The Gut Hormones in Appetite Regulation

Obesity has received much attention worldwide in association with an increased risk of cardiovascular diseases, diabetes, and cancer. At present, bariatric surgery is the only effective treatment for obesity in which long-term weight loss is achieved in patients. By contrast, pharmacological interventions for obesity are usually followed by weight regain. Although the exact mechanisms of long-term weight loss following bariatric surgery are yet to be fully elucidated, several gut hormones have been implicated. Gut hormones play a critical role in relaying signals of nutritional and energy status from the gut to the central nervous system, in order to regulate food intake. Cholecystokinin, peptide YY, pancreatic polypeptide, glucagon-like peptide-1, and oxyntomodulin act through distinct yet synergistic mechanisms to suppress appetite, whereas ghrelin stimulates food intake. Here, we discuss the role of gut hormones in the regulation of food intake and body weight

Presentation, Treatment, and Prognosis of Secondary Melanoma within the Orbit

BackgroundOcular melanoma is a rare but often deadly malignancy that arises in the uvea, conjunctiva, or orbit. Uveal melanoma is the most common type, with conjunctival melanoma being the second most frequently observed. Melanoma accounts for 5–10% of metastatic or secondary orbital malignancies, but only a minute proportion of primary orbital neoplasia. The aim of this study was to characterize the clinical presentation, treatment, and prognosis in patients presenting with melanoma metastatic to, or secondary within, the orbit.MethodsA retrospective cohort study of patients presenting to a tertiary referral orbital unit from 1982 to 2016 was performed. Eighty-nine patients with biopsy-proven diagnosis of melanoma within the orbit were included in the study. The clinical notes, radiological imaging, histology, surgical notes, and outcome data for the patients were reviewed. The main outcome measures of interest were the interval between primary malignant melanoma and orbital presentation, survival after orbital presentation, and clinical parameters (such as gender, age at presentation, and treatment approach).ResultsThe commonest primary source of tumor was choroidal melanoma, with conjunctival and cutaneous melanomas being relatively common; eyelid and naso-sinus tumors occurred in a few cases. The mean age at presentation with orbital disease was 65 years (31–97 years). The interval between primary malignancy and orbital disease (either local spread/recurrence or true metastatic disease) showed wide variability, with almost one-third of patients having orbital disease at the time of primary diagnosis, but others presenting many years later; indeed, the longest orbital disease-free interval was over 34 years. Twenty-three patients were considered to have had late orbital metastases—that is, at more than 36 months after primary tumor. The median survival following presentation with orbital involvement was 24 months. Patients with tumors of cutaneous origin had worst survival, whereas those with conjunctival tumors had the best prognosis.ConclusionA high index of suspicion for orbital recurrence should be maintained in any patient with prior history of melanoma, however distant the primary tumor is in site or time. Furthermore, giving a prognosis for orbital melanoma remains problematic due to highly variable survival, and further investigation will be necessary to understand the likely genetic basis of this phenomenon

Insulin-like peptide 3 (INSL3) in congenital hypogonadotrophic hypogonadism (CHH) in boys with delayed puberty and adult men

Background: Delayed puberty in males is almost invariably associated with constitutional delay of growth and puberty (CDGP) or congenital hypogonadotrophic hypogonadism (CHH). Establishing the cause at presentation is challenging, with “red flag” features of CHH commonly overlooked. Thus, several markers have been evaluated in both the basal state or after stimulation e.g. with gonadotrophin releasing hormone agonist (GnRHa). Insulin-like peptide 3 (INSL3) is a constitutive secretory product of Leydig cells and thus a possible candidate marker, but there have been limited data examining its role in distinguishing CDGP from CHH. In this manuscript, we assess INSL3 and inhibin B (INB) in two cohorts: 1. Adolescent boys with delayed puberty due to CDGP or CHH and 2. Adult men, both eugonadal and having CHH. Materials and methods: Retrospective cohort studies of 60 boys with CDGP or CHH, as well as 44 adult men who were either eugonadal or had CHH, in whom INSL3, INB, testosterone and gonadotrophins were measured. Cohort 1: Boys with delayed puberty aged 13-17 years (51 with CDGP and 9 with CHH) who had GnRHa stimulation (subcutaneous triptorelin 100mcg), previously reported with respect to INB. Cohort 2: Adult cohort of 44 men (22 eugonadal men and 22 men with CHH), previously reported with respect to gonadotrophin responses to kisspeptin-54. Results: Median INSL3 was higher in boys with CDGP than CHH (0.35 vs 0.15 ng/ml; p=0.0002). Similarly, in adult men, median INSL3 was higher in eugonadal men than CHH (1.08 vs 0.05 ng/ml; p<0.0001). However, INSL3 more accurately differentiated CHH in adult men than in boys with delayed puberty (auROC with 95% CI in adult men: 100%, 100-100%; boys with delayed puberty: 86.7%, 77.7-95.7%). Median INB was higher in boys with CDGP than CHH (182 vs 59 pg/ml; p<0.0001). Likewise, in adult men, median INB was higher in eugonadal men than CHH (170 vs 36.5 pg/ml; p<0.0001). INB performed better than INSL3 in differentiating CHH in boys with delayed puberty (auROC 98.5%, 95.9-100%), than in adult men (auROC 93.9%, 87.2-100%). Conclusion: INSL3 better identifies CHH in adult men, whereas INB better identifies CHH in boys with delayed puberty

Adverse cardiovascular events and mortality in men during testosterone treatment : an individual patient and aggregate data meta-analysis

Funding National Institute for Health Research Health Technology Assessment Programme. Acknowledgments This work was supported by the National Institute for Health Research Health Technology Assessment (NIHR HTA) Programme (project no 17/68/01). The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR HTA Programme, or the Department of Health and Social Care, UK. The funders were not actively involved in the research process at any stage. The study design; collection, analysis, and interpretation of data; writing of the manuscript; and decision to submit for publication were performed independent of the funders. The Health Services Research Unit at the University of Aberdeen is funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates. The Section of Endocrinology and Investigative Medicine at Imperial College London is funded by grants from the Medical Research Council, Biotechnology and Biological Sciences Research Council, NIHR, an Integrative Mammalian Biology Capacity Building Award, an FP7-HEALTH-2009-241592 EuroCHIP grant, and is supported by the NIHR Biomedical Research Centre Funding Scheme. The following authors are also funded as follows: NIHR Research Professorship (WSD), NIHR post-doctoral fellowship (CNJ). SBhasin receives National Institutes of Health research grant funding. The authors are grateful to Prakash Abraham, Alison Avenell, Craig Ramsay, Graham Scotland, Neil Scott, and Finlay MacKenzie for their advice; and to the many individuals from academia and industry who helped in the conduct of this study.Peer reviewedPublisher PD

Symptomatic benefits of testosterone treatment in patient subgroups : a systematic review, individual participant data meta-analysis, and aggregate data meta-analysis

Acknowledgments This work was supported by the UK National Institute for Health and Care Research (NIHR)'s Health Technology Assessment Programme (project number 17/68/01). The views expressed herein are those of the authors and not necessarily those of the National Health Service, the NIHR Health Technology Assessment Programme, or the UK Department of Health and Social Care. The Health Services Research Unit at the University of Aberdeen is funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates. The Section of Endocrinology and Investigative Medicine at Imperial College London is funded by grants from the Medical Research Council, the Biotechnology and Biological Sciences Research Council, NIHR, an Integrative Mammalian Biology Capacity Building Award, and an FP7-HEALTH-2009-241592 EuroCHIP grant, and is supported by the NIHR Biomedical Research Centre Funding Scheme. WSD is funded by an NIHR Research Professorship. CNJ is funded by an NIHR Post-Doctoral Fellowship. ShB receives NIH research grant funding. The authors are grateful to the clinical and methodological experts and patient partners who contributed to the advisory group for this study.Peer reviewedPublisher PD

Symptomatic benefits of testosterone treatment in patient subgroups: a systematic review, individual participant data meta-analysis, and aggregate data meta-analysis

Background Testosterone replacement therapy is known to improve sexual function in men younger than 40 years with pathological hypogonadism. However, the extent to which testosterone alleviates sexual dysfunction in older men and men with obesity is unclear, despite the fact that testosterone is being increasingly prescribed to these patient populations. We aimed to evaluate whether subgroups of men with low testosterone derive any symptomatic benefit from testosterone treatment. Methods We did a systematic review and meta-analysis to evaluate characteristics associated with symptomatic benefit of testosterone treatment versus placebo in men aged 18 years and older with a baseline serum total testosterone concentration of less than 12 nmol/L. We searched major electronic databases (MEDLINE, Embase, Science Citation Index, and the Cochrane Central Register of Controlled Trials) and clinical trial registries for reports published in English between Jan 1, 1992, and Aug 27, 2018. Anonymised individual participant data were requested from the investigators of all identified trials. Primary (cardiovascular) outcomes from this analysis have been published previously. In this report, we present the secondary outcomes of sexual function, quality of life, and psychological outcomes at 12 months. We did a one-stage individual participant data meta-analysis with a random-effects linear regression model, and a two-stage meta-analysis integrating individual participant data with aggregated data from studies that did not provide individual participant data. This study is registered with PROSPERO, CRD42018111005. Findings 9871 citations were identified through database searches. After exclusion of duplicates and publications not meeting inclusion criteria, 225 full texts were assessed for inclusion, of which 109 publications reporting 35 primary studies (with a total 5601 participants) were included. Of these, 17 trials provided individual participant data (3431 participants; median age 67 years [IQR 60–72]; 3281 [97%] of 3380 aged ≥40 years) Compared with placebo, testosterone treatment increased 15-item International Index of Erectile Function (IIEF-15) total score (mean difference 5·52 [95% CI 3·95–7·10]; τ²=1·17; n=1412) and IIEF-15 erectile function subscore (2·14 [1·40–2·89]; τ²=0·64; n=1436), reaching the minimal clinically important difference for mild erectile dysfunction. These effects were not found to be dependent on participant age, obesity, presence of diabetes, or baseline serum total testosterone. However, absolute IIEF-15 scores reached during testosterone treatment were subject to thresholds in patient age and baseline serum total testosterone. Testosterone significantly improved Aging Males’ Symptoms score, and some 12-item or 36-item Short Form Survey quality of life subscores compared with placebo, but it did not significantly improve psychological symptoms (measured by Beck Depression Inventory). Interpretation In men aged 40 years or older with baseline serum testosterone of less than 12 nmol/L, short-to-mediumterm testosterone treatment could provide clinically meaningful treatment for mild erectile dysfunction, irrespective of patient age, obesity, or degree of low testosterone. However, due to more severe baseline symptoms, the absolute level of sexual function reached during testosterone treatment might be lower in older men and men with obesity

Male Oxidative Stress Infertility (MOSI): Proposed Terminology and Clinical Practice Guidelines for Management of Idiopathic Male Infertility

Despite advances in the field of male reproductive health, idiopathic male infertility, in which a man has altered semen characteristics without an identifiable cause and there is no female factor infertility, remains a challenging condition to diagnose and manage. Increasing evidence suggests that oxidative stress (OS) plays an independent role in the etiology of male infertility, with 30% to 80% of infertile men having elevated seminal reactive oxygen species levels. OS can negatively affect fertility via a number of pathways, including interference with capacitation and possible damage to sperm membrane and DNA, which may impair the sperm’s potential to fertilize an egg and develop into a healthy embryo. Adequate evaluation of male reproductive potential should therefore include an assessment of sperm OS. We propose the term Male Oxidative Stress Infertility, or MOSI, as a novel descriptor for infertile men with abnormal semen characteristics and OS, including many patients who were previously classified as having idiopathic male infertility. Oxidation-reduction potential (ORP) can be a useful clinical biomarker for the classification of MOSI, as it takes into account the levels of both oxidants and reductants (antioxidants). Current treatment protocols for OS, including the use of antioxidants, are not evidence-based and have the potential for complications and increased healthcare-related expenditures. Utilizing an easy, reproducible, and cost-effective test to measure ORP may provide a more targeted, reliable approach for administering antioxidant therapy while minimizing the risk of antioxidant overdose. With the increasing awareness and understanding of MOSI as a distinct male infertility diagnosis, future research endeavors can facilitate the development of evidence-based treatments that target its underlying cause