OBJECTIVE: Zearalenone (ZEA) is a mycotoxin with potent estrogenic effects. Saffron is an herbal product that has antioxidant activities. The objective of this study was to investigate the protective role of saffron against reproductive toxicity induced by ZEA in female mice. METHODS: Ninety 8-week-old female mice were randomly allocated into three treatment groups. The first group received an intraperitoneal injection of ZEA (2.5 mg/kg) on alternate days. The second group received ZEA (2.5 mg/kg) on alternate days plus oral saffron daily (50 mg/kg). The third group was treated with a vehicle of 1% dimethyl sulfoxide (DMSO) on alternate days, as a control. Ten mice were euthanized from each group at 30, 60, and 90 days of treatment. Serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), and progesterone (P) were assessed. The uterus and ovaries were examined for changes in size or morphology. RESULTS: Serum levels of LH, FSH, E2, and P in the female mice treated with ZEA plus saffron were significantly higher than in those treated with ZEA alone, and were not significantly different from those treated with 1% DMSO. The female mice treated with ZEA alone showed a reduction in size of the uterus and abnormal architecture of the ovaries. CONCLUSION: The administration of saffron to female mice resulted in a significant reduction in ZEA-induced alterations in reproductive hormone levels, the size of the uterus, and the morphology of the ovaries.
Animals ; Antioxidants ; Crocus* ; Dimethyl Sulfoxide ; Estradiol ; Estrogens ; Female* ; Follicle Stimulating Hormone ; Humans ; Injections, Intraperitoneal ; Luteinizing Hormone ; Mice* ; Ovary ; Progesterone ; Uterus ; Zea mays ; Zearalenone

OBJECTIVE: To investigate the effects of in vitro myo-inositol (Myo-Ins) supplementation of cryopreserved human semen on the cryo-survival rate (CSR). METHODS: Semen samples were obtained from 41 infertile men. Following routine semen analysis, each sample was divided into two equal aliquots (0.5 mL each). One aliquot was treated with 1 mg of Myo-Ins dissolved in 10 µL of sperm preparation medium. The second aliquot was treated with 10 µL of the same medium (control). Both aliquots were incubated for 20 minutes prior to freezing to slow the freezing process. The frozen samples were examined for post-thaw percentages of total motility (TM), progressive motility (PM), and the CSR, defined as the percentage of post-thaw TM divided by the percentage of pre-freeze TM and multiplied in 100. The results were expressed as median and interquartile range (25th and 75th percentiles). RESULTS: The pre-freeze TM (50% [30%–50%]) and PM (35% [20%–35%]) were significantly higher than the post-thaw TM and PM in the Myo-Ins group (15% [10%–35%] and 10% [5%–20%]; p < 0.001 and p < 0.001, respectively) and the control group (10% [6%–30%] and 5% [3%–15%]; p < 0.001 and p < 0.001, respectively). The CSR of the 41 semen aliquots supplemented with Myo-Ins (40% [25%–70%]) was significantly higher than that of the control samples (30% [13%–58%], p=0.041). The CSR of the 26 abnormal semen samples that were supplemented with Myo-Ins (38% [20%–50%]) was significantly higher than that of the control samples (23% [12%–30%], p=0.031). CONCLUSION: In vitro Myo-Ins supplementation of ejaculated human sperm from infertile men resulted in a significant increase in the CSR in samples with abnormal pre-freeze sperm parameters.
Freezing ; Humans* ; In Vitro Techniques* ; Male ; Semen ; Semen Analysis ; Spermatozoa*

Purpose: Systematic reviews and meta-analyses (SRMAs) are used to generate evidence-based guidelines. Although the number of SRMAs published in the literature has increased dramatically in the last decade, the training and the experience of the researchers performing the SRMAs are usually not explained in the SRMAs’ methodology, and this may be a source of bias. Although some studies pointed out the need for quality control of SRMAs and training in proper statistical methods, to the best of our knowledge, no study has reported the importance of training the researchers that conduct the SRMAs. The aim of this study is to describe a training program designed to impart the essential knowledge and skills required for the conduct of an SRMA and to assess the need for, and outcome of, such a training. Materials and Methods: Researchers were trained for use of Scopus, study eligibility, assessment of the quality of evidence (QoE) through the Cambridge Quality Checklist for observational studies, as well as the Cochrane Risk of Bias tool, the Consolidated Standards of Reporting Trials (CONSORT) guidelines, and the Jadad score for randomized controlled trials (RCTs), Population, Intervention, Comparison, Outcome (PICO) questions and data extraction. A total of 35 of them were approved to join a planned SRMA. At the end of the SRMA, they were administered 43 multiple-choice questions (MCQs) on demographics, motivation for participation in the SRMA, self-perceived change in knowledge before and after conducting the SRMA, and self-assessment of performance. The senior researchers then revised the spreadsheet of the SRMA and, based on the mistakes found, organized a training focused on the correct assessment of the study design, where 43 researchers (9 joined midway) and 11 trainees with no experience in conducting SRMA attended. They all were tested through a 5 MCQ assessment that was administered before and after the training. Those scoring poorly were re-trained and re-tested, and only those scoring satisfactorily were admitted to further SRMAs. Results: Approximately 54.3% of the participants were medical doctors (MD), 31.4% were urologists and 48.6% had previous experience with SRMAs. Joining an international collaborative study was the main motivation, chosen by 19.7% of researchers. The results of the self-perceived change in knowledge showed a significant improvement in the use of Scopus, checklists for QoE, PICO questions, data required to perform a meta-analysis, and critical reading of scientific articles. Also, the majority of the researchers ranked the quality of their work as high. The pre-test results of the 5 MCQ showed a low score, which was not different from that achieved by a group of fresh trainees (median, 2; IQR 1–3 vs. median, 1; IQR, 1–2; p=0.3). Post-training there was significant improvement in both groups (researchers: median, 4; IQR, 3–5 vs. median, 2; IQR, 1–3; p<0.001; trainees: median, 4; IQR, 3–4 vs. median, 1; IQR, 1–2; p=0.02). Out of the 44 researchers, 12 (27.3%) scored poorly (≤3). After re-training, all of them scored satisfactorily (>3) and were admitted to subsequent SRMAs. Conclusions At the end of our model, 100% of researchers participating in this study were validated to be included in a meta-analysis. This validation required the involvement of the MT, two meetings, a self-evaluation survey, and one or two sets of objective tests with explanations and corrections. Our results indicate that even well-trained clinicians are naïve when it comes to the methodology of SRMA. All the researchers performing an SRMA need comprehensive training that must cover each aspect of the SRMA methodology. This paper provides a replicable training program that could be used by other investigators to train the researchers to perform high-quality SRMAs.

The controlled generation of very low amounts of reactive oxygen species (ROS) appears to regulate normal sperm functions, while high levels of ROS endanger sperm viability and function. Oxidative stress (OS) develops as a consequence of excessive production of ROS and/or impaired antioxidant defense system. It is proposed that such OS precipitates a range of pathologies currently thought to afflict male reproductive function. ROS-mediated peroxidative damage to the sperm plasma membrane may account for defective sperm function observed in a high proportion of infertility patients. Excessive generation of ROS may also attack integrity of DNA in the sperm nucleus. DNA bases are susceptible to oxidative stress, and peroxidation of these structures can cause base modification, DNA strand breaks and chromatin cross-linking. DNA damage induced by excessive ROS may accelerate the process of germ cell apoptosis, leading to decline in sperm counts associated with male infertility, and may explain the apparent deterioration of semen quality observed during the past four to five decades. For almost a decade, our research team in the Cleveland Clinic Foundation has identified the critical role of OS in male infertility. The main objective of our research was to transfer this important knowledge from the research bench to clinical practice. We designed studies with the aims of: 1. understanding the exact mechanisms by which OS develops in semen, which we thought will help setup strategies to overcome the problem, 2. establishing assays for accurate assessment of OS status and running the quality control studies for this purpose, 3. testing the correlation between OS and sperm nuclear DNA damage, and 4. identifying the clinical significance of seminal OS assessment in male infertility practice.
DNA ; metabolism ; DNA Damage ; Humans ; Infertility, Male ; genetics ; metabolism ; Male ; Oxidative Stress ; physiology ; Reactive Oxygen Species ; metabolism ; Spermatozoa ; physiology

There have been many significant scientific advances in the diagnostics and treatment modalities in the field of male infertility in recent decades. Examples of these include assisted reproductive technologies, sperm selection techniques for intracytoplasmic sperm injection, surgical procedures for sperm retrieval, and novel tests of sperm function. However, there is certainly a need for new developments in this field. In this review, we discuss advances in the management of male infertility, such as seminal oxidative stress testing, sperm DNA fragmentation testing, genetic and epigenetic tests, genetic manipulations, artificial intelligence, personalized medicine, and telemedicine. The role of the reproductive urologist will continue to expand in future years to address different topzics related to diverse questions and controversies of pathophysiology, diagnosis, and therapy of male infertility, training researchers and physicians in medical and scientific research in reproductive urology/ andrology, and further development of andrology as an independent specialty.

Premature ejaculation (PE) is the most common male sexual dysfunction, which represents a diagnostic as well as a therapeutic challenge for physicians. However, no universally accepted definition is currently available for PE. As a result, physicians continue to diagnose patients with PE according to major guidelines set by the professional societies. These guidelines either recommend the use of validated questionnaires or patient-reported outcomes. Recent efforts directed toward classifying PE may help provide a better understanding of the prevalence and risk factors of this disorder. While the exact etiology of PE has not been clearly elucidated, several risk factors have been strongly reported in the literature. Clearly, to understand the revised definition of PE, its etiology and pathophysiology is necessary to improve the clinical management of this medical condition and form the basis of future research in this regard. In this review, we highlight the past and current definitions of PE and present an appraisal on the classifications and theories suggested for the etiopathogenesis of PE.
Humans ; Male ; Premature Ejaculation/physiopathology*

Purpose: In this systematic review and meta-analysis, we investigated assisted reproductive technology (ART) success in infertile men with clinical varicocele and abnormal semen parameters who underwent varicocele repair (VR) before the ART procedure as compared to those who did not. Materials and Methods: A comprehensive search of the Scopus, PubMed, Embase, and Cochrane Library databases was conducted using a specific query string to identify studies examining the impact of VR on ART outcomes, including fertilization rate, clinical pregnancy, pregnancy loss, and live-birth rate, until October 2023. Outcomes were analyzed based on the type of ART. Studies on VR in infertile men with non-obstructive azoospermia and those who underwent ART only due to female factor infertility were excluded from the study. Results: Out of 1,554 articles reviewed, only 9 met the inclusion criteria for the study. All the included articles were observational studies. The variability in study quality in the included literature resulted in a moderate overall risk of bias. Data analysis showed that for intrauterine insemination, there was no difference in the clinical pregnancy rate (odds ratio [OR] 1.01, 95% confidence interval [CI]: 0.42, 2.45; p=0.97). However, for intracytoplasmic sperm injection (ICSI), men with VR showed a significant improvement in fertilization rate (mean difference 10.9, 95% CI: 5.94, 15.89; p<0.01), clinical pregnancy rate (OR 1.38, 95% CI: 1.07, 1.78; p=0.01) and live-birth rate (OR 2.07, 95% CI: 1.45, 2.97; p<0.01), compared to men who did not undergo VR. Conclusions The findings of this systematic review and meta-analysis suggest that VR has a positive impact on pregnancy and live birth rates after ICSI. However, biases like small sample sizes and heterogeneous populations highlight the need for larger, well-designed prospective studies to validate these findings.

Purpose: Despite the significant role of varicocele in the pathogenesis of male infertility, its association with anti-sperm antibodies (ASA) remains controversial. This systematic review and meta-analysis (SRMA) aims to investigate the frequency of ASA positivity in men with varicocele. Materials and Methods: This SRMA is conducted in accordance with the Meta-analysis of Observational Studies in Epidemiology guidelines. We investigated the frequency of ASA positivity in ejaculates or serum of men with varicocele as compared to men without varicocele (controls). A literature search was performed using the Scopus and PubMed databases following the Population Exposure Comparison Outcome, Study Design model. Data extracted from eligible studies were meta-analyzed and expressed as odds ratios (ORs) and confidence intervals (CIs). Results: Out of 151 abstracts identified during the initial screening, 6 articles met the inclusion criteria and were included in the meta-analysis. Using mixed antiglobulin reaction (MAR) assay, 61 out of the 153 (39.8%) patients with varicocele tested positive for ASA in their ejaculates as compared to 22 out of the 129 control subjects (17%, OR=4.34 [95% CI: 1.09–17.28]; p=0.04). Using direct or indirect immunobead test, 30 out of 60 cases diagnosed with varicocele (50%) had shown ASA positivity in their ejaculates as compared to 16 out of 104 controls (15.4%, OR=3.57 [95% CI: 0.81–15.68]; p=0.09). Using enzyme-linked immunosorbent assay (ELISA), out of 89 varicocele patients, 33 (37.1%) tested positive for serum ASA as compared to 9 out of 57 participants in the control group (15.8%, OR=7.87 [95% CI: 2.39–25.89]; p<0.01). Conclusions This SRMA indicates that ASA positivity is significantly higher among men with varicocele when tested by direct method (MAR) or indirect method (ELISA). This data suggests an immunological pathology in infertile men with varicocele and may have implications for the management of these patients.

Purpose: In this systematic review and meta-analysis, we investigated assisted reproductive technology (ART) success in infertile men with clinical varicocele and abnormal semen parameters who underwent varicocele repair (VR) before the ART procedure as compared to those who did not. Materials and Methods: A comprehensive search of the Scopus, PubMed, Embase, and Cochrane Library databases was conducted using a specific query string to identify studies examining the impact of VR on ART outcomes, including fertilization rate, clinical pregnancy, pregnancy loss, and live-birth rate, until October 2023. Outcomes were analyzed based on the type of ART. Studies on VR in infertile men with non-obstructive azoospermia and those who underwent ART only due to female factor infertility were excluded from the study. Results: Out of 1,554 articles reviewed, only 9 met the inclusion criteria for the study. All the included articles were observational studies. The variability in study quality in the included literature resulted in a moderate overall risk of bias. Data analysis showed that for intrauterine insemination, there was no difference in the clinical pregnancy rate (odds ratio [OR] 1.01, 95% confidence interval [CI]: 0.42, 2.45; p=0.97). However, for intracytoplasmic sperm injection (ICSI), men with VR showed a significant improvement in fertilization rate (mean difference 10.9, 95% CI: 5.94, 15.89; p<0.01), clinical pregnancy rate (OR 1.38, 95% CI: 1.07, 1.78; p=0.01) and live-birth rate (OR 2.07, 95% CI: 1.45, 2.97; p<0.01), compared to men who did not undergo VR. Conclusions The findings of this systematic review and meta-analysis suggest that VR has a positive impact on pregnancy and live birth rates after ICSI. However, biases like small sample sizes and heterogeneous populations highlight the need for larger, well-designed prospective studies to validate these findings.

Purpose: Despite the significant role of varicocele in the pathogenesis of male infertility, its association with anti-sperm antibodies (ASA) remains controversial. This systematic review and meta-analysis (SRMA) aims to investigate the frequency of ASA positivity in men with varicocele. Materials and Methods: This SRMA is conducted in accordance with the Meta-analysis of Observational Studies in Epidemiology guidelines. We investigated the frequency of ASA positivity in ejaculates or serum of men with varicocele as compared to men without varicocele (controls). A literature search was performed using the Scopus and PubMed databases following the Population Exposure Comparison Outcome, Study Design model. Data extracted from eligible studies were meta-analyzed and expressed as odds ratios (ORs) and confidence intervals (CIs). Results: Out of 151 abstracts identified during the initial screening, 6 articles met the inclusion criteria and were included in the meta-analysis. Using mixed antiglobulin reaction (MAR) assay, 61 out of the 153 (39.8%) patients with varicocele tested positive for ASA in their ejaculates as compared to 22 out of the 129 control subjects (17%, OR=4.34 [95% CI: 1.09–17.28]; p=0.04). Using direct or indirect immunobead test, 30 out of 60 cases diagnosed with varicocele (50%) had shown ASA positivity in their ejaculates as compared to 16 out of 104 controls (15.4%, OR=3.57 [95% CI: 0.81–15.68]; p=0.09). Using enzyme-linked immunosorbent assay (ELISA), out of 89 varicocele patients, 33 (37.1%) tested positive for serum ASA as compared to 9 out of 57 participants in the control group (15.8%, OR=7.87 [95% CI: 2.39–25.89]; p<0.01). Conclusions This SRMA indicates that ASA positivity is significantly higher among men with varicocele when tested by direct method (MAR) or indirect method (ELISA). This data suggests an immunological pathology in infertile men with varicocele and may have implications for the management of these patients.