The effect of lipid modifying drugs on male reproductive parameters

Bhadula, Cebisa (2019-04)

Thesis (MSc)--Stellenbosch University, 2019.

Thesis

ENGLISH ABSTRACT: The risk of cardiovascular disease (CVD) is prevalent and on the increase globally. Lipid-lowering drugs, have been found to reduce CVD. They act by either reducing LDL or increasing HDL. Thus reducing the serum cholesterol which plays a pivotal role in male reproduction as it is a precursor for steroid hormone biosynthesis and forms an integral part of the sperm membrane. During spermatogenesis these hormones are necessary for normal sperm development and activation of genes in Sertoli cells, which promote differentiation of spermatogonia. The widespread prophylactic use of statins, especially by men of reproductive age, gives rise to concerns regarding the effect thereof on the male reproductive system. Aim: To determine if lipid-modifying drugs (Simvastatin and Fenofibrate) have any effects on male reproductive parameters. Methods: Male Wistar rats (n=60) were randomly divided into four groups and treated for 6 weeks as follows: Control, Simvastatin (0.5 mg/kg), Fenofibrate (100mg/kg) and Simvastatin + Fenofibrate (S+F). Sperm morphology was assessed using Computer-Aided Sperm Morphology Analysis (CASMA). The plasma concentration of Total Cholesterol and Triglycerides (TG) were analyzed by the veterinary section of PathCare, a private pathology company. Testosterone and Estradiol concentrations were measured by ELISA kits. Testicular and epididymal histomorphometrics were measured by staining the testis with H&E and quantified using Zeiss imaging software. Testicular oxidative status was assessed by measuring the activity of Catalase (CAT), Superoxide Dismutase (SOD) as well as lipid peroxidation using a microplate reader. Data was analyzed by GraphPad Prism® V5.00. Results were expressed as Mean ± SEM using One-way ANOVA. p≤0.05 determine statistical significance. Results: The body weight of animals was not significantly different between the groups (p=0.0753). However, the Simvastatin treated group presented with general increased body weight and significantly higher peritoneal fat compared to the Fenofibrate and S+F groups (p≤0.05). The Fenofibrate treated group had significantly higher fasted blood glucose levels compared to the Simvastatin group (p≤0.05). The total cholesterol and TG levels were generally reduced in treated animals compared to control animals. There were alterations observed in testosterone levels between the groups (p=0.0077). The S+F group receiving combination treatment had significantly lower testosterone levels compared to the Simvastatin (p<0.05) and Fenofibrate (p<0.05) groups, but did not differ from the control. There were no differences observed in sperm vitality when comparing the groups. The percentage of morphological normal spermatozoa was significantly lower in the Fenofibrate as well as S+F groups compared to the control group (p<0.05), while no differences were observed when comparing the Simvastatin group to the control group. When assessing testicular histomorphometrices, there were no significant differences found in seminiferous tubules’ area (p=0.0987), lumen diameter of the seminiferous tubules (p=0.914) and epithelial height (p=0.3401). When assessing the epididymal tubules’ parameters, luminal diameter did not show any significant differences (p=0.0620) and the mean heights of the epithelium also did not differ significantly (p=0.5101) between the treatment groups. Conclusion: Short-term exposure to cholesterol-lowering drugs can alter male reproductive parameters, however, more studies using longer treatment regimens are needed. In the interim, it is advised that physicians treating men with infertility should take cognisance of this fact.

AFRIKAANSE OPSOMMING: Die risiko vir kardiovaskulêre siekte (KVS) is algemeen en wêreldwyd aan die toeneem. Lipiedverlagende middels is voorheen bewys om die voorkoms van KVS te verminder. Hierdie middels tree op deur óf LDL te verminder of HDL te verhoog en gevolglik word serum cholesterol verlaag. Laasgenoemde speel ook ʼn sentrale rol in manlike reproduksie as ʼn voorloper vir steroïd hormoon biosintese en maak ʼn integrale deel uit van die sperm selmembraan. Gedurende spermatogenese word hierdie hormone ook benodig vir normale sperm ontwikkeling en aktivering van gene in Sertoli selle wat die differensiasie van spermatogonia bevorder. Die wydverspreide profilaktiese gebruik van statiene, veral deur mans in hul reproduktiewe ouderdom is kommerwekkend, veral oor die moontlike uitwerking daarvan op die manlike reproduktiewe stelsel. Doelstelling: Om te bepaal of lipiedverlagende middels (Simvastatien and Fenofibraat) enige uitwerking op manlike reproduktiewe parameters het. Metodes: Manlike Wistar rotte (n = 60) is ewekansig verdeel in vier groepe en daarna vir ses weke behandel soos volg: kontrole, Simvastatien (0.5 mg/kg), Fenofibraat (100mg/kg) en Simvastatien + Fenofibraat (S + F). Rekenaargesteunde spermmorfologie-analise (CASMA) is gebruik om sperm morfologie te evalueer. Die totale cholesterol en trigliseried (TG) konsenstrasies van die rot plasma was ontleed deur die veterinêre afdeling van PathCare, 'n privaat patologie maatskappy. Testosteroon en estradiol konsentrasies is met behulp van ELISA kits gemeet. Testikulêre en epididimale histomorfometrie is gemeet deur die testis met H&E te kleur. Daarna is dit gekwantifiseer met behulp van Zeiss beeldingsagteware. Testikulêre oksidatiewe status was geassesseer deur die ensiem aktiwiteit van Katalase (CAT), Superoksied Dismutase (SOD) sowel as lipied peroksidasie te meet met behulp van 'n mikroplaat leser. Al die data was ontleed met behulp van GraphPad prisma® V5.00. Resultate is as gemiddelde ± SEM uitgedruk. Vir statistiese vergelykings is eenrigting ANOVA gebruik en 'n p-waarde <0.05 is gebruik om statistiese betekenisvolheid aan te dui. Resultate: Daar was nie ‘n beduidende verskil tussen die groepe diere se liggaamsgewigte nie (p = 0. 0753), maar die simvastatien behandelde groep het ‘n verhoogde algemene liggaamsgewig asook ‘n aansienlik hoër totale peritoneale vet gehad in vergelyking met die Fenofibraat en S + F groepe (p<0.05). Die Fenofibraat behandelde groep het ‘n hoër vastende bloedglukose vlak gehad in vergelyking met die simvastatien groep (p<0.05). Die totale cholesterol en TG vlakke was oor die algemeen verminder in die behandelde diere in vergelyking met kontrole diere. ‘n Beduidende verskil is gevind in testosteroon vlakke tussen al die groepe (p=0.0077). Die S + F groep wat die kombinasie behandeling ontvang het, het ʼn aansienlik laer testosteroon vlak gehad invergeleke met die simvastatien (p<0.05) en Fenofibrate (p<0.05) groepe, maar het nie verskil van die kontrole groep nie. Geen verskille in sperm vitaliteite is tussen die groepe waargeneem nie. Die persentasie morfologies normale sperm selle was aansienlik hoër in die kontrole groep in vergelyking met die Fenofibraat en S + F behandelde groepe (p<0.05), maar nie in vergelyking met die Simvastatien groep nie. Met die evaluering van die testikulêre histomorfometrie is daar geen beduidende verskille gevind in die seminifereuse tubule area, luminale deursnit van die seminifereuse tubule en die epiteel hoogte nie. Daar was geen beduidende verskil tussen groepe met betrekking tot die luminale deursnee analise van epididimale tubule parameters nie. Met betrekking tot die gemiddelde lengtes van die epiteel, was daar ook nie ‘n beduidende verskil tussen die behandelde groepe nie. Gevolgtrekking: Korttermyn blootstelling aan Cholesterol-verlagende middels kan manlike reproduktiewe parameters verander, maar studies met langer behandelingsregimens is nodig om hierdie stelling te ondersteun. In tussentyd word dit aanbeveel dat dokters wat onvrugbare mans behandeling van hierdie feit kennis neem.

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