Male Factor Infertility Research Articles (Page 1)

Persistent Müllerian duct syndrome (PMDS) is a rare difference of sex development, characterized by the presence of Müllerian duct derivatives in 46,XY individuals with male-typical development. PMDS typically presents during childhood with features of cryptorchidism, inguinal hernia or transverse testicular ectopia. Untreated PMDS is associated with risks of infertility and malignancy. Infertility is common, arising from cryptorchidism, anatomical malformations (such as epididymal aplasia) or extrinsic compression of the ejaculatory duct by Müllerian structures. At the time of diagnosis, just one in five men with PMDS are reported to have conceived naturally. Preservation of fertility potential requires prompt diagnosis and management via a holistic patient-centred approach that addresses the underlying cause. With cryptorchidism, which is a common manifestation of PMDS, early orchidopexy is the key initial intervention. The input of fertility specialists and assisted reproductive techniques can further support successful conception. Beyond its effects on fertility, PMDS carries a risk of malignant transformation in the testes and Müllerian structures, warranting complex management with inclusion of a multi-disciplinary team and consideration of orchidopexy, orchidectomy, excision of Müllerian remnants and onward surveillance. Thus, although rare, PMDS is an important cause of male factor infertility that might be encountered by urologists. Preservation of fertility potential requires a high index of clinical suspicion and timely intervention. Raising awareness of PMDS among clinicians is crucial to improve its detection, advance its clinical management and provide a basis for future research.

Intracytoplasmic sperm injection (ICSI) was first developed to overcome male factor infertility. ICSI has increased in uptake globally, including in cases where its use is non-essential for fertilisation. To identify temporal trends in the use of, and indications for ICSI in an Australian context. A statewide descriptive cohort study examining the trends in ICSI uptake and reported indication/s for ICSI use. The cohort included women undergoing IVF between 2005 and 2017 at IVF clinics across Victoria, Australia that resulted in a birth after 20 weeks' gestation. The dataset comprised 32 102 assisted reproduction cycles: 22 873 (71.3%) ICSI and 9229 (28.7%) conventional IVF. In 2005, ICSI accounted for 60.6% (1182/1952) of cycles, increasing to 79.5% (2344/2947) by 2017 (ptrend < 0.001). Testicular sperm retrieval as an indication for ICSI remained consistent over time (ptrend = 0.15). Male factor infertility as an indication decreased over time (ptrend = 0.007). Vitrified oocyte thaw (ptrend = 0.016) and 'unexplained subfertility' (ptrend = 0.30) cycles did not surpass 1.7% (39/2293) and 0.4% (9/2048), respectively of total cycles in any year. Donor sperm (ptrend = 0.001), pre-implantation genetic testing (ptrend = 0.004), female factors associated with poor IVF outcome (ptrend = 0.005) and advanced maternal age (ptrend = 0.005) all increased as indications for ICSI over time. 'Unspecified' indication accounted for the majority of ICSI cycles after 2008 (ptrend = 0.015). During our study period, the total use of ICSI increased by 18.9%. Notably, most of these cycles were not medically indicated.

Oxidative stress is a proven factor in male infertility. Recently, there is increasing evidence that 8-hydroxy-2'- deoxyguanosine (8-OHdG) is considered an accurate and sensitive biomarker of oxidative DNA damage. Studies that revealed ethnospecificity of the course of lipoperoxidation processes suggest differences in oxidation of not only lipids but also DNA in men of different ethnogroups. Aim of the study was to evaluate free-radical lipid oxidation intensity and 8-OHdG level as a possible marker of oxidative stress in men of different ethnic groups in idiopathic infertility. Material and methods . The study involved 672 men with idiopathic infertility, representatives of Russian (n = 225) and Buryat (n = 447) ethnic groups. Two control groups of practically healthy men of the corresponding ethnic groups with realized reproductive function were formed. Lipid and DNA free-radical oxidation product content was determined using spectrophotometric, fluorimetric and enzyme immunoassay methods. Results. It is confirmed that oxidative DNA damage may be important in the etiology of male infertility. In men with idiopathic infertility of the Caucasian ethnic group, a significantly higher level of 8-OHdG in serum was found compared to fertile men, indicating the presence of changes at the cellular DNA level. There were no such changes in the Mongoloids, which indicates a difference in the intensity of metabolic processes among representatives of different ethnic groups.

Cholesterol metabolism as a key target in triphenyl phosphate-induced testosterone biosynthesis disorder: Implications for male reproductive health.

Do IVF laboratory workflows influence the mean blastulation rate per cohort of inseminated metaphase II oocytes (m-BR)? Neither the total number of procedures nor the workload per operator affected m-BR; instead, each additional hour in the interval from ovulation trigger to oocyte denudation (range 36-44 h) was associated with a measurable decline, especially beyond the 40-h threshold. Control of laboratory conditions and standardized protocols are essential for optimizing m-BR in IVF. While advancements in technology and culture systems have improved ART outcomes, the effect of laboratory managerial decisions and procedural timing on embryological outcomes remains unclear. Previous studies have suggested that factors, such as prolonged oocyte handling, suboptimal culture conditions, and organizational inefficiencies, may affect in vitro embryo development, but available data are still limited. This retrospective study analyzed 7986 ICSI cycles performed between 2015 and 2022 at a private IVF center. Data were automatically registered and then retrospectively extracted from an Electronic Witnessing System to evaluate workload distribution and procedural timings. The study aimed to assess whether variations in laboratory managerial decisions influence the m-BR. The study included all patients undergoing ICSI with fresh own oocytes. Metrics under investigation included the number of daily procedures overall and per operator and procedural timings, such as the interval between ovulation trigger and oocyte denudation. Results were adjusted for confounders, including maternal age, male factor infertility, and culture conditions. Multivariate linear regression and generalized estimating equations were used to assess associations with m-BR, accounting for repeated measures in couples undergoing multiple retrievals. The overall m-BR was 35.7 ± 28.1% with 79% of the cycles resulting in at least one blastocyst obtained. No significant association was found between daily workload and m-BR, indicating that the number of daily procedures did not impact laboratory performance. After adjusting for confounders (maternal age, sperm factor, incubation conditions, and culture medium type), only the timing between ovulation trigger and oocyte denudation emerged as critical. A consistent and significant decline in m-BR was observed with each additional hour of delay between 36- and 44-h post-trigger (unstandardized coefficient B: -1.6%, 95% CI: -2.1 to -1.1%). The time between oocyte retrieval and denudation (range: 2-6 h) showed a significant association with a lower chance to obtain at least one blastocyst in each ICSI cycle (adjusted OR: 0.91, 95% CI: 0.86-0.96, P < 0.001). This was a retrospective single-center study. While the findings are robust and relevant for high-volume IVF laboratories, they may not be directly generalizable to smaller clinics with different workflows or lower caseloads. Additionally, only ICSI cycles were included; further studies are needed to confirm the findings for conventional IVF in different settings and patient populations. These findings suggest that even large workloads can be managed without compromising IVF performance, provided that lab schedules and personnel are carefully coordinated to meet ideal timing requirements. In the future, artificial intelligence models may support these lab management activities by predicting workloads and helping maintain timely schedules. No funding. The authors declare no conflict of interest related with the content of this study. N/A.

Both absolute and presumably active rDNA (with a hypomethylated promoter region) copy number (CN) in the haploid human sperm genome are highly variable among individuals. Using a combination of droplet digital PCR and deep bisulfite sequencing, we have quantified absolute and presumably active rDNA CN in sperm samples (N = 190) with normal (NSPs) vs. abnormal semen parameters (ASPs), as well as in samples leading or not leading to a clinical pregnancy. ASP samples had a significantly lower presumably active CN (104 ± 31) than normozoospermic samples (115 ± 31). The loss of presumably active rDNA copies is explained by an increased promoter methylation (13.9% in ASP vs. 12.1% in NSP). When correcting for confounding factors, most importantly semen quality, samples not leading to a clinical pregnancy after IVF/ICSI displayed a significantly lower absolute (225 ± 51) and presumably active CN (103 ± 30) than samples with pregnancy (249 ± 62 and 115 ± 31, respectively). This between-group difference was most noticeable in normozoospermic males: absolute CN 220 ± 54; presumably active CN 107 ± 32 in samples without pregnancy and absolute CN 246 ± 63; presumably active CN 120 ± 28 in samples with pregnancy. We propose that absolute/active rDNA CN in sperm is a modulating factor contributing to idiopathic male infertility. In NSP samples, presumably active CN increases with absolute CN, which may have a positive impact on fertility and ART outcome. Our results suggest that approximately 60 active sperm rDNA copies are sufficient to establish a pregnancy.

Canonical splicing variants (±2) contribute significantly to genetic disorders, yet the clinical significance of non-canonical splicing variants (NCSVs) that occur outside of canonical splicing sites remains unknown in male infertility. A comprehensive evaluation of reported studies on hereditary male infertility revealed that the 2,404 pathogenic variants contained 120 canonical splicing variants and 32 NCSVs. Among the remaining 2,252 variants, the splicing variant analytical strategy identified 17 novel NCSVs that disrupt normal mRNA splicing from previously classified missense variants. This expands the contribution of NCSVs by 53.13% (17/32), with NCSVs accounting for 28.99% (49/169) of all the splicing variants. Moreover, thirteen positively validated NCSVs are identified in 12 of 718 idiopathic male infertility patients with negative results by conventional genetic analysis. The first pathogenic variant in the TATA element modulatory factor 1 (TMF1: c.2859+4A>G) results in TMF1 exon 14 skipping and decreased progressive sperm motility and morphological abnormalities in a patient with male infertility. Tmf1 NCSV knock-in mice recapitulated human phenotype, showing significantly decreased sperm count, motility, ultrastructural head defects, and subfertility. This study provides the first comprehensive landscape of NCSVs in male infertility, suggesting that NCSVs may constitute a hidden etiological factor for male infertility.

ABSTRACTInfertility impacts 48 million couples globally, and accumulating evidence suggests that micronutrients potentially influence reproductive health. This Mendelian randomization study investigates causal relationships between 15 micronutrients and infertility in both males and females, aiming to complement existing nutritional epidemiology insights. Genetic association estimates for micronutrient biomarkers (including selenium, iron, β‐carotene, calcium, magnesium, phosphorus, folate, vitamins B6, B12, C, D, zinc, copper, iodine, and manganese) and infertility phenotypes were derived from European‐ancestry genome‐wide association study (GWAS) cohorts. For causal inference, inverse‐variance weighted MR served as the primary analytical method, supplemented by MR‐Egger and weighted median approaches. In female, genetically predicted higher levels of selenium (OR = 0.94; 95% CI = 0.90–0.99; p = 0.019), iron (OR = 0.89; 95% CI = 0.80–0.98; p = 0.023), and β‐carotene (OR = 0.87; 95% CI = 0.80–0.96; p = 0.005) demonstrated inverse associations with risk, suggesting potential protective effects. In males, higher phosphorus exhibited a strong positive correlation with infertility (OR = 4.05; 95% CI = 1.37–11.96; p = 0.011). No significant associations were observed for the remaining micronutrients. This Mendelian randomization study comprehensively evaluates the causal effects of 15 micronutrients on infertility in both sexes. The findings highlight potential protective roles of selenium, iron, and β‐carotene in female infertility and identify phosphorus as a risk factor for male infertility. These results support the development of sex‐specific nutritional strategies for fertility improvement.

Background and objective Ovarian endometriosis (OE), characterized by endometriotic cysts, adversely affects ovarian function and comprises in vitro fertilization and embryo transfer (IVF-ET) outcomes. Acupoint application therapy (AAT), which integrates transdermal drug delivery with acupoint stimulation, may offer therapeutic benefits; however, its underlying mechanisms remain unclear. Methods In this randomized trial, 81 IVF-ET patients were stratified into: a treatment group comprising OE patients (n=27) undergoing a gonadotropin hormone-releasing hormone (GnRH) antagonist protocol with medicated AAT, a placebo group consisting of OE patients (n=26) following an identical protocol but receiving a sham patch, and a control group, including patients with male-factor infertility (n=28) undergoing the standard protocol without additional interventions. Follicular fluid metabolomics (assessed by Ultra High-Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS/MS) System)and IVF parameters were analyzed. Results Significant intergroup differences were observed (one-way ANOVA, P &amp;lt; 0.05). The treatment group exhibited a shorter Gn duration (9.00 ± 0.68 days) compared to the placebo group (10.62 ± 2.43 days; P &amp;lt; 0.05), with a duration comparable to the male-factor control group (9.32 ± 1.89 days; NS). Similarly, the total Gn dose was lower in the treatment group (2112.50 ± 483.17 IU) than in the placebo group (2549.04 ± 677.44 IU; P &amp;lt; 0.05), and comparable to the control group (2105.89 ± 690.24 IU; NS). Regarding IVF outcomes, the treatment group yielded more oocytes retrieved (12.41 ± 7.27) than the placebo group (8.85 ± 7.89; P &amp;lt; 0.05), though fewer than the control group (15.25 ± 7.77). Fertilized oocytes were also higher in the treatment group (7.59 ± 4.58) compared to the placebo group (4.46 ± 3.40; P &amp;lt; 0.05), but fewer than in the control group (9.21 ± 4.82). The number of transferable embryos was comparable between the treatment group (3.33 ± 2.30) and the control group (3.43 ± 2.13; NS), and significantly higher than in the placebo group (1.69 ± 1.87; P &amp;lt; 0.05). Furthermore, the treatment group produced more high-quality embryos (3.04 ± 1.89) than the placebo group (1.35 ± 1.99; P &amp;lt; 0.05), and more than the control group (2.43 ± 1.95). No significant intergroup difference was found in fertilization rates (64.40% vs. 62.90% vs. 60.90%; NS). However, the high-quality embryo rate was significantly higher in the treatment group (47.02%) compared to both the placebo (31.15%; P &amp;lt; 0.05) and control (29.05%; P &amp;lt; 0.05) groups. Finally, the treatment group demonstrated a significantly greater reduction in peri-menstrual abdominal pain scores (Δ=−1.15 ± 0.36) compared to the placebo group (Δ=−0.35 ± 0.49; F = 6.84, P = 0.01). Metabolomic analysis revealed that the steroid hormone biosynthesis pathway was the most significantly disturbed in OE patients, characterized by markedly elevated levels of key intermediates such as 17α-hydroxyprogesterne. Critically, the levels of 17α-hydroxyprogesterone exhibited a significant negative correlation with oocyte yield (r = -0.286, p = 0.012), directly linking this metabolic dysregulation to impaired clinical outcome. Furthermore, oxidative stress metabolites showed a strong positive correlation with the luteinization marker 20α-hydroxy-4-pregnen-3-one (r = 0.43, p = 0.001), suggesting a potential interaction between oxidative stress and aberrant steroidogenesis. The AAT intervention effectively normalized this dysregulated steroidogenic profile, which underpinned the observed therapeutic benefits. Conclusion AAT significantly alleviates peri-menstrual pain and enhances IVF outcomes in ovarian endometriosis patients, which may be attributed to the restoration of granulosa cell steroid metabolism, evidenced by normalized levels of 17α-hydroxyprogesterone and attenuation of oxidative stress. Clinical trial registration https://www.chictr.org.cn/ , identifier ChiCTR2200057339.

Disclosure: R. Cannarella: None. M. Suryavanshi: None. A. Miller: None. A.E. Calogero: None.Background: Spermatozoa carry RNAs that may influence early embryo development. A pilot study (PMID: 39312692) suggests that sperm Insulin-like growth factor 2 (IGF2) mRNA levels impact embryo development timing. This study aims to validate these findings with a larger cohort and introduce a control group of fertile men to explore sperm IGF2 mRNA’s role in human fertility and embryogenesis. Methods: This 3-year prospective study included 50 infertile couples undergoing assisted reproductive technique (ART) for idiopathic or male factor infertility. Excluding female factor infertility due to impaired oocyte reserve, we included those with tubal factor or anovulation. Sperm samples used in ART were tested for IGF2 mRNA, and levels were compared to a control group of men with recent fatherhood (within 12 months). Embryo kinetic parameters were correlated with sperm IGF2 mRNA, adjusting for female age, body mass index (BMI), and anti-Müllerian hormone (AMH). Correlation analysis was conducted on the full cohort, embryos reaching blastocyst, and transferred blastocysts. A ROC curve was used to assess IGF2 mRNA’s predictive value for normal embryo development timing. Results: Fifty infertile patients and ten controls were enrolled. Sperm IGF2 mRNA levels were significantly lower in patients (0.0319 ± 0.04807) than in controls (1.0493 ± 0.75410; p<0.0001), with no significant correlation to conventional sperm parameters. In the full embryo cohort (n=505), IGF2 mRNA levels negatively correlated with the time to pronucleus fading (r=-0.12, p=0.0075) and positively correlated with key milestones of embryo development, including compaction (r=0.27, p<0.0001), morula formation (r=0.22, p<0.0001), blastulation (r=0.23, p<0.0001), full blastocyst (r=0.30, p<0.0001), and expanded blastocyst formation (r=0.27, p<0.0001). These correlations remained significant after adjusting for female factors and were further confirmed in embryos that reached the blastocyst stage (n=268) and in the group of transferred blastocysts (n=231). Embryos that reached the two-cell stage (t2) within the normal time range (21.4 h< t2< 34.8 h, PMID: 23585186) exhibited higher IGF2 mRNA levels (0.0364±0.0451) compared to those with altered t2 timing (0.02206±0.0341; p=0.03). An IGF2 mRNA threshold of >0.0207 predicted normal t2 timing with 44.2% sensitivity and 86% specificity (AUC 0.572, p=0.036). Conclusion: Sperm IGF2 mRNA levels vary between infertile and fertile individuals and play a positive role in early embryo kinetics. These findings challenge the view that spermatozoa only carry paternal DNA, suggesting that IGF2 mRNA in healthy sperm is crucial for early embryo development. This may represent a novel aspect of reproductive biology, offer insights into infertility mechanisms, and provide diagnostic and therapeutic opportunities for infertile couples.Presentation: Saturday, July 12, 2025

Abstract STUDY QUESTION At which arrest stage can spermatocytes be rescued by injection into meiotic oocytes? SUMMARY ANSWER In mice, spermatocytes arrested at the diplotene stage, but not at the pachytene stage, can resume meiosis within immature oocytes and support full-term embryonic development. WHAT IS KNOWN ALREADY In mice, at least some of the spermatocyte arrest mutations can be overcome by injecting spermatocytes into immature oocytes. STUDY DESIGN, SIZE, DURATION The study was carried out from October 2019 to April 2025. Adult azoospermic mice (at 4–26 weeks of age) from nine strains carrying spermatocyte arrest mutations were used as spermatocyte donors. Adult B6D2F1 females at 9–12 weeks of age were used as oocyte donors for spermatocyte injection. Adult ICR strain pseudopregnant females at 9–12 weeks of age were used as recipients for embryo transfer experiments. PARTICIPANTS/MATERIALS, SETTING, METHODS The most advanced stage of spermatocytes from each mutant strain was assessed by chromosome spread analysis. These most advanced spermatocytes of each strain were injected into metaphase I (MI) oocytes. About half a volume of the ooplasm had been removed from the recipient oocytes to ensure more stable chromosome behaviours during meiosis. The spermatocyte-injected oocytes were allowed to mature in vitro to the metaphase II (MII) stage, and their ooplasm was refreshed with the ooplasm from intact MII oocytes. After activation with SrCl2, the reconstructed oocytes that reached the 2-cell stage were transferred into the oviducts of pseudopregnant females. On day 19.5, recipient females were euthanized and their uteri were examined for live fetuses. MAIN RESULTS AND THE ROLE OF CHANCE Based on spermatocyte spread analysis, sperm mutants were categorized into three classes: Class 1, arrest at mid-diplotene or later stage; Class 2, arrest at early diplotene stage; and Class 3, arrest at pachytene stage. All four Class 1 mutants could resume normal meiosis following injection into MI oocytes, as evidenced by births of normal offspring. Similarly, one of two Class 2 mutants could be rescued, but the other could not. By contrast, three Class 3 mutants did not support embryo development to term because of complete implantation failure, indicating that reconstructed embryos carried severe chromosomal aberrations. LARGE-SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION The number of mutant strains examined was limited. Nevertheless, the findings were consistent: the more advanced the arrest stage of spermatocytes, the higher the likelihood of a successful rescue. WIDER IMPLICATIONS OF THE FINDINGS In humans, a considerable proportion of spermatogenic arrest occurs at the primary spermatocyte stage. Spermatocyte injection might be an option to treat human male-factor infertility due to azoospermia in the future. However, numerous ethical and technical challenges remain to be addressed, and the reproductive physiological differences between mice and humans must be carefully taken into account. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by Grants-in-Aid for Scientific Research (KAKENHI) from the Japan Society for the Promotion of Science to A.O. (grant number: JP19H05758), K. I. (grant number: 23H04956), M.I. (grant number: JP23K20043) and N.O. (grant number: 25H01372), and 2023 and 2025 grants of the University of Castilla-La Mancha for stays in foreign universities and research centres to E.C.-E. The authors declare that they have no conflicts of interest.

Abstract Background and Aims Infertility is known to affect quality of life (QoL) and mental health in otherwise healthy couples. Parenthood and pregnancy are key life events for many people, including those with CKD. However, neither are typically integrated into QoL assessments for women with CKD, who often have complex emotional needs when considering pregnancy. Despite the increasing prevalence of CKD for women of childbearing age, there is very limited research investigating the impact of infertility on quality of life. FertiQOL is a validated instrument to measure QoL in individuals experiencing fertility problems. The aim of the study was to investigate how infertility affects the quality of life in people with chronic kidney disease (CKD) compared to the general population using the FertiQOL questionnaire. Method A prospective observational multi-centre cohort study of women with CKD and controls (healthy volunteers). The study was conducted over a 12-month period from October 2022–23 and recruited 107 women. Women with CKD were recruited from four tertiary hospital sites. Controls were healthy women undergoing treatment for male factor infertility. All controls had no fertility issues, determined by detailed history, hormonal blood profile and ultrasound scan. Ethical approval was provided by the Health Research Authority and written informed consent was obtained. Prior fertility treatment, active attempts to conceive, age, body mass index, ethnicity and medical history were recorded. All participants completed the FertiQOL survey; a validated instrument measuring QoL in individuals experiencing fertility problems divided into 6 domains (emotional, mind-body, relational, social, environment and tolerability) with raw and scaled (out of 100) scores. Difference between groups was assessed using Mann Whitney-U test. Linear regression models were performed on significant associations adjusting for age, BMI and parity. Results A total of 73 (68.2%) women with CKD and 34 (31.8%) controls were recruited. Women with CKD were older than controls (35.1 ± 6.7 vs. 31.2 ± 4.6 years) and were less likely to be nulliparous (46.1% vs. 73.5%) or desire pregnancy (73.5% vs. 100%). Both groups were comparable for BMI, ethnicity, attempts to conceive, and prior fertility treatment. FertiQoL raw and scaled total scores were similar between groups. The CKD total median raw score of 66.2 (IQR 54.8–77.8) compared to the control group score of 60.4 (IQR 55.4–72.2). This suggests infertility affects the QoL in women with CKD as much as in the general population. However, women with CKD had significantly lower scores in the raw environmental domain (CKD = 12.0; Controls = 16.0, P = 0.02). This assesses external factors that affect access to and experience of fertility treatment such as treatment availability, quality of care and financial burden of fertility services. Among participants who had undergone fertility treatment (n = 20), those with CKD had lower total scaled FertiQoL scores (51.0 vs. 63.5, P = 0.047) and significantly lower emotional (37.5 vs. 54.2, P = 0.04) and social (54.2 vs. 79.2, P = 0.007) scaled scores. The emotional domain reflects feelings like sadness, jealousy and resentment; the social domain evaluates social inclusion, stigma and impact of infertility on relationships. Conclusion Scores were similar between CKD and control groups. However, women with CKD and prior fertility treatment had significantly higher emotional burden and greater negative social impact than controls. Limitations include the two groups were not matched for age or parity. However linear regression modelling adjusting for age, BMI and parity did not impact significant differences. This is the first study evaluating the impact of infertility on QoL in women with CKD. Although infertility impacts this group's QoL as much as the general population's, we identified fertility treatment may have a more pronounced emotional and social effect emphasizing the importance of tailored, holistic support in treating this growing population.

BackgroundTo evaluate the association between seasonal temperature variations and clinical outcomes of in vitro fertilization (IVF), aiming to provide theoretical foundations for optimizing protocol timing in reproductive medicine.MethodsThis retrospective cohort study analyzed 2,551 first fresh IVF-embryo transfer (IVF-ET) cycles performed at a tertiary reproductive center of The First Affiliated Hospital of Shandong University of Traditional Chinese Medicine between January 2009 and January 2024. The study population comprised normo-ovulatory women aged < 35 years without uterine anomalies or severe male factor infertility (sperm concentration >1 × 106/mL). Cycles were stratified into four seasonal cohorts based on gonadotropin initiation dates: spring (March-May, n = 709), summer (June-August, n = 787), autumn (September-November, n = 640), and winter (December-February, n = 415). Primary outcomes included clinical pregnancy rate (CPR), live birth rate (LBR), miscarriage rate (MR), and Full-Term delivery rate (FTBR), analyzed through multivariable logistic regression models adjusting for mean daily temperature (°C), relative humidity (%), and daylight hours (h).ResultsCompared with the winter control group, risk of miscarriage in cycles initiated in spring showed a statistically significant increase (95% CI 1.019, 2.846; P = 0.042). Although CPR showed no seasonal variation (spring: 54.30%, summer: 52.22%, autumn: 50.47%, winter: 50.36%; P = 0.464), the spring cohort exhibited a numerically higher Full-Term delivery rate (39.07 vs. 34.22%; P = 0.105). Sensitivity analysis using weighted analysis to balance sample sizes across groups revealed significantly higher full-term birth rates in spring compared to winter (P = 0.046) and the live birth rate in spring was also significantly higher than in winter (P = 0.029). For each unit increase in sunlight intensity on the trigger day, the probability of successful pregnancy decreases to approximately 0.978 times the original value (OR = 0.978 per lux-unit increase, 95% CI 0.960–0.997; P = 0.025).ConclusionSeasonal microenvironmental factors during ovarian stimulation may modulate IVF success trajectories, suggesting potential benefits of climate-adaptive protocol personalization in temperate monsoon regions.Clinical trial registrationThis is a retrospective case-control study.

Complement (C) proteins have been linked to infertility and reproductive outcomes. This study was undertaken to determine the association of complement proteins in non-obese women before in vitro fertilization (IVF) with unexplained infertility (UI) compared to women with male factor infertility (MFI) as controls. We hypothesized that complement protein factors may provide evidence for the underlying mechanism in UI. In this exploratory pilot study, 25 women (UI = 14 and MFI = 11) undergoing IVF had blood drawn on day 21 of the luteal phase. Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement was undertaken for 25 complement pathway-related proteins. Student’s t-test was used to compare group means and Pearson’s correlations to examine relationships with complement proteins. Baseline demographics and hormonal parameters did not differ between groups, and parameters of the response following IVF did not differ. In the UI group compared to the MFI group, there were lower levels of properdin (p = 0.03) that may reduce endometrial receptivity and impact follicular development, lower C3a anaphylatoxin des arginine (C3adesArg) (p = 0.02) that may reduce endometrial vascularity, lower C4 (C4) (p = 0.04), indicating reduced alternate pathway activation, and lower C8 (C8) (p = 0.04) that also may affect the endometrium. In UI alone, properdin negatively correlated with high-density lipoprotein cholesterol (HDL-c), and C8 positively correlated with thyroid-stimulating hormone (TSH) and Free-triiodothyronine (Free-T3) (p < 0.05). These preliminary findings indicate reduced complement activity among UI women, warranting further mechanistic investigation.

Our goal was to investigate IgG1 and IgG3 antibody responses to Chlamydia trachomatis proteins Pgp3 and Hsp60 in males of subfertile couples and to explore the association of these antibodies with semen parameters and male factor infertility. Serum samples were collected from 256 male partners of subfertile couples. Serum IgG1 and IgG3 antibodies to C. trachomatis Pgp3 and Hsp60 were measured using enzyme immune assays (EIA). Semen samples were analyzed for volume, sperm concentration and motility according to World Health Organization (WHO) criteria. Altogether, 74 (29.8%) men were seropositive to either C. trachomatis Pgp3 IgG1 or IgG3, and 67 (27.0%) to either Hsp60 IgG1 or IgG3. C. trachomatis Pgp3 IgG1 and IgG3 antibodies were associated with impaired sperm motility (asthenozoospermia) (18.6% vs. 6.3%, p=0.006 for Pgp3 IgG1; and 21.4% vs. 8.0%, p=0.03 for Pgp3 IgG3). After adjusting for smoking, alcohol risk consumption and BMI, the association between serum C. trachomatis Pgp3 IgG1 seropositivity and asthenozoospermia remained statistically significant (OR 3.0 [1.12 -8.01], p=0.03). The presence of Hsp60 IgG1 antibody was associated with a higher teratozoospermia index (1.47 ± 0.15 vs. 1.39 ± 0.16, p=0.001). Our results suggest that prior Chlamydia trachomatis infection, as indicated by Pgp3 seropositivity, may negatively impact male fertility potential by affecting sperm motility and morphology.

A reduced fertilization rate is a frustrating condition for patients and embryologists. This study aimed develop a statistical metric, LOW FERTILIZATION, to determine whether a distinct pathological entity underliesreduced fertilization or if it merely reflects statistical variability. An indirect argument inspired by proof by contradiction was developed using a statistical model based on two assumptions: (1) fertilization occurs with same probability (P) for all oocytes with P based on Istanbul Consensus benchmarks, (2) no underlying clinical condition affects the couple. Withthese assumptions, oocytes fertilization in a single cycle follows a binomial distribution, with LOW FERTILIZATION defined as outcomeoccurring with an expected probability below 5% under the null hypothesis. Afterwards, we appliedfindings to a real-world population evaluating thefrequency of LOW FERTILIZATION,predictive factors, and recurrence risk. We provided a table indicating the maximum number of fertilized oocytes to define low fertilization, alongside R code, to facilitate reproducibility. Forreal-world data in2653 women, LOW FERTILIZATION was observed in 118 cases (4.5%, 95%CI: 3.7-5.3%), occurring in 3.6% of cIVF and 5.2% of ICSI cycles. Severe male factor infertility was associated with LOW FERTILIZATION in ICSI (adjusted OR = 2.60, 95% CI: 1.37-4.73). The adjusted OR of recurrence of LOW FERTILIZATION was 3.70 (95%CI: 1.40-8.71), rising to 7.26 (95%CI: 2.48-19.93) for couples undergoing ICSI in both cycles. The LOW FERTILIZATION metric demonstrates a clinical condition, although relatively rare, associated with reduced fertilization. It also offers a valuable tool to guide future research investigating factors associated with this condition.

BackgroundFertility preservation is an important aspect of care for breast cancer patients. This study was designed to compare the ovarian function including ovarian reserve and ovarian stimulation response in breast cancer patients undergoing controlled ovarian stimulation (COS) for fertility preservation before chemotherapy, and oocyte donors as healthy women.MethodsThis historical cohort study enrolled 78 breast cancer patients who underwent COS for fertility preservation between April 2014 and March 2022 at the Infertility Center of Royan Institute, Tehran, Iran. Sixty-six healthy oocyte donors were included as a control group during the same time period. The inclusion criteria were female patients aged ≤ 35 years, with confirmed breast cancer with indication of chemotherapy, who were elected for ovarian stimulation before chemotherapy for oocyte retrieval. Women with the diagnosis of poor ovarian response, polycystic ovary syndrome, severe male factor infertility, endometriosis, and those who used oral contraceptives excluded from the study. Main outcome measure was retrieved total number of mature oocytes.ResultsThe mean age was significantly higher and mean body mass index was significantly lower in the breast cancer group than in the oocyte donor group. There were also significant differences between groups in terms of hormonal profiles of luteinizing hormone and anti-mullerian hormone (AMH), gonadotropin starting dose, total dose of gonadotropin used and oocyte maturation rate. Based on the results, there was a significant correlation between Metaphase II and AMH in breast cancer group (r = 626; P < 0.001).ConclusionIt appears that patients with cancer experience diminished ovarian reserve prior to cancer treatment. Further prospective studies with larger sample sizes are recommended.Clinical trial numberNot applicable.

Obesity is a prevalent modifiable cause of male factor infertility. Preconception guidelines recommend men maintain a healthy weight; however, they provide limited guidance regarding methods or volume of weight loss for men with obesity. First-line interventions for weight loss involve lifestyle optimization (healthy diet and exercise), followed by pharmacotherapy or bariatric surgery in severe cases. Each modality has differing weight loss potential and complications for which the reproductive implications are currently unclear. To synthesize the available evidence regarding the reproductive effects of obesity interventions in men with obesity. Where possible, to evaluate whether the observed effects depend on the magnitude of weight loss. Searches for articles published in English was performed using PubMed, Web of Science, Embase, Cochrane Central Register of Controlled Trials and Scopus from inception until December 2024, using prespecified keywords pertaining to four categories: male, overweight/obesity, weight loss (bariatric surgery, nutrition, diet, lifestyle, exercise, pharmacotherapy) and fertility (conception, assisted reproduction, sperm, semen). Studies of reproductive-aged men (18-50 years) who underwent an obesity intervention with established weight loss benefits and undertook repeated assessment of reproduction capacity (semen analysis, conception rates, assisted reproduction outcomes) before and after the intervention were included. Meta-analysis was performed when two or more studies of the same modality assessed an outcome measure in a manner suitable for meta-analysis. A meta-regression considering weight loss achieved was performed when five or more suitable studies were available. Narrative review of studies not suitable for meta-analysis occurred. 32 studies were included in the analysis, with one study assessing both lifestyle interventions and pharmacotherapy. Assessment of conception rates and assisted reproduction was limited across all modalities. In almost all cases, the effect of obesity interventions on semen quality was examined as a surrogate for reproductive capacity and the certainty of evidence was low. Bariatric surgery was assessed in 18 studies, including 12 quasi-experimental studies, one randomized controlled trial, one case series and four case reports. Fixed- and random-effects meta-analysis of randomized controlled trials identified no differences in sperm parameters between control and intervention arms across any intervention, although small sample size limits interpretability. Random-effects meta-analyses of pre-post outcomes identified no clinically significant semen parameters or DNA damage changes following bariatric surgery. Pharmacotherapy (metformin and liraglutide) was assessed in five studies, including four quasi-experimental studies and one case report. There were insufficient data to draw clear conclusions regarding the impact of these agents on fertility outcomes. Lifestyle interventions were assessed in 10 studies, including five quasi-experimental studies and five randomized controlled trials. Fixed-effect meta-analysis identified improvements in sperm normal morphology (Mean difference = 0.59%, 95% Confidence interval = [0.23, 0.94]), and progressive motility (10.56% [8.97, 12.15]) following a lifestyle intervention. Data regarding weight loss interventions and male fertility is limited primarily to observational studies examining semen quality. Improvements in semen quality following lifestyle interventions suggest a potential benefit of optimizing nutrition and physical activity, whereas a limited change with bariatric surgery indicates obesity-associated sperm dysfunction does not resolve in a dose-dependent manner with weight loss and/or negative effects of rapid weight loss exist. Substantial knowledge gaps were identified, including limited randomized trials, inadequate examination of conception outcomes and limited assessment of GLP-1 agonist effects. CRD 42022349665.

This study aims to identify molecular markers with prognostic value for biochemical pregnancy in follicular fluid (FF) samples from women with endometriosis after assisted reproductive technology (ART) intervention. Levels of growth differentiation factor-9 (GDF-9), bone morphogenetic protein-15 (BMP-15), and anti-Mullerian hormone (AMH) proteins were semi-quantified by Western blotting and microRNAs 20a_1, 145_1, 320a_1, 125-b-5p, 212-3p, and 199_a by qPCR in FF samples from women submitted to ART with a previous diagnosis of endometriosis (n = 20) or male factor infertility (controls) (n = 44). An increase in GDF-9 and BMP-15 and a decrease in AMH mature protein were observed, as well as an increase in miR20a_1 (p = 0.04), miR145_1 (p = 0.003), and miR320a_1 (p = 0.006) in FF samples collected from women with endometriosis compared with controls. A reduction was observed in miR125b-5p (p = 0.004) and 212-3p (p = 0.02) in endometriosis. Receiver operating characteristic (ROC) curve analysis indicated that miR125b-5p, miR212-3p, and miR-145_1 are potential predictors of endometriosis, and miR145_1 and miR320a_1 of biochemical pregnancy in controls. Although limited by a small sample size, the current study demonstrated alterations in AMH, BMP-15, GDF-9, and specific miRNA levels in FF samples harvested from women with endometriosis, emphasizing their potential roles in endometriosis-related infertility. These microRNAs, dysregulated in women with endometriosis, unveil their biomarker properties and their predictive value for ART success.

Infertility is a complex disease, characterized by the incapability to achieve pregnancy after 24 months of regular unprotected sexual intercourse. Various studies have highlighted the role of sex hormone-related genes in contributing to the risk of male infertility. However, research on sex hormone-binding globulin (SHBG) – a glycoprotein involved in transporting sex hormones to target tissues, remains limited. Therefore, this study aimed to investigate whether SHBGrs727428 variant is associated with idiopathic male infertility in Vietnam. A total of 287 DNA samples (123 cases and 164 controls) were genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) method. The results showed that genotype frequencies conformed to the Hardy-Weinberg equilibrium. Importantly, an association between SHBG rs727428 and male infertility was identified in three models: additive model (TT genotype, OR = 0.428, 95%CI 0.197 – 0.885, p-value = 0.021), dominant model (TT genotypes, OR = 0.473, 95%CI 0.229 – 0.928, p-value= 0.029) and allele model (T allele, OR = 0.680, 95% CI: 0.481-0.95, p-value = 0.028). This study enhances our understanding of the role of genetic factors in male infertility among the Vietnamese population.