Ovarian aging, characterized by declining ovarian reserve, is a pacemaker of aging in the female body. Oxidative stress leads to apoptosis, mitochondrial dysfunction, inflammation, and telomere shortening, accelerating ovarian aging. Scavenging reactive oxygen species (ROS) has been shown to delay ovarian aging; however, there remains a significant lack of antioxidants with both proven efficacy and minimal side effects. DNA tetrahedral nanostructure (DTN) is a promising nucleic acid framework with antioxidant and anti-apoptotic properties. We developed FSH-DTN, a modified nanoparticle equipped with a follicle-stimulating hormone receptor-targeting peptide (FSH33-53) to enhance ovarian accumulation. Compared to native DTN, FSH-DTN showed superior ovarian targeting efficiency as confirmed by in vivo imaging. In both in vivo and in vitro models of acute, subacute, and chronic ovarian aging, FSH-DTN demonstrated superior antioxidant, anti-apoptotic, and anti-aging effects. Further investigation revealed that FSH-DTN can directly eliminate ROS in the ovaries while enhancing ovarian antioxidant capacity by activating the NRF2 signaling pathway, thereby protecting ovarian function. In this study, we offer a new strategy for neutralizing oxidative stress to delay ovarian aging.

Inadequate ovarian function suppression and endocrine therapy manipulations in premenopausal patients with early breast cancer on adjuvant LHRH agonist and aromatase inhibitor: a cohort study.

Fertility preservation remains a significant concern for individuals undergoing gonadotoxic treatments. While traditional fertility preservation techniques are well-established, these methods can be time-consuming and limited by various medical or logistical barriers. In recent years, the potential of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) has emerged as a promising, paradigm-shifting approach in fertility preservation. Preclinical studies have demonstrated the protective and regenerative properties of EVs in chemotherapy-induced ovarian and testicular damage in animal models. EVs provide a cell-free therapy that can potentially preserve ovarian function in females and spermatogenesis in males without the need for surgery or delay in cancer treatment. Additionally, using MSC-derived EVs offers advantages over traditional stem cell therapies, such as a reduced risk of immune rejection, targeted treatment, and avoidance of safety concerns associated with stem cell-based therapies. Future directions include enhancing the therapeutic potential of MSC-derived EVs through genetic engineering or cell priming techniques to target specific tissues and further optimize their utilization in fertility preservation. Given the potential of MSC-derived EVs to protect fertility in both females and males, this approach could revolutionize treatment in oncofertility. Further research, including clinical trials, is necessary to confirm the safety and efficacy of MSC-derived EVs, focusing on premature ovarian insufficiency. Looking ahead, MSC-derived EVs could revolutionize fertility preservation, offering hope for cancer patients and individuals exposed to various environmental risks affecting reproduction, including in space exploration, where protection from cosmic radiation is essential.

Younger premenopausal women (typically defined as those aged <40 years) diagnosed with oestrogen receptor (ER)-positive early-stage breast cancer have disproportionately poorer outcomes relative to older women, with age-related differences being especially pronounced in this subtype. Emerging evidence suggests that this age-related disparity is underpinned by distinct biological and genomic features - such as enrichment in copy number alterations, homologous recombination deficiency and unique immune microenvironments - that are not fully addressed by current therapeutic strategies. Endocrine therapy remains the cornerstone of treatment for premenopausal women with ER-positive early-stage breast cancer, yet strategies for its use continue to evolve. Clinical studies have highlighted the importance of ovarian function suppression (OFS) in improving the outcomes in patients with high-risk disease, as well as the benefit of adding CDK4/6 inhibitors to standard-of-care (SOC) endocrine therapies and the expanding role of molecular profiling in guiding treatment decisions. In this Review, we describe how treatment paradigms are now challenging the conventional sequencing of chemotherapy and endocrine therapy in younger women. A biology-driven approach - incorporating germline status, gene expression and immune signatures - will better guide therapy in this population and transform clinical decision-making beyond chronological age. We propose that future trials involving women with premenopausal ER-positive disease must prioritize biology over age in defining eligibility, incorporate OFS as a SOC in the control arm and expand biomarker-driven approaches to refine both treatment escalation and de-escalation. A genomically and immunologically informed strategy is essential to improve the outcomes in this under-represented population.

Female reproductive aging is characterized by progressive deterioration of ovarian function, yet the molecular mechanisms driving these changes remain incompletely understood. Here, we used long-read direct RNA-sequencing to map transcript isoform changes in mouse ovaries across reproductive age. Comparing young and aged mice after controlled gonadotropin stimulation, we identified widespread alternative splicing changes, including shifts in exon usage, splice site selection, and transcript boundaries. Aged ovaries exhibited increased isoform diversity, favoring distal start and end sites, and a significant rise in exon skipping and intron retention events. Many of these age-biased splicing events altered open reading frames, introduced premature stop codons, or disrupted conserved protein domains. Notably, several mitochondrial genes involved in the respiratory chain were affected. We highlight Ndufs4, a mitochondrial Complex I subunit, as a case in which aging promotes the alternative splicing of a short isoform lacking the canonical Pfam domain. Structural modeling suggests this splice variant could impair Complex I function, resulting in increased ROS production. Our data suggest a mechanistic link between splicing and mitochondrial dysfunction in the aging ovary. These findings support the model of the splicing-energy-aging axis in ovarian physiology, wherein declining mitochondrial function and adaptive or maladaptive splicing changes are intertwined. Our study reveals that alternative splicing is not merely a byproduct of aging but a dynamic, transcriptome-wide regulatory layer that may influence ovarian longevity. These insights open new avenues for investigating post-transcriptional mechanisms in reproductive aging and underscore the need to consider isoform-level regulation in models of ovarian decline.

Implications of early-life BPS-induced thyroid disruption on adult female reproductive disorders.

Yulinzhu activates ESR1-mediated germline stem cell regeneration to improve diminished ovarian reserve.

Menstrual stoppage, follicular dysplasia, and hypergonadotropic hypoestrogenism in women under forty are among the symptoms of premature ovarian failure (POF). This study aimed to explore the role and mechanism of amygdalin on ovarian function in a POF mouse model. A POF mouse model was established via injection of D-galactose (D-gal), followed by amygdalin treatment. Histological staining of ovarian tissues was applied to determine follicular development and granulosa cell apoptosis. Levels of malondialdehyde (MDA), glutathione peroxidase (GSH-px), and superoxide dismutase (SOD) were measured in ovarian tissues. Enzyme-linked immunosorbent assay was used to detect levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), progesterone (P), estradiol (E2), anti-Müllerian hormone (AMH), and reactive oxygen species (ROS) in serum, and tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 levels in ovaries. D-gal increased levels of FSH, LH, ROS, MDA, TNF-α, IL-1β, IL-6, Bax, atretic follicles, and granulosa cell apoptosis, and decreased P, E2, AMH, SOD, GSH-px, Bcl-2, and primordial, primary, secondary, and total follicles (p<0.01). Amygdalin with different concentrations reversed the effects of D-gal on mice (p<0.05). Amygdalin improved ovarian function in POF mice through inhibiting oxidative stress, inflammation, and granulosa cell apoptosis. These results suggested that amygdalin may be a potential antioxidant for POF treatment.

Ovarian tissue transplantation using autologous platelet-rich plasma: a pilot clinical trial.

Surface-charge-dependent ovarian toxicity of polystyrene microplastics: Insights into accumulation, mitochondrial damage, and macrophage polarization.

Oncologically safe minimally invasive management of a 25cm cystic abdominopelvic mass using contained, controlled drainage and removal.

Multi-omic biomarkers in premature ovarian insufficiency.

The aim of this study was to describe and compare the effect of different lighting protocols on sexual cyclicity and serum melatonin in domestic female cats. Additionally, anti-Müllerian hormone (AMH) concentrations and ultrasound or histological imaging of the ovaries were included. For this purpose, three experiments (Expt.) were conducted under controlled lighting conditions: Expt. I: A short photoperiod (SP) vs. a long photoperiod (LP), Expt. II: LP preceded by a SP, and Expt. III: Prolonged 6-month SP. In both Expt. I and II LP increased most of the ovarian functionality parameters, prior exposure to a SP did not increase functionality. In Expt. I, AMH serum concentrations did not differ between both photoperiods. In Expt. II, ultrasound ovarian volume and follicle diameters were larger in LP than in SP. Intraovarian arteries' resistance index was lower in LP. In Expt. III, cyclicity was maintained without quantitative differences between the first and the second half. At the end of Expt. III, the ovaries presented a proportion of 92.08% primordial, 2.35% primary, 2.26% secondary, and 3.31% small antral follicles. Corpora lutea also appeared in three queens. In the three experiments, spontaneous ovulation frequency was not influenced by the photoperiod. In both Expt. I and II, serum melatonin concentrations were not different between photoperiods. These concentrations did not also differ at the end of Expt. III. It was concluded that although sexual activity was more intense under this artificial LP, independently of the previous photoperiod, cyclicity and ovulation were maintained under a SP.

As health awareness grows, more people are turning to weight loss-yet excessive slimming or dietary imbalance is quietly triggering a wave of fertility problems. Researches show that low BMI or excessive exercise can negatively impact fertility, but its specific cellular mechanism remain unclear. In this study, we investigated how adipose tissue influences ovarian function under energy-restricted conditions by establishing a peri-ovarian adipose tissue (POAT) removal mouse model. We showed that POAT removal resulted in a significant decrease in litter size, impaired follicle development, and an increased apoptosis rate in granulosa cells (GCs). Additionally, the lipid droplets (LDs) content in the ovaries and GCs was significantly reduced. We also observed that Rab14 expression was upregulated in GCs after POAT removal. Functional experiments further showed that Rab14 overexpression significantly enhanced lipophagy activity, reduced the number and volume of LDs, and inhibited the expression of lipid droplet protein PLIN2. Meanwhile, Rab14 overexpression inhibited the phosphorylation level of AKT and induced the apoptosis of granulosa cells, suggesting that Rab14 may activate the cell death pathway mediated by lipophagy. Taken together, POAT may support ovarian function by maintaining lipid homeostasis within GCs. The role of Rab14 in the regulation of lipophagy may link local adipose-derived signaling with GCs survival and female fertility.

Objective: Accumulating evidence demonstrates that melatonin is involved in modulating granulosa cell function and follicular development. lncRNAs (long non-coding RNAs) and circRNAs (circular RNAs) have been reported to participate in multiple biological processes. This study aimed to explore the candidate circRNAs and lncRNAs related to molecular mechanisms when exploring the role of melatonin in regulating ovarian function. Methods: Bovine ovary granulosa cells were collected 48 h after treatment with melatonin at 10−7 M. The lncRNA and circRNA profiles of bovine granulosa cells were further explored using high-throughput sequencing in the absence/presence of melatonin. The differentially expressed lncRNAs and circRNAs were analyzed through the annotation information of source transcripts for GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes). Results: We identified 99 differentially expressed lncRNAs and 28 differentially expressed circRNAs. Enrichment analysis of differentially expressed lncRNAs and circRNAs showed they were enriched in multiple pathways involved in development, apoptosis, and reproductive function, such as the mTOR (mammalian Target of Rapamycin) signaling pathway, FoxO (Forkhead box O) signaling pathway, MAPK (Mitogen-Activated Protein Kinase) signaling pathway, Hippo signaling pathway, TGF-beta (Transforming Growth Factor-β) signaling pathway, PI3K-Akt (Phosphatidylinositol 3-Kinase-Akt) signaling pathway, apoptosis, and Rap1 (Ras-related protein 1), most of which were mainly related to granulosa cell function and the crosstalk between granulosa cells and oocytes. The present analysis indicated the potential role of melatonin in granulosa cell function by regulating lncRNA and circRNA expression and, thus, mediating follicular development. An lncRNA/circRNA and miRNA regulatory network was also constructed to take their interactions into account. Conclusions: Our study offers details of lncRNA and circRNA expression in bovine granulosa cells and further provides insight into the potential role of melatonin in regulating reproduction by modulating lncRNA and circRNA expression.

Sickle cell anaemia (SCA), the most common monogenic disorder, affects 20-25million people globally and is prevalent in Sub-Saharan Africa, especially Nigeria, where the prevalence is 1-3%. Beyond its haematological complications, SCA is associated with chronic anaemia and oxidative stress, which may adversely affect ovarian function; however, this relationship remains poorly understood. This study aimed to evaluate ovarian reserve in women with SCA using Anti-Mullerian Hormone (AMH) and Antral Follicle Count (AFC) and assess the role of oxidative stress. This was a comparative cross-sectional study, conducted at Lagos State University Teaching Hospital, over a 6-month period, in which 75 women with SCA (HbSS) in a steady/stable clinical state and 75 age-matched women with normal haemoglobin genotype (HbAA), were consecutively recruited. Relevant data was collected with the aid of interviewer-administered structured questionnaires. The study participants had their body mass index (BMI), venous blood AMH levels and oxidative stress markers (superoxide dismutase, glutathione peroxidase and malondialdehyde) levels, and transvaginal ultrasound for AFC assessed according to standard. Women aged < 18 or > 45 years and women on antioxidant medications were excluded. Data were analyzed using relevant inferential statistics with significance level set at 0.05%. HbSS participants had significantly lower median AMH (1.52 ng/ml, IQR 1.0-2.1) and AFC (12.0, IQR 9.0-13.0) compared to the HbAA group (AMH 3.80 ng/ml, IQR 2.7-7.8; AFC 15.0, IQR 12.0-16.0; p < 0.001 for both). Age showed a significant negative correlation with AMH and AFC in HbSS women (r = -0.301, p = 0.010; r = -0.360, p = 0.001). Superoxide dismutase levels were significantly reduced in the HbSS group (median 1.50 vs. 2.00 nmol/ml, p < 0.001), while glutathione peroxidase and malondialdehyde levels did not differ significantly. BMI and parity also differed, with HbSS women more likely to be underweight and nulliparous. Women with HbSS exhibited significantly lower ovarian reserve markers and altered oxidative stress profiles compared to their HbAA counterparts, with age emerging as a key determinant of ovarian reserve in HbSS. Within the oxidative stress parameters assessed, no significant correlation with ovarian reserve markers was observed. These findings suggest that other disease-related factors, beyond the oxidative stress indices measured in this study, may contribute to ovarian dysfunction in SCA.

Comparison of suboptimal versus adequate ovarian function suppression in premenopausal women with early breast cancer treated with adjuvant endocrine therapy: An exploratory analysis of two prospective studies.

Premature ovarian insufficiency (POI) impacts ~1-3.7% of women under the age of 40 globally and is characterised by an absence or complete loss of ovarian function. POI is clinically heterogenous in nature and researchers have identified >100 causative genes harbouring variants responsible for POI thus far. Genes identified to date include those associated with cell differentiation/development, mitochondrial maintenance, hormone receptors, transcription/translation factors, DNA repair/replication, and metabolic processes. Genes encoding cell components that facilitate these processes should therefore also be considered in POI gene candidature. The RNA exosome is a critical component in RNA processing, degradation, and biogenesis in eukaryotic cells. Catalytic activity of the RNA exosome is supplied by two subunits, DIS3 and EXOSC10. Dysregulation of RNA exosome function results in conditions known as exosomopathies that have a broad spectrum of phenotypic severity. RNA transcript regulation is essential in transcriptionally inactive maturing mammalian oocytes with its disruption negatively impacting meiosis and fertilization. Notably, oocyte depletion of Exosc10 significantly impacts the fertility of female mice. Herein we identified, via whole exome sequencing, the first instance of a human POI patient with an EXOSC10 homozygous missense variant. Using Drosophila melanogaster we modelled the impact of knockdown of the EXOSC10 ortholog, Rrp6, on both somatic and germline ovarian cells. We observed that Rrp6 is required in ovarian development in Drosophila. Due to the conserved role of EXOSC10 in fertility maintenance across species we contend that variants in EXOSC10 identified in POI patients may be causative.

Guilu Erxian Glue combined with Wuzi Yanzong Pill attenuates granulosa cell apoptosis and ameliorates cyclophosphamide-induced diminished ovarian reserve via the lncRNA NEAT1/miR-204-5p/ESR1 axis.

Introduction Adjuvant endocrine therapy for hormone receptor–positive, human epidermal growth factor receptor 2–negative (HR+/HER2−) breast cancer improves survival but may worsen cardiometabolic health; the cardiovascular impact of aromatase inhibitor plus ovarian function suppression (AI+OFS) in premenopausal women remains unclear. We compared endocrine regimens on subclinical atherosclerosis and 24-month lipid trajectories and explored potential modulatory effects of Sanhuang Decoction (SHD). Methods In this retrospective cohort of 280 HR+/HER2− patients, initial endocrine therapy was AI+OFS (n = 95), tamoxifen (TAM; n = 141), or TAM+OFS (n = 44). Lipid profiles (total cholesterol, triglycerides, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C]) were analyzed using mixed-effects models adjusted for cardiometabolic and treatment covariates. New-onset or worsening fatty liver, new-onset carotid plaque, and initiation of lipid-lowering therapy were evaluated with Kaplan–Meier and Cox models. Results In adjusted mixed-effects models, AI+OFS versus TAM was associated with higher LDL-C (β 0.088 mmol/L; 95% confidence interval [CI] 0.013–0.163) and lower HDL-C (β −0.046 mmol/L; 95% CI −0.090 to −0.003), whereas total cholesterol and triglycerides did not differ between regimens. Incidences of fatty liver, carotid plaque, and initiation of lipid-lowering therapy varied across groups, but most adjusted Cox models showed no significant regimen effects. AI+OFS showed a trend toward a higher hazard of new-onset carotid plaque versus TAM (hazard ratio [HR] 3.09; 95% CI 0.96–9.93), and higher baseline glycated hemoglobin predicted earlier initiation of lipid-lowering therapy (HR 2.54; 95% CI 1.29–4.99). In exploratory interaction analyses, among SHD users TAM+OFS versus TAM was associated with lower LDL-C and total cholesterol, whereas in AI+OFS versus TAM SHD use was associated with lower HDL-C. Conclusion In premenopausal women with HR+/HER2− breast cancer, AI+OFS was associated with an adverse lipid profile and a possible increase in carotid plaque compared with TAM-based regimens. Regimen-dependent associations between SHD and lipid profiles support individualized cardiovascular monitoring and cautious use of adjunctive SHD in this population.