Search Results (67)

Ovarian reserve and reproductive life are closely linked concepts in female reproductive biology. The ovarian reserve consists of primordial follicles and refers to the number and quality of oocytes (eggs) remaining in the ovaries at any given time. Follicular dynamics shape a woman’s reproductive lifespan, ultimately leading to menopause. Elucidating the underlying genetic and molecular pathways of follicle maturation and depletion is thus crucial for understanding menopausal onset and progression, both in normal and pathophysiological contexts, such as primary ovarian insufficiency, defined as menopause before the age of 40. A key factor in ovarian differentiation and fertility maintenance is FOXL2, a forkhead family transcription factor that plays a crucial role in follicle formation and development, ovarian maintenance, and sex determination. By employing a ChIP-Seq approach in mice, we identified a previously unreported binding of FOXL2 to a Tsc1 regulatory region. Our data, along with a thorough literature review, support the hypothesis that FOXL2-mediated activation of Tsc1 in granulosa cells can help maintain primordial follicles in a dormant state by suppressing mTORC1 signalling. Understanding the mechanisms behind ovarian reserve may lay the foundation for developing novel fertility preservation strategies, improving fertility treatment protocols and promoting in vitro activation of cryopreserved ovarian tissue to support folliculogenesis. Full article

Background/Objectives: Chronic pelvic pain (CPP) is defined as pelvic pain lasting longer than six months and is a common yet often overlooked condition, affecting over 40% of women worldwide and accounting for about 10% of gynecological consultations. Despite extensive investigation, including laparoscopy, no cause is identified in up to half of cases. Pelvic congestion syndrome (PCS), also referred to as pelvic venous insufficiency (PVI), has been estimated to account for up to 30% of CPP cases, although it remains underdiagnosed. PCS is caused by venous reflux or obstruction in pelvic veins and is characterized by dull, aching pain worsened by standing, intercourse, post-orgasm, and the premenstrual period. It occurs predominantly in premenopausal women, often after pregnancy. This narrative review aims to improve understanding of PCS and provide practical guidance to support diagnosis and treatment in routine gynecologic practice. Methods: We performed a comprehensive review of the current literature focusing on the clinical presentation, pathophysiology and diagnostic and treatment performance of various modalities. Special emphasis was placed on identifying accessible, non-interventional tools suitable for primary gynecological care. Results: PCS, CPP and endometriosis exhibit significant clinical overlap, including dysmenorrhea, dyspareunia and chronic pain. However, pathognomonic features like post-coital pain and pain-exacerbation by prolonged standing, combined with specific ultrasound markers, allow for early differentiation. While laparoscopy is often used to investigate CPP, it has limited sensitivity for PCS due to CO₂-pneumoperitoneum-induced venous compression, and Trendelenburg position, compared to venography, the diagnostic gold standard. In contrast, transvaginal ultrasound (TVUS) serves as a potent first-line tool. Key diagnostic criteria include ovarian vein diameter (>7–8 mm), low flow velocity (<3 cm/s), and myometrial vein dilatation (>5 mm). Furthermore, the frequent co-occurrence of endometriosis and PCS requires a multimodal diagnostic approach to avoid “diagnostic bias.” Conclusions: To improve patient outcomes and reduce diagnostic delay, office-based gynecologists should integrate specific vascular TVUS into the routine workup of CPP, not only to diagnose endometriosis but also to identify PCS. Future efforts should focus on standardized TVUS protocols and interdisciplinary care pathways involving gynecologists and interventional radiologists to enable integrated diagnostic and therapeutic approaches for patients with coexisting endometriosis and PCS, addressing both surgical and non-surgical options, as well as the bidirectional relationship and mutual pathophysiological influence between these entities. Full article

Cisplatin-induced ovarian damage is a significant concern for young women receiving chemotherapy. Although propolis, a polyphenol- and flavonoid-rich natural product, has been proposed as a protective agent, its effects on cisplatin-related ovarian injury remain insufficiently defined. This study aimed to investigate whether propolis mitigates cisplatin-induced ovarian toxicity. In this study, 36 adult female Wistar rats were randomly allocated into six groups: Control, Propolis (50 mg/kg), Propolis (100 mg/kg), Cisplatin (7 mg/kg), Cisplatin + Propolis (50 mg/kg), and Cisplatin + Propolis (100 mg/kg). Cisplatin was administered as a single intraperitoneal dose on day 1, while propolis was given orally by gavage once daily for 14 days. Biochemical, histopathological, and endoplasmic reticulum (ER)-stress-related parameters were evaluated. Histopathologically, cisplatin caused significant vascular congestion, hemorrhage, edema, and follicular degeneration (p < 0.01), accompanied by marked reductions in primordial, primary, secondary, and tertiary follicle counts and a significant increase in atretic follicles. Propolis co-administration significantly ameliorated these lesions and partially preserved follicular counts, particularly at the 100 mg/kg dose (p < 0.01). Cisplatin markedly increased malondialdehyde (MDA) levels and ER stress markers (GRP78, ATF6, and CHOP), while reducing glutathione (GSH). Propolis treatment ameliorated these changes, decreased TNF-α and caspase-3 levels, and attenuated oxidative, inflammatory, and apoptotic responses. Propolis exerts strong antioxidant, anti-inflammatory, anti-apoptotic, and ER-stress-modulating effects that collectively counteract cisplatin-induced ovarian injury. Full article

Background/Objectives: Dynein axonemal heavy chain (DNAH) genes, including DNAH6, are implicated in male infertility, particularly multiple morphological abnormalities of the spermatozoa flagellum (MMAF). However, an underlying mechanism is unclear. Methods: This in silico study analyzed 19 previously reported DNAH6 mutations to elucidate their effects on the structural, mechanical, and microstructural aspects and axonemal assembly of flagellum and how these changes impact reproductive health, correlating with pathogenicity scores, ATP binding capacity, and protein interactions. Results: DNAH mutations were associated with CDGP (52.63%), male infertility (36.84%), and primary ovarian insufficiency (10.53%). MMAF-linked mutations exhibited higher SNAP2 scores (57.25 ± 5.68 vs. −32.58 ± 44.85, p = 0.002), reduced ATP binding affinity (−6.27 ± 4.20 vs. −8.92 ± 0.23 kcal/mol, p = 0.05), and smaller catalytic cavity size (17,646 ± 13,005 vs. 27190 ± 3485 ų, p = 0.04). These mutations showed reduced DNAH6-CLIP4 binding affinity (−303.90 ± 5.23 vs. −313.60 ± 4.28 kcal/mol, p = 0.002). Literature-based semen analysis revealed correlations between Phred scores and absent flagella (r = 0.952, p = 0.012) and inverse correlations between ATP binding capacity and absent flagella (r = −0.902, p = 0.036) or irregular width (r = −0.949, p = 0.014). A mathematical model of ATP binding kinetics predicted reduced flagellar motility in MMAF mutants due to impaired dynein function. Ultrastructural analyses indicated that high pathogenicity scores and reduced ATP binding correlate with absent inner dynein arms and radial spokes, while impaired DNAH6-CLIP4 interactions disrupt axonemal assembly. Conclusions: In silico analyses, integrated with microstructural, axonemal, and mathematical modeling data, demonstrate that DNAH6 mutations cause MMAF by impairing ATP binding, protein interactions, and axonemal assembly, leading to severe flagellar dysfunction and thereby negatively affecting reproductive health. Full article

Primary ovarian insufficiency (POI) affects up to 3% of reproductive-aged women and is a critical yet underrecognized contributor to infertility and systemic accelerated aging. While most cases remain idiopathic, advances in genomics increasingly reveal a genetic basis, implicating pathways that govern DNA repair, meiosis, chromosomal stability, and folliculogenesis. This review synthesizes the multifactorial etiology of POI, integrating genetic contributions with emerging evidence on epigenetic dysregulation, mitochondrial dysfunction, and environmental influences such as toxins and lifestyle factors. These mechanisms converge on core cellular processes, driving premature follicular depletion and shortening reproductive lifespan. We also highlight racial and ethnic disparities in POI prevalence and research representation, alongside the profound psychosocial burden experienced by affected individuals. Addressing these challenges through integrative strategies that unite mechanistic insight with equity is essential, not only for improving POI care but also for advancing precision approaches to ovarian aging and safeguarding reproductive health across the lifespan. Full article

The functional deterioration of granulosa cells (GCs), essential for follicular growth, steroidogenesis, and oocyte competence, indicates ovarian aging and reduced fertility. An expanding corpus of research indicates that oxidative stress is a primary molecular contributor to granulosa cell dysfunction, culminating in mitochondrial impairment, reduced metabolic support for oocytes, and the activation of regulated apoptotic pathways that end in follicular atresia. Ferroptosis, an emergent type of iron-dependent lipid peroxidation, has been identified as a crucial mechanism contributing to chemotherapy-induced ovarian insufficiency, polycystic ovary syndrome (PCOS), and granulosa cell death in aging ovaries, in addition to conventional apoptosis. The SIRT1-Nrf2 axis acts as a crucial anti-oxidative and anti-ferroptotic system that protects GC viability, maintains mitochondrial homeostasis, and upholds redox equilibrium. SIRT1 promotes mitochondrial biogenesis and metabolic resilience by deacetylating downstream proteins, including FOXO3 and PGC-1α. Nrf2 simultaneously controls the transcriptional activation of detoxifying and antioxidant enzymes, including HO-1, SOD2, NQO1, and GPX4, which are critical inhibitors of ferroptosis. Disruption of SIRT1-Nrf2 signalling accelerates GC senescence, follicular depletion, and reproductive aging. In contrast, pharmaceutical and nutraceutical therapies, including metformin, melatonin, resveratrol, and agents that increase NAD⁺ levels, may reverse ovarian deterioration and reactivate SIRT1-Nrf2 activity. This narrative review highlights innovative treatment prospects for ovarian aging, fertility preservation, and assisted reproduction by synthesising current evidence on ferroptotic pathways, SIRT1-Nrf2 interactions, and oxidative stress in granulosa cells. An understanding of these interrelated biological networks enables the development of tailored therapies that postpone ovarian ageing and enhance reproductive outcomes for women receiving fertility therapy. Full article

Microplastics (MPs) and nanoplastics (NPs) are widespread environmental contaminants with documented impacts on human health, particularly on the female reproductive system. Defined as polymeric fragments smaller than 5 mm, MPs (typically ranging from 1 µm to 5 mm) and NPs (smaller than 1 µm, often <100 nm) originate either from primary sources—intentionally manufactured for specific industrial applications—or from secondary sources through physical, chemical, or biological degradation of macroplastics. Human exposure occurs via multiple routes, including ingestion, inhalation, dermal absorption, and iatrogenic introduction, with growing evidence that these particles can accumulate in the ovaries, oocytes, and placental tissue. Experimental studies in rodents demonstrate that MPs and NPs induce oxidative stress, trigger inflammatory responses, and promote granulosa cell apoptosis, ultimately diminishing ovarian reserve and impairing folliculogenesis. Clinical and pilot human studies have confirmed the presence of MPs in placentas, umbilical cord blood, and meconium, indicating exposure from the earliest stages of development. Moreover, MPs and NPs may disrupt the hypothalamic–pituitary–ovarian axis, contributing to endocrine dysregulation and hormonal imbalance. Analytical methods such as Fourier-transform infrared spectroscopy, Raman spectroscopy, and scanning electron microscopy enable detection of these particles in biological samples, although methodological standardization remains insufficient. This paper summarizes current evidence on the exposure pathways, toxicological effects, and reproductive consequences of MPs and NPs in women. It further highlights existing research gaps and evaluates available analytical approaches to support future studies and develop strategies aimed at mitigating their detrimental impact on women’s reproductive health and fertility. Full article

Gynecological endocrine disorders, including polycystic ovary syndrome (PCOS), endometriosis as well as primary ovarian insufficiency (POI)/premature ovarian failure (POF), significantly impact women’s reproductive health and overall well-being. While these conditions are primarily driven by disturbances of the hypothalamic–pituitary–gonadal axis, yet growing evidence indicates that oxidative stress plays a crucial role in their development and progression. The combined impact of hormonal imbalance and impaired redox homeostasis contributes to infertility, metabolic dysfunction, and other co-morbidities, such as increased cardiovascular risk. Given that women may live for many years with these chronic conditions, investigating their pathophysiology and associated complications is of particular importance. This narrative review summarizes current knowledge on PCOS, endometriosis, and POI/PMF, emphasizing the contribution of oxidative stress and also highlights the association between these disorders and cardiovascular risk. Furthermore, the utility of rat models is presented to support the advancement of preventive and therapeutic research. Full article

Background: Despite life-saving newborn screening programs and a life-long galactose-restricted diet, many patients with classic galactosemia continue to develop long-term debilitating neurological deficits, speech dyspraxia, and primary ovarian insufficiency (POI). In an earlier study, we showed that administration of an experimental human GALT mRNA predominantly expressed in the liver of the GalT gene-trapped mouse model augmented the expression of hepatic GALT activity, which reduced build-up of galactose and its toxic metabolites not only in the liver but also in the peripheral tissues. Moreover, we showed that the administration of GALT mRNA in the mutant mice restored whole-body galactose oxidation (WBGO), which is a functional biomarker. Methods: In this pilot study, we extended our proof-of-concept efficacy studies to a disease-relevant phenotype: motor impairment. GalT-KO mice aged 3 and 6 weeks old administered biweekly intravenous injections of 100 µL GALT mRNA at a dose of 2 mg/kg for 2 months. Motor performance was assessed using rotarod testing and composite phenotype scoring, 3 and 9 weeks following the dosing regimen. Results: Preliminary results showed that a biweekly dosing at 2 mg/kg for 2 months improved the motor performance of the animals in rotarod and composite phenotype scoring tests in a short-term experiment. Conclusions: Despite being a small-scale study, our findings suggest that when treated early in life, the experimental GALT mRNA is effective in improving the motor-related phenotypes in GalT-KO mice using the specified dosing regimen. These findings highlight the potential of mRNA-based therapies for mitigating neurological symptoms in Classic galactosemia. Full article

Background/Objectives: Fertility preservation is a key component of oncological care. This study evaluated the effectiveness of different controlled ovarian stimulation (COS) protocols, including dual stimulation (DuoStim), for oocyte preservation, with a specific focus on breast cancer patients, and aimed to identify predictors of mature oocyte yield. Methods: A retrospective single-center study was conducted on 203 women under 40 years undergoing fertility preservation before cancer treatment between August 2013 and May 2024 at the Fertility Unit of the University Hospital of Pisa. COS protocols were stratified by menstrual cycle phase: early follicular (EFP), late follicular (LFP), luteal (LP), and DuoStim. The primary outcome was fertility preservation, assessed by the number of mature oocytes retrieved (MII). Independent predictors of oocyte yield were assessed using multivariable Poisson regression. Results: A total of 244 COS cycles were analyzed. The DuoStim group showed a lower median number of MII oocytes collected during the second stimulation compared to EFP, LFP, and LP (all adjusted p-value < 0.05, FDR); however, cumulative MII counts across both stimulations were comparable to other protocols. Oocyte maturity rates were similar across groups. Multivariable analysis identified AMH and AFC, but not age, basal FSH, hormonal parameters, and year of cryopreservation, as independent predictors of MII oocyte yield. Conclusions: COS is effective for fertility preservation across different cycle phases without delaying cancer treatment. DuoStim is not inferior but rather a valuable strategy for poor responders with insufficient oocyte yield after an initial cycle, thereby broadening opportunities for cryopreservation in time-sensitive oncological settings. Full article

Primary ovarian insufficiency (POI) in adolescents and young women is a rare but serious endocrine disorder with far-reaching reproductive, metabolic, and psychological implications. This study aimed to evaluate diagnostic timelines, treatment patterns, and psychosocial outcomes among affected individuals in a secondary care setting in Saudi Arabia. A retrospective observational analysis was conducted on 96 patients aged 13–39 years diagnosed with POI between 2018 and 2024. Data were extracted from electronic medical records and assessed using validated clinical and psychological tools, including the MENQOL and HADS. The mean age at diagnosis was 22.9 years, with one-third of patients experiencing diagnostic delays exceeding 18 months. Hormone replacement therapy was initiated in 69.8% of cases, while fertility counselling and bone mineral density screening were provided to 61.5% and 74.0% of patients, respectively. Over 60% exhibited clinically significant symptoms of anxiety or depression. Multivariate analysis revealed that delayed diagnosis, absence of hormone therapy, and lack of fertility counselling significantly increased the risk of psychological distress. These findings underscore the importance of timely diagnosis, multidisciplinary intervention, and integrated mental health support in the management of POI. Comprehensive, culturally responsive care models are essential to improving quality of life and long-term outcomes in this vulnerable population. Full article

Proteases play crucial roles in ovarian folliculogenesis, regulating several processes from primordial follicle activation to ovulation and corpus luteum formation. This review synthesizes the current knowledge on the diverse functions of proteases in ovarian physiology and pathology. We discuss the classification and regulation of proteases, highlighting their importance in extracellular matrix remodeling, cell signaling, and apoptosis during ovarian follicular development. We explore the roles of several proteases including matrix metalloproteinases, tissue inhibitors of metalloproteinases, the plasminogen activator system, and cathepsins, and their roles in the critical functions of ovarian biology including follicle dynamics and senescence. Furthermore, we address the involvement of proteases in ovarian pathologies, including cancer, polycystic ovary syndrome, and primary ovarian insufficiency. By integrating recent findings from clinical genomics and animal models, this review provides a comprehensive overview of protease functions in the ovary, emphasizing their potential use for therapeutic interventions in reproductive medicine. Full article

Background: Breast cancer (BC) patients with germline BRCA1/2 pathogenic variants (PVs) often face unique challenges compared to non-carriers. However, the impact of PVs on treatment patterns, clinical outcomes, and quality of life (QoL) remains insufficiently explored. This study aims to assess these factors in these individuals. Methods: A retrospective analysis was conducted using data from the Medical University of Vienna Center for Familial Breast and Ovarian Cancer between 2011 and 2021. Among 1285 individuals identified, 338 were included (120 BRCA1 PVs, 47 BRCA2 PVs, and 171 non-carriers). Clinical data including treatment patterns and outcomes were collected; QoL was assessed in BRCA1/2 PV carriers using the SF-12 questionnaire. Results: Among 338 BC patients, BRCA1 PV carriers were significantly younger at disease onset and more likely to present with triple-negative BC, with higher Ki-67 (>10%) than BRCA2 or non-carriers. Platinum-based chemotherapy was more frequently administered to BRCA PV carriers for neoadjuvant treatment (OR 7.7, p < 0.001), and therapeutic bilateral mastectomy was more common in BRCA1 carriers (44.7%) compared to BRCA2 (37.8%, p = 0.114) and non-carriers (25.2%, p = 0.003). Epirubicin was the primary agent for adjuvant chemotherapy across all groups compared to other chemotherapeutic agents. QoL assessments revealed significant physical health challenges, particularly among those who underwent neoadjuvant chemotherapy and surgery, while mental health scores remained relatively high. Conclusions: This study highlights the distinct treatment patterns and tumor characteristics associated with BRCA1/2 carriers, including the impact of treatments on quality of life. Nevertheless, our findings ought to be interpreted with caution due to the small sample size. Larger prospective studies with more complete treatment data, including PARP inhibitor use, and further research on supportive care strategies are needed for this high-risk population. Full article

Cisplatin, a widely used chemotherapeutic agent, is known to induce premature ovarian insufficiency (POI) and infertility in women of reproductive age. Among the contributing factors, cisplatin-induced apoptosis of ovarian granulosa cells is considered a primary driver of ovarian dysfunction; however, the underlying mechanisms remain incompletely understood. In this study, we investigated the cytotoxicity of cisplatin on the granulosa cell line KGN in vitro and explored the associated mechanisms. Our results demonstrate that cisplatin induces KGN cell apoptosis in a dose-dependent manner and impairs mitochondrial function, as evidenced by excessive ROS production, membrane potential collapse, and reduced ATP synthesis. Mitophagy, a key cellular self-protection mechanism that selectively removes damaged mitochondria, was activated following cisplatin treatment, mitigating its detrimental effects on KGN cells. Activation of mitophagy with urolithin A (UA) ameliorated cisplatin-induced mitochondrial dysfunction and apoptosis, whereas inhibition of mitophagy with cyclosporine A (CsA) exacerbated these effects. Furthermore, pretreatment with the clinical drug melatonin significantly enhanced mitophagy, effectively attenuating cisplatin-induced apoptosis in KGN cells. This study proposes a novel therapeutic strategy for patients undergoing tumor chemotherapy, aiming to preserve treatment efficacy while reducing the adverse effects of chemotherapeutic agents on ovarian function, thereby improving patients’ quality of life. Full article

Background: This paper briefly reviews the most important endocrine features of primary ovarian insufficiency (POI) and shows their relevance for the diagnosis and treatment of this condition. Introduction: Endocrine disturbances in POI cause problems for both the fertility and general health status of the affected women. Both subfertility and infertility result from the depletion of growing ovarian follicles which, in its turn, is the causative factor of hypoestrogenism; this is responsible for most of the general health problems affecting women. Method: Search of literature. Results and conclusion: A combination of high-serum follicle-stimulating hormone (FSH) and low 17β-estradiol (E2) concentrations is a key feature characterizing POI and is the decisive element for POI diagnosis. However, an in-depth search for possible genetic and non-genetic causes is important for adequate counseling regarding prevention and early intervention. The treatment of general health problems, based on correcting hypoestrogenism through hormone replacement therapy (HRT), is relatively easy. On the other hand, resolving infertility is a much more difficult task, and oocyte donation is the only really efficient instrument. Fertility preservation is a suitable alternative in patients with early POI diagnosis, in whom some viable follicles are still present in the ovaries. In patients who refuse oocyte donation, intraovarian injection of autologous platelet-rich plasma and in vitro activation of dormant follicles may be considered. Other innovative treatments, such as stem cell therapies or nuclear transfer, are currently under investigation. Full article