Search Results (1,189)

Women with polycystic ovary syndrome (PCOS) and insulin resistance (IR) commonly have elevated serum advanced glycation end-products (AGEs) that accumulate in their ovaries, potentially altering ovarian function. AGEs have been shown to interfere with insulin signaling in granulosa cells (GCs) by suppressing the translocation of glucose transporters. Additionally, PCOS has been associated with insulin receptor substrate (IRS)-1 polymorphisms and upregulation in IRS-1 gene expression in GCs. We hypothesize that AGEs are partly responsible for ovarian IR by altering IRS-1 in human GCs. Cumulus granulosa cells from women undergoing IVF were cultured in control media or media containing human glycated albumin (HGA) as a source of AGEs. The quantification of mRNA expression was compared using RT-PCR for receptors for AGEs (RAGE), IRS-1, IRS-2, Glucose Transporter Type (GLUT)-1, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). In addition, IRS-1 protein intensity was assessed by immunofluorescence. Compared to the control group, HGA-treated GCs showed a statistically significant upregulation in RAGE mRNA by 314% and in IRS-1 mRNA by 423%. Even though there was a 183% increase in GLUT-1 mRNA, it did not reach statistical significance. There was no change in IRS-2 or NF-κB mRNA expression levels. Immunofluorescence showed that IRS-1 deposition was visualized in GCs, and the addition of HGA resulted in a significant increase in the intensity of IRS-1 protein compared to control cells. The AGE-induced upregulation in IRS-1, the primary insulin receptor substrate, in GCs could indicate compensation for insulin action deficiency and potentially IR. Additionally, immunofluorescence analysis of GLUT-4 revealed a statistically significant reduction in cytoplasmic GLUT-4 signal in HGA-treated GCs compared to controls (2.10 ± 0.21 vs. 3.81 ± 0.22 arbitrary units; p = 0.010), consistent with AGE-mediated disruption of glucose transporter localization. These results suggest that AGE exposure may initiate early molecular changes consistent with altered insulin signaling, but do not establish insulin resistance per se. Full article

Rosmarinic acid (RA), a naturally occurring polyphenolic compound, has demonstrated promising anticancer activity; however, its combinatorial potential with conventional chemotherapeutic agents remains incompletely characterized. This study investigated the cytotoxic, pro-apoptotic, oxidative stress-associated, and cytokine-associated effects of RA alone and in combination with doxorubicin (DOX) in 4T1 murine breast cancer cells and HaCaT human keratinocyte cells as a non-cancerous control model. Cellular viability, apoptosis, cell cycle progression, oxidative stress, mitochondrial function, cytokine responses, and apoptosis-associated molecular alterations were evaluated using complementary cellular and molecular approaches. In addition, three-dimensional (3D) tumor spheroid experiments were performed to assess treatment responses under physiologically relevant tumor-like conditions. Results demonstrated that RA synergistically enhanced DOX-induced cytotoxicity in 4T1 cells while exhibiting comparatively lower toxicity toward HaCaT cells. Combination treatment significantly increased apoptotic cell death, mitochondrial depolarization, intracellular reactive oxygen species (ROS) accumulation, apoptotic DNA fragmentation, and G₂/M-phase accumulation. N-acetylcysteine (NAC)-mediated rescue experiments partially reversed ROS elevation and treatment-associated cytotoxicity in both monolayer and 3D spheroid models. Furthermore, the RA+DOX combination markedly disrupted spheroid integrity and reduced spheroid viability compared with monotherapies. Collectively, these findings indicate that RA enhances the anticancer activity of DOX and support further investigation of this combination strategy in breast cancer models. Full article

Importance: Most couples who turn to assisted reproductive technology (ART) treatment do so, usually, after giving up emotionally on the chances of conceiving naturally. Others undergo ovulation induction with intrauterine insemination (IUI) and turn to ART after the latter has failed. Spontaneous conception after having experienced the exhausting process of ART, whether it was successful or not, could be very surprising and confusing for many couples. Objective: Review all the scenarios within which an unexpected spontaneous conception can occur and the likelihood of its occurrence. These are four such scenarios: (1) after being referred to ART but before the actual initiation of ART; (2) between ART cycles; (3) after a successful ART pregnancy; (4) after giving up on treatment. We have found only a systematic review on #3, but not the other three. Evidence Review: We collected all PubMed citations for the terms “spontaneous conception” and ART or IVF. Thereafter, we realized that no AI tool can filter only the relevant literature. Hence, we exhausted all possible cross-references by manual search to ensure the completeness of the search. Findings: In each of the four scenarios, spontaneous conceptions occur. Before treatment, a critical element is the length of the waiting time, as is the gap between treatments when already treated, with the cost of treatment being a critical determinant. After the conclusion of treatment, whether successful or failed, the main determinants of the chance for spontaneous conception are age, length of infertility, and the leading etiology for infertility. Overall, the chances range from as little as 2% and up to 25%, with severe male factor and a woman’s age being the most notable for low rates. Conclusion and Relevance: Each couple entering ART treatment should be informed of the chances for spontaneous conception, whether as an aid to the decision to enter or the decision to leave after a failure, and on the more cheerful side, to be aware of the chances for unplanned pregnancy after a successful treatment. Full article

The pineal gland regulates circadian physiology through the periodic production of melatonin (MLT). In addition to its established role as a chronobiotic agent, MLT regulates redox homeostasis and mitochondrial physiology. Mitochondria and redox-active molecules, particularly reactive oxygen species (ROS), play essential roles in reproduction, including gamete physiology, fertilization, and early embryonic development. Although excessive oxidative stress (OS) impairs fertility, controlled ROS signaling is necessary for normal reproductive function. This comprehensive review synthesizes current evidence regarding MLT as a key intermediary linking circadian signaling with mitochondrial physiology and redox homeostasis. We discuss molecular pathways through which MLT regulates mitochondrial function, including activation of the Nrf2 signaling pathway, modulation of mitochondrial permeability transition, regulation of electron transport chain (ETC) efficiency, and apoptotic signaling. Furthermore, this study investigates MLT’s ability to scavenge free radicals and activate antioxidant defense mechanisms. Moreover, we review novel findings regarding the effects of MLT in experimental animals and humans, assisted reproductive technologies (ART) such as in vitro fertilization (IVF), and consider the translational significance of the hormone as an enhancer of fertility. We also highlight gaps in the literature, including methodological inconsistencies, supraphysiologic doses, and insufficient data from large human cohorts. Lastly, we discuss an integrative model whereby MLT may function as an important regulator of mitochondrial redox balance, with potential implications for reproductive physiology and reproductive outcomes, and propose new avenues for investigation. Full article

Oocyte formation occurs successfully within a meticulously controlled follicular environment characterized by well-documented endocrine, metabolic, and paracrine signals. Yet, the immunological landscape of the follicle and its role in influencing oocyte competency has received less attention in research. Growing research indicates that the ovarian follicle functions as an immunological-active niche necessitating a precise equilibrium between controlled inflammation and targeted immune tolerance. The programmed cell death-1 (PD-1) receptor and its ligand PD-L1 constitute a crucial immune checkpoint pathway, essential for sustaining peripheral immunological tolerance and averting excessive immune activation. Despite their comprehensive research in cancer biology and maternal–fetal interactions, their possible function in the follicular microenvironment remains mostly unexamined. We propose that PD-1/PD-L1 signaling may facilitate the formation of a localized immune-tolerant milieu inside the follicle to safeguard the developing oocyte from inflammatory injury and immune-mediated stress. The disturbance of this suggested equilibrium may lead to a pro-inflammatory follicular environment, compromised granulosa cell function, and modified oocyte maturation, hence affecting fertilization and embryonic developmental potential. In clinical contexts with immunological dysregulation, such as endometriosis, polycystic ovarian syndrome, and unexplained IVF failure, such processes may be especially significant. The purpose of this narrative review is to assimilate the current comprehension of immune regulation in the follicle with the established biology of PD-1/PD-L1 and to investigate a potential correlation between immune checkpoint signaling, oocyte competence, and assisted reproductive outcomes. Considering the follicle as an immune-regulated microenvironment offers a new paradigm for comprehending infertility and identifying novel indicators or therapeutic targets. Full article

Background/Objectives: The role of the endometrial microbiome in reproductive failure remains incompletely understood. This study aimed to describe the composition of the endometrial microbiome in women evaluated for infertility or recurrent miscarriage. Methods: In this single-center descriptive study, endometrial samples were collected from women evaluated for infertility or recurrent miscarriage. Microbiome profiling was performed using 16S rRNA gene next-generation sequencing. Samples were classified as Lactobacillus-dominant when Lactobacillus spp. accounted for ≥90% of the total bacterial community. Alpha diversity was assessed using the Shannon and Simpson indices, while beta diversity was evaluated using Bray–Curtis dissimilarity, principal coordinates analysis (PCoA), PERMANOVA, and PERMDISP. Results: Of the 60 samples, 20 (33.3%) were Lactobacillus-dominant and 40 (66.7%) were non-Lactobacillus-dominant. Across all samples, Firmicutes was the predominant phylum (76.6%). Non-Lactobacillus-dominant samples showed significantly higher alpha diversity than Lactobacillus-dominant samples for both the Shannon and Simpson indices (p = 1.19 × 10⁻⁶ and p = 1.51 × 10⁻⁶, respectively), as well as higher observed taxa richness (p = 0.000017). PCoA based on Bray–Curtis dissimilarity demonstrated clear separation between microbiome profiles, supported by PERMANOVA (pseudo-F = 13.87, R² = 0.193, p = 0.001). PERMDISP showed significantly greater dispersion among non-Lactobacillus-dominant samples (F = 566.94, p < 0.001). Non-Lactobacillus-dominant samples showed greater representation of Enterococcus and Prevotella. Conclusions: In this cohort non-Lactobacillus-dominant communities were more frequent with greater diversity, richness, and compositional heterogeneity than Lactobacillus-dominant communities. These findings highlight the need for larger, standardized studies with appropriate control populations to clarify their clinical significance. Full article

Background: Hysteroscopic endometrial fundal incision (HEFI) is a novel addition to the standard IVF procedure. This study aimed to evaluate whether different depths of incision during HEFI could affect reproductive outcomes in oocyte recipients. Methods: A prospective analysis was conducted on women who underwent HEFI 1–2 months prior to embryo transfer with donor oocytes. Patients were categorized into three groups based on the depth of incision: U2a (superficial level) U2aa (intermediate level), and U2aaa (deep level). Pregnancy and live birth rates were assessed. Results: A total of 212 women without intrauterine pathology were included. Positive pregnancy rates were 78% in U2a, 76.9% in U2aa, and 77.1% in U2aaa (p = 0.95). Live birth rates were 58.5%, 57.1%, and 56.4%, respectively (p = 0.97). Early and late miscarriage rates and biochemical pregnancies showed no significant differences between the groups. Conclusions: Based on the results obtained, we could speculate that the depth of infiltration during HEFI does not significantly influence reproductive outcomes in oocyte recipients without intrauterine pathology. However, these findings should be interpreted with caution, given the limitations of the study, including its non-randomized design and differences among groups, such as variations in the number of embryos transferred and intraoperative group allocation. Therefore, further randomized clinical trials should be performed to more comprehensively understand the impact of incision depth on reproductive outcomes. Full article

Implantation failure remains a major challenge in IVF, and the contribution of the gut microbiota to implantation success is still poorly defined. We conducted a pilot matched case–control study (February 2023–December 2024) to compare gut microbiota profiles between women with RIF (defined according to ESHRE good practice recommendations) and fertile controls with documented fertility (≥1 prior spontaneous pregnancy). All participants underwent standardized clinical and nutritional assessment of medical history, dietary habits, anthropometry, and body composition. Stool samples were collected for 16S rRNA gene sequencing. In women with RIF, sampling occurred within 1 year after the last failed embryo transfer. Of 45 enrolled women, 41 completed the study (20 RIF and 21 controls; mean age 38.46 ± 4.53 years), with no significant between-group age differences. Women with RIF showed reduced alpha diversity (Shannon p = 0.003; inverse Simpson p = 0.002) and a distinct community structure versus controls (Bray–Curtis PERMANOVA F = 7.16; R² = 0.16; p = 0.001), which remained significant after adjustment for clinical covariates including waist-to-hip ratio (p = 0.018). At the phylum level, women with RIF had fewer Firmicutes (52.7% vs. 65.0%; p = 0.012) and more Proteobacteria (9.1% vs. 3.6%; p < 0.001). These findings support an association between gut dysbiosis and a history of implantation failures and warrant confirmation in larger, longitudinal cohorts. Full article

Health tourism represents a dynamic sector operating at the intersection of medical services, international patient mobility, and tourism development. Despite its growing prominence, the academic literature frequently conflates health tourism with medical and wellness tourism—a conceptual ambiguity that complicates the establishment of robust, sustainable legal frameworks. Addressing this gap, the present paper conceptualizes health tourism as an overarching framework that encompasses recovery, wellness, and medical sub-sectors. Within this comprehensive paradigm, we explore the contemporary landscape of health tourism in Northern Cyprus through a stakeholder-driven qualitative lens. Utilizing a qualitative case study design, data were gathered via semi-structured interviews with 40 key respondents representing healthcare, travel, public administration, academia, and related professional domains, and subsequently subjected to thematic analysis using NVivo 15 software. The findings reveal that the sector in Northern Cyprus is heavily skewed toward medical tourism, with a concentrated focus on in vitro fertilization (IVF), cosmetic surgery, dental care, and bariatric procedures. Conversely, wellness and rehabilitation tourism remain largely untapped strategic niches. The analysis further indicates that sectoral growth is constrained by structural bottlenecks, including fragmented governance, limited international recognition, transport and accessibility barriers, inadequate accreditation systems, lack of stakeholder synergy, and ethical concerns regarding advertising and patient safety. Moving beyond standard environmental sustainability, this research underscores that long-term destination resilience requires ethical governance, clinical quality controls, patient-rights advocacy, transparent legal frameworks, and community-level economic integration. Ultimately, this study proposes an integrated, stakeholder-centric paradigm tailored to the unique socio-political and structural realities of Northern Cyprus, offering actionable policy recommendations that enrich the discourse on sustainable medical tourism from a small-island perspective. Full article

Background/Objectives: Male infertility is a significant global public health concern, with sperm abnormalities contributing to nearly half of all cases. This retrospective study addressed a critical gap by analyzing 1182 semen records from subfertile Jordanian men at the IVF unit. Methods: We quantified the prevalence of specific abnormalities, oligozoospermia, asthenozoospermia, teratozoospermia, and azoospermia, and investigated the interrelationships between sperm count, motility, and morphology. Results: Oligozoospermia was the most prevalent single abnormality (29%), while normozoospermia was found in 28% of cases. Combined defects were frequent; oligoasthenoteratozoospermia, with low count, poor motility, and abnormal morphology, was identified in 17% of cases, highlighting the multifactorial nature of subfertility. Correlation analysis showed significant interdependencies. A strong positive correlation was found between normal morphology and progressive motility (r = 0.484, p < 0.0001), suggesting structural integrity is closely linked to movement. Sperm count showed moderate positive correlations with normal morphology (r = 0.508, p < 0.0001) and non-progressive motility (r = 0.522, p < 0.0001). Abnormal morphology exhibited the strongest positive correlation with immotile sperm (r = 0.559, p < 0.0001), consistent with asthenoteratozoospermia. Conclusions: These findings suggest semen issues in Jordanian men include multiple parameters simultaneously. Comprehensive semen analysis is essential for accurate fertility assessment, as focusing on a single parameter like sperm count may overlook critical factors contributing to infertility. Full article

Advanced maternal age is a significant social and clinical issue associated with the natural decline in a woman’s ovarian reserve. This prospective, single-center study included women with primary infertility who presented to the Gyncentrum Clinic in Katowice and analyzed 77 ovarian follicles. The study group consisted of patients of advanced reproductive age with diminished ovarian reserve, who underwent hormonal stimulation in preparation for oocyte retrieval. Each metaphase II (MII) oocyte was fertilized in vitro and cultured individually in a time-lapse incubator. Follicular fluid obtained during oocyte retrieval was collected separately from each follicle and used for non-invasive biochemical analysis of prognostic factors using a Multiplex assay. The concentrations of interleukin 10 (IL-10), granulocyte colony-stimulating factor (G-CSF), granulocyte–macrophage colony-stimulating factor (GM-CSF), and C-type natriuretic peptide (CNP) were evaluated. The analysis showed that lower concentrations of GM-CSF and CNP were associated with an increased probability of oocyte fertilization, whereas higher levels of IL-10 and G-CSF had the greatest impact on blastocyst formation. This model was supported by continuous embryo monitoring. An eightfold increase in the likelihood of blastocyst formation was observed when early embryo cleavage occurred between 25 and 27 h after insemination. Furthermore, prolonged duration of the first cytokinesis reduced the probability of blastocyst development, while an extended cell cycle at the two-blastomere stage significantly affected further embryo development. These findings may support non-invasive embryo selection strategies. Full article

Background: Women undergoing in vitro fertilization (IVF) often experience poor well-being. Social support and family resilience are considered protective factors, but their combined roles in the anxiety–fertility-related quality of life (FertiQoL) relationship remain unclear. Design: A cross-sectional study was conducted with women undergoing IVF at the reproductive medicine department of a tertiary hospital in Shanghai, China, between March and December 2024. Methods: Participants completed validated measures of anxiety, social support, family resilience, and QoL. Associations and indirect effects were examined using mediation analysis, and sensitivity analyses were conducted. Results: A total of 419 women participated in the study (response rate = 98.6%; mean age = 33.3 ± 4.7 years). Anxiety was negatively associated with social support, family resilience, and FertiQoL (all p < 0.001). The total indirect association between anxiety and FertiQoL involving social support and family resilience was statistically significant (B = −0.15, p = 0.03). However, the specific indirect effects, including the hypothesized sequential pathway through social support and family resilience, were not statistically significant. The total association between anxiety and FertiQoL was significant (β = −0.32, p < 0.001). Conclusions: Anxiety was associated with poorer FertiQoL among women undergoing IVF. Although the findings suggest an overall indirect association involving social support and family resilience, the hypothesized sequential mediation pathway was not supported. Therefore, the results should be interpreted cautiously, and longitudinal studies are needed to clarify the temporal and causal relationships among these psychosocial factors. Full article

Background and Objectives: The optimal oocyte yield in gonadotropin-releasing hormone (GnRH) antagonist in vitro fertilization (IVF) cycles remains debated, and data specific to antagonist protocols are limited. This study evaluated the discriminative and independent predictive performance of oocyte count for clinical pregnancy in GnRH antagonist IVF cycles. Materials and Methods: This retrospective cohort included 1171 women undergoing their first GnRH antagonist IVF cycle with fresh embryo transfer at a single tertiary center (September 2007–December 2021). The primary outcome was an institutional composite pregnancy outcome (sustained β-hCG positivity with subsequent ongoing intrauterine pregnancy or live birth; biochemical and ectopic pregnancies were negative). Patients were grouped by oocytes retrieved (1–5, 6–10, 11–15, ≥16). Performance was assessed with logistic regression, ROC with 2000-iteration bootstrap, integrated discrimination improvement (IDI), continuous net reclassification improvement (NRI), and restricted cubic spline. Predefined subgroup analyses by age, regimen, and antral follicle count tertile were performed. Results: A positive outcome occurred in 430 patients (36.7%). After adjustment, oocyte count was not an independent predictor (adjusted odds ratio 0.999, 95% CI 0.979–1.020; p = 0.96). The full model (AUC 0.564, 95% CI 0.529–0.598) did not outperform oocyte count alone (AUC 0.532; bootstrap p = 0.11). IDI (0.011) and NRI (0.135) were statistically detectable but clinically trivial. Spline regression showed no non-linearity (p = 0.47). Findings were consistent across subgroups, and the narrow confidence interval excluded per-oocyte effects ≥1.10. Conclusions: In GnRH antagonist IVF cycles, oocyte count showed weak discriminatory performance and was not independently associated with fresh-cycle pregnancy. Oocyte yield should be interpreted alongside—rather than as a substitute for—established parameters such as age and ovarian reserve. The principal clinical value of a higher oocyte response may lie in cumulative rather than fresh-cycle success. Live-birth outcomes were not available, and the source institution was permanently closed in 2025; these limitations define the boundary of inference. Full article

The first six contributions considered in this Editorial provide a coherent view of the modern laboratory as an integrated system of safety governance, digital education, measurement confidence, diagnostic implementation, and clinical quality assurance. The papers considered here address occupational hygiene and health monitoring in university laboratories, the predictive modeling of chemical exposure risks among cleaning staff, the design of an immersive virtual reality laboratory for multidisciplinary student experiences, the evolving concept of measurement uncertainty in accredited laboratories, the field implementation of a near point-of-care HIV drug-resistance assay in Kenya, and the optimization of embryo culture conditions in IVF laboratories. Although these studies span different fields, they converge on a common message: laboratory excellence depends not only on instruments and protocols but also on human factors, training, exposure control, usability, uncertainty management, and translation into real-world decisions. This Editorial synthesizes these contributions and identifies future priorities for Laboratories as a forum for interdisciplinary laboratory science and practice. Full article

Background/Objectives: Endometrial B-cell lymphoma 6 (BCL6) overexpression has been proposed as a marker of progesterone resistance, occult endometriosis, and endometrial dysfunction in infertile women. Its possible association with reproductive outcomes and its potential role in guiding management before embryo transfer have attracted increasing interest. However, the prognostic and clinical significance of BCL6 across infertility settings remains incompletely defined. We systematically reviewed the literature on endometrial BCL6 expression and reproductive outcomes in infertile women. Methods: This systematic review was conducted according to a prospectively registered PROSPERO protocol. Studies evaluating endometrial BCL6 expression on biopsy in infertile women were eligible if they reported reproductive outcomes or clinically relevant comparative data. Two prespecified questions were addressed: whether high or abnormal BCL6 expression is associated with poorer reproductive outcomes than low or normal expression, and whether treatment before embryo transfer improves outcomes in BCL6-positive women. Thirteen studies were included in the review. Because the included studies differed substantially in infertility phenotype, embryo context, hormonal preparation, biopsy timing, and outcome reporting, findings were synthesized narratively. Results: The available evidence suggests that abnormal or elevated endometrial BCL6 expression may be associated with poorer reproductive outcomes in some infertility populations, particularly in women with unexplained infertility undergoing IVF, although this pattern was less evident in selected euploid embryo transfer cohorts. Treatment-oriented studies suggested a possible benefit of pre-transfer medical suppression or surgical management in some BCL6-positive women, but findings were variable across studies. Supportive non-comparative and mechanistic studies further indicated that interpretation of BCL6 is influenced by hormonal preparation, endometrial context, and whether BCL6 is considered in isolation or within a broader biological or multimarker framework. Interpretation of the available evidence was constrained by the limited number of comparative studies, observational study designs, variability in clinical populations, and incomplete standardization of reproductive outcome reporting. Conclusions: Endometrial BCL6 appears biologically and clinically relevant as a marker of endometrial dysfunction in selected infertility settings, but current evidence is insufficient to support routine stand-alone clinical use or strong treatment recommendations. Its apparent prognostic and clinical utility varies across patient populations and reproductive settings. Larger prospective comparative studies with harmonized biopsy protocols, standardized outcome reporting, and independent external validation are needed to clarify the role of BCL6 in reproductive medicine. Full article