Search Results (2,525)

Background/Objectives: Ovarian function suppression (OFS) is part of endocrine therapy treatment for high-risk premenopausal women with hormone receptor-positive (HR+) breast cancer (BC). Incomplete OFS may occur and compromise treatment efficacy. Methods: We conducted a retrospective single-center cohort study of premenopausal patients with HR + BC treated with OFS therapy at the Centre des maladies du sein (CMS) of the CHU de Québec (Québec, Canada). Ovarian function suppression failure was defined as either biochemical failure (estradiol (E2) levels within the premenopausal range according to local immunoassays used) or clinical failure (return of menstrual bleeding). Patients’ characteristics, treatment specifics and side effects, timing and type of OFS failure, recurrence, and mortality were analyzed. Results: Among 208 included patients, 17 (8.2%) experienced at least one episode of OFS failure during a median follow-up of 62.6 months. Most failures occurred early, with 76.2% occurring within the first year of treatment. No significant differences were observed between patients with and without OFS failure regarding age, body mass index (BMI), or prior chemotherapy exposure. Patients with OFS failure had a significantly younger age at first pregnancy and higher rates of active smoking. No BC recurrence or death occurred among patients with OFS failure. Treatment-related side effects were common, and 23.0% of OFS regimens were discontinued due to adverse effects. Conclusions: In this study, OFS failure occurred in fewer than 10% of premenopausal patients. Younger age at first pregnancy and active smoking may be associated with OFS failure, but further data are needed to validate these exploratory associations. These findings reinforce the need for larger prospective studies to better assess OFS failure and develop standardized monitoring strategies to optimize treatment efficacy. Full article

Ovarian function relies on a network of well-coordinated molecular mechanisms that regulate follicular development, oocyte maturation, ovulation, and corpus luteum function. When these processes are disrupted, infertility can result. Extracellular matrix (ECM) remodeling represents a central regulatory component in these processes and is essential for follicle rupture and oocyte release. This mechanism involves metalloproteinases (MMPs), mainly MMP-2 and MMP-9, which degrade the ECM and allow the necessary structural changes. Other ECM-modulating proteases, such as ADAM and ADAMTS families, also contribute to this process. Their activity is tightly regulated by tissue inhibitors of metalloproteinases (TIMPs), ensuring that tissue remodeling occurs in a controlled manner. Disruption of the balance between MMPs and TIMPs increases the risk of infertility-related conditions such as polycystic ovary syndrome (PCOS), endometriosis, luteinizing hormone (LH) deficiency syndrome, and ovarian aging. In addition to the ECM, other factors, including intracellular signaling pathways, oxidative stress (OS), and mitochondrial function, contribute to ovarian physiology and directly affect oocyte quality and viability. This narrative review focuses on the molecular mechanisms governing ovarian function, with particular emphasis on the remodeling of the ECM by MMPs during ovulation, and examines how their disorders contribute to infertility. A deeper understanding of these mechanisms may lead to the identification of new therapeutic targets and the improvement of assisted reproduction outcomes. Full article

This study reviews the main candidate genes involved in the pathophysiology of Polycystic Ovary Syndrome (PCOS). PCOS is a common endocrine–metabolic disorder in women of reproductive age, characterized by menstrual irregularity, hyperandrogenism, and polycystic ovarian morphology. It is associated with increased metabolic and cardiovascular risk and is a leading cause of infertility. Although its pathophysiology is not fully understood, alterations in the hypothalamic–pituitary–ovarian axis, insulin metabolism, and steroidogenesis have been described. Polymorphisms in genes encoding hormones, enzymes, and receptors in these pathways contribute to clinical variability and ethnic differences, offering potential for early diagnosis and personalized medicine. This review summarizes key candidate genes related to insulin metabolism (INS, INSR, IRS-1), the hypothalamic–pituitary–ovarian axis (LHβ, LHCGR, FSHR, GnRHR, AMH, AMHR2, KISS1, CAPN10), steroidogenesis (CYP11A, CYP17A1, CYP19A1, CYP21, 17β-HSD, SHBG, AR, STAR), and other clinically relevant mechanisms such as obesity, lipid metabolism (PPARG, VDR, FTO), and follicular development (ACE). Full article

To investigate the effects of three alternative protein sources—Hermetia illucens larvae meal (HIM), Chlorella meal (CM) and stickwater meal (SWM)—on the vitellogenin in female largemouth bass (Micropterus salmoides), these protein sources were used to replace 0% (control group, FM; containing 40% fishmeal), 25% and 50% of the fishmeal in the diet. A total of seven isonitrogenous and isolipidic diets were formulated (FM, 25% HIM, 50% HIM, 25% CM, 50% CM, 25% SWM and 50% SWM). The healthy female fish with an initial body weight of 353.57 ± 28.12 g were fed the experimental diets for eight weeks. The results showed that the viscerosomatic index, gonadosomatic index and oocyte diameter of broodstock in the 50% HIM group were significantly higher than those in the FM group. The 50% HIM group showed the highest rate of stage IV oocytes and the lowest share of stage II oocytes. Hepatic vitellogenin (Vg) mRNA expression was significantly upregulated in the 50% HIM group, whereas ovarian mRNA expression of Vg and vitellogenin receptor (VgR) was significantly upregulated in the 25% SWM and 50% SWM groups. In conclusion, replacing 50% of dietary fishmeal with Hermetia illucens larvae meal can promote ovarian development in largemouth bass broodstock by increasing the gonadosomatic index and the expression of genes involved in vitellogenin synthesis. Full article

Background: In recent years, time-lapse incubators (TLs), which can maintain a stable culture environment, have been developed for use in in vitro fertilization (IVF) treatment. Methods: In this retrospective cross-sectional study, data from 1200 women who visited the Creation and Love fertility center between April 2021 and October 2023 were reviewed. Among them, the electronic medical records of 400 women aged 22–45 years who underwent IVF treatment were selected and divided into two groups according to the type of incubator used: 100 in the TL group and 300 in the conventional incubator (CI) group, to evaluate differences in embryo development. Among these participants, pregnancy outcomes were assessed in 150 women who underwent day 3 (cleavage-stage) fresh embryo transfer. Controlled ovarian stimulation was performed using a standard antagonist protocol. The primary outcome was a good embryo rate, and the secondary outcomes were the clinical pregnancy rate and live birth rate. Results: The mean age of the study population was 34.6 ± 5.4 years. The groups had similar good embryo rates (67.7% vs. 65.5%, p = 0.84), clinical pregnancy rates (49.0% vs. 52.0%, p = 0.86), and live birth rates (35.0% vs. 42.0%, p = 0.76). Furthermore, subgroup analyses showed that the live birth rate in women aged ≥ 35 years was higher in the TL group than the CI group (38.0% vs. 23.4%, p = 0.03). Conclusions: Based on the comparative analysis of live birth rates between women cultured using TLs and those using the CI during day 3 fresh-embryo transfer cycles, our study demonstrated a statistically significant increase in live birth rates among women ≥ 35 years in the TL group. Full article

Genes involved in sexual development have been identified in many teleost fishes, including the turbot, a flatfish of high commercial value in aquaculture. In this species, a major sex determination (SD) Quantitative Trait Locus has been identified, and Sox2 has been proposed as the SD gene. Although RT-PCR, qPCR, and transcriptomic analyses have been performed on turbot gonads, histological studies remain limited. Here, we examined the tissue-specific expression patterns of several sex-related genes in turbot using in situ hybridization on paraffin sections (SISH) of differentiated ovaries and testes of juvenile and adult specimens. Vasa, Foxl2, Amh, Sox2 and Sox17 transcripts were detected in both male and female gonads, whereas Cyp19a1a and Sox19 expression was restricted to the ovary; these results support previous gene expression analyses and suggest a role for these genes in gonadal development and reproductive functions in this species. SISH provides complementary information to molecular analyses by identifying the specific cell types expressing the sex-related genes analyzed in gonadal tissue, thereby offering a more comprehensive understanding of gonadal differentiation in turbot. Comparison with results reported for the gonads of other teleost species revealed similar tissue-specific gene expression patterns during sexual development. Full article

Background/Objectives: Claudin-6 (CLDN6) is an oncofetal tight junction protein that has recently emerged as a promising therapeutic target in various solid tumors. Despite this potential, the clinical significance of CLDN6 expression in advanced-stage high-grade serous ovarian carcinoma (HGSC)—specifically its role in platinum resistance—remains poorly understood. Methods: This retrospective study analyzed 119 patients with newly diagnosed FIGO stage III–IV HGSC who received platinum-based chemotherapy at a single tertiary center between 2015 and 2025. CLDN6 expression was evaluated via immunohistochemistry (IHC) on formalin-fixed paraffin-embedded (FFPE) tumor samples. High CLDN6 expression was defined as moderate-to-strong membranous staining in ≥50% of tumor cells. Clinicopathologic associations were assessed using chi-square tests, while logistic regression analysis identified predictors of platinum resistance. Finally, overall survival (OS) and progression-free survival (PFS) were evaluated using Kaplan–Meier methods and Cox proportional hazards models. Results: High CLDN6 expression was observed in 31 patients (26%). CLDN6 expression was not significantly associated with age, CA-125 level, lymph node metastasis, distant metastasis, surgical approach, or residual disease status. However, high CLDN6 expression was significantly associated with platinum resistance (61.3% vs. 28.4%, p = 0.001). In multivariable logistic regression analysis, residual disease (OR = 10.12, p > 0.001), high CLDN6 expression (OR = 4.52, p = 0.008), and elevated CA-125 levels (OR = 0.64, p = 0.041) were independently associated with platinum resistance. Median OS for the entire cohort was 43.8 months. High CLDN6 expression was associated with shorter OS (38.0 vs. 45.7 months, p = 0.042) and remained an independent predictor of mortality in multivariable Cox analysis (HR = 1.90, p = 0.026). CLDN6 expression showed a trend toward shorter PFS but did not reach statistical significance (p = 0.096). Conclusions: High CLDN6 expression is associated with platinum resistance and inferior overall survival in patients with advanced-stage HGSC. These findings suggest that CLDN6 may serve as a clinically relevant biomarker for chemoresistance and tumor aggressiveness. In the context of emerging CLDN6-targeted therapies, routine assessment of CLDN6 expression may facilitate the development of biomarker-driven therapeutic strategies for advanced ovarian cancer. Full article

Endometriosis is a chronic estrogen-dependent disorder affecting approximately 10% of women of reproductive age. Increasing epidemiological and molecular evidence indicates that it may represent a precursor condition for a subset of ovarian malignancies collectively defined as endometriosis-associated ovarian cancer (EAOC), predominantly endometrioid and clear cell carcinomas. Malignant transformation is driven by the interplay between chronic inflammation, oxidative stress, and local hyperestrogenism within the endometriotic microenvironment. Recurrent hemorrhage and persistent immune activation further promote genomic instability and clonal expansion. Shared somatic mutations have been identified in both atypical endometriosis and adjacent carcinomas, supporting a model of stepwise tumorigenesis. Dysregulation of signaling pathways and epigenetic mechanisms, including microRNA alterations, further contribute to tumor development. Although the absolute risk of malignant transformation remains low, women with ovarian endometriosis and deep infiltrating disease show an increased risk of ovarian cancer. EAOC is frequently diagnosed at earlier stages and generally demonstrates a more favorable prognosis than high-grade serous carcinoma, although clear cell histotypes may exhibit chemoresistance and distinct molecular vulnerabilities. This review summarizes current evidence on the pathogenesis, molecular mechanisms, and clinical implications of EAOC, highlighting future strategies for risk stratification and personalized surveillance. Full article

Background/Objective: RNA modifications, including N⁶-methyladenosine (m⁶A), 5-methylcytosine (m⁵C), 7-methylguanosine (m⁷G), N¹-methyladenosine (m¹A), pseudouridine (Ψ), N⁴-acetylcytidine (ac⁴C), 5-methoxycarbonylmethyl-2-thiouridine (mcm⁵s²U) and adenosine-to-inosine (A-to-I) editing, constitute a critical layer of post-transcriptional regulation that influences RNA stability, splicing, translation and degradation. This review aims to systematically summarise the current understanding of the molecular mechanisms and regulatory networks of RNA modifications in the female reproductive physiology and to evaluate their pathological implications in obstetric and gynaecologic disorders. Methods: We conducted a comprehensive literature review, synthesising findings from high-throughput sequencing studies, functional experiments and clinical investigations. The review integrates evidence across multiple RNA modification types, their regulatory enzymes (writers, erasers and readers) and their roles in physiological processes (germ cell development, oocyte maturation, embryogenesis and endometrial function) and pathological conditions (gynaecologic cancers, preeclampsia, endometriosis, polycystic ovary syndrome and premature ovarian insufficiency). Results: RNA modifications function as dynamic and reversible regulators that orchestrate key reproductive events, including primordial germ cell differentiation, oocyte meiosis, the maternal-to-zygotic transition, the establishment of uterine receptivity, and placental development. These modifications operate through coordinated writer–eraser–reader networks that fine tune transcripts’ stability, translation efficiency and RNA decay. The dysregulation of these epitranscriptomic networks is strongly implicated in the pathogenesis of gynaecologic malignancies (cervical, ovarian, endometrial cancers and choriocarcinoma), pregnancy-related disorders (preeclampsia, gestational diabetes mellitus and recurrent miscarriage), reproductive endocrine disorders (polycystic ovary syndrome and premature ovarian insufficiency) and benign gynaecological conditions (endometriosis and adenomyosis). Emerging evidence also reveals complex crosstalk among RNA modifications, such as cooperative interactions between m⁶A and m⁵C in translation regulation and antagonistic relationships between m⁶A and A-to-I editing. Conclusions: RNA modifications represent an essential and multifaceted regulatory layer in female reproduction, with broad implications for disease pathogenesis. Their unique reversibility and context-dependent functions offer promising opportunities for the development of diagnostic biomarkers and targeted therapeutic interventions. Future researchers should prioritise integrated multi-omics approaches, enhanced human-relevant models and clinical translation to fully realise the potential of epitranscriptomic medicine in reproductive health. Full article

Proper steroid hormone synthesis is essential for maintaining fertility in female animals. Tribbles pseudokinase 1 (Trib1), a member of the Tribbles pseudokinase family, exerts its functions mainly through interacting with other molecules. Numerous studies have shown that Trib1 plays a central role in regulating cell proliferation. In mammals, the proliferation of granulosa cells (GCs) is a hallmark event in follicular development, which is essential for follicular maturation and successful ovulation. However, whether Trib1 regulates ovarian steroid hormone synthesis remains largely unexplored. In this study, we found that Trib1 is predominantly expressed in ovarian GCs. Knockdown of Trib1 in GCs significantly reduced their capacity for steroid hormone synthesis. Furthermore, Trib1 KO female mice were completely infertile, exhibiting impaired transition from primary to antral follicles, increased follicle atresia, and defective steroid hormone secretion. Ovarian RNA-Seq analysis revealed that differential expressed genes (DEGs) were significantly enriched in cholesterol metabolism and steroid biosynthesis pathways following Trib1 deletion. Notably, FOSL2, a transcription factor that potentially bound to the promoters of the pivotal steroidogenic genes Star and Cyp11a1, was significantly down-regulated in Trib1 KO mice. Crucially, overexpression of FOSL2 in Trib1-deficient GCs restored Star and Cyp11a1 expression and significantly rescued the ability of steroid hormone synthesis in GCs. Our findings unveil a novel Trib1 gene governing steroidogenesis in GCs and is essential for fertility in female mice, providing profound insights into the female reproductive endocrinology and potential therapeutic targets. Full article

Background/Objectives: Osteoarthritis has been increasingly described as associated with systemic inflammation, raising the question of how it would affect fertility in young women with or without reproductive hormone administration. We studied oogenesis in mice with collagenase-induced osteoarthritis (CIOA) as a model system with fewer ethical limitations after estradiol (E2) or follicle-stimulating hormone (FSH) treatment. Methods: Oocytes have been isolated from mice subjected to various treatment regimens. The meiotic spindle, the chromatin, and the actin cap were fluorescently labeled and analyzed. Results: In addition to reduced maturation rates, specific oocyte abnormalities were registered when CIOA, FSH, or E2 were applied in isolation. Combined treatments showed that the spindle, chromatin, and actin cytoskeleton parameters were differently affected in oocytes from groups with CIOA treated by estradiol and those treated with FSH. Enlarged spindles, ooplasmic tubulin asters, aligned metaphases, and predominantly normal actin caps, often with an actin halo, were typical for groups with CIOA combined with estradiol. The groups with CIOA and FSH had slightly enlarged spindles, unaligned metaphases with degenerated chromatin surrounded by a cloud of depolymerized tubulin, and small actin caps. Conclusions: Our results show that experimental osteoarthritis with or without exogenous reproductive hormones negatively affects oogenesis, presumably due to systemic inflammatory factors making the ovarian microenvironment less capable of supporting oocyte maturation. Estradiol supplementation does not benefit oogenesis. FSH treatment induced cytoskeletal and chromatin abnormalities that presumably disturb the fertilization and development potential of affected oocytes. These data can have implications for assisted reproduction in cases of patients with osteoarthritis. Full article

Oocyte competency is a crucial determinant of fertilisation success and the initial development of embryos in assisted reproductive technologies. The metabolic and biochemical environment of the ovarian follicle is crucial for determining oocyte developmental potential, alongside genetic integrity. The follicular microenvironment includes a complex network of signalling chemicals that regulate mitochondrial activity, steroidogenesis, oxidative balance, and cellular energy metabolism. Recently, metabolic hormones originating from adipose tissue and skeletal muscle, namely, adipokines and myokines, have received considerable focus as crucial regulators of ovarian physiology. Adiponectin, irisin, and the recently identified hormone asprosin have emerged as crucial metabolic regulators influencing granulosa cell activity, mitochondrial bioenergetics, insulin signalling pathways, and redox homeostasis inside the follicular niche. Adiponectin mostly provides metabolic protection by activating AMP-activated protein kinase (AMPK) and improving insulin sensitivity, which in turn enhances mitochondrial efficiency and steroidogenic function in granulosa cells. Irisin, derived from the breakdown of fibronectin type III domain-containing protein 5 (FNDC5), aids the developing oocyte by facilitating mitochondrial biogenesis, augmenting oxidative phosphorylation, and altering cellular defence mechanisms against oxidative stress. Conversely, asprosin has been associated with glucogenic signalling, metabolic stress, and probable mitochondrial malfunction, suggesting a possible relationship between systemic metabolic problems and negative reproductive consequences. Clinical and experimental research indicate that the levels of these metabolic regulators in follicular fluid may correlate with ovarian response, oocyte quality, fertilisation rates, and embryo development during in vitro fertilisation cycles. This review consolidates current molecular, cellular, and clinical information, clarifying the pathways by which adipokines and myokines influence follicular metabolism and impact oocyte competency. Understanding the metabolic connections between systemic endocrine signals and the follicular milieu may provide novel indicators for reproductive prognosis and provide new treatment targets to improve assisted reproduction outcomes. Full article

Objectives: Platinum resistance remains a critical bottleneck in ovarian cancer management, yet reliable pre-treatment predictive tools are lacking. Existing markers like the platinum-free interval are retrospective, while genomic profiling is often cost-prohibitive. This study aimed to develop an accessible, machine learning-based dynamic weighted fusion (DWF) model using routine laboratory data to provide bidirectional risk stratification, particularly to reliably rule out platinum resistance before treatment initiation. Methods: In this retrospective study (2019–2023), seventy baseline clinical features were collected to differentiate platinum-resistant from platinum-sensitive ovarian cancer patients. We developed a DWF framework that dynamically integrates the top-performing classifiers from a library of 168 algorithms (combining 14 feature selection and 12 machine learning methods). Class imbalance was addressed via oversampling, and model efficacy was evaluated using area under the curve (AUC), accuracy, sensitivity, and specificity. Results: The DWF model achieved a robust AUC of 0.760 (95% CI: 0.683–0.837), outperforming all individual base classifiers. Subgroup analysis demonstrated highly consistent overall discrimination across initial treatment strategies (AUC of 0.755 for primary debulking surgery and 0.761 for neoadjuvant chemotherapy). Feature interpretation highlighted that resistance is driven by synergistic dysregulation of systemic inflammation and hypercoagulability, rather than single biomarkers. Conclusions: The proposed DWF model effectively leverages low-cost, standardized clinical data to serve as a robust bidirectional stratification tool. Its exceptional ability to rule out resistance provides clinicians with the evidence-based confidence to proceed with standard therapies, while its high-risk alerts identify candidates for early therapeutic adjustments and enhanced surveillance in ovarian cancer care. Full article

Halogenated derivatives of polycyclic aromatic hydrocarbons (PAHs), such as chlorinated PAHs (ClPAHs), are an emerging class of contaminants that are being detected in the environment as well as in wildlife and human populations. Previous studies have shown that chemical substitution of PAHs, including chlorination, may alter the toxicity of parent PAHs; however, whether chlorination affects their endocrine-disrupting potential remains unexplored. In this study, we examined the effects of phenanthrene (Phe), one of the most prevalent PAHs, and its chlorinated congeners, 9-chlorophenanthrene (9ClPhe) and 9,10-dichlorophenanthrene (9,10Cl₂Phe), on hormone production in granulosa cells, key hormone-secreting cells of the ovary. We observed that Phe and its chlorinated congeners differentially altered anti-Müllerian hormone (AMH), estradiol (E2), and progesterone (P4) secretion. Since mitochondria are central to steroidogenesis, we further evaluated mitochondrial function. While Phe increased ATP production, both 9ClPhe and 9,10Cl₂Phe increased ROS, decreased mitochondrial membrane potential, and reduced the expression of markers for mitochondrial dynamics and mitophagy without altering ATP levels. We further tested impacts on cell fate and found that neither Phe nor its chlorinated congeners altered granulosa cell apoptosis. Together, these results suggest that chlorination of Phe leads to dose-dependent, differential effects on hormone production and mitochondrial pathways without inducing cell death in granulosa cells. This study highlights the potential adverse impacts of ClPAH exposure on ovarian follicle development and female fertility by disrupting steroidogenesis and mitochondrial quality control. Full article

Background: Mirvetuximab soravtansine (MIRV) improves outcomes in FRα-positive, platinum-resistant ovarian cancer; however ocular adverse events (OAEs), particularly corneal epithelial toxicity, are frequent and warrant structured ophthalmologic monitoring. Methods: In this retrospective observational study, 31 consecutive patients receiving MIRV for FRα-positive gynecologic malignancies underwent standardized ophthalmic assessments at baseline and prior to each treatment cycle (every 21 days). The protocol included best corrected visual acuity (BCVA), slit-lamp biomicroscopy, anterior-segment optical coherence tomography (AS-OCT), corneal topography, and tear film analysis. OAEs were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0, based on symptom severity and functional impairment. Results: OAEs occurred in all patients (31/31, 100%), predominantly grade 1–2. Corneal epithelial toxicity was documented in 28/31 patients (90.3%), while no grade ≥ 3 events were observed. Symptoms typically developed 7–14 days after the second infusion. AS-OCT and corneal topography consistently revealed epithelial microcysts and surface irregularities, which were usually detected during scheduled pre-cycle ophthalmologic evaluations. Tear-film instability (break-up time ≤ 5 s) developed in 19/31 patients (61.3%), generally within 10 days after the second infusion, and improved in all but 2 patients (6.5%) following prophylactic lubrication. Transient refractive changes occurred in 28/31 patients (90.3%) and were associated with a temporary BCVA reduction (mean nadir ~20/32 Snellen), followed by recovery during follow-up. Conclusions: MIRV-related ocular alterations are frequent but reversible and clinically manageable. Multimodal imaging combined with functional and refractive assessment provides sensitive markers of corneal epithelial toxicity and supports integrated ophthalmologic monitoring to preserve visual function and maintain oncologic treatment continuity. Full article