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The use of next-generation sequencing (NGS) has recently enabled the discovery of genetic causes of primary ovarian insufficiency (POI) with high genetic heterogeneity. In contrast, the causes of diminished ovarian reserve (DOR) remain poorly understood. Here, we identified by NGS and whole exome sequencing (WES) the cause of isolated DOR in a 14-year-old patient. Two frameshift mutations in BRCA1 (NM_007294.4) were found: in exon 8 (c.470_471del; p.Ser157Ter) and in exon 11 (c.791_794del, p.Ser264MetfsTer33). Unexpectedly, the patient presented no signs of Fanconi anemia (FA), i.e., no developmental abnormalities or indications of bone marrow failure. However, high chromosomal fragility was found in the patient's cells, consistent with an FA diagnosis. RT-PCR and Western-blot analysis support the fact that the c. 791_794del BRCA1 allele is transcribed and translated into a shorter protein (del11q), while no expression of the full-length BRCA1 protein was found. DNA damage response (DDR) studies after genotoxic agents demonstrate normal activation of the early stages of the DDR and FANC/BRCA pathway. This is consistent with the maintenance of residual repair activity for the del11q BRCA1 isoform. Our observation is the first implication of bi-allelic BRCA1 mutations in isolated ovarian dysfunction or infertility in humans, without clinical signs of FA, and highlights the importance of BRCA1 in ovarian development and function. [ABSTRACT FROM AUTHOR]

Diminished ovarian reserve (DOR) and primary ovarian insufficiency (POI) are major causes of female infertility. We recently found a monogenic etiology in 29.3% of POI, leading to personalized medicine. The genetic landscape of DOR is unknown. A prospective study (2018–2023) of an international cohort of 120 patients with unexplained DOR was performed using a large custom targeted next-generation sequencing panel including all known POI-causing genes. The diagnostic yield, based on the American College of Medical Genetics, was 24, 2%. Genes belong to different pathways: metabolism and mitochondria (29.7%), follicular growth (24.3%), DNA repair/meiosis (18.9%), aging (16.2%), ovarian development (8.1%), and autophagy (2.7%). Five genes were recurrently found: LMNA, ERCC6, SOX8, POLG, and BMPR1B. Six genes identified in single families with POI were involved in DOR, GNAS, TGFBR3, XPNPEP2, EXO1, BNC1, ATG, highlighting their role in maintaining ovarian reserve. In our cohort, 26 pregnancies were recorded, but no pregnancy was observed when meiosis/DNA repair genes were involved, suggesting severely impaired oocyte quality. Additional studies should confirm these preliminary results. This study with a large NGS panel defines the genetic landscape of a large cohort of DOR. It supports routine genetic diagnosis. Genetics could be a biomarker predicting infertility and progression to POI. [ABSTRACT FROM AUTHOR]

In adolescent gynaecology clinic, we can encounter conditions that solely occur at this specific time in development and that we otherwise do not come across in other aspects of our working life. Though a patient may present with a 'menstrual disorder', this may well be the first manifestation of an endocrine disease or underlying congenital abnormality. When caring for adolescent gynaecology patients, it is essential we are alert to these possibilities, equipped with the specific knowledge pertaining to this patient group and that we investigate diligently so as not to miss a potentially serious condition. This article comprises key learning points for important adolescent gynaecology conditions including genital tract anomalies such as Mayer-Rokitansky-Kuster-Hauser and OHVIRA (obstructed hemivagina, ipsilateral renal anomalies) syndromes, genetic conditions such as Turner's syndrome, endocrine disorders such as androgen insensitivity and congenital adrenal hyperplasia, as well as abnormal uterine bleeding, primary ovarian insufficiency and polycystic ovarian syndrome. [ABSTRACT FROM AUTHOR]

Background: Primary ovarian insufficiency (POI) manifests with hormonal imbalances, menstrual irregularities, follicle loss, and infertility. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are emerging as a promising treatment for POI. This systematic review aims to assess the effects of MSC-EVs on follicle number, hormonal profile, and fertility in POI animal models. Methods: A systematic search of PubMed, Scopus, and Web of Science databases up to December 14th, 2023 was conducted. Two reviewers independently conducted screening, risk of bias assessment, and data extraction. Meta-analysis was performed to analyze treatment versus control outcomes using a random effects model. Publication bias was assessed using Egger's regression test and sensitivity analysis was assessed using the leave-one-out method. Subgroup analyses and meta-regressions were conducted based on EV source, induction model, type of animal, study quality, administration route, administration frequency and route, and dose. Results: a total of 29 studies were included. MSC-EVs treatment significantly increased total follicle count (SMD, (95CI), p-value; 3.56, (0.91, 6.21), < 0.001), including primordial (SMD, (95CI), p-value; 2.86, (1.60, 4.12), < 0.001), primary (SMD, (95CI), p-value; 3.17, (2.28, 4.06), < 0.001), mature (SMD, (95CI), p-value; 2.26, (1.02, 3.50), < 0.001), and antral follicles (SMD, (95CI), p-value; 2.44, (1.21, 3.67), < 0.001). Administration frequency and route did not affect this outcome, but EV source affected primordial, primary, secondary and antral follicle count. Additionally, MSC-EVs treatment elevated anti-müllerian hormone (SMD, (95CI); 3.36, (2.14, 4.58)) and estradiol (SMD, (95CI); 3.19, (2.20, 4.17)) levels while reducing follicle stimulating hormone levels (SMD, (95CI); -2.68, (-4.42, -0.94)). Unlike EV source, which had a significant impact on all three hormones, administration frequency, route, and EV dose did not affect this outcome. Moreover, treatment increased offspring number (SMD, (95CI); 3.70, (2.17, 5.23)) and pregnancy odds (OR, (95CI); 10.25, (4.29, 24.46)) compared to controls. Publication bias and a high level of heterogeneity was evident in all analyses, except for the analysis of the pregnancy odds. However, sensitivity analysis indicated that all of the analyses were stable. Conclusion: MSC-EVs therapy shows promise for POI treatment, potentially facilitating clinical translation. However, Further research is warranted to optimize methodology and assess side effects. [ABSTRACT FROM AUTHOR]

Background: Primary ovarian insufficiency (POI) is an early decline in ovarian function that leads to ovarian failure. Conventional treatments for POI are inadequate, and treatments based on mesenchymal stem cells (MSCs) have emerged as an option. However, the lack of consideration of the estrogen niche in ovarian tissue significantly reduces the therapeutic efficacy, with an unclear mechanism in the MSCs in POI treatment. Furthermore, the disruption of circadian rhythm associated with POI has not been previously addressed. Methods: Conditioned medium (CM) and estradiol-conditioned medium (E2-CM) were generated from estrogen receptor positive MSCs (ER+pcMSCs). Chemotherapy-induced POI models were established using C57BL/6 mice (in vivo) and KGN cells (in vitro) treated with cyclophosphamide (CTX) or 4-hydroperoxycyclophosphamide (4-OOH-CP). Gene/protein expressions were detected using RT-qPCR, Western blotting, and immunohistochemistry assays. Locomotor activity was monitored for behavioral circadian rhythmicity. Cytokine arrays and miRNA analysis were conducted to analyze potential factors within CM/E2-CM. Results: The secretome of ER+pcMSCs (CM and E2-CM) significantly reduced the CTX-induced defects in ovarian folliculogenesis and circadian rhythm. CM/E2-CM also reduced granulosa cell apoptosis and rescued angiogenesis in POI ovarian tissues. E2-CM had a more favorable effect than the CM. Notably, ER+pcMSC secretome restored CTX-induced circadian rhythm defects, including the gene expressions associated with the ovarian circadian clock (e.g., Rora, E4bp4, Rev-erbα, Per2 and Dbp) and locomotor activity. Additionally, the cytokine array analysis revealed a significant increase in cytokines and growth factors associated with immunomodulation and angiogenesis, including angiogenin. Neutralizing the angiogenin in CM/E2-CM significantly reduced its ability to promote HUVEC tube formation in vitro. Exosomal miRNA analysis revealed the miRNAs involved in targeting the genes associated with POI rescue (PTEN and PDCD4), apoptosis (caspase-3, BIM), estrogen synthesis (CYP19A1), ovarian clock regulation (E4BP4, REV-ERBα) and fibrosis (COL1A1). Conclusion: This study is the first to demonstrate that, in considering the estrogen niche in ovarian tissue, an estrogen-priming ER+pcMSC secretome achieved ovarian regeneration and restored the circadian rhythm in a CTX-induced POI mouse model. The potential factors involved include angiogenin and exosomal miRNAs in the ER+pcMSC secretome. These findings offer insights into potential stem cell therapies for chemotherapy-induced POI and circadian rhythm disruption. [ABSTRACT FROM AUTHOR]

Purpose: Is it safe and effective to perform controlled ovarian stimulation (COS) and oocyte retrieval (OR) in prepubertal and peripubertal patients? Methods: In this retrospective cohort study, data of 20 pre-/peripubertal patients who underwent COS and OR for the purpose of oocyte cryopreservation (OC) between 2008 and 2023 were reviewed. Following COS, all OR procedures were performed transabdominally using a vaginal ultrasound probe. Ovarian reserve was assessed by serum FSH, LH, estradiol, AMH, and antral follicle counts (AFC) in all subjects. All mature oocytes were vitrified. Results: Mean age of the patients was 15.05 ± 1.87, mean AMH was 0.84 ± 0.8 ng/ml, mean FSH was 6.39 ± 3.95 IU/L, mean estradiol was 61.6 ± 51.9 pg/ml, mean LH was 4.69 ± 3.46 IU/L, and mean AFC was 5.5 ± 5.82. Among the patients, 12 had regular menstrual cycle, 5 had irregular menstrual cycle, whereas 3 patients still did not have their menarche yet. The indications for OC were as follows: primary ovarian insufficiency (n = 7), ovarian surgery for ovarian tumors (n = 5) or ovarian torsion (n = 1), mosaic Turner syndrome (n = 2), acute lymphoblastic leukemia (n = 1) anaplastic B-cell lymphoma (n = 1), Ewing's sarcoma (n = 1), Noonan syndrome (n = 1), and Thalassemia (n = 1). The mean number of oocytes retrieved, MII oocytes frozen, and maturation rate were 5.11 ± 5.0, 3.92 ± 4.48, and 75.1 ± 25.6%, respectively. Stepwise linear regression analysis demonstrated a positive correlation between AFC and number of total oocytes retrieved and number of MII oocytes. In the case diagnosed with Noonan syndrome, all 7 retrieved oocytes were MI and all frozen at MI phase. No patient had any complication related to COS or OR. Conclusion: Even though number of the enrolled subjects is limited and mean AMH is lower in our cohort, we demonstrated that performing COS and OR is safe in pre-/peripubertal patients. If required, transabdominal route can be performed in this age group for OR. AFC appears as a prognostic factor for stimulation outcome in this age group. Pediatric patients or young adolescents at risk for primary ovarian insufficiency should not be discouraged from utilizing OC. [ABSTRACT FROM AUTHOR]

Background: Primary ovarian insufficiency (POI) is a disorder characterized by the premature decline in ovarian function, leading to significant fertility and health impacts on women under 40. The unclear etiology of POI hinders the development of effective treatments, highlighting the need for novel therapeutic targets. Methods: This study employed genome-wide association analysis (GWAS) integrated with expression quantitative trait loci (eQTL) data from the GTEx and eQTLGen databases. Mendelian randomization (MR) and colocalization analyses were conducted to investigate causal relationships between genetic variants and POI and to identify potential therapeutic targets. Results: We identified 431 genes with available index cis-eQTL signals, of which four (HM13, FANCE, RAB2A, and MLLT10) were significantly associated with POI. Colocalization analysis revealed strong evidence for FANCE and RAB2A, indicating their potential as therapeutic targets. Subsequent druggability assessments identified FANCE and RAB2A as promising candidates for POI treatment, supported by their involvement in DNA repair and autophagy regulation, respectively. Conclusions: Our study establishes a causal link between specific genes and POI, highlighting FANCE and RAB2A as potential drug targets. These findings provide a foundation for future research and therapeutic development, aiming to improve outcomes for women with POI. Validation in further trials is necessary to confirm these potential targets. [ABSTRACT FROM AUTHOR]

Background: Primary ovarian insufficiency (POI) is one of the leading female infertility diseases in which ovarian function stops before the age of 40. Reports that POI is associated with transforming growth factor (TGF)-β/bone morphogenetic protein (BMP) signaling pathway–associated genes (e.g., TGF-β, and BMP15) have been continuous since publication that the TGF-β superfamily acts as important regulators for ovary and placenta function in humans. Mechanistically, the secretion of follicle-stimulating hormone, progesterone, and estrogen is affected by the TGF-β superfamily in granulosa cells, which are involved in the development of theca cells, oocytes, and granulosa cells. Objective: This study aimed to identify the association between genes related to the TGF-β/BMP signaling pathway and the risk of POI pathogenesis. Methods: Possible associations between six gene polymorphisms and POI susceptibility were examined in 139 patients with POI and 345 control subjects. Results: Allele combination of TGFBR1 rs334348 G > A and TGFBR3 rs1805110G > A exhibited association with decreased POI risk (adjusted odds ratio [AOR] = 0.165; 95% confidence interval [CI] 0.032–0.847; P = 0.031). Also, TGFBR1 rs1590 G > T and rs334348 G > A and TGFBR3 rs1805110 G > A allele combination exhibited association with decreased POI risk (OR = 0.553; 95% CI 0.374–0.816; P = 0.003). Conclusion: This study suggests that polymorphisms in the TGF-β signaling pathway genes can be useful biomarkers for POI diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Abstract Background Primary ovarian insufficiency (POI) manifests with hormonal imbalances, menstrual irregularities, follicle loss, and infertility. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are emerging as a promising treatment for POI. This systematic review aims to assess the effects of MSC-EVs on follicle number, hormonal profile, and fertility in POI animal models. Methods A systematic search of PubMed, Scopus, and Web of Science databases up to December 14th, 2023 was conducted. Two reviewers independently conducted screening, risk of bias assessment, and data extraction. Meta-analysis was performed to analyze treatment versus control outcomes using a random effects model. Publication bias was assessed using Egger’s regression test and sensitivity analysis was assessed using the leave-one-out method. Subgroup analyses and meta-regressions were conducted based on EV source, induction model, type of animal, study quality, administration route, administration frequency and route, and dose. Results a total of 29 studies were included. MSC-EVs treatment significantly increased total follicle count (SMD, (95CI), p-value; 3.56, (0.91, 6.21),

Abstract Background Primary ovarian insufficiency (POI) is an early decline in ovarian function that leads to ovarian failure. Conventional treatments for POI are inadequate, and treatments based on mesenchymal stem cells (MSCs) have emerged as an option. However, the lack of consideration of the estrogen niche in ovarian tissue significantly reduces the therapeutic efficacy, with an unclear mechanism in the MSCs in POI treatment. Furthermore, the disruption of circadian rhythm associated with POI has not been previously addressed. Methods Conditioned medium (CM) and estradiol-conditioned medium (E2-CM) were generated from estrogen receptor positive MSCs (ER+pcMSCs). Chemotherapy-induced POI models were established using C57BL/6 mice (in vivo) and KGN cells (in vitro) treated with cyclophosphamide (CTX) or 4-hydroperoxycyclophosphamide (4-OOH-CP). Gene/protein expressions were detected using RT-qPCR, Western blotting, and immunohistochemistry assays. Locomotor activity was monitored for behavioral circadian rhythmicity. Cytokine arrays and miRNA analysis were conducted to analyze potential factors within CM/E2-CM. Results The secretome of ER+pcMSCs (CM and E2-CM) significantly reduced the CTX-induced defects in ovarian folliculogenesis and circadian rhythm. CM/E2-CM also reduced granulosa cell apoptosis and rescued angiogenesis in POI ovarian tissues. E2-CM had a more favorable effect than the CM. Notably, ER+pcMSC secretome restored CTX-induced circadian rhythm defects, including the gene expressions associated with the ovarian circadian clock (e.g., Rora, E4bp4, Rev-erbα, Per2 and Dbp) and locomotor activity. Additionally, the cytokine array analysis revealed a significant increase in cytokines and growth factors associated with immunomodulation and angiogenesis, including angiogenin. Neutralizing the angiogenin in CM/E2-CM significantly reduced its ability to promote HUVEC tube formation in vitro. Exosomal miRNA analysis revealed the miRNAs involved in targeting the genes associated with POI rescue (PTEN and PDCD4), apoptosis (caspase-3, BIM), estrogen synthesis (CYP19A1), ovarian clock regulation (E4BP4, REV-ERBα) and fibrosis (COL1A1). Conclusion This study is the first to demonstrate that, in considering the estrogen niche in ovarian tissue, an estrogen-priming ER+pcMSC secretome achieved ovarian regeneration and restored the circadian rhythm in a CTX-induced POI mouse model. The potential factors involved include angiogenin and exosomal miRNAs in the ER+pcMSC secretome. These findings offer insights into potential stem cell therapies for chemotherapy-induced POI and circadian rhythm disruption.

Abstract Background Primary ovarian insufficiency (POI) is a disorder characterized by the premature decline in ovarian function, leading to significant fertility and health impacts on women under 40. The unclear etiology of POI hinders the development of effective treatments, highlighting the need for novel therapeutic targets. Methods This study employed genome-wide association analysis (GWAS) integrated with expression quantitative trait loci (eQTL) data from the GTEx and eQTLGen databases. Mendelian randomization (MR) and colocalization analyses were conducted to investigate causal relationships between genetic variants and POI and to identify potential therapeutic targets. Results We identified 431 genes with available index cis-eQTL signals, of which four (HM13, FANCE, RAB2A, and MLLT10) were significantly associated with POI. Colocalization analysis revealed strong evidence for FANCE and RAB2A, indicating their potential as therapeutic targets. Subsequent druggability assessments identified FANCE and RAB2A as promising candidates for POI treatment, supported by their involvement in DNA repair and autophagy regulation, respectively. Conclusions Our study establishes a causal link between specific genes and POI, highlighting FANCE and RAB2A as potential drug targets. These findings provide a foundation for future research and therapeutic development, aiming to improve outcomes for women with POI. Validation in further trials is necessary to confirm these potential targets.

Abstract Background Accumulating studies have highlighted the significant role of circulating metabolomics in the etiology of reproductive system disorders. However, the causal effects between genetically determined metabolites (GDMs) and reproductive diseases, including primary ovarian insufficiency (POI), polycystic ovary syndrome (PCOS), and abnormal spermatozoa (AS), still await thorough clarification. Methods With the currently most comprehensive genome-wide association studies (GWAS) data of metabolomics, systematic two-sample Mendelian randomization (MR) analyses were conducted to disclose causal associations between 1,091 blood metabolites and 309 metabolite ratios with reproductive disorders. The inverse-variance weighted (IVW) method served as the primary analysis approach, and multiple effective MR methods were employed as complementary analyses including MR-Egger, weighted median, constrained maximum likelihood (cML-MA), contamination mixture method, robust adjusted profile score (MR-RAPS), and debiased inverse-variance weighted method. Heterogeneity and pleiotropy were assessed via MR-Egger intercept and Cochran’s Q statistical analysis. Outliers were detected by Radial MR and MR-PRESSO methods. External replication and metabolic pathway analysis were also conducted. Results Potential causal associations of 63 GDMs with POI were unearthed, and five metabolites with strong causal links to POI were emphasized. Two metabolic pathways related to the pathogenesis of POI were pinpointed. Suggestive causal effects of 70 GDMs on PCOS were detected, among which 7 metabolites stood out for strong causality with elevated PCOS risk. Four metabolic pathways associated with PCOS mechanisms were recognized. For AS, 64 GDMs as potential predictive biomarkers were identified, particularly highlighting two metabolites for their strong causal connections with AS. Three pathways underneath the AS mechanism were identified. Multiple assessments were conducted to further confirm the reliability and robustness of our causal inferences. Conclusion By extensively assessing the causal implications of circulating GDMs on reproductive system disorders, our study underscores the intricate and pivotal role of metabolomics in reproductive ill-health, laying a theoretical foundation for clinical strategies from metabolic insights.

Primary ovarian insufficiency (POI) is the development of primary hypogonadism before the age of 40 years in women with normal karyotypes. Patients present with symptoms that are similar to those of menopause, including irregular periods, reduced fertility, and climacteric symptoms due to hypoestrogenism, such as hot flashes, vaginal dryness, dyspareunia, irritability, and night sweats. The incidence of spontaneous POI is approximately 1 in 250 by 35 years of age and 1 in 100 by 40 years of age. Genetic, inflammatory, metabolic, autoimmune, and idiopathic factors contribute to POI. POI pathophysiology is explained by the presence of fewer primordial follicles and their rapid degeneration. Detailed history and examination are important for diagnosis. Diagnosis requires biochemical evidence and laboratory testing, including measurements of follicle-stimulating hormone, thyroid-stimulating hormone, prolactin, and estradiol (E2) levels. In addition, transvaginal ultrasound is preferred to evaluate ovarian reserve. POI should be managed through a multidisciplinary approach involving gynecologists, endocrinologists, and psychologists. Hormonal replacement therapy is the mainstay treatment for all women with POI. Lifestyle modifications such as weight-bearing exercises, smoking cessation, and Vitamin D and calcium supplementation are highly recommended to improve bone density and reduce fractures. Psychological care has been suggested to improve self-esteem and social support, along with family planning guidance. Despite recent discoveries, additional screening techniques are needed.

Primordial follicles (PFs) function as the long‐term reserve for female reproduction, remaining dormant in the ovaries and becoming progressively depleted with age. Oxidative stress plays an important role in promoting female reproductive senescence during aging, but the underlying mechanisms remain unclear. Here, we find that low levels of reactive oxygen species (ROS) are essential for sustaining PF dormancy. Compared to growing follicles, oocytes within PFs were shown to be more susceptible to ROS, which accumulates and damages PFs to promote reproductive senescence. Mechanistically, oocytes within PFs were shown to express high levels of the intracellular antioxidant enzyme superoxide dismutase 1 (SOD1), counteracting ROS accumulation. Decreased SOD1 expression, as a result of aging or through the experimental deletion of the Sod1 gene in oocytes, resulted in increased oxidative stress and triggered ferroptosis within PFs. In conclusion, this study identified antioxidant defense mechanisms protecting PFs in mouse ovaries and characterized cell death mechanisms of oxidative stress‐induced PF death. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate if adipose-derived stromal vascular fraction (SVF) treatment has any protective effect on ovarian function in rats with cyclophosphamide (CP) induced ovarian damage. Design: This was an experimental animal study. Participants/Materials, Setting, Methods: 25 mature cycling Wistar-Albino rats were randomized into four groups (n = 5 per group). Rats in groups 1 and 2 received single dose of intraperitoneal (i.p.) 1 mL/kg sodium chloride 0.9% (NaCl). Groups 3 and 4 received single dose of 75 mg/kg i.p. CP. On seventh day, SVF was prepared from adipose tissues of 5 additional rats and groups 1 and 3 received 0.9% NaCl i.p. injections while groups 2 and 4 received 0.2 mL i.p. injections of SVF. On day 21 all rats were euthanized, and serum anti-mullerian hormone (AMH) levels, primordial, primary, secondary, antral, and atretic follicle counts, AMH positive staining follicle counts along with AMH staining intensity of the follicles were evaluated. Results: Among two CP induced ovarian damaged groups, SVF treated group showed significantly higher secondary and antral follicle and lower atretic follicle counts, significantly higher mean serum AMH levels, AMH positive antral follicle count and higher intensity of AMH positive follicle scores for primary, secondary, and antral follicles when compared to untreated group. Moreover, group 1 showed no significant difference for all parameters except antral follicle count and AMH positive staining intensity scores for antral follicles when compared to group 4. Limitations: This study was conducted on experimental rat model. Conclusion: Our study demonstrated a significant protective effect of SVF against CP-induced ovarian damage which reveals the apparent need for further investigation of its precise mechanisms of action as it may provide a new treatment approach for women with premature ovarian failure. [ABSTRACT FROM AUTHOR]

Background: Accumulating studies have highlighted the significant role of circulating metabolomics in the etiology of reproductive system disorders. However, the causal effects between genetically determined metabolites (GDMs) and reproductive diseases, including primary ovarian insufficiency (POI), polycystic ovary syndrome (PCOS), and abnormal spermatozoa (AS), still await thorough clarification. Methods: With the currently most comprehensive genome-wide association studies (GWAS) data of metabolomics, systematic two-sample Mendelian randomization (MR) analyses were conducted to disclose causal associations between 1,091 blood metabolites and 309 metabolite ratios with reproductive disorders. The inverse-variance weighted (IVW) method served as the primary analysis approach, and multiple effective MR methods were employed as complementary analyses including MR-Egger, weighted median, constrained maximum likelihood (cML-MA), contamination mixture method, robust adjusted profile score (MR-RAPS), and debiased inverse-variance weighted method. Heterogeneity and pleiotropy were assessed via MR-Egger intercept and Cochran's Q statistical analysis. Outliers were detected by Radial MR and MR-PRESSO methods. External replication and metabolic pathway analysis were also conducted. Results: Potential causal associations of 63 GDMs with POI were unearthed, and five metabolites with strong causal links to POI were emphasized. Two metabolic pathways related to the pathogenesis of POI were pinpointed. Suggestive causal effects of 70 GDMs on PCOS were detected, among which 7 metabolites stood out for strong causality with elevated PCOS risk. Four metabolic pathways associated with PCOS mechanisms were recognized. For AS, 64 GDMs as potential predictive biomarkers were identified, particularly highlighting two metabolites for their strong causal connections with AS. Three pathways underneath the AS mechanism were identified. Multiple assessments were conducted to further confirm the reliability and robustness of our causal inferences. Conclusion: By extensively assessing the causal implications of circulating GDMs on reproductive system disorders, our study underscores the intricate and pivotal role of metabolomics in reproductive ill-health, laying a theoretical foundation for clinical strategies from metabolic insights. [ABSTRACT FROM AUTHOR]

Purpose: Oocytes from women presenting primary ovarian insufficiency (POI) generate viable embryos at a lower rate than non-POI women, but the mechanisms responsible for the lower oocyte quality remain elusive. Due to the scarcity of human oocytes for research, animal models provide a promising way forward. We aimed at investigating the molecular events characterizing final maturation in POI oocytes in a well-defined POI-like bovine model. Methods: Single-cell RNA-sequencing of bovine control and POI-like, GV, and MII oocytes (n = 5 per group) was performed. DEseq2 was used to identify differentially expressed genes. Further, a Gene set enrichment analysis and a transcriptomic meta-analysis between bovine and human oocytes were performed. Results: In control cows, we found 2223 differentially expressed genes between the GV and MII stages. Specifically, the affected genes were related to RNA processing and transport, protein synthesis, organelle remodeling and reorganization, and metabolism. The meta-analysis with a set of young human oocytes at different maturation stages revealed 315 conserved genes through the GV-MII transition in cows and humans, mostly related to meiotic progression and cell cycle. Gene expression analysis between GV and MII of POI-like oocytes showed no differences in terms of differentially expressed genes, pointing towards a substantial failure to properly remodel the transcriptome in the POI model, and with the clustering analysis indicating that the cow's genetic background had a higher impact than the oocyte's maturation stage. Conclusion: Overall, we have identified and characterized a valuable animal model of POI, paving the way to identifying new molecular mechanisms involved in POI. [ABSTRACT FROM AUTHOR]

Per- and polyfluoroalkyl substances (PFASs) are a class of anthropogenic organic compounds widely present in the natural and human living environments. These emerging persistent pollutants can enter the human body through multiple channels, posing risks to human health. In particular, exposure to PFASs in women may cause a series of reproductive health hazards and infertility. Based on a review of the existing literature, this study preliminarily summarizes the effects of PFAS exposure on the occurrence and development of female reproductive endocrine diseases, such as polycystic ovary syndrome (PCOS), endometriosis, primary ovarian insufficiency (POI), and diminished ovarian reserve (DOR). Furthermore, we outline the relevant mechanisms through which PFASs interfere with the physiological function of the female ovary and finally highlight the role played by nutrients in reducing the reproductive health hazards caused by PFASs. It is worth noting that the physiological mechanisms of PFASs in the above diseases are still unclear. Therefore, it is necessary to further study the molecular mechanisms of PFASs in female reproductive diseases and the role of nutrients in this process. [ABSTRACT FROM AUTHOR]

STUDY QUESTION What is the effect of the chemical in vitro activation (cIVA) protocol compared with fragmentation only (Frag, also known as mechanical IVA) on gene expression, follicle activation and growth in human ovarian tissue in vitro ? SUMMARY ANSWER Although histological assessment shows that cIVA significantly increases follicle survival and growth compared to Frag, both protocols stimulate extensive and nearly identical transcriptomic changes in cultured tissue compared to freshly collected ovarian tissue, including marked changes in energy metabolism and inflammatory responses. WHAT IS KNOWN ALREADY Treatments based on cIVA of the phosphatase and tensin homolog (PTEN)-phosphatidylinositol 3-kinase (PI3K) pathway in ovarian tissue followed by auto-transplantation have been administered to patients with refractory premature ovarian insufficiency (POI) and resulted in live births. However, comparable effects with mere tissue fragmentation have been shown, questioning the added value of chemical stimulation that could potentially activate oncogenic responses. STUDY DESIGN, SIZE, DURATION Fifty-nine ovarian cortical biopsies were obtained from consenting women undergoing elective caesarean section (C-section). The samples were fragmented for culture studies. Half of the fragments were exposed to bpV (HOpic)+740Y-P (Frag+cIVA group) during the first 24 h of culture, while the other half were cultured with medium only (Frag group). Subsequently, both groups were cultured with medium only for an additional 6 days. Tissue and media samples were collected for histological, transcriptomic, steroid hormone, and cytokine/chemokine analyses at various time points. PARTICIPANTS/MATERIALS, SETTING, METHODS Effects on follicles were evaluated by counting and scoring serial sections stained with hematoxylin and eosin before and after the 7-day culture. Follicle function was assessed by quantification of steroids by ultra-performance liquid chromatography tandem-mass spectrometry at different time points. Cytokines and chemokines were measured by multiplex assay. Transcriptomic effects were measured by RNA-sequencing (RNA-seq) of the tissue after the initial 24-h culture. Selected differentially expressed genes (DEGs) were validated by quantitative PCR and immunofluorescence in cultured ovarian tissue as well as in KGN cell (human ovarian granulosa-like tumor cell line) culture experiments. MAIN RESULTS AND THE ROLE OF CHANCE Compared to the Frag group, the Frag+cIVA group exhibited a significantly higher follicle survival rate, increased numbers of secondary follicles, and larger follicle sizes. Additionally, the tissue in the Frag+cIVA group produced less dehydroepiandrosterone compared to Frag. Cytokine measurement showed a strong inflammatory response at the start of the culture in both groups. The RNA-seq data revealed modest differences between the Frag+cIVA and Frag groups, with only 164 DEGs identified using a relaxed cut-off of false discovery rate (FDR) <0.1. Apart from the expected PI3K–protein kinase B (Akt) pathway, cIVA also regulated pathways related to hypoxia, cytokines, and inflammation. In comparison to freshly collected ovarian tissue, gene expression in general was markedly affected in both the Frag+cIVA and Frag groups, with a total of 3119 and 2900 DEGs identified (FDR < 0.001), respectively. The top enriched gene sets in both groups included several pathways known to modulate follicle growth such as mammalian target of rapamycin (mTOR)C1 signaling. Significant changes compared to fresh tissue were also observed in the expression of genes encoding for steroidogenesis enzymes and classical granulosa cell markers in both groups. Intriguingly, we discovered a profound upregulation of genes related to glycolysis and its upstream regulator in both Frag and Frag+cIVA groups, and these changes were further boosted by the cIVA treatment. Cell culture experiments confirmed glycolysis-related genes as direct targets of the cIVA drugs. In conclusion, cIVA enhances follicle growth, as expected, but the mechanisms may be more complex than PI3K–Akt–mTOR alone, and the impact on function and quality of the follicles after the culture period remains an open question. LARGE SCALE DATA Data were deposited in the GEO data base, accession number GSE234765. The code for sequencing analysis can be found in https://github.com/tialiv/IVA%5fproject. LIMITATIONS, REASONS FOR CAUTION Similar to the published IVA protocols, the first steps in our study were performed in an in vitro culture model where the ovarian tissue was isolated from the regulation of hypothalamic–pituitary–ovarian axis. Further in vivo experiments will be needed, for example in xeno-transplantation models, to explore the long-term impacts of the discovered effects. The tissue collected from patients undergoing C-section may not be comparable to tissue of patients with POI. WIDER IMPLICATIONS OF THE FINDINGS The general impact of fragmentation and short (24 h) in vitro culture on gene expression in ovarian tissue far exceeded the effects of cIVA. Yet, follicle growth was stimulated by cIVA, which may suggest effects on specific cell populations that may be diluted in bulk RNA-seq. Nevertheless, we confirmed the impact of cIVA on glycolysis using a cell culture model, suggesting impacts on cellular signaling beyond the PI3K pathway. The profound changes in inflammation and glycolysis following fragmentation and culture could contribute to follicle activation and loss in ovarian tissue culture, as well as in clinical applications, such as fertility preservation by ovarian tissue auto-transplantation. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by research grants from European Union's Horizon 2020 Research and Innovation Programme (Project ERIN No. 952516, FREIA No. 825100), Swedish Research Council VR (2020-02132), StratRegen funding from Karolinska Institutet, KI-China Scholarship Council (CSC) Programme and the Natural Science Foundation of Hunan (2022JJ40782). International Iberian Nanotechnology Laboratory Research was funded by the European Union's H2020 Project Sinfonia (857253) and SbDToolBox (NORTE-01-0145-FEDER-000047), supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund. No competing interests are declared. [ABSTRACT FROM AUTHOR]

BackgroundPrevious studies have suggested that acupuncture could improve the clinical outcomes of women with premature ovarian insufficiency (POI) and polycystic ovary syndrome (PCOS). However recent meta-analyses have provided inconclusive findings. This umbrella meta-analysis aimed to explore the effect of acupuncture therapies on PCOS and POI outcomes.MethodsA systematic literature search was carried out in in PubMed, Scopus, Web of Science, and Chinese databases, including Wan Fang Data Knowledge Service Platform, CBM, CNKI, and VIP up until April 2024 to gather relevant studies. Inclusion criteria were meta-analyses on the effect of acupuncture or combined therapies with standard medications or traditional Chinese medicine (TCM) on PCOS and POI. The outcomes were pregnancy rates, ovulation rates, hormone levels, glycemic indices, resumption of menstruation, endometrial thickness, live birth rates, abortion rates, and body mass index (BMI). Studies with irrelevant interventions, animal studies, reviews without quantitative analysis, and studies with insufficient data were excluded. Standardized mean difference (SMD) with a 95% confidence interval (CI) and relative risk (RR) with a 95% CI were used as effect sizes to pool the data using a random effects model.ResultsA total of 38 meta-analyses, 20 studies (sample size: 27,106 patients) for PCOS and 18 studies (sample size: 19,098 patients) for POI, were included. Overall, in women with PCOS, acupuncture therapies were significantly associated with a higher pregnancy rate, ovulation rate, and reduced serum levels of luteinizing hormone (LH), testosterone, LH/follicle-stimulating hormone (FSH), insulin resistance, and BMI. Moreover, FSH, fasting glucose, and fasting insulin levels were improved in subgroup analyses. For POI, acupuncture significantly improved serum levels of LH, FSH, LH/FSH ratio, and estradiol.ConclusionAcupuncture-related therapies improve pregnancy rate, and metabolic and hormonal imbalances in patients with POI and PCOS.Systematic review registrationThe protocol of the study was registered in PROSPERO (CRD42024572893). Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024572893.

Purpose: The simultaneous occurrence of primary ovarian insufficiency (POI) and autoimmune diseases has been noted and debated in some epidemiological research. This bidirectional two-sample Mendelian randomization (MR) study aimed to investigate the causal relationships between autoimmune diseases and POI. Methods: We obtained summary-level data for ten autoimmune diseases and POI from published large-scale genome-wide association studies and the FinnGen consortium of European ancestry. A series of filtering steps was performed to discern independent genetic variants. Causal estimates were mainly calculated by the inverse variance weighting method and verified through multiple sensitivity analyses. Results: Of the ten autoimmune diseases, genetically predicted Addison's disease (odds ratio [OR] = 1.26, 95% confidence interval [CI]: 1.09–1.47, P = 0.003) and systemic lupus erythematosus (OR = 1.12, 95% CI 1.02–1.24, P = 0.021) were associated with an increased risk of POI, and sensitivity analyses confirmed the robustness of the results. In addition, there were weak associations between liability to POI and elevated risks of type 1 diabetes (OR = 1.05, 95% CI 1.00–1.10, P = 0.046) and autoimmune thyroid disease (OR = 1.03, 95% CI 1.01–1.05, P = 0.015). Conclusion: This study revealed that Addison's disease and systemic lupus erythematosus are potential risk factors for POI, underscoring the necessity to consider the impact of autoimmune factors in the diagnosis and treatment of POI. [ABSTRACT FROM AUTHOR]

Available data on the clinical significance of low serum anti-Müllerian hormone (AMH) levels in female adolescents are limited. The aim of this study was to elucidate age-related changes in low serum AMH levels in adolescents and to identify predictive factors for AMH progression. A retrospective review was conducted on a series of female adolescents aged 11-19 years with low serum AMH levels (<1.19 ng/mL) who underwent additional AMH tests at least 1 year apart. Participants who showed an increase in the subsequent AMH test (>1.6 ng/mL) (Group 1) were compared with those who did not (Group 2). Among 1655 adolescents who underwent AMH testing at least once from 2010 to 2022, 75 participants (4.5%) exhibited low AMH levels (<1.19 ng/mL), excluding primary ovarian insufficiency. A notable increase in serum AMH levels (>1.6 ng/mL) was confirmed in 7 (30.4%) of 23 female adolescents who underwent relevant follow-up testing. Group 1 had higher initial AMH levels and lower initial follicle-stimulating hormone levels than Group 2 (1.0 vs 0.59 ng/mL, P =.001 and 4.4 vs 9.8 mIU/mL, P =.015, respectively). Ovarian volume did not differ between the groups (3.8 vs 4.4 cm3, P =.465). None of the participants with initial AMH levels under 0.75 ng/mL showed an increase in AMH levels during follow-up. These findings suggest that low serum AMH levels in adolescents may have other explanations in addition to being indicative of a low ovarian reserve. Prospective studies involving a larger number of participants will aid in predicting AMH improvement in adolescents. [ABSTRACT FROM AUTHOR]

Menopause and chronic graft-versus-host disease (cGvHD) are the leading causes of morbidity after allogeneic hematopoietic stem cell transplantation (alloHSCT). Genitalia are one of the target organs of cGvHD causing sexual dysfunction and local symptoms, which may impair women's quality of life. The aim of this study is to describe the prevalence and clinical characteristics of genital cGvHD. A retrospective cross-sectional observational study was performed including 85 women with alloHSCT. All women were diagnosed and counseled by a trained gynecologist. Health-related quality of life was assessed by the Cervantes Short-Form Scale and sexual function was evaluated by the Female Sexual Function Index. Seventeen women (20%) included in the study were diagnosed with genital cGvHD. The main complaints were vulvovaginal dryness (42.2%) and dyspareunia (29.4%), the presence of erythema/erythematous plaques (52.9%) being the most frequent sign. Median time from transplant to diagnosis of genital cGvHD was 17 months among those with mild involvement, 25 months for moderate and 42 months for severe forms. Mortality was 29.4% in patients who developed cGvHD with genital involvement versus 8.8% among those without (p = 0.012). Early gynecological evaluation might allow to identify patients with mild forms of genital cGvHD, potentially enabling better management and improved outcomes. [ABSTRACT FROM AUTHOR]

There are limited studies on urogenital symptoms in women who experience menopause before the age of 40 years due to primary ovarian insufficiency (POI) or bilateral oophorectomy (surgical POI). This study aimed to compare the urogenital symptoms, including sexuality, of women with POI to those without the condition. This cross-sectional study conducted was in seven Latin American countries, in which postmenopausal women (with POI and non-POI) were surveyed with a general questionnaire, the Menopause Rating Scale (MRS) and the six-item Female Sexual Function Index (FSFI-6). The association of premature menopause with more urogenital symptoms and lower sexual function was evaluated with logistic regression analysis. Women with POI experience more urogenital symptoms (MRS urogenital score: 3.54 ± 3.16 vs. 3.15 ± 2.89, p < 0.05) and have lower sexual function (total FSFI-6 score: 13.71 ± 7.55 vs. 14.77 ± 7.57 p < 0.05) than women who experience menopause at a normal age range. There were no significant differences in symptoms when comparing women based on the type of POI (idiopathic or surgical). After adjusting for covariates, our logistic regression model determined that POI is associated with more urogenital symptoms (odds ratio [OR]: 1.38, 95% confidence interval [CI] 1.06–1.80) and lower sexual function (OR: 1.67, 95% CI 1.25–2.25). POI, whether idiopathic or secondary to bilateral oophorectomy, is associated with symptoms that affect vaginal and sexual health. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Autoimmune polyglandular syndrome type 1 (APS‐1) is a rare disorder defined by the presence of at least two of the following conditions: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism, and Addison's syndrome. Despite the lack of CMC and autoimmune history, APS‐1 can be diagnosed using genetic testing. We present the case of a 28‐year‐old female patient with a history of hypocalcemia due to hypoparathyroidism since the age of 2 years. She presented to the endocrine clinic with hypogonadism, primary amenorrhea, and primary ovarian insufficiency. Addison's disease was eventually diagnosed, despite a negative Synacthen test. The adrenal crisis required intravenous hydrocortisone therapy. No CMC was documented, and there was no family history of such conditions. The diagnosis of APS‐1 was confirmed by genetic testing, revealing homozygous pathogenic variants of the autoimmune regulator gene. Management included oral calcium and calcitriol and oral hydrocortisone and fludrocortisone for Addison's disease. Hormonal induction of secondary sexual characteristics was initiated. The patient received combined oral estrogen and progesterone pills. This case highlights the critical significance of early recognition, thorough evaluation, and tailored treatment for patients with APS‐1 to enhance their quality of life and mitigate potentially life‐threatening complications. This underscores the importance of screening for associated minor autoimmune diseases as part of a holistic approach to care. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to retrospectively estimate cumulative reproductive outcomes in women with primary ovarian insufficiency (POI) in assisted reproductive technology (ART) therapy. Methods: A total of 139 patients diagnosed with POI were reviewed in this study. Firstly, they were divided into two groups according to oocyte origin: using their own oocytes (OG group) or accepting oocyte donations (OD I group). Secondly, the patients were split depending on the pregnancy outcome. In the OG group, nine patients decided to use others' oocytes after a failure of attempting to use their own, and this population was the oocyte donation II group (OD II group). Results: There were 88 patients who used their own oocytes, while 51 patients accepted oocyte donations. In the OG group, there are only 10 (7.2%) patients who got pregnant, and patients in the OD group had worse hormone levels (FSH 71.37 ± 4.18 vs. 43.98 ± 2.53, AMH 0.06 ± 0.04 vs. 1.15 ± 0.15, and AFC 0.10 ± 0.06 vs. 1.15 ± 0.15) and more years of infertility (5.04 ± 0.48 vs. 3.82 ± 0.30), which explained why they choose oocyte donation. In all the three groups, baseline characteristics were comparable between pregnant women and nonpregnant women. Of the 10 pregnant patients in the OG group, four of them used luteal-phase short-acting long protocol and had pregnancies successfully in their first cycles. Conclusion: Ovarian stimulation in POI women requires more cost and time. For those with a stronger desire to have genetic offspring, luteal-phase short-acting long protocol may help them obtain pregnancy rapidly. [ABSTRACT FROM AUTHOR]

Introduction: Premature ovarian insufficiency (POI) is a primary cause of infertility with variable clinical manifestations. POI is a multifactorial disease with both environmental and known genetic etiologies, but data on the genetic variations associated with POI in the Middle East and North Africa (MENA) region are scarce. The aim of this study was to systematically review all known genetic causes of POI in the MENA region. Methods: The PubMed, Science Direct, ProQuest, and Embase databases were searched from inception to December 2022 for all reports of genetic variants associated with POI in the MENA region. Clinical and genetic data were collected from eligible articles, and ClinVar and PubMed (dbSNP) were searched for variants. Results: Of 1,803 studies, 25 met the inclusion criteria. Fifteen studies were case-control studies and ten were case reports representing 1,080 nonsyndromic POI patients in total. Seventy-nine variants in 25 genes associated with POI were reported in ten MENA countries. Of the 79 variants, 46 were rare and 33 were common variants. Of the 46 rare variants, 19 were pathogenic or likely pathogenic according to ACMG classification guidelines and ClinVar. No clear phenotype-genotype association was observed. Male family members carrying pathogenic variants also had infertility problems. Discussion: To our best knowledge, this is the first systematic review of the genetic variants associated with POI in the MENA region. Further functional studies are needed to assess the disease-causing molecular mechanisms of these variants. Knowledge of the genetic basis of POI in the Middle East could facilitate early detection of the condition and thus early implementation of therapeutic interventions, paving the way for precision medicine options in specific populations. [ABSTRACT FROM AUTHOR]

Background: Primary ovarian insufficiency (POI) is a common clinical endocrine disorder with a high heterogeneity in both endocrine hormones and etiological phenotypes. However, the etiology of POI remains unclear. Herein, we unraveled the causality of genetically determined metabolites (GDMs) on POI through Mendelian randomization (MR) study with the overarching goal of disclosing underlying mechanisms. Methods: Genetic links with 486 metabolites were retrieved from GWAS data of 7824 European participants as exposures, while GWAS data concerning POI were utilized as the outcome. Via MR analysis, we selected inverse-variance weighted (IVW) method for primary analysis and several additional MR methods (MR-Egger, weighted median, and MR-PRESSO) for sensitivity analyses. MR-Egger intercept and Cochran's Q statistical analysis were conducted to assess potential heterogeneity and pleiotropy. In addition, genetic variations in the key target metabolite were scrutinized further. We conducted replication, meta-analysis, and linkage disequilibrium score regression (LDSC) to reinforce our findings. The MR Steiger test and reverse MR analysis were utilized to assess the robustness of genetic directionality. Furthermore, to deeply explore causality, we performed colocalization analysis and metabolic pathway analysis. Results: Via IVW methods, our study identified 33 metabolites that might exert a causal effect on POI development. X-11437 showed a robustly significant relationship with POI in four MR analysis methods (P IVW=0.0119; P weightedmedian =0.0145; PMR-Egger =0.0499; PMR-PRESSO =0.0248). Among the identified metabolites, N-acetylalanine emerged as the most significant in the primary MR analysis using IVW method, reinforcing its pivotal status as a serum biomarker indicative of an elevated POI risk with the most notable P-value (P IVW=0.0007; PMR-PRESSO =0.0022). Multiple analyses were implemented to further demonstrate the reliability and stability of our deduction of causality. Reverse MR analysis did not provide evidence for the causal effects of POI on 33 metabolites. Colocalization analysis revealed that some causal associations between metabolites and POI might be driven by shared genetic variants. Conclusion: By incorporating genomics with metabolomics, this study sought to offer a comprehensive analysis in causal impact of serum metabolome phenotypes on risks of POI with implications for underlying mechanisms, disease screening and prevention. [ABSTRACT FROM AUTHOR]

This editorial discusses the field of developmental endocrinology and its importance in understanding the role of hormones in the growth and development of living organisms, particularly in women's health. It highlights the historical underinvestment in women's healthcare and research as a core disparity that needs to be addressed. The article also explores various studies on the pathophysiology and management of amenorrhea and estradiol deficiency in girls and young women, emphasizing the significance of hormone replacement therapy and the need for further research in this area. Overall, the editorial calls for increased funding and innovative approaches to support women's health research and bridge the existing health disparities. Another article examines the relationship between socioeconomic status, negative life events, and antenatal anxiety and depression in women. The study found that women with low socioeconomic status experienced a greater impact of negative life events on their mental health during pregnancy. This research provides valuable insights into the factors that contribute to antenatal mental health and highlights the importance of addressing socioeconomic disparities in healthcare. [Extracted from the article]

Premature ovarian insufficiency (POI) is a clinical syndrome in women who develops ovarian insufficiency before the age of 40 years, which manifests itself as a weakening of reproductive and endocrine functions, and is one of the most important factors leading to female infertility, but the pathogenesis is unknown and the treatment is limited. Melatonin is a neuroendocrine hormone mainly synthesized and secreted by the pineal gland, which exerts effects in regulating circadian rhythms, antioxidant activity, and scavenging free radicals. Studies have shown that melatonin is involved in regulating ovarian steroid hormone synthesis, follicular development, ovulation and oocyte quality. Animal models for studies of POI have found that melatonin can alleviate oxidative stress, reduce apoptosis, regulate ovarian function and delay POI through the regulation of multiple signaling pathways. Clinical studies have shown that melatonin can improve ovarian function and pregnancy rate in POI patients. Its potential value in assisted reproduction provides a new direction to improve the fertility of POI patients. [ABSTRACT FROM AUTHOR]

Around 70 percent of cases of Primary Ovarian Insufficiency (POI) etiology remain unexplained. The aim of our study is to contribute to the etiology and genetic background of POI. A total of 37 POI patients and 30 women in the reproductive period were included in this prospective, case-control study between August 2020 and December 2021. The women were examined for 36 genes with next-generation sequencing (NGS) panel. Gene variations were detected in 59.5 percent of the patients in the case group. FSHR p.S680N (rs6166, c.2039 G>A) and FSHR p.A307T (rs6165, c.919 G>A) gene variants, which are most frequently located in exon 10 of the FSHR gene, were detected in both groups. Although it was not found that these gene variants were significantly different between the groups, it was also found that they were significantly different in POI patients under 30 years of age and in those with a family history of POI. Variations were detected in 12 genes in POI patients. Two gene variants (FGFR1 [c.386A>C, rs765615419] and KISS1 [c.58 G>A, rs12998]) were detected in both groups, and the remaining gene variants were detected only in POI patients. No differences were detected between the groups in terms of gene variations. However, the gene variations detected only in POI patients may play a role in the etiology of POI. [ABSTRACT FROM AUTHOR]

The term "ovarian insufficiency" describes the decline of ovarian function resulting in fertility loss and the marked decrease of ovarian steroid hormone production. From a clinical standpoint, ovarian insufficiency presents in three different settings. The first is natural menopause at midlife occurring at the average age of 51 years. The second arises after surgical oophorectomy owing to disease or elective cancer prophylaxis. Finally, primary or premature ovarian insufficiency is characterized by menopause occurring before age 40, often of undetermined etiology, but at times linked with genetic mutations, autoimmune syndromes, metabolic conditions, iatrogenic etiologies, and toxic exposures. Each clinical situation presents unique concerns and management challenges. The majority of women with intact ovaries who live to age 51 experience natural menopause, with early menopause <45 years. In the United States, surgical menopause with bilateral oophorectomy occurs in ∼600,000 women per year. The timing and specific clinical indication for oophorectomy alters management. Primary ovarian insufficiency occurs in 1% of women, although recent estimates suggest the prevalence may be increasing. Symptoms of ovarian insufficiency include hot flashes or vasomotor symptoms, mood disorders, sleep disruption, and vaginal/urinary symptoms. Health concerns include bone, cardiovascular, and cognitive health. Management of symptoms and preventive strategies varies depending upon the age, clinical situation, and specific health concerns of each individual. Treatment options for symptom relief include cognitive behavior therapy and hypnosis, nonhormonal prescription therapies, and hormone therapy. Tailoring the therapeutic approach over time in response to age, emerging medical issues, and patient desires constitutes individualized care. [ABSTRACT FROM AUTHOR]

• Primary ovarian insufficiency (POI) is associated with osteopenia and osteoporosis. • Patients with POI have an increased risk of long-term fracture morbidity and mortality. • Early medical intervention (e.g., hormone replacement therapy) is needed in patients with POI. Premature menopause is a major complication of primary ovarian insufficiency (POI), and this loss is closely relates to bone mineral density (BMD). Previous research has indicated potential associations between BMD and POI. This study set out to provide the first systematic literature review and meta -analysison account of BMD content among women with POI. Studies including women with POI and controls were eligible from PubMed, Embase, Cochrane Library and Web of Science databases (from their inception to April 2022). Two reviewers independently evaluated study eligibility. The meta -analysis was performed using the DerSimonian and Laird random effects model. Ten studies featuring 578 women with POI and 480 controls were selected. BMD content of femur neck (SMD:-0.76; 95 % CI: −1.20 to −0.31; P = 0.0008), the BMD content of nondominating forearm (SMD:-0.67; 95 % CI: −1.15 to −0.18; P = 0.007) were significantly decreased in women with POI. However, no differences were seen in other regions (lumbar spine, total hip, hipneck). The results of this study indicate that BMD content altered in patients with primary ovarian insufficiency. An implication of this is the possibility that hormone replacement therapy to minimize the prevalence of fracture morbidity and mortality associated with osteopenia in patients with POI. [ABSTRACT FROM AUTHOR]

Summary: Background: The KITL-KIT interaction is known as an important initiator in oocyte activation through the downstream pathway of PI3K-AKT-FOXO3 signalling. Previous studies utilising germ cell-specific Kit mutant knockin and kinase domain knockout models with Vasa-Cre suggested the crucial role of KIT in oocyte activation at the primordial follicle stage. Methods: We utilised mice with complete postnatal deletion of KIT expression in oocytes via Gdf9-iCre and conducted analyses on ovarian follicle development, specific markers, hormone assays, and fertility outcomes. Findings: Our findings reveal contrasting phenotypes compared to previous mouse models with prenatal deletion of Kit. Specifically, postnatal deletion of Kit exhibit no defects in germ cell nest breakdown, follicle activation, and folliculogenesis during development. Remarkably, upon reaching full maturity, mice with postnatal deletion of Kit experience a complete loss of ovarian reserve, growing follicles, and ovarian function. Furthermore, mice display smaller ovarian size and weight, delayed folliculogenesis, and phenotypes indicative of primary ovarian insufficiency (POI), including elevated serum levels of FSH, reduced AMH, and absence of ovarian follicles, ultimately resulting in infertility. Additionally, the ovaries exhibit randomly distributed expression of granulosa and theca cell markers such as Inhibin α, ACVR2B, and LHR. Notably, there is the uncontrolled expression of p-SMAD3 and Ki67 throughout the ovarian sections, along with the widespread presence of luteinised stroma cells and cleaved Caspase-3-positive dying cells. Interpretation: These genetic studies underscore the indispensable role of KIT in oocytes for maintaining the survival of ovarian follicles and ensuring the reproductive lifespan. Funding: This work was supported by National Institutes of Health grant R01HD096042 and startup funds from UNMC (S.Y.K.).

Abstract Background Clinically, hormone replacement therapy (HRT) is the main treatment for primary ovarian insufficiency (POI). However, HRT may increase the risk of both breast cancer and cardiovascular disease. Exosomes derived from human umbilical cord mesenchymal stem cell (hUC-MSC) have been gradually applied to the therapy of a variety of diseases through inflammation inhibition, immune regulation, and tissue repair functions. However, the application and study of hUC-MSC exosomes in POI remain limited. Methods Here, we first constructed four rat animal models: the POI-C model (the “cyclophosphamide-induced” POI model via intraperitoneal injection), the POI-B model (the “busulfan-induced” POI model), the POI-U model (the “cyclophosphamide-induced” POI model under ultrasonic guidance), and MS model (the “maternal separation model”). Second, we compared the body weight, ovarian index, status, Rat Grimace Scale, complications, and mortality rate of different POI rat models. Finally, a transabdominal ultrasound-guided injection of hUC-MSC exosomes was performed, and its therapeuticy effects on the POI animal models were evaluated, including changes in hormone levels, oestrous cycles, ovarian apoptosis levels, and fertility. In addition, we performed RNA-seq to explore the possible mechanism of hUC-MSC exosomes function. Results Compared with the POI-C, POI-B, and MS animal models, the POI-U model showed less fluctuation in weight, a lower ovarian index, fewer complications, a lower mortality rate, and a higher model success rate. Second, we successfully identified hUC-MSCs and their exosomes, and performed ultrasound-guided intraovarian hUC-MSCs exosomes injection. Finally, we confirmed that the ultrasound-guided exosome injection (termed POI-e) effectively improved ovarian hormone levels, the oestrous cycle, ovarian function, and fertility. Mechanically, hUC-MSCs may play a therapeutic role by regulating ovarian immune and metabolic functions. Conclusions In our study, we innovatively constructed an ultrasound-guided ovarian drug injection method to construct POI-U animal models and hUC-MSC exosomes injection. And we confirmed the therapeutic efficacy of hUC-MSC exosomes on the POI-U animal models. Our study will offer a better choice for new animal models of POI in the future and provides certain guidance for the hUC-MSCs exosome therapy in POI patients. Graphical abstract The schema of construction of different animal models, extraction and identifying hUC-MSCs and exosomes, therapy of ultrasound-guided hUC-MSCs exosome injection. Note: POI: premature ovarian insufficiency; hUC-MSCs: Human umbilical cord mesenchymal stem cells; POI-C: POI-cyclophosphamide; POI-B: POI-cyclophosphamide + Busulfan; POI-U: POI-Ultrasonic guidance cyclophosphamide injection; MS: POI-Maternal separation. POI-e: ultrasound-guided hUC-MSCs exosome injection; AMH: Anti-müllerian hormone; LH: Luteinizing hormone; FSH: Follicle-stimulating hormone; DA: dopamine; T: Testosterone; PRL: prolactin; GnRH: Gonadotropin-releasing hormone.

Premature ovarian insufficiency (POI) is associated with decreased ovulation in the precursor stage which leads to ovarian failure in the end stage. Metabolic–bariatric surgery (MBS) can improve women's reproductive status, including the release of sex hormones, ovulation, and fertilization. Here, we report a spontaneous pregnancy following MBS despite potential ovarian insufficiency. A 38‐year‐old woman with severe obesity underwent three cycles of assisted reproduction that were not successful. Oligomenorrhea ≥ 4 months, laboratory indices, and previous poor ovarian response approved the diagnosis of diminished ovarian reserve and could be considered as the precursor stage of POI. Then a gastric bypass was applied, and a spontaneous pregnancy occurred in the 22nd month after surgery, with 45.80% reduction in body mass index. MBS in women with obesity and idiopathic ovarian insufficiency may increase the chance of spontaneous ovulation and successful pregnancy. [ABSTRACT FROM AUTHOR]

Premature loss of ovarian function (POI) is associated with numerous negative side effects, including vasomotor symptoms, sleep and mood disturbances, disrupted urinary function, and increased risks for osteoporosis and heart disease. Hormone replacement therapy (HRT), the standard of care for POI, delivers only a subset of ovarian hormones and fails to mimic the monthly cyclicity and daily pulsatility characteristic of healthy ovarian tissue in reproductive-aged individuals whose ovarian tissue contains thousands of ovarian follicles. Ovarian tissue allografts have the potential to serve as an alternative, cell-based HRT, capable of producing the full panel of ovarian hormones at physiologically relevant doses and intervals. However, the risks associated with systemic immune suppression (IS) required to prevent allograft rejection outweigh the potential benefits of comprehensive and dynamic hormone therapy. This work investigates whether the age of ovarian tissue donor animals affects the function of, and immune response to, subcutaneous ovarian grafts. We performed syngeneic and semi-allogeneic ovarian transplants using tissue from mice aged 6–8 (D7) or 20–22 (D21) days and evaluated ovarian endocrine function and immune response in a mouse model of POI. Our results revealed that tissue derived from D7 donors, containing an ample and homogeneous primordial follicle reserve, was more effective in fully restoring hypothalamic–pituitary–ovarian feedback. In contrast, tissue derived from D21 donors elicited anti-donor antibodies with higher avidity compared to tissue from younger donors, suggesting that greater immunogenicity may be a trade-off of using mature donors. This work contributes to our understanding of the criteria donor tissue must meet to effectively function as a cell-based HRT and explores the importance of donor age as a factor in ovarian allograft rejection. [ABSTRACT FROM AUTHOR]

Objectives: We investigated the potential of glutathione to protect ovarian function in rats exposed to cyclophosphamide by measuring serum anti-Mullerian hormone (AMH) levels, follicle counts, and related parameters. Design: Forty-two adult female Sprague-Dawley rats were randomly divided into six groups and treated with various combinations of cyclophosphamide, glutathione, and sodium chloride. On day 21, the rats were anesthetized, and their ovaries were removed for examination. Participants/Materials, Setting, Methods: Histopathological examination, serum AMH concentrations, follicle counts, AMH-positive staining of follicle percentages were analyzed. Statistical analysis was performed using a one-way analysis of variance and Tukey's test, with significance set at p < 0.05. Secondary measures encompassed histopathological examination and percentages of AMH-positive staining of follicles. Results: Significant differences were observed in follicle counts, AMH-positive follicle parameters, and serum AMH concentrations among the six groups. Group 2 (treated with cyclophosphamide) had the lowest primordial, primary, secondary, and antral follicle counts and the highest atretic count. Group 6, treated with cyclophosphamide and 200 mg/kg glutathione, showed improved follicle counts compared to those in group 2. Reducing the glutathione dose to 100 mg/kg was ineffective. Limitations: This was an experimental animal investigation with a comparatively modest sample size. Experimental studies should be conducted to determine the optimal dosage and duration of glutathione therapy. Information gathered from an experimental animal model may not yield precisely similar outcomes in humans; therefore, additional investigations are necessary to examine the impact of glutathione on women experiencing POI. Conclusions: The anti-oxidative protective effect of directly administered glutathione was demonstrated for the first time. Low-dose glutathione was ineffective, whereas a high dose yielded significant ovarian protection against cyclophosphamide. Our findings provide valuable insights for supplementing clinical trials on the protective effects of glutathione against ovarian damage. [ABSTRACT FROM AUTHOR]

Vaginal atrophy is often underestimated in the routine practice of an obstetrician-gynecologist, as specialists expect active complaints from postmenopausal patients. At the same time, vaginal or urogenital atrophy can occur in women of any age due to temporary or permanent estrogen deficiency. Research continues to find effective and safe methods of treatment for this pathology in order to alleviate symptoms and improve the quality of life of women. The objective: to study the effectiveness of using vaginal suppositories in eliminating the manifestations of vaginal atrophy in women of reproductive age with primary ovarian insufficiency. Materials and methods. 23 women from 24 to 35 years old with primary ovarian insufficiency (POI) were involved in the study, they were divided into groups depending on the duration of the disease: I group – 8 women with POI duration up to 5 years, II group II – 8 women with POI duration from 5 to 7 years, III group – 7 patients with a duration of POI of more than 7 years. The set of examinations carried out before the start of the study and after treatment included an assessment of the patients’ complaints, speculum examination of the vagina and cervix with the determination of the vaginal health index in points, study of the condition of the vaginal microbiota (pH-metry, bacterioscopic examination of smears of vaginal secretions). Results. Despite receiving systemic menopausal hormone therapy, all patients had varying intensity of vaginal atrophy, while the frequency and severity of disorders increased with increasing duration of the course of POI. As the duration of POI increased, the frequency and severity of vaginal dryness, bloody discharge during intercourse increased, and the frequency of abnormal vaginal discharge decreased. Manifest vaginal atrophy was diagnosed in 12.5% of patients in I group, 37.5% of patients in II group and 71.4% of patients in III group, moderate atrophy in 37.5%, 37.5% and 28.6% of women, respectively. The obtained data indicate a gradual progression of the phenomena of vaginal atrophy in patients with POI. After treatment, there was a tendency to decrease the pH values of the vaginal contents from 5.6–5.8 to 4.7. The dynamics of patients’ complaints showed that the effectiveness of using vaginal suppositories is the highest for the duration of POI up to 5 years, and for a longer duration of vaginal atrophy, it is 80.0%. At the stage of inclusion in the study, no normocenosis was detected in any of the examined patients (100%), the intermediate state of the microbiota prevailed – 73.9%, nonspecific vaginitis was diagnosed in 13.0% of patients, and bacterial vaginosis in 13.0%. After a course of treatment with vaginal suppositories, vaginal normocenosis was diagnosed in 52.2% of patients, an intermediate state of microbiota in 56.5% in the absence of inflammatory and dysbiotic changes. The effectiveness of normalizing the condition of the vaginal microbiota was 73.9%. Conclusions. Vaginal suppositories are an original combination of components with a pronounced reparative, antipruritic, anti-inflammatory effect, which helps to eliminate the inflammatory process in the vulvovaginal area, support intensive regeneration of the vaginal mucosa and its moisture, restore the physiological protective barrier of the mucous membrane, improve local blood microcirculation, eliminate the itching, discomfort and dryness, normalization of the condition of the vaginal microbiota. [ABSTRACT FROM AUTHOR]

Objective NR5A1 is a key regulator of sex differentiation and has been implicated in spleen development through transcription activation of TLX1. Concerns exist about hypo- or asplenism in individuals who have a difference of sex development (DSD) due to an NR5A1 disease-causing variant. We aimed to assess spleen anatomy and function in a clinical cohort of such individuals and in their asymptomatic family member carriers. Design Cross-sectional assessment in 22 patients with a DSD or primary ovarian insufficiency and 5 asymptomatic carriers from 18 families, harboring 14 different NR5A1 variants. Methods Spleen anatomy was assessed by ultrasound, spleen function by peripheral blood cell count, white blood cell differentiation, percentage of nonswitched memory B cells, specific pneumococcal antibody response, % pitted red blood cells, and Howell–Jolly bodies. Results Patients and asymptomatic heterozygous individuals had significantly decreased nonswitched memory B cells compared to healthy controls, but higher than asplenic patients. Thrombocytosis and spleen hypoplasia were present in 50% of heterozygous individuals. Four out of 5 individuals homozygous for the previously described p.(Arg103Gln) variant had asplenia. Conclusions Individuals harboring a heterozygous NR5A1 variant that may cause DSD have a considerable risk for functional hyposplenism, irrespective of their gonadal phenotype. Splenic function should be assessed in these individuals, and if affected or unknown, prophylaxis is recommended to prevent invasive encapsulated bacterial infections. The splenic phenotype associated with NR5A1 variants is more severe in homozygous individuals and is, at least for the p.(Arg103Gln) variant, associated with asplenism. [ABSTRACT FROM AUTHOR]

Pathogenic heterozygous variants in DHX16 have been recently identified in association with a variety of clinical features, including neuromuscular disease, sensorineural hearing loss, ocular anomalies, and other phenotypes. All DHX16 disease‐causing variants previously reported in affected individuals are missense in nature, nearly all of which were found to be de novo. Here we report on a patient with neuromuscular disease, hearing loss, retinal degeneration, and previously unreported phenotypic features including mitochondrial deficiency and primary ovarian insufficiency, in whom a novel de novo likely pathogenic variant in DHX16 NM_003587.4:c.2033A > G (p.Glu678Gly) was identified. Furthermore, we conducted an in‐depth literature review of DHX16's role in disease and utilized high‐performing in silico prediction algorithms to compare and contrast the predicted effects of all reported disease‐associated DHX16 variants on protein structure and function. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This study was designed to compare the serum vaspin levels between patients with primary ovarian insufficiency (POI) and healthy fertile women. STUDY DESIGN: Sixty-nine patients diagnosed with idiopathic POI and 70 age-matched healthy fertile women were included in this case-control study. General gynecological and physical examination findings and serum basal hormone levels were recorded. Vaspin levels in serum samples were determined using the Enyzme-Linked ImmunoSorbent Assay (ELISA) method. RESULTS: The mean age of the patients with POI was 31.9±5.4 years, while it was 31.2±3.8 years in the control group. There were no statistically significant differences in body mass index, gravidity, parity, and cigarette consumption between the groups. However, the mean follicle-stimulating hormone level in POI patients was 55.4±25.1 IU/L, significantly higher than the 6.2±1.8 IU/L observed in the control group. Luteinizing hormone levels were also significantly higher in POI patients, while estradiol and anti-Mullerian hormone values were significantly lower. Furthermore, the mean serum vaspin level in POI patients was 0.79±0.56 ng/mL, compared to 1.08±0.64 ng/mL in the control group (p<0.001). CONCLUSIONS: Serum vaspin levels were found to be decreased in women with POI. Therefore, monitoring the serum vaspin levels in women with POI may help in the early identification of patients with POI. [ABSTRACT FROM AUTHOR]

Key Clinical Message Autoimmune polyglandular syndrome type 1 (APS‐1) is a rare disorder defined by the presence of at least two of the following conditions: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism, and Addison's syndrome. Despite the lack of CMC and autoimmune history, APS‐1 can be diagnosed using genetic testing. We present the case of a 28‐year‐old female patient with a history of hypocalcemia due to hypoparathyroidism since the age of 2 years. She presented to the endocrine clinic with hypogonadism, primary amenorrhea, and primary ovarian insufficiency. Addison's disease was eventually diagnosed, despite a negative Synacthen test. The adrenal crisis required intravenous hydrocortisone therapy. No CMC was documented, and there was no family history of such conditions. The diagnosis of APS‐1 was confirmed by genetic testing, revealing homozygous pathogenic variants of the autoimmune regulator gene. Management included oral calcium and calcitriol and oral hydrocortisone and fludrocortisone for Addison's disease. Hormonal induction of secondary sexual characteristics was initiated. The patient received combined oral estrogen and progesterone pills. This case highlights the critical significance of early recognition, thorough evaluation, and tailored treatment for patients with APS‐1 to enhance their quality of life and mitigate potentially life‐threatening complications. This underscores the importance of screening for associated minor autoimmune diseases as part of a holistic approach to care.

Estrogen is critical for bone health from puberty onwards. Various clinical scenarios in adolescence can impact skeletal exposure to estrogen during this vulnerable time. Primary ovarian insufficiency, premature menopause, and anorexia nervosa necessitate prompt evaluation, treatment, and replacement of estrogen in order to optimize accrual of peak bone mass. We have much still to learn about the skeletal impact of delaying puberty and gender affirming hormones in gender diverse individuals. While the choice of hormonal contraception in adolescence is often driven by patient preference and concerns about adherence, providers and patients much take the long-term impact on bone health into consideration. Key Concepts: (1) Delayed, diminished or absent estrogen during adolescence has a negative impact on peak bone mass accrual. (2) Hormone replacement therapy is essential for patients with primary ovarian insufficiency and premature menopause. (3) Recovery from anorexia nervosa does not lead to a complete catch-up of bone density lost/not gained. (4) Not all hormonal contraception methods are created equal for the adolescent skeleton. (5) Skeletal health of trans youth is an emerging focus.

IntroductionPremature ovarian insufficiency (POI) is a primary cause of infertility with variable clinical manifestations. POI is a multifactorial disease with both environmental and known genetic etiologies, but data on the genetic variations associated with POI in the Middle East and North Africa (MENA) region are scarce. The aim of this study was to systematically review all known genetic causes of POI in the MENA region.MethodsThe PubMed, Science Direct, ProQuest, and Embase databases were searched from inception to December 2022 for all reports of genetic variants associated with POI in the MENA region. Clinical and genetic data were collected from eligible articles, and ClinVar and PubMed (dbSNP) were searched for variants.ResultsOf 1,803 studies, 25 met the inclusion criteria. Fifteen studies were case-control studies and ten were case reports representing 1,080 non-syndromic POI patients in total. Seventy-nine variants in 25 genes associated with POI were reported in ten MENA countries. Of the 79 variants, 46 were rare and 33 were common variants. Of the 46 rare variants, 19 were pathogenic or likely pathogenic according to ACMG classification guidelines and ClinVar. No clear phenotype-genotype association was observed. Male family members carrying pathogenic variants also had infertility problems.DiscussionTo our best knowledge, this is the first systematic review of the genetic variants associated with POI in the MENA region. Further functional studies are needed to assess the disease-causing molecular mechanisms of these variants. Knowledge of the genetic basis of POI in the Middle East could facilitate early detection of the condition and thus early implementation of therapeutic interventions, paving the way for precision medicine options in specific populations.

Resumen: Introducción: La insuficiencia ovárica prematura (POI) conlleva importante morbilidad, causando infertilidad, disfunción sexual, disminución de la densidad ósea, riesgo cardiovascular, alteraciones emocionales y mortalidad precoz. Objetivo: Conocer la incidencia y el manejo actual de la POI en supervivientes a un tumor sólido en la infancia y/o adolescencia en nuestro medio. Material y métodos: Estudio observacional multicéntrico. Mujeres entre 12 y 18 años con diagnóstico de tumor sólido y criterios clínicos y/o analíticos de POI. El riesgo se estima según los criterios «The Pediatric Initiative Network of the Oncofertility Consortium». Resultados: Incidencia de 1,5 (30 casos de POI). Edad media 14 ± 2,09. Los tumores sólidos que más se asociaron a la POI fueron: sarcoma de Ewing, tumores cerebrales y germinales. El 83% de los casos no realizó preservación previa al tratamiento. Un 63% no referían menarquia al diagnóstico de la POI. El 97% cumplían criterios de alto riesgo de toxicidad gonadal, a pesar de ello el 47% no realizó ninguna vigilancia previa al diagnóstico. La mediana de tiempo tras el diagnóstico y la aparición del evento es de 43,5 y 29,5 meses tras finalizar tratamiento. Las curvas de Kaplan-Meier, muestran que al 30% de los casos, aparecen en los 2 años tras el diagnóstico y las mujeres con estadio puberal 1 desarrollan insuficiencia más tardíamente que aquellas con estadio 5. Conclusiones: El seguimiento de mujeres en riesgo de la POI, es susceptible de mejora. Las herramientas actuales facilitan conocer el riesgo al planificar los tratamientos del tumor y realizar vigilancia, educación, diagnóstico precoz, preservación e instauración de tratamiento sustitutivo. Todo ello, supondría importantes mejoras en salud. Abstract: Introduction: Primary ovarian insufficiency (POI) carries significant morbidity, causing infertility, sexual disfunction, decreased bone density, cardiovascular risk, emotional distress and early mortality. Objective: To know the incidence and current management of POI in childhood/adolescent solid tumour survivors. Material and methods: We conducted a multicentre observational study. It included female patients aged 12 to 18 years with a diagnosis of solid tumour and meeting clinical or biochemical criteria for POI. The risk was estimated based on the criteria of the Pediatric Initiative Network of the Oncofertility Consortium. Results: We found an incidence of 1.5 (30 cases of POI): The median age at the time of the event was 14 years (standard deviation, 2.09). The solid tumours associated most frequently with POI were Ewing sarcoma and brain and germ cell tumours. Eighty-three percent of patients did not undergo fertility preservation. Sixty-three percent reported not having undergone menarche at the time of ovarian failure. Ninety-seven percent were at high risk of gonadal toxicity, yet 47% were not monitored before the diagnosis. The median time elapsed to the occurrence of the event was 43.5 months after diagnosis and 29.5 months after completing treatment. The Kaplan-Meier curves showed that approximately 30% of POI cases developed within 2 years of diagnosis and that women at Tanner stage 1 developed insufficiency later than women at Tanner stage 5. Conclusions: There is room for improvement in the followup of women at risk of POI in Spain. The tools currently available facilitate risk assessment at the time of treatment planning and allow the implementation of monitoring, education, early diagnosis, fertility preservation, and replacement therapy as needed. All of this would achieve significant improvement in health outcomes.

Per- and polyfluoroalkyl substances (PFASs) are a class of anthropogenic organic compounds widely present in the natural and human living environments. These emerging persistent pollutants can enter the human body through multiple channels, posing risks to human health. In particular, exposure to PFASs in women may cause a series of reproductive health hazards and infertility. Based on a review of the existing literature, this study preliminarily summarizes the effects of PFAS exposure on the occurrence and development of female reproductive endocrine diseases, such as polycystic ovary syndrome (PCOS), endometriosis, primary ovarian insufficiency (POI), and diminished ovarian reserve (DOR). Furthermore, we outline the relevant mechanisms through which PFASs interfere with the physiological function of the female ovary and finally highlight the role played by nutrients in reducing the reproductive health hazards caused by PFASs. It is worth noting that the physiological mechanisms of PFASs in the above diseases are still unclear. Therefore, it is necessary to further study the molecular mechanisms of PFASs in female reproductive diseases and the role of nutrients in this process.

Abstract Background Recent studies have suggested a potential link between systemic inflammatory regulators and primary ovarian insufficiency (POI); however, a causal relationship between them remains unclear. In this study, we explored the causal link between systemic inflammatory regulators and POI risk using a bidirectional, two-sample Mendelian randomization (MR) strategy. Results This approach utilized the most extensive genome-wide association study involving 41 systemic inflammatory regulators in a sample of 8,293 Finnish individuals and POI data from the FinnGen consortium (254 cases vs. 118,228 controls). The inverse variance weighting approach served as a primary MR method, and four additional MR techniques (Maximum Likelihood, MR-Egger, Weighted Median, and constrained maximum likelihood and model averaging Bayesian information criterion ) were applied to support and validate results. Cochran’s Q statistics were used to assess the heterogeneity of instrumental variables, whereas the MR-Egger and MR Pleiotropy Residual Sum and Outlier tests detected horizontal pleiotropy. The MR Steiger test evaluated the strength of a causal association. Our findings suggest that lower levels of vascular endothelial growth factor (odds ratio [OR] = 0.73, 95% confidence interval [CI]: 0.54–0.99, P = 0.046) and interleukin-10 (OR = 0.54, 95% CI: 0.33–0.85, P = 0.021) are associated with an increased risk of POI. Reverse MR analysis revealed no significant effect of POI on the expression of these 41 systemic inflammatory regulators. No notable heterogeneity or horizontal pleiotropy was observed in the instrumental variables. Conclusions This study revealed a causal association between 41 systemic inflammatory regulators and POI, demonstrating that decreased levels of VEGF and IL-10 are linked to an elevated risk of POI. Further investigations are necessary to assess the potential of these biomarkers as early predictors, preventive strategies, and therapeutic targets for POI.