The psychological impact of adult-onset craniopharyngioma: A qualitative study of the experience of patients and clinicians.

Purpose ndividuals who experience social and emotional difficulties struggle to maintain successful social relationships and incur an increased risk of developing mood disorders. These, in turn, have a significant impact on psychological and physical wellbeing. A small number of medical studies suggest that patients with adult-onset craniopharyngioma (AoC) report poorer quality of life, however, no in-depth psychological research has been carried out. The present study aimed to capture a rich understanding of whether patients with AoC experience a psychological impact from their diagnosis and whether psychological factors may contribute to a poorer quality of life. Method Both patients with AoC and clinicians with experience of working with patients with AoC were invited to take part in a semi-structured interview. Participants were recruited from three geographically disperse National Health Service (NHS) units across the United Kingdom (UK). Eight patients and 10 clinicians took part in the study. Interviews were recorded and transcribed verbatim and analysed using inductive thematic analysis. Results Two key themes, with multiple subthemes, were identified: 1) Patients experience psychological impacts of AoC; and 2) Patients also experience common physical symptoms. Conclusions Patients and clinicians recognised significant psychological impact as a result of AoC, and these impacts contributed to overall poorer quality of life. Crucially, both parties also felt that further research into psychological impact of AoC was both interesting and useful

Long-term health outcomes in young women with Polycystic Ovary Syndrome: a narrative review

Polycystic ovary syndrome (PCOS) has long been recognized as a common disorder in young women leading to reproductive and cutaneous sequelae. However, the associated health risks are now known to extend beyond these familiar manifestations to a range of longer-term comorbidities. Here we review the evidence for an association of PCOS with adverse long-term health outcomes, discussing the pathophysiological mechanisms involved in addition to opportunities for therapeutic intervention. Cross-sectional and longitudinal studies point to an increased risk of type 2 diabetes, hypertension and dyslipidaemia, with recent data confirming that these translate to an increased risk of cardiovascular events independently of obesity. Obstructive sleep apnoea, nonalcoholic fatty liver disease and endometrial cancer are also more prevalent, while mental health disorders, notably anxiety and depression, are common but under-appreciated associations. Uncertainties remain as to whether these risks are apparent in all patients with PCOS or are confined to particular subtypes, whether risks persist post-menopausally and how risk may be affected by ethnicity. Further work is also needed in establishing if systematic screening and targeted intervention can lead to improved outcomes. Until such data are available, clinicians managing women with PCOS should counsel patients on long-term health risks and invest in strategies that limit progression to metabolic and non-metabolic morbidities

White matter microstructure and cognitive function in young women with polycystic ovary syndrome

Context: Polycystic ovary syndrome (PCOS) is a disorder characterized by insulin resistance and hyperandrogenism, which leads to an increased risk of type 2 diabetes in later life. Androgens and insulin signaling affect brain function but little is known about brain structure and function in younger adults with PCOS. Objective: To establish whether young women with PCOS display altered white matter microstructure and cognitive function. Patients, interventions, and main outcome measures: Eighteen individuals with PCOS (age, 31 ± 6 y; body mass index [BMI] 30 ± 6 kg/m2) and 18 control subjects (age, 31 ± 7 y; BMI, 29 ± 6 kg/m2), matched for age, IQ, and BMI, underwent anthropometric and metabolic evaluation, diffusion tensor MRI, a technique especially sensitive to brain white matter structure, and cognitive assessment. Cognitive scores and white matter diffusion metrics were compared between groups. White matter microstructure was evaluated across the whole white matter skeleton using tract-based spatial statistics. Associations with metabolic indices were also evaluated. Results: PCOS was associated with a widespread reduction in axial diffusivity (diffusion along the main axis of white matter fibers) and increased tissue volume fraction (the proportion of volume filled by white or grey matter rather than cerebrospinal fluid) in the corpus callosum. Cognitive performance was reduced compared with controls (first principal component, t = 2.9, P = .007), reflecting subtle decrements across a broad range of cognitive tests, despite similar education and premorbid intelligence. In PCOS, there was a reversal of the relationship seen in controls between brain microstructure and both androgens and insulin resistance. Conclusions: White matter microstructure is altered, and cognitive performance is compromised, in young adults with PCOS. These alterations in brain structure and function are independent of age, education and BMI. If reversible, these changes represent a potential target for treatment

Women with Polycystic Ovary Syndrome have an increased risk of major cardiovascular events: a population study

Context The effects of Polycystic Ovary Syndrome (PCOS) on cardiovascular morbidity and mortality are unclear. Objective To establish the relative risk of myocardial infarction (MI), stroke, angina, revascularization and cardiovascular mortality for women with PCOS. Design Data were extracted from the Clinical Practice Research Datalink Aurum database. Patients with PCOS were matched to controls (1:1) by age, body mass index (BMI) category and primary care practice. The primary outcome was the time to major adverse cardiovascular event (MACE); a composite endpoint incorporating MI, stroke, angina, revascularization and cardiovascular mortality. Secondary outcomes were the individual MACE endpoints. Results Of 219,034 with a diagnosis of PCOS, 174,660 (79.7%) met the eligibility criteria and were matched. Crude rates of the composite endpoint, MI, stroke, angina, revascularization and cardiovascular mortality were respectively 82.7, 22.7, 27.4, 32.8, 10.5 and 6.97 per 100,000 patient-years for cases, and 64.3, 15.9, 25.7, 19.8, 7.13 and 7.75 per 100,000 patient-years for controls. In adjusted cox proportional hazard models (CPHM), the hazard ratios [HR] were 1.26 (95% confidence interval=1.13-1.41), 1.38 (1.11-1.72), 1.60 (1.32-1.94) and 1.50 (1.08-2.07) for the composite outcome, MI, angina and revascularization, respectively. In a time-dependent CPHM, weight gain (HR 1.01 [1.00-1.01]), prior type 2 diabetes (T2DM) (HR 2.40 [1.76-3.30]) and social deprivation (HR 1.53 [1.11-2.11]) increased risk of progression to the composite endpoint. Conclusions The risk of incident MI, angina and revascularization is increased in young women with PCOS. Weight and T2DM are potentially modifiable risk factors amenable to intervention

Salivary cortisol response to ACTH stimulation is a reliable alternative to serum cortisol in evaluating hypoadrenalism

Context The serum total cortisol response to the ACTH stimulation test is widely used to assess adrenocortical function but is affected by changes in cortisol-binding globulin (CBG) concentration. Salivary cortisol reflects free cortisol concentrations and may offer a reliable alternative. Objectives 1: To establish the salivary cortisol response to ACTH stimulation in healthy volunteers and patients with altered CBG concentrations. 2. To evaluate the performance of a lower reference limit (LRL) determined in healthy volunteers in patients with suspected hypoadrenalism (SH-patients). Design A 250 µg-ACTH stimulation test was undertaken in 139 healthy volunteers, 24 women taking an estradiol-containing oral contraceptive pill (OCP-females), 10 patients with low serum protein concentration (LP-patients) and 30 SH-patients. Salivary cortisol was measured by liquid chromatography-tandem mass spectrometry. Mean and LRL of the 30-minute salivary cortisol response (mean - 1.96 standard deviation) were derived from log-transformed concentrations. The LRL was applied as a diagnostic cut-off in SH-patients, with comparison to the serum response. Results Mean CBG concentrations [range] were 58 [42-81] mg/L, 64 [43-95] mg/L, 41 [28-60] mg/L and 116 [84-159] mg/L in males, females, LP-patients and OCP-females, respectively. The mean 30-minute salivary cortisol concentration was 19.3 [2.5th-97.5th percentile 10.3-36.2] nmol/l in healthy volunteers. Corresponding values were not different in OCP-females (19.7 [9.5-41.2] nmol/l; p = 0.59) or LP-patients (19.0 [7.7-46.9] nmol/l; p = 0.97). Overall diagnostic agreement between salivary and serum responses in SH-patients was 79%. Conclusions Salivary cortisol response to ACTH stimulation offers a reliable alternative to serum and may be especially useful in conditions of altered CBG concentration

Characterisation of adipocyte-derived extracellular vesicles released pre- and post-adipogenesis

Extracellular vesicles (EVs) are submicron vesicles released from many cell types, including adipocytes. EVs are implicated in the pathogenesis of obesity-driven cardiovascular disease, although the characteristics of adipocyte-derived EVs are not well described. We sought to define the characteristics of adipocyte-derived EVs before and after adipogenesis, hypothesising that adipogenesis would affect EV structure, molecular composition and function. Using 3T3-L1 cells, EVs were harvested at day 0 and day 15 of differentiation. EV and cell preparations were visualised by electron microscopy and EVs quantified by nanoparticle tracking analysis (NTA). EVs were then assessed for annexin V positivity using flow cytometry; lipid and phospholipid composition using 2D thin layer chromatography and gas chromatography; and vesicular protein content by an immuno-phenotyping assay. Pre-adipogenic cells are connected via a network of protrusions and EVs at both time points display classic EV morphology. EV concentration is elevated prior to adipogenesis, particularly in exosomes and small microvesicles. Parent cells contain higher proportions of phosphatidylserine (PS) and show higher annexin V binding. Both cells and EVs contain an increased proportion of arachidonic acid at day 0. PREF-1 was increased at day 0 whilst adiponectin was higher at day 15 indicating EV protein content reflects the stage of adipogenesis of the cell. Our data suggest that EV production is higher in cells before adipogenesis, particularly in vesicles <300 nm. Cells at this time point possess a greater proportion of PS (required for EV generation) whilst corresponding EVs are enriched in signalling fatty acids, such as arachidonic acid, and markers of adipogenesis, such as PREF-1 and PPARγ

Complement activation in polycystic ovary syndrome occurs in the post-prandial and fasted state, and is influenced by obesity and insulin sensitivity

Objective: Polycystic ovary syndrome (PCOS) is associated with metabolic risk. Complement proteins regulate inflammation and lipid clearance but their role in PCOS‐associated metabolic risk is unclear. We sought to establish whether the complement system is activated in PCOS in the fasting and postprandial state. Design: Case‐control study. Patients: Fasting complement levels were measured in 84 women with PCOS and 95 healthy controls. Complement activation post‐oral fat tolerance test (OFTT) was compared in 40 additional subjects (20 PCOS, 20 controls). Measurements: Activation pathway (C3, C4, C3a(desArg), factor B, factor H, properdin, Factor D) and terminal pathway (C5, C5a, terminal complement complex [TCC]) proteins were measured by commercial or in‐house assays. Results: Fasting C3, C3a(desArg) and TCC concentrations were increased in insulin‐resistant (adjusted differences: C3 0.13 g/L [95%CI 0‐0.25]; C3a(desArg) 319.2 ng/mL [19.5‐619]; TCC 0.66 μg/mL [0.04‐1.28]) but not in insulin‐sensitive women with PCOS. C3 and factor H levels increased with obesity. Post‐OFTT, C3 and C4 levels increased to a similar extent in PCOS subjects and controls, whist factor H levels increased more in women with PCOS compared to controls (adjusted differences (area under the curve): 12 167 μg min/mL [4942‐19 392]), particularly in the presence of concomitant obesity. Conclusions: Activation and terminal complement pathway components are elevated in patients with PCOS, especially in the presence of insulin resistance and obesity

Diabetic Retinopathy in Newly Diagnosed Subjects With Type 2 Diabetes Mellitus: Contribution of β-Cell Function

Purpose: The association of hyperglycemia and diabetic retinopathy (DR) in established type 2 diabetes mellitus (T2DM) subjects is well accepted. However, the association between β-cell responsiveness and insulin sensitivity leading to fasting and postprandial hyperglycemia with DR in newly diagnosed treatment-naïve T2DM subjects remain unreported. Methods: A total of 544 newly diagnosed treatment-naïve T2DM subjects were screened for DR (digital photography) and underwent a standardized meal tolerance test. Serial plasma glucose and insulin levels were measured, and fasting (M0) and postprandial β-cell responsiveness calculated Calculating Pancreatic Response Program along with homeostasis model assessment-β cell function (HOMA-B) and HOMA-Insulin Sensitivity. A subgroup of 201 subjects also underwent a frequently sampled IV glucose tolerance test and the acute insulin response to glucose, insulin sensitivity, and glucose effectiveness (SG) estimated (MINMOD model). Results: A total of 16.5% (90) subjects had DR at diagnosis. Subjects with DR had significantly reduced M0, HOMA-B and SG leading to higher fasting and postprandial (2 hour) glucose and significantly lower fasting and postprandial (2 hour) insulin. Factors independently associated with DR in multivariate logistic regression analysis were M0, HOMA-B, and SG with fasting and postprandial (2 hour) glucose and insulin. There was no statistical difference in glycated hemoglobin, systolic blood pressure, acute insulin response to glucose, and insulin sensitivity between those with or without DR. Principal Conclusions: In this cohort of newly diagnosed T2DM subjects, DR is associated with reduced β-cell responsiveness, resulting from β-cell failure rather than insulin resistance, leading to fasting and postprandial hyperglycemia and hypoinsulinemi

Evidence for adipocyte-derived extracellular vesicles in the human circulation

Adipocyte-derived extracellular vesicles (EVs) may serve as novel endocrine mediators of adipose tissue and impact upon vascular health. However, it is unclear whether adipocyte-derived EVs are present in the human circulation. Therefore, the purpose of this study was to seek evidence for the presence of adipocyte-derived EVs in circulating plasma. Size exclusion chromatography of platelet-free plasma identified fractions 5-10 as containing EVs by a peak in particle concentration, which corresponded with the presence of EV and adipocyte proteins. Pooling fractions 5-10 and subjecting to ultracentrifugation yielded a plasma EV sample, as verified by transmission electron microscopy (TEM) showing EV structures and Western blotting for EV (e.g. CD9 and Alix) and adipocyte markers. Magnetic beads and a solid phase assay were used to deplete the EV sample of the four major families of circulating EVs: platelet-, leukocyte-, endothelial- and erythrocyte-derived EVs. Post-depletion samples from both techniques contained EV structures as visualized by TEM, as well as CD9, Alix and classic adipocyte proteins. Post-depletion samples also contained a range of other adipocyte proteins from an adipokine array. Adipocyte proteins and adipokines are expressed in optimally processed plasma EV samples, suggesting that adipocyte-derived EVs are secreted into the human circulation

HIIT’ing or MISS’ing the optimal management of polycystic ovary syndrome: a systematic review and meta-analysis of high- versus moderate-intensity exercise prescription

Introduction: Polycystic Ovary syndrome (PCOS) is a metabolic disorder associated with increased cardiovascular disease risk. Exercise is an effective treatment strategy to manage symptoms and reduce long-term health risk. High-intensity interval training (HIIT) has been suggested as a more efficient exercise mode in PCOS; however, it is not clear whether HIIT is superior to moderate intensity steady state exercise (MISS). Methods: We synthesized available data through a systematic review and meta-analysis to compare the effectiveness of isolated HIIT and MISS exercise interventions. Our primary outcome measures were cardiorespiratory fitness and insulin resistance, measured using V˙O2max and HOMA-IR respectively. Results: A total of 16 studies were included. Moderate-quality evidence from 16 studies identified significant improvements in V˙O2max following MISS (Δ = 1.081 ml/kg/min, p < 0.001, n = 194), but not HIIT (Δ = 0.641 ml/kg/min, p = 0.128, n = 28). Neither HIIT nor MISS improved HOMA-IR [(Δ = −0.257, p = 0.374, n = 60) and (Δ = −0.341, p = 0.078, n = 159), respectively]. Discussion: A significant improvement in V˙O2max was evident following MISS, but not HIIT exercise in women with PCOS. This contrasts with previous literature in healthy and clinical cohorts that report superior benefits of HIIT. Therefore, based on available moderate-quality evidence, HIIT exercise does not provide superior outcomes in V˙O2max compared with MISS, although larger high-quality interventions are needed to fully address this. Additional dietary/pharmacological interventions may be required in conjunction with exercise to improve insulin sensitivity