Vpliv testosterona na žilne in presnovne kazalce pri moških s sladkorno boleznijo tipa 2

Groti Antonić, Kristina (author), Pfeifer, Marija (mentor)

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.

• Language: Slovenian
• Keywords: testosteron, hipogonadizem, sladkorna bolezen, visceralna debelost, inzulinska rezistenca, metabolni sindrom, NAFLD, endotelijska funkcija
• Work type: Doctoral dissertation
• Organization: MF - Faculty of Medicine
• Year: 2018
• PID: 20.500.12556/RUL-105075
• Publication date in RUL: 25.10.2018

Secondary language

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

Abstract

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.

• Keywords: testosterone, hypogonadism, diabetes mellitus, visceral obesity, insulin resistance, metabolic syndrome, NAFLD, endothelial function