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The WHO Classification of Endocrine Tumours designates pituitary neoplasms as adenomas. A proposed nomenclature change to pituitary neuroendocrine tumors (PitNETs) has been met with concern by some stakeholder groups. The Pituitary Society coordinated the Pituitary Neoplasm Nomenclature (PANOMEN) workshop to address the topic. Experts in pituitary developmental biology, pathology, neurosurgery, endocrinology, and oncology, including representatives nominated by the Endocrine Society, European Society of Endocrinology, European Neuroendocrine Association, Growth Hormone Research Society, and International Society of Pituitary Surgeons. Clinical epidemiology, disease phenotype, management, and prognosis of pituitary adenomas differ from that of most NETs. The vast majority of pituitary adenomas are benign and do not adversely impact life expectancy. A nomenclature change to PitNET does not address the main challenge of prognostic prediction, assigns an uncertain malignancy designation to benign pituitary adenomas, and may adversely affect patients. Due to pandemic restrictions, the workshop was conducted virtually, with audiovisual lectures and written précis on each topic provided to all participants. Feedback was collated and summarized by Content Chairs and discussed during a virtual writing meeting moderated by Session Chairs, which yielded an evidence-based draft document sent to all participants for review and approval. There is not yet a case for adopting the PitNET nomenclature. The PANOMEN Workshop recommends that the term adenoma be retained and that the topic be revisited as new evidence on pituitary neoplasm biology emerges., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

The 13th Acromegaly Consensus Conference was held in November 2019 in Fort Lauderdale, Florida, and comprised acromegaly experts including endocrinologists and neurosurgeons who considered optimal approaches for multidisciplinary acromegaly management. Focused discussions reviewed techniques, results, and side effects of surgery, radiotherapy, and medical therapy, and how advances in technology and novel techniques have changed the way these modalities are used alone or in combination. Effects of treatment on patient outcomes were considered, along with strategies for optimizing and personalizing therapeutic approaches. Expert consensus recommendations emphasize how best to implement available treatment options as part of a multidisciplinary approach at Pituitary Tumor Centers of Excellence.

Competing Interests: Declaration of competing interest SAP, ESK, EAT, SK, AL, AM, HT, IC, AG, MWG, DAV, AA and FC have no competing interests. ME is a member of the advisory board for AMRA-Medical. SX has received research funding from Target RWE, restricted research funding from Axcella Health and consulting with Intercept Pharmaceuticals. CSM has been a shareholder of and reports grants through his institution and personal consulting fees from Coherus Incand Pangea Inc., reports grants through his institution and personal consulting fees from Novo Nordisk, reports personal consulting fees and in kind support with research reagents from Ansh -Ιnc., reports personal consulting fees from Genfit, P.E.S., Amgen, Intercept, Astra Zeneca, Aegerion and Regeneron, reports in kind support (meals during educational activities) from Amarin, Jansen, Boehringer Ingelheim and travel support and fees from TMIOA, the California Walnut Commission and the cardio metabolic health conference.

DNA methylation could provide a link between environmental, genetic factors and weight control and can modify gene expression pattern. This study aimed to identify genes, which are differentially expressed and methylated depending on adiposity state by evaluating normal weight women and obese women before and after bariatric surgery (BS). We enrolled 24 normal weight (BMI: 22.5 ± 1.6 kg/m 2 ) and 24 obese women (BMI: 43.3 ± 5.7 kg/m 2 ) submitted to BS. Genome-wide methylation analysis was conducted using Infinium Human Methylation 450 BeadChip (threshold for significant CpG sites based on delta methylation level with a minimum value of 5%, a false discovery rate correction (FDR) of q < 0.05 was applied). Expression levels were measured using HumanHT-12v4 Expression BeadChip (cutoff of p ≤ 0.05 and fold change ≥2.0 was used to detect differentially expressed probes). The integrative analysis of both array data identified four genes (i.e. TPP2, PSMG6, ARL6IP1 and FAM49B) with higher methylation and lower expression level in pre-surgery women compared to normal weight women: and two genes (i.e. ZFP36L1 and USP32) that were differentially methylated after BS. These methylation changes were in promoter region and gene body. All genes are related to MAPK cascade, NIK/NF-kappaB signaling, cellular response to insulin stimulus, proteolysis and others. Integrating analysis of DNA methylation and gene expression evidenced that there is a set of genes relevant to obesity that changed after BS. A gene ontology analysis showed that these genes were enriched in biological functions related to adipogenesis, orexigenic, oxidative stress and insulin metabolism pathways. Also, our results suggest that although methylation plays a role in gene silencing, the majority of effects were not correlated.

Obesity is an emerging condition, with a prevalence of ~20%. Although the simple measurement of BMI is likely a simplistic approach to obesity, BMI is easily calculated, and there are currently no data showing that more sophisticated methods are more useful to guide the endocrine work-up in obesity. An increased BMI leads to a number of hormonal changes. Additionally, concomitant hormonal diseases can be present in obesity and have to be properly diagnosed - which in turn might be more difficult due to alterations caused by body fatness itself. The present European Society of Endocrinology Clinical Guideline on the Endocrine Work-up in Obesity acknowledges the increased prevalence of many endocrine conditions in obesity. It is recommended to test all patients with obesity for thyroid function, given the high prevalence of hypothyroidism in obesity. For hypercortisolism, male hypogonadism and female gonadal dysfunction, hormonal testing is only recommended if case of clinical suspicion of an underlying endocrine disorder. The guideline underlines that weight loss in obesity should be emphasized as key to restoration of hormonal imbalances and that treatment and that the effect of treating endocrine disorders on weight loss is only modest.

Objective: The increasing prevalence of obesity is expected to promote the demand for endocrine testing. To facilitate evidence guided testing, we aimed to assess the prevalence of endocrine disorders in patients with obesity. The review was carried out as part of the Endocrine Work-up for the Obesity Guideline of the European Society of Endocrinology., Design: Systematic review and meta-analysis of the literature., Methods: A search was performed in MEDLINE, EMBASE, Web of Science and COCHRANE Library for original articles assessing the prevalence of hypothyroidism, hypercortisolism, hypogonadism (males) or hyperandrogenism (females) in patients with obesity. Data were pooled in a random-effects logistic regression model and reported with 95% confidence intervals (95% CI)., Results: Sixty-eight studies were included, concerning a total of 19.996 patients with obesity. The pooled prevalence of overt (newly diagnosed or already treated) and subclinical hypothyroidism was 14.0% (95% CI: 9.7-18.9) and 14.6% (95% CI: 9.2-20.9), respectively. Pooled prevalence of hypercortisolism was 0.9% (95% CI: 0.3-1.6). Pooled prevalence of hypogonadism when measuring total testosterone or free testosterone was 42.8% (95% CI: 37.6-48.0) and 32.7% (95% CI: 23.1-43.0), respectively. Heterogeneity was high for all analyses., Conclusions: The prevalence of endocrine disorders in patients with obesity is considerable, although the underlying mechanisms are complex. Given the cross-sectional design of the studies included, no formal distinction between endocrine causes and consequences of obesity could be made.

The dome-binding suture (DBS) and hemitransdomal suture (HTS) are suture techniques used to narrow and define the nasal tip. The DBS can create a pinched, unnatural appearance, while the HTS puts the lateral crus in a more favorable orientation. This allows a natural contour between the nasal tip and alar lobule while maintaining alar margin support. Objective measurement of the rotational axis of the lateral crus between the DBS and the HTS has not been reported in the literature. To determine whether the DBS or HTS technique results in a more favorable rotational axis of the lateral crus as measured by the alar surface septal angle (ASSA). Open rhinoplasty with cephalic trim and placement of a DBS or HTS was performed in 6 cadaveric heads, for a total of 12 lower lateral cartilages at the VirtuOHSU Simulation and Surgical Training Center at Oregon Health and Science University (OHSU). ASSA measurements were taken at baseline and after placement of either a DBS or HTS. A total of 36 ASSA measurements were obtained. The median baseline ASSA prior to suture placement was 142 degrees (interquartile range [IQR]: 131.5-145 degrees), following DBS placement was 141 degrees (IQR: 33-150.5 degrees), and following HTS placement was 112 degrees (IQR: 108-117 degrees). There was no statistically significant difference of ASSA measurements between baseline and DBS placement ( p  = 0.24), but there was a statistically significant difference between baseline and HTS ( p  < 0.0001) and between DBS and HTS ( p  < 0.0001). The HTS technique creates a more favorable rotational axis of the lateral crus as compared with the DBS, as measured by the ASSA. This study provides objective data to support the use of the HTS for nasal tip contouring., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: frailty is associated with an increased risk of fragility fractures. Less is known, however, about the association between frailty and bone health., Methods: men aged 40-79 years were recruited from population registers in eight European centres for participation in the European Male Aging Study. Subjects completed a comprehensive assessment which included quantitative ultrasound (QUS) scan of the heel (Hologic-SAHARA) and in two centres, dual-energy bone densitometry (dual-energy x-ray absorptiometry, DXA). Frailty was defined based on an adaptation of Fried's phenotype criteria and a frailty index (FI) was constructed. The association between frailty and the QUS and DXA parameters was determined using linear regression, with adjustments for age, body mass index and centre., Results: in total, 3,231 subjects contributed data to the analysis. Using the Fried categorisation of frailty, pre-frail and frail men had significantly lower speed of sound (SOS), broadband ultrasound attenuation (BUA) and quantitative ultrasound index (QUI) compared to robust men (P< 0.05). Similar results were seen using the FI after categorisation into 'high', 'medium' and 'low' levels of frailty. Using the Fried categorisation, frail men had lower femoral neck bone mineral density (BMD) compared to robust men (P < 0.05), but not lower lumbar spine BMD. Using the FI categorisation, a 'high' level of frailty (FI > 0.35) was associated with lower lumbar spine BMD (P < 0.05) when compared to those with low (FI < 0.2), but not lower femoral neck BMD. When analysed as a continuous variable, higher FI was linked with lower SOS, BUA and QUI (P < 0.05)., Conclusions: optimisation of bone health as well as prevention of falls should be considered as strategies to reduce fractures in frail older people., (© The Author 2016. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Purpose: In recent years, the incidence of childhood obesity in Europe, and Spain in particular, has increased dramatically. Bariatric surgery could play a major role in treating of adolescents with severe obesity. However, no specific guidelines for bariatric surgery currently exist in Spain., Methods: The Board of the Spanish Society for Obesity Surgery and Metabolic Diseases (SECO) proposed a study of childhood obesity by using the Delphi method. This prospective study involved 60 experts from nine national societies. Each society leader recruited experts from their society in obesity-related fields. Two online questionnaires were taken, and consensus on guidelines for various obesity treatments was reached according to the percentage of answers in favor or against inclusion of a given guideline. Based on these results, preoperative, surgical management and follow-up of childhood obesity management among others were analyzed., Results: The survey results indicated significant concern among all societies regarding obesity. There was strong consensus with regard to adolescents and obesity, medical treatment, dietary recommendations, environmental and social factors, and goals for adolescents with obesity. Consensus on the use of intragastric balloons and other techniques was not reached. However, biliopancreatic diversion was rejected as a primary treatment, and mandatory psychological/psychiatric assessment was agreed upon. Inclusion criteria accepted were similar to those for adults with the exception of surgery in those with a body mass index <40., Conclusions: Spanish obesity-related societies are aware of the societal problem of childhood obesity. Multisociety development of national approaches may arise from consensus-building studies among specialists.

Dorsal hump reduction is a central component of western aesthetic rhinoplasty. Surgical success begins with knowledge of aesthetic ideals and accurate preoperative analysis. Knowledge of the patient's distortion from aesthetic ideals informs approach, technique, and instrument selection. Both endonasal and external approaches are suitable for dorsal hump reduction, though the latter affords more versatility when other surgical modifications are necessary. The main techniques consist of en bloc, Skoog, and component resection. Each has their distinct advantage, though a surgeon's comfort level with each should impact technique selection. Completion of the dorsal reduction often leaves a defect that must be reconstructed. Failure to anticipate the potential long-term sequelae and appropriately manage the dorsal defect can lead to a poor result and patient dissatisfaction., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: Home enteral nutrition (HEN) is a therapeutic method used in patients who are unable to ingest the required amounts of nutrients but retain a functional gastrointestinal tract. The objective of this study was to compose a specific questionnaire for measuring health-related quality of life (HRQoL) in HEN patients irrespective of their underlying condition and HEN route of administration., Methods: Literature review, focus groups and semi-structured interviews were used to propose an initial version of the questionnaire which was answered by 165 participants. The responses were analyzed using the Rasch methodology. Firstly, the appropriateness of response options was assessed. Then, the differential item functioning (DIF) was evaluated. Finally, the item fit statistics, infit and outfit, were determined., Results: Rasch analysis was performed on the responses given to the 43 items included in the initial questionnaire. Four items were excluded because more than 50% of respondents answered that the situation proposed did not apply to them. Seven items that showed overlapping and disordered categories were also removed. Pairwise DIF analysis were performed in subgroups defined by underlying disease and administration route. Eleven items presented DIF and were eliminated from the questionnaire. Finally, four items were deleted after analyzing the fit statistics, three of which did not fit the Rasch model and one did not belong to either of the dimensions. The final version of NutriQoL® includes 17 items., Conclusions: NutriQoL® is a useful instrument to assess the HRQoL of HEN patients with any disease and any administration route., Competing Interests: Not applicableNestlé Health Science sponsored the study. The authors Cuerda C, Apezetxea A, Carrillo L, Casanueva F, Cuesta F, Irles JA and Virgilli N, state they have no conflict of interest. Layola M works at Nestlé Health Science. Lizan L works for an independent research organization (Outcomes’10, S.L.) which has received fees for its contribution to the development and coordination of the original research project and to the writing of this manuscript.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Importance: The dome binding suture (DBS) used for nasal tip refinement creates the unwanted effects of nasal tip pinching owing to shadowing and loss of alar support. The hemitransdomal suture (HTS), however, refines the nasal tip while maintaining a natural contour between the nasal tip and the alar lobule. To our knowledge, no objective comparison between the DBS and HTS techniques has been described in the literature to date., Objective: To determine whether the DBS or HTS technique results in an objectively satisfactory outcome in nasal tip contouring when assessed from the perspective of the basal view., Design, Setting, and Participants: Postoperative basal view photographs of cosmetic rhinoplasty procedures performed on 112 Hispanic/Mestizo patients (85 [76%] women, and 27 [24%] men) in a facial plastic surgery practice in Chile, from May 2013 to May 2015 were reviewed. Only patients who underwent either DBS or HTS were included. Follow-up ranged from 6-24 months. Comparison of the nasal contour to the ideal tip-lobule line was performed and classified as satisfactory or unsatisfactory., Main Outcomes and Measures: Satisfactory or unsatisfactory nasal tip contour in the basal view as analyzed by comparison with the ideal tip-lobule line., Results: A total of 143 rhinoplasty procedures were performed over a 2-year period (May 2013-May 2015). A total of 112 patients met inclusion criteria. Of the 112 participants, mean (SD) age was 30 (9) years; 22 patients underwent DBS and 90 underwent HTS. Of the patients who underwent DBS, 5 of 22 (22.7%) had satisfactory contours. Of the patients who underwent HTS, 84 of 90 (93.3%) had satisfactory contours., Conclusions and Relevance: Comparison of nasal contour in the basal view with the ideal tip-lobule line demonstrates a statistically significant improvement in the rate of satisfactory outcomes using the HTS compared with the DBS technique. This study is the first, to our knowledge, to provide objective data to support the use of this technique when performing tip contouring in rhinoplasty., Level of Evidence: 4.

Introduction: Health-related quality of life (HRQoL) provides a global view of the state of health of a patient receiving home enteral nutrition (HEN)., Objective: To evaluate the HRQoL of patients receiving HEN using the NutriQoL® questionnaire, a specific instrument regardless of the underlying disease and route of administration., Materials and Methods: Observational, prospective and multicentre study conducted in the context of the validation and assessment of the NutriQoL® questionnaire's psychometric properties., Results: One-hundred-and-forty individuals [disease: cancer (58.6%), malabsorption and other (27.1%), neurological (13.6%); HEN: supplement (61.4%), sole source of nutrition (35.7%); administration route: oral (54.3%), ostomy (31.4%), nasoenteric tube (12.1%)] participated. NutriQoL® was reliable [ICC: 0.88 (95%CI: 0.80-0.93); Cronbach's α: 0.77 (1st visit) and 0.83 (2nd visit)], valid (significant Rho), lowly sensitive to changes (effect size 0.23), can be completed by either patients or caregivers (ICC: 0.82). The mean HRQoL (SD) with NutriQoL® was 14.98 (14.86), EQ-5D tariff: 53(0.25), EQ-5D VAS: 54.15 (20.64) and COOP/WONCA charts: 23.32(5.66). HRQoL with NutriQoL® was better (p < 0.05) for oral HEN [19.54 (13,23)], than nasoenteric tube [14(11.71)], ostomy [7.02 (15.48)]; administered orally [19.54 (13.23)], than by gravity [10.97 (14.46)], pump [8.5 (19.78)] or syringe bolus [7 (11.40)]; as a supplement [19.33 (13.73)] instead of sole source of nutrition [8.18 (14.23)]., Conclusions: NutriQoL® is valid, reliable, even if lowly sensitive to change, and useful to measure HRQoL in this population. More studies are needed to know HRQoL in routine practice.

Introduction: Home enteral nutrition (HEN) is indicated in patients with a functional gastrointestinal tract but who are unable to meet their nutritional requirements with normally consumed foodstuffs. HEN allows patients to remain in their social and family environment, thus reducing complications and costs associated with hospital admission, while increasing health-related quality of life (HRQoL). HRQoL in patients with HEN is mainly evaluated by generic instruments, which are not sensitive enough to identify certain specific patient-related outcomes of HEN., Objective: To develop a specific instrument to measure HRQoL in patients receiving HEN whose results allow interpretation regardless of the underlying disease and nutritional support administration route: the NutriQoL ® questionnaire., Materials and Methods: The development of the NutriQoL entailed a literature review, focus groups with experts, semistructured interviews with patients, an assessment of face validity and feasibility, and Rasch analysis conducted on data from a sample of 141 patients and 24 caregivers., Results: Of the 52 items initially proposed on the basis of the literature review, expert focus group, and semi-structured interviews with patients and caregivers, 17 items were finally selected through the development process to make up the final version of the NutriQoL, as well as a visual analog scale for global HRQoL scoring. The selected items were evaluated as adequate for frequency, importance, and clarity. Furthermore, they have been shown to be independent of the underlying condition and HEN administration route., Conclusion: A new instrument for measuring the HRQoL of patients with HEN in Spain has been developed, whose results are independent of the underlying condition and administration route. The next step will be the validation of the questionnaire to ensure that the instrument is valid, reliable, and sensitive to health status changes in patients, to be used periodically in usual clinical practice., Competing Interests: The authors MC Cuerda, A Apezetxea, L Carrillo, F Casanueva, F Cuesta, JA Irles, and MN Virgilli state that they have no conflicts of interest. M Layola works at Nestlé Health Science. L Lizan works for an independent research organization (Outcomes’10, S.L.) which has received fees for its contribution to the development and coordination of the original research project and to the writing of this manuscript.

Introduction: NutriQoL ® (Nestlé Health Science, Vevay, Switzerland) is a questionnaire developed to assess the health-related quality-of-life (HRQoL) of patients with home enteral nutrition (HEN) irrespective of their underlying condition and route of administration. The aim of this work is assessing the questionnaire's reliability and responsiveness to change., Methods: Two cohorts of patients with HEN and their primary caregivers were enrolled to assess reliability and responsiveness, respectively. All participants had to be 18 years of age or older, without mental deterioration (≤3 or 4 errors in the Pfeiffer's test) and with sufficient functional status (>40 points on Karnovsky's performance status scale). When the patients' ability to respond to the questionnaire was impaired due to underlying disease, their caregivers answered on their behalf. NutriQoL was administered in two and three visits to reliability and responsiveness cohorts, respectively. Test-retest reliability and internal consistency were assessed by the intra-class correlation coefficient (ICC) and the Cronbach's α, respectively. Responsiveness was evaluated by standardized effect size and standardized response mean between basal visit and third visit. Finally, the minimal clinically important difference (MCID) was estimated., Results: A total of 54 and 86 participants were recruited to the reliability and responsiveness cohort, respectively. Thirty-five caregivers were selected to assess the inter-observer reliability. ICC values confirmed the good reproducibility level (ICC >0.75) of the questionnaire in both "physical functioning and activities of daily living" and "social life" domains and total score. The assessment of internal consistency in both domains of the questionnaire showed good internal consistency in visit 2. ICC showed the excellent agreement level between caregiver and patient in the global NutriQoL score. Finally, patients classified as having a minimal change in their health reported a mean (standard deviation) MCID in NutriQoL score of 0.63 (11.51)., Conclusion: NutriQoL is a reliable and unique instrument to measure the HRQoL in HEN patients. NutriQoL detects changes in the health status of the patient. Nevertheless, further research is needed to determine the full extent of the questionnaire responsiveness.

Scope: Changes in genetic variations affecting the taste receptor, type 2, member 38 (TAS2R38) may identify the interacting mechanism leading to obesity and potential associations with proteins partaking in innate immunity, such as surfactant protein D (SPD) and mannan-binding lectin (MBL)., Methods and Results: We evaluated haplotypes of the bitter-taste receptor TAS2R38 in an identification sample of 210 women in different weight conditions, including anorexia nervosa and obesity. The association with SPD and MBL was tested in an independent sample picturing general population (n = 534). The relationship with obesity was validated in an extended final sample of 1319 participants. In the sample comprised of women in extreme weight conditions, increased obesity was identified in AVI/AVI subjects (OR = 2.5 [1.06-6.11], p = 0.035). In the sample picturing general population, increased SPD and MBL concentrations were found in nonsmoking AVI carriers. In this cohort, smoking and obesity blunted associations between TAS2R38 haplotypes and SPD and MBL. In the extended sample, the association of AVI/AVI haplotypes with increased obesity was also identified (OR = 1.4 [0.99/1.85], p = 0.049), being more robust in subjects aged <40 years (OR = 1.9 [1.06/3.42], p = 0.031)., Conclusion: Current data reinforce the impact of TAS2R38 gene on phenotypic and clinical outputs affecting obesity, showing significant associations with extreme weight conditions (i.e., obesity and anorexia nervosa), and changes in both olfactory capacity and immune traits., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: The association between low levels of vitamin D and the occurrence of chronic widespread pain (CWP) remains unclear. The aim of our analysis was to determine the relationship between low vitamin D levels and the risk of developing CWP in a population sample of middle age and elderly men., Methods: Three thousand three hundred sixty nine men aged 40-79 were recruited from 8 European centres for a longitudinal study of male ageing, the European Male Ageing Study. At baseline participants underwent assessment of lifestyle, health factors, physical characteristics and gave a fasting blood sample. The occurrence of pain was assessed at baseline and follow up (a mean of 4.3 years later) by shading painful sites on a body manikin. The presence of CWP was determined using the ACR criteria for fibromyalgia. Serum 25-hydroxyvitamin D (25-(OH) D) was assessed by radioimmunoassay. Logistic regression was used to determine the relationship between baseline vitamin D levels and the new occurrence of CWP., Results: Two thousand three hundred thirteen men, mean age 58.8 years (SD = 10.6), had complete pain and vitamin data available and contributed to this analysis. 151 (6.5%) developed new CWP at follow up and 577 (24.9%) were pain free at both time points, the comparator group. After adjustment for age and centre, physical performance and number of comorbidities, compared to those in upper quintile of 25-(OH) D ( ≥36.3 ng/mL), those in the lowest quintile (<15.6 ng/mL) were more likely to develop CWP (Odds Ratio [OR] = 1.93; 95% CI = 1.0-3.6). Further adjustment for BMI (OR = 1.67; 95% CI = 0.93-3.02) or depression (OR = 1.77; 95% CI = 0.98-3.21), however rendered the association non-significant., Conclusions: Low vitamin D is linked with the new occurrence of CWP, although this may be explained by underlying adverse health factors, particularly obesity and depression.

Objectives: Hypoglycemia is a limiting factor in the achievement of strict glycemic control. The primary objective of this 9-week study was to determine the frequency of hypoglycemia in patients with stable insulin-treated type 2 diabetes mellitus by comparing self-monitored blood glucose (SMBG) measurement with continuous glucose monitoring (CGM)., Methods: This was an observational prospective study. Included in the study were 63 stable, insulin-treated patients with type 2 diabetes. They were instructed to record 2 daily capillary blood glucose readings, pre- and/or postprandial, in a sequential way during 8 consecutive weeks. A CGM system was worn during an additional week. We evaluated the frequency of hypoglycemia using the 8-week SMBG profile and the 1 CGM week., Results: SMBG revealed that 50% of the patients had experienced hypoglycemia. CGM found hypoglycemia in 59% of patients. Significantly higher percentages of hyperglycemic and hypoglycemic episodes were detected by CGM than by capillary blood glucose measurements (61.1% vs. 50.8%; p=0.047) and (3.8% vs. 1.7%; p=0.016); 33% of patients experienced nocturnal hypoglycemia, and 19% of patients who had no data concerning hypoglycemia recorded in the capillary blood glucose diary had experienced hypoglycemia as measured by CGM, and the hypoglycemia occurred mainly during the nocturnal period., Conclusions: In stable well-controlled, insulin-treated patients with type 2 diabetes, CGM showed higher numbers of hypoglycemic events than did SMBG, especially at night. CGM is a useful tool that provides clinically valuable information about glucose control in these patients., (Copyright © 2015 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.)

Background: Several evidences indicate that gut microbiota is involved in the control of host energy metabolism., Objective: To evaluate the differences in the composition of gut microbiota in rat models under different nutritional status and physical activity and to identify their associations with serum leptin and ghrelin levels., Methods: In a case control study, forty male rats were randomly assigned to one of these four experimental groups: ABA group with food restriction and free access to exercise; control ABA group with food restriction and no access to exercise; exercise group with free access to exercise and feed ad libitum and ad libitum group without access to exercise and feed ad libitum. The fecal bacteria composition was investigated by PCR-denaturing gradient gel electrophoresis and real-time qPCR., Results: In restricted eaters, we have found a significant increase in the number of Proteobacteria, Bacteroides, Clostridium, Enterococcus, Prevotella and M. smithii and a significant decrease in the quantities of Actinobacteria, Firmicutes, Bacteroidetes, B. coccoides-E. rectale group, Lactobacillus and Bifidobacterium with respect to unrestricted eaters. Moreover, a significant increase in the number of Lactobacillus, Bifidobacterium and B. coccoides-E. rectale group was observed in exercise group with respect to the rest of groups. We also found a significant positive correlation between the quantity of Bifidobacterium and Lactobacillus and serum leptin levels, and a significant and negative correlation among the number of Clostridium, Bacteroides and Prevotella and serum leptin levels in all experimental groups. Furthermore, serum ghrelin levels were negatively correlated with the quantity of Bifidobacterium, Lactobacillus and B. coccoides-Eubacterium rectale group and positively correlated with the number of Bacteroides and Prevotella., Conclusions: Nutritional status and physical activity alter gut microbiota composition affecting the diversity and similarity. This study highlights the associations between gut microbiota and appetite-regulating hormones that may be important in terms of satiety and host metabolism.

Adrenal insufficiency (AI) is a rare endocrine disease, associated to increased mortality if left untreated. It can be due to a primary failure of the adrenal glands (primary AI) or malfunctioning of the hypothalamic-pituitary-adrenal axis (HPA) (secondary AI). The lack of data on incidence/prevalence of adrenal insufficiency in Spain complicates any evaluation of the magnitude of the problem in our country. Initial symptoms are non-specific, so often there is a delay in diagnosis. Current therapy with available glucocorticoids is associated with decreased quality of life in patients with treated AI, as well as with increased mortality and morbidity, probably related to both over-treatment and lack of hydrocortisone, associated with non-physiological peaks and troughs of the drug over the 24 hours. The availability of a new drug with a modified dual release (immediate and retarded), that requires one only daily dose, improves and simplifies the treatment, increases compliance as well as quality of life, morbidity and possibly mortality. This revision deals with the knowledge on the situation both globally and in Spain, prior to the availability of this new drug., (Copyright © 2012 SEEN. Published by Elsevier Espana. All rights reserved.)

Background: Concerning continuous subcutaneous insulin infusion (CSII), there are controversial results related to changes in glycemic response according to the meal composition and bolus design. Our aim is to determine whether the presence of protein and fat in a meal could involve a different postprandial glycemic response than that obtained with only carbohydrates (CHs)., Subjects and Methods: This was a crossover, randomized clinical trial. Seventeen type 1 diabetes (T1D) patients on CSII wore a blinded continuous glucose monitoring system sensor for 3 days. They ingested two meals (meal 1 vs. meal 2) with the same CH content (50 g) but different fat (8.9 g vs. 37.4 g) and protein (3.3 g vs. 28.9 g) contents. A single-wave insulin bolus was used, and the interstitial glucose values were measured every 30 min for 3 h. We evaluated the different postprandial glycemic response between meal 1 and meal 2 by using mixed-effects models., Results: The postmeal glucose increase was 22 mg/dL for meal 1 and 31 mg/dL for meal 2. In univariate analysis, at different times not statistically significant differences in glucose levels between meals occurred. In mixed-model analysis, a time×meal interaction was found, indicating a different response between treatments along the time. However, most of the patients remained in the normoglycemic range (70-180 mg/dL) during the 3-h postmeal period (84.4% for meal 1 and 93.1% for meal 2)., Conclusions: The presence of balanced amounts of protein and fat determined a different glycemic response from that obtained with only CH up to 3 h after eating. The clinical relevance of this finding remains to be elucidated.

Background: Mutations in SCN9A, encoding the alpha subunit of the voltage-gated sodium channel (Nav1.7), have caused severe pain disorders and congenital insensitivity to pain. The aim of this study was to validate the previously reported association between a common non-synonymous polymorphism (R1150W, rs6746030) in SCN9A and chronic widespread pain (CWP), in independent population-based cohorts., Findings: Genotype data for rs6746030 was available in four population-based cohorts (EPIFUND, the European Male Ageing Study (EMAS), the Framingham study and the Dyne Steel DNA Bank of Ageing and Cognition). Pain was assessed using body manikins and CWP was scored using American College of Rheumatology (ACR) criteria in all cohorts, except the Framingham study which assessed widespread pain (WP) using ACR criteria on a joint pain homunculus. Controls were subjects who reported no pain. Logistic regression (additive genetic model) was used to test for association between rs6746030 and CWP compared to controls, adjusting for study centre in EMAS. Generalised estimating equation regression was used to test for association between rs6746030 and WP, whilst accounting for relatedness between subjects in the Framingham study.Genotype data for rs6746030 was available for 1071 CWP cases and 3212 controls. There was no significant association between CWP and rs6476030 in individual cohorts or when combined in a fixed-effects meta-analysis (Odds Ratio = 0.96 (95% confidence interval 0.82, 1.11) p = 0.567)., Conclusions: In contrast to a previous study, no association between a non-synonymous polymorphism in SCN9A and CWP was observed in multiple population-based cohorts.

Functional defects in growth hormone (GH) secretion and its efficacy as a complementary treatment have been suggested for fibromyalgia. This study investigated the efficacy and safety of low-dose GH as an add-on therapy in patients with both severe FM and low insulin-like growth factor 1 levels. A total of 120 patients were enrolled in a multicenter, placebo-controlled study for 18 months. They were randomly assigned to receive either 0.006 mg/kg/day of GH subcutaneously (group A, n=60) or placebo (group B, n=60) for 6 months (blind phase). The placebo arm was switched to GH treatment from month 6 to month 12 (open phase), and a follow-up period after GH discontinuation was performed until month 18. Standard treatment for fibromyalgia (selective serotonin re-uptake inhibitors, opioids, and amitriptyline) was maintained throughout the study. Number and intensity of tender points, Fibromyalgia Impact Questionnaire (FIQ) with its subscales, and EuroQol 5 dimensions test (EQ5D) with visual analogue scale (VAS) were assessed at different time points. At the end of the study, 53% of group A patients obtained fewer than 11 positive tender points, vs 33% of group B patients (P<.05). 39.1% vs 22.4% reached more than 50% improvement in VAS (P<.05). Group A patients showed significantly improved FIQ scores (P=.01) compared with group B. Although GH discontinuation worsened all scores in both groups during follow-up, impairment in pain perception was less pronounced in the GH-treated group (P=.05). In this largest and longest placebo-controlled trial performed in FM (NCT00933686), addition of GH to the standard treatment is effective in reducing pain, showing sustained action over time., (Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Background: Hypoglycemia limits the efficacy of intensive insulin therapy, especially in patients with great glucose variability. The extent to which continuous subcutaneous insulin infusion (CSII) overcomes this limitation is unclear. Our aim was to determine whether CSII is helpful for decreasing glucose variability and hypoglycemia, mainly in patients with the greatest variability., Method: Twenty-four patients with type 1 diabetes wore a continuous glucose monitoring system sensor for three days before starting therapy with CSII and 6 months later. Glucose variability (SD, MAGE, M) and hypoglycemia duration (area under the curve (AUC) <70mg/dL) were compared in all patients and in those with the greatest MAGE (highest quartile)., Results: At 6 months, a decreased glucose variability was seen, as measured by MAGE, M, and SD (median: -28mg/dL (interquartile range, -48 to 1), p=0.03; -22(-40 to 0), p=0.04; -11(-23 to 0), p=0.009; respectively). Patients with the greatest initial glucose variability (MAGE quartile 4) showed a greater decrease in both MAGE (-47mg/dL (-103 to -34) vs -20 (-36 to 17), p=0.01) and AUC <70 (-10.7mg/dL x day (-15 to 0) vs -1.1 (-4.7 to 3.8), p=0.03) as compared to all others. Patients with longer initial hypoglycemia (AUC quartile 4) achieved a greater reduction in AUC <70 (-9.7mg/dL x day(-15 to -6.5) vs -0.08 (-2.9 to 3.8), p=0.003). A correlation was found between ΔMAGE-ΔAUC (r 0.4, p=0.03)., Conclusions: During CSII, glucose variability significantly decreased, especially in patients with the greatest initial variability. Hypoglycemia was also markedly less in patients with greater variability, with the greatest reduction occurring in those who experienced more marked hypoglycemia with CSII., (Copyright © 2011 SEEN. Published by Elsevier Espana. All rights reserved.)

Objective: To assess the influence of sex hormones on markers of bone turnover and to explore the association between these markers and bone health in middle-aged and elderly European men., Design: A cross-sectional population-based survey., Methods: Men aged 40-79 years were recruited from population registers in eight European centres. Subjects completed a postal questionnaire which included questions concerning lifestyle and were invited to undergo quantitative ultrasound (QUS) of the calcaneus and to provide a fasting blood sample from which the bone markers serum N-terminal propeptide of type 1 procollagen (P1NP) and crosslinks (β C-terminal cross-linked telopeptide (β-cTX)), total testosterone, total oestradiol (E(2)), sex hormone-binding globulin (SHBG) and insulin-like growth factor 1 (IGF1) were measured. Dual-energy X-ray absorptiometry (DXA) of the hip and lumbar spine was performed in two centres., Results: A total of 3120, mean age 59.9 years (s.d.=11.0) were included. After adjustment for centre, age, height, weight, lifestyle factors, season and other hormones, total and free E(2) were negatively associated with β-cTX but not P1NP while SHBG, IGF1 and parathyroid hormone (PTH) were positively associated with both β-cTX and P1NP. Total or free testosterone was not independently associated with either bone marker. After the same adjustments, higher levels of both bone markers were significantly associated with lower QUS parameters and lower DXA-assessed bone density at the total hip and lumbar spine., Conclusions: E(2), SHBG, IGF1 and PTH contribute significantly to the regulation/rate of bone turnover in middle-aged and older European men. Higher rates of bone remodelling are negatively associated with male bone health.

Background: Few published data link overweight and obesity with measures of quality of life (QoL) including sexual health in men., Objective: To assess the association of overweight/obesity with impairment of physical and psychological QoL and sexual functions in men., Design and Setting: Cross-sectional, multicentre survey of 3369 community-dwelling men aged 40-79 (mean±s.d., 60±11) years randomly selected from eight European centres., Outcomes: Adiposity was assessed by body mass index (BMI) and waist circumference (WC), QoL and functional impairments by physical and psychological function domains of the Short Form-36 questionnaire, Beck's Depression Inventory and the European Male Ageing Study sexual function questionnaire., Results: Complete data on sexual activities and erectile function were available in 2734 (92%) and 3193 (95%) of the participants respectively. From the population studied, 814 men were obese (BMI ≥30 kg/m(2)) and 1171 had WC ≥102 cm, 25% of all men were unable to do vigorous activity and 2-13% reported depressive symptoms. Symptoms of sexual dysfunction ranged between 22% (low sexual desire) and 40% (infrequent morning erections) of the participants. Among obese men with both BMI ≥30 kg/m(2) and WC ≥102 cm, at least one symptom of impaired physical, psychological and sexual function was reported by 41, 43 and 73% of the participants respectively. Compared with the reference group of non-obese men (BMI <30 kg/m(2) and WC <102 cm), men with BMI ≥30 kg/m(2) and WC ≥102 cm more frequently reported at least one symptom of impaired physical function (odds ratio (OR)=2.67; confidence interval (CI): 2.07-3.45, P<0.001), impaired psychological function (OR=1.48; CI: 1.14-1.90, P<0.01) and impaired sexual function (OR=1.45; CI: 1.14-1.85, P<0.01). These functional impairments were also more prevalent in men who had WC ≥102 cm even with BMI <30 kg/m(2), but those with BMI ≥30 kg/m(2) and WC <102 cm generally did not suffer from increased impaired physical or sexual health. Men with high BMI and WC were at even greater likelihood of having a composite of two or more or three or more symptoms compared with those with normal BMI and WC., Conclusions: Men with high WC, including those who are 'non-obese' with BMI <30 kg/m(2), have poor QoL with symptoms of impaired physical, psychological and sexual functions. Health promotion to improve QoL should focus on prevention of obesity and central fat accumulation.

Recently, it has been described the role of fatty acid ethanolamides in the control of feeding behavior. Oleoylethanolamide (OEA) is a member of this family of lipid mediators regulating feeding. OEA acts suppressing feeding behavior through, at least partially, a peripheral mechanism. However, the interaction between this acylethanolamide and other orexigenic or anorexigenic mediators is mostly not well characterized. The aim of this study was to evaluate whether anorectic actions of OEA were mediated through the modulation of central and peripheral signals involved in the regulation of feeding. Experiments were performed in male Wistar rats under free-feeding and fasting conditions. We measured hypothalamic neuropeptides and monoamines by in situ hybridization and HPLC respectively as well as plasmatic levels of relevant endocrine signals. OEA administration induced changes in hypothalamic monoaminergic activity and in the anorexigenic neuropeptide CART expressed in the paraventricular nucleus (PVN) but lacked effect on neuropeptides expression in nucleus arcuatus. In addition, OEA induced peripheral changes in gut peptides, with marked effects on PYY and Ghrelin. These results further suggest that anorexigenic properties of OEA are mediated by peripheral signals and by central alterations in neuropeptides expressed by feeding-involved hypothalamic structures receiving input from peripheral sensory systems, such as the PVN., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: A number of single nucleotide polymorphisms (SNPs) have been associated with broadband ultrasound attenuation (BUA) and speed of sound (SOS) as measured by quantitative ultrasound (QUS) at the calcaneus in the Framingham 100K genome-wide association study (GWAS) but have not been validated in independent studies. The aim of this analysis was to determine if these SNPs are associated with QUS measurements assessed in a large independent population of European middle-aged and elderly men. The association between these SNPs and bone mineral density (BMD) measured using dual-energy X-ray absorptiometry (DXA) was also tested., Methods: Men aged 40-79 years (N = 2960) were recruited from population registers in seven European centres for participation in an observational study of male ageing, the European Male Ageing Study (EMAS). QUS at the calcaneus was measured in all subjects and blood was taken for genetic analysis. Lumbar spine (LS), femoral neck (FN) and total hip (TH) BMD were measured by DXA in a subsample of 620 men in two centres. SNPs associated with BUA or SOS in the Framingham study with p < 10-4 were selected and genotyped using SEQUENOM technology. Linear regression was used to test for the association between SNPs and standardised (SD) bone outcomes under an additive genetic model adjusting for centre. The same direction of effect and p < 0.05 indicated replication., Results: Thirty-four of 38 selected SNPs were successfully genotyped in 2377 men. Suggestive evidence of replication was observed for a single SNP, rs3754032, which was associated with a higher SOS (β(SD) = 0.07, p = 0.032) but not BUA (β(SD) = 0.02, p = 0.505) and is located in the 3'UTR of WDR77 (WD repeat domain 77) also known as androgen receptor cofactor p44. A single SNP, rs238358, was associated with BMD at the LS (β(SD) = -0.22, p = 0.014), FN (β(SD) = -0.31,p = 0.001) and TH (β(SD) = -0.36, p = 0.002) in a locus previously associated with LS BMD in large-scale GWAS, incorporating AKAP11 and RANKL., Conclusions: We found suggestive evidence of association between a single SNP located in the 3'UTR of WDR77 with calcaneal ultrasound parameters. The majority of SNPs, associated with QUS parameters in the Framingham Study, were not replicated in an independent population sample of European men.

Purpose: Genome-wide association studies (GWAS) have identified 6q25, which incorporates the oestrogen receptor α gene (ESR1), as a quantitative trait locus for areal bone mineral density (BMD(a)) of the hip and lumbar spine. The aim of this study was to determine the influence of this locus on other bone health outcomes; calcaneal ultrasound (QUS) parameters, radial peripheral quantitative computed tomography (pQCT) parameters and markers of bone turnover in a population sample of European men., Methods: Eight single nucleotide polymorphisms (SNP) in the 6q25 locus were genotyped in men aged 40-79 years from 7 European countries, participating in the European Male Ageing Study (EMAS). The associations between SNPs and measured bone parameters were tested under an additive genetic model adjusting for centre using linear regression., Results: 2468 men, mean (SD) aged 59.9 (11.1) years had QUS measurements performed and bone turnover marker levels measured. A subset of 628 men had DXA and pQCT measurements. Multiple independent SNPs showed significant associations with BMD using all three measurement techniques. Most notably, rs1999805 was associated with a 0.10 SD (95%CI 0.05, 0.16; p = 0.0001) lower estimated BMD at the calcaneus, a 0.14 SD (95%CI 0.05, 0.24; p = 0.004) lower total hip BMD(a), a 0.12 SD (95%CI 0.02, 0.23; p = 0.026) lower lumbar spine BMD(a) and a 0.18 SD (95%CI 0.06, 0.29; p = 0.003) lower trabecular BMD at the distal radius for each copy of the minor allele. There was no association with serum levels of bone turnover markers and a single SNP which was associated with cortical density was also associated with cortical BMC and thickness., Conclusions: Our data replicate previous associations found between SNPs in the 6q25 locus and BMD(a) at the hip and extend these data to include associations with calcaneal ultrasound parameters and radial volumetric BMD.

Objectives: The aim of this study was to investigate the association between the catechol-O-methyltransferase (COMT) 'pain sensitivity' haplotypes and chronic widespread pain (CWP) in two distinct cohorts., Methods: Cases of CWP and controls free of pain were selected from two population-based studies: the Epidemiology of Functional Disorders study (EPIFUND) (UK) and the European Male Ageing Study (European). The number of cases and controls were 164 and 172, and 204 and 935, respectively. Identical American College of Rheumatology criteria were used in both studies to ascertain CWP status. The EPIFUND study had three time points and cases were classified as subjects with CWP at two or three time points and controls as those free of pain at all three time points. Four single nucleotide polymorphisms (SNP): rs6269, rs4633, rs4818 and rs4680 (V158M) were genotyped using Sequenom technology. Allele and genotype frequencies were compared and haplotype analysis was conducted using PLINK software., Results: No differences in allele or genotype frequencies for any of the four SNP were observed between cases and controls for either cohort. Haplotype analysis also showed no difference in the frequency of haplotypes between cases and controls., Conclusions: There was no evidence of association between the COMT 'pain sensitivity' haplotypes and CWP in two population-based cohorts.

The aim of this study was to determine if single-nucleotide polymorphisms (SNPs) in RANKL, RANK, and OPG influence bone turnover and bone mineral density (BMD) in men. Pairwise tag SNPs (r(2) > or = 0.8) were selected for RANKL, RANK, and OPG and their 10-kb flanking regions. Selected tag SNPs plus five SNPs near RANKL and OPG, associated with BMD in published genome-wide association studies (GWAS), were genotyped in 2653 men aged 40 to 79 years of age recruited for participation in a population-based study of male aging, the European Male Ageing Study (EMAS). N-terminal propeptide of type I procollagen (PINP) and C-terminal cross-linked telopeptide of type I collagen (CTX-I) serum levels were measured in all men. BMD at the calcaneus was estimated by quantitative ultrasound (QUS) in all men. Lumbar spine and total-hip areal BMD (BMD(a)) was measured by dual-energy X-ray absorptiometry (DXA) in a subsample of 620 men. Multiple OPG, RANK, and RANKL SNPs were associated with bone turnover markers. We also identified a number of SNPs associated with BMD, including rs2073618 in OPG and rs9594759 near RANKL. The minor allele of rs2073618 (C) was associated with higher levels of both PINP (beta = 1.83, p = .004) and CTX-I (beta = 17.59, p = 4.74 x 10(-4)), and lower lumbar spine BMD(a) (beta = -0.02, p = .026). The minor allele of rs9594759 (C) was associated with lower PINP (beta = -1.84, p = .003) and CTX-I (beta = -27.02, p = 6.06 x 10(-8)) and higher ultrasound BMD at the calcaneus (beta = 0.01, p = .037). Our findings suggest that genetic variation in the RANKL/RANK/OPG signaling pathway influences bone turnover and BMD in European men.

Introduction: A study was undertaken to test the hypothesis that musculoskeletal pain is associated with low vitamin D levels but the relationship is explained by physical inactivity and/or other putative confounding factors., Methods: Men aged 40-79 years completed a postal questionnaire including a pain assessment and attended a clinical assessment (lifestyle questionnaire, physical performance tests, 25-hydroxyvitamin D3 (25-(OH)D) levels from fasting blood sample). Subjects were classified according to 25-(OH)D levels as 'normal' (> or = 15 ng/ml) or 'low' (< 15 ng/ml). The relationship between pain status and 25-(OH)D levels was assessed using logistic regression. Results are expressed as ORs and 95% CIs., Results: 3075 men of mean (SD) age 60 (11) years were included in the analysis. 1262 (41.0%) subjects were pain-free, 1550 (50.4%) reported 'other pain' that did not satisfy criteria for chronic widespread pain (CWP) and 263 (8.6%) reported CWP. Compared with patients who were pain-free, those with 'other pain' and CWP had lower 25-(OH)D levels (n=239 (18.9%), n=361 (23.3) and n=67 (24.1%), respectively, p<0.05). After adjusting for age, having 'other pain' was associated with a 30% increase in the odds of having low 25-(OH)D while CWP was associated with a 50% increase. These relationships persisted after adjusting for physical activity levels. Adjusting for additional lifestyle factors (body mass index, smoking and alcohol use) and depression attenuated these relationships, although pain remained moderately associated with increased odds of 20% of having low vitamin D levels., Conclusions: These findings have implications at a population level for the long-term health of individuals with musculoskeletal pain.

Objective: The objective of the study was to asses the possible influence of hypothalamo-pituitary deficiencies, and growth hormone (GH) deficiency in particular, on cognition in adult patients with traumatic brain injury (TBI). TBI is a recently identified risk factor for cognitive deficits and hypopituitarism. Even the patients with favorable outcome after TBI may present with persistent bodily, psychosocial, and cognitive impairments, resembling patients with untreated partial or complete pituitary insufficiency., Design: We performed retrospective and cross-sectional study of endocrine and cognitive function in TBI in 61 patients (aged 37.7 +/- 1.7 years) of both sexes (44 m,17 f), at least 1 year after TBI (3.9 +/- 0.6 years). Serum insulin-like growth factor 1 (IGF-I), thyroxin, thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone (in men), prolactin, and cortisol were measured, and GH secretion was assessed by growth hormone releasing hormone (GHRH) + growth hormone releasing peptide-6 (GHRP-6) test. Cognitive function was assessed by using a standard neuropsychological battery., Results: GH deficiency (GHD) and GH insufficiency (GHI) were found in 20 patients (32.8%). After adjustment for confounders [age, body mass index (BMI), education level, time elapsed from TBI], there were no significant differences in results of neuropsychological tests between patients with TBI with GHD, GHI, and normal GH secretion. There were no correlations of neuropsychological variables with stimulated peak GH secretion or IGF-I level., Conclusions: GHD persists long after the TBI, independently of trauma severity and age at traumatic event. GH secretion is more sensitive to TBI than other pituitary hormones. No evidence is found for an association of cognitive function impairment and somatotropic axis impairment in adult patients tested more than 1 year after the TBI.

Objective: To determine whether perturbations of insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) were associated with the presence of chronic widespread pain (CWP) in men., Methods: The European Male Ageing Study (EMAS) is an 8-center population-based study of men aged 40-79 years recruited from population registers. A questionnaire asked about the presence and duration of musculoskeletal pain, from which subjects reporting CWP were identified. Subjects also had an interviewer-assisted questionnaire: levels of physical activity and mood were assessed, and height and weight were measured. IGF-1 and IGFBP-3 were assayed from a fasting blood sample. Logistic regression models were used to determine the association between IGF measures and CWP. Results were expressed as odds ratios or relative risk ratios., Results: A total of 3206 subjects provided full data. Of those, 1314 (39.0%) reported no pain in the past month and 278 (8.3%) reported pain that satisfied criteria for CWP. IGF-1 concentrations were similar among subjects who reported no pain and those with CWP: 131.5 mg/l and 128.4 mg/l, respectively. This was true also for IGFBP-3 (4.3 and 4.3 mg/l). Obesity was associated with low IGF-1 and a high IGFBP-3/IGF-1 ratio, indicating less bioavailable IGF-1, irrespective of pain status. This relationship persisted after adjustment for comorbidities, depression, smoking, alcohol consumption, and quality of life., Conclusion: Overall CWP was not associated with perturbations in IGF-1 and IGFBP-3 concentrations. Hypofunctioning of the axis was noted among subjects who were obese and this was not specific to CWP. These data suggest that IGF-1 is unlikely to be etiologically important in relation to CWP, although the relationship with growth hormone remains to be elucidated.

Objectives: To determine whether among middle-aged and elderly men there is evidence of international differences in the prevalence of chronic widespread pain (CWP) and whether any such differences could be explained by psychological, psychosocial factors or differences in physical health status., Methods: The European Male Ageing Study (EMAS) sampled from population registers in cities (centres) of eight European countries. Each centre recruited an age-stratified sample of men aged 40-79 years. Information on pain was collected by questionnaire and subjects were classified according to whether they satisfied the American College of Rheumatology definition of CWP. Information was collected on social status, mental health, recent life events and co-morbidities., Results: Across all centres 3963 subjects completed a study questionnaire, with participation rates ranging from 24% in Hungary to 72% in Estonia. There were significant differences in prevalence: between 5% and 7% in centres in Italy, England, Belgium and Sweden, 9-15% in centres in Spain, Poland and Hungary and 15% in Estonia. There were strong relationships between poor mental health, adverse recent life events, co-morbidities and CWP. Adjustment for these factors explained between half and all of the excess risk in the eastern European centres: the excess risk in Poland was explained (odds ratio (OR) 1.1, 95% CI 0.9 to 1.2) but there remained excess risk in Hungary (OR 1.6, 95% CI 1.4 to 1.8) and Estonia (OR 2.6, 95% CI 2.2 to 2.9)., Conclusions: This study is the first directly to compare the occurrence of CWP internationally. There is an excess prevalence in countries of eastern Europe and this excess is associated with adverse psychosocial factors as well as poorer psychological and physical health.

Genes involved in sex hormone pathways are candidates for influencing bone strength. Polymorphisms in these genes were tested for association with heel quantitative ultrasound (QUS) parameters in middle-aged and elderly European men. Men 40-79 yr of age were recruited from population registers in eight European centers for the European Male Aging Study (EMAS). Polymorphisms were genotyped in AR, ESR1, ESR2, CYP19A1, CYP17A1, SHBG, SRD5A2, LHB, and LHCGR. QUS parameters broadband ultrasound attenuation (BUA) and speed of sound (SOS) were measured in the heel and used to derive BMD. The relationships between QUS parameters and polymorphisms were assessed using linear regression adjusting for age and center. A total of 2693 men, with a mean age of 60.1 +/- 11.1 (SD) yr were included in the analysis. Their mean BUA was 80.0 +/- 18.9 dB/Mhz, SOS was 1550.2 +/- 34.1 m/s, and BMD was 0.542 +/- 0.141 g/cm(2). Significant associations were observed between multiple SNPs in a linkage disequilibrium (LD) block within CYP19A1, peaking at the TCT indel with the deletion allele associating with reduced ultrasound BMD in heterozygotes (beta =-0.016, p = -0.005) and homozygotes (beta = -0.029, p = 0.001). The results for BUA and SOS were similar. Significant associations with QUS parameters were also observed for the CAG repeat in AR and SNPs in CYP17A1, LHCGR, and ESR1. Our data confirm evidence of association between bone QUS parameters and polymorphisms in CYP19A1, as well as modest associations with polymorphisms in CYP17A1, ESR1, LHCGR, and AR in a population sample of European men; this supports a role for genetically determined sex hormone actions in influencing male bone health.

Life expectancy is increasing in most developed countries, in part due to improved socioeconomic conditions and in part to advances in healthcare. It is widely acknowledged that the promotion of healthy ageing by delaying, minimizing or preventing disabilities or diseases is one of the most important public health objectives in this century. In contrast to the menopausal transition in females, we know relatively little about the contribution of androgens and anabolic hormones to the quality of ageing in men. The European Male Ageing Study (EMAS) is a multicentre prospective cohort designed to examine the prevalence, incidence and geographical distribution of gender-specific and general symptoms of ageing in men, including their endocrine, genetic and psychosocial predictors. Men aged 40-79 years were recruited from eight European centres: Florence (Italy), Leuven (Belgium), Lodz (Poland), Malmö (Sweden), Manchester (UK), Santiago de Compostela (Spain), Szeged (Hungary) and Tartu (Estonia). Subjects were recruited from population registers and those who agreed to take part completed a detailed questionnaire including aspects of personal and medical history, lifestyle factors and sexual function. Objective measures of body size, cognition, vision, skeletal health and neuromuscular function were obtained. Blood and DNA specimens were collected for a range of biochemical and genetic analyses. After an average of 4 years, it is planned to resurvey the participants with similar assessments. A total of 3369 men with a mean age of 60 +/- 11 years were recruited. The mean centre response rate was 43%, and highest in those aged 50-59 years. Those who participated were marginally younger than those who were invited but declined to participate (60.0 vs. 61.1 years). Participants left education slightly later than a sample of non-participants, though there were no consistent differences in levels of general health, physical activity, or smoking. EMAS will provide new population-based data concerning the main features that characterize ageing in men and its critical determinants, particularly with reference to age-related changes in hormone levels. Such information is an important prerequisite to develop effective strategies to reduce age-related disabilities and optimise health and well-being into old-age.

Context: The individual variability in the waning androgenic-anabolic functions of aging men may be influenced by the CAG repeat polymorphism in exon 1 of the androgen receptor (AR), affecting androgen sensitivity. However, findings on its phenotypic effects are inconclusive., Objective: The aim was to investigate the relationships between health status, various reproductive hormones, and the AR CAG repeat length., Design: We conducted a multinational prospective cohort observational study with cross-sectional baseline data., Setting: This was a population survey of community-dwelling men., Participants: Men (40-79 yr old; n = 3369) were randomly recruited from centers in eight European countries; CAG repeat analysis was performed in 2878 men., Main Outcome Measures: We measured the correlations of the CAG repeat length with selected endocrine, metabolic, and phenotypic parameters related to aging and sex hormone action., Results: Only minor differences were found in CAG repeat lengths between the eight European countries. They showed significant positive association with total, free, and bioavailable levels of testosterone (T) and estradiol. FSH but not LH correlated inversely with CAG repeat length. Significant associations were found with bone ultrasound parameters at the calcaneus. Negative correlation was found with triglycerides, but not with other blood lipids or with anthropometry, blood pressure, hemoglobin, insulin sensitivity, or sexual and prostatic functions., Conclusions: The AR CAG repeat length correlates significantly with serum T and estradiol of aging men. Weaker transcriptional activity of the AR with longer CAG-encoded polyglutamine repeats appears to be totally or nearly totally compensated for by higher T levels. The residual phenotypic correlations may reflect differences in estrogen levels/actions after aromatization of the higher T levels.

Starvation exerts critical influence on somatotroph and leptin secretion. Fasting enhances GH levels in normal subjects, but not in GH hyposecretory states, while it always inhibits leptin secretion. We aimed to clarify the GH/IGF-I and metabolic response to short-term fasting in a GH hypersecretory state such as acromegaly. To this goal, in 8 active acromegalic (ACRO) and in 7 normal women (NS) we evaluated mean GH (mGHc), leptin (mLEPc), insulin (mINSc), glucose (mGLUc) concentrations as well as IGF-I, IGF binding protein (IGFBP)-3, IGFBP-1, and free fatty acid (FFA) levels before and after 36-h fasting. Before fasting, mGHc, IGF-I, mINSc, mGLUc, and FFA levels in ACRO were higher (p<0.01) than in NS. IGFBP-3, IGFBP-1, and mLEPc were similar in ACRO and in NS. Fasting clearly (p<0.02) increased mGHc in NS only. After 36-h fasting, significant IGF-I reduction was recorded in NS only (p<0.03). IGFBP-3 did not change both in ACRO and NS. IGFBP-1 significantly increased (p<0.05) after fasting in both groups but in ACRO were lower (p<0.03) than in NS. Fasting decreased (p<0.03) mLEPc, mGLUc, and mINSc in ACRO as well as in NS; mINSc and mGLUc after fasting in ACRO persisted higher (p<0.005) than in NS. FFA levels were increased by fasting in NS (p<0.02), but not in ACRO. This study shows that GH/IGF-I axis, glucose metabolism, and lypolisis but not leptin display some degree of refractoriness to short-term fasting in acromegaly. The lack of any GH response to fasting in acromegaly would likely reflect neuroendocrine alterations secondary to the GH hypersecretory state. On the other hand, the lack of somatotropic response and the peculiarly blunted metabolic reaction to short-term fasting would partially reflect the delayed adaptation of insulin resistance to starvation.

The V Consensus Group Meeting on 'Guidelines for Treatment of GH Excess and GH Deficiency in the Adult' was an international workshop held on February 20-22, 2006 in Santa Monica, California, USA. The principal aim of this meeting was to provide guidelines for the evaluation and treatment of adults with either form of abnormal GH secretion: GH excess or GH deficiency. The workshop included debates as to the choice of primary treatment, discussions of the targets for adequate treatment, and concluded with presentations on open issues germane to adult GH treatment including the role of GH in malignancies, the impact of longterm treatment on bone, and a cost-benefit analysis. The meeting was comprised of 66 delegates representing 13 different countries.

Context: The cause of declining testosterone (T) in aging men and their relationships with risk factors are unclear., Objective: The objective of the study was to investigate the relationships between lifestyle and health with reproductive hormones in aging men., Design: This was a baseline cross-sectional survey on 3200 community-dwelling men aged 40-79 yr from a prospective cohort study in eight European countries., Results: Four predictors were associated with distinct modes of altered function: 1) age: lower free T (FT; -3.12 pmol/liter.yr, P < 0.001) with raised LH, suggesting impaired testicular function; 2) obesity: lower total T (TT; -2.32 nmol/liter) and FT (-17.60 pmol/liter) for body mass index (BMI; > or = 25 to < 30 kg/m(2)) and lower TT (-5.09 nmol/liter) and FT (-53.72 pmol/liter) for BMI 30 kg/m(2) or greater (P < 0.001-0.01, referent: BMI < 25 kg/m(2)) with unchanged/decreased LH, indicating hypothalamus/pituitary dysfunction; 3) comorbidity: lower TT (-0.80 nmol/liter, P < 0.01) with unchanged LH in younger men but higher LH in older men; and 4) smoking: higher SHBG (5.96 nmol/liter, P < 0.001) and LH (0.77 U/liter, P < 0.01) with increased TT (1.31 nmol/liter, P < 0.001) but not FT, compatible with a resetting of T-LH-negative feedback due to elevated SHBG., Conclusions: Complex multiple alterations in the hypothalamic-pituitary-testicular axis function exist in aging men against a background of progressive age-related testicular impairment. These changes are differentially linked to specific risk factors. Some risk factors operate independently of but others interact with age, in contributing to the T decline. These potentially modifiable risk factors suggest possible preventative measures to maintain T during aging in men.

Objective: Ghrelin, a potent stimulator of GH secretion, also acts as an orexigenic hormone. Plasma ghrelin levels rise before meals with postprandial reduction, suggesting that circulating levels of enteroinsular hormones might influence ghrelin secretion., Aim: The aim of this study was to evaluate the effects of ghrelin on enteroinsular hormones in healthy men., Design: Three tests were performed on 3 different days in 6 healthy men: On the first day, saline was infused from 0-120 minutes followed by a ghrelin bolus (1 microg/kg) administration (Test 1); on the second experimental day, GHRH was administered at 0 min, and a ghrelin bolus was given at 120 min (Test 2); on the third experimental day, GHRP-6 was administered at 0 min, followed by a ghrelin bolus at 120 min (Test 3). Plasma glucose, insulin, proinsulin, C-Peptide Glucagone Like Peptide one (GLP-1) determined at 0, 15, 30, 60, 90, and 120 min of the test period., Results: There was a significant increase in AUC glucose (526.41+/-22.91 mmol . ml(-1) . min vs. 566.37+/-15.64 mmol . ml(-1) . min; p<0.05) and AUC insulin (756.25+/-107.56 mU . ml(-1) . min vs. 981.62+/-180.32 mU . ml(-1) . min; p<0.05) and a significant decrease in AUC GLP-1 (2346.87+/-874.28 pmol . ml(-1) . min vs. 1769.5+/-784 pmol . ml(-1) . min; p<0.05) after ghrelin administration in Test 1 compared to Test 3. There was a mild but non-significant increase in AUC for insulin, proinsulin, and C-Peptide and a mild reduction in AUC GLP-1 after every ghrelin administration., Conclusion: There was no evidence of a direct effect of ghrelin administration on enteroinsular hormone levels in this study. However, ghrelin may potentiate the glucose-insulin stimulatory effects of GHRP-6. More studies should be carried out for further evaluation of ghrelin-enteroinsular hormones interplay.

Ghrelin, the endogenous ligand of GH secretagogue receptor type 1a, has emerged as a pleiotropic modulator of diverse biological functions, including energy homeostasis and, lately reproduction. Here, we review recent reports evaluating the reproductive effects and sites of action of ghrelin, with particular emphasis regarding its role as a molecule integrating reproductive function and energy status. Data gleaned from rodent studies clearly show that besides having direct gonadal effects, ghrelin may participate in the regulation of gonadotropin secretion and it may influence the timing of puberty. In addition, experimental data showing that ghrelin and/or its receptor are expressed in normal human ovary and testis as well as in human ovarian and testicular tumors raise the possibility that the ghrelin system may be involved in the control of cell proliferation in these tumors. We propose that ghrelin either acting as an endocrine and/or paracrine signal may play a major role in the endocrine network that integrates energy balance and reproduction.