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"Infertility, Male"
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Male infertility due to testicular disorders
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.
Journal Article
Oxidative stress and male infertility: current knowledge of pathophysiology and role of antioxidant therapy in disease management
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.
Journal Article
Sperm DNA fragmentation testing: Summary evidence and clinical practice recommendations
We herein summarise the evidence concerning the impact of sperm DNA fragmentation in various clinical infertility scenarios and the advances on sperm DNA fragmentation tests. The collected evidence was used to formulate 41 recommendations. Of these, 13 recommendations concern technical aspects of sperm DNA fragmentation testing, including pre‐analytical information, clinical thresholds and interpretation of results. The remaining 28 recommendations relate to indications for sperm DNA fragmentation testing and clinical management. Clinical scenarios like varicocele, unexplained infertility, idiopathic infertility, recurrent pregnancy loss, intrauterine insemination, in vitro fertilisation/intracytoplasmic sperm injection, fertility counselling for men with infertility risk factors and sperm cryopreservation have been contemplated. The bulk evidence supporting the recommendations has increased in recent years, but it is still of moderate to low quality. This guideline provides clinicians with advice on best practices in sperm DNA fragmentation testing. Also, recommendations are provided on possible management strategies to overcome infertility related to sperm DNA fragmentation, based on the best available evidence. Lastly, we identified gaps in knowledge and opportunities for research and elaborated a list of recommendations to stimulate further investigation.
Journal Article
Effects of the microfluidic chip technique in sperm selection for intracytoplasmic sperm injection for unexplained infertility: a prospective, randomized controlled trial
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
Journal Article
The impact of vitamin E supplementation on sperm analysis in varicocelectomy patients: a triple-blind randomized controlled trial
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.
Journal Article
Effects of alpha-lipoic acid on sperm quality in patients with varicocele-related male infertility: study protocol for a randomized controlled clinical trial
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
Journal Article
Male infertility
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.
Journal Article
Interplay of Ferroptosis, Cuproptosis, Autophagy and Pyroptosis in Male Infertility: Molecular Crossroads and Therapeutic Opportunities
Male infertility is intricately linked to dysregulated cell death pathways, including ferroptosis, cuproptosis, pyroptosis, and autophagy. Ferroptosis, driven by iron-dependent lipid peroxidation through the Fenton reaction and inactivation of the GPX4/Nrf2/SLC7A11 axis, disrupts spermatogenesis under conditions of oxidative stress, environmental toxin exposure, or metabolic disorders. Similarly, cuproptosis—characterized by mitochondrial dysfunction and disulfide stress due to copper overload—exacerbates germ cell apoptosis via FDX1 activation and NADPH depletion. Pyroptosis, mediated by the NLRP3 inflammasome and gasdermin D, amplifies testicular inflammation and germ cell loss via IL-1β/IL-18 release, particularly in response to environmental insults. Autophagy maintains testicular homeostasis by clearing damaged organelles and proteins; however, its dysregulation impairs sperm maturation and compromises blood–testis barrier integrity. These pathways intersect through shared regulators; reactive oxygen species and mTOR modulate the autophagy–pyroptosis balance, while Nrf2 and FDX1 bridge ferroptosis–cuproptosis crosstalk. Therapeutic interventions targeting these mechanisms have shown promise in preclinical models. However, challenges persist, including the tissue-specific roles of gasdermin isoforms, off-target effects of pharmacological inhibitors, and transgenerational epigenetic impacts of environmental toxins. This review synthesizes current molecular insights into the cell death pathways implicated in male infertility, emphasizing their interplay and translational potential for restoring spermatogenic function.
Journal Article
Varicocele-Mediated Male Infertility: From the Perspective of Testicular Immunity and Inflammation
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.
Journal Article