Search Results (351)

Obesity affects nearly one in three women of reproductive age worldwide and consistently reduces success rates in in vitro fertilization, yet the molecular basis for this reduction remains fragmented across separate lines of evidence. Circadian clock genes, particularly BMAL1, orchestrate metabolic and reproductive physiology through transcription–translation feedback loops present in adipose tissue, ovarian granulosa cells, and endometrial stroma. Adiposity-driven metabolic shifts, including altered PPAR-γ signaling and reduced glutamine–methionine uptake, degrade BMAL1 expression and flatten its rhythmic oscillation in peripheral tissues. Within granulosa cells, loss of BMAL1 rhythmicity impairs mitochondrial biogenesis and disrupts UPRmt-mediated proteostasis, driving reactive oxygen species accumulation and compromising oocyte competence. Parallel disruption of clock-controlled transcription factors in endometrial epithelium and stroma is proposed to alter decidualization programs and displace the window of implantation, which would produce a receptivity defect independent of oocyte quality if confirmed directly in human tissue. Clinical data are consistent with a dual mechanism: obese women undergoing donor-oocyte cycles—where oocyte quality is controlled for—show reduced implantation rates in several but not all cohorts—a pattern compatible with an endometrial contribution distinct from oocyte-level damage, rather than proof of it. Synthesizing evidence from adipocyte biology, ovarian physiology, and endometrial receptivity research drawn largely from rodent models, cultured cell systems, and observational human cohorts, this review proposes BMAL1 dysregulation as a candidate unifying mechanism connecting obesity to impaired IVF outcomes at the gametic and uterine level, while acknowledging that direct causal evidence in humans is still lacking. Chronotherapeutic strategies, including melatonin supplementation and the timing of weight-loss interventions relative to ovarian stimulation, are discussed as hypotheses for future testing rather than current clinical recommendations. BMAL1 dysregulation is presented here as one candidate contributor among several interacting mechanisms, and any translational strategy would need to be part of a broader, coordinated approach to obesity-related IVF failure rather than a stand-alone intervention. Full article

Diminished ovarian reserve (DOR) and poor ovarian response (POR) remain among the most challenging conditions in assisted reproductive technology, and no optimal stimulation strategy has been established. Clomiphene citrate (CC), a selective estrogen receptor modulator that augments endogenous gonadotropin secretion and modulates the intraovarian androgenic milieu, has been proposed as an adjuvant to reduce exogenous gonadotropin requirements. This mini-review summarizes clinical evidence published between January 2015 and March 2025 on the co-administration of CC with gonadotropins in women with DOR or POR undergoing IVF/ICSI. Eleven primary studies (four randomized controlled trials, six observational cohort studies and one before–after study) were identified through a structured, PRISMA-informed literature search. Across mild, standard, and high-dose regimens, CC co-administration consistently reduced total gonadotropin consumption and stimulation duration, whereas oocyte yield, clinical pregnancy, and live-birth rates were largely comparable to conventional protocols. Cost analyses suggest a meaningful reduction in the expenditure per treatment cycle, although the cost per delivery is driven predominantly by the low absolute success rates in this population. Careful monitoring of endometrial thickness is warranted given the anti-estrogenic effect of CC, and a freeze-all strategy may be preferable when endometrial development is suboptimal. In the wider context of adjuvant therapy for POR, CC occupies a position comparable to that of letrozole: it reduces treatment burden without demonstrable improvement in live birth. Larger, adequately powered multicentre randomized trials with live birth as the primary endpoint are needed to define the role of CC in this population. Full article

In pigs, the establishment of pregnancy depends on tightly coordinated molecular interactions between the conceptus and the maternal endometrium during the peri-implantation period. Adipokines, peptide hormones produced by adipose tissue, function as endocrine mediators linking metabolic status with uterine function. Omentin-1, a hormone belonging to the adipokines group, is hypothesized to play a potential role in regulating female reproductive functions through its influence on uterine functions. Therefore, this study investigated the effects of omentin-1 on endometrial progesterone and oestradiol secretion using radioimmunoassay, on the abundance of key steroidogenic proteins and Akt phosphorylation using Western blot, and on endometrial cell proliferation and apoptosis using flow cytometry. Results showed that its actions are characterised by promotion of progesterone-dominant conditions, selective modulation of steroidogenic pathways, activation of Akt signalling, and cell-type-specific regulation of proliferation and apoptosis. This combination of effects positions omentin-1 as a previously unrecognised regulator of endometrial adaptation and suggests that adipokines may represent an important mechanistic link between metabolic status and reproductive success. Full article

Endometrial cancer (EC) is the most common gynecological malignancy in high-income countries. Extracellular vesicles (EVs) are key mediators of intercellular communication and metabolic reprogramming, but their molecular cargo in EC remains poorly characterized. EVs were isolated from four EC cell lines representing Type I and Type II subtypes (AN3CA, ISHIKAWA, HEC1A, and KLE). Untargeted metabolomics was performed by HILIC-LC-MS/MS, proteomics by data-independent acquisition (DIA) mass spectrometry, and multi-omics integration using MetaboAnalyst and OmicsNet. Metabolomic profiling identified 1463 annotated features and revealed significant differences among EC cell lines (PERMANOVA, p = 0.002). Twenty-eight differentially abundant metabolites, including lactic acid, succinic acid, and uric acid, were identified. Proteomic analysis quantified 8513 proteins with subtype-specific expression patterns. Integrated analysis revealed seven significantly enriched pathways, including glycolysis/gluconeogenesis, central carbon metabolism in cancer, and the pentose phosphate pathway. Increased LDHA abundance in metastatic AN3CA-derived EVs was confirmed by Western blot (p = 0.047). EC-derived EVs display subtype- and metastatic-status-specific metabolo-proteomic signatures, with glycolysis, TCA cycle remodeling, and central carbon metabolism as convergent pathway signatures of molecular reprogramming. These findings establish a multi-omics framework for characterizing EV cargo in EC and identify candidate enzyme–metabolite nodes for future biomarker validation in patient-derived specimens. Full article

Background/Objectives: Embryo donation/adoption separates the recipient environment from the genetic origin of the embryo and provides a clinical model for studying offspring sex distribution after assisted reproduction. We evaluated whether recipient body mass index (BMI) was associated with sex distribution among live-birth events after frozen embryo transfer involving embryo donation/adoption. Methods: This retrospective cohort study included frozen embryo transfer cycles involving embryo donation/adoption performed between January 2018 and December 2024 at a tertiary fertility center. All embryos were generated by intracytoplasmic sperm injection, cultured to the day-5 blastocyst stage, transferred singly, and not subjected to preimplantation genetic testing. The analytical cohort comprised 104 independent live-birth transfer events representing 104 unique recipients and 104 unique embryo–donor couples. Recipient BMI was evaluated across quartiles and in an exploratory adjusted logistic regression model including female embryo donor BMI and age, endometrial thickness, serum progesterone concentration, and top-quality embryo status. Results: The cohort included 51 male and 53 female live-birth events. Recipient BMI was higher in female than male live-birth events (25.6 ± 4.3 versus 23.5 ± 4.2 kg/m²; p = 0.007). In a descriptive quartile analysis, male live-birth event proportions were 69.2% in the lowest BMI quartile and 34.6% in the highest quartile, with corresponding female proportions of 30.8% and 65.4% (p for trend = 0.007). In the primary adjusted model, higher recipient BMI was associated with lower odds of a male live-birth event (adjusted OR 0.88 per 1 kg/m²; 95% CI 0.80–0.98; p = 0.017). Conclusions: Recipient BMI was associated with sex distribution among live-birth events after embryo donation/adoption. The observed pattern is compatible with a recipient-side post-fertilization association but does not establish a selection mechanism, causality, or the developmental stage at which the association arose. Full article

Cancer remains one of the leading causes of global mortality, with its incidence continuing to rise due to population growth, aging, lifestyle factors, and environmental exposures. Despite significant advances in early diagnosis and therapeutic strategies, the clinical management of cancer is still hindered by drug resistance, limited selectivity, and treatment-related toxicity. Consequently, increasing attention has been directed toward natural products as sources of novel anticancer agents with improved efficacy and reduced adverse effects. Pogostemon cablin (patchouli), a medicinal plant widely used in traditional medicine, has emerged as a promising candidate owing to its diverse bioactive constituents and broad pharmacological properties. This review systematically summarizes and critically evaluates current evidence on the anticancer potential of patchouli leaves, with particular emphasis on molecular mechanisms and translational relevance. Based on available experimental and preclinical studies, patchouli and its major phytochemicals exhibit notable anticancer activity against a wide range of malignancies, including endometrial, ovarian, liver, skin, nasopharyngeal, prostate, hematological, colorectal, and lung cancers. Mechanistically, these effects are primarily associated with the modulation of apoptosis, cell cycle regulation, oxidative stress, and key oncogenic signaling pathways, as well as potential synergistic interactions with conventional chemotherapeutic agents. Overall, this review highlights the therapeutic promise of patchouli leaves as a source of anticancer agents, identifies current knowledge gaps, and outlines future research directions to facilitate their development and clinical translation. Full article

Background: This review aims to systematically summarize the lineage origins, subtype classification, and functional dynamics of endometrial macrophages, clarify their mechanisms of action in normal reproductive physiology (menstrual cycle, pregnancy) and common reproductive diseases, integrate cognitive breakthroughs brought by cutting-edge research technologies, and provide theoretical support for basic research and clinical translation in reproductive medicine. Methods: Recent basic and clinical research studies related to endometrial macrophages were retrieved, with a focus on incorporating findings from technologies such as single-cell sequencing and multi-omics. The reviewed content covers core aspects including macrophage origins (embryonic-derived, bone marrow-derived), subtype classification (M1/M2 and novel metabolism-related subtypes), cycle- and pregnancy-specific functions, and disease-associated mechanisms. A comprehensive analysis of the regulatory networks of endometrial macrophages under physiological and pathological conditions was conducted. Results: Endometrial macrophages, by virtue of their phenotypic plasticity and functional heterogeneity, play a central role in cyclical endometrial remodeling, pregnancy establishment, and the regulation of reproductive immune homeostasis. Dysregulation of their function is closely associated with various reproductive disorders such as recurrent spontaneous abortion and endometriosis. In-depth exploration of their biological characteristics and regulatory mechanisms holds great significance for filling knowledge gaps in the field of reproductive immunology and advancing precise prevention and treatment of related diseases. Conclusions: Endometrial macrophages are core regulators of the reproductive immune microenvironment, and their spatiotemporal dynamic functions are closely linked to reproductive health. The revelation of novel classification systems and regulatory mechanisms provides new perspectives for in-depth understanding of reproductive physiological and pathological processes, as well as important targets for immune-targeted therapy of reproductive-related diseases. This holds great clinical translational significance for promoting the precision development of reproductive medicine. Full article

Endometriosis is a chronic, oestrogen-responsive inflammatory disease characterised by endometrial-like tissue outside the uterine cavity. Because retrograde menstruation is common, lesion establishment probably requires cellular competence and a permissive ectopic microenvironment. This hypothesis-driven narrative review evaluates fascin (FSCN1) as a candidate cytoskeletal effector and considers antecedent eutopic priming versus induction after ectopic adhesion. Functional evidence was integrated with a targeted public-data screen. Donor-level reanalysis of GSE179640 found no conclusive overall eutopic case–control difference and predominantly non-epithelial expression. Exploratory analysis of GSE203191 suggested higher FSCN1 expression within a HSPA6+ stromal subcluster in diagnosed cases, without a comparable epithelial signal or detectable increase in subcluster abundance. This small post hoc analysis remains hypothesis-generating. FSCN1 was absent from the published HECA stromal/macrophage differential-expression lists and was not prioritised by the 2023 endometriosis GWAS. The current evidence therefore argues against uniform epithelial or whole-eutopic overexpression but permits a lineage-restricted stromal state. Fascin participates in autophagy- and miR-145-sensitive invasion networks, although these pathways are pleiotropic. Validation requires cycle- and lineage-resolved tissue mapping, compositional controls, matched lesions, and direct FSCN1 perturbation. Fascin should currently be regarded as a candidate multi-marker component and preclinical target, not a validated biomarker or systemic therapeutic target. Full article

Background/Objectives: Primary renal endometriosis with extrapelvic locations of endometriosis lesions is deemed extremely rare. Therefore, the aim of this review was to assess the current literature on renal endometriosis, encompassing a summary of recorded living-patient cases, imaging and pathological features, chosen therapeutic approaches, and patient outcomes. Methods: We performed a narrative review with a systematic identification and presentation of published cases of histopathologically proven kidney endometriosis. A literature search was carried out across PubMed, Scopus, and Web of Science for relevant studies, i.e., case reports and series that met predefined inclusion and exclusion criteria specified by the modified PECOS framework. Results: A total of 19 publications reporting a total of 20 reported cases were included in the in-depth analysis. The noted condition affected women of reproductive age, with a mean age of 37.4, with the most common presenting symptoms being lumbar or flank pain, gross hematuria, abdominal pain, and tenderness. Most were single-mass lesions detected on the right kidney, with a mean largest diameter of 6.7 cm. Most were CT-characterized as either hyperattenuating lesions, septate lesions with foci of calcifications and soft tissue components, or areas of necrosis or cystic change. As CT presented features that would not allow the exclusion of malignant kidney tumors, most patients were treated surgically with nephrectomy. Diagnosis was confirmed by histopathology of recorded endometrial glands and stroma. Conclusions: The diagnosis of these lesions is exceptionally challenging because of their nonspecific symptoms, the rare association with the menstrual cycle, the rarity of dysmenorrhea, and the occasional coexistence of ovarian endometriosis, with no distinct endometriosis-specific clinical and imaging pattern emerging. Full article

Endometriosis is a chronic inflammatory disorder characterized by the ectopic growth of endometrial-like tissue, leading to pelvic pain and infertility. Although cepharanthine has well-established anti-inflammatory properties, its therapeutic potential and underlying mechanisms in endometriosis remain largely unexplored. In this study, the effects of cepharanthine were evaluated using a surgically induced mouse model and immortalized human endometrial stromal cell models. Cepharanthine treatment significantly reduced the calculated lesion volume, whereas wet lesion weight did not differ significantly between the groups. Cepharanthine was also accompanied by reduced spleen weight and alterations in the CD4+ helper T-cell population in vivo. In immortalized human ovarian endometriotic stromal cells (ihOESCs), cepharanthine significantly decreased cell viability, induced apoptosis, and disrupted cell-cycle progression. Cepharanthine altered autophagy-related signaling, accompanied by increased acidic vesicle-associated signals and accumulation of LC3B-II and p62/SQSTM1; however, the direction of autophagic flux remains unclear. These changes were associated with elevated reactive oxygen species production, intracellular Ca²⁺ redistribution, and mitochondrial dysfunction. Collectively, these findings indicate that cepharanthine reduces calculated lesion volume in vivo and alters mitochondrial function, autophagy-related signaling, apoptosis and cell-cycle progression in ihOESCs, supporting its potential as a therapeutic candidate. Full article

Background/Objectives: Extra virgin olive oil (EVOO), a key component of the Mediterranean diet, has attracted research interest because olive-derived phenolics demonstrate potential anticancer activity in experimental models. This review summarizes evidence concerning whole EVOO, phenolic-enriched EVOO, olive phenolic extracts, and the isolated compounds hydroxytyrosol, oleuropein, oleocanthal, and oleacein. Methods: A structured narrative search of PubMed, Web of Science, ScienceDirect, and Google Scholar was conducted for literature published between 2015 and 2025. Evidence was reviewed for breast, prostate, colorectal, pancreatic, bone, oral, liver, gastric, hematological, and brain cancers. Comparatively limited evidence concerning cervical, endometrial, ovarian, melanoma, non-melanoma skin, and thyroid cancers was summarized separately. Results: The molecular evidence was derived primarily from cell culture and animal studies using isolated phenolics and concentrated extracts. Preclinical studies indicate that EVOO phenolics may demonstrate anticancer activity through multiple mechanisms, including antioxidant activity, anti-inflammatory effects, cell cycle arrest, induction of apoptosis, inhibition of metastasis, anti-angiogenic activity, and modulation of key signaling pathways, such as PI3K/AKT/mTOR, MAPK/ERK, NF-κB, JAK/STAT, Wnt/β-catenin, p53, and epithelial–mesenchymal transition-related pathways. Most molecular and pathway-level evidence was obtained using isolated phenolic compounds in cell culture or animal models, whereas evidence directly examining whole EVOO consumption was largely observational and substantially more limited. Experimental studies also reported that oleocanthal induced lysosomal membrane permeabilization, whereas hydroxytyrosol and oleuropein promoted mitochondria-mediated apoptosis. Furthermore, preclinical combination studies suggested enhanced tumor-cell sensitivity to selected chemotherapeutic, targeted, and immunotherapeutic agents. However, these effects have not been established in patients. Human evidence remains limited mainly to observational dietary associations and small exploratory interventions, with no conclusive demonstration of cancer prevention or therapeutic efficacy. Conclusions: Isolated EVOO-derived phenolic compounds demonstrated promising anticancer mechanisms in preclinical models. However, these results should not be directly extrapolated to dietary EVOO because experimentally administered doses, bioavailability, metabolism, and food-matrix interactions differ substantially from human dietary exposure. Therefore, well-designed studies using chemically characterized EVOO, pharmacokinetic investigations, and controlled human trials are required before dietary or clinical recommendations can be made. Full article

Women with polycystic ovary syndrome (PCOS) have a substantially increased risk of endometrial cancer (EC), yet the biological mechanisms underpinning this association, to support future prevention and therapeutics, remain incompletely understood. Insulin-like growth factor (IGF)-associated signaling has been implicated, but existing evidence is conflicting. In this pilot translational study, serum IGF1 and IGFBP-3 were measured in women with PCOS (n = 12 for IGF1 and n = 6 for IGFBP-3) and controls (n = 24 for IGF1 and n = 7 for IGFBP-3). Pooled serum, stratified by IGF bioactivity, was applied to human EC cells to further assess effects on cell viability, cell cycle distribution, and downstream signaling. Computational analysis of publicly available endometrial cancer datasets was used to contextualize experimental findings. Serum IGF1 and IGFBP-3 levels did not differ significantly between PCOS and control groups. However, pooled PCOS serum was associated with increased EC cell viability, altered cell cycle progression and PI3K/AKT/mTOR signaling compared with control serum in this exploratory model. Pharmacological inhibition of IGF1R partially attenuated these effects, suggesting that IGF-associated pathways may contribute but are unlikely to act in isolation. In silico analysis identified frequent alterations in PI3K/AKT/mTOR-related genes in EC, consistent with pathway-level vulnerability rather than IGF1-specific dependence. These findings suggest that PCOS serum contains factors that are associated with increased EC cell viability and altered signaling pathways with partial involvement of IGF signaling; however, these findings should be interpreted cautiously given the exploratory pooled-serum design, small subgroup sizes, and use of a single EC cell line. However, multiple metabolic and hormonal pathways are likely to contribute. Larger, better-controlled studies incorporating insulin, sex steroids, and multiple EC models are required before causal inferences can be made. Full article

Melatonin is not only produced by the pineal gland but is also synthesized in extrapineal organs. It plays a key role in antioxidant defense and immune regulation during pregnancy. Two key rate-limiting enzymes are involved in the melatonin synthesis, aralkylamine N-acetyltransferase (AANAT), and acetylserotonin O-methyltransferase (ASMT). Nevertheless, it remained unclear whether pregnancy affects the expression of AANAT and ASMT in extrapineal organs. In this study, ovine maternal thymus, spleen, liver, lymph nodes, thyroid, duodenum, and endometrium were collected on day 16 of the estrous cycle (N16), and on days 13, 16, 25, and 70 (G70) of gestation (n = 6 per group). The expression of AANAT and ASMT in these extrapineal organs was analyzed using RT-qPCR, Western blot, and immunohistochemistry. The results revealed that pregnancy upregulated the expression of AANAT in the liver and ASMT in the thymus and duodenum, but downregulated AANAT expression in the lymph nodes and duodenum. Moreover, AANAT expression was elevated in the thymus and spleen but reduced in the thyroid and endometrium at G70 compared with N16. ASMT expression was increased in the lymph nodes yet decreased in the spleen, liver, and thyroid at G70 compared with N16. Notably, endometrial ASMT expression showed a pregnancy-stage-specific manner with no significant difference between N16 and G70. In summary, this paper reports, for the first time in sheep, that pregnancy modulates the expression of AANAT and ASMT in these extrapineal organs in a pregnancy-stage- and tissue-specific manner. Full article

Selective remodeling of nuclear architecture under pharmacological stress remains incompletely characterized in three-dimensional cancer models, particularly at the ultrastructural level. Lithium chloride (LiCl) is widely used as a cellular stressor capable of altering membrane organization, proliferation, and organelle dynamics; however, its effects on nucleus-associated structural remodeling in three-dimensional tumor systems remain unclear. In the present study, Ishikawa endometrial carcinoma spheroids were exposed to LiCl (10 or 50 mM) for up to 96 h, and cellular responses were evaluated using cell cycle analysis, 5-bromo-2′-deoxyuridine (BrdU) incorporation, viability assays, and transmission electron microscopy. LiCl exposure was associated with sustained accumulation of cells in the G₀/G₁ phase and suppression of DNA synthesis without evidence of a dominant apoptotic or necrotic response under the examined conditions. Ultrastructural analyses showed prominent nuclear envelope elongation, membrane reorganization, and perinuclear double-membraned structures, particularly under prolonged LiCl exposure. These alterations were observed alongside mitochondrial and endomembrane remodeling, supporting the presence of a broader stress-associated ultrastructural adaptation response within LiCl-treated spheroids. Importantly, the present study is morphology-focused and descriptive in scope. Although some ultrastructural features were morphology-compatible with nucleophagy-associated remodeling, no molecular validation using LC3, p62/SQSTM1, LAMP1/lysosomal colocalization, lamin degradation, or autophagic-flux assays was performed. Therefore, the findings should be interpreted as evidence of stress-associated nuclear envelope remodeling rather than mechanistic proof of nucleophagy. Collectively, this study identifies nucleus-associated ultrastructural remodeling as a prominent cellular response to LiCl-induced stress in 3D endometrial cancer spheroids and highlights the utility of three-dimensional tumor models for investigating stress-related architectural adaptations in cancer cells. Full article

Long COVID affects multiple organ systems and disproportionately affects women, raising concerns about reproductive health. This updated narrative review summarizes evidence from PubMed, Scopus, and Web of Science through March 2026 and extends previous reviews by distinguishing Long COVID-specific findings from acute and early post-infection observations and integrating newer evidence on ovarian reserve, follicular-fluid biology, assisted reproduction, and endometrial function. Reported menstrual changes include irregular cycles, heavy or prolonged bleeding, intermenstrual bleeding, and amenorrhea. Evidence regarding ovarian reserve remains inconsistent: some studies reported lower anti-Müllerian hormone (AMH) levels and/or antral follicle count (AFC), whereas others found no significant changes. Case reports describe premature ovarian insufficiency (POI) and possible autoimmune oophoritis but do not establish causality. Proposed mechanisms include immune dysregulation, inflammation, oxidative stress, endothelial dysfunction, and hypothalamic–pituitary–ovarian axis disturbance. Available evidence does not indicate adverse effects of COVID-19 vaccination on ovarian reserve or fertility outcomes. Most studies suggest transient changes. Direct Long COVID-specific evidence for persistent ovarian or endometrial injury remains limited. However, short follow-up precludes conclusions regarding ovarian aging, menopausal timing, lifetime fertility, or long-term endometrial receptivity. Symptom-guided assessment may include menstrual tracking, AMH, early-follicular-phase follicle-stimulating and luteinizing hormones, and pelvic ultrasonography when clinically indicated. Full article