OBJECTIVE: To explore the role of reactive oxygen species (ROS) and lactate dehydrogenase isoenzyme X (LDH-X) in the changes of sperm mitochondrial membrane potential (MMP) in infertility patients with varicocele (VC). METHODS: This study included 38 infertility patients with VC (VCinf), 35 non-VC infertile males (NVCinf), and 30 normal fertile men as controls. We obtained the routine semen parameters using the sperm quality analysis system, examined the contents of LDH-X in the seminal plasma and sperm with the automatic biochemical analyzer, measured the level of malondialdehyde (MDA) in seminal plasma by thiobarbituric acid (TBA) colorimetry, and determined the expressions of mitochondrial membrane potential (MMP) and LDH-X mRNA in the sperm using JC-1 fluorescence probe and RT-PCR. RESULTS: No statistically significant differences were observed among the three groups of subjects in age, semen pH value, semen volume and sperm concentration (P > 0.05). Compared with the normal fertile controls, the patients in the VCinf and NVCinf groups showed significantly decreased sperm motility (［52.36 ± 12.48］% vs ［34.74 ± 15.23］% vs ［25.76 ± 13.73］%, P< 0.05), percentage of progressively motile sperm (PMS) (［42.54 ± 13.58］% vs ［29.10 ± 14.17］% vs ［20.95 ± 12.33］%, P< 0.05), sperm LDH-X (［16.46 ± 5.47］ vs ［13.63 ± 4.50］ vs ［10.18 ± 3.00］ mU/106, P< 0.05), sperm MMP (［48.04 ± 11.62］% vs ［40.86 ± 12.69］% vs ［34.41 ± 13.93］%, P< 0.05) and expression of sperm LDH-X mRNA (P< 0.05). but increased seminal plasma LDH-X (［935.36 ± 229.48］ vs ［1241.05 ± 337.07］ vs ［1425.08 ± 469.35］ U/L, P< 0.05), seminal plasma/whole sperm LDH-X (［1.06 ± 0.35］ vs ［1.40 ± 0.34］ vs ［1.63 ± 0.66］, P< 0.05), and content of seminal plasma MDA (［1.10 ± 0.19］ vs ［1.59 ± 0.27］ vs ［2.00 ± 0.22］ nmol/ml, P< 0.05). CONCLUSION Excessive ROS in the reproductive system of VCinf patients reduces the content of MMP and causes the overflow of LDH-X out of sperm cells. Therefore the decrease of sperm LDH-X may be accompanied by that of MMP.
Humans ; Male ; Infertility, Male/etiology* ; Varicocele/metabolism* ; Adult ; Reactive Oxygen Species/metabolism* ; Spermatozoa/metabolism* ; L-Lactate Dehydrogenase/metabolism* ; Membrane Potential, Mitochondrial ; Isoenzymes/metabolism* ; Case-Control Studies ; Young Adult ; Mitochondrial Membranes/metabolism*

OBJECTIVE: The aim of this study is to analyze the clinical features and genetic etiology of a patient with multiple morphological abnormalities of the sperm flagella (MMAF) retrospectively. METHODS: A severely oligospermic patient from the Reproductive Center of the First Affiliated Hospital of Ningbo University was selected as the study subject. Clinical data and examination results were collected. High-throughput sequencing and bioinformatics were used to analyze the genetic etiology. And Sanger sequencing was employed to validate findings in the family. Transmission electron microscopy (TEM) was used to observe the sperm ultrastructure, and immunofluorescence analysis was performed to examine the localization of FSIP2 protein in the sperm. RESULTS: The patient presented with severe oligospermia, and sperm morphology displayed MMAF. TEM revealed fibrous sheath and 9+2 microtubule structural disruptions in the sperm. Sequencing identified compound heterozygous variants in the FSIP2 gene (c.17798C > T, c.5927T > G), inherited from the father and mother, respectively. According to the guidelines of the American College of Medical Genetics and Genomics, the variants were classified as pathogenic. The patient's spouse underwent intracytoplasmic single sperm injection, resulting in one embryo, but no clinical pregnancy occurred after embryo transfer. CONCLUSION This study reported the mutation of FSIP2 gene c.17798C > T, c.5927T > G in a patient with MMAF. These findings expand the mutational spectrum of the FSIP2 gene and provide insights for genetic and assisted reproductive counseling for patients with MMAF.
Humans ; Male ; Sperm Tail/pathology* ; Heterozygote ; Oligospermia/genetics* ; Spermatozoa ; Mutation ; Infertility, Male/genetics* ; Adult ; Pedigree ; Retrospective Studies ; Sperm Injections, Intracytoplasmic

Bisphenol A (BPA) is a kind of exogenous chemicals presenting in the human living environment widely which affects the action of endocrine hormones in the human body. Numerous studies have shown that BPA has reproductive toxicity in the spermatogenic function damage of the testes through a variety of mechanisms such as interfering with endocrine function, inducing oxidative stress, promoting spermatogonial cell apoptosis, destroying the integrity of the blood-testis barrier, and regulating epigenetic inheritance, thereby destroying male fertility. Relevant studies have shown that TCM can improve male fertility by reversing BPA-induced reproductive damage through multi-component, multi-target and multi-mechanisms. However, there is no systematic review on the mechanism of TCM to reduce the reproductive toxicity of BPA. Based on the existing studies, this article will systematically introduce the mechanisms of BPA-induced reproductive impairment in men and the progress of TCM interventions, with a view to providing reference targets and research directions for the development of new Chinese medicines.
Humans ; Benzhydryl Compounds/adverse effects* ; Male ; Phenols/adverse effects* ; Medicine, Chinese Traditional ; Infertility, Male/chemically induced* ; Testis/drug effects* ; Drugs, Chinese Herbal/therapeutic use* ; Bisphenol A Compounds

Prostate cancer is one of the most common tumor, with the disease progressing from inert to aggressive tumors, and rapidly progressing to castration-resistant prostate cancer. Early-stage prostate cancer is usually asymptomatic. And by the time that symptoms appear, the disease has progressed to an incurable stage. Therefore, early diagnosis and treatment is especially important to control prostate cancer, which prolongs the survival period of patients. Digital rectal examination and prostate-specific antigen have been widely used in the diagnosis of prostate cancer. However, there are certain limitations that lead to overdiagnosis and overtreatment. Although prostate needle biopsy is still the gold standard for diagnosing prostate cancer, with the wide application of multiparametric magnetic resonance examination and PSMA-PET/CT and other technologies in recent years, as well as the emergence of new biomarkers with higher sensitivity and specificity, its status as the gold standard has been challenged. And the diagnostic mode of prostate cancer has also undergone great changes. On this basis, the radical prostatectomy without prostate needle biopsy has been attempted clinically to treat prostate cancer, which gains the good clinical results. This article provides a review of the latest research advances in early screening and diagnostic models for prostate cancer.
Humans ; Male ; Benzhydryl Compounds/adverse effects* ; Drugs, Chinese Herbal/therapeutic use* ; Infertility, Male/chemically induced* ; Medicine, Chinese Traditional ; Phenols/adverse effects* ; Testis/drug effects* ; Bisphenol A Compounds

Male infertility has become a global concern, accounting for 20-70% of infertility. Dysfunctional spermatogenesis is the most common cause of male infertility; thus, treating abnormal spermatogenesis may improve male infertility and has attracted the attention of the medical community. Mitochondria are essential organelles that maintain cell homeostasis and normal physiological functions in various ways, such as mitochondrial oxidative phosphorylation (OXPHOS). Mitochondrial OXPHOS transmits electrons through the respiratory chain, synthesizes adenosine triphosphate (ATP), and produces reactive oxygen species (ROS). These mechanisms are vital for spermatogenesis, especially to maintain the normal function of testicular Sertoli cells and germ cells. The disruption of mitochondrial OXPHOS caused by external factors can result in inadequate cellular energy supply, oxidative stress, apoptosis, or ferroptosis, all inhibiting spermatogenesis and damaging the male reproductive system, leading to male infertility. This article summarizes the latest pathological mechanism of mitochondrial OXPHOS disorder in testicular Sertoli cells and germ cells, which disrupts spermatogenesis and results in male infertility. In addition, we also briefly outline the current treatment of spermatogenic malfunction caused by mitochondrial OXPHOS disorders. However, relevant treatments have not been fully elucidated. Therefore, targeting mitochondrial OXPHOS disorders in Sertoli cells and germ cells is a research direction worthy of attention. We believe this review will provide new and more accurate ideas for treating male infertility.
Male ; Humans ; Infertility, Male/metabolism* ; Oxidative Phosphorylation ; Mitochondria/metabolism* ; Spermatogenesis/physiology* ; Sertoli Cells/metabolism* ; Oxidative Stress/physiology* ; Animals ; Reactive Oxygen Species/metabolism*

BACKGROUND: Infertility is a burdensome, often overlooked condition. This study aimed to investigate the global distribution and trends in the burden of infertility from 1990 to 2021. METHODS: We obtained data on the prevalence and years lived with disability (YLDs) related to infertility from the Global Burden of Disease 2021 study and evaluated them by calculating the estimated annual percentage change in age-standardized rates. We investigated the relationship between sociodemographic index (SDI) and the burden of infertility on the global, regional, and national levels. RESULTS: In 2021, there were 143,261,562 female and 55,481,380 male infertility cases worldwide, respectively. In China, female and male infertility cases accounted for 23.59% and 21.47% of the global totals, reaching 33,795,944 and 11,909,889, respectively. Compared with 2019, the global number of female and male infertility cases increased by 5,286,227 in females and 2,017,271 in males. In contrast, China saw a decline in both female and male infertility cases, with reductions of 698,735 and 154,591, respectively. From 1990 to 2021, the age-standardized prevalence rate (ASPR) and age-standardized YLDs rate (ASYR) for female infertility both increased by 0.59% annually, whereas these two corresponding indicators for male infertility increased by 0.50% annually worldwide. The burden of female infertility was consistently higher than that of male infertility and demonstrated a faster rate of increase. East Asia had the highest ASPR and ASYR for female infertility, whereas Eastern Europe had the highest metrics for male infertility. A horizontal S-shaped association was observed between the SDI and ASPR and ASYR of infertility, with a rapid decline in the infertility burden when the SDI exceeded 0.7. CONCLUSIONS The global burden of infertility has increased over the years, with a higher burden on women and underdeveloped regions. These findings emphasize the need to prioritize healthcare for patients with infertility to address the rising burden.
Humans ; Female ; Male ; Global Burden of Disease ; Prevalence ; Infertility/epidemiology* ; Adult ; Infertility, Male/epidemiology* ; Persons with Disabilities/statistics & numerical data* ; Middle Aged ; Infertility, Female/epidemiology* ; China/epidemiology* ; Disability-Adjusted Life Years

Recently, male reproductive health has attracted extensive attention, with the adverse effects of circadian disruption on male fertility gradually gaining recognition. However, the mechanism by which circadian disruption leads to damage to male reproductive system remains unclear. In this review, we first summarized the dual regulatory roles of circadian clock genes on the male reproductive system: (1) circadian regulation of testosterone synthesis via the hypothalamic-pituitary-testicular (HPT) and hypothalamic-pituitary-adrenal (HPA) axes; (2) non-circadian regulation of spermatogenesis. Next, we further listed the possible mechanisms by which circadian disruption impairs male fertility, including interference with the oscillatory function of the reproductive system, i.e., synchronization of the HPT axis, crosstalk between the HPT axis and the HPA axis, as well as direct damage to germ cells by disturbing the non-oscillatory function of the reproductive system. Future research using spatiotemporal omics, epigenomic assays, and neural circuit mapping in studying the male reproductive system may provide new clues to systematically unravel the mechanisms by which circadian disruption affects male reproductive system through circadian clock genes.
Male ; Humans ; Animals ; Circadian Clocks/physiology* ; Hypothalamo-Hypophyseal System/physiology* ; Circadian Rhythm/genetics* ; Spermatogenesis/physiology* ; Pituitary-Adrenal System/physiology* ; Testis/physiology* ; Testosterone/biosynthesis* ; CLOCK Proteins ; Infertility, Male/physiopathology*

Varicocele is a prevalent condition in the infertile male population. However, to date, which patients may benefit most from varicocele repair is still a matter of debate. The purpose of this study was to evaluate whether certain preintervention sperm parameters are predictive of successful varicocele repair, defined as an improvement in total motile sperm count (TMSC). We performed a retrospective study on 111 patients with varicocele who had undergone varicocele repair, collected from the Department of Endocrinology, Metabolic Diseases and Nutrition, University of Catania (Catania, Italy), and the Unit of Urology at the Selcuk University School of Medicine (Konya, Türkiye). The predictive analysis was conducted through the use of the Brain Project, an innovative tool that allows a complete and totally unbiased search of mathematical expressions that relate the object of study to the various parameters available. Varicocele repair was considered successful when TMSC increased by at least 50% of the preintervention value. For patients with preintervention TMSC below 5 × 10 6 , improvement was considered clinically relevant when the increase exceeded 50% and the absolute TMSC value was >5 × 10 6 . From the preintervention TMSC alone, we found a model that predicts patients who appear to benefit little from varicocele repair with a sensitivity of 50.0% and a specificity of 81.8%. Varicocele grade and serum follicle-stimulating hormone (FSH) levels did not play a predictive role, but it should be noted that all patients enrolled in this study were selected with intermediate- or high-grade varicocele and normal FSH levels. In conclusion, preintervention TMSC is predictive of the success of varicocele repair in terms of TMSC improvement in patients with intermediate- or high-grade varicoceles and normal FSH levels.
Humans ; Varicocele/complications* ; Male ; Retrospective Studies ; Machine Learning ; Adult ; Treatment Outcome ; Sperm Count ; Infertility, Male/etiology* ; Sperm Motility ; Follicle Stimulating Hormone/blood* ; Young Adult

Infertility has become one of the most serious diseases worldwide, and 50% of this disease can be attributed to male-related factors. Spermatogenesis, by definition, is a complex process by which spermatogonial stem cells (SSCs) self-renew to maintain stem cell population within the testes and differentiate into mature spermatids. It is of great significance to uncover gene regulation and signaling pathways that are involved in the fate determinations of SSCs with aims to better understand molecular mechanisms underlying human spermatogenesis and identify novel targets for gene therapy of male infertility. Significant achievement has recently been made in demonstrating the signaling molecules and pathways mediating the fate decisions of mammalian SSCs. In this review, we address key gene regulation and crucial signaling transduction pathways in controlling the self-renewal, differentiation, and apoptosis of SSCs, and we illustrate the networks of genes and signaling pathways in SSC fate determinations. We also highlight perspectives and future directions in SSC regulation by genes and their signaling pathways. This review could provide novel insights into the genetic regulation of normal and abnormal spermatogenesis and offer molecular targets to develop new approaches for gene therapy of male infertility.
Humans ; Male ; Signal Transduction/physiology* ; Apoptosis/physiology* ; Spermatogenesis/physiology* ; Cell Differentiation ; Adult Germline Stem Cells/physiology* ; Spermatogonia/cytology* ; Gene Expression Regulation ; Animals ; Infertility, Male/genetics* ; Cell Self Renewal/genetics*

Spermatozoa have a highly complex RNA profile. Several of these transcripts are suggested as biomarkers for male infertility and contribute to early development. To analyze the differences between sperm RNA quantity and expression of protamine ( PRM1 and PRM2 ) and testis-specific histone 2B ( TH2B ) genes, spermatozoa from 33 patients who enrolled in assisted reproduction treatment (ART) program were analyzed. Sperm RNA of teratozoospermic (T), oligoteratozoospermic (OT), and normozoospermic (N) samples was extracted, and the differences in transcript levels among the study groups were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). The correlations of total RNA per spermatozoon and the expression of the transcripts were evaluated in relation to sperm characteristics and preimplantation embryo development. The mean (±standard deviation) RNA amount per spermatozoon was 28.48 (±23.03) femtogram in the overall group and was significantly higher in the OT group than that in N and T groups. Total sperm RNA and gene expression of PRM1 and PRM2 genes were related to preimplantation embryo development and developmental arrest. Specific sperm characteristics were correlated with the expressions of PRM1 , PRM2 , or TH2B genes. We conclude that the sperm RNA amount and composition are important factors and might influence early embryonic development and also differ in different cases of male infertility.
Male ; Humans ; Protamines/metabolism* ; Spermatozoa/metabolism* ; Embryonic Development/genetics* ; Adult ; RNA/genetics* ; Histones/genetics* ; Infertility, Male/genetics* ; Teratozoospermia/genetics* ; Oligospermia/genetics*