Osteoporoza pri moških – pomen hipogonadizma

Osteoporoza je sistemska bolezen kosti z znižano mineralno kostno gostoto in spremenjeno mikroarhitekturo kostnine, kar vodi do zlomov ob majhni sili. Čeprav pogosteje prizadene ženske, imajo moški zaradi osteoporoze več zapletov in višjo umrljivost po zlomih. Pri moških diagnozo osteoporoze večkrat postavimo šele po zlomu. Pogosteje je sekundarna, med najpomembnejšimi sekundarnimi vzroki je hipogonadizem, ki je prav tako podcenjeno, premalo prepoznano ter preredko diagnosticirano in zdravljeno stanje. Zdravljenje osteoporoze pri moških je kompleksno, vključuje nefarmakološke in farmakološke ukrepe. Cilj zdravljenja je preprečevanje zlomov. Nadomestno zdravljenje s testosteronom poleg pozitivnih učinkov na skelet pri hipogonadnih moških izboljša tudi kakovost življenja. Neposrednih dokazov, da bi zdravljenje s testosteronom zmanjšalo tveganje za osteoporozne zlome, zaenkrat ni. Pred uvedbo testosterona skupaj z bolnikom skrbno pretehtamo koristi in tveganja. Bisfosfonati, denosumab in teriparatid izboljšajo mineralno kostno gostoto in zmanjšajo tveganje za zlome vretenc. Učinkoviti so tudi pri moških z osteoporozo in s hipogonadizmom

Synthesis of 2′-O-methyl-RNAs incorporating a 3-deazaguanine, and UV melting and computational studies on its hybridization properties

2′-O-Methyl-RNAs incorporating 3-deazaguanine (c(3)G) were synthesized by use of N,N-diphenylcarbamoyl and N,N-dimethylaminomethylene as its base protecting groups to suppress sheared-type 5′-GA-3′/5′-GA-3′ tandem mismatched base pairing which requires the N(3) atom. These modified RNAs hybridized more weakly with the complementary and single mismatch-containing RNAs than the unmodified RNAs. The T(m) experiments were performed to clarify the effects of replacement of the fifth G with c(3)G on stabilization of 2′-O-methyl-(5′-CGGCGAGGAG-3′)/5′-CUCCGAGCCG-3′ and 2′-O-methyl-(5′-CGGGGACGAG-3′)/5′-CUCGGACCCG-3′duplexes, which form sheared-type and face-to-face type 5′-GA-3′/5′-GA-3′ tandem mismatched base pairs, respectively. Consequently, this replacement led to more pronounced destabilization of the former duplex that needs the N(3) atom for the sheared-type base pair than the latter that does not need it for the face-to-face type base pair. A similar tendency was observed for 2′-O-methyl-RNA/DNA duplexes. These results suggest that the N(3) atom of G plays an important role in stabilization of the canonical G/C base pair as well as the base discrimination and its loss suppressed formation of the undesired sheared-type mismatched base pair. Computational studies based on ab initio calculations suggest that the weaker hydrogen bonding ability and larger dipole moment of c(3)G can be the origin of the lower T(m)

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

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]; τ 2=1·17; n=1412) and IIEF-15 erectile function subscore (2·14 [1·40-2·89]; τ 2=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-medium-term 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. FUNDING: National Institute for Health and Care Research Health Technology Assessment Programme

The impact of testosterone replacement therapy on vascular function and components of metabolic syndrome in obese hypogonadal men with type 2 diabetes

IZHODIŠČE: Študije so pokazale, da ima približno 50 % starejših debelih moških, ki se zdravijo za sladkorno boleznijo tipa 2 (SB2), znižane ravni testosterona. Hipogonadizem pri moških vpliva na slabšo urejenost sladkorne bolezni, prezgodnji nastanek srčno-žilnih bolezni, lahko povzroča osteoporozo, erektilno disfunkcijo, je vzrok za upad mišične mase in kopičenje visceralne maščobe ter nastanek debelosti. In obratno, visceralna debelost, ki je pomembna komponenta metabolnega sindroma (MS), lahko vodi do nastanka hipogonadizma preko zaviranja tvorbe testosterona. Klinični pomen funkcionalnega (pozno nastalega) hipogonadizma še naprej priteguje veliko pozornosti in sproža razprave. Rezultati študij o učinkih nadomestnega zdravljenja s testosteronom (NZT) so nasprotujoči, pojavili pa so se tudi pomisleki glede morebitnega povečanja tveganja za srčno-žilne dogodke. NAMEN DELA: Namen našega dela je bil oceniti prevalenco hipogonadizma pri debelih moških bolnikih s SB2 in ugotoviti učinke NZT na urejenost komponent MS, žilno funkcijo in morfologijo, jetrno zamaščenost, mineralno kostno gostoto ter subjektivno počutje bolnikov. S svojim delom smo želeli prispevati k izboljšanju razumevanja medsebojne povezanosti SB2 in hipogonadizma. HIPOTEZE: (1) Prevalenca hipogonadizma pri debelih moških s SB2 pri nas je podobna kot v primerljivih tujih državah(2) NZT pri debelih hipogonadnih bolnikih s SB2 pozitivno vpliva na urejenost glikemije, inzulinsko rezistenco in ostale komponente MS, jetrno zamaščenost, mineralno kostno gostoto ter na subjektivno počutje bolnikov. ZASNOVA RAZISKAVE: Raziskava je potekala v dveh delih. V prvem delu smo izvedli presečno študijo, da bi ugotovili prevalenco hipogonadizma med debelimi bolniki s SB2, ki se vodijo v diabetični ambulanti SB Celje. Nato smo v randomizirano, dvojno slepo, s placebom kontrolirano študijo vključili 55 bolnikov s SB2 in potrjenim hipogonadizmom. Bolniki v skupini P so prvo leto prejemali placebo, bolniki v skupini T so prejemali testosteron. Drugo leto raziskave so bolniki v obeh skupinah prejemali testosteron. V prvem letu smo primerjali učinke testosterona in placeba na urejenost glikemije in komponente MS, endotelijsko funkcijo in morfologijo žil. V drugem letu smo nadaljevali z zdravljenjem s testosteronom in primerjali dolgoročnejše učinke NZT še na stanje jetrne zamaščenosti, mineralno kostno gostoto in subjektivno počutje. METODE: Na začetku študije smo pri vseh preiskovancih ocenjevali endotelijsko funkcijo z ultrazvočnimi metodami (FMD – od endotelija odvisna, in NMD – od endotelija neodvisna vazodilatacija brahialne arterije), žilno morfologijo (IMT – debelino intime-medije) in stopnjo jetrne zamaščenosti (UZ jeter) ter opravili meritev kostne gostote z dvoenergijsko rentgensko absorpciometrijo (DXA). Po enem letu študije smo opravili kontrolne meritve FMD, NMD in IMT in primerjali učinke placeba in NZT. Na koncu raziskave, po dveh letih, smo poleg omenjenih žilnih preiskav opravili še kontrolno ultrazvočno preiskavo jeter in DXA. Bolniki so ob začetku in ob koncu raziskave izpolnili AMS vprašalnik o simptomih hipogonadizma. Statistično analizo podatkov smo opravili s paketom SPSS 17.0. REZULTATI: Prevalenco hipogonadizma med debelimi bolniki s SB2, ki se kontrolirajo v diabetični ambulanti SB Celje, smo ocenili na 52,7 %. Po enem letu NZT se je v skupini T vrednost HOMA-IR znižala za 4,64 ± 4,25 (p < 0,001), HbA1c znižala za 0,94 ± 0,88 % točke (p < 0,001), FMD pa zvišala za 2,40 ± 4,16 % točke (p = 0,005). Po dveh letih NZT se je izboljšala ocena stanja jetrne zamaščenosti ter zvišala MKG lumbalne hrbtenice za 0,075 ± 0,114 g/cm2 (p = 0,019). Tudi v skupini P je po enem letu NZT (po drugem letu študije) prišlo do znižanja HOMA-IR za 3,87 ± 2,93 (p < 0,001), znižanja HbA1c za 0,97 ± 0,54 % točke (p < 0,001), zvišanja FMD za 3,87 ± 5,67 % točke (p = 0,002) in izboljšanja ocene jetrne zamaščenosti. Izboljšala se je tudi subjektivna ocena seksualnih simptomov (AMS vprašalnik) v obeh skupinah. ZAKLJUČEK: V naši raziskavi smo ugotovili, da je prevalenca hipogonadizma med debelimi bolniki s SB2 primerljiva s podatki v tuji literaturi. Pokazali smo, da (1) NZT pomembno izboljša inzulinsko občutljivost in urejenost glikemije, (2) izboljša endotelijsko funkcijo brahialne arterije, (3) izboljša stopnjo jetrne steatoze, (4) izboljša MKG ter (5) simptome hipogonadizma pri debelih hipogonadnih moških s SB2.BACKGROUND: Studies have shown that approximately 50 % of older obese males, who are being treated for diabetes mellitus 2 (DM2), also exhibit low testosterone levels. Hypogonadism negatively affects glycemic control, exacerbates early cardio-vascular disease, causes osteoporosis, erectile disfunction, reduces lean body mass, accelerates the accumulation of visceral fat and leads to obesity. Conversely, visceral obesity, an important component of the metabolic syndrome (MS), can lead to hypogonadism by stemming testosterone biosynthesis. Clinical aspects of late-onset hypogonadism continue to attract attention and are the subject of many a debate. Study results on effects of testosterone replacement therapy (TRT) are contradicting. Furthermore, concerns have been raised regarding the potentially increased risk of cardio-vascular events. AIM: We aimed to ascertain the prevalence of hypogonadism in obese male patients with DM2, and to investigate the effects of TRT on MS components, vascular function and morphology, grade of non-alcoholic fatty liver disease (NAFLD), bone mineral density (BMD) and health-related quality of life. Another goal of our research was to improve the understanding of the intertwined relation of DM2 and hypogonadism. HYPOTHESES: (1) Prevalence of hypogonadism in obese males with DM2 is comparable with prevalence figures abroad(2) TRT exerts positive effects on glycemic control, insulin resistance and other MS components, NAFLD, BMD and sexual symptoms in obese hypogonadal DM2 patients. STUDY DESIGN: Our study consisted of two parts. Prevalence of hypogonadism among obese DM2 patients being treated at the diabetic outpatient clinic at General Hospital Celje was determined with a cross-sectional study in the first part. In the second part, 55 patients with DM2 and confirmed hypogonadism were enrolled into a randomized, double-blind, placebo-controlled clinical study. P group patients were receiving placebo throughout the first year of this study and T group patients were receiving testosterone. Both groups were receiving TRT throughout the second year of this study. Effects of TRT and placebo on glycemic control, MS components, endothelial function and blood vessel morphology were compared after first year. TRT continued through the second year and long-term effects of TRT on NAFLD, BMD and symptoms of hypogonadism were then observed. METHODS: Ultrasound assessment of endothelial function (FMD – flow-mediated dilatation and NMD – nitroglycerine-mediated dilatation of the brachial artery), blood vessel morphology (IMT – intima-media thickness) and grade of NAFLD along with BMD employing dual-energy X-ray absorptiometry (DXA) were performed at the beginning of this clinical trial. FMD, NMD and IMT assessments were then repeated after first year of the study and effects of TRT compared to placebo, followed by the full battery of tests at the conclusion of our study (after two years). Study participants were also asked to take AMS questionary on symptoms of hypogonadism. Statistical analysis was performed using SPSS 17.0 software package. RESULTS: Prevalence of hypogonadism among obese DM2 patients, monitored by the DM2 outpatient clinic at the General Hospital Celje, was found to be 52.7 %. HOMA-IR decreased by 4.64 ± 4.25 (p < 0.001), HbA1c decreased by 0.94 ± 0.88 % points (p < 0.001) and FMD increased by 2.40 ± 4.16 % points (p = 0.005) as the result of one year of TRT in study group T. NAFLD grade improved and lumbar spine BMD increased by 0.075 ± 0.114 g/cm2 (p = 0.019) after two years of TRT in this group. Study group P also exhibited decrease in HOMA-IR by 3.87 ± 2.93 (p < 0.001), decrease in HbA1c by 0.97 ± 0.54 % točke (p < 0.001), increase in FMD by 3.87 ± 5.67 % points (p = 0.002) and an improvement in NAFLD grade following the one year of TRT (during second year of this study). Self-assessed quality of life, specifically the three sexual symptoms of the AMS questionnaire, have also improved in both study groups. CONCLUSION: Our study has shown that prevalence of hypogonadism among obese DM2 patients is quite in line with figures found in foreign studies. We have proven that TRT (1) improves insulin sensitivity and glycemic control, (2) improves endothelial function in the brachial artery, (3) improves grade of NAFLD (4) improves BMD and (5) quells the symptoms of hypogonadism in obese hypogonadal older men with DM2

Men, testosterone and Covid‐19

Men have more severe Coronavirus disease 2019 (Covid‐19) outcomes and higher mortality rates than women, and it was suggested that testosterone levels might promote severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection and Covid‐19 severity. However, clinical studies have not supported this theory. Studies have consistently shown that serum testosterone concentrations during acute Covid‐19 in men are inversely proportional to the inflammatory cytokines and severity of illness. It is likely that lower testosterone concentrations in this setting are a result of acute Covid‐19 illness on the hypothalamic–pituitary–testicular axis. Clinical trials that attempted to lower testosterone concentrations further or block androgen signaling acutely during Covid‐19 in men did not result in improved Covid‐19 outcomes. Additionally, pre‐existing male hypogonadism, diagnosed before Covid‐19 pandemic, was found to be a risk factor for hospitalization from Covid‐19. In this review, we also discuss the preclinical and mechanistic studies that have evaluated the role of androgens in SARS‐CoV‐2 infection and illness. Finally, long‐term consequences of Covid‐19 on male reproductive health are reviewed. SARS‐CoV‐2 virus is known to infiltrate testis and induce orchitis in men, but it is unclear if Covid‐19 leads to an increase in incidence of male hypogonadism