Masculinising testosterone treatment and effects on preclinical cardiovascular disease, muscle strength and power, aggression, physical fitness and respiratory function in transgender men : protocol for a 10-year, prospective, observational cohort study in Denmark at the Body Identity Clinic (BIC)

Introduction The number of individuals with gender dysphoria seeking gender-affirming treatment is increasing. The short-term and long-term effects of masculinising treatment with testosterone are debated as serum testosterone increases up to 20-fold compared with cisgender women. We will investigate short-term and long-term effects of masculinising testosterone treatment on preclinical and clinical coronary disease, muscle strength and power, oxygen consumption (VO2) max, cardiac and respiratory function and quality of life including aggression in transgender men. Methods and analyses Prospective, single-centre, observational cohort study at the Body Identity Clinic (BIC), Odense University Hospital, Denmark. Investigations are performed at inclusion and following 1, 3, 5 and 10 years of testosterone therapy. Non-calcified coronary plaque volume and calcium score are estimated by coronary CT angiography. CT is only performed at inclusion and following 1 and 10 years. Upper body muscle strength and power are measured by a 'low row' weight stack resisted exercise machine. Evaluation of aggression and quality of life is assessed by questionnaires, VO2 max is estimated by maximal testing on bike ergometer, and cardiac and respiratory functions are measured by echocardiography and spirometry, respectively. Markers of cardiovascular risk and inflammation and also cortisol and cortisone are assessed in blood, diurnal urine and/or hair samples. Our cohort (BIC), including dropouts, will be an embedded subcohort in a future national registry study in all individuals with gender dysphoria and controls. Data are available on International Statistical Classification of Diseases and Related Health Problems 10(th) version diagnostic codes, prescriptions, socioeconomics and causes of death. Ethics and dissemination The Regional Committee on Health Research Ethics for Southern Denmark (S-20190108) and the Danish Data Protection Agency (19/27572) approved the study. Signed informed consent will be obtained from all participants. All findings will be published in peer-reviewed journals or at scientific conferences

Microvesicles Correlated with Components of Metabolic Syndrome in Men with Type 2 Diabetes Mellitus and Lowered Testosterone Levels But Were Unaltered by Testosterone Therapy

Aims. To investigate how circulating microvesicle phenotypes correlate with insulin sensitivity, body composition, plasma lipids, and hepatic fat accumulation. We hypothesized that changes elicited by testosterone replacement therapy are reflected in levels of microvesicles. Methods. Thirty-nine type 2 diabetic males with lowered testosterone levels were assigned to either testosterone replacement therapy or placebo and evaluated at baseline and after 24 weeks. Microvesicles were analysed by flow cytometry and defined as lactadherin-binding particles within the 0.1–1.0 μm gate. Microvesicles of platelet, monocyte, and endothelial cell origin were identified by cell-specific markers and their expression of CD36 was investigated. Results. Triglycerides correlated positively with all investigated microvesicle phenotypes in this study (p<0.05), and indicators of hepatic fat accumulation, alanine aminotransferase, and gamma glutamyltransferase correlated with platelet and endothelial microvesicles and CD36-expressing microvesicles from platelets and monocytes (p<0.05). BMI, waist circumference, and fat percentage correlated with CD36-expressing monocyte microvesicles (p<0.05), while insulin sensitivity did not correlate with any microvesicle phenotypes. Microvesicle levels were unaffected by testosterone therapy. Conclusions. Metabolic syndrome components and hepatic fat accumulation correlated with microvesicle phenotypes, supporting the involvement of especially CD36 on monocytes in metabolic syndrome pathogenesis. Although testosterone therapy improved body composition measures, microvesicle phenotype levels were unaffected. This trial was registered at ClinicalTrials.gov (NCT01560546)

Intraoperative low field MRI in transsphenoidal pituitary surgery

Background: Intraoperative low field MRI (iMRI, 0.15 T) during transsphenoidal surgery on pituitary adenomas (PAs) may significantly improve tumor removal. However, extensive surgery can lead to pituitary hormone deficiency. Furthermore, introduction of iMRI will prolong duration of surgery, which may elevate risk of postoperative infections. Methods: Overall, 180 transsphenoidal surgeries for PAs from 2007 to 2015 were included. IMRI was available from 2011 to 2015, during this period 67/78 (86%) surgeries were with iMRI (iMRI, n = 67). A total of 113 surgeries were performed without iMRI (controls). All surgical procedures were performed by microscopic technique. Tumor size, hormonal status and vision were assessed before surgery and 3–5 months postoperatively. Results: Gross total resection (GTR), mean tumor remnant volume and Δ-volumes were comparable between iMRI and controls: 15% (10/66) vs 23% (26/109) (P = 0.17), 2.97 cm3 (0.9–5) vs 2.1 cm3 (1.6–2.6) (P = 0.3) and 4.5 cm3 (3.6–5.5) vs 5.1 cm3 (4.2–6) (P = 0.4), respectively. Duration of surgery was significantly longer during iMRI vs controls: 126 min (117–135) vs 98 min (92–103) (P 0.1). Conclusion: Tumor remnant after pituitary surgery was not significantly reduced using intraoperative low field MRI. Duration of surgery was increased in iMRI, but was not associated with increased infection rate. Pituitary hormonal function and vision were comparable between iMRI and controls

Normo- and hyperandrogenic women with polycystic ovary syndrome exhibit an adverse metabolic profile through life

Objective: To compare the metabolic profiles of normo- and hyperandrogenic women with polycystic ovary syndrome (PCOS) with those of control women at different ages during reproductive life. Design: Case-control study. Setting: Not applicable. Patient(s): In all, 1,550 women with normoandrogenic (n = 686) or hyperandrogenic (n = 842) PCOS and 447 control women were divided into three age groups: 39 years). Interventions(s): None. Main Outcome Measure(s): Body mass index (BMI), waist circumference, blood pressure, glucose, insulin, cholesterol, lipoproteins, triglycerides and high-sensitivity C-reactive protein. Result(s): Both normo- and hyperandrogenic women with PCOS were more obese, especially abdominally. They had increased serum levels of insulin (fasting and in oral glucose tolerance tests), triglycerides, low-density lipoprotein, and total cholesterol, higher blood pressure, and lower high-density lipoprotein levels independently from BMI compared with the control population as early as from young adulthood until menopause. The prevalence of metabolic syndrome was two-to fivefold higher in women with PCOS compared with control women, depending on age and phenotype, and the highest prevalence was observed in hyperandrogenic women with PCOS at late reproductive age. Conclusion(s): When evaluating metabolic risks in women with PCOS, androgenic status, especially abdominal obesity and age, should be taken into account, which would allow tailored management of the syndrome from early adulthood on. (C) 2016 by American Society for Reproductive Medicine.Peer reviewe

Higher blood pressure in normal weight women with PCOS compared to controls

Objective: Obesity is considered to be the strongest predictive factor for cardio-metabolic risk in women with polycystic ovary syndrome (PCOS). The aim of the study was to compare blood pressure (BP) in normal weight women with PCOS and controls matched for age and BMI. Methods: From a Nordic cross-sectional base of 2615 individuals of Nordic ethnicity, we studied a sub cohort of 793 normal weight women with BMI = 140/90 mmHg was 11.1% (57/ 512) in women with PCOS vs 1.8% (5/281) in controls, P = 35 years the prevalence of BP >= 140/90 mmHg was comparable in women with PCOS and controls (12.7% vs 9.8%, P = 0.6). Using multiple regression analyses, the strongest association with BP was found for age, waist circumference, and total cholesterol in women with PCOS. Conclusions: Normal weight women with PCOS have higher BP than controls. BP and metabolic screening are relevant also in young normal weight women with PCOS.Peer reviewe

Corticotroph Aggressive Pituitary Tumors and Carcinomas Frequently Harbor ATRX Mutations

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

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

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

Wellbeing and resilience:Mechanisms of transmission of health and risk in parents with complex mental health problems and their offspring—The WARM Study

The WARM study is a longitudinal cohort study following infants of mothers with schizophrenia, bipolar disorder, depression and control from pregnancy to infant 1 year of age. Background: Children of parents diagnosed with complex mental health problems including schizophrenia, bipolar disorder and depression, are at increased risk of developing mental health problems compared to the general population. Little is known regarding the early developmental trajectories of infants who are at ultra-high risk and in particular the balance of risk and protective factors expressed in the quality of early caregiver-interaction. Methods/Design: We are establishing a cohort of pregnant women with a lifetime diagnosis of schizophrenia, bipolar disorder, major depressive disorder and a non-psychiatric control group. Factors in the parents, the infant and the social environment will be evaluated at 1, 4, 16 and 52 weeks in terms of evolution of very early indicators of developmental risk and resilience focusing on three possible environmental transmission mechanisms: stress, maternal caregiver representation, and caregiver-infant interaction. Discussion: The study will provide data on very early risk developmental status and associated psychosocial risk factors, which will be important for developing targeted preventive interventions for infants of parents with severe mental disorder