNL, S100A8/A9, and PDGFD significantly increased after disease control (P < .05). VAT correlated with HTRA1 (R = 0.73) and S100A8/A9 (R = 0.55) (P < .05 for both). CONCLUSION: AT in active acromegaly is associated with a gene expression profile of fibrosis and inflammation, which may corroborate the hyper-metabolic state and provide a means for identifying novel biomarkers.

Apoplexy of microprolactinomas during pregnancy: report of five cases and review of the literature.

CONTEXT: Prolactinomas frequently cause amenorrhoea, galactorrhoea and infertility and require dopamine agonist (DA) treatment to normalize prolactin levels and hence, restore ovulation. The vast majority of female patients harbour microprolactinomas in whom DA treatment is usually discontinued at the time of pregnancy diagnosis and surveillance is generally limited as the symptomatic growth is considered very rare. CASE DESCRIPTIONS: We report five cases of women harbouring a microprolactinoma in whom symptomatic pituitary apoplexy occurred during pregnancy. Only one necessitated surgery during pregnancy, while the others were treated conservatively by reintroducing DAs in three. A systematic literature review found reports of four additional cases among 20 cases of prolactinomas (both macro- and micro-prolactinomas) complicated by apoplexy during pregnancy. CONCLUSION: During pregnancy, pituitary apoplexy may occur in pre-existing microprolactinomas, causing tumour enlargement and headache, which may be self-limiting but may require intervention by re-initation of dopamine agonists or surgery. Our literature review confirms that this clinical event is rare; nevertheless, physicians managing pregnant patients with microprolactinomas must be aware that symptomatic pituitary apoplexy may incidentally occur in all trimesters of pregnancy and require prompt radiological, endocrine and ophthalmological assessment and treatment.

Corticotroph Aggressive Pituitary Tumors and Carcinomas Frequently Harbor ATRX Mutations.

CONTEXT: Aggressive pituitary tumors (APTs) are characterized by unusually rapid growth and lack of response to standard treatment. About 1% to 2% develop metastases being classified as pituitary carcinomas (PCs). For unknown reasons, the corticotroph tumors are overrepresented among APTs and PCs. Mutations in the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene, regulating chromatin remodeling and telomere maintenance, have been implicated in the development of several cancer types, including neuroendocrine tumors. OBJECTIVE: To study ATRX protein expression and mutational status of the ATRX gene in APTs and PCs. DESIGN: We investigated ATRX protein expression by using immunohistochemistry in 30 APTs and 18 PCs, mostly of Pit-1 and T-Pit cell lineage. In tumors lacking ATRX immunolabeling, mutational status of the ATRX gene was explored. RESULTS: Nine of the 48 tumors (19%) demonstrated lack of ATRX immunolabelling with a higher proportion in patients with PCs (5/18; 28%) than in those with APTs (4/30;13%). Lack of ATRX was most common in the corticotroph tumors, 7/22 (32%), versus tumors of the Pit-1 lineage, 2/24 (8%). Loss-of-function ATRX mutations were found in all 9 ATRX immunonegative cases: nonsense mutations (n = 4), frameshift deletions (n = 4), and large deletions affecting 22-28 of the 36 exons (n = 3). More than 1 ATRX gene defect was identified in 2 PCs. CONCLUSION: ATRX mutations occur in a subset of APTs and are more common in corticotroph tumors. The findings provide a rationale for performing ATRX immunohistochemistry to identify patients at risk of developing aggressive and potentially metastatic pituitary tumors.

Sex differences in acromegaly at diagnosis: A nationwide cohort study and meta-analysis of the literature.

OBJECTIVE: Data on sex differences in acromegaly at the time of diagnosis vary considerably between studies. DESIGN: A nationwide cohort study including all incident cases of acromegaly (1978-2010, n = 596) and a meta-analysis on sex differences in active acromegaly (40 studies) were performed. METHOD: Sex-dependent differences in prevalence, age at diagnosis, diagnostic delay, pituitary adenoma size, insulin-like growth factor 1 (IGF-I) and growth hormone (GH) concentrations were estimated. RESULTS: The cohort study identified a balanced gender distribution (49.6% females) and a comparable age (years) at diagnosis (48.2 CI95% 46.5-49.8 (males) vs. 47.2 CI95% 45.5-48.9 (females), p = 0.4). The incidence rate significantly increased during the study period (R2  = 0.42, p < 0.01) and the gender ratio (F/M) changed from female predominance to an even ratio (SR: 1.4 vs. 0.9, p = 0.03). IGF-ISDS was significantly lower in females compared to males, whereas neither nadir GH nor pituitary adenoma size differed between males and females. In the meta-analysis, the weighted percentage female was 53.3% (CI95% 51.5-55.2) with considerable heterogeneity (I2  = 85%) among the studies. The mean age difference at diagnosis between genders was 3.1 years (CI95% 1.9-4.4), and the diagnostic delay was longer in females by 0.9 years (CI95% -0.4 to 2.1). Serum IGF-I levels were significantly lower in female patients, whereas nadir GH, and pituitary adenoma size were comparable. CONCLUSION: There are only a minor sex differences in the epidemiology of acromegaly at the time of diagnosis except that female patients are slightly older and exhibit lower IGF-I concentrations and a longer diagnostic delay.

ESE audit on management of Adult Growth Hormone Deficiency in clinical practice.

Guidelines recommend adults with pituitary disease in whom GH therapy is contemplated, to be tested for GH deficiency (AGHD); however, clinical practice is not uniform. AIMS: 1) To record current practice of AGHD management throughout Europe and benchmark it against guidelines; 2) To evaluate educational status of healthcare professionals about AGHD. DESIGN: On-line survey in endocrine centres throughout Europe. PATIENTS AND METHODS: Endocrinologists voluntarily completed an electronic questionnaire regarding AGHD patients diagnosed or treated in 2017-2018. RESULTS: Twenty-eight centres from 17 European countries participated, including 2139 AGHD patients, 28% of childhood-onset GHD. Aetiology was most frequently non-functioning pituitary adenoma (26%), craniopharyngioma (13%) and genetic/congenital mid-line malformations (13%). Diagnosis of GHD was confirmed by a stimulation test in 52% (GHRH+arginine, 45%; insulin-tolerance, 42%, glucagon, 6%; GHRH alone and clonidine tests, 7%); in the remaining, ≥3 pituitary deficiencies and low serum IGF-I were diagnostic. Initial GH dose was lower in older patients, but only women <26 years were prescribed a higher dose than men; dose titration was based on normal serum IGF-I, tolerance and side-effects. In one country, AGHD treatment was not approved. Full public reimbursement was not available in four countries and only in childhood-onset GHD in another. AGHD awareness was low among non-endocrine professionals and healthcare administrators. Postgraduate AGHD curriculum training deserves being improved. CONCLUSION: Despite guideline recommendations, GH replacement in AGHD is still not available or reimbursed in all European countries. Knowledge among professionals and health administrators needs improvement to optimize care of adults with GHD.

Phenotypic and genotypic features of a large kindred with a germline AIP variant.

CONTEXT: Acromegaly is usually a sporadic disease, but familial cases occur. Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are associated with familial pituitary adenoma predisposition. However, the pathogenicity of some AIP variants remains unclear and additional unknown genes may be involved. OBJECTIVE: To explore the phenotype and genotype of a large kindred carrying the p.R304Q AIP variant. METHODS: The family comprised 52 family members at risk of carrying the p.R304Q AIP variant including a case with gigantism and one with acromegaly and several family members with acromegalic features. Nine family members (three trios) underwent exome sequencing to identify putative pathogenic variants. RESULTS: We identified 31 p.R304Q carriers, and based on two cases with somatotropinomas, the disease penetrance was 6%. We observed physical signs of acromegaly in several family members, which were independent of AIP status. Serum insulin-like growth factor-I (IGF-I) levels in all family members were above the mean for age and sex (IGF-I SDS: +0.6 [CI95% +0.4-0.9], P < .01). Exome analysis identified two candidate genes: PDE11A, known to be associated with the development of adrenal tumours, and ALG14. Ten asymptomatic p.R304Q family members (age >50 years) were screened for the PDE11A and ALG14 variant; both variants were present in five of ten persons. CONCLUSIONS: This large family adds new information on the p.R304Q AIP variant, and data suggest two new candidate genes could be associated with growth hormone excess.

Growth hormone upregulates ANGPTL4 mRNA and suppresses lipoprotein lipase via fatty acids: Randomized experiments in human individuals.

OBJECTIVES: Lipoprotein lipase (LPL) catalyzes the hydrolysis of circulating triglycerides into free fatty acids (FFA) and thereby promotes FFA uptake in peripheral tissues. LPL is negatively regulated by angiopoietin-like protein 4 (ANGPTL4) presumably by an FFA-dependent mechanism. Growth hormone (GH) suppresses LPL activity, but it is unknown whether this is mediated by FFA and ANGPTL4. Therefore, we investigated the concerted effect of GH on ANGPTL4 and LPL in the presence and absence of lipolysis in two in vivo studies in human subjects. METHODS: In a randomized, placebo-controlled, cross-over study, nine obese men were examined after injection of 1) a GH bolus, and 2) a GH-receptor antagonist followed by four adipose tissue biopsies obtained over a 5-h period. In a second study, nine hypopituitary men were examined in a 2 × 2 factorial design including GH and acipimox (an anti-lipolytic agent), with biopsies from adipose tissue and skeletal muscle obtained during a basal period and a subsequent hyperinsulinemic-euglycemic clamp. The mRNA expression of ANGPTL4 and LPL as well as LPL activity were analyzed in the biopsies. RESULTS: In both studies, GH increased serum FFA levels, upregulated ANGPTL4 mRNA expression and suppressed LPL activity. In study 2, acipimox completely suppressed FFA levels and antagonized the effects of GH on ANGPTL4 and LPL. CONCLUSIONS: These human in vivo studies demonstrate that GH upregulates ANGPTL4 mRNA and suppresses LPL activity via an FFA-dependent mechanism.

Growth hormone replacement in adults: Real-world data from two large studies in US and Europe.

OBJECTIVE: This report describes the effectiveness and safety of growth hormone replacement in 3180 adult patients with growth hormone deficiency followed-up for 0.0-12.2 years in two completed, complementary, non-interventional, multicentre studies, NordiNet® International Outcome Study (IOS) (NCT00960128) and the American Norditropin® Studies: Web-Enabled Research (ANSWER) Program (NCT01009905). DESIGN: In both studies, Norditropin® (somatropin; Novo Nordisk A/S, Denmark) was administered at the discretion of the treating physician and according to routine practice. We present data on baseline characteristics, growth hormone dose, safety data and change from baseline in waist circumference, body mass index and bioimpedance (NordiNet® IOS only). RESULTS: Mean (SD) baseline characteristics (effectiveness analysis set) in NordiNet® IOS (n = 971) and ANSWER (n = 304): females, 45%; 69%; mean growth hormone dose (mg/day) (female, 0.338 [0.177]; male, 0.289 [0.157]); (female, 0.501 [0.313]; male, 0.505 [0.351]). Most patients had BMI ≥25 kg/m2. Median (P10,P90) exposure (females, 3.5 [0.42,11.0]; 1.6 [3.2; 0.3,8.6]; males, 4.1 [0.33,10.8]; 2.3 [2.9; 0.0,7.5] years). Mean (SD) change from baseline for waist circumference (-0.46 [6.38] cm [n = 403], BMI (0.30 [3.30] kg/m2 [n = 857]) and bioimpedance (-17.4 (59.19) ohm [n = 239]) were associated with growth hormone dose (waist/bioimpedance) and duration of follow-up (BMI/bioimpedance). No new safety signals were observed among patients in the full analysis set (NordiNet® IOS, n = 2321; ANSWER, n = 859). CONCLUSIONS: Long-term growth hormone replacement is associated with an improvement in body composition. The accumulated data from >10 years of follow-up support the long-term effectiveness and safety of growth hormone replacement as prescribed in clinical practice.

Insulin Resistance in Patients With Acromegaly.

Acromegaly is characterized by chronic overproduction of growth hormone (GH) that leads to insulin resistance, glucose intolerance and, ultimately, diabetes. The GH-induced sustained stimulation of lipolysis plays a major role not only in the development of insulin resistance and prediabetes/diabetes, but also in the reduction of lipid accumulation, making acromegaly a unique case of severe insulin resistance in the presence of reduced body fat. In the present review, we elucidate the effects of GH hypersecretion on metabolic organs, describing the pathophysiology of impaired glucose tolerance in acromegaly, as well as the impact of acromegaly-specific therapies on glucose metabolism. In addition, we highlight the role of insulin resistance in the development of acromegaly-associated complications such as hypertension, cardiac disease, sleep apnea, polycystic ovaries, bone disease, and cancer. Taken together, insulin resistance is an important metabolic hallmark of acromegaly, which is strongly related to disease activity, the development of comorbidities, and might even impact the response to drugs used in the treatment of acromegaly.

Risk of cancer in patients with thyroid disease and venous thromboembolism.

OBJECTIVE: Risk of venous thromboembolism (VTE) is increased in patients with hypo/hyperthyroidism. It is unknown whether VTE may be a presenting symptom of occult cancer in these patients. DESIGN: Nationwide population-based cohort study based on Danish medical registry data. METHODS: We identified all patients diagnosed with VTE during 1978-2013 who had a previous or concurrent diagnosis of hypothyroidism (N=1481) or hyperthyroidism (N=1788). We followed them until a first-time cancer diagnosis, death, emigration, or study end, whichever came first. We calculated 1-year absolute cancer risk and standardized incidence ratios (SIRs) for cancer incidence in the study population compared with national cancer incidence in the general population. RESULTS: During the first year after a VTE diagnosis, the 1-year absolute cancer risk was 3.0% among patients with hypothyroidism and 3.9% among those with hyperthyroidism. During the first year of follow-up, SIRs for cancer in the study population compared with the general population were 1.96 (95% CI: 1.42-2.64) among patients with hypothyroidism and 2.67 (95% CI: 2.07-3.39) among those with hyperthyroidism. SIRs declined substantially after 1 year but remained increased during the remainder of the follow-up period (up to 36 years) (SIR for hypothyroidism=1.16 [95% CI: 0.97-1.39]; SIR for hyperthyroidism=1.26 [95% CI: 1.08-1.46]). CONCLUSION: VTE may be a marker of underlying occult cancer in patients with hypothyroidism or hyperthyroidism.

Benign Thyroid Diseases and Risk of Thyroid Cancer: A Nationwide Cohort Study.

Context: Thyroid nodules, adenomas, and goiter have consistently been associated with thyroid cancer risk. Few studies have assessed whether thyroid dysfunction and thyroid autoimmunity influence this risk. Objective: To examine thyroid cancer risk after diagnoses of a wide range of benign thyroid conditions. Design: Hospital and cancer registry linkage cohort study for the years 1978 to 2013. Setting: Nationwide (Denmark). Participants: Patients diagnosed with hyperthyroidism (n = 85,169), hypothyroidism (n = 63,143), thyroiditis (n = 12,532), nontoxic nodular goiter (n = 65,782), simple goiter (n = 11,582), other/unspecified goiter (n = 21,953), or adenoma (n = 6,481) among 8,258,807 residents of Denmark during the study period. Main Outcome Measures: We computed standardized incidence ratios (SIRs) for differentiated thyroid cancer, excluding the first 12 months of follow-up after benign thyroid disease diagnosis. Results: SIRs were significantly elevated for all benign thyroid diseases apart from hypothyroidism. SIRs were higher for men than women and in the earlier follow-up periods. Elevated SIRs were observed for localized and regional/distant thyroid cancer. After excluding the first 10 years of follow-up, hyperthyroidism [n = 27 thyroid cancer cases; SIR = 2.00; 95% confidence interval (CI): 1.32 to 2.92], nontoxic nodular goiter (n = 83; SIR = 4.91; 95% CI: 3.91 to 6.09), simple goiter (n = 8; SIR = 4.33; 95% CI: 1.87 to 8.53), other/unspecified goiter (n = 20; SIR = 3.94; 95% CI: 2.40 to 6.08), and adenoma (n = 9; SIR = 6.02; 95% CI: 2.76 to 11.5) remained positively associated with thyroid cancer risk. Conclusions: We found an unexpected increased risk of differentiated thyroid cancer, including regional/distant disease, following diagnosis of hyperthyroidism and thyroiditis that could not be solely attributed to increased medical surveillance. Hypothyroidism was less clearly associated with thyroid cancer risk.

Diagnosis of hyponatremia and increased risk of a subsequent cancer diagnosis: results from a nationwide population-based cohort study.

BACKGROUND: Hyponatremia has recently been associated with subsequent cancer risk. This population-based nationwide study assessed whether the diagnosis of hyponatremia can predict a cancer diagnosis within most common cancers. MATERIAL AND METHODS: Using Danish medical registries, we identified 16,220 patients with a first-time diagnosis of hyponatremia, without a cancer diagnosis, from January 2006 through November 2013. We quantified the relative risk of a subsequent cancer diagnosis by standardized incidence ratios (SIRs), comparing observed cancer incidence among patients diagnosed with hyponatremia to that expected, based on national cancer incidence during that period. RESULTS: During 40,207 person-years of follow-up, we observed 1546 cancer diagnoses compared to 956 expected (SIR: 1.62; 95% confidence interval (CI), 1.54-1.70). The increase in risk of a cancer diagnosis following a hyponatremia diagnosis was most pronounced within 0-6 months of follow-up (SIR 4.16; 95% CI, 3.85-4.48) and in the younger age group; 0-29 years (SIR 8.71; 95% CI, 2.82-20.28), 30-49 years (SIR 3.16; 95% CI, 2.26-4.31), 50-69 years (SIR 2.29; 95% CI, 2.10-2.48) and 70 + years (SIR 1.35; 95% CI, 1.27-1.44). Within six months after a hyponatremia diagnosis, the SIRs increased 10-fold for cancers of the lung (SIR 17.14; 95% CI, 15.15-19.32), brain (SIR 13.52; 95% CI, 8.90-19.66) and liver (SIR 13.26; 95% CI, 7.57-21.53) and increased 5 to 10-fold for cancers of the pancreas (SIR 8.25; 95% CI, 5.72-11.53), esophagus (SIR 6.59; 95% CI, 3.15-12.12), kidney (SIR 6.36; 95% CI, 3.39-10.88), pharynx (SIR 6.15; 95% CI, 1.27-17.97) and non-Hodgkin lymphoma (SIR 6.10; 95% CI, 4.17-8.61). The rate increased across virtually all types of cancers, except melanoma and basal cell carcinomas. CONCLUSIONS: A diagnosis of hyponatremia may be a marker of occult neoplasms, especially cancers of the lung, brain, liver, pancreas, esophagus, kidney, pharynx and non-Hodgkin lymphoma. Hyponatremia may aid in early detection of cancer.

Cushing's syndrome in children and adolescents: a Danish nationwide population-based cohort study.

OBJECTIVE: Cushing's syndrome (CS) affects all age groups, but epidemiologic data in young patients are very limited. We therefore examined the incidence, prevalence and hospital morbidity of CS in children and adolescents. DESIGN: In a nationwide cohort study, we included all Danish citizens aged 0-20 years from 1977 to 2012. Data were obtained from the Danish National Patient Registry using the International Classification of Diseases (ICD) codes and the Danish Civil Registration System. The diagnosis and treatment were validated by means of individual patient charts. Incidence rate of CS patients aged 0-20 years at diagnosis were computed (standardized to the age and sex distribution of the Danish population). The patients were followed for a maximum of 36 years. Standardized incidence ratios (SIRs) of different hospital-recorded outcomes based on the ICD codes in patients with CS compared to the general population were assessed. RESULTS: We identified a total of 40 pediatric patients with CS, yielding an annual incidence of 0.89 cases/106 population (95% confidence interval (CI) = 0.63-1.16). The median age at the time of diagnosis was 13.8 years (interquartile range: 10.5-18.2 years), 58% were female and 70% had adrenocorticotropic hormone-producing pituitary adenomas. During follow-up, CS patients (excluding three malignant cases) were at increased risk of being diagnosed with infections (SIR: 3.24, 95% CI: 1.05-7.54) and infertility (SIR: 4.56, 95% CI: 1.48-10.63). The three patients with an adrenocortical carcinoma died shortly after diagnosis, but mortality was not increased in the remaining patients. CONCLUSIONS: CS is rare in the pediatric population. The risk of morbidity related to infections and infertility is elevated and merits further attention.

Erythropoietin does not activate erythropoietin receptor signaling or lipolytic pathways in human subcutaneous white adipose tissue in vivo.

BACKGROUND: Erythropoietin (Epo) exerts direct effects on white adipose tissue (WAT) in mice in addition to its erythropoietic effects, and in humans Epo increases resting energy expenditure and affect serum lipid levels, but direct effects of Epo in human WAT have not been documented. We therefore investigated the effects of acute and prolonged Epo exposure on human WAT in vivo. METHOD: Data were obtained from two clinical trials: 1) acute Epo exposure (rHuEpo, 400 IU/kg) followed by WAT biopsies after 1 h and 2) 10 weeks treatment with the erythropoiesis-stimulating agent (ESA) Darbepoietin-alpha. Biopsies were analyzed by PCR for Epo receptor (Epo-R) mRNA. A new and highly specific antibody (A82, Amgen) was used to evaluate the presence of Epo-R by western blot analysis in addition to Epo-R signaling proteins (Akt, STAT5, p70s6k, LYN, and p38MAPK), activation of lipolytic pathways (ATGL, HSL, CGI-58, G0S2, Perilipin, Cidea, Cidec, AMPK, and ACC), and mitochondrial biogenesis (VDAC, HSP90, PDH, and SDHA). RESULTS: No evidence of in vivo activation of the Epo-R in WAT could be documented despite detectable levels of Epo-R mRNA. CONCLUSION: Thus, in contradiction to animal studies, Epo treatment within a physiological relevant range in humans does not exert direct effects in a subcutaneous WAT.

DIAGNOSIS OF ENDOCRINE DISEASE: Prevalence of hypercortisolism in type 2 diabetes patients: a systematic review and meta-analysis.

OBJECTIVE: Type 2 diabetes (T2D) and Cushing's syndrome (CS) share clinical characteristics, and several small studies have recorded a high prevalence of hypercortisolism in T2D, which could have therapeutic implications. We aimed to assess the prevalence of endogenous hypercortisolism in T2D patients. DESIGN: Systematic review and meta-analysis of the literature. METHODS: A search was performed in SCOPUS, MEDLINE, and EMBASE for original articles assessing the prevalence of endogenous hypercortisolism and CS in T2D. Data were pooled in a random-effect logistic regression model and reported with 95% confidence intervals (95% CI). RESULTS: Fourteen articles were included, with a total of 2827 T2D patients. The pooled prevalence of hypercortisolism and CS was 3.4% (95% CI: 1.5-5.9) and 1.4% (95 CI: 0.4-2.9) respectively. The prevalence did not differ between studies of unselected patients and patients selected based on the presence of metabolic features such as obesity or poor glycemic control (P = 0.41 from meta-regression). Imaging in patients with hypercortisolism (n = 102) revealed adrenal tumors and pituitary tumors in 52 and 14% respectively. CONCLUSIONS: Endogenous hypercortisolism is a relatively frequent finding in T2D, which may have therapeutic implications.

Glucose and Fat Metabolism in Acromegaly: From Mice Models to Patient Care.

Patients with active acromegaly are frequently insulin resistant, glucose intolerant, and at risk for developing overt type 2 diabetes. At the same time, these patients have a relatively lean phenotype associated with mobilization and oxidation of free fatty acids. These features are reversed by curative surgical removal of the growth hormone (GH)-producing adenoma. Mouse models of acromegaly share many of these characteristics, including a lean phenotype and proneness to type 2 diabetes. There are, however, also species differences with respect to oxidation rates of glucose and fat as well as the specific mechanisms underlying GH-induced insulin resistance. The impact of acromegaly treatment on insulin sensitivity and glucose tolerance depends on the treatment modality (e.g. somatostatin analogs also suppress insulin secretion, whereas the GH antagonist restores insulin sensitivity). The interplay between animal research and clinical studies has proven useful in the field of acromegaly and should be continued in order to understand the metabolic actions of GH.

Adrenal Insufficiency in Corticosteroids Use: Systematic Review and Meta-Analysis.

OBJECTIVE: We aimed to estimate pooled percentages of patients with adrenal insufficiency after treatment with corticosteroids for various conditions in a meta-analysis. Secondly, we aimed to stratify the results by route of administration, disease, treatment dose, and duration. METHODS: We searched seven electronic databases (PubMed, MEDLINE, EMBASE, COCHRANE, CENTRAL, Web of Science, and CINAHL/Academic Search Premier) in February 2014 to identify potentially relevant studies. Original articles testing adult corticosteroid users for adrenal insufficiency were eligible. RESULTS: We included 74 articles with a total of 3753 participants. Stratified by administration form, percentages of patients with adrenal insufficiency ranged from 4.2% for nasal administration (95% confidence interval [CI], 0.5-28.9) to 52.2% for intra-articular administration (95% CI, 40.5-63.6). Stratified by disease, percentages ranged from 6.8% for asthma with inhalation corticosteroids only (95% CI, 3.8-12.0) to 60.0% for hematological malignancies (95% CI, 38.0-78.6). The risk also varied according to dose from 2.4% (95% CI, 0.6-9.3) (low dose) to 21.5% (95% CI, 12.0-35.5) (high dose), and according to treatment duration from 1.4% (95% CI, 0.3-7.4) (<28 d) to 27.4% (95% CI, 17.7-39.8) (>1 year) in asthma patients. CONCLUSIONS: 1) Adrenal insufficiency after discontinuation of glucocorticoid occurs frequently; 2) there is no administration form, dosing, treatment duration, or underlying disease for which adrenal insufficiency can be excluded with certainty, although higher dose and longer use give the highest risk; 3) the threshold to test corticosteroid users for adrenal insufficiency should be low in clinical practice, especially for those patients with nonspecific symptoms after cessation.

Hormone and Cytokine Responses to Repeated Endotoxin Exposures-No Evidence of Endotoxin Tolerance After 5 Weeks in Humans.

Endotoxin administrations are used in experimental models of inflammatory disease. Short-term endotoxin tolerance in response to repeated endotoxin exposure is well known, but the duration of endotoxin tolerance in humans remains unknown. The main purpose of this study was to test whether endotoxin tolerance is present in vivo when separating endotoxin exposures with more than 5 weeks, a time span often used between individual investigations in clinical experimental studies. Seventeen healthy young men were exposed twice to Escherichia coli endotoxin. The inflammatory response was calculated as area under the curve between the first and second endotoxin exposures for heart rate, mean arterial blood pressure, temperature, cortisol, tumor necrosis factor α, and interleukin (IL)-1ß, IL-6, and IL-10. The median interval between exposures was 90 days (range, 37-244). The ratio between the inflammatory responses during the second and the first endotoxin exposures was 0.89 ± 0.09 (P = 0.28) for tumor necrosis factor α, 0.96 ± 0.07 (P = 0.53) for IL-1ß, 0.97 ± 0.11 (P = 0.78) for IL-6, 1.30 ± 0.18 (P = 0.12) for IL-10, and 0.92 ± 0.04 (P = 0.10) for cortisol. Our data do not show evidence of in vivo tolerance to repeated endotoxin exposure when administrations are separated with at least 5 weeks. This observation is important in the planning and interpretation of future experimental endotoxin studies.