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In this study, we aimed to correlate embryonic ploidy status studied with non-invasive preimplantation genetic testing for aneuploidy with the basic patient characteristics of the infertile couple to gain insight into the effects of parental physical health on embryo ploidy. We recruited 131 couples, who were stratified into 4 groups based on female age. We gathered general patient characteristics of the couple and determined the female’s hormonal status. We included 316 embryos in our study. Embryos were either transferred in the uterus in a fresh cycle or vitrified for later use. We collected spent embryo culture medium on either day 5 or 6 and performed whole genome amplification before using Next Generation Sequencing. Pregnancy outcomes were noted and cross-referenced with patient characteristics and the embryo’s ploidy status in a retrospective manner. While we have indirectly observed a level of maternal contamination, we nevertheless found a significant correlation between embryo ploidy status and cell free deoxyribonucleic acid concentration in spent embryo culture, as well a correlation between female age and embryo ploidy status. We observed a significant correlation between male body mass index and cell free deoxyribonucleic acid concentration in spent embryo culture medium and between male body mass index and pregnancy outcome. We illustrated a connection between male body mass index and cell free deoxyribonucleic acid, independent of female markers. This is the first study to observe not only female but male parameters in correlation to cell free deoxyribonucleic acid.

The window of implantation is a critical period for embryo implantation. Ovarian stimulation can disrupt endometrial receptivity, potentially through altered gene expression and downstream protein profiles. However, the impact on the endometrial proteome remains underexplored. Identifying biomarkers of endometrial receptivity may provide an opportunity to develop targeted interventions aimed at improving implantation outcomes. This prospective, case-crossover, open-label study was conducted at the Department of Human Reproduction, Division of Obstetrics and Gynecology, University Medical Centre Ljubljana, Slovenia, from September 2023 to June 2024. The study included 15 women aged <43 years with primary infertility and poor ovarian response. Endometrial samples were collected using a pipelle biopsy during the window of implantation in spontaneous and stimulated cycles and analyzed using protein microarrays targeting 1,466 proteins. Differential protein abundance was assessed using a multi-factorial linear model, including patient-specific effects as an additional factor to account for the paired case-crossover design. Effect sizes are reported as log2-fold changes with corresponding 95% confidence intervals. Differential abundance was defined a priori as |log2FC| > 0.5 with FDR-adjusted p-value < 0.05. Comparison of endometrial samples from spontaneous and stimulated cycles revealed 114 antibodies with differential abundance. Key proteins were associated with immune response (IL-8, proteins S100-A8 and S100-A9, CAMP) and extracellular matrix remodeling (MMP-9). Exploratory KEGG pathway mapping suggested involvement of immune and inflammatory pathways, including cytokine–cytokine receptor interaction and IL-17 signaling. Cluster analysis demonstrated distinct proteomic patterns, with all stimulated-cycle samples showing alterations and a subset of stimulated-cycle samples (40%) exhibiting more pronounced changes. The findings indicate that ovarian stimulation is associated with measurable alterations in the endometrial proteomic profile during the window of implantation. These changes may be relevant to biological pathways involved in endometrial receptivity and implantation. Further studies in larger cohorts are needed to validate the identified candidate markers and determine their clinical relevance for implantation outcomes. Trial registration: ClinicalTrials.gov NCT06804174.

Background Recent research in male infertility genetics has identified numerous candidate genes, some of which were also involved in DNA repair. Mismatch repair (MMR) genes, such as MSH4 and MSH5 , have been linked to male infertility due to their role in meiosis, suggesting that other MMR genes may also contribute to impaired spermatogenesis. To investigate the role of MMR genes in male infertility, we first conducted a systematic review focusing on their involvement in impaired spermatogenesis, which was followed by a multicenter cohort study assessing the occurrence of rare deleterious variants in MMR genes among men with severely impaired fertility. The present study aimed to assess the contribution of MMR genes to male infertility and to evaluate their potential clinical utility in the diagnostic workup of men with severely impaired fertility. Methods A systematic review was conducted through a PubMed database search with a focus on the role of MMR genes in spermatogenesis. We additionally prepared a cohort study, including whole-exome sequencing data from 244 infertile men presenting azoospermia or severe oligozoospermia (< 5 million spermatozoa/ml). Rare, deleterious variants in MMR genes were classified using the ACGS Guidelines for Variant Classification 2020. Results Following a systematic review of the literature, we gathered robust evidence supporting the strong involvement of MSH4 and MSH5 variants in male infertility, moderate evidence for MLH3 , and limited evidence for other MMR genes. From our cohort, we identified likely pathogenic or pathogenic variants in two individuals: one with two MSH4 variants and another with a PMS2 variant. Conclusions The present study identifies MSH4 and MSH5 as strong candidate genes for male infertility, supporting the integration of their testing into the clinical diagnosis of infertile men, particularly those exhibiting non-obstructive azoospermia. Although current evidence suggests that genetic variants in most MMR genes do not cause infertility, genetic defects in MMR genes can still impair spermatogenesis due to their critical role in sperm DNA repair and maintenance of genome integrity.

Evaluation of male infertility has been based on semen analysis for years. As this method can be subjective at times, there is a scientific tendency to discover stable and quantifiable biomarkers. This study included 28 couples who underwent an in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycle. The couples were assigned into two groups, according to sperm morphology. Couples where the males were normozoospermic were placed in the control group (15 participants), while couples where males had teratozoospermia were placed in the study group (13 participants). Thirteen candidate miRNAs were selected for qPCR analysis, based on our literature search. We determined significant under-expression of nine miRNAs (miR-10a-5p/-15b-5p/-26a-5p/-34b-3p/-122-5p/-125b-5p/-191-5p/-296-5p and let-7a-5p) in spermatozoa from patients with teratozoospermia compared to the controls, whereas expression levels of four miRNAs (miR-92a-3p/-93-3p/-99b-5p/-328-3p) did not significantly differ between the study and control groups. The expression levels of all 13 included miRNAs were significantly positively correlated with each other and significantly positively associated with spermatozoa morphology, excluding miR-99b-5p. There were no other significant associations between miRNA expression and sperm quality parameters. Only expression levels of miR-99b-5p were significantly positively correlated with good-quality day 3 embryo rate (ρ = 0.546; p = 0.003), while other variables of the IVF/ICSI cycle outcome showed no significant associations with miRNA expression profiles. This is one of the rare studies providing an insight directly into miRNA profiles in regard to sperm morphology. We identified nine miRNAs that could serve as biomarkers of spermatozoa quality in regard to teratozoospermia.

The latest reports suggest that it is better to transfer embryos to the uterus on day five of preimplantation development compared to other days of development, but it is not clear if this stands when there are only one-two embryos obtained in the cycle. Therefore, to address this issue, we performed a retrospective study of such cycles. Our study included all of the stimulated IVF/ICSI cycles performed at our institution in the period between 1 January 2004 and 31 December 2018 in which one-two embryos were obtained in the IVF/ICSI cycle and met our inclusion criteria, and we compared the data between day three and day five embryo transfer (ET). The analysis revealed that the day three ET group of patients was significantly older (p < 0.001), were administered a significantly higher dose of gonadotrophins (p = 0.015), and retrieved a lower mean number of aspirated oocytes per cycle (p < 0.001) and lower mean number of embryos (p < 0.001). The birth rate per ET was significantly higher in the day five ET group (p = 0.045) and further analysis indicated that this could be due the trend observed in a group of patients under 36 years old, while in older patients there was no such difference. To conclude, our retrospective study indicates that it might be better to perform ET on day five instead of day three when there are only one-two embryos obtained in the cycle, but probably only when patients are under 36 years old.

Purpose The present study aimed to determine clinical IVF parameters and gene expression in cumulus cells (CCs) in obese and normal weighting women after administration of 150 mcg of corifollitropin alfa for controlled ovarian hyperstimulation (COH). Methods 150 mcg of corifollitropin alfa and gonadotropin releasing hormone antagonist were used for COH. Analysis of CC gene expression was performed using quantitative real-time PCR. Results We did not find significant differences in biochemical and clinical pregnancy rates between obese and normal weighting women. Obese women required twice as much of additional gonadotropins for ovarian stimulation and had a significantly lower proportion of good quality embryos on day 5 of IVF cycle. Expression of PGR and PTX3 was significantly higher in CCs of obese women. Conclusion Obese women require significantly larger amounts of gonadotropins to achieve similar IVF success rates as normal weighting women. Differences in CC gene expression and smaller proportion of good quality embryos may imply that oocytes derived from obese women are of lower quality. Further studies are needed to evaluate whether obesity itself or the higher amount of gonadotropins used in obese women causes this effect.

Background and Objectives: Polycystic ovary syndrome (PCOS) is a major cause of anovulatory infertility, and ovulation induction is the first-line treatment. If this fails, laparoscopic ovarian drilling (LOD) is used to induce mono-ovulations. There have been implications, that LOD can cause destruction of ovarian tissue and therefore premature ovarian failure. Furthermore, unexpected poor ovarian response (POR) to gonadotrophins can occur in PCOS women after LOD. There have been reports about FSH receptor polymorphisms found in women with PCOS that are related to higher serum FSH levels and POR to gonadotrophins. Materials and Methods: In the present study, we retrospectively analyzed data of 144 infertile PCOS women that had LOD performed before IVF. Results: Thirty of included patients (20.8%) had POR (≤3 oocytes) to ovarian stimulation with gonadotrophins. Women with POR had significantly higher median levels of basal serum FSH (7.2 (interquartile range (IQR), 6.0–9.2) compared to women with normal ovarian response (6.0 (IQR, 5.0–7.4); p = 0.006). Furthermore, women with POR used a significantly higher median cumulative dose of gonadotrophins (1875 IU (IQR, 1312.5–2400) for ovarian stimulation compared to women with normal ovarian response (1600 IU (IQR, 1200–1800); p = 0.018). Conclusion: Infertile PCOS women who experience POR after LOD have significantly higher serum FSH levels compared to women with normal ovarian response after LOD. As these levels are still within the normal range, we speculate that LOD is not the cause of POR. We presume that women with PCOS and POR after LOD could have FSH-R genotypes associated with POR and higher serum FSH levels.

Fertility preservation is an important aspect of quality of life in oncological patients, and in men is achieved by semen cryopreservation prior to treatment. Results of fertilization (IVF) procedures in healthy infertile couples are comparable, regardless of whether fresh or cryopreserved semen is used, but are scarce in male oncological patients. We performed a retrospective analysis of IVF/intracytoplasmic sperm injection (IVF/ICSI) procedures in infertile couples where men had been treated for cancer in the past. We additionally compared the results of IVF/ICSI procedures with respect to the type of semen used (fresh, cryopreserved). We compared the success rates of 214 IVF/ICSI cycles performed in the years 2004-2018. Pregnancy (30.0% . 21.4%; p = 0.12) and live-birth rates (22.3% . 17.9%; p = 0.43) per oocyte aspiration were similar between the groups in fresh cycles; however embryo utilization (48.9% . 40.0%; p = 0.006) and embryo cryopreservation rates (17.3% . 12.7%; p = 0.048) were significantly higher in the cryopreserved semen group. The cumulative pregnancy rate (60.6% . 37.7%; p = 0.012) was significantly higher, and the live-birth rate (45.1% . 34.0%; p = 0.21) non-significantly higher, in the cryopreserved semen group. The success of IVF/ICSI procedures in couples where the male partner was treated for cancer in the past are the same in terms of pregnancies and live-births in fresh cycles regardless of the type of semen used. However, embryo utilization and embryo cryopreservation rates are significantly higher when cryopreserved semen is used, leading to a significantly higher cumulative number of couples who achieved at least one pregnancy.

Background It has already been found that very small embyronic-like stem cells (VSELs) are present in adult human tissues and organs. The aim of this study was to find if there exists any similar population of cells in cell cultures of reproductive tissues and embryonic stem cells, and if these cells have any relation to pluripotency and germinal lineage. Methods and results Here we report that a population of small SSEA-4-positive cells with diameters of up to 4 μm was isolated by fluorescence-activated cell sorting (FACS) from the human ovarian cell cultures after enzymatic degradation of adult cortex tissues. These small cells – putative ovarian stem cells – were also observed during cell culturing of up to 6 months and more. In general, small putative ovarian stem cells, isolated by FACS, showed a relatively low gene expression profile when compared to human embryonic stem cells (hESCs) and human adult fibroblasts; this may reflect the quiescent state of these cells. In spite of that, small putative ovarian stem cells expressed several genes related to primordial germ cells (PGCs), pluripotency and germinal lineage, including VASA . The PGC-related gene PRDM1 was strongly expressed in small putative ovarian stem cells; in both hESCs and fibroblasts it was significantly down-regulated. In addition, putative ovarian stem cells expressed other PGC-related genes, such as PRDM14 and DPPA3 . Most of the pluripotency and germinal lineage-related genes were up-regulated in hESCs (except VASA ). When compared to fibroblasts, there were several pluripotency-related genes, which were up-regulated in small putative ovarian stem cells. Similar populations of small cells were also isolated by FACS from human testicular and hESC cultures. Conclusions Our results confirm the potential embryonic-like character of small putative stem cells isolated from human adult ovaries and their possible relation to germinal lineage.

Small stem cells with diameters of up to 5 μm previously isolated from adult human ovaries indicated pluripotency and germinal lineage, especially primordial germ cells, and developed into primitive oocyte-like cells in vitro . Here, we show that a comparable population of small stem cells can be found in the ovarian tissue of women with borderline ovarian cancer, which, in contrast to small stem cells in “healthy” ovaries, formed spontaneous tumour-like structures and expressed some markers related to pluripotency and germinal lineage. The gene expression profile of these small putative cancer stem cells differed from similar cells sorted from “healthy” ovaries by 132 upregulated and 97 downregulated genes, including some important forkhead box and homeobox genes related to transcription regulation, developmental processes, embryogenesis, and ovarian cancer. These putative cancer stem cells are suggested to be a novel population of ovarian tumour-initiating cells in humans.