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Abstract Context Male infertility is defined as the inability to conceive following 1 year of regular unprotected intercourse. It is the causative factor in 50% of couples and a leading indication for assisted reproductive techniques (ART). Testicular failure is the most common cause of male infertility, yet the least studied to date. Evidence Acquisition The review is an evidence-based summary of male infertility due to testicular failure with a focus on etiology, clinical assessment, and current management approaches. PubMed-searched articles and relevant clinical guidelines were reviewed in detail. Evidence Synthesis/Results Spermatogenesis is under multiple levels of regulation and novel molecular diagnostic tests of sperm function (reactive oxidative species and DNA fragmentation) have since been developed, and albeit currently remain as research tools. Several genetic, environmental, and lifestyle factors provoking testicular failure have been elucidated during the last decade; nevertheless, 40% of cases are idiopathic, with novel monogenic genes linked in the etiopathogenesis. Microsurgical testicular sperm extraction (micro-TESE) and hormonal stimulation with gonadotropins, selective estrogen receptor modulators, and aromatase inhibitors are recently developed therapeutic approaches for men with the most severe form of testicular failure, nonobstructive azoospermia. However, high-quality clinical trials data is currently lacking. Conclusions Male infertility due to testicular failure has traditionally been viewed as unmodifiable. In the absence of effective pharmacological therapies, delivery of lifestyle advice is a potentially important treatment option. Future research efforts are needed to determine unidentified factors causative in “idiopathic” male infertility and long-term follow-up studies of babies conceived through ART.

Infertility is a global health problem involving about 15% of couples. Approximately half of the infertility cases are related to male factors. The oxidative stress, which refers to an imbalance in levels of reactive oxygen species (ROS) and antioxidants, is one of the main causes of infertility in men. A small amount of ROS is necessary for the physiological function of sperm including the capacitation, hyperactivation and acrosomal reaction. However, high levels of ROS can cause infertility through not only by lipid peroxidation or DNA damage but inactivation of enzymes and oxidation of proteins in spermatozoa. Oxidative stress (OS) is mainly caused by factors associated with lifestyle. Besides, immature spermatozoa, inflammatory factors, genetic mutations and altering levels of sex hormones are other main source of ROS. Since OS occurs due to the lack of antioxidants and its side effects in semen, lifestyle changes and antioxidant regimens can be helpful therapeutic approaches to overcome this problem. The present study aimed to describe physiological ROS production, roles of genetic and epigenetic factors on the OS and male infertility with various mechanisms such as lipid peroxidation, DNA damage, and disorder of male hormone profile, inflammation, and varicocele. Finally, the roles of oral antioxidants and herbs were explained in coping with OS in male infertility.

Objective To evaluate the impact of vitamin E supplementation on sperm analysis results in patients post-varicocelectomy. Martials and method This single-center, triple-blind, randomized controlled trial was conducted at Imam Reza Hospital, Mashhad, Iran. Ninety male patients, aged 15–25 years, with infertility and varicocele grade 2 or 3, were randomized into two groups. The intervention group received 400 units of vitamin E daily for 3 months, while the control group received a placebo. Sperm analysis was conducted before and 3 months after the intervention. Statistical analyses were performed using SPSS version 23, with significance set at P  < 0.05. Results A total of 90 patients were enrolled and equally randomized into two groups ( n  = 45 per group). The mean age was 30.68 ± 6.31 years. Post-intervention, the improvement in sperm motility was significantly higher in the vitamin E group compared to the placebo group ( P  = 0.03). Both groups showed significant improvements in sperm motility, count, and morphology from pre- to post-intervention ( P  < 0.001). Conclusion Vitamin E supplementation post-varicocelectomy is associated with improved sperm parameters, suggesting potential benefits in the management of male infertility related to varicocele. However, varicocelectomy alone also results in significant improvements. Trial registration This study is registered at the Iranian Registry of Clinical Trials (IRCT20200911048689N1). Registered on October 10, 2020.

PurposeThe new-generation spermatozoon selection method, microfluidic technique called Fertile Chip® gives the chance to select spermatozoa with lower DNA fragmentation indexes. We aimed to determine the effect of microfluidic techniques for spermatozoon selection in ICSI treatment in patients with unexplained infertility.MethodsThis prospective randomized controlled study was conducted at a university hospital. One hundred twenty-two couples with unexplained infertility were included, in which 61 of them were treated with conventional swim-up techniques (control group) and another 61 with the microfluidic technique (study group) for spermatozoon selection in IVF treatment. The fertilization rates and the quality of embryos were the primary outcomes, and clinical pregnancy (CPR) and live birth rates (LBR) were the secondary outcomes of our study.ResultsCPR in the study group and control group were 48.3% and 44.8% (p = 0.35) and LBR were 38.3% and 36.2% (p = 0.48), respectively. The fertilization rates were similar (63.6% and 57.4%, p = 0.098). A total number of grade 1 embryos were significantly higher in microfluidic technique group than in control group (1.45 ± 1.62 vs. 0.83 ± 1.03, p = 0.01). There were more surplus top quality embryos leftover to freeze in the study group (0.71 ± 1.48 vs. 0.22 ± 0.69, p = 0.02).ConclusionOur study showed that the microfluidic technique does not change fertilization, CPR, and LBR during IVF treatment for couples with unexplained infertility. Despite the fact that the total number of grade 1 embryos after ICSI treatment and the surplus number of grade 1 embryos after embryo transfer were higher in the microfluidic technique group, the study was not powered to detect this difference.Trial registrationNCT02488434

Background Varicocele is a high incidence and is considered to be the most common and correctable cause of male infertility. Oxidative stress (OS) plays a central role in the pathogenesis of varicocele-related male infertility. In addition to varicocelectomy, antioxidant supplementation seems to be an effective scheme for the treatment of varicocele-related male infertility, but it is still controversial. The purpose of this study is to determine the effects of alpha-lipoic acid (ALA) supplementation on sperm quality in patients with varicocele-related male infertility. Methods In this randomized controlled clinical trial, we will randomize 80 patients with varicocele-related male infertility from Guilin People’s Hospital. The non-surgical observation group ( n = 20) will receive ALA, the non-surgical control group ( n = 20) will receive vitamin E, the surgical observation group ( n = 20) will receive ALA after the operation, and the surgical control group ( n = 20) will receive vitamin E after the operation. The course of treatment will be 3 months. The results will compare the changes in semen parameters, sex hormones, testicular volume, sperm DNA fragment index (DFI), seminal plasma malondialdehyde (MDA), and total antioxidant capacity (TAC) between the groups at baseline and after 3 months of antioxidant supplementation. Discussion Whether it is necessary to use antioxidants in varicocele-related male infertility, how potent antioxidants should be used, postoperative application or non-surgical independent application still needs to be explored. This study attempts to compare the effects of two antioxidants (ALA and vitamin E) on sperm quality in patients with varicocele-related male infertility (surgical or non-surgical) and attempted to answer the above questions. Trial registration Chinese Clinical Trial Registry (ChiCTR) ChiCTR2100054958. Registered on 29 December 2021

It is estimated that infertility affects 8–12% of couples globally, with a male factor being a primary or contributing cause in approximately 50% of couples. Causes of male subfertility vary highly, but can be related to congenital, acquired, or idiopathic factors that impair spermatogenesis. Many health conditions can affect male fertility, which underscores the need for a thorough evaluation of patients to identify treatable or reversible lifestyle factors or medical conditions. Although semen analysis remains the cornerstone for evaluating male infertility, advanced diagnostic tests to investigate sperm quality and function have been developed to improve diagnosis and management. The use of assisted reproductive techniques has also substantially improved the ability of couples with infertility to have biological children. This Seminar aims to provide a comprehensive overview of the assessment and management of men with infertility, along with current controversies and future endeavours.

Background Infertility affects an estimated 15% of couples globally, amounting to 48.5 million couples. Males are found to be solely responsible for 20-30% of infertility cases and contribute to 50% of cases overall. However, this number does not accurately represent all regions of the world. Indeed, on a global level, there is a lack of accurate statistics on rates of male infertility. Our report examines major regions of the world and reports rates of male infertility based on data on female infertility. Methods Our search consisted of systematic reviews, meta-analyses, and population-based studies by searching the terms “epidemiology, male infertility, and prevalence.” We identified 16 articles for detailed study. We typically used the assumption that 50% of all cases of infertility are due to female factors alone, 20-30% are due to male factors alone, and the remaining 20-30% are due to a combination of male and female factors. Therefore, in regions of the world where male factor or rates of male infertility were not reported, we used this assumption to calculate general rates of male factor infertility. Results Our calculated data showed that the distribution of infertility due to male factor ranged from 20% to 70% and that the percentage of infertile men ranged from 2·5% to 12%. Infertility rates were highest in Africa and Central/Eastern Europe. Additionally, according to a variety of sources, rates of male infertility in North America, Australia, and Central and Eastern Europe varied from 4 5-6%, 9%, and 8-12%, respectively. Conclusion This study demonstrates a novel and unique way to calculate the distribution of male infertility around the world. According to our results, at least 30 million men worldwide are infertile with the highest rates in Africa and Eastern Europe. Results indicate further research is needed regarding etiology and treatment, reduce stigma & cultural barriers, and establish a more precise calculation.

Varicocele (VC) is present in 35 - 40% of men with infertility. However, current surgical and antioxidant treatments are not completely effective. In addition to oxidative stress, it is likely that other factors such as testicular immune microenvironment disorder contribute to irreversible testicular. Evidence suggests that VC is associated with anti-sperm antibodies (ASAs), spermatogenesis and testosterone secretion abnormalities, and testicular cytokine production. Moreover, inhibition of inflammation can alleviate VC-mediated pathogenesis. The normal function of the testis depends on its immune tolerance mechanism. Testicular immune regulation is complex, and many infectious or non-infectious diseases may damage this precision system. The testicular immune microenvironment is composed of common immune cells and other cells involved in testicular immunity. The former includes testicular macrophages, T cells, dendritic cells (DCs), and mast cells, whereas the latter include Leydig cells and Sertoli cells (SCs). In animal models and in patients with VC, most studies have revealed an abnormal increase in the levels of ASAs and pro-inflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha in the seminal plasma, testicular tissue, and even peripheral blood. It is also involved in the activation of potential inflammatory pathways, such as the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing (NLRP)-3 pathway. Finally, the development of VC-mediated infertility (VMI) may be facilitated by abnormal permeability of proteins, such as claudin-11, that constitute the blood-testis barrier (BTB). The testicular immune response, including the production of ASAs and inflammatory factors, activation of inflammatory pathways, and destruction of the BTB may be involved in the pathogenesis of VMI it is necessary to further explore how patient outcomes can be improved through immunotherapy.

Key Points Male infertility is a complex lifestyle-related disorder Oxidative stress has adverse effects on the structural and functional integrity of sperm and is a major cause of defective sperm function and male infertility Oxidative stress causes damage to both mitochondrial and nuclear DNA and also affects the sperm epigenome, resulting in infertility, recurrent pregnancy loss, poor pregnancy outcomes and an increased disease burden in the offspring Spermatozoa are most vulnerable to oxidative stress and oxidative DNA damage (ODD) as these cells have limited antioxidant defence mechanisms and a limited capacity for detection and repair of DNA damage A number of intrinsic and extrinsic factors can regulate oxidative stress, and these must be maintained at moderate levels for optimal sperm function and the maintenance of cellular homeostasis and redox-sensitive signal-transduction pathways Simple lifestyle modifications and interventions can substantially reduce levels of testicular inflammation, oxidative stress and ODD and improve the quality of life of infertile couples High levels of seminal oxidative stress lead to sperm DNA damage and male factor infertility. In this review, the authors describe the mechanisms of oxidative-stress-induced male factor infertility, and how lifestyle-related interventions might reduce levels of seminal oxidative stress, ameliorate infertility and potentially improve the health of the children of men with high levels of seminal oxidative stress. DNA damage, largely owing to oxidative stress, is a leading cause of defective sperm function. High levels of oxidative stress result in damage to sperm DNA, RNA transcripts, and telomeres and, therefore might provide a common underlying aetiology of male infertility and recurrent pregnancy loss, in addition to congenital malformations, complex neuropsychiatric disorders, and childhood cancers in children fathered by men with defective sperm cells. Spermatozoa are highly vulnerable to oxidative stress owing to limited levels of antioxidant defence and a single, limited DNA-damage detection and repair mechanism. Oxidative stress is predominantly caused by a host of lifestyle-related factors, the majority of which are modifiable. Antioxidant regimens and lifestyle modifications could both be plausible therapeutic approaches that enable the burden of oxidative-stress-induced male factor infertility to be overcome. Lifestyle interventions including yoga and meditation can substantially improve the integrity of sperm DNA by reducing levels of oxidative DNA damage, regulating oxidative stress and by increasing the expression of genes responsible for DNA repair, cell-cycle control and anti-inflammatory effects. Oxidative stress is caused by various modifiable factors, and the use of simple interventions can decrease levels of oxidative stress, and therefore reduce the incidence of both infertility and complex diseases in the resultant offspring.