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Context Urinary bladder paraganglioma (UBPGL) is rare. Objective We aimed to characterize the presentation and outcomes of patients diagnosed with UBPGL. Methods We conducted a multicenter study of consecutive patients with pathologically confirmed UBPGL evaluated between 1971 and 2021. Outcomes included repeat bladder surgery, metastases, and disease-specific mortality. Results Patients (n=110 total; n=56 [51%] women) were diagnosed with UBPGL at a median age of 50 years (interquartile range [IQR], 36-61 years). Median tumor size was 2 cm (IQR, 1-4 cm). UBPGL was diagnosed prior to biopsy in only 37 (34%), and only 69 (63%) patients had evaluation for catecholamine excess. In addition to the initial bladder surgery, 26 (25%) required multiple therapies, including repeat surgery in 10 (9%). Synchronous metastases were present in 9 (8%) patients, and 24 (22%) other patients with UBPGL developed metachronous metastases at a median of 4 years (IQR, 2-10 years) after the initial diagnosis. Development of metachronous metastases was associated with younger age (hazard ratio [HR] 0.97; 95% CI, 0.94-0.99), UBPGL size (HR 1.69; 95% CI, 1.31-2.17), and a higher degree of catecholamine excess (HR 5.48; 95% CI, 1.40-21.39). Disease-specific mortality was higher in patients with synchronous metastases (HR 20.80; 95% CI, 1.30-332.91). Choice of initial surgery, genetic association, sex, or presence of muscular involvement on pathology were not associated with development of metastases or mortality. Conclusions Only a minority of patients were diagnosed before biopsy/surgery, reflecting need for better diagnostic strategies. All patients with UBPGL should have lifelong monitoring for development of recurrence and metastases.

BACKGROUND: Chronic pain and opioid treatment are associated with increased risk of male hypogonadism and subsequently decreased muscle function. A diagnosis of hypogonadism is based on the presence of low total testosterone and associated symptoms. The effect of testosterone replacement therapy on muscle function in men with chronic pain and low total testosterone remains to be investigated.OBJECTIVES: To investigate the effects of testosterone replacement therapy on muscle function and gait performance in men treated with opioids for chronic non-cancer pain.MATERIALS AND METHODS: A double-blind, placebo-controlled study. Forty-one men (>18 years) with opioid-treated chronic pain and serum total testosterone < 12 nmol/L were randomized to 24 weeks testosterone replacement therapy (testosterone undecanoate injection three times/6 months, n = 20) or placebo injections (n = 21). Muscle function was measured as leg press maximal voluntary contraction, leg extension power using the Nottingham power rig and handgrip strength using a handheld dynameter. Gait performance was measured at usual and maximal gait speed on a 10-m track. Body composition (lean body mass and fat mass) was determined by dual-energy X-ray absorptiometry. Mann-Whitney tests were performed on ∆-values (24-0 weeks) between testosterone replacement therapy and placebo.RESULTS: At baseline, median (interquartile range) age was 55 ± 13 years and BMI was 30.7 ± 5.2 kg/m2 . ∆-muscle function and ∆-gait performance were similar between testosterone replacement therapy and placebo. Median ∆-leg press maximal voluntary contraction was 174.2 ± 406.7 Newton, following testosterone replacement therapy, and 7.6 ± 419.1 Newton, after placebo, p = 0.091. ∆-lean body mass was significantly higher following testosterone replacement therapy compared to placebo, 3.6 ± 2.7 versus 0.1 ± 3.5 kg, respectively (p < 0.001).DISCUSSION: Testosterone replacement therapy, compared to placebo, did not improve muscle function or gait performance despite increased lean body mass. Changes in body composition did not infer any changes in muscle function.CONCLUSION: 24 weeks testosterone replacement therapy in opioid-treated men with pain-related male hypogonadism did not improve muscle function.

Background Hypogonadism is prevalent during opioid treatment, but the effect of testosterone replacement treatment (TRT) on body composition, pain perception, and adrenal function is unclear. Purpose To measure changes in body composition, pain perception, quality of life, and adrenal function after TRT or placebo in opioid-treated men with chronic non-malignant pain. Methods Double-blind, placebo-controlled study in 41 men (>18 years) with total testosterone n = 20) or placebo (placebo-injections, n = 21). Outcomes Body composition (lean body mass and fat mass assessed by DXA), clinical pain intensity (numerical rating scale), and experimental pain perception (quantitative sensory assessment), quality of life (SF36), and adrenocorticotrophic hormone (ACTH) test. Data were presented as median (quartiles). Mann–Whitney tests were performed on delta values (24–0 weeks) between TRT and placebo. Results The median age was 55 years (46; 59) and total testosterone before intervention was 6.8 (5.0; 9.3) nmol/L. TRT was associated with change of testosterone levels: 12.3 (7.0; 19.9) nmol/L (P P Conclusions Six months of TRT improved body composition in men with opioid-induced hypogonadism without significant changes in outcomes of pain perception, quality of life, or adrenal function.

Background: The imprinted gene Delta like non-canonical Notch ligand 1 (Dlk1) is considered an inhibitor of adipogenesis, but its in vivo impact on fat mass indeed remains elusive and controversial. Methods: Fat deposits were assessed by MRI and DXA scanning in two cohorts of non-diabetic men, whereas glucose disposal rate (GDR) was determined during euglycemic hyperinsulinemic clamp. Blood analyte measurements were used for correlation and mediation analysis to investigate how age, BMI, and fat percentage affect the relation between DLK1 and GDR. Confirmatory animal studies performed in normal (NC) and high fat diet (HFD) fed Dlk1+/+ and Dlk1−/− mice included DXA scanning, glucose tolerance tests (GTTs), blood measurements, and skeletal muscle glucose uptake studies by positron emission tomography (PET), histology, qRT-PCR, and in vitro cell studies. Findings: Overall, DLK1 is positively correlated with fat amounts, which is consistent with a negative linear relationship between DLK1 and GDR. This relationship is not mediated by age, BMI, or fat percentage. In support, DLK1 also correlates positively with HOMA-IR and ADIPO-IR in these humans, but has no linear relationship with the early diabetic inflammation marker MCP-1. In Dlk1−/− mice, the increase in fat percentage and adipocyte size induced by HFD is attenuated, and these animals are protected against insulin resistance. These Dlk1 effects seem independent of gluconeogenesis, but at least partly relies on increased in vivo glucose uptake in skeletal muscles by Dlk1 regulating the major glucose transporter Glut4 in vivo as well as in two independent cell lines. Interpretation: Thus, instead of an adipogenic inhibitor, Dlk1 should be regarded as a factor causally linked to obesity and insulin resistance, and may be used to predict development of type 2 diabetes. Fund: The Danish Diabetes Academy supported by the Novo Nordisk Foundation, The Danish National Research Council (#09-073648), The Lundbeck Foundation, University of Southern Denmark, and Dep. Of Clinical Biochemistry and Pharmacology/Odense University Hospital, the Swedish Research Council, the Swedish Diabetes Foundation, the Strategic Research Program in Diabetes at Karolinska Institute and an EFSD/Lilly grant. Keywords: Dlk1, Type 2 diabetes, Obesity, Insulin resistance, Glucose uptake

Background Long-term testosterone replacement therapy (TRT) increases muscle mass in elderly men with subnormal testosterone levels. However, the molecular mechanisms underlying this effect of TRT on protein balance in human skeletal muscle in vivo remain to be established. Methods Here, we examined skeletal muscle biopsies obtained before and 24-h after the last dose of treatment with either testosterone gel (n = 12) or placebo (n = 13) for 6 months in aging men with subnormal bioavailable testosterone levels. The placebo-controlled, testosterone-induced changes (β-coefficients) in mRNA levels, protein expression and phosphorylation were examined by quantitative real-time PCR and western blotting. Results Long-term TRT increased muscle mass by β = 1.6 kg (p = 0.01) but had no significant effect on mRNA levels of genes involved in myostatin/activin/SMAD or IGF1/FOXO3 signalling, muscle-specific E3-ubiquitin ligases, upstream transcription factors (MEF2C, PPARGC1A-4) or myogenic factors. However, TRT caused a sustained decrease in protein expression of SMAD2 (β = −36%, p = 0.004) and SMAD3 (β = −32%, p = 0.001), which was accompanied by reduced protein expression of the muscle-specific E3-ubiquitin ligases, MuRF1 (β = −26%, p = 0.004) and Atrogin-1/MAFbx (β = −20%, p = 0.04), but with no changes in FOXO3 signalling. Importantly, TRT did not affect muscle fibre type distribution between slow-oxidative (type 1), fast-oxidative (type 2a) and fast-glycolytic (type 2×) muscle fibres. Conclusions Our results indicate that long-term TRT of elderly men with subnormal testosterone levels increases muscle mass, at least in part, by decreasing protein breakdown through the ubiquitin proteasome pathway mediated by a sustained suppression of SMAD-signalling and muscle-specific E3-ubiquitin ligases.

BACKGROUND: Transgender men are assigned female sex at birth, but identify as men. The anabolic and androgenic sex hormone testosterone has been positively associated with aggression. Therefore, transgender men are warned of increasing aggression when initiating testosterone therapy.AIM: To explore the literature regarding the effects of testosterone therapy on aggression-related constructs in transgender men.METHODS: Following PRISMA-guidelines, PsycINFO, MEDLINE®, EMBASE, and PubMed® were searched in November 2019. Risk of bias was analyzed using the Newcastle-Ottawa-Scale, and result-synthesis was grouped by aggression-outcome.RESULTS: Seven prospective cohort studies investigating aggression-dimensions pre- and post-testosterone therapy, reporting on data from 664 transgender men, were eligible. The studies had moderate to high risk of bias due to non-randomization, lack of appropriate control groups, and reliance on self-report. The behavioral tendency to react aggressively increased in three studies out of four (at three months follow-up), whereas only one study out of five found angry emotions to increase (at seven months follow-up). In contrast, one out of three studies reported a decrease in hostility after initiation of testosterone therapy. The remaining studies found no change in aggressive behavior, anger or hostility during hormone therapy.DISCUSSION AND CONCLUSION: Four out of seven studies reported an increase in aggression-related constructs, while one study reported a decrease. In all studies reporting changes, the follow-up period was less than 12 months, indicating that gender-affirming testosterone therapy could have a short-term impact on aggression-related constructs. However, the available studies carried a risk of bias, which indicates a need for further research.

IntroductionThe 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 analysesProspective, 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 10th version diagnostic codes, prescriptions, socioeconomics and causes of death.Ethics and disseminationThe 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.Trial registration numberNCT04254354.

ObjectiveRecent studies have indicated that serum testosterone in aging men is associated with insulin sensitivity and expression of genes involved in oxidative phosphorylation (OxPhos), and that testosterone treatment increases lipid oxidation. Herein, we investigated the effect of testosterone therapy on regulators of mitochondrial biogenesis and markers of OxPhos and lipid metabolism in the skeletal muscle of aging men with subnormal bioavailable testosterone levels.MethodsSkeletal muscle biopsies were obtained before and after treatment with either testosterone gel (n=12) or placebo (n=13) for 6 months. Insulin sensitivity and substrate oxidation were assessed by euglycemic–hyperinsulinemic clamp and indirect calorimetry. Muscle mRNA levels and protein abundance and phosphorylation of enzymes involved in mitochondrial biogenesis, OxPhos, and lipid metabolism were examined by quantitative real-time PCR and western blotting.ResultsDespite an increase in lipid oxidation (PPPARGC1A,PRKAA2, andPRKAG3), OxPhos (NDUFS1,ETFA,SDHA,UQCRC1, andCOX5B), or lipid metabolism (ACADVL,CD36,CPT1B,HADH, andPDK4). Consistently, protein abundance of OxPhos subunits encoded by both nuclear (SDHAandUQCRC1) and mitochondrial DNA (ND6) and protein abundance and phosphorylation of AMP-activated protein kinase and p38 MAPK were unaffected by testosterone therapy.ConclusionThe beneficial effect of testosterone treatment on lipid oxidation is not explained by increased abundance or phosphorylation-dependent activity of enzymes known to regulate mitochondrial biogenesis or markers of OxPhos and lipid metabolism in the skeletal muscle of aging men with subnormal bioavailable testosterone levels.