Idiopathic Male Factor Infertility Research Articles

Association between embryo morphokinetic development and intracytoplasmic sperm injection with epididymal sperm via time-lapse imaging.

The objective of this study was to investigate the impact of sperm source on embryo morphokinetics and the clinical outcomes of intracytoplasmic sperm injection (ICSI) cycles by considering the clustering of data (multiple embryos per patient that share a comparable developmental timing). This matched cohort study was performed at a private university-affiliated in vitro fertilization center. Women who underwent ICSI with epididymal sperm between January 2019 and December 2020 (the percutaneous epididymal sperm aspiration group, n = 32 cycles) were matched with women who underwent ICSI with ejaculated sperm because of idiopathic male factor infertility (the male factor infertility [MFI] group, n = 32 cycles) or female infertility (the control group, n = 32 cycles). Embryos were cultured in a time-lapse imaging incubator, and morphokinetic development was recorded and compared among the groups. Significantly slower divisions were observed in embryos derived from epididymal sperm than in those derived from the MFI and control groups. Embryos derived from epididymal sperm had a significantly lower KIDScore (3.1 ± 0.2) than did those derived from ejaculated spermatozoa from the MFI (5.4 ± 0.1) and control (5.6 ± 0.2, p < 0.001) groups. Epididymal sperm-derived embryos showed a significantly greater occurrence of multinucleation (23.2%) than did those derived from ejaculated sperm from the MFI and control groups (2.8% and 3.7%, p < 0.001, respectively). Epididymal sperm-derived embryos were significantly more likely to undergo direct or reverse cleavage (11.1%) than ejaculated sperm-derived embryos in the control group (4.3%, p = 0.001). In conclusion, delayed cell cleavage and increased incidences of blastomere multinucleation and abnormal cleavage patterns are observed when epididymal-derived sperm are used for ICSI.

Effects of Lycopene on Sperm Parameter in Healthy Male: A Review

Infertility is an ability of couple to have a baby after one year of unprotected intercourse affects 48.5million couple in worldwide. Out one of four couple are affected by infertility. A minimum 30 million men world-wide are infertile and male factor are responsible for approximately 20-30% in all infertile cases. It is now understood that oxidative stress plays a significant role in the aetiology of male infertility. Reactive oxygen species (ROS) in excess lead to an oxidative stress condition that reduces sperm viability and motility by causing DNA damage, apoptosis, and lipid peroxidation of the sperm membrane. Increased ROS levels are a crucial role in idiopathic male factor infertility, which is a disease that is becoming more prevalent in society today. Due to its antioxidant qualities, lycopene, the most effective singlet oxygen quencher of all carotenoids, may be used to treat male infertility. Lycopene may minimise the occurrence of oxidative stress and, consequently, the harm that would otherwise be done to spermatozoa by interacting with and neutralising free radicals. We have analysed data from a number of sources and provided information regarding lycopene and its impact on male infertility in this review paper. The focus of this review is on how lycopene affects sperm parameters in healthy men.

Human sperm proteome reveals the effect of environmental borne seminal polyaromatic hydrocarbons exposome in etiology of idiopathic male factor infertility.

Introduction: Polyaromatic hydrocarbons (PAHs) are considered as redox active environmental toxicants inducing oxidative stress (OS) mediated injury to cells. Oxidative predominance is reported in 30%-80% of idiopathic male infertility (IMI) patients. Hence, this work aims to unravel correlation, if any, between seminal PAH exposome and sperm function in IMI patients through a proteomic approach. Methods: Seminal PAH exposome was analyzed in 43 fertile donors and 60 IMI patients by HPLC and receiver operating characteristic (ROC) curve was applied to find out the cut-off limits. Spermatozoa proteome was analyzed by label free liquid chromatography mass spectroscopy (LC-MS/MS) followed by molecular pathway analysis using bioinformatic tools. Validation of key proteins' expression and protein oxidative modifications were analyzed by western blot. Results and discussion: Of the 16 standards toxic PAH, 13 were detected in semen. Impact of the different PAHs on fertility are Anthracene < benzo (a) pyrene < benzo [b] fluoranthene < Fluoranthene < benzo (a) anthracene <indol (123CD) pyrene < pyrene < naphthalene < dibenzo (AH) anthracene < fluorene < 2bromonaphthalene < chrysene < benzo (GH1) perylene as revealed by ROC Curve analysis (AUCROC). Benzo [a] pyrene is invariably present in all infertile patients while naphthalene is present in both groups. Of the total 773 detected proteins (Control: 631 and PAH: 717); 71 were differentially expressed (13 underexpressed, 58 overexpressed) in IMI patients. Enrichment analysis revealed them to be involved in mitochondrial dysfunction and oxidative phosphorylation, DNA damage, Aryl hydrocarbon receptor (AHR) signaling, xenobiotic metabolism and induction of NRF-2 mediated OS response. Increased 4-hydroxynonenal and nitrosylated protein adduct formation, and declined antioxidant defense validates induction of OS. Increased GSH/GSSG ratio in patients may be an adaptive response for PAH metabolism via conjugation as evidenced by over-expression of AHR and Heat shock protein 90 beta (HSP90β) in patients. Seminal PAH concentrations, particularly benzo (a) pyrene can be used as a marker to distinguish IMI from fertile ones with 66.67% sensitivity and 100% specificity (95% confidence interval) along with oxidative protein modification and expression of AHR and HSP90β.

Assessment of Seminal Plasma Creatine Kinase Activity and Malondialdehyde Concentration among Normozoospermia but Infertile Men

Background: Despite the considerable research efforts that have been made by Reproductive Biologists to understand the etiologies of male infertility, idiopathic male factor infertility still remains unexplained. It occurs in about 10% cases of infertility. Since the etiologies cannot be identified using routine semen analysis, it is important to identify cellular and sub-cellular sperm complications that may help to explain the cause(s) of the infertility, thus stimulate caregivers to direct the further work-up, diagnosis and counseling of affected individuals. The objective of this study was to determine seminal plasma creatine kinase (CK) activity and malondialdehyde (MDA) concentration among normozoospermia but infertile males. Materials and Methods: After routine semen analysis, seminal plasma CK activity and MDA were determined among 75 normozoospermia but infertile men and 50 men of proven fertility using spectrophotometric method. Unpaired Students-t-test and regression analysis were used to compare and associate CK activity and MDA concentration with sperm characteristics. Results: Significantly higher (p&lt;0.001) level of MDA and CK activity were observed among infertile subjects than control group. Sperm count, percent motility, and viability were significantly lower (p&lt;0.05) among study participants than control subjects. Similarly, percentage abnormal morphology was significantly higher (p&lt;0.05) among infertile subjects than control group. The Odds of elevated CK activity to impair sperm motility, viability and morphology were 9.12(CI 102.6, 318.3), 3.18 (CI 129.9, 170.8) and 1.9 (CI 192.2, 208.1) times respectively higher among infertile group than controls. Similarly, the Odds of higher levels of MDA to impair sperm cell motility, viability and morphology were 5.02(CI 2.14, 4.6), 2.26(CI 2.34, 3.64) and 2.9 (CI 2.12, 3.73) times respectively higher among infertile group than control subjects. Conclusions: The seminal plasma CK activity and MDA constitute good indicators of functional metabolic activity and fertility potentials of spermatozoa among subjects with unexplained infertility.

O-208 Use of epididymal spermatozoa in in vitro fertilization cycles impacts the morphokinetics of embryos cultured in a time-lapse imaging incubator system

Abstract Study question Does sperm origin impact embryo morphokinetics (the moments at which an embryo reaches a developmental milestone) and clinical outcomes of intracytoplasmic sperm injection (ICSI) cycles? Summary answer The use of epididymal sperm correlates with late cell cleavages, and higher multinucleation and abnormal cleavage rates compared to those from men without infertility factor. What is known already ICSI with sperm surgically retrieved from the epididymis (PESA) dramatically altered the pregnancy prognosis in couples with severe male factor infertility, including obstructive azoospermia. The integration of time-lapse imaging (TLI) into the in vitro fertilization (IVF) laboratory allowed for an in-depth analysis of embryonic development. However, the impact of the use of epididymal sperm on embryonic morphokinetics has been poorly studied. We hypothesized that factors related to sperm origin may interfere with the speed and pattern of cell divisions. Study design, size, duration Women undergoing ICSI with epididymal sperm between Jan/2019 and Dec/2020 in a private university-affiliated IVF center were included (PESA group, n = 32 cycles/276 embryos). A matching was performed to form two groups of women undergoing ICSI using ejaculated sperm from partners with idiopathic male factor infertility (IMF group, n = 32 cycles/284 embryos) or without male factor infertility (Control group, n = 32 cycles/246 embryos). Generalized linear models followed by Bonferroni post hoc were used to compare morphokinetics between groups. Participants/materials, setting, methods Embryos were cultured in the EmbryoScope incubator, which recorded the following kinetic markers: timing to pronuclei appearance and fading (tPNa and tPNf), two (t2), three (t3), four (t4), five (t5), six (t6), seven (t7), and eight cells (t8), morulae (tM), start of blastulation (tSB) and blastulation (tB). Durations of second and third cell cycles (cc2 and cc3) and timing to complete synchronous divisions s1, s2, and s3 were calculated. The KIDScore ranking was recorded. Main results and the role of chance Embryos derived from epididymal sperm showed significantly slower divisions compared to those from ejaculated sperm (Table 1). The KIDScore rank was significantly lower for embryos deriving from epididymal sperm (3,1 ± 0.2) compared to those deriving from ejaculated sperm from IMF and control groups (5.4 ± 0.1 and 5.6 ± 0.2, p &amp;lt; 0.001, respectively). The incidence of multinucleation was significantly higher in embryos deriving from epididymal sperm (23.2%) compared to those deriving from ejaculated sperm from IMF and control groups (2.8% and 3.7%, p &amp;lt; 0.001, respectively). The incidence of abnormal cleavage patterns (direct or reverse) was significantly higher in embryos deriving from epididymal sperm (11.1%) compared to those deriving from ejaculated sperm from control group (4.3%, p = 0.001). Similar clinical outcomes were observed between the groups. Limitations, reasons for caution Retrospective nature of this study and the small sample size may be a reason for caution. Wider implications of the findings The use of epididymal sperm for ICSI correlates with delayed cell cleavage, and increased incidences of multinucleation and abnormal cleavage patterns. This finding highlights the importance of TLI for the identification and de-selection of slow-growing embryos for transfer, in ICSI cycles with surgical sperm retrieval. Trial registration number not applicable

Does testicular sperm retrieval adversely impact spermatogenesis over the long-term?

Testicular sperm retrieval (TSR) techniques are valuable in the context of severe idiopathic male factor infertility; however, there are few studies in the literature examining the long-term impact of TSR on testicular function. The objective was to determine whether testicular sperm aspiration (TESA) or microdissection testicular sperm extraction (micro-TESE) worsens the pre-existing spermatogenesis deficiency in men with either cryptozoospermia or severe oligozoospermia. The study population consisted of 145men with either cryptozoospermia or severe oligozoospermia that underwent TESA or micro-TESE and had long-term post-operative semen analyses (SA). Patients with SA prior to and following TSR were included (n=24). Amongst them, 16men underwent TESA and 8 underwent micro-TESE. The follow-up SA was obtained at a mean of 3.0±2.0years following TSR (range: 0.3-8.3years) amongst all participants. The post-operative semen parameters in the TESA group were similar to the pre-intervention parameters (p>0.1). Similarly, the micro-TESE cohort did not demonstrate significant alterations in semen parameters post-intervention (p>0.05). None of the men in the study became azoospermic following the TSR. Our study indicates TESA or micro-TESE do not appear to worsen the pre-existing spermatogenesis deficiencies in cryptozoospermic and oligozoospermic men over a long-term period. Larger studies are required to corroborate these findings.

Is There a Relevant Clinical Impact in Differentiating Idiopathic versus Unexplained Male Infertility?

Overall, male factor infertility (MFI) accounts for up to 50% of etiologies of couple's infertility, with almost 30% of MFI cases being idiopathic in nature. Idiopathic MFI does not support a tailored treatment work-up in clinical practice. To investigate rates of and characteristics of men presenting for idiopathic versus unexplained primary infertility as compared with same-ethnicity, age-comparable fertile men. Demographic, clinical and laboratory data from 3,098 primary infertile men consecutively evaluated were analyzed and compared with those of 103 fertile controls. Idiopathic male infertility (IMI) was defined for abnormality at semen analysis with no previous history of diseases affecting fertility and normal findings on physical examination and genetic and laboratory testing. Unexplained male infertility (UMI) was defined as infertility of unknown origin with completely normal findings at semen analysis. Descriptive statistics and logistic regression models tested the association between clinical variables and idiopathic infertility status. Overall, 570 (18.5%) and 154 (5.0%) patients depicted criteria suggestive for either IMI or UMI, respectively. Groups were similar in terms of age, BMI, CCI, recreational habits, hormonal milieu, and sperm DNA fragmentation indexes. Conversely, testicular volume was lower in IMI (p<0.001). Vitamin D3 levels were lower in IMI vs. UMI vs. fertile controls (p=0.01). At multivariable logistic regression analysis only vitamin D3 deficiency (OR, 9.67; p=0.03) was associated with IMI. Characteristics suggestive for IMI versus UMI were observed in almost 20% and 5% of men, respectively. Overall, clinical differences between groups were slightly significant and certainly not supportive of a tailored management work-up. Current findings further support the urgent need of a more detailed and comprehensive assessment of infertile men to better tailoring their management work-up in the everyday clinical setting.

Morphokinetic parameter comparison between embryos from couples with high or low sperm DNA fragmentation index

To study whether time-lapse imaging can identify morphokinetic events impacted by a high sperm DNA fragmentation index (DFI). Historical cohort study. Private university-affiliated invitro fertilization center. A total of 978 zygotes cultured until day 5 in a time-lapse imaging incubator between March 2019 and August 2020, derived from 118 patients undergoing intracytoplasmic sperm injection as a result of idiopathic male factor infertility. Kinetic markers from the point of insemination were recorded. Generalized linear mixed models adjusted for potential confounders followed by the Bonferroni post hoc test were used to compare the timing of specific events in patients with a low (<30%) or high (≥30%) sperm DFI. The recorded kinetic markers were the following: timing to pronuclei appearance and fading; timing to 2, 3, 4, 5, 6, 7, and 8 cells; and timing to start blastulation and blastulation. Timing to blastulation. Embryos derived from sperm samples with ≥30% DFI showed significantly slower divisions compared with those with <30% DFI (mean differences of 0.7 hours in timing to pronuclei appearance, 1.2 hours in timing to pronuclei fading, 1.5 hours in timing to 2 cells, 2.5 hours in timing to 3 cells, 1.8 hours in timing to 4 cells, 3.3 hours in timing to 5 cells, 3.1 hours in timing to 6 cells, 3.2 hours in timing to 7 cells, 2.7 hours in timing to 8 cells, 8.4 hours in timing to start blastulation, and 3.8 hours in timing to blastulation). The incidences of reverse or direct cleavages (9.3% vs. 4.4%; odds ratio [OR], 2.24; 95% confidence interval [CI], 1.32-3.77) and multinucleation at 2-cell (18.9% vs. 12.0%; OR, 1.70; 95% CI, 1.12-2.58) and 4-cell (14.2% vs. 6.4%; OR, 2.42; 95% CI, 1.57-3.74) stages were significantly higher in embryos deriving from ≥30% DFI than from <30% DFI. The KIDScore ranked significantly different between embryos derived from samples with <30% and ≥30% DFI. Continuous DFI was positively correlated with all timings of specific events and with the incidences of abnormal cleavage patterns (OR, 1.042; 95% CI, 1.025-1.059) and multinucleation at 2-cell stage (OR, 1.053; 95% CI, 1.030-1.076) and inversely correlated with the KIDScore rank (B, -0.218; 95% CI, -0.044 to -0.007). No significant differences were observed in clinical outcomes between the groups. Embryo morphokinetic parameters are negatively impacted by high sperm DFI, resulting in delayed cell cleavage and blastulation.

MP21-14 CAUSAL FACTORS REPRESENT THE PATHOPHYSIOLOGICAL CONNECTION BETWEEN MALE FACTOR INFERTILITY AND GENERAL HEALTH STATUS: INFERENCE FROM REAL LIFE DATA

You have accessJournal of UrologyInfertility: Epidemiology & Evaluation I (MP21)1 Sep 2021MP21-14 CAUSAL FACTORS REPRESENT THE PATHOPHYSIOLOGICAL CONNECTION BETWEEN MALE FACTOR INFERTILITY AND GENERAL HEALTH STATUS: INFERENCE FROM REAL LIFE DATA Eugenio Ventimiglia, Luca Boeri, Paolo Capogrosso, Edorado Pozzi, Belladelli Federico, Giuseppe Fallara, Luigi Candela, Nicolò Schifano, Costantino Abbate, Corsini Christian, Colagrande Gianmarco, Francesco Montorsi, and Salonia Andrea Eugenio VentimigliaEugenio Ventimiglia More articles by this author , Luca BoeriLuca Boeri More articles by this author , Paolo CapogrossoPaolo Capogrosso More articles by this author , Edorado PozziEdorado Pozzi More articles by this author , Belladelli FedericoBelladelli Federico More articles by this author , Giuseppe FallaraGiuseppe Fallara More articles by this author , Luigi CandelaLuigi Candela More articles by this author , Nicolò SchifanoNicolò Schifano More articles by this author , Costantino AbbateCostantino Abbate More articles by this author , Corsini ChristianCorsini Christian More articles by this author , Colagrande GianmarcoColagrande Gianmarco More articles by this author , Francesco MontorsiFrancesco Montorsi More articles by this author , and Salonia AndreaSalonia Andrea More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002006.14AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Men with male factor infertility (MFI) have an increased risk of developing comorbid diseases during their lifetime compared to the general population, although a biological explanation for this observation is still lacking. We hypothesize that the underlying causal factors represent an appraisal of both MFI and systemic status, determining both MFI severity and general health status impairment. METHODS: We collected complete clinical and demographic data of 1768 primary infertile men. Comorbidities were categorized with the Charlson Comorbidity index (CCI). Six different causal categories for MFI (genetic abnormalities, cryptorchidism, obstructive causes, hypogonadism, varicocele, and other causes) were established. Odds ratios (ORs) and 95%CIs for the association between causal categories and presence of comorbidities (CCI>0) have been estimated, adjusting for possible confounding variables (age; educational status). Similarly, we tested the association between causal factors and total motile sperm count (TMSC) <5, as a proxy of MFI severity (Hamilton et al, 2015). RESULTS: Median (IQR) age of the study cohort was 37 (33, 41) years. Of all, comorbidities (CCI>0) were found in 117 (7%) patients. The most commonly identified cause for MFI was hypogonadism (any type) (655, 37%), whereas 367 (21%) men had idiopathic MFI. Men with comorbidities were older (age: 40 (36, 45) vs. 37 (34, 40) in the and more frequently azoospermic (35% vs. 24%) compared to men with CCI=0. Causes with a potential systemic action, such as genetic abnormalities and hypogonadism, were more prevalent in men with comorbidities vs. those without comorbidities (7% vs. 5% for genetic factors, and 47% vs. 36% for hypogonadism), whereas local ones were more frequent in healthy men (e.g. varicocele, 28% vs. 13%). Genetic causes and hypogonadism were causal factor showing the strongest association with both presence of comorbidities (OR 3.16 [95% CIs: 1.27, 7.91] and OR 2.38 [1.29, 4.40], respectively) and MFI severity (OR 5.6 [2.10-14.94] and OR 3.32 [2.29-4.81], respectively). Men with varicocele had the most favourable profile in terms of both comorbidities (OR 0.63 [0.34-1.38]) and MFI (OR 1.18 [0.83-1.70]). CONCLUSIONS: Specific causes of MFI, especially systemic ones, are associated with decreased general health status as well as impaired sperm production. In this context, patients with genetic abnormalities and hypogonadism should be more carefully followed-up due to their very high risk of developing comorbid diseases. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e351-e351 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Eugenio Ventimiglia More articles by this author Luca Boeri More articles by this author Paolo Capogrosso More articles by this author Edorado Pozzi More articles by this author Belladelli Federico More articles by this author Giuseppe Fallara More articles by this author Luigi Candela More articles by this author Nicolò Schifano More articles by this author Costantino Abbate More articles by this author Corsini Christian More articles by this author Colagrande Gianmarco More articles by this author Francesco Montorsi More articles by this author Salonia Andrea More articles by this author Expand All Advertisement Loading ...

P–072 Pregnancy rate in male factor infertility with oligoastheneteratozoospermia - evaluation of Letrozole and Coenzyme Q10 supplementation on sperm parameter

Abstract Study question Male infertility due to idiopathic oligoasthenoteratozoospermia- Does combining Letrozole as antiestrogenic with Coenzyme Q10 as antioxidant give better pregnancy rate ? Summary answer Combination of Co enzyme Q10 with Letrozole can significantly improve semen parameters and outcome of clinical pregnancy rate in idiopathic oligoasthenoteratozoospermic patients. What is known already Elevated levels of reactive oxygen species(ROS) are a major cause of idiopathic male factor infertility which results in sperm membrane lipid peroxidation, DNA damage and apoptosis leading to decrease sperm viability and motility. Antioxidant like Coenzyme Q10 have been used empiricallyin the treatment of oligoasthenozoospermia based on its ability to reverse oxidative stress and sperm dysfunction. Aromatase inhibitor like Letrozolehave been used in idiopathic male infertility by reducing estrogenic effect on spermatogenesis and reducing feedback inhibition of hypothalamopituatarygonadal axis. Thus a therapeutic strategy would need to use supplements to increase sperm energy metabilism, minimise free radical damage. Study design, size, duration Study design: prospective comperative clinical study Primary purpose: treatmenr Size: 60 infertile male attending OPD of SHRISTI HEALTHCARE diagnosed as idiopathic oligoasthenoteratozoospermia Duration: from March2018 to February 2020 Primary outcome: improvement in sperm count, motility and morphology after treatment Secondary outcome: clinical pregnancy rate and live birth rate. Participants/materials, setting, methods Exclusion criteria: Smoker, drug and alcohol abuse, medical treatment with gonadotropin and steroids, varicocele.60 patients were randomisedinto 3 groups. Gr A(N = 20) received Letrozole 2.5mg/day + Co enzyme Q10 300mg/day for 3 months, Gr B(N = 20) received Letrozole 2.5mg/day for 3 months, and Gr C(N = 20) received Coenzyme Q10 300mg/day for 3 months. History taking, general examination, semen analysis, sr.FSH,LH, Testesteron, E2 and scrotal duplex were done for all patients. Main results and the role of chance After treatment, Gr A as compared to Gr B and C showed significant imprivement in all 3 parameters of semen eg sperm count( 3.15±3.38 - 20.9±2.11, p &amp;lt; 0.001), sperm motility( 5.25±3.25 - 42.85±3.30, p &amp;lt; 0.001), sperm morphology( 2.26±7.81 - 25.89±7.05, p &amp;lt; 0.001). Improvement in sperm count and morphology was seen in Gr B(Letrozole gr) but not in sperm motility whereas Gr C ( Co enzyme Q10 gr)showed significant improvement in sperm motility and morphology but not in sperm count. 10 pregnancies occured during follow up period of 1 yr. Clinical pregnancy rate was 30%in Gr A(6/20), 5% in Gr B(1/20), AND 15% in Gr C( 3/20). Live birth rate was 83% in Gr A(5/6), 33.3% inGr C(1/3) whereas sponteneous abortion occured in Gr B pregnancy. Limitations, reasons for caution Limitation of my study was the small sample sizewhich could have some bias in outcome. I did not evaluate DNA fragmentation and level of ROS. Latest evidences report that evaluating ROS can be a diagnostic tool in predictingthe best responder to supplementation. Wider implications of the findings: Majority of studies had investigated the effect of antioxidant and aromatase inhibitor on semen parameter but few concluded their effect on live birth rate. Assisted reproductive techniques are expensive and not universally available, so any pharmacological agent with satisfactory effectiveness should be considered as 1st line treatment of oligoasthenoteratozoospermia. Trial registration number Not applicable

The Role of the LINC Complex in Sperm Development and Function.

The LINC (LInker of Nucleoskeleton and Cytoskeleton) complex is localized within the nuclear envelope and consists of SUN (Sad1/UNc84 homology domain-containing) proteins located in the inner nuclear membrane and KASH (Klarsicht/Anc1/Syne1 homology domain-containing) proteins located in the outer nuclear membrane, hence linking nuclear with cytoplasmic structures. While the nucleoplasm-facing side acts as a key player for correct pairing of homolog chromosomes and rapid chromosome movements during meiosis, the cytoplasm-facing side plays a pivotal role for sperm head development and proper acrosome formation during spermiogenesis. A further complex present in spermatozoa is involved in head-to-tail coupling. An intact LINC complex is crucial for the production of fertile sperm, as mutations in genes encoding for complex proteins are known to be associated with male subfertility in both mice and men. The present review provides a comprehensive overview on our current knowledge of LINC complex subtypes present in germ cells and its central role for male reproduction. Future studies on distinct LINC complex components are an absolute requirement to improve the diagnosis of idiopathic male factor infertility and the outcome of assisted reproduction.

Evolutionary and functional analysis of RBMY1 gene copy number variation on the human Y chromosome.

Human RBMY1 genes are located in four variable-sized clusters on the Y chromosome, expressed in male germ cells and possibly associated with sperm motility. We have re-investigated the mutational background and evolutionary history of the RBMY1 copy number distribution in worldwide samples and its relevance to sperm parameters in an Estonian cohort of idiopathic male factor infertility subjects. We estimated approximate RBMY1 copy numbers in 1218 1000 Genomes Project phase 3 males from sequencing read-depth, then chose 14 for valid ation by multicolour fibre-FISH. These fibre-FISH samples provided accurate calibration standards for the entire panel and led to detailed insights into population variation and mutational mechanisms. RBMY1 copy number worldwide ranged from 3 to 13 with a mode of 8. The two larger proximal clusters were the most variable, and additional duplications, deletions and inversions were detected. Placing the copy number estimates onto the published Y-SNP-based phylogeny of the same samples suggested a minimum of 562 mutational changes, translating to a mutation rate of 2.20 × 10−3 (95% CI 1.94 × 10−3 to 2.48 × 10−3) per father-to-son Y-transmission, higher than many short tandem repeat (Y-STRs), and showed no evidence for selection for increased or decreased copy number, but possible copy number stabilizing selection. An analysis of RBMY1 copy numbers among 376 infertility subjects failed to replicate a previously reported association with sperm motility and showed no significant effect on sperm count and concentration, serum follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone levels or testicular and semen volume. These results provide the first in-depth insights into the structural rearrangements underlying RBMY1 copy number variation across diverse human lineages.

Genetic susceptibility to male infertility: news from genome‐wide association studies

A thorough understanding of the genetic basis of male infertility has eluded researchers in spite of significant efforts to identify novel genetic causes of the disease, particularly over the past decade. Approximately half of male factor infertility cases have no known cause; however, it is likely that the majority of idiopathic male factor infertility cases have some unidentified genetic basis. Well-established genetic causes of male infertility are limited to Y chromosome microdeletions and Klinefelter's syndrome, together accounting for 10-20% of cases of severe spermatogenic failure. In addition to these, several genetic polymorphisms have been demonstrated to be significantly associated with male infertility. The discovery of new genetic associations with male infertility has been hampered by two primary factors. First, most studies are underpowered because of insufficient sample size and ethnic and phenotypic heterogeneity. Second, most studies evaluate a single gene, an approach that is very inefficient in the context of male infertility, considering that many hundreds of genes are involved in the process of testicular development and spermatogenesis. Significant recent advances in microarray and next-generation sequencing technologies have enabled the application of whole-genome approaches to the study of male infertility. We recently performed a pilot genome-wide association study (GWAS) for severe spermatogenic failure, and several additional male infertility GWAS have since been published. More recently, genomic microarray tools have been applied to the association of copy number variants with male infertility. These studies are beginning to shed additional light on the genetic architecture of male infertility, and whole-genome studies have proven effective in identifying novel genetic causes of the disease. This review will discuss some of the recent findings of these whole-genome studies as well as future directions for this research that will likely be the most productive moving forward.

Lycopene and male infertility

Excessive amounts of reactive oxygen species (ROS) cause a state of oxidative stress, which result in sperm membrane lipid peroxidation, DNA damage and apoptosis, leading to decreased sperm viability and motility. Elevated levels of ROS are a major cause of idiopathic male factor infertility, which is an increasingly common problem today. Lycopene, the most potent singlet oxygen quencher of all carotenoids, is a possible treatment option for male infertility because of its antioxidant properties. By reacting with and neutralizing free radicals, lycopene could reduce the incidence of oxidative stress and thus, lessen the damage that would otherwise be inflicted on spermatozoa. It is postulated that lycopene may have other beneficial effects via nonoxidative mechanisms in the testis, such as gap junction communication, modulation of gene expression, regulation of the cell cycle and immunoenhancement. Various lycopene supplementation studies conducted on both humans and animals have shown promising results in alleviating male infertility—lipid peroxidation and DNA damage were decreased, while sperm count and viability, and general immunity were increased. Improvement of these parameters indicates a reduction in oxidative stress, and thus the spermatozoa is less vulnerable to oxidative damage, which increases the chances of a normal sperm fertilizing the egg. Human trials have reported improvement in sperm parameters and pregnancy rates with supplementation of 4–8 mg of lycopene daily for 3–12 months. However, further detailed and extensive research is still required to determine the dosage and the usefulness of lycopene as a treatment for male infertility.

Polymorphisms in Aryl Hydrocarbon Receptor Gene Are Associated With Idiopathic Male Factor Infertility

We wanted to determine whether genetic polymorphisms of aryl hydrocarbon receptor (AhR) gene are associated with susceptibility to male infertility. This study comprised 176 men with idiopathic infertility and 352 healthy fertile men who served as controls. Seven single-nucleotide polymorphisms (SNPs) of the AhR gene (rs2066853, rs1476080, rs10250822, rs10247158, rs2282885, rs6960165, and rs7811989) were selected and genotyped by the polymerase chain reaction-restriction fragment length polymorphism analysis. The serum levels of reproductive and thyroid hormones and inhibin B were also measured. After multiple regression analysis, 2 of the 7 studied SNPs were significantly associated with the occurrence of male infertility. Men with rs2066853 AA genotype had 33% decreased risk of being infertile (odds ratio [OR] = 0.67, 95% confidence interval [CI]: 0.46-0.87; P = .003). The C allele of rs2282885 was significantly associated with infertility risk, with an OR of 2.14 (95% CI: 1.64-3.72) for heterozygotes and 3.54 (95% CI: 2.25-5.84) for homozygotes. When haplotypes were composed of 7 AhR SNP sites, patients with AACACAG haplotype harbored more than 75% decreased risk of being infertile (OR = 0.21, 95% CI: 0.11-0.32; P = .001). Conversely, carriers of the AACACGA haplotype had more than 12-fold increased risk of being infertile (OR = 12.62, 95% CI: 2.77-52.74; P = .00001). Homozygosity for the rs2066853 A allele and rs2282885 C allele decreases and increases the risk of developing male infertility, respectively.

In vitro biological assessment of berberis vulgaris and its active constituent, berberine: antioxidants, anti-acetylcholinesterase, anti-diabetic and anticancer effects

BackgroundBerberis vulgaris is a well known plant with traditional herbal medical history. The aims of this study was to bioscreen and compare the in vitro biological activity (antioxidant, cholinergic, antidaibetic and the anticancer) of barberry crude extract and berberine active compound.MethodsThe effect of B. vulgaris extract and berberine chloride on cellular thiobarbituric acid reactive species (TBARS) formation, diphenyle–α-picrylhydrazyl (DPPH) oxidation, cellular nitric oxide (NO) radical scavenging capability, superoxide dismutase (SOD), glutathione peroxidase (GPx), acetylcholinesterase (AChE) and α-gulcosidase activities were spectrophotometrically determined. On the other hand, the effect of extract and berberine as anticancer was estimated on three different cell lines which were MCF-7, HepG-2, and Caco-2 cells by using neutral red uptake assay which compared with control normal cells (PBMC).ResultsOur results showed that barberry crude extract contains 0.6 mg berberine/mg crude extract. Barberry extract showed potent antioxidative capacity through decreasing TBARS, NO and the oxidation of DPPH that associated with GPx and SOD hyperactivation. Inhibitory effect of berberis crude extract on α-glucosidase was more potent than that of berberine chloride, while both had the same AChE inhibitory effect. Besides, different concentrations of both berberine chloride and barberry ethanolic extract showed to have no growth inhibitory effect on normal blood cells (PBMC). Otherwise, both berberine chloride and barberry ethanolic extract showed to have inhibitory effect on the growth of breast, liver and colon cancer cell lines (MCF7, HepG2 and CACO-2, respectively) at different incubation times starting from 24 hrs up to 72 hrs and the inhibitory effect increased with time in a dose dependant manner.ConclusionThis work demonstrates the potential of the barberry crude extract and its active alkaloid, berberine, on suppressing lipid peroxidation, suggesting a promising use in the treatment of hepatic oxidative stress, Alzheimer and idiopathic male factor infertility. Beside, berberis vulgaris ethanolic extract is safe non-toxic extract as it was not inhibit the growth of PBMC that can induce cancer cell death that could return to its powerful antioxidant activity.

Body mass index is not associated with sperm-zona pellucida binding ability in subfertile males.

Lifestyle factors, such as weight and nutritional status may affect male fertility, including sperm fertilization ability. The objective of this retrospective study was to evaluate the association between body mass index (BMI) and sperm-zona pellucida binding ability assessed according to the zona binding (ZB) test, which has been described to be a relevant diagnostic tool for the prediction of in vitro fertilization (IVF) ability. Three hundred and six male patients from couples diagnosed with primary idiopathic or mild male factor infertility were included. Correlations between BMI and semen parameters according to ZB test indices were assessed, together with frequencies of positive and negative tests across the BMI categories. In this selected population, BMI was not related to conventional semen parameters or sperm quality assessed according to the ability of spermatozoa to bind to the zona pellucida. The previously described poor outcomes of IVF procedures in cases of male obesity could be due to other sperm defects, such as alterations of sperm capacitation or acrosome reaction. The link between male BMI and biological outcomes during IVF procedures, such as fertilization rates, should be further evaluated.

Influence of laboratory studies on choice of empiric medical therapy for idiopathic male factor infertility: a survey of us urologists

Factors involved in the choice of empiric medical therapy (EMT) for male factor idiopathic infertility is controversial. Laboratory studies guiding the initiation of EMT or evaluating the effectiveness of therapy have yet to be established. The objective of this study is to identify critical laboratory studies influencing the recommendation and medication choice for EMT.

Oxidative stress and antioxidants for idiopathic oligoasthenoteratospermia: Is it justified?

Oxidative stress contributes to defective spermatogenesis and the poor quality of sperm associated with idiopathic male factor infertility. The aim of this study was to review the current literature on the effects of various types of antioxidant supplements in patients to improve fertilization and pregnancy rates in subfertile males with idiopathic oligoasthenoteratozoospermia (iOAT). Review of recent publications through PubMed and the Cochrane database. Oxidative stress is implicated in impaired spermatogenesis leading to the poor semen parameters and increased DNA damage and apoptosis in iOAT. Strategies to modulate the level of oxidative stress within the male reproductive tract include the use of oral antioxidant compounds to reinforce the body's defence against oxidative damage. In our evaluation, carnitines were considered the most established pharmacotherapeutic agent to treat iOAT, as evidence and data concerning carnitine supplementation have been shown to be most consistent and relevant to the population of interest. Other therapies, such as combined vitamin E and C therapy, are still considered controversial as vitamin C can act as a pro-oxidant in certain instances and the results of randomized controlled trials have failed to show significant benefit to sperm parameters and pregnancy rates. There is a need for further investigation with randomized controlled studies to confirm the efficacy and safety of antioxidant supplementation in the medical treatment of idiopathic male infertility as well as the need to determine the dosage required to improve semen parameters, fertilization rates and pregnancy outcomes in iOAT.

A prospective double‐blind randomized placebo‐controlled study of the effect of saffron (Crocus sativusLinn.) on semen parameters and seminal plasma antioxidant capacity in infertile men with idiopathic oligoasthenoteratozoospermia

Male factor infertility is a multifactorial disorder that affects a significant percentage of infertile couples; however, many of them remained untreated. In recent years, considerable numbers of infertile men have sought 'herbal remedies' as an effective treatment. Among 'herbal remedies', saffron is recommended for male infertility in our community. The effect of saffron was evaluated compared with placebo for the treatment of idiopathic male factor infertility. The study included 260 infertile men with idiopathic oligoasthenoteratozoospermia (OAT) who were randomized to saffron 60 mg/day (130, group 1) or a similar regimen of placebo (130, group 2) for 26 weeks. The two groups were compared for changes in semen parameters and total seminal plasma antioxidant capacity. Saffron administration did not result in beneficial effects. At the end of the study no statistically significant improvements were observed in either group in any of the studied semen parameters (sperm density, morphology and motility) (all p = 0.1). At the end of the trial, patients in group 1 had a mean motility of 25.7 ± 2.4%, which was not statistically different from the mean of 24.9 ± 2.8% in the placebo group (p = 0.1). Normal sperm morphology was 18.7 ± 4.7% and 18.4 ± 4.3%, in groups 1 and 2, respectively (p = 0.1). Patients treated with saffron and placebo had a mean sperm density of 20.5 ± 4.6% and 21.4 ± 4.6% per mL, respectively (p = 0.1). Saffron administration did not improve total seminal plasma antioxidant capacity, compared with baseline (p = 0.1) and placebo subjects (p = 0.1). Based on Pearson correlations, each semen parameter did not correlate significantly with treatment duration, including sperm density (r = 0.146, p = 0.13), percent of motile sperm (r = 0.145, p = 0.15) and percent of sperm with normal morphology (r = 0.125, p = 0.30). Saffron does not statistically significantly improve semen parameters in infertile men with idiopathic OAT. If medical professionals want to prescribe herbal remedies for male infertility, previous rigorous scientific investigations, documenting their safety and efficacy are required.