Search Results (32)

Background/Objectives: The zona pellucida (ZP) is an extracellular matrix surrounding the oocyte. It is unclear whether mean ZP thickness is associated with reproductive age or developmental competence in women with diminished ovarian reserve (DOR). We examined pre-ICSI ZP thickness in relation to age, ovarian response, and early reproductive outcomes. Methods: This prospective observational study included 255 women aged 22–46 years with clinically diagnosed DOR who underwent intracytoplasmic sperm injection. ZP thickness was measured at three equidistant points before injection, independently verified by two observers, and summarized as the patient-level mean across the available metaphase II oocytes. Women aged <35 and ≥35 years were compared. The association between ZP thickness and chronological age was also evaluated using Spearman correlation. A transfer-adjusted logistic regression model evaluated beta-hCG positivity using age group, mean ZP thickness, laser-assisted hatching, day-5 transfer, and metaphase II oocyte count. Results: Median patient-level mean ZP thickness was similar in women aged <35 and ≥35 years (36.99 [34.90–40.61] vs. 36.91 [34.04–40.87] µm; p = 0.875). Mean ZP thickness was not correlated with chronological age (Spearman’s ρ = −0.059; p = 0.347). Younger women had higher AMH levels, antral follicle counts, retrieved oocyte counts, and metaphase II oocyte counts. Beta-hCG positivity was also higher in younger women (31.8% vs. 14.6%; p = 0.006). In the adjusted model, ZP thickness was not independently associated with beta-hCG positivity (OR 1.03 per µm, 95% CI 0.95–1.11; p = 0.487), whereas age ≥ 35 years was associated with lower odds of beta-hCG positivity. Conclusions: In this DOR cohort, mean pre-ICSI ZP thickness was not associated with chronological age, either as a continuous variable or after categorization at 35 years. It was also not independently associated with beta-hCG positivity. These findings do not exclude age-related changes in other structural, mechanical, or dynamic properties of the ZP that were not measured in this study. Full article

Background: The aim of this study was to investigate the impact of intraovarian platelet-rich plasma (PRP) treatment on ovarian reserve markers, hormonal profiles, oocyte yield, fertilization potential, and pregnancy outcomes in infertile women with diminished ovarian reserve. Methods: This retrospective single-center study was conducted at a tertiary referral center between January 2021 and December 2024 in the Department of Obstetrics and Gynecology, IVF Clinic, Private Diyarlife Hospital, Diyarbakır, Turkey. A total of 78 infertile women with diminished ovarian reserve (DOR) were included. DOR was defined in the present study as an AMH level < 1.1 ng/mL and/or an antral follicle count (AFC) < 5 follicles. Pre-PRP and post-PRP measurements were compared in the same patients. Hormonal and clinical parameters, including prolactin, thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), anti-Müllerian hormone (AMH), estradiol, endometrial thickness, gonadotropin dosage, antral follicle count (AFC), mature metaphase II (MII) oocyte count, and two-pronuclear (2PN) zygote count, were evaluated before and after PRP treatment. Results: Significant increases were observed in AMH and prolactin levels, whereas FSH levels significantly decreased following PRP treatment (all p < 0.001). Post-PRP AFC, MII oocyte count, and 2PN zygote count were significantly higher than pre-PRP values (all p < 0.001). A total of 21 pregnancies (26.9%) were achieved, including 17 clinical pregnancies (81.0% of pregnancies; 21.8% of all patients), 4 biochemical pregnancies (19.0% of pregnancies; 5.1% of all patients), 11 miscarriages (52.4% of pregnancies; 14.1% of all patients), and 6 live births (28.6% of pregnancies; 7.7% of all patients). Significant positive correlations were identified between post-PRP AFC and MII oocyte count (r = 0.803, p < 0.001), post-PRP AFC and 2PN zygote count (r = 0.624, p < 0.001), and MII oocyte count and 2PN zygote count (r = 0.728, p < 0.001). Conclusions: Intraovarian PRP administration was associated with improvements in ovarian reserve markers, oocyte maturation, and fertilization-related outcomes in women with DOR. Significant increases in AFC, MII oocyte count, and 2PN zygote count were observed after PRP treatment. However, these improvements in ovarian reserve markers were not associated with significant differences between women who achieved pregnancy and those who did not. Because of the retrospective design and the absence of a control group, these findings should be interpreted as associations rather than evidence of a causal treatment effect. Although clinical pregnancies and live births were observed during follow-up, larger, multicenter randomized controlled trials are required to confirm these findings and to further evaluate the effect of PRP on reproductive outcomes. Full article

Background/Objective: Phoenixin (PNX), a recently identified neuropeptide, has been shown to regulate the hypothalamic–pituitary–gonadal axis and play a role in folliculogenesis and oocyte maturation. However, its clinical relevance in ovarian reserve remains unclear. This study aimed to evaluate the association between serum PNX-14 and PNX-20 levels and ovarian reserve and to determine whether these peptides provide additional information regarding ovarian reserve status in women with diminished ovarian reserve (DOR). Methods: This prospective case–control study included 160 women of reproductive age. Participants were categorized according to anti-Müllerian hormone (AMH) levels and antral follicle count (AFC). Serum PNX-14 and PNX-20 levels were measured using ELISA. Statistical analyses included group comparisons, Spearman correlation, receiver operating characteristic (ROC) analysis, and logistic regression. Results: PNX-14 levels differed significantly across AMH-defined groups (p < 0.001), with higher levels observed in women with DOR. In contrast, PNX-20 levels showed no significant differences (p = 0.305). PNX-14 demonstrated excellent diagnostic performance for identifying DOR (AUC = 0.921), with a sensitivity of 78.7% and a specificity of 95.3% at a cut-off value of 183 pg/mL. A significant negative correlation was found between AMH and PNX-14 (r = −0.639, p < 0.001), whereas PNX-20 showed no significant correlation. In logistic regression analysis, PNX-14 was significantly associated with DOR in unadjusted and partially adjusted models; however, this association was attenuated after adjustment for AFC. Conclusions: PNX-14 is significantly associated with ovarian reserve status and may provide complementary information regarding DOR when interpreted alongside established ovarian reserve markers. In contrast, PNX-20 does not appear to have clinical utility in this context. Full article

Objectives: Diminished ovarian reserve (DOR) significantly compromises in vitro fertilization (IVF) success. Although systemic markers such as anti-Müllerian hormone (AMH) serve as valuable clinical indicators of the ovarian reserve, they lack the sensitivity to reflect the qualitative deterioration of the follicular microenvironment. Therefore, in this study, we aimed to characterize the inflammatory proteome of follicular fluid (FF) to establish a high-performance auxiliary diagnostic model for DOR. Methods: Utilizing the ultra-sensitive Olink proximity extension assay, we quantified 92 inflammation-related proteins in the FF of 88 participants (67 with DOR and 21 normal controls). Differentially expressed proteins (DEPs) were identified, and their relationships with key clinical indices were evaluated. A robust predictive signature was refined through integrated Least Absolute Shrinkage and Selection Operator (LASSO) regression and Random Forest algorithms, with diagnostic performance assessed via 10-fold cross-validation. Results: Thirty-five DEPs were significantly dysregulated in the FF of patients with DOR, demonstrating strong associations with serum AMH and basal estradiol concentrations. A minimized diagnostic panel comprising four core proteins, adenosine deaminase (ADA), vascular endothelial growth factor A (VEGFA), eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), and matrix metalloproteinase-1 (MMP-1), was established. This multivariable model achieved an excellent area under the receiver operating characteristic curve (AUC) of 0.953. Conclusions: The identified four-protein signature reflects localized chronic inflammation and early pathophysiological shifts in the DOR follicular microenvironment. As a high-performance molecular index, this panel could complement conventional systemic assessments, provide a reliable means of evaluating follicular viability, and optimize individualized therapeutic strategies. Full article

Objectives: To systematically evaluate the efficacy and safety of intraovarian platelet-rich plasma (PRP) administration in women with diminished ovarian reserve (DOR) and related conditions, given the growing clinical interest and the conflicting evidence from uncontrolled and controlled studies. Methods: This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Comprehensive searches were performed in PubMed, Web of Science, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), and Scopus up to January 2026. Eligible studies included randomized controlled trials (RCTs), prospective cohort studies, and before–after studies investigating PRP-based interventions in women diagnosed with DOR, premature ovarian insufficiency (POI), or poor ovarian response (POR). Given the limited availability of controlled data, these populations were analyzed together with cautious interpretation. Study quality was assessed using the Joanna Briggs Institute (JBI) checklists and the Critical Appraisal Skills Programme (CASP) tool for RCTs. Pooled estimates were calculated using random- or fixed-effects models depending on heterogeneity (I²). Results: Nineteen studies involving 1794 women were included, of which two were randomized controlled trials. In single-arm and before–after analyses, PRP administration was associated with increases in serum anti-Müllerian hormone (AMH) levels and antral follicle count (AFC), as well as a reduction in serum follicle-stimulating hormone (FSH). In addition, the number of metaphase II (MII) oocytes retrieved and transferable embryos increased following PRP treatment. However, pooled analyses of controlled studies, including RCTs, did not demonstrate consistent improvements in mature oocyte yield compared with control groups. In single-arm analyses, the pooled clinical pregnancy rate and live birth rate following PRP treatment were 15.5% (95% CI: 11.1–21.2%) and 10.7% (95% CI: 6.7–16.6%), respectively. No major procedure-related adverse events were reported across included studies. Conclusions: In conclusion, intraovarian PRP is associated with improvements in ovarian reserve markers such as AMH and AFC in uncontrolled studies. However, evidence from randomized controlled trials does not demonstrate a consistent benefit in pregnancy and live birth. Well-designed RCTs with standardized protocols are needed before clinical recommendation. Full article

Female infertility diseases such as polycystic ovary syndrome (PCOS), endometriosis, diminished ovarian reserve (DOR), and recurrent implantation failure (RIF) have different clinical phenotypes. However, they might be epigenetically convergent, and thus the therapeutic targets may be potential. This study utilized transcriptome data, microRNA (miRNA), and DNA methylation data from the granulosa cells of four Gene Expression Omnibus (GEO) datasets, GSE138518, GSE105765, GSE232306, and GSE92324, to conduct integrated bioinformatics analysis. We focused on differentially expressed genes (DEGs), constructed a miRNA–mRNA network, performed ROC curve analysis, and conducted function enrichment and drug repurposing studies. Our findings identified eight dysregulated genes (H19, SULT1A4, HCK, SPI1, CARD16, NFE2, LST1, and KRT8) common to PCOS, DOR, and RIF, which may serve to distinguish PCOS specifically. Moreover, these DEGs are associated with pathways such as innate immune activation, inflammatory responses, the NOD-like receptor signaling pathway, and Fc gamma R-mediated phagocytosis. Notably, MiRNAs differentially expressed in endometriosis (specifically hsa-miR-202-5p and hsa-miR-141-3p) were found to directly target this gene set, highlighting the role of epigenetic regulation across infertility diseases. Additionally, our drug repurposing analysis identified several FDA-approved drugs, including Abacavir and Peginterferon Alfa-2b, suggesting that the HCK gene may be a viable target for drug development to address female infertility. Furthermore, we identified 192 genes that correlated with DNA methylation and expression levels in PCOS. Thus, this study underscores the epigenetic convergence of different female infertility diseases and highlights potential biomarkers and therapeutic options that could enhance treatment in reproductive medicine. Full article

Background: Diminished ovarian reserve is characterized by a decrease in oocyte count and estrogen levels, which leads to infertility. The genetic and epigenetic mechanisms in MI to MII transition or complete MII phase in the oocyte maturation process estrogen receptor alpha and piRNA relationship were evaluated. Methods: This study analyzed 100 cumulus oophorous complex samples from normoresponder and DOR patients undergoing IVF, subdivided into metaphase I and metaphase II stages. To elucidate the ER-α, PIWIL3, piR-651, and piR-823 genes qRT-PCR was used and qualitative ER-α protein expressions were determined by immunohistochemistry. Pearson’s correlation analysis was utilized to evaluate the interactions between genes within each experimental group. Results: The DOR samples exhibited significant downregulation of ER-α gene and protein expression compared to the NOR controls. PIWIL3 gene, piR-651, and piR-823 expressions reduced in DOR MI and MII. Strong positive correlations among ER-α, PIWIL3, piR-651, and piR-823 were observed in NOR, whereas DOR showed weaker correlations and immunohistochemistry verified lower ER-α protein levels in DOR. Conclusions: The disruption of ER-α and piRNA-related gene networks in DOR may underlie the suboptimal maturation of oocytes, and monitoring ER-α, PIWIL3, piR-651, and piR-823 expressions could facilitate early determination of maturation stages and improve assessment of ovarian reserve. The potential for transposition to MII in NOR and DOR oocytes was observed in relation to the association between ER-α protein/gene expression and PIWIL3, which regulates ER-α. Moreover, piR-651 and piR-823, whose expressions depend on estrogen level, indirectly regulate oocyte maturation from MI to MII in both NOR and DOR epigenetically. We suggest that the MI and MII stages of oocytes could be determined earlier in NOR and DOR cases by controlling ER-α, PIWIL3, piR-651 and piR-823 expressions. These molecular markers indicate promise for diagnostic applications in reproductive medicine, warranting further validation in larger cohorts. Full article

Diminished ovarian reserve (DOR) is a major cause of female infertility with limited treatment options, and lifestyle interventions such as supervised, structured exercise therapy may support ovarian function. In this pilot study, we evaluated the effect of a supervised, physiotherapy-based exercise program combined with antioxidant supplementation on ovarian reserve markers and spontaneous pregnancy rates in 24 infertile women aged 20–42 years, with body mass index (BMI) 18.5–30 kg/m², regular menstruation, anti-Müllerian hormone (AMH) < 1.1 ng/mL, and antral follicle count ≥3 measured on days 2–4 of the cycle. Participants were randomized into two groups of 12: Both groups received standardized oral therapy, while the intervention group additionally participated in a three-month supervised, structured exercise therapy programme. Analysis of covariance was used to adjust for baseline differences in AMH and BMI, as groups differed significantly in BMI at baseline. At post-treatment assessment, AMH levels were significantly higher in the intervention group, whereas FSH, LH, estradiol, prolactin, and TSH levels did not change significantly. Spontaneous pregnancies were recorded both during the intervention period and throughout a follow-up period of up to six months. Spontaneous pregnancy occurred in 7 out of 12 participants in the intervention group versus 1 out of 12 in the control group, resulting in four and one live births, respectively. These findings suggest that combining supervised, structured exercise therapy with antioxidant supplementation may enhance ovarian reserve and improve the likelihood of spontaneous pregnancy in women with diminished ovarian reserve. Full article

Background and Objectives: Klotho (KL) is a multifunctional protein involved in reproductive physiology; however, its precise role in ovarian reserve and in vitro fertilization (IVF) outcomes remains unclear. This study aimed to evaluate the relationship between follicular fluid KL levels, ovarian reserve markers, and key IVF success parameters. Materials and Methods: This prospective study included a total of 150 women undergoing IVF, of whom 82 had diminished ovarian reserve (DOR) and 68 had normal ovarian reserve (NOR). All participants underwent controlled ovarian stimulation using a standard antagonist protocol. During oocyte pick-up (OPU), the first aspirated follicular fluid sample was collected, processed, and analyzed for KL concentrations using a Human Klotho ELISA kit. Hormonal profiles, ovarian reserve markers, and IVF outcomes were compared between groups. Results: Follicular fluid KL levels were significantly lower in the DOR group compared with the NOR group (117.07 ± 28.88 pg/mL vs. 266.13 ± 58.29 pg/mL; p < 0.001). Anti-Müllerian hormone (AMH) levels were reduced, whereas follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) levels were significantly higher in the DOR group (all p < 0.001). Implantation and clinical pregnancy rates were also significantly lower in the DOR group compared with the NOR group (p < 0.001 and p = 0.003, respectively). KL levels showed a strong positive correlation with the number of fertilized oocytes in both groups (DOR: r = 0.690; NOR: r = 0.552). Each one-unit increase in KL was associated with a 3.7% increase in implantation probability and a 3.2% increase in clinical pregnancy probability in the DOR group, and with corresponding increases of 4.4% and 1.2% in the NOR group (all p < 0.05). Conclusions: This study demonstrates significant associations between follicular fluid KL levels and fertilization, implantation, and clinical pregnancy outcomes. These associations appear to be more pronounced than those observed with traditional ovarian reserve markers such as AMH and antral follicle count. Reduced KL levels are associated with fewer fertilized oocytes, whereas higher KL concentrations correspond to increased implantation and clinical pregnancy probabilities. Nevertheless, similar to other non-invasive biomarkers, current evidence is insufficient to support routine clinical use of KL. Large-scale, well-designed, multicenter studies are therefore required to validate its clinical relevance and to determine whether KL can serve as a reliable and practical predictor of IVF success. Full article

Background/Objectives: Thyroid autoimmunity, particularly anti-thyroid peroxidase antibodies (anti-TPO), has been implicated in reduced fertility and diminished ovarian reserve. However, the stratified effects of anti-TPO across age groups, body mass index (BMI) categories, and polycystic ovary syndrome (PCOS) status remain unclear. This study aims to investigate the association between anti-TPO positivity and ovarian reserve markers—antral follicle count (AFC), anti-Müllerian hormone (AMH), and follicle-stimulating hormone (FSH)—in euthyroid infertile women. Methods: This retrospective study included 1460 infertile women aged 18–45 years, evaluated between 2022 and 2025. Participants were categorized based on anti-TPO levels (≥9 vs. <9 IU/mL) using Beckman Coulter-DXI 800 analyzer, which uses chemiluminescent immunoassays to measure results. BMI (<30 vs. ≥30 kg/m²), and PCOS status. Age was categorized into five strata (18–25, 25–30, 30–35, 35–40, and 40–55 years), and <35 vs. ≥35 years. Linear regression models were used to assess the impact of anti-TPO on AMH and AFC within each subgroup. Additional logistic regression was performed to evaluate the odds of diminished ovarian reserve (DOR: AMH < 1 ng/mL or AFC < 5) after adjusting for age, BMI, and TSH. Results: Anti-TPO positivity (17.6% prevalence) was significantly associated with reduced AMH (1.47 ± 1.52 vs. 3.33 ± 3.03 ng/mL, p < 0.0001), reduced AFC (8.18 ± 5.06 vs. 15.88 ± 8.18, p < 0.0001), and elevated FSH (9.40 ± 6.21 vs. 8.06 ± 4.79 mIU/mL, p = 0.001). These associations remained significant in non-obese and PCOS-negative subgroups. Regression models revealed stronger associations in younger women (<35 years) and showed significant Anti-TPO × Age and Anti-TPO × BMI interactions. Logistic regression confirmed Anti-TPO ≥ 9 IU/mL as a strong predictor of diminished ovarian reserve (AMH < 1 ng/mL: OR = 3.13; AFC < 5: OR = 6.48). ROC analysis indicated modest predictive ability (AUC: 0.665–0.694), and path modeling confirmed direct effects of Anti-TPO on AMH and AFC independent of TSH or BMI. Conclusions: Elevated Anti-TPO levels are independently associated with diminished ovarian reserve in euthyroid women, particularly in younger, non-obese, and PCOS-negative individuals. Anti-TPO may serve as a useful biomarker in fertility risk assessment and personalized reproductive counseling, even in the absence of overt thyroid dysfunction. Full article

Premature ovarian insufficiency (POI) and diminished ovarian reserve (DOR) are two related conditions characterized by a reduced ovarian reserve. Their etiologies are multifactorial, encompassing iatrogenic causes such as chemotherapy, pelvic surgery, or radiotherapy, as well as non-iatrogenic factors including genetic and chromosomal abnormalities, environmental exposures, autoimmune mechanisms and idiopathic sources. Early recognition of these conditions is essential, as timely and appropriate management can significantly impact both reproductive potential and long-term health. In women with POI, hormone replacement therapy is required to prevent the detrimental effects of estrogen deficiency on wellbeing and overall health, while in women with DOR, management focuses on counseling, fertility preservation when pregnancy is not an immediate goal, and strategies to optimize assisted reproductive outcomes when conception is desired. In addition, emerging research into ovarian rejuvenation offers promising new avenues for future therapeutic approaches. This review summarizes current knowledge on the pathophysiology, diagnosis, and management of POI and DOR, while highlighting innovative developments in reproductive medicine. Full article

Managing women with diminished ovarian reserve for in vitro fertilization (IVF) is challenging, often resulting in low oocyte yield and cycle failures. We hypothesize that coupling in vitro fertilization (IVF) with rescue in vitro maturation (r-IVM) can improve overall maturation rates without compromising the overall IVF outcome. Our study compared DOR and normal ovarian reserve (NOR) cohorts by evaluating 15 immature oocyte progressions following r-IVM. We analyzed the gene expression of cumulus cells related to GREM1, PTGS2, and HAS2 to correlate with OQ, EQ, and overall IVF outcome. Significant differences were noted in AMH levels, AFCs, and oocyte numbers (p < 0.05). Following r-IVM, the DOR cohort achieved a 50% maturation rate with improved overall quality; however, the difference was not statistically significant (p > 0.05). Fertilization rates were comparable, but EQ was better in DOR. All genes in DOR were upregulated post-r-IVM, whereas NOR showed downregulation of PTGS2 and GREM1 (p < 0.05). Otherwise, DOR exhibited higher pregnancy rates and live birth rates, although the difference was not statistically significant (p > 0.05). Overall, our findings suggest that r-IVM could provide improved fertility outcomes for DOR women in standard IVF cycles. Full article

Infertility remains a major global health concern, with diminished ovarian reserve (DOR), premature ovarian insufficiency (POI), polycystic ovary syndrome (PCOS), and impaired endometrial receptivity representing key contributors to poor assisted reproductive technology (ART) outcomes. Platelet-rich plasma (PRP), an autologous blood-derived concentrate enriched with growth factors and cytokines, has emerged as a promising regenerative therapy with angiogenic, anti-apoptotic, and proliferative properties. In reproductive medicine, intraovarian PRP has been evaluated for its potential to restore ovarian function in women with DOR and POI, improve oocyte competence and embryo euploidy, and promote ovulation in PCOS. Similarly, intrauterine PRP infusion or subendometrial zone injections has shown encouraging results in women with recurrent implantation failure and thin endometrium, enhancing endometrial thickness, receptivity, and implantation potential. Evidence from preclinical animal models and early clinical studies suggests multi-level mechanisms of action, including modulation of endocrine pathways, reduction in oxidative stress, activation of dormant follicles, and improvement of endometrial angiogenesis and receptivity. Despite these promising findings, results remain inconsistent due to heterogeneity in PRP preparation protocols, administration routes, timing, and study designs. Even though robust randomized controlled trials with standardized methodologies are needed to determine the efficacy and long-term reproductive outcomes of PRP in infertility treatment and anovulation in PCOS, PRP represents a novel and potentially transformative adjunct in reproductive endocrinology. Full article

Ovarian aging is characterized by a gradual decline in both reproductive and endocrine functions, ultimately culminating in the cessation of ovarian activity around the age of 50, when most women experience natural menopause. The decline begins early, as follicular attrition is initiated in utero and continues throughout childhood and reproductive life. Most follicles undergo atresia without progressing through substantial stages of growth. With increasing age, a pronounced reduction occurs in the population of resting follicles within the ovarian reserve, accompanied by a decline in the size of growing follicular cohorts. Around the age of 38, the rate of follicular depletion accelerates, sometimes resulting in diminished ovarian reserve (DOR). The subsequent menopausal transition involves complex, irregular hormonal dynamics, manifesting as increasingly erratic menstrual patterns, primarily driven by fluctuations in circulating estrogens and a rising incidence of anovulatory cycles. In parallel with the progressive depletion of the follicular pool, the serum concentrations of anti-Müllerian hormone (AMH) decline gradually, while reductions in inhibin B levels become more apparent during the late reproductive years. The concomitant decline in both inhibin B and estrogen levels leads to a compensatory rise in circulating follicle-stimulating hormone (FSH) concentrations. Together, these endocrine changes, alongside the eventual exhaustion of the follicular reserve, converge in the onset of menopause, which is defined by the absence of menstruation for twelve consecutive months. The mechanisms contributing to ovarian aging are complex and multifactorial, involving both the oocyte and the somatic cells within the follicular microenvironment. Oxidative stress is thought to play a central role in the age-related decline in oocyte quality, primarily through its harmful effects on mitochondrial DNA integrity and broader aspects of cellular function. Although granulosa cells appear to be relatively more resilient, they are not exempt from age-associated damage, which may impair their hormonal activity and, given their close functional relationship with the oocyte, negatively influence oocyte competence. In addition, histological changes in the ovarian stroma, such as fibrosis and heightened inflammatory responses, are believed to further contribute to the progressive deterioration of ovarian function. A deeper understanding of the biological processes driving ovarian aging has facilitated the development of experimental interventions aimed at extending ovarian functionality. Among these are the autologous transfer of mitochondria and stem cell-based therapies, including the use of exosome-producing cells. Additional approaches involve targeting longevity pathways, such as those modulated by caloric restriction, or employing pharmacological agents with geroprotective properties. While these strategies are supported by compelling experimental data, robust clinical evidence in humans remains limited. Full article

Granulosa cell (GC) dysfunction contributes to diminished ovarian reserve (DOR). We collected GC and follicular fluid samples from the patients of normal ovarian reserve (NOR) and DOR. RNA-seq of GCs showed that cholesterol/sterol metabolism and biosynthesis and extracellular matrix organization were enriched in the DOR group. Metabolomics of follicular fluid revealed enrichment in steroid hormone biosynthesis, tryptophan metabolism, and fatty acid β-oxidation in DOR. The apoptosis rate was increased, whereas the proliferative rate was decreased in GCs of DOR. The Prussian blue staining rate was increased whilst GPX4 and SLC7A11 expression were downregulated in GCs of DOR. Mitochondrial morphology displayed the features of ferroptosis in GCs of DOR. FSHR, CYP19A1, NR5A1, and phosphorylated CREB levels were substantially downregulated in GCs, accompanied by increased androgen levels in follicular fluids in DOR. The key factors linked to the mevalonate pathway, HMGCR, SQLE, and SREBF2, were robustly increased in DOR. FSHR and NR5A1 levels were correlated with CYP19A1 levels, whilst CYP19A1 levels were positively correlated with GPX4 and SLC7A11 levels. Our findings indicate ferroptosis and dysregulation of cholesterol/sterol metabolism and biosynthesis occurrence in GCs of DOR, which might be associated with reduced FSHR signaling and decreased conversion of androgen to estrogen. Full article