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).
CONCLUSIONS: This study suggests that polymorphisms in the TGF-β signaling pathway genes can be useful biomarkers for POI diagnosis and treatment.

Premature ovarian failure (POF), a condition influenced by genetic and immune factors, remains incurable despite years of intensive research and significant efforts. This persisting challenge underscores the urgency to address this escalating health concern. Fortunately, stem cell regenerative medicine has emerged as a promising avenue for developing therapeutic strategies and innovative treatments for POF. Bibliometric analysis, renowned for its objectivity, systematic approach, and comprehensive coverage of a given field, has yet to be applied to the study of stem cell research in POF. This study used CiteSpace software to assess contributions and co-occurrence relationships among various countries/regions, institutes, journals, and authors. This approach also allowed us to identify research hotspots and promising future trends within this field. Additionally, we generated visualizing maps utilizing the Web of Science Core Collection (WOSCC) and PubMed publications. By providing valuable information and references, we aim to enhance the understanding of the challenges involved in translating stem cell regeneration into clinical therapeutic potential for POF. Furthermore, our analysis and findings guide researchers and clinicians, facilitating future collaborative research and clinical intervention efforts.

Premature ovarian failure (POF) is intricately linked to cellular fates such as senescence, apoptosis, and impaired granulosa cell (GC) differentiation, each of which contributes to ovarian dysfunction and follicular depletion. Autophagy is essential in preventing POF by maintaining cellular homeostasis through the degradation and recycling of damaged organelles and proteins, thereby preserving ovarian function and preventing follicular depletion. Recent studies have revealed that the targeted regulation and disruption of autophagy through various molecular mechanisms ultimately lead to the pathogenesis of POF. In this review, we provide a comprehensive analysis of the disruption in regulatory mechanisms of autophagy contributing to POF. Specifically, we elucidate the molecular mechanisms that can be targeted to restore autophagy homeostasis, offering therapeutic potential for the treatment of POF.

BACKGROUND: There has been a significant surge in animal studies of stem cell-derived extracellular vesicles (EVs) therapy for the treatment of premature ovarian failure (POF) but its efficacy remains unknown and a comprehensive and up-to-date meta-analysis is lacking. Before clinical translation, it is crucial to thoroughly understand the overall impact of stem cell-derived EVs on POF.
METHODS: PubMed, EMBASE, Cochrane Library, Web of Science were searched up to February 18, 2024. The risk of bias was evaluated according to Cochrane Handbook criteria, while quality of evidence was assessed using the SYRCLE system. The PRISMA guidance was followed. Trial sequential analysis was conducted to assess outcomes, and sensitivity analysis and publication bias analysis were performed using Stata 14.
RESULTS: Data from 25 studies involving 339 animals were extracted and analyzed. The analysis revealed significant findings: stem cell-derived EVs increase ovary weight (SMD = 3.88; 95% CI: 2.50 ~ 5.25; P < 0.00001; I2 = 70%), pregnancy rate (RR = 3.88; 95% CI: 1.94 ~ 7.79; P = 0.0001; I2 = 0%), count of births (SMD = 2.17; 95% CI: 1.31 ~ 3.04; P < 0.00001; I2 = 69%) and counts of different types of follicles. In addition, it elevates the level of AMH (SMD = 4.15; 95% CI: 2.75 ~ 5.54; P < 0.00001; I2 = 88%) and E2 (SMD = 2.88; 95% CI: 2.02 ~ 3.73; P < 0.00001; I2 = 80%) expression, while reducing FSH expression (SMD = -5.05; 95% CI: -6.60 ~ -3.50; P < 0.00001; I2 = 90%). Subgroup analysis indicates that the source of EVs, animal species, modeling method, administration route, and test timepoint affected efficacy. Trial sequential analysis showed that there was sufficient evidence to confirm the effects of stem cell-derived EVs on birth counts, ovarian weights, and follicle counts. However, the impact of stem cell-derived EVs on pregnancy rates needs to be further demonstrated through more animal experimental evidence.
CONCLUSIONS: Stem cell-derived EVs demonstrate safety and efficacy in treating POF animal models, with potential improvements in fertility outcomes.
BACKGROUND: PROSPERO registration number: CRD42024509699.

OBJECTIVE: To describe the prevalence of multimorbidity among individuals with premature ovarian insufficiency (POI) and early menopause, in comparison to average age of menopause.
METHODS: Prospective cohort SUBJECTS: This prospective cohort encompassed female postmenopausal individuals from the Canadian Longitudinal Study on Aging (CLSA). The CLSA collected cross-sectional data from 50,000 community-dwelling Canadians aged 45 to 85 between 2010 and 2015.
METHODS: The primary exposure was primary ovarian insufficiency (defined by onset of menopause younger than 40 years). Comparators included average age of menopause (age 46 to 55 years), early menopause (40-45 years), late onset menopause (56-65 years), and those who underwent a hysterectomy.
METHODS: The primary outcome was multimorbidity, which was defined as two or more chronic conditions. The secondary outcome was severe multimorbidity (defined as three or more chronic conditions) as well as frequencies of specific chronic conditions among a comprehensive list of 15 individual conditions. We assessed the association between multimorbidity and age at menopause using logistic regression and odds ratios, with confidence intervals set at 95%. Odds ratios were adjusted for known predictors of multimorbidity, including age, menopause hormone therapy (MHT), education, ethnicity, self-reported loneliness, living alone, BMI, smoking habits, nutritional risk, social participation, and physical activity.
RESULTS: A total of 12,339 postmenopausal participants were included, of which 374 (3.0%) experienced POI and 1396 (11.3%) experienced early menopause. The prevalence of multimorbidity was 64.8% and 51.1% among those with POI and early menopause respectively. In contrast, only 43.9% of individuals with average age of menopause (age 46 to 55 years) had multimorbidity. The OR for multimorbidity in the POI population was 2.5 (95% CI 2.0-3.1) in comparison to those who underwent the average age of menopause. This relationship was maintained after adjustment for confounders (aOR 2.0, 95% CI: 1.5-2.5). The prevalence of severe multimorbidity was also double in the POI group in comparison in the average age group (39.2% versus 21.1%). There was significantly increased risk of ischemic heart disease (aOR 2.8, 95% CI: 1.7-4.7), gastric ulcers (aOR 1.6, 95% CI: 1.1-2.3) and osteoporosis (aOR 1.6, 95% CI: 1.2-2.1) in the POI group.
CONCLUSIONS: Individuals with POI and early menopause experience increased multimorbidity in comparison to those undergoing menopause at an average age. This trend persists even after adjusting for significant multimorbidity risk factors.

The relationship between premature ovarian insufficiency (FXPOI) and premutation in the FMR1 gene is well established. In recent years, though, a potential relationship between the latter and a low ovarian reserve has been suggested. To explore it, we conducted a retrospective study in an IVF program at a university tertiary referral center in Barcelona (Spain). Data were obtained retrospectively from a total of 385 women referred for FMR1 gene testing at our institution from January 2018 to December 2021. We compared the prevalence of FMR1 gene premutation between 93 of them, younger than 35 years, with a diminished ovarian reserve (DOR), characterized by levels of anti-Mullerian hormone < 1.1 ng/mL and antral follicle count < 5; and 132 egg donors screened by protocol that served as the controls. We found a higher prevalence of FMR1 premutation in the DOR group (seven patients (7.69%)) than in the control group (one patient (1.32%)), Fisher-exact test p-value = 0.012). We concluded that compared with the general population represented by young egg donors, the prevalence of FMR1 gene premutation is higher in young patients with a diminished ovarian reserve. Although these findings warrant further prospective validation in a larger cohort of patients within DOR, they suggest that, in clinical practice, FMR1 premutation should be determined in infertile young patients with DOR in order to give them adequate genetic counselling.

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.

BACKGROUND: It is challenging to improve the effects of chemotherapy and reduce its adverse impact on the ovaries. Our previous study suggested that the combination of galaxamide could enhance the antitumor effect of cisplatin (CIS) in HeLa cell xenograft mice. However, their potential effects on ovarian tissues remain unknown.
METHODS: The Hela tumor-bearing female BALB/c mice model was established and randomly divided into three groups: control group (PBS group), CIS group (0.3 mg/kg CIS group) and galaxamide group (0.3 mg/kg CIS + 3 mg/kg galaxamide-treated group). The serum sex hormones levels, ovarian morphology, functional and molecular characterisation were determined and compared with those of the control group.
RESULTS: The hormonal effects indicated premature ovarian insufficiency (POI) associated with CIS-induced tumor-bearing mice. CIS induces the apoptosis in primordial and developing follicles and subsequently increases follicular atresia, eventually leading to follicle loss. After cotreatment, galaxamide significantly increased anti-Mullerian hormone (AMH) and follicle-stimulating hormone receptor (FSHR) expression and prevented the CIS-induced PI3K pathway, which triggers follicle activation, apoptosis or atresia.
CONCLUSIONS: These findings demonstrate that galaxamide could attenuate CIS-induced follicle loss by acting on the PI3K signaling pathway by stimulating AMH and/or FSHR and thus provides promising therapeutic options for patients with cervical cancer.

Age at menopause (AOM) has a substantial impact on fertility and disease risk. While many loci with variants that associate with AOM have been identified through genome-wide association studies (GWAS) under an additive model, other genetic models are rarely considered1. Here through GWAS meta-analysis under the recessive model of 174,329 postmenopausal women from Iceland, Denmark, the United Kingdom (UK; UK Biobank) and Norway, we study low-frequency variants with a large effect on AOM. We discovered that women homozygous for the stop-gain variant rs117316434 (A) in CCDC201 (p.(Arg162Ter), minor allele frequency ~1%) reached menopause 9 years earlier than other women (P = 1.3 × 10-15). The genotype is present in one in 10,000 northern European women and leads to primary ovarian insufficiency in close to half of them. Consequently, homozygotes have fewer children, and the age at last childbirth is 5 years earlier (P = 3.8 × 10-5). The CCDC201 gene was only found in humans in 2022 and is highly expressed in oocytes. Homozygosity for CCDC201 loss-of-function has a substantial impact on female reproductive health, and homozygotes would benefit from reproductive counseling and treatment for symptoms of early menopause.

OBJECTIVE: To investigate the effect of Chinese medicine He\'s Yangchao recipe on premature ovarian insufficiency (POI) and its relationship with mitochondrial function of ovarian granulose cells in an animal model.
METHODS: Thirty-six female C57BL/6J mice were randomly divided into blank control group, model group, low-, medium- and high-dose He\'s Yangchao recipe treatment group and coenzyme Q10 (Q10) treatment group (positive control). The POI model was induced by a single intraperitoneal injection of cyclophosphamide (90 mg/kg). The animals were sacrificed after 21 days. Primary granulose cells were obtained from POI mice and treated with He\'s Yangchao recipe, ERβ inhibitor PHTPP, and He\'s Yangchao recipe+PHTPP in vitro for 24 h, respectively. Ovarian histopathological changes were observed by hematoxylin-eosin (HE) staining, ATP levels were detected by luciferase assay, mtDNA copy numbers were detected by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), mitochondrial structure changes were observed by transmission electron microscopy, protein and mRNA expression levels of estrogen receptor β (ERβ), peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), mitochondrial transcription factor A (TFAM), and superoxide dismutase 2 (SOD2) were detected by Western blotting and qRT-PCR.
RESULTS: The ovarian tissue in model group exhibited few secondary and tertiary follicles, whereas the He\'s Yangchao recipe groups and Q10 group had abundant secondary and tertiary follicles. Compared with the blank control group, ATP and mtDNA levels in model group decreased (P<0.01), mitochondrial crista disappeared or abnormal vacuolated structure increased; the protein and mRNA levels of ERβ, PGC1α, TFAM, and SOD2 decreased (all P<0.01). ATP production increased in granulose cells of high-dose He\'s Yangchao recipe group and Q10 group; mtDNA copy numbers increased (P<0.05 or P<0.01); abnormal mitochondrial structure was reduced; the protein and mRNA expressions of ERβ, PGC1α, TFAM, and SOD2 increased (P<0.05 or P<0.01). Compared with the PHTPP intervention group, the proportion of normal mitochondrial structure in the granulose cells of He\'s Yangchao recipe + PHTPP group was higher; ATP content increased (P<0.05 or P<0.01); mtDNA copy numbers increased (P<0.05 or P<0.01); the protein and mRNA expression of ERβ, PGC1α, TFAM and SOD2 increased (P<0.05 or P<0.01).
CONCLUSIONS: He\'s Yangchao recipe can regulate mitochondrial biogenesis through ERβ/PGC1α/TFAM pathway to improve ovarian function in POI mice.
目的: 探究何氏养巢方（简称“养巢方”）提高卵巢颗粒细胞线粒体功能的机制。方法: 取36只6~8周龄C57BL/6J雌鼠随机分为空白对照组，模型对照组，养巢方小、中、大剂量组和阳性对照组。均予环磷酰胺90 mg/kg单次腹腔注射以建立原发性卵巢功能不全（POI）模型后，分组灌胃21 d后处死。另取6只6~8周龄C57BL/6J雌鼠造模后获取原代颗粒细胞，分为养巢方组、PHTPP（一种雌激素受体阻滞剂）组、养巢方+PHTPP组，分别予养巢方含药血清或PHTPP或同时给予两者干预培养24 h。分别采用苏木精-伊红（HE）染色观察卵巢组织病理学变化；荧光素酶法检测颗粒细胞腺苷三磷酸（ATP）水平；定量逆转录聚合酶链反应（qRT-PCR）检测线粒体DNA（mtDNA）的拷贝数；透射电镜观察线粒体结构变化；蛋白质印迹法检测雌激素受体β（ERβ）、过氧化物异酶体增殖物激活受体γ共激活因子1α（PGC1α）、线粒体转录因子A（TFAM）、超氧化物歧化酶2（SOD2）蛋白表达；qRT-PCR检测Erβ、Pgc1α、Tfam、Sod2 mRNA表达。结果: 模型对照组卵巢组织次级及三级卵泡较少，养巢方各剂量组及阳性对照组次级及三级卵泡较多。与空白对照组比较，模型对照组颗粒细胞ATP和mtDNA水平均下降（均P<0.01），线粒体嵴消失或空泡化结构异常比例增加，ERβ、PGC1α、TFAM、SOD2蛋白及其mRNA表达均下降（均P<0.01）。养巢方中、大剂量组及阳性对照组颗粒细胞内ATP生成增多、mtDNA拷贝数增加（P<0.05或P<0.01）；颗粒细胞内结构异常线粒体减少，ERβ、PGC1α、TFAM、SOD2蛋白及其mRNA表达均增加（P<0.05或P<0.01）。体外实验中，与PHTPP组比较，养巢方+PHTPP组线粒体结构正常比例更高，线粒体ATP含量增加（P<0.05或P<0.01），mtDNA拷贝数增加（P<0.05或P<0.01）；ERβ、PGC1α、TFAM、SOD2蛋白及其mRNA表达均上升（P<0.05或P<0.01）。结论: 养巢方可以通过ERβ/PGC1α/TFAM通路提高线粒体生物发生从而改善POI小鼠卵巢功能。.