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Apelin/APJ receptor (R) is involved in many oxidative stress-induced pathological conditions. Since this system is not yet explored in male reproduction, we studied apelin/APJ-R in human semen and testis. Semen of 41 infertile patients with varicocele, genitourinary infections, unexplained infertility and 12 fertile men was analysed (WHO guidelines, 2021). Apelin was quantified by ELISA in seminal fluid and spermatozoa, interleukin (IL)-1β in seminal fluid. Apelin/APJ-R were immunolocalized in spermatozoa and testis. Apelin was present in spermatozoa and its levels were negatively correlated with normal sperm morphology% (r = -0.857; p < 0.001), and positively with IL-1β levels (r = 0.455; p < 0.001). Apelin and IL-1β concentrations were increased in patients' samples with varicocele (apelin p < 0.01; IL-1β p < 0.05) and infections (apelin p < 0.01; IL-1β p < 0.001). By logistic regression analysis, apelin (OR 1.310; p = 0.011) and IL-1β (OR 1.572; p = 0.005) were predictors of inflammatory diseases (varicocele, infections). Apelin and APJ-R immunofluorescence labels were weak in sperm tail of fertile men and intense along tail, cytoplasmic residues and post-acrosomal sheath of sperm from infertile men. In testis, apelin and APJ-R labels were evident in Leydig cells and weak inside the seminiferous tubule. Apelin/APJ-R system is present in human spermatozoa and testicular tissue and probably involved in human fertility., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The impact of male aging on male fertility has only recently become of interest to the scientific community. This study aims to assess the relationship between age and fertility among a sample of men, considering the individual and pathological characteristics. In this retrospective study data of semen analysis and medical history of 1294 Italian male patients were considered. Semen analysis was performed by light microscopy and transmission electron microscopy mathematically elaborated. A generalized linear model was used to explore the influence of male age on semen quality, considering as confounders wine consumption, smoking habits, presence of varicocele, consanguinity and positive semen bacteriological analysis and urethral swab. The mean age of the participants was 36.41 ± 6.379. Male aging without impact of confounders was correlated with a decrease in sperm concentration and motility and an increased in sperm necrosis. Sperm concentration and progressive motility were negatively related to the presence of confounders as wine consumption (sperm motility), urogenital infection (sperm concentration and motility), varicocele (sperm concentration) and consanguinity (sperm motility). Urogenital infection, varicocele and consanguinity positively correlated with sperm necrosis. The most important finding was the observation of a negative effect of male aging on sperm parameters such as concentration, motility, and viability. It is possible to hypothesize age-dependent changes of testicular environment, probably related to reactive oxygen species production. The demonstration, in a large sample of patients, that aging influences sperm quality strongly motivates further research focused on the mechanisms involved in this phenomenon and its effects on offspring fitness.

The evaluation of the seminal plasma plays a relevant role in the definition of male infertility and in assisted reproduction outcomes; for this reason, it would be recommended to find biochemical markers able to characterize sperm pathology. In this study, 53 infertile patients (grouped by the presence leukocytospermia, idiopathic infertility, or varicocele) and 10 fertile men were selected. Spermiogram was performed by light microscopy, and sperm ultrastructure was evaluated by transmission electron microscopy (TEM) mathematically elaborated. Testosterone (TESTO), estradiol (E2), ferritin (FERR), iron (Fe), transferrin (TRSF), triglycerides (TRG), cholesterol (CHOL), and isoprostanes (F 2 -IsoPs) were detected in seminal plasma. Sperm characteristics and biochemical components were correlated by Spearman's rank correlation coefficient in the whole population and in each group. The levels of TESTO and E2 were positively correlated with sperm quality in particular, and E2 was correlated with fertility index expressing the number of sperm free of ultrastructural defects evaluated by TEM. On the contrary, the indices of iron metabolism (FERR, Fe, and TRSF) were positively associated with low sperm quality and sperm necrosis, particularly in leukocytospermia and varicocele groups, pathologies in which an inflammatory status and oxidative stress condition are present. The study of the seminal plasma composition deserves attention because the levels of the various components seem to be associated with specific reproductive pathologies.

Objectives: Fatty acids (FA) modulate oxidative stress, reactive oxygen species (ROS) production, and inflammatory processes in spermatogenesis., Methods: The amount of 17 different FAs and the level of F 2 -isoprostanes (F 2 -IsoPs) and cytoplasmic phospholipase A 2 (cPLA 2 ) were compared and correlated to sperm characteristics; these last ones were evaluated by light and electronic microscopy in varicocele and idiopathic infertile patients., Results: Total n-3 polyunsaturated acids (PUFAs) and docosahexaenoic acid (DHA), one of the n-3 PUFAs, were significantly reduced in idiopathic infertile men compared to controls ( P < 0.05). In the whole studied population, oleic acid and total monounsaturated acids (MUFAs) correlated negatively with sperm concentration, progressive motility, normal morphology, vitality, and fertility index and positively with sperm necrosis. Eicosapentaenoic acid (EPA) amount was positively correlated with the percentage of sperm necrosis and cPLA 2 level and negatively with sperm concentration. Sperm vitality was negatively correlated with the saturated fatty acids (SFAs). In infertile groups, cPLA 2 was negatively correlated with DHA and n-3 PUFAs (both P < 0.05) and positively with EPA ( P < 0.05). In the varicocele group, sperm vitality was negatively correlated with palmitoleic acid and total n-6 PUFAs ( P < 0.05); sperm apoptosis was positively correlated with the total SFA percentage ( P < 0.05)., Conclusions: FA composition in sperm membrane and the metabolism of sperm FAs are interrelated parameters, both relevant in sperm maturation processes and fertility., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Giulia Collodel et al.)

The aim of this paper was to investigate the relevance of isoprostanoids i.e., F 2 -isoprostanes (F 2 -IsoPs), F 4 -neuroprostanes (F 4 -NeuroPs) and F 2 -dihomo-isoprostanes (F 2 -dihomo-IsoPs) in semen quality. Isoprostanoid levels were detected in semen of fertile and infertile men with varicocele or idiopathic infertility. Semen quality was assessed by light microscopy and transmission electron microscopy; the relationships between isoprostanes and semen parameters were also explored. F 2 -IsoPs levels were significantly different in the varicocele group compared to idiopathic infertile group and fertile men (P < 0.01 and P < 0.001 respectively). Moreover, F 2 -dihomo-IsoP values were significantly higher in varicocele group respect to fertile men (P < 0.05). No significant statistical differences were found regarding F 4 -NeuroP concentrations. In the whole population, F 2 -IsoPs positively correlated with F 2 -dihomo-IsoPs and both isoprostanoids showed a positive correlation with immaturity and a negative correlation with sperm motility. F 2 -IsoP levels were positively correlated with the percentage of immaturity in infertile varicocele groups (P < 0.01) whereas a significant relationship between F 4 -NeuroP values and the percentage of sperm necrosis was shown in idiopathic infertility group (P < 0.01). A significant negative correlation of F 4 -NeuroPs with sperm morphology was detected in infertile varicocele subjects (P < 0.05). This study suggests that isoprostanoid semen levels appear to be associated with male infertility being related to the sperm quality and confirming the important role of fatty acids profiling in human sperm maturation., Competing Interests: Declaration of Competing Interest The authors have declared that no conflict of interest exists., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Ghrelin and obestatin are involved in many biological functions including reproduction. Growing evidences suggest that both peptides could exert protective and antioxidant activities. In this study, the relationships between ghrelin/obestatin, interleukin-6 (IL-6), tumor necrosis factor- α (TNF- α ), malondialdehyde (MDA), reduced glutathione (GSH), oxidized glutathione (GSSG), expressed as the GSH/GSSG ratio, catalase (CAT), and semen parameters in infertile patients with varicocele or leukocytospermia and controls were investigated. Fifty-six infertile patients (32 with leukocytospermia and 24 with varicocele) and 14 controls participated in this study. Semen analysis was performed following the WHO guidelines. Apoptotic and necrotic sperm were scored by annexin V/propidium iodide assay. Seminal plasma samples were used for the following determinations: ghrelin, obestatin, IL-6, and TNF- α were measured by an immunological method, GSH/GSSG by an enzymatic method, and CAT by spectrophotometric determination. With respect to controls, both the leukocytospermia and varicocele groups showed altered sperm parameters, significantly increased sperm apoptosis ( P = 0.009 and P = 0.011, respectively), IL-6 ( P = 0.0001 and P = 0.004, respectively), and TNF- α levels ( P = 0.0001 and P = 0.002, respectively); both groups had significantly decreased levels of ghrelin ( P = 0.0001), obestatin ( P = 0.0001 and P = 0.006, respectively), and GSH/GSSG ratio ( P = 0.003 and P = 0.0001, respectively). The MDA concentration was significantly increased in the leukocytospermia group vs. controls ( P = 0.0001), in the varicocele group vs. controls ( P = 0.011), and in the leukocytospermia group vs. the varicocele group ( P = 0.008). CAT activity was augmented in both the leukocytospermia and varicocele groups ( P = 0.0001) vs. controls. The results indicate that both ghrelin and obestatin may play a protective role in human semen and this effect is probably due to their antioxidant properties., Competing Interests: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (Copyright © 2019 Lucia Micheli et al.)

Polyunsaturated fatty acid damages lead to alterations in sperm function. This study aimed to investigate the involvement of F 2 -isoprostanes (F 2 -IsoPs), oxidized lipid products from arachidonic acid, in sperm quality impairment. For this purpose, F 2 -IsoP levels in semen and F 2 -IsoP localization in spermatozoa were explored in infertile subjects affected by idiopathic infertility or varicocele, as well as in fertile men. As compared to fertile men, in the idiopathic infertility and varicocele groups, sperm concentration, motility, morphology, viability, and fertility index were significantly lower and the mean scores concerning sperm apoptosis, necrosis, and immaturity were significantly higher. The idiopathic infertile group showed a reduction in sperm motility and fertility index, as well as an increase of apoptosis and necrosis percentages, in comparison to the varicocele group. The varicocele group showed the highest levels of F 2 -IsoPs, a significant increase of sperm immaturity, and a significant correlation between F 2 -IsoP levels and sperm immaturity. 8-Iso Prostaglandin F 2 α , biomarker of in vivo F 2 -IsoP, was clearly localized in sperm midpiece and cytoplasmic residues. Data show that F 2 -IsoP formation is relevant in semen and sperm from infertile patients with varicocele and high percentage of immaturity, suggesting that a correct fatty acid integrity is needed for sperm maturation.

Objective: To explore the relationships between resistin, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) and semen parameters, sperm apoptosis, and necrosis in infertile patients and in control subjects with unknown reproductive potential with/without smoking habits, leukocytospermia, and varicocele., Design: Prospective study., Setting: Sperm laboratory., Patient(s): A total of 110 selected men., Intervention(s): Family history, clinical/physical examination, ELISA determination (resistin, IL-6, TNF-α), semen analysis, annexin V/propidium iodide assay., Main Outcome Measure(s): Relationships among resistin, IL-6, and TNF-α and semen parameters in the presence of smoking habits, varicocele, leukocytospermia, and in infertile subjects., Result(s): Resistin level was higher in semen than in serum. Resistin semen levels showed negative correlations with sperm motility and positive correlations with apoptotic, necrotic sperm and TNF-α and IL-6 levels. Resistin, TNF-α, and IL-6 levels were higher in smokers compared with nonsmokers and in cases with leukocytospermia, in which an increase in necrotic sperm and a decrease in the number of sperm with normal morphology and motility were observed. Cytokine levels were significantly higher in infertile patients compared with control subjects with unknown reproductive potential. A total of 74.5% of infertile patients showed leukocytospermia., Conclusion(s): Semen resistin correlated with IL-6, TNF-α, and sperm quality; in cases of leukocytospermia and smoking habits, resistin concentrations were increased, suggesting that resistin may play a regulatory role in inflammation of the male reproductive system., (Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The idea that varicocele plays a detrimental role in fertility is supported by the presence of a higher frequency of affected men among the infertile population than among men with normal semen parameters. In this research we examined ejaculates from a large group of selected men affected by varicocele by light and electron microscopy. The effect of varicocele on chromosome meiotic segregation was investigated by fluorescence in situ hybridization (FISH). The potential benefits of varicocelectomy on sperm quality were evaluated by analyzing sperm characteristics before and after surgical correction of varicocele. Transmission electron microscopy (TEM) analysis, elaborated previously, showed that the incidence of immaturity, apoptosis, and necrosis was higher in the varicocele group than in controls. FISH analysis performed on sperm nuclei from selected patients with varicocele showed that the mean frequencies of disomies and diploidies were generally out of the normal range, indicating a severe disturbance in meiotic segregation. Sperm characteristics evaluated before and after varicocele repair showed a general improvement. As a consequence, the varicocele seem to affect sperm morphology and function concomitantly with meiotic segregation derangement. In consideration of these data, we suggest that TEM and FISH analyses should be performed for all varicocele patients.

This study aims to investigate the role of ferroptosis, an iron-dependent form of regulated cell death, in male infertility. The motivation behind this research stems from the increasing recognition of oxidative stress and iron metabolism dysregulation as critical factors in male reproductive health. In this study, 28 infertile patients (grouped by the presence of urogenital infections or varicocele) and 19 fertile men were selected. Spermiograms were performed by light microscopy (WHO, 2021). Testosterone, ferritin, transferrin-bound iron, transferrin, and F2-isoprostanes (F2-IsoPs) were detected in seminal plasma. Glutathione peroxidase 4 (GPX4) and acyl coenzyme A synthetase long chain family member 4 (ACSL4) were also assessed in sperm cells using enzyme-linked immunosorbent assays (ELISA). All the variables were correlated (statistically significant Spearman's rank correlations) in the whole population, and then the comparison between variables of the different groups of men were carried out. Seminal ferritin and transferrin positively correlated with seminal F2-IsoPs, which had positive correlations with ACSL4 detected in sperm cells. Ferritin and ACSL4 negatively correlated with the seminal parameters. No correlation was detected for GPX4. Comparing the variables in the three examined groups, elevated levels of ACSL4 were observed in infertile patients with urogenital infections and varicocele; GPX4 levels were similar in the three groups. These results suggested a mechanism of ferroptosis, identified by increased ACSL4 levels and the occurrence of lipid peroxidation. Such events appear to be GPX4-independent in reproductive pathologies such as varicocele and urogenital infections. [ABSTRACT FROM AUTHOR]

Nerve growth factor (NGF) signalling affects spermatogenesis and mature sperm traits. In this paper, we aimed to evaluate the distribution and the role of NGF and its receptors (p75NTR and TrKA) on the reproductive apparatus (testis and epididymis) and sperm of fertile men (F) and men with different pathologies, namely varicocele (V) and urogenital infections (UGIs). We collected semen samples from 21 individuals (31–40 years old) subdivided as follows: V (n = 7), UGIs (n = 7), and F (n = 7). We submitted the semen samples to bacteriological analysis, leucocyte identification, and analysis of sperm parameters (concentration, motility, morphology, and viability). We determined the seminal plasma levels of NGF, interleukin 1β (IL-1β), and F2-isoprostanes (F2-IsoPs), and the gene and protein expression of NGF receptors on sperm. We also used immunofluorescence to examine NGF receptors on ejaculated sperm, testis, and epididymis. As expected, fertile men showed better sperm parameters as well as lower levels of NGF, F2-IsoPs, and IL-1β compared with men with infertility. Notably, in normal sperm, p75NTR and TrKA were localised throughout the entire tail. TrKA was also found in the post-acrosomal sheath. This localisation appeared different in patients with infertility: in particular, there was a strong p75NTR signal in the midpiece and the cytoplasmic residue or coiled tails of altered ejaculated sperm. In line with these findings, NGF receptors were intensely expressed in the epididymis and interstitial tissue of the testis. These data suggest the distinctive involvement of NGF and its receptors in the physiology of sperm from fertile men and men with infertility, indicating a possible role for new targeted treatment strategies. [ABSTRACT FROM AUTHOR]

Purpose: Omentin-1/intelectin (ITLN)1 is an adipocytokine with both anti-inflammatory and anti-oxidative stress properties, and little is known about its role in male reproduction. This study was aimed at exploring the relationships among omentin-1/ITLN1, semen parameters and F2-isoprostanes (F2-IsoPs), a maker of oxidative stress, in groups of patients affected by different pathologies. In addition, omentin-1/ITLN1 immunolocalization was assessed in ejaculated spermatozoa and in tissues of male reproductive system. Patients and Methods: Semen samples of infertile patients with varicocele (n = 27), genitourinary infections (n = 17), idiopathic infertility (n = 15) and fertile men (n = 21) were analyzed following WHO guidelines, and seminal plasma were used to determine omentin-1/ITLN1 by ELISA and F2-IsoP levels by gas chromatography/negative-ion chemical ionization tandem mass spectrometry. Omentin-1/ITLN1 was localized in human sperm and in the tissue of male reproductive system. Results: Considering all participants, F2-IsoP and omentin-1/ITLN1 levels were positively correlated (p = 0.000), and both these indices were negatively correlated with sperm parameters. Infertile patients showed lower sperm parameters than fertile ones; varicocele and infection groups had significantly increased levels of F2-IsoPs (both p = 0.000) and omentin-1/ITLN1 (p = 0.000 and p = 0.001, respectively). Omentin-1/ITLN1 signal was located as a spot in the connecting piece (in 43.5% of cases midpiece was also labeled) of sperm from fertile men and in cytoplasmic residue and in the entire tail in sperm of patients with varicocele and genitourinary infections. A focal omentin-1/ITLN1 immunolabelling was evident in the basal area of epididymal tubule, and a diffuse signal was present in the seminal vesicle epithelium. Conclusion: Semen omentin-1/ITLN1 originates from seminal vesicles, its levels increase in inflammatory conditions and are negatively correlated with sperm parameters. For this reason, a sort of protective role of omentin-1/ITLN1 can be postulated, as this adipokine shows anti-inflammatory properties also in many other biological systems. Graphical [ABSTRACT FROM AUTHOR]

Human seminal fluid is a complex mixture of secretions originated from epididymis and the male accessory sex glands. It contains a variety of both inorganic and organic components, among which proteins are a major part of the high molecular-mass substances. In this study, 83 human seminal plasma samples were analyzed using a combined Nuclear Magnetic Resonance (NMR) Spectroscopy and Principal Component Analysis (PCA) approach to discriminate patients in relation to semen characteristics and/or conditions affecting the fertility status. Results showed a discrimination between patients with leukocytospermia and with the concomitant presence of varicocele/ex varicocele and leukocytospermia. Patients with testicular cancer, necrozoospermia, and azoospermia were separated from the other patient clusters. In addition, a differentiation of semen quality was also possible. This study represents to first use of sperm parameters together with NMR data as variables in the PCA analysis. Furthermore, this methodology allows the identification of the metabolites which play the most important role in identifying differences among human seminal plasma samples. [ABSTRACT FROM AUTHOR]