{"paper_id":"b5a4c9ed-2926-4149-9b6a-4e2422b9c344","body_text":"According to the WHO, infertility is the inability\nto conceive after one year of unprotected intercourse.\nIt is one of the most common problems in the world,\nexperienced by about 15% of couples ( 1 ). Infertility\nand its associated individual and social problems are\nan important issue for couples, because the cause of\nmale infertility is pathologically that is detectable only\nin 40% of cases ( 2 ). Therefore, infertility treatment is more difficult in men than in women, especially in\ndeveloping countries where treatment is associated with\nhigh cost ( 3 ). The major causes of male infertility are\ncongenital or acquired anomaly of the genitourinary\nsystem, malignancies, urogenital infections, increased\nscrotal temperature (such as varicocele), endocrine\ndisorders, genetic abnormalities, and immunological\nproblems. However, infertility is idiopathic in 30-40%\nof infertile men that may have a variety of causes,\nincluding environmental pollution, Oxygen free radicals,\nand genetic and epigenetic abnormalities ( 4 ). Male\ninfertility may have other factors, such as seminal tract\nobstruction, sperm problems (low count, low motility,\ndysmorphology). A male factor is involved in about\nhalf of all infertility cases. The presence of the male\nfactor is often based on abnormal sperm parameters\n(azoospermia to oligozoospermia) ( 2 ). Impaired sperm\nproduction, function and damage to the spermatogenesis\nprocess are among the most common causes of male\ninfertility. Trauma or anatomical defects in the genital\nsystem and the use of certain drugs to treat diseases can\nlead to impaired sperm production and consequently\nmale infertility ( 5 ).\nThe increased oxidative stress and reactive oxygen\nspecies have recently been identified by many studies\nto be among the physiological causes of male infertility,\nand antioxidants have been shown to play a major\nrole in its prevention. All the effective factors change\nthe motility, morphology and concentration of sperm\nin a way that can be detected by experiment ( 6 ). A\nvariety of chemical drugs such as clomiphene citrate,\ntamoxifen, etc. are used for the treatment of infertility\nwith male factor that they may have many side effects.\nTherefore, infertile men prefer to use supplements,\nsuch as CoQ10 instead. Coenzyme Q10 is one of the\nimportant components in oxidative phosphorylation in\nmitochondria and adenosine triphosphate production\n( 6 ). This coenzyme is produced in the intracellular\nenvironment of the body which is one of the important\ncomponents in the structure of tyrosine ( 7 ). It is a\nvitamin-like compound similar to vitamin K and has\nthree known biological performance. It increases ATP\nin mitochondria that has an antioxidant function,\nand increases the stability of cell membranes ( 8 ,\n 9 ). According to recent studies, this substance can\nbe effective in muscular dystrophy, asthma, AIDS,\nbreast cancer, diabetes, thyroid problems, and male\ninfertility ( 10 ). Many studies have investigated\nthe role of CoQ10 and antioxidants in general as a\nfactor influencing infertility. Some of them show that\ncoenzyme Q10 can play an effective role in infertility\nby increasing sperm volume and concentration ( 11 ).\nConsidering the current growing demand for the use\nof antioxidant supplements in the treatment of male\ninfertility and the undeniable side effects of medical\ndrugs used for this purpose, as well as unpredictable\neffectiveness of CoQ10 antioxidants, the current\nresearchers have sought to compare the effects of the\nantioxidant supplement of Q 10 and placebo in the\ntreatment of male infertility.\n\nThe randomized controlled trial study was\nrecorded with the Iranian Registry of Clinical Trial\n(IRCT20120215009014N322) and was approved by the\nEthics Committee of Hamadan University of Medical\nSciences under code (IR.UMSHA.REC.1398.729). All\nparticipants signed a research consent form.\nDetermining the effect of CoQ10 Supplement on\nSpermogram Parameters, male hormones, and Sexual\nFunction of Infertile Men.\nThis study was performed as a two-group , doubleblind, placebo-controlled randomized clinical trial with\nparallel design in 1: 1 ration, performed on idiopathic\ninfertile men who had visited the subspecialty clinic of\nFatemieh Hospital in Hamadan in 2019 for infertility\ntreatment. The sample size was calculated in Stata\n13 software with Sampsi module. The sample size\nwas determined 30 for each group based on the data\nobtained from Balercia et al.’s study ( 12 ) [M1=10.43,\nM2=15.11, Sd1=3.52, Sd2=7.34, α=0.05, power=0.80\nand considering the 25% loss].\nThe inclusion criteria were a man age of under 40\nyears of age with primary infertility, abnormality\nof at least one of the semen parameters (volume,\nconcentration, sperm count, motility, and morphology\nof sperm), lack of infertility-related disorders such\nas chromosomal abnormalities, testicular failure,\nvaricocele, cryptorchidism, lack of chronic diseases\nsuch as diabetes, kidney disease, infectious diseases,\ngenital infections, thyroid, having a body mass index\n(BMI) less than 30, non-use of drugs and alcohol, nonuse of drugs that disrupt spermatogenesis (methotrexate,\nnitrofurantoin, colchicine and chemotherapy),\npituitary suppressants [testosterone injections,\ngonadotropin-releasing hormone (GnRh) analogues],\nanti-androgens (cimetidine, spironolactone), drugs\nthat cause ejaculatory dysfunction (alpha-blockers,\nantidepressants, phenothiazines), drugs that cause\nerectile dysfunction (beta-blockers, thiazide diuretics,\nmetoclopramides) and long-term use of drugs such as\nanabolic steroids, cannabis, heroin and cocaine, no\nhistory of testicular and vas deferens surgery, lack of\ncontact with pesticides, heavy metals and solvents, nonuse of metals and solvents, and non-use of antioxidant\nsupplements in the last three months ( 13 ). Infertile\nmen using drug and alcohol, using the creatinine more\nthan twice, strenuous physical activity, fertility during\nthe study, diet for weight loss, and change of location\nwere not included in the study. A semen sample was\ninitially collected from men referring for infertility treatment. Samples were collected in case of three-day\nsexual abstinence. Incubation was performed for 30 to\n60 minutes to convert the samples from bulk to liquid.\nTo evaluate sperm parameters in accordance with the\nWHO standards, 200 microliters of fluid sample was\nexamined ( 14 ).\nComputer semen analysis was used to assess sperm\nmotility. Also, microscopic tests were performed to\nevaluate and determine parameters such as sperm\nconcentration per milliliter of semen, sperm viability\nand sperm morphology. The research goals and\nmethods were explained to those who had the inclusion\ncriteria and then written consent was obtained from all\nvolunteers of the research. The data collection form of\nthe general characteristics of the patients was completed.\nFurthermore, 10 cc of blood was collected from patients\nat the beginning of the study to measure their sex\nhormones [luteinizing hormone (LH), follicle-stimulating\nhormone (FSH), prolactin, and testosterone] and thyroid\nstimulating hormone (TSH).\nThe allocation sequence and concealment was\ndetermined by using random blocking with 4 blocks\nbefore the study by a person not present in the study.\nBased on the predetermined sequence, the drugs were\nplaced in sealed and opaque envelopes and numbered\nrespectively. Each patient was given an envelope upon\nadmission. Therefore, the patients were placed into two\ngroups of CoQ10 and placebo ( Fig .1 ).\nFlowchart of sampling.\nThe researchers and the patients were blind to the study\ngroups. The CoQ10 group received 1 daily dose of 100-\nmg coenzyme Q10 capsules made by Walmark, USA and\nthe second group received a placebo treatment containing\n100 mg of lactose prepared by the School of Pharmacy of\nHamadan University of Medical Sciences.\nThe selection of the prescribed dose in the present\nstudy was also based on a pilot study conducted by\nthe researchers. This pilot study was performed on ten\nidiopathic infertile by examining the effect of CoQ10\nsupplements on sperm parameters. Follow-up of\npatients was conducted by phone once every 15 days\nin order to control the use of capsules and prevent the\nloss of samples. Moreover, by counting the remaining\ncapsules, patients who had not used more than 10%\nof their capsules were excluded finally. Patients were\nalso advised not to change their diet. Finally, after the\nintervention, the semen samples were evaluated for\nspermogram and blood samples were examined for sex\nhormones. LH and FSH were measured using the ELISA\nmethod with the CSB E12654r kit made by the Japanese\nCUSABIO Company. Serum levels of Testosterone,\nprolactin and TSH were respectively measured using the\nELISA hormone measurement kits made by the German\nDRG Instruments GmbH Company with hormonal\nsensitivity of 0.083 ng/ml and the RIA prepared by the\nIranian Padyab Teb Diagnostic Company with hormonal\nsensitivity of 0.09.\nIt should be noted that sexual function was examined\nin the infertile men with the inclusion criteria of two\ngroups in two stages before and after the intervention\nusing the IIEF. This index was completed by researchers\nvia interviews. It contains 15 standard questions which\nis divided into 5 subscales, namely erectile function,\norgasmic function, sexual desire, satisfaction with\nintercourse and overall satisfaction. It is scored from\nzero to five and the total score is obtained by adding the\nscores of the questions of each dimension. Higher score\nindicates the most optimal sexual function. The scores\nrange from 15 to 75, with scores within the 15-25 range\nindicating low sexual function, scores within the 25-50\nrange indicating moderate sexual function, and scores\nhigher than 50 indicating high sexual function. In previous\nstudies, the reliability of the questionnaire was confirmed\nwith the Cronbach's alpha of 0.85% ( 15 ).\nData were analyzed by using Stata 13 software\n(StataCorp Company, Canada). Kolmogorov-Smirnov\ntest was used to investigate the distribution of quantitative\nvariables. Demographic and background variables were\ncompared with the independent t test if the distribution was\nnormal and otherwise with the Mann-Whitney test. Chisquare test and Fisher’s exact test were used to compare\nsemen and hormone parameters and binomial regression\ntest was used to control the effect of pre-test status.\nComparison of different dimensions of sexual function\nwas also performed by Mann-Whitney and Wilcoxon\ntests. A significance level of 0.05 was considered.\n\nThe analysis of demographic and background variables\nindicated that the mean (standard deviation) age was 34.07 (5.26) years in the CoQ10 group and 34.83 (6.22) years\nin the placebo group. The mean (SD) BMI was higher in\nthe placebo group than in the CoQ10 one and the majority\nof members of the two groups had less than high school\ndiploma. The results showed that the two groups are\nhomogeneous in terms of the variables mentioned in the\ntable with no statistically significant difference observed\nbetween them.\nComparison of semen fluid parameters in the preintervention stage showed that 85.7% of the CoQ10\ngroup and 78.3% of the placebo group members had\na normal volume of semen (P=0.71). 75% of the\nCoQ10 group members had normal sperm counts,\nwhile this rate was about 74% in the placebo group\n(P=0.92). In terms of progressive motility, the normal\nmotility rate was higher in the placebo group than in\nthe CoQ10 group (P=0.43). Sperm shape and WBC\ncount were also normal in the majority of members\nof the two groups. None of these parameters showed\na statistically significant difference between the two\ngroups ( Table 1 ).\nThe results of multivariate analysis showed that, by\ncontrolling the values of semen in the pre-intervention\nstage, there was an increase in the normal volume\nof semen by 9% (P=0.10), normal viscosity by 10%\n(P=0.55), normal sperm count by 12% (P=0.28), and\nnormal sperm motility by 12% (P=0.33) in the CoQ10\ngroup compared with the placebo group, but none of\nthese results was statistically significant. The normal\nsperm morphology increased by 31% in the CoQ10\ngroup compared with the placebo group, which was\nstatistically significant (P=0.01,  Table 2 ).\nComparison of the mean scores of erectile function\nin the pre-intervention stage showed that this score\nwas higher in the placebo group than in the CoQ10\ngroup, but this difference was not statistically\nsignificant (P=0.16). In the post-intervention stage,\nthe score of the CoQ10 group was higher than that\nof the placebo group, but this difference was not\nstatistically significant (P=0.95). Comparison of\nthe mean scores of orgasm function in the preintervention stage showed that this score was higher\nin the placebo group than in the CoQ10 group, but\nthis difference was not statistically significant\n(P=0.51). In the post-intervention stage, the score of\nthe CoQ10 group [7.90 (1.89)] was higher than that\nof the placebo group [7.84 (2.24)], but this difference\nwas not statistically significant (P=0.86). Comparison\nof the mean scores of sexual desire showed that\nhis rate was higher in the CoQ10 group than the\nplacebo group in the pre-intervention stage, and the\nscore of the placebo group was higher than that of\nthe CoQ10 group in the post-intervention stage, but\nthese differences were not statistically significant\n(respectively P=0.86 and P=0.55). Comparison of the\nmean scores of satisfaction with sexual intercourse\nin both pre- and post-intervention stages showed that\nthis score was higher in the CoQ10 group than in the\nplacebo group, but the difference was not significant\n(respectively P=0.94 and P=0.61). Comparison of the\nmean scores of overall satisfaction in both pre- and\npost-intervention stages revealed that this score was\nhigher in the placebo group than in the CoQ10 group,\nbut this difference was not statistically significant\n(respectively P=0.36 and P=0.69). Comparison of\nthe mean total scores of the International Erection\nPerformance Index in the post-intervention stage\nshowed that this score was higher in the CoQ10\ngroup than the other ones, but this difference was not\nstatistically significant (P=0.82). Also Within-group\ncomparisons did not show a statistically significant\ndifference compared with the pre-intervention stage\n(P=0.12,  Table 3 ).\nComparison of semen analysis results before intervention between groups\nData are presented as n (%). WBC; White blood cell, and *; Chi-square test. The rest: Fisher's exact test.\nComparison of semen analysis results after intervention between groups*\nWBC; White blood cell, CI; Confidence interval, and *; Binomial regression.\nComparison within and between groups of the total score of sexual function domains before and after the intervention\nData are presented as mean ± SD. *; Mann–Whitney U test and **; Wilcoxon test.\nThe results of pre-intervention comparisons of\nhormone levels showed that normal LH, normal FSH\nand normal prolactin were more frequent in the CoQ10\ngroup than in the placebo one (respectively P=0.14,\nP=0.58 and P=0.54), but the normal testosterone and\nnormal TSH levels were more frequent in the placebo\ngroup than in the CoQ10 group (respectively P=0.61\nand P=0.61). The results of statistical analysis did not\nshow a statistically significant difference between the\ntwo groups ( Table 4 ).\nThe results of multivariate analysis in terms of hormone\nstatus showed that by controlling hormone levels in the\npre-intervention stage, there was an increase in normal\nFSH levels by 13% (P=0.20) and in normal testosterone\nlevels by 16% (P=0.30) in the CoQ10 group compared\nwith the placebo patients, but these differences were not\nstatistically significant. For the other hormones mentioned\nin the table, the normal level of hormones in the CoQ10\ngroup was slightly lower than that in the placebo group,\nwhich was not statistically significant ( Table 5 ).\nComparison of hormones levels before the intervention between groups\nData are presented as n (%). *; Chi-square test and the rest of Fisher's exact test.\nComparison of hormones levels after the intervention between groups*\nData are presented as n (%). *; Binomial regression and CI; Confidence interval.\n\nInfertility is one of the disorders with an increasing\nrate of prevalence under the influence of various\nfactors. However, increased oxidative stress is one of\nthe strongest factors that can increase the prevalence of\nthis disorder by influencing various factors. Therefore,\nantioxidants can improve fertility parameters by\nincreasing the level of antioxidant capacity. One of these\nantioxidants, used in large quantities in the treatment\nof male infertility, is CoQ10. The results of our study\ndemonstrated that the normal volume of semen, normal\nviscosity, normal count, normal motility, and normal\nshapes of sperm increased as a result of CoQ10 use.\nOxidative stress is one of the most common factors\ninvolved in infertility ( 16 ). Sperm cells are rich in\nunsaturated fatty acids. Sperm parameters change in\ninfertile individuals and become abnormal. In such\nindividuals, sperms are very vulnerable to oxidative\nstress due to a lack of antioxidant enzymes in the\ncytoplasm as well as the presence of unsaturated fatty\nacids in the plasma membrane. Hence, oxidative stress\nreduces the quality of semen through damage to DNA\nand destruction of plasma membranes ( 17 ). Coenzyme\nQ10 is a compound with antioxidant properties and\none of the components of the respiratory chain. It\ncan be effective against heart disease, hypertension,\ndiabetes, infertility, and many other diseases. The\nfunction of this coenzyme in energy production in the\ncell and its acting as an antioxidant depends on its\nability to exchange two electrons between ubiquinol\nand ubiquinone ( 18 ). Decreased 8-isoprostane, a\nmeasure of lipid peroxidation, has also been shown\nto be effective in reducing oxidative stress in infertile\nindividuals. Catalase and superoxide dismutase are the\nfirst line of defense of the enzyme against oxidative\nstress. In a study on 47 infertile men, 200 mg/day of\nCoQ10 supplement increased the activity of catalase\nand SOD enzymes. The results of this study indicated\nthat, despite the improvement of oxidative stress\nresulting from the activity of these two enzymes, sperm\nmotility and morphology did not improve.\nAnother study showed that the increased levels of\nthese two enzymes cause stability of sperm parameters\n( 19 ). Another study found a relationship between\nreduced 8-isoprostane and improved sperm motility and morphology. A study on 194 infertile men showed\nthat daily intake of 300 mg of CoQ10 supplement\nimproved sperm motility and morphology ( 20 ).\nHowever, another study indicated no relationship\nbetween the concentration of CoQ10 in the seminal\nfluid and the improvement of sperm motility ( 19 ). A\nqualitative analysis of the literature has shown that\nCoQ10 supplements, alone or with other antioxidant\nmolecules, has an effective effect on semen quality,\nespecially in sperm motility. Indirect symptoms result\nfrom improved semen antioxidant capacity and sperm\nchromatin integrity. Improvement in semen parameters\nbegins after 3-6 months of treatment but disappears\nwhen the supplement is discontinued. Further\nstudies are needed to determine the optimal dose of\nCoQ10 ( 11 ). Although most studies have shown an\nimprovement in sperm motility, studies of sperm\nconcentration and density have shown contradictory\nresults. A clinical trial on 22 infertile men receiving\n400 mg/day of CoQ10 supplement showed no effect\non sperm morphology and concentration. Another\nstudy indicated the positive effect of CoQ10 on sperm\nmorphology and concentration without statistically\nsignificant differences ( 12 ).\nA study on 287 infertile men demonstrated that 600 mg/\nday of CoQ10 improved sperm motility, concentration,\nand morphology ( 21 ). Also, The present study indicated\nthe greater mean scores of the CoQ10 group in the\nsubscales of orgasm function, IIEF, satisfaction with\nsexual intercourse, and overall scores of the questionnaire\nin comparison with the placebo group. Safarinejad ( 22 )\nfound a significant difference between the mean score\nof penile pain and the mean score of post-treatment\nfunction in patients with early chronic Pyeronie's Disease\nwho had received CoQ10, so that improvement in the\nfunction score was observed in the CoQ10 group. Also,\nthere was a significant difference between the average\nvolume of plaque and the penile curvature in the two\ngroups of CoQ10 and placebo. Increased plaque size and\nworsened penile curvature in the placebo group have\nshown the potential protective effect of CoQ10. One\nway to boost sperm is to use CoQ10. It is one of the most\nimportant antioxidants needed to protect cell DNA from\nfree radical damage. Thus, CoQ10 affects sperms by\nmaintaining their motility and health. This antioxidant is\nmostly found in seafood and meat, but it is very difficult\nto get it through diet. Taking ubiquinol, a coenzyme\nQ10 supplement, is the best solution to get coenzyme\nQ10 in order to boost male sperm. The amount of this\nsubstance decreases in the body with aging. The use of\nCoQ10 is useful in improving male sexual function. The\nresults of our study indicated the higher normal levels\nof FSH and testosterone in the CoQ10 group than in\nthe placebo group. However, studies have shown that\nincreased free radicals and generated oxidative stress\nreduce the potential of mitochondrial membranes and\nincrease lipid peroxidation in testicular tissue which\nhave a destructive effect on this tissue. Cao et al. ( 23 )\nfound that an increase in oxidative stress leads to a\ndecrease in the levels of important enzymatic and nonenzymatic oxidants in Leydig cells as well as reduction\nin testosterone synthesis and secretion.\nGhanbarzadeh et al. ( 24 ) found that increased\ncoenzyme Q10 decreased the level of free radicals and\nincreased the level of sex hormones in isoproterenoltreated rats. Safarinejad et al. ( 21 ) conducted a study\non 228 infertile men, finding a significant decrease in\nLH and FSH levels as well as a significant increase\nin serum inhibin B levels after receiving 200 mg of\nCoQ10 for 26 weeks. However, there was no significant\nchange in the amount of testosterone, although there\nwas a slight increase. After 12 weeks of follow-up, the\nFSH level still decreased significantly. The positive\neffect of CoQ10 supplement on spermatogenesis by\ndecreasing FSH levels and increasing inhibin B levels\nhas also been confirmed. Inhibin B is produced by\nSertoli cells and its serum level is strongly associated\nwith the testis. Inhibin B controls FSH secretion via\na negative feedback ( 25 ). Therefore, an increase in\ninhibin B along with a decrease in FSH level strongly\nindicates an improvement in testicular performance.\nIn any case, the beneficial effects of CoQ10 on semen\nparameters diminish after cessation of treatment ( 11 ).\nStudies on male infertility have not shown a significant\neffect of coenzyme Q10 supplement on testosterone\nlevels yet. They have shown no beneficial effect of\ncoenzyme Q10 supplement on infertile men. Similarly,\nanimal studies have not shown a positive effect of\ncoenzyme Q10 on testosterone. However, coenzyme\nQ10 supplementation is widely used to counteract\ntestosterone reduction caused by toxins generated in\nchemical drugs. In order to increase testosterone, other\nalternative treatment strategies may be needed instead\nof coenzyme Q10 supplementation. Further research\nneeds to be done in this area ( 26 ).\n\nThe use of CoQ10 supplement was shown able to\nimprove sperm morphology; however, in other sperm\nparameters and also in some hormones that increased\nafter the intervention, this was not statistically significant\nand therefore the result is not conclusive.","source_license":"public-domain-us","license_restricted":false}