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Probiotics, Antioxidants, Oligospermia, Male infertility, Andrology, What&,rsquo s Known Idiopathic oligoasthenoteratozoospermia treatment, as a leading cause of male infertility, poses various challenges. Current treatment hinges on conventional treatments, especially antioxidants. Probiotics are an accidentally found treatment for oligoasthenoteratozoospermia. This study, which stands as the first one, is an endeavor to indicate the application of probiotics and compare their therapeutic effects with antioxidants. What&,rsquo s New Probiotic and antioxidant, compared to baseline, exerted significant improvement in sperm concentration, motility, and morphology. Probiotics significantly outperformed placebo in sperm concentration, motility, and morphology. Additionally, probiotics indicated superiority to antioxidants in motility and morphology parameters. IntroductionApproximately 15% of all couples attempting to conceive experience infertility. 1, Infertility is defined as the inability to achieve pregnancy naturally after a year of regular and unprotected intercourse. 2, In about half of infertility cases, men are involved, while 20-30% of infertility cases are solely attributed to male factors. 3, Some identifiable causes of infertility include varicocele, cryptorchidism, and hypogonadism. However, in some cases, no apparent reasons for abnormal semen analysis lead to a diagnosis of idiopathic oligoasthenoteratozoospermia (iOAT). 1, iOAT, a diagnosis of exclusion, accounts for nearly 30% of male infertility cases, where sperm concentration and the proportion of motile and morphologically normal sperm are below the World Health Organization (WHO) standards. 1, iOAT is typically treated empirically due to its multifactorial nature, making it difficult to pinpoint the exact cause through laboratory methods. 4, Several therapeutic approaches, including both hormonal and non-hormonal drugs, have been proposed to treat iOAT. One effective non-hormonal treatment option is the use of oral antioxidants. 5, Reactive oxygen species (ROS) play a significant role in male infertility, with higher levels found in infertile men. Therefore, antioxidants can be protective against the effects of ROS. 1, In recent years, probiotics have gained recognition as a therapeutic option across diverse medical domains. Their limited adverse effects and wide-ranging impacts on different physiological systems make them an attractive choice for medical interventions. 6, Many studies suggest that probiotics can improve women&,rsquo s fertility. 7, In 2017, Maretti and colleagues serendipitously found that iOAT patients who received probiotics for digestive issues showed improvements in their semen parameters. 4, Following this discovery, further research has confirmed the positive effects of probiotics on semen parameters. 8, - 10, Two prior Iranian studies indicated the positive advantages of probiotics in enhancing semen parameters. Abbasi and colleagues, 8, showed the effectiveness of the symbiotic regimen in sperm parameters, including concentration, motility, and morphology in infertile males compared to placebo. Another study by Asadi and colleagues, 11, also stated the superiority of probiotics over placebo in terms of sperm concentration and morphology in infertile men who underwent varicocelectomy. However, no study has compared the efficacy of probiotics versus antioxidants. Hence, considering the promising findings of probiotics&,rsquo effects, their affordability, and the lower risk of complications, this randomized clinical trial (RCT) aims to compare the effects of probiotics and antioxidants on iOAT patients&,rsquo sperm parameters.Materials and Methods Study Population Male patients who visited the Yazd Infertility Center (Yazd, Iran) and Isfahan Urology Clinic (Isfahan, Iran) with primary idiopathic infertility were screened for eligibility. Men under the age of 45 who met the 2010 WHO infertility criteria, including having sperm parameters below the 5th percentile (sperm count &,lt 15,000,000/mL, normal morphology &,lt 4%, and motility A+B+C &,lt 40%), were included in the study. 12, The following individuals were excluded from the study, those with pyospermia, varicocele, a history of testis surgery or varicocelectomy, undergoing chemotherapy or radiotherapy, smokers, those with a history or current use of drugs that affect spermatogenesis such as tamoxifen, human Chorionic Gonadotropin (hCG), cytotoxic drugs, immunosuppressants, anticonvulsants, or androgens, those with a history of sexually transmitted diseases, epididymo-orchitis, testis trauma and/or torsion, prostatitis, chromosomal abnormalities, and those who declined to participate in the study. Study Design This is a three-month-long, multi-center, triple-blinded, randomized, placebo-controlled clinical trial that was conducted from July 2021 to April 2022. A total of 203 male patients with infertility who were referred to both centers, 136 and 67 from Isfahan and Yazd centers, respectively, were evaluated for eligibility. Patients were evaluated by an experienced urologist specializing in infertility. They were interviewed to gather demographic information, ascertain the duration of infertility, and obtain a history of any illnesses or medication usage. Following the completion of the patient history, a testis examination was conducted. Subsequently, the patients were randomly divided into three parallel groups using the Random Allocation Software. 13, All patients who were referred to both centers and satisfied the primary criteria were further evaluated for inclusion. After obtaining informed consent, the patient would be randomly and uniformly assigned to each of three groups at the first visit, and would stay blind to the process through the study. Simple randomization was used to allocate participants into three parallel groups (probiotic, antioxidant, and placebo) in a 1,1,1 ratio. This was conducted using Random Allocation Software, which assigned each participant a random code to ensure allocation concealment. Each new patient at the time of enrollment was assigned to the next available random code, which corresponded to a concealed group assignment. Subsequently, the participant, care provider, and analyzer were blinded. A per-protocol approach was considered to ensure the robustness of analyzing the results in the post hoc analysis. Both centers, which were tertiary academic hospitals, adhered to a shared protocol in study design, patient selection, and follow-up. The first group was administered a daily diet of two capsules of probiotic Familact&,reg (Zist Takhmir, Iran), the second group received two capsules of mineral multivitamin Sperigen&,reg (Hayat Darou, Iran), and the third group received two capsules of the placebo, which was also produced by Zist Takhmir Company. The placebo and the probiotic were indistinguishable in appearance but slightly different from the antioxidant. All medications were in capsule form. Each patient took a capsule every 12 hours for 90 days. Familact&,reg is a synbiotic that contains a variety of beneficial strains, including Lactobacillus casei, Lactobacillus rhamnosus, Lactobacillus acidophilus, Lactobacillus bulgaricus, Streptococcus thermophilus, Bifidobacterium longum, and Bifidobacterium breve. Additionally, it includes fructooligosaccharides as prebiotics. 8, Sperigen&,reg comprises a combination of group B vitamins, vitamin A, vitamin C, vitamin E, selenium, zinc, glutathione, L-carnitine, L-arginine, CoQ10, and other supplements. Sample Collection and Semen Analysis Four semen samples were collected from each patient. Two samples were obtained before the intervention, and two samples were collected three months after the intervention. In both instances, the samples were taken one week apart following 48 hours of ejaculatory abstinence. The semen samples were collected via masturbation in a private room at the laboratory and analyzed using the Computer-Assisted Sperm Analysis (CASA, Video Test, Version Sperm 2.1&,copy , Russia)&,nbsp method within 30 min. The average value of the two samples was calculated both before and after the intervention.The main outcome of the study was post-intervention semen parameters. Sperm concentration was measured using a sperm counting chamber (Shivani Scientific Industries, Mumbai, India). Sperm motility and morphology were assessed using a computerized sperm analysis system called Video Test (CASA, Video Test, Ltd, version Sperm 2.1, Russia). The interpretation of semen parameters was conducted according to the WHO 2010 criteria. 12, Both centers utilized the same sample-gathering and analyzing procedures. Ethical Considerations This RCT adhered to the principles outlined in the 1964 Helsinki Declaration and its further updates. The study was conducted from July 2021 to April 2022, following approval by the local research ethics committee, under the ethical code of IR.MUI.MED.REC.1400.443. Informed consent was obtained from all participants before their involvement in the study. The RCT has been registered on the Iranian Registry of Clinical Trials under the code IRCT20150420021869N5. Statistical Analysis Statistical analyses were conducted using SPSS&,reg version 26.0 (SPSS Inc., Chicago, IL, USA). Continuous variables were presented as mean&,plusmn standard deviation. The normality of the data was assessed using the Kolmogorov-Smirnov test. All four key semen parameters (volume, concentration, motility, morphology) were analyzed using linear mixedeffects models with restricted maximum likelihood estimation (REML) and an unstructured covariance matrix for the repeated measures. In each model, time (baseline vs. 3 months), group (antioxidant/probiotic vs. probiotic vs. placebo), and their interaction (Time&,times Group) were included as fixed effects, and patient ID was included as a random intercept. We also adjusted for the center as a fixed effect. Estimated marginal means (EMMs) and their standard errors (SEs) at each time point and group were obtained, and pairwise comparisons at 3 months were Bonferroniadjusted. The primary hypothesis test was the Type III Ftest of the Time&,times Group interaction P&,lt 0.05 was considered statistically significant.Results Baseline Characteristics Table 1, presents the basic characteristics of the patients included in the study. A total of 110 men with a mean age of 34.3&,plusmn 4.5 years were included in the final analysis. Sixty-three patients were recruited from Center 1, and 47 patients were recruited from Center 2. Among them, 38, 35, and 37 patients were assigned to the antioxidant, probiotic, and placebo groups, respectively (figure 1,). In assessing treatment compliance, 94.9%, 97.2%, and 92.7% of patients in the placebo, probiotic, and antioxidant groups, respectively, adhered to their prescribed treatment regimen. Antioxidant (n=38)Probiotic (n=35)Placebo (n=37)P valueaAge (years, median [Q1-Q3])34 (29-38)35 (30-39)32 (28-36)0.158Infertility period (months, median [Q1-Q3])31 (24-40)31 (25-38)32 (26-42)0.326aKruskal-Wallis H test, P&,lt 0.05 was considered significant. |