To date, there remains a paucity of prospective studies examining the association between premature ovarian insufficiency (POI) and cardiovascular diseases (CVD). The objective of this study was to investigate the potential association between POI and CVD utilizing the method of Mendelian randomization (MR). MR analyses utilized summary statistics from the most extensive genome-wide association studies (GWAS) on POI and CVD extracted from European ancestry cohorts and the FinnGen biobank. The inverse variance-weighted (IVW) method was the primary MR analysis technique. Supplementary analyses were performed using MR-Robust Adjusted Profile Score (MR-RAPS). Cochran's Q statistic, MR-Egger, and weighted median MR models were employed to further assess heterogeneity and horizontal pleiotropy. Causal effects of POI on coronary heart disease (odds ratio [OR] = 1.048, 95% confidence interval [CI]: 1.006-1.091; p = 0.023)] and ischemic stroke (OR = 1.010, 95% CI: 1.000-1.020; p = 0.0498) were found. However, we did not observe a significant correlation between POI and hypertension (OR = 0.999, 95% CI: 0.994-1.004, p = 0.691), heart failure (OR = 1.009, 95% CI: 0.999-1.020, p = 0.0725), atrial fibrillation (OR = 0.995, 95% CI: 0.986-1.004, p = 0.3035), and myocardial infarction (OR = 1.002, 95% CI: 0.991-1.013, p = 0.7061). POI was causally associated with coronary heart disease and ischemic stroke, with no apparent impact on hypertension, heart failure, atrial fibrillation, or myocardial infarction. The causal relationship between POI and CVD underscores the imperative for proactive cardiovascular risk management in individuals with POI.

To explore the global burden of female infertility from 1990 to 2021 by examining trends in prevalence and years lived with disability (YLD).

Data from the Global Burden of Disease Study 2021 (GBD 2021) were analyzed with a focus on the prevalence and YLD of female infertility in women aged 15-49 years. Statistical models were used to estimate ASPRs and YLD across regions and countries.

The global prevalence of female infertility was 110.1 million in 2021, with an age-standardized rate of 2,764.6 per 100,000 population. The YLD for infertility in 2021 was 601,134, which represented a 33.1% increase since 1990. Regionally, East Asia and Eastern Europe had the highest rates of infertility, whereas Australasia had the lowest rate.

The study highlights a significant rise in the burden of female infertility, particularly in high-income regions. Study findings emphasize the need for targeted public health strategies and healthcare interventions to address this growing issue.

Objectives: Premature ovarian insufficiency (POI) is a serious condition that affects women worldwide, In recent years, the number of research publications on POI has increased over the last decades because of the advancement of cutting-edge research in gynecology and the deepening of disciplinary interactions. At the same time, there is a more urgent need to systematically analyze and review existing studies to generalize the research paradigm and disciplinary structure of the field under technological changes.

Materials and methods: We selected the top 100 most cited papers in the Web of Science (WOS) SCI-Expanded database. Knowledge graphs were constructed through the VOS viewer, Cite Space, and Scimago Graphica software, and then relevant information retrieved from the literature was edited using Excel to assess research priorities and trends in the field.

Results: A total of 53 periodicals from 34 different nations and regions published the 100 most-cited publications between 1999 and 2024. The Journal of Clinical Endocrinology & Metabolism published the majority of the papers, while The Lancet had the highest average number of citations per piece. The United States of America produced the highest contribution in terms of publications, with China and France closely trailing after. In terms of total publications, Erasmus MC, Shanghai Jiao Tong University, and Shandong University each contributed the highest number of papers. The main categories were obstetrics and gynecology, endocrinology and metabolism, and reproductive biology. The top five keywords were: failure, women, ANTI-MULLERIAN HORMONE, NATURAL MENOPAUSE, and AGE. The study of HERITAGE AND GENETICS, CARDIOVASCULAR DISEASES, and CELL BIOLOGY AND IMMUNOGENETICS is becoming more and more popular in POI, as shown by cluster analysis.

Conclusions: Bibliometric analysis enables POI researchers to efficiently and visibly pinpoint the cutting-edge areas and focal points of their study. Potential topics of future study may include genetic and molecular biological pathways, cardiovascular pathology, and immunology.

Huyang Yangkun Formula (HYF) is a Chinese herbal remedy used for premature ovarian insufficiency (POI), though its active ingredients and mechanisms are not well understood.This study aims to identify HYF's chemical components and investigate its mechanism in treating POI. Using UHPLC-QE Focus HRMS, chemical profiling and quantification were conducted. The therapeutic effects and target validation of HYF were examined using a POI rat model, human ovarian granulosa cells (COV434), and network pharmacology. Molecular docking was used to predict the affinity of active compounds for the key target TP53. 125 compounds were identified in HYF, including flavonoids, organic acids, saponins and phenylethanoid glycosides. By using network pharmacological analysis, a total of 123 potential targets for the HYF treatment of POI were identified. PIK3R1, AKT1, EGFR, MMP2 and TP53 were deduced to be core targets of HYF for treating POI, and the main pathway included HIF-1, PI3K-Akt and P53 signaling pathway. HYF enhances follicle development and ovarian function by reducing apoptosis in ovarian granulosa cells in VCD-POI rats. In vitro, HYF decreased VCD-induced COV434 cell death. qRT-PCR and WB experiments identified the P53-mitochondrial apoptosis signaling pathway as the main target, with molecular docking showing Hyperoside, Isochlorogenic acid B, and Baohuoside I having the highest binding affinity to TP53.The potential active components and mechanisms of HYF in relation to POI were investigated through chemical profiling, network pharmacology, and both in vitro and in vivo experimental validation.

The menopausal transition, defined by the cessation of menstruation due to declining ovarian follicular function, results in a marked decrease in endogenous estrogen levels. This phase is associated with significant metabolic changes and a shift towards a more atherogenic lipid profile. Specifically, there are increases in total cholesterol, low-density lipoprotein cholesterol, and triglycerides and unfavorable alterations in high-density lipoprotein cholesterol and lipoprotein(a) levels. These lipid changes, which contribute to an increased risk of atherosclerotic cardiovascular disease, are influenced by diminished estrogen levels and chronological aging. However, the specific mechanisms driving this increased risk are not fully understood. A thorough understanding of these lipid profile alterations is important for developing strategies to reduce cardiovascular disease risk in women. This review provides an overview of how lipid metabolism is affected during the menopausal transition and the resulting implications for cardiovascular risk.

While Chinese herbal medicines have been used to treat premature ovarian insufficiency (POI), their efficacy is currently unclear. The present study aimed to review and evaluate the efficacy of the Kuntai capsule combined with hormone replacement therapy (HRT) in treating POI. The China National Knowledge Infrastructure, WanFang, Chinese Biomedical Literature, PubMed, Embase and Cochrane Library databases were searched from the inception of the database to 25th October 2020, for studies comparing the therapeutic effect of Kuntai capsule combined with HRT vs. HRT alone in women with POI. The Cochrane Risk of Bias assessment tool was used to assess the quality of the studies, and the results were reported as weighted mean differences (MD) with 95% confidence intervals (CI). The present study included 10 trials involving 742 women with POI. When compared with HRT alone, HRT combined with Kuntai capsule significantly increased the number of antral follicles (AFC) (MD=0.88; 95% CI, 0.48-1.29; P<0.00001), anti-Müllerian hormone (AMH) levels (MD=0.24, 95% CI, 0.13 to 0.35, P<0.00001) and significantly improved peri-menopausal symptoms [MD=-2.26; 95% CI, -3.77-(-0.75); P=0.003]. The combined treatment regimen significantly decreased the levels of follicle-stimulating hormone [MD=-5.60; 95% CI, -7.98-(-3.22); P<0.00001] and luteinizing hormone [MD=-2.42; 95% CI, -3.40-(-1.44), P<0.00001] and significantly increased the level of estradiol (MD=13.94; 95% CI, 4.16-23.71; P<0.00001). Therefore, the Kuntai capsule combined with HRT could potentially be used as a supplementary therapy to alleviate menstrual disorders and peri-menopausal symptoms and improve serum sex hormone levels in women with POI. The observed increase in the number of AFC in patients with POI treated with the combined therapy was indicative of improved ovarian reserve function. Therefore, combining the Kuntai capsule and HRT had am improved curative effect for POI treatment compared with HRT alone. However, as the present study was limited by the quality of the included reports, additional high-quality studies with extensive sample sizes are required to verify the findings.

This study aims to explore the mitigative impact of levomilnacipran (LVM) against cyclophosphamide (CPA)-induced premature ovarian insufficiency by targeting TLR4/p38 MAPK/NF-κB p65, and klotho expression.

Rats were allocated into five groups as follows: control, LVM, CPA, CPA + LVM, and CPA + TRI. Serum hormones and histopathological examination were performed. To assess oxidative stress, ovarian MDA, GSH, and SOD were evaluated. The ovarian contents of caspase-3 and inflammatory markers were assessed using the ELISA method. The expression of ovarian NF-κB p65 was examined using an immunohistochemical technique. RT-qPCR was used to measure Bax and Bcl-2 mRNA expression. Utilizing a Western blot, the TLR4, p38 MAPK, α-Klotho, and cleaved caspase-3 levels were estimated. The estrous cycle was also monitored.

LVM attenuated CPA-induced ovarian toxicity by regulating hormones and alleviating histopathological aberrations. It also raised SOD and GSH levels and lowered MDA's ovarian content. Moreover, Bcl-2 levels were raised, Bax and caspase-3 expression levels were reduced, and IL-18, IL-1β, and TNF-α levels were all reduced. LVM-induced ovarian protection by diminishing TLR4/p38 MAPK/NF-κB p65 expression and boosting the protein levels of α-Klotho.

LVM mitigated POI caused by CPA by downregulating TLR4/p38 MAPK/NF-κB p65, enhancing the α-Klotho level and attenuating caspase-3 derived apoptosis.

To report a case with combined pituitary hormone deficiency (CPHD) and Fibroblast growth factor receptor 1 (FGFR1) gene defect, and summarize the clinical characteristics of similar cases by reviewing the current reports from the literature.

A 24-year-old woman was admitted to the outpatient endocrinology unit with a diagnosis of primary amenorrhea, history of Growth Hormone deficiency and multiple congenital anomalies including rectal atresia. The subsequent hormonal investigation led to the diagnosis of hypogonadotropic hypogonadism and persistent GH deficiency. Abdominal and pelvic ultrasounds were normal whereas the brain MRI revealed a hypoplastic sella turcica with a hypoplastic anterior pituitary lobe, an ectopic posterior pituitary lobe and a thin pituitary stalk. The genetic analysis revealed a novel pathogenic missense heterozygous variant (c.1958G > A, p.Agr635Gln) in exon 15 of FGFR1 gene. PubMed, Scopus, and Web of Science were searched for the identification of studies reporting cases of CPHD with FGFR1 gene defects.

Of the 648 records retrieved, 10 were included in this review. A comprehensive overview of the cases was summarized, and their clinical and genetic characteristics were presented.

Although FGFR1 variants have been associated with Kallmann syndrome and isolated hypogonadotropic hypogonadism and recently with CPHD, the patient's phenotype includes phenotypic alterations not previously described, to the best of our knowledge, within the spectrum of non-reproductive features of either of these entities. Isolated GH deficiency combined with other non-common abnormalities exerts a great possibility for subsequent CPHD manifestation.

BaZiBuShen (BZBS) is an innovative, patented traditional Chinese medicine known for its kidney-tonifying and anti-aging effects. It contains active ingredients such as flavonoids and amino acid analogues, which have anti-inflammatory and antioxidant properties, and is used to alleviate symptoms of "kidney essence" deficiency.

This study evaluated the efficacy of BZBS on cyclophosphamide (CTX)-induced premature ovarian insufficiency (POI) and explored its possible mechanism of action.

POI models in rats were established using CTX to assess the therapeutic effects of BZBS. HPLC-MS was used to analyze the components, while ELISA was adopted to determine the serum hormone levels. Ovarian morphology and number of follicles were evaluated by H&E staining. The ultrastructure of mitochondria was examined by TEM. The expression levels of proteins related to ferroptosis and the NF2-YAP signalling pathway were analyzed using immunohistochemistry, immunofluorescence, and Western blotting.

In CTX-induced POI rats, BZBS treatment effectively restored ovarian weight, while simultaneously decreasing serum FSH and LH levels and increasing E2 levels. Histological analysis of the ovaries revealed that BZBS significantly increased the number of primordial, growing, and mature follicles, as well as reducing the number of atretic follicles. Furthermore, BZBS treatment mitigated ferroptosis by decreasing key markers Fe2+, TFR, ACSL4, and restoring the levels of GSH and GPX4. Additionally, BZBS modulated the expression of critical proteins involved in ferroptosis and cell signalling pathways. Specifically, it down-regulated p-RB1, while up-regulating SLC7A11 and RB1. Moreover, BZBS upregulates NF2 while downregulating YAP expression and its nuclear translocation, thereby regulating the NF2-YAP signaling pathway involved in ferroptosis.

In a CTX-induced POI rat model, BZBS effectively restores hormonal levels, mitigates ovarian damage, and curbs excessive primordial follicle activation. It also modulates ferroptosis-related protein expression, activates the NF2-YAP pathway, and could provide a potential therapeutic approach for POI.

Premature ovarian insufficiency (POI), affecting 3.5 % of women under 40, significantly impacts reproductive health. The unknown etiology in over 50 % of POI cases impedes accurate diagnosis and treatment. Evidence shows that environmental agents can adversely affect health and reduce fertility. Trace elements are critical pollutants impacting human health. However, research on populations with POI and their links to these elements is limited. We enrolled 367 female patients, dividing them into a POI group and a control group. We employed ICP-MS to measure 25 trace elements in follicular fluid. Bayesian kernel machine regression analyzed combined exposure effects and restricted cubic splines evaluated the relationships between individual trace elements and ovarian reserve markers, focusing on anti-Müllerian hormone (AMH) and basal FSH (bFSH). Logistic regression assessed the association between specific element concentrations and POI occurrence, and the posterior inclusion probability model tested the robustness of key driving factors. The study identified 24 trace elements in follicular fluid samples, revealing significant differences in 23 elements between the two groups. There were positive correlations between Cu, I, Se, and Zn with AMH levels, while negative correlations were observed for Ca, Co, Li, and AMH. Nonlinear relationships were noted for Ba, Cd, Fe, Mg, Mn, Mo, and Pb. Ca, Li, and Ni showed a significant positive correlation with bFSH, while Cu, I, Mg, Se, and Zn demonstrated a significant negative correlation with bFSH. Additionally, Ba, Mn, and Pb exhibited a nonlinear correlation with bFSH. Individuals in the medium and high tertiles for Cu, I, Pb, Se, and Zn were less likely to develop POI. In contrast, those in the medium and high tertiles for Ba, Ca, Cd, Li, Mn, and Ni had an increased likelihood of POI. Our study addresses a crucial gap by examining trace element exposure in follicular fluid and its link to POI risk, enhancing understanding of their effects on female ovarian function. This study lays a foundation for monitoring female fertility and emphasizes the importance of environmental pollutants on reproductive health.

It was a true honor to be invited as President to deliver the Pieter Van Keep oration at the 2024 International Menopause Society (IMS) Congress in Melbourne, Australia. There was never any doubt that the topic of my lecture would be premature ovarian insufficiency (POI). POI is a condition which has been neglected for far too long given its greater global prevalence than originally estimated and its implications to the sufferers, both in terms of quality of life and long-term well-being. The hope is that we are now entering a new era of awareness given the recent update of the European Society of Human Reproduction (ESHRE) POI guideline, achieved through a partnership of the ESHRE, American Society for Reproductive Medicine (ASRM), Centre for Research Excellence in Women's Health in Reproductive Life (CRE WHiRL) at Monash University and IMS with support from numerous global stakeholder organizations. Whilst as a minimum the update of the guideline is expected to improve clinical management of this condition, the process has also identified key areas of much-needed research, where currently only practical guidance can be given due to the lack of data. The aim of my Pieter Van Keep lecture, and therefore this article, was not to replicate the extensive work already conducted to systematically review the literature for the guideline. The aim was to provide a state-of-the-art commentary highlighting the key controversial topics regarding this distressing condition, and how these are being addressed, or should be addressed in the future, for the sake of sufferers and their families.

Premature ovarian insufficiency (POI) poses a significant threat to female reproductive health and currently lacks effective interventions. Recent studies highlight the promising potential of human pluripotent stem cell-derived mesenchymal stem cells (hPSC-MSC) in regenerative medicine. However, research on hPSC-MSC-based treatments for POI remains limited, particularly in the characterization of the intermediate differentiation stages from hPSC to MSC. This study presents an accelerated differentiation protocol for generating hPSC-MSC via neural crest cells (NCC) and evaluates their therapeutic potential in chemotherapy-induced POI.

We modified a canonical small molecule-mediated protocol for hPSC-NCC-MSC differentiation. Systematic characterization of differentiated-cells was performed using qPCR, immunofluorescence, cell viability assays, flow cytometry and trilineage differentiation. In vivo, hPSC-NCC-MSC were transplanted into chemotherapy-induced POI SD rat models, and parameters such as body weight, ovarian weight, estrous cycle, hormone levels, follicle count, and mating were assessed. Granulosa cells (GC) apoptosis was analyzed using TUNEL assay and immunohistochemistry. In vitro, their effects on apoptosis inhibition and oxidative stress alleviation were investigated in a cultured GC cell line. Additionally, comparisons between umbilical cord MSC (UC-MSC) and hPSC-NCC-MSC in chemotherapy-induced POI was conducted.

Our optimized protocol, combining CHIR99021 and SB431542, efficiently induced NCC from both human embryonic stem cells (hESC) and human induced pluripotent stem cells (hiPSC). The programmed hPSC-NCC-MSC, characterized by specific NCC markers (P75, HNK1, SOX10, and AP2α), exhibited typical MSC morphology, trilineage differentiation potential, favorable cell viability, and prominent anti-senescence properties. Among these, NCC differentiated from H1-hESCs (H1-NCC) demonstrated the highest induction efficiency (72.45%), and H1-NCC-derived MSC (H1-NCC-MSC) displayed superior proliferation and anti-senescence properties compared to UC-MSC. Besides, H1-NCC-MSC exhibited therapeutic efficacy comparable to UC-MSC in both in vivo and in vitro models of chemotherapy-induced POI, potentially through mechanisms involving reduced GC apoptosis, alleviated oxidative stress, and improved mitochondrial function.

Our findings propose a modified hPSC-NCC-MSC differentiation protocol, offering an inexhaustible and stable source for regenerative therapies. Furthermore, we provide the first experimental evidence that hPSC-NCC-MSC have therapeutic potential comparable to UC-MSC in restoring chemotherapy-induced POI. The underlying mechanisms are likely associated with paracrine-mediated effects on GC apoptosis, oxidative stress, and mitochondrial dysfunction.

This study aims to investigate the protective impact of buspirone (BUS) against cyclophosphamide (CPA)-induced premature ovarian insufficiency (POI) by focusing on pyroptosis, apoptosis, and the AMPK/Nrf2/HO-1 signaling pathway. POI was achieved by i.p. injection of CPA in female Wistar albino rats. CPA toxicity was evaluated using biochemical analysis of the serum hormones (AMH, FSH, inhibin B, and estrogen) and histopathological examination. Oxidative stress markers (MDA, SOD) were also evaluated. Levels of inflammatory indicators (TNF-α, IL-1β, and IL-18), apoptotic marker (caspase-3), ovarian p-AMPK, ovarian NF-κB, Nrf2, and HO-1 were evaluated. RT-qPCR was used to measure Bax and Bcl-2 mRNA expression. A western blot assay was used to determine the expression of α-Klotho, NLRP3, and caspase 1. The estrous cycle and the weights of the body and ovaries were also observed. BUS, in a dose-dependent manner, attenuated CPA-induced ovarian toxicity by regulating hormonal and estrous cycle irregularities and alleviating the histopathological aberrations. It also lowered MDA levels and increased SOD activity. Furthermore, it reduced NF-κB, TNF-α, IL-1β, and IL-18 levels, as well as BAX and caspase-3 expression, while raising Bcl-2 levels. Additionally, BUS enhanced Nrf2 and HO-1 expression and boosted the protein levels of p-AMPK and α-Klotho. As well, it diminished pyroptosis by decreasing NLRP3 and caspase-1 expression. BUS attenuated POI induced by CPA, showing potential for effective protection via increasing the activity of Nrf2/HO-1 and reducing the activity of NLRP3/Caspase-1 through the participation of α-Klotho and p-AMPK, as well as inhibiting caspase-3-driven apoptosis.

Women are increasingly choosing to delay childbirth, and those with low ovarian reserves indicative of primary ovarian insufficiency are at risk for sub- and infertility and also the early onset of menopause. Experimental strategies that promise to extend the duration of ovarian function in women are currently being developed. One strategy is to slow the rate of loss of existing primordial follicles (PFs), and a second is to increase, or 'boost', the number of autologous PFs in the human ovary. In both cases, the duration of ovarian function would be expected to be lengthened, and menopause would be delayed. This might be accompanied by an extended production of mature oocytes of sufficient quality to extend the fertile lifespan.

In this work, we consider how slowing physiological ovarian aging might improve the health and well-being of patients, and summarize the current state-of-the-art of approaches being developed. We then use mathematical modeling to determine how interventions are likely to influence the duration of ovarian function quantitatively. Finally, we consider efficacy benchmarks that should be achieved so that individuals will benefit, and propose criteria that could be used to monitor ongoing efficacy in different patients as these strategies are being validated.

Current methods to estimate the size of the ovarian reserve and its relationship to the timing of the menopausal transition and menopause were compiled, and publications establishing methods designed to slow loss of the ovarian reserve or to deliver additional ovarian PFs to patients were identified.

We review our current understanding of the consequences of reproductive aging in women, and compare different approaches that may extend ovarian function in women at risk for POI. We also provide modeling of primordial reserve decay in the presence of therapies that slow PF loss or boost PF numbers. An interactive online tool is provided that estimates how different interventions would impact the duration of ovarian function across the natural population. Modeling output shows that treatments that slow PF loss would need to be applied as early as possible and for many years to achieve significant delay of menopause. In contrast, treatments that add additional PFs should occur as late as possible relative to the onset of menopause. Combined approaches slowing ovarian reserve loss while also boosting numbers of (new) PFs would likely offer some additional benefits in delaying menopause.

Extending ovarian function, and perhaps the fertile lifespan, is on the horizon for at least some patients. Modeling ovarian aging with and without such interventions complements and helps guide the clinical approaches that will achieve this goal.

Not applicable.

Premature ovarian insufficiency (POI) is characterized by ovarian dysfunction that develops from diminished ovarian reserve (DOR). The exact aetiology of POI remains poorly understood. This study aims to elucidate the role of CKAP5 in the regulation of ovarian function and fertility.

Bulk RNA sequencing of granulosa cells was conducted in the control group and in the patients with DOR to screen for candidate genes, which were further validated by gene burden analysis in a next-generation sequencing cohort of POI and control individuals. Additionally, ovarian reserve was evaluated in heterozygous Ckap5 knockout mice, alongside the ovarian and oocyte single-cell transcriptome analysis. The regulatory mechanism of CKAP5 was studied through in vivo and in vitro experiments.

CKAP5 was identified as a key hub gene associated with ovarian ageing. Heterozygous Ckap5 knockout mice exhibited a POI-like phenotype, characterized by a reduced primordial follicle pool and accelerated follicular atresia. CKAP5 promotes autophagy via ATG7 and simultaneously supports DNA damage repair through the ATM. Finally, a variant in CKAP5 (NM_0001008938.4, c.630 + 7_630 + 11delCAAAA) was identified in patients with POI, resulting in protein truncation and loss of function.

CKAP5 deficiency induces premature ovarian insufficiency in both humans and mice.

The National Key R&D Program of China (2017YFC1001100), the National Natural Science Foundation of China (81501248, 81471453 and 81801295), the Health Research Project of Hunan Provincial Health Commission (W20243018), the Science and Technology Innovation Program of Hunan Province (2021RC3031), the National Natural Science Foundation of Hunan Province (2022JJ30066), the Scientific Research Program of Hunan Provincial Health Commission (202205033471 and 21B0058), the Open Research Fund of Hunan Provincial Key Laboratory of Regional Hereditary Birth Defects Prevention and Control (HPKL2023013).

To establish a murine model of chemotherapy-induced diminished ovarian reserve (DOR) and investigate residual fertility after chemotherapy exposure.

Two different chemotherapy protocols were tested to establish a valid DOR model by comparing follicle densities in mice given either protocol or physiological solution. An ovarian stimulation protocol was then selected from among different gonadotropins by counting the number of day 2 embryos obtained from normal mice. Finally, DOR mice were stimulated 5 and 8 weeks after chemotherapy with the chosen gonadotropin protocols, and day 2 embryos were recovered after mating, as was ovarian tissue for further immunohistologic analyses.

Seventy-two Naval Medical Research Institute mice.

Two different chemotherapy protocols.

This study compared day 2 embryo counts in both normal and chemotherapy-induced DOR mice. Ovarian histology and morphology were also investigated by follicle counting and classification, as was immunostaining for apoptosis (cleaved caspase-3), activation (phospho-Akt), and proliferation (Ki67).

A dose of 12 mg/kg of busulfan (Bu) + 120 mg/kg of cyclophosphamide (Cy) was chosen to establish the DOR model as it significantly reduced the ovarian reserve compared to both control mice (physiological solution) and the 1.2 mg/kg of Bu + 12 mg/kg of Cy protocol, without depleting it completely. When stimulated with 3.75 IU of Menopur, normal mice produced significantly more embryos than DOR mice given 12 mg/kg of Bu + 120 mg/kg of Cy (41.40 ± 14.74 vs. 23.67 ± 15.55 day 2 embryos). Although the follicle count was statistically diminished after single-dose chemotherapy administration, the remaining follicles did not display any difference in terms of apoptosis, activation, or proliferation rates.

We successfully established a chemotherapy-induced DOR model using 12 mg/kg of Bu + 120 mg/kg of Cy, as evidenced by lower, but not completely depleted, follicle numbers and fewer retrieved embryos. Histologic study of ovarian tissue exposed to DOR-inducing chemotherapy revealed that surviving follicles were of the similar quality as tissue not exposed to chemotherapy.

Fracture is an under-recognized but common complication of diabetes mellitus, with an incidence approaching twofold in type 2 diabetes mellitus (T2DM) and up to sevenfold in type 1 diabetes mellitus (T1DM) compared with that in the general population. Both T1DM and T2DM induce chronic hyperglycaemia, leading to the accumulation of advanced glycosylation end products that affect osteoblast function, increased collagen crosslinking and a senescence phenotype promoting inflammation. Together with an increased incidence of microvascular disease and an increased risk of vitamin D deficiency, these factors reduce bone quality, thereby increasing bone fragility. In T1DM, reduced anabolic stimuli as well as the presence of autoimmune conditions might also contribute to reduced bone mass and increased fragility. Diabetes mellitus is the most common cause of kidney failure, and fracture risk is exacerbated when chronic kidney disease (CKD)-related mineral and bone disorders are superimposed on diabetic changes. Microvascular pathology, cortical thinning and trabecular deterioration are particularly prominent in patients with T1DM and CKD, who suffer more fragility fractures than do other patients with CKD. This Review explores the pathophysiology of bone fragility in patients with diabetes mellitus and CKD and discusses techniques to predict fracture and pharmacotherapy that might reduce fracture risk.

Autosomal recessive severe congenital neutropenia (SCN) has been associated with homozygous variants in the HAX1 gene. The aim of this cross-sectional study was to evaluate the gonadal function and pubertal development in pediatric patients with SCN due to HAX1 gene variant (HAX1-SCN).

Forty-five patients, including 24 females (median age 11.3 [1.5-31] years, 13 pubertal, 11 prepubertal), and 21 males (median age 9.5 (3-18.8) years, 7 pubertal, 14 prepubertal), followed in seven centers, were included. POI is defined as a menstrual disturbance with increased follicle-stimulating hormone (FSH) and low anti-Mullerian hormone (AMH). We classified prepubertal female patients as impending POI when they had low AMH and high FSH values, indicating impaired ovarian function.

A homozygous single nucleotide insertion (position 130-131insA) leading to a premature stop codon; p.Trp44*(c.132G>A) variant in HAX1 gene was detected in 42 (93.3%) affected individuals. Other homozygous variants were p.Arg86*(c.256C>T) and p.Glu60Aspfs*25(c.180delA). We detected elevated serum FSH levels in 10/11 (90.9%) of prepubertal female patients, supporting the diagnosis of impending POI, and in 12/13 (92.3%) of pubertal female patients, classifying them as POI. All female patients had low AMH levels. Male patients did not exhibit gonadal insufficiency.

This is the first and largest case series covering early childhood to evaluate patients with HAX1-SCN for gonadal function. It has been observed that pubertal females develop POI, prepubertal females are at increased risk for gonadal failure, and male patients are not affected. Our results suggest that HAX1 has an important role in ovarian maturation and/or function.

Inflammation is a key feature of neoplastic diseases, especially cancer. Predicting follicular density (FD) in ovarian cortical tissue is essential for evaluating ovarian tissue cryopreservation (OTC) outcomes in fertility preservation. However, to date, no studies have explored the role of inflammatory markers in predicting FD in OTC patients. This study aims to investigate the relationship between blood inflammatory parameters and FD in this population.

We conducted a retrospective observational study on 101 OTC patients. The primary goal was to assess whether parameters from Complete Blood Count (CBC) that include White Blood Cells (WBC), absolute neutrophil count, absolute lymphocyte count, Neutrophil/Lymphocyte Ratio (NLR), Mean Platelet Volume (MPV), Platelet Count (PC), MPV/PC and the Platelet/Lymphocyte Ratio (PLR) could predict FD. We also evaluated the impact of factors such as oncological diagnosis, smoking, Body Mass Index (BMI), and germline BRCA mutations. Spearman's correlation coefficient and the Mann-Whitney test were used for analysis.

Significant correlations were found in patients aged between 27 and 31. In this group, NLR was inversely correlated with FD (Rho = -0.374, p = 0.032), while lymphocyte count (Rho = 0.371, p = 0.034) and MPV/PC (Rho = 0.365, p = 0.037) were positively correlated with FD. An inverse correlation was also found between PLR and FD (Rho = -0.38, p = 0.028).

Our findings suggest that NLR, lymphocyte count, MPV/PC and PLR may be useful in predicting FD in a subgroup of OTC patients. Larger studies are needed to confirm these results.

What is the association between endometriosis and the type and age of menopause?

Women with endometriosis had a 7-fold increased risk of undergoing surgical menopause rather than natural menopause and were more likely to experience premature or early menopause, both surgically and naturally.

Endometriosis is associated with reduced ovarian reserve, but evidence on its relationship with the type of menopause (surgical vs natural) and timing (especially premature and early menopause) is limited. Women with endometriosis are more likely to undergo hysterectomy and/or oophorectomy (either unilateral or bilateral), but the average age of these surgeries remains unclear.

The study analysed individual-level data from 279 948 women in five cohort studies conducted in the UK, Australia, Sweden, and Japan between 1996 and 2022.

Women whose menopause type and age could not be determined due to premenopausal hysterectomy with ovarian preservation or use of menopausal hormone therapy were excluded. Endometriosis was identified through self-reports and administrative data. Surgical menopause was defined as premenopausal bilateral oophorectomy. Fine-Gray subdistribution hazard models estimated hazard ratios (HRs) for surgical and natural menopause. Age at menopause was determined by the ages at the final menstrual period or bilateral oophorectomy. Linear regression assessed mean differences in menopause age, while multinomial logistic regression estimated odds ratios (ORs) for categorical menopause age: <40 (premature), 40-44 (early), 45-49, 50-51 (reference), 52-54, and ≥55 years. Spontaneous premature ovarian insufficiency (POI) was defined as natural menopause before age 40 years.

Endometriosis was identified in 3.7% of women. By the end of follow-up, 7.9% had surgical menopause and 58.2% experienced natural menopause. Using a competing risk model, women with endometriosis had a 7-fold increased risk of surgical menopause (HR: 7.54, 95% CI 6.84, 8.32) and were less likely to experience natural menopause (HR: 0.40, 95% CI 0.33, 0.49). On average, surgical menopause occurred 1.6 years (19 months) earlier (β: -1.59, 95% CI -1.77, -1.42) in women with endometriosis. Among women who experienced natural menopause, it was 0.4 years (5 months) earlier (β: -0.37, 95% CI -0.46, -0.28) for those with endometriosis. Women with endometriosis were twice as likely to experience premature surgical menopause (<40 years) (OR: 2.11, 95% CI 2.02, 2.20) or 1.4 times more likely to develop spontaneous POI (OR: 1.36, 95% CI 1.17, 1.59). They were also at increased odds of early surgical and natural menopause (40-44 years).

This study could not differentiate between subtypes and stages of endometriosis or assess treatments for ovarian endometrioma, which may impact ovarian reserve. Self-reported menopause type and age could introduce recall bias.

Given the consistent findings across individual studies, our results are likely to be generalizable to different populations, highlighting the need for tailored management of endometriosis to prevent medically induced or premature menopause. Long-term monitoring of women with endometriosis is recommended, given their elevated risk of surgical menopause and premature or early menopause, which are associated with adverse health outcomes in later life.

The InterLACE Consortium is funded by the Australian National Health and Medical Research Council project grant (APP1027196) and Centres of Research Excellence (APP1153420). G.D.M. is funded by the Australian National Health and Medical Research Council Leadership Fellowship (APP2009577). This research is funded in part by the Japan Society for the Promotion of Science (JSPS KAKENHI: 19KK0235, 23KK0167). The authors have no conflict of interest. Where authors are identified as personnel of the International Agency for Research on Cancer or WHO, the authors alone are responsible for the views expressed in this article, and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer or WHO.

N/A.

With the acceleration of the pace of modern life and the increase of environmental pressure, women are facing increasingly prominent health problems, ovarian dysfunction will not only lead to fertility decline, but also may lead to a series of endocrine disorders, seriously affecting women's quality of life. The purpose of this study was to explore the potential role of American panax panax in improving ovarian dysfunction by activating the BDNF/AKT/Bcl-2/Bax signaling pathway via miR-151-5p based on infrared thermal imaging technology. The study constructed an animal model of ovarian dysfunction, and used infrared thermal imaging technology to monitor the ovarian region in real time and record its temperature changes to evaluate the treatment effect. Through these data, we analyzed the activation effect of American ginseng extract on the signaling pathway and its relationship with the improvement of ovarian function. The results of the study showed that the infrared thermography of the ovarian region treated with American ginseng extract showed a significant increase in temperature, indicating increased ovarian blood flow and enhanced metabolic activity. These changes suggest that American ginseng extract can effectively activate the BDNF/AKT/Bcl-2/Bax signaling pathway, thereby improving ovarian dysfunction. The results showed that American ginseng extract can effectively promote the repair and functional recovery of ovarian tissue, and infrared thermal imaging technology has a good application prospect in monitoring the therapeutic effect.

Primary ovarian insufficiency (POI) patients often require prolonged stimulation for follicular growth. Anti-Müllerian hormone (AMH), produced by granulosa cells of early-stage follicles, is a potential a biomarker for predicting follicular development in POI patients undergoing ovarian stimulation. This retrospective study analyzed 165 patients undergoing 504 long controlled ovarian stimulation cycles. AMH levels were measured three weeks after stimulation initiation using a highly sensitive assay to guide decisions on extending stimulation beyond four weeks. Follicular development occurred in 9.7% of cycles among 41 patients, who had shorter amenorrhea durations and lower baseline follicle-stimulating hormone levels. Three-week AMH levels showed superior predictive ability for follicular development (area under the curve: 0.957; optimal threshold: 2.45 pg/ml) and were negatively correlated with time to follicular detection (R = - 0.326, P < 0.05). However, AMH levels did not significantly affect the precise time required for follicular development or show significant differences in oocyte yield or embryo quality. The study concludes that three-week AMH levels can predict follicular growth in POI patients. These findings suggest that a highly sensitive AMH assay could be a valuable tool for guiding ovarian stimulation in POI patients, potentially improving treatment outcomes.

How updated expression and genomic data combined with a disease/disorder-specific classification system can be used to correct a gene model for a better evaluation of the pathogenicity of variants found in patients?

By combining available genomic and transcriptomic data from several species and a quantitative classification framework with primary ovarian insufficiency (POI)-adjusted parameters, we correct the human NOBOX (newborn ovary homeobox) gene model and provide a reclassification of variants previously reported in POI cases.

The NOBOX gene, encoding a gonad-specific transcription factor with a crucial role in early folliculogenesis and considered a major gene involved in POI, is currently described as being expressed as four transcripts, the longest one considered canonical. All the variants identified in POI cases have been evaluated according to this canonical transcript, and the various functional tests have been performed using the corresponding predicted protein.

We refined and corrected the NOBOX gene model using available genomic and RNAseq data in human and 16 other mammalian species. Expression data were selected for tissue specificity, strand specificity, and coverage. The analysis of RNAseq data from different ovarian fetal stages allows for a time-course description of NOBOX isoforms. Literature was scanned to retrieve NOBOX variants reported in POI cases, and NOBOX variants present in ClinVar and GnomAD 4 databases were also retrieved.

Strand-specific RNAseq data from human fetal ovaries and human adult testes were analysed to infer the correct human NOBOX gene isoforms. The conservation of the gene structure was verified by combining the aligned genomic sequences from 17 mammalian species covering a wide phylogenetic range and the relevant RNAseq data. As changing a gene model implies a reclassification of variants, we set up a quantitative framework with updated variant frequencies from GnomAD4 and POI-adjusted parameters following the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. Using this framework, we reclassified 44 NOBOX variants reported in POI patients and families, 117 NOBOX variants reported in ClinVar, and 2613 NOBOX variants present in GnomAD4.

The corrected NOBOX gene model proposes the invalidation of two transcripts, including the canonical one. The two correct isoforms were present in fetal ovarian samples, and only one was detected in adult testes. Only 14 variants remained as possibly causative for POI. Furthermore, this re-evaluation strongly suggests that NOBOX biallelic variants are the most likely cause of POI.

Large tables are provided as supplementary data sets on the Zenodo repository.

The proposed gene model is robust but relies on available transcriptomic data covering a range of time points and tissues. Our scoring system was manually adjusted and other laboratories can implement it with different parameters.

For the NOBOX variants that cannot be considered pathogenic or causative anymore, the genome/exome sequencing data of the corresponding patients should be reanalysed. Furthermore, the functional studies performed using the obsolete coding sequence should be reconsidered. The corrected gene model should be taken into account when evaluating novel NOBOX variants identified in POI patients. Our results highlight the importance of the careful assessment of the most updated expression data for validating a gene model, enabling a correct evaluation of the pathogenicity of variants found in patients. The proposed quantitative framework developed here can be used for the classification of variants in other genes underlying POI. Furthermore, the global approach based on quantitatively adjusting the ACMG/AMP guidelines could be extended to other inherited pathologies.

This project was not funded. All the authors have no conflict of interest to disclose.

To assess the ovarian reserve and in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) outcomes after various laparoscopic approaches in infertile patients with endometriomas and suspected compromised ovarian reserve, and the operated and non-operated/healthy ovaries were also compared, aiming to determine the most appropriate laparoscopic approach for each patient.

A total of 132 infertile patients with endometriomas and suspected compromised ovarian reserve (anti-Müllerian hormone [AMH] <2.0 ng/mL or antral follicle count [AFC] <8) were treated by various laparoscopic approaches at the Sir Run Run Shaw Hospital from January 2021 to December 2023, followed by IVF/ICSI. Patients were divided into three groups-group A (n = 33) received anhydrous alcohol instillation, group B (n = 65) underwent fenestration/coagulation, and group C (n = 34) underwent ovarian cystectomy. The clinical characteristics, ovarian reserve, and IVF/ICSI outcomes were evaluated among the three groups. The operated side and non-operated/healthy side in patients undergoing initial surgery were also compared.

The proportion of bilateral endometriomas was higher in group A (63.6%, 21/33) than in group B (40.0%, 26/65) and group C (32.4%, 11/34) (P = 0.023). There was no statistically significant difference in serum AMH in group A before and after surgery (median 1.32 [0.84-1.86 ng/mL] vs. 1.13 [0.59-1.86 ng/mL], P = 0.098). However, significant postoperative decreases were observed in groups B (median 1.30 [0.97-1.76 ng/mL] vs. 0.91 [0.50-1.23 ng/mL], P = 0.009) and C (median 1.52 [1.02-1.81 ng/mL] vs. 1.15 [0.76-1.67 ng/mL], P = 0.006). In group C, the follicle-stimulating hormone/luteinizing hormone ratio also increased postoperatively (median 1.75 [1.33-2.50] vs. 2.29 [1.84-3.61], P = 0.005), while no significant differences were seen in groups A (median 1.72 [1.56-2.80] vs. 2.89 [1.89-3.54], P = 0.096) and B (median 2.14 [1.67-2.82] vs. 2.37 [1.83-3.03], P = 0.189). The clinical pregnancy rate was significantly higher in group A than in group C (60.6%, 20/33 vs. 36.4%, 12/33; P = 0.042), but not significantly different between groups A and B (60.6%, 20/33 vs. 46.9%, 30/64; P = 0.143) or groups B and C (P = 0.220). Compared with the control group, there was a statistically significant difference in preoperative AFC in the group anhydrous ethanol instillation side (median 4.0 [2.0-5.0] vs. 2.0 [0.75-3.25], P < 0.001), the group fenestration/coagulation side (median 2.0 [0-3.0] vs. 2.0 [0.75-3.25], P < 0.001), and the group ovarian cystectomy side (median 2.0 [0-4.0] vs. 2.0 [0.75-3.25], P = 0.003), with no significant differences among the three groups themselves. Compared with the control group, significant differences were also observed between the group fenestration/coagulation side (median 2.0 [1.0-3.75] vs. 2.0 [1.0-3.0], P = 0.014) and the group ovarian cystectomy side (median 2.0 [1.0-4.0] vs. 2.0 [1.0-3.0], P = 0.040), in the 15-20 mm follicles, while no significant differences were found in the group anhydrous ethanol instillation side (median 3.0 [2.0-5.0] vs. 2.0 [1.0-3.0], P = 0.108).

This study suggests that laparoscopic anhydrous ethanol treatment prior to IVF/ICSI in infertile patients with ovarian endometrioma and suspected compromised ovarian reserve may be superior to fenestration/coagulation and ovarian cystectomy.

Premature ovarian failure (POF) is a condition where the ovaries lose their function before the age of 40, leading to significant impacts on reproductive health and overall well-being. Current treatment options are limited and often ineffective at restoring ovarian function. This review explores the role of autophagy- a cellular process that helps maintain homeostasis by recycling damaged components-in the development and potential treatment of POF. Autophagy is crucial for the survival of follicle cells and can be disrupted by various stressors associated with POF, such as oxidative damage and mitochondrial dysfunction. We review several key molecular pathways involved in autophagy, including the PI3K/AKT/mTOR, PINK1-Parkin, JAK2/STAT3, MAPK and AMPK/FOXO3a pathways, which have been implicated in POF. Each pathway offers unique insights into how autophagy can be modulated to counteract POF-related damage. Additionally, we discuss emerging therapeutic strategies that target these pathways, including chemical compounds, peptides, hormones, RNA therapy, extracellular vesicles and traditional Chinese medicine. These approaches aim to restore autophagic balance, promote follicle survival and improve ovarian function. By targeting autophagy, new treatments may offer hope for better management and potential reversal of POF, thus improving the quality of life for affected individuals.

Premature ovarian insufficiency (POI) is a condition marked by premature depletion of ovarian function, affecting a significant portion of women. The objective of this study is to assess the therapeutic efficacy of Yijing Hugui decoction (YJHGD) in the treatment of POI and to elucidate its pharmacological mechanisms. In this study, network pharmacology was used to identify key bioactive compounds in YJHGD, and the components were characterized using LC-MS. In vitro, we used KGN cells treated with cyclophosphamide (CP) to model POI. In vivo, a CP-induced POI mouse model was established. The in vitro therapeutic effects of β-sitosterol on CP-treated KGN cells were evaluated through various parameters. These parameters encompass cell viability, oxidative markers, antioxidant indexes, ATP concentration, intracellular ROS levels, apoptosis rate, and apoptosis-related protein expression. The in vivo therapeutic effects of β-sitosterol in POI mice were assessed through H&E staining, circulating reproductive hormone level detection, reproductive hormone receptor expression measurement, oxidative stress profile, and apoptosis assay. The potential protein target of β-sitosterol was identified utilizing molecular docking in conjunction with drug affinity responsive target stability (DARTS). β-sitosterol was identified as a major active component of YJHGD contributing to its therapeutic effects. In β-sitosterol-treated KGN human granulosa cells, oxidative stress and apoptosis were significantly reduced (P < 0.05). The interaction between β-sitosterol and AKT1 was verified. Furthermore, β-sitosterol significantly activated the AKT1/Nrf2 signaling pathway in vivo and in vitro (P < 0.05). AKT1 activator insulin significantly alleviated CP-induced oxidative stress (P < 0.05). Our results suggest that β-sitosterol inhibits oxidative stress and apoptosis by targeting AKT1 and activating the Keap1/Nrf2/HO-1 signaling. In vivo studies demonstrated that β-sitosterol significantly restored ovarian tissue damage in mice, reduced the circulating levels of reproductive hormones, downregulated the expression of reproductive hormone receptors, alleviated oxidative stress and ROS generation, and improved apoptosis (P < 0.05), which was achieved through the AKT1/Nrf2 pathway. In Conclusion, YJHGD possesses therapeutic potential for the treatment of POI. The active compound, β-sitosterol, demonstrated significant anti-POI effects through its interaction with AKT1, leading to the activation of AKT1/Nrf2 signaling pathway. This interaction contributes to the reduction of oxidative stress and the prevention of cellular apoptosis. Our results suggest that β-sitosterol may represent a novel therapeutic approach.

The online version contains supplementary material available at 10.1007/s10616-025-00740-8.

Despite a high burden of osteoporosis and minimal trauma fractures worldwide, there is still a treatment gap in timely diagnosis and optimal treatment. There is also a lack of international consensus and guidelines on the management of bone fragility in premenopausal women. This review article provides an overview of the current understanding of factors impacting women's bone health across the adult lifespan, as well as dilemmas in the diagnosis, assessment and management of osteoporosis in premenopausal and postmenopausal women, premature ovarian insufficiency and bone health following breast cancer.

To study the impact of unilateral ovariectomy for ovarian tissue cryopreservation (OTC) on the function of the remaining ovary in girls with Turner syndrome.

A prospective cohort study as a follow-up of OTC in a research setting (the TurnerFertility trial, NCT03381300).

A total of 28 girls with Turner syndrome with follicles in their cryopreserved ovarian cortex tissue, aged 5-19 years. Of the 28 girls, 21 had a 45,X/46,XX mosaic karyotype; 5 had structural aberrations of the X chromosome; 1 had a 45,X monosomy; and 1 had a 45,X/47,XXX karyotype.

Girls were monitored annually after OTC for pubertal development and levels of antimüllerian hormone (AMH), follicle-stimulating hormone, luteinizing hormone, estradiol, and inhibin B.

Thelarche, menarche, and onset of premature ovarian insufficiency.

The girls were monitored for a median duration of 3.4 years (maximum 6.6 years). The pubertal development of five prepubertal girls is still unknown; all were aged <10 years and had low gonadotropin and estradiol levels at the end of the follow-up. Seven of the eight girls of approximately pubertal age (10-12 years) experienced spontaneous thelarche, although one received medication to induce puberty. Eleven of the 14 girls between the ages of 14-17 years experienced spontaneous menarche; three other girls with thelarche still had ongoing puberty at the end of follow-up with normal gonadotropins and AMH levels above the detection limit. Approximately 6-12 months after OTC, a decline in AMH concentration was observed in 57% (16/28) of girls, followed by an increase in AMH concentration in the following years. Six of the total 28 girls started hormone replacement therapy because of symptoms of premature ovarian insufficiency, and all had AMH levels <0.50 μg/L before OTC.

Pubertal development progressed after unilateral ovariectomy for OTC in most girls with Turner syndrome. Hormone replacement therapy was required within a few years for girls with unfavorable parameters before OTC, such as AMH levels <0.50 μg/L. Decisions regarding OTC should be personalized, considering the girl's preferences and specific characteristics.

NCT03381300.

Premature ovarian insufficiency (POI) refers to the severe decline or failure of ovarian function in women younger than 40 years of age. It is a serious hazard to women's physical and mental health, but current treatment options are limited. Mesenchymal stem cell-derived exosomes (MSC-Exo) exhibit promising potential as a therapeutic approach for POI. However, their clinical application is hindered by their instability and low long-term retention rate in vivo.

In this study, miR-21 was identified as the predominant miRNA with low-expression in follicular fluid exosomes of POI patients and was shown to possess antiapoptotic activity. Next, we loaded miR-21 agomir to MSC-Exo to form Agomir21-Exo, which significantly reversed the apoptosis of granulosa cells in vitro. Moreover, we successfully developed GelMA hydrogel microspheres for encapsulating Agomir21-Exo through microfluidic technology, named GelMA-Ag21Exo, which had good injectability and significantly enhanced the stability and long-term retention of Agomir21-Exo in mice through sustained release. The release of Agomir21-Exo from GelMA-Ag21Exo notably alleviated the apoptosis of ovarian granulosa cells and improved the ovarian reserve and fertility in POI mice.

Our findings illustrate that activating miR-21 through Agomir21-Exo could improve the function of ovarian granulosa cells. The GelMA-Ag21Exo enhanced the exosome-based therapeutic efficacy of the Agomir21-Exo in vivo. These findings provide a novel and promising treatment strategy for POI patients.

This study aimed to compare the coagulation and platelet parameters in women with spontaneous premature ovarian insufficiency (POI) with those in age-matched controls.

This case-control study recruited 202 women with POI and 202 age-matched women with benign gynecological diseases as controls. Coagulation parameters, including prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (APTT), and thrombin time (TT), fibrinogen, and platelet parameters, including platelet count (PLT), mean platelet volume (MPV), plateletcrit (PCT), and platelet distribution width (PDW), were compared between women with POI and controls. Factors associated with coagulation and platelet parameters were also analyzed in women with POI.

In women with POI, higher fibrinogen levels and PDW, lower PLT, MPV, and PCT levels, and shorter TT were observed (p < 0.001). Linear regression analysis further revealed that women with POI were more likely to exhibit increased serum fibrinogen levels (β = 0.465, 95% confidence interval [CI] 0.366-0.564) and PDW (β = 0.340, 95% CI 0.300-0.379), decreased TT (β = -1.101, 95% CI -1.233--0.969), PLT (β = -50.985, 95% CI -65.087--36.882), MPV (β = -1.498, 95% CI -1.875 to -1.120), PCT levels (β = -0.084, 95% CI -0.095--0.973). Additionally, follicle-stimulating hormone levels were positively associated with fibrinogen levels in women with POI. There were no statistically significant differences in PT, INR, and APTT between women with POI and controls.

Women with POI exhibited decreased platelet numbers, abnormal platelet morphology, and elevated fibrinogen concentrations, potentially implicating POI's etiopathogenesis or contributing to an increased risk of cardiovascular disease in women with POI. No coagulation abnormalities were observed in women with POI.

The Fragile X mental retardation type 1 gene (FMR1) contains a CGG triplet cluster of varied length (30 repeats on average) located in its 5' UTR. In its premutated state (54-200 repeats), FMR1 contributes to the pathogenesis of premature ovarian insufficiency (POI). Its gray zone alleles (41-54 repeats) are supposed to impair the ovarian function as well. In the case of a CGG repeat length > 200, Fragile X syndrome occurs. Post-transcriptional expression of FMR1 is regulated by microRNAs. Although miR-323a-3p overexpression suppresses FMR1 in various tissues, this relationship has not been evaluated in the human ovary. Additionally, this microRNA targets SMADs, which are suggested regulators of ovarian cell proliferation, growth, and function. This study investigated how FMR1 allele lengths with CGG repeat numbers n < 55 (normal and gray zone genotypes) relate to miR-323a-3p expression and how they may impact associated SMAD expression in human granulosa cells. COV434 cells and patient-derived GCs were used to evaluate FMR1, miR-323a-3p, and BMP/SMAD-pathway member expression levels. Briefly, miR-323a-3p was significantly upregulated in GCs of the gray zone group compared to the normal allele group (p < 0.0001), while the FMR1 level did not vary. Furthermore, the gray zone group showed a significant upregulation of BMPR2, SMAD1, SMAD4, and SMAD9. In contrast, the miR-323a-3p transfection of COV434 cells significantly downregulated SMAD3, SMAD4, SMAD5, and SMAD9, while the FMR1 and SMAD1 levels remained stable. Our findings highlight a CGG repeat number-dependent upregulation of miR-323a-3p and an alteration of the BMP/SMAD pathway, suggesting that these changes happen and contribute to impaired ovarian function independently.

Premature ovarian insufficiency (POI) refers to loss of ovarian activity before the age 40 years. POI has significant detrimental effects on health (infertility, cardiovascular diseases, type 2 diabetes, reduced bone density, dementia), well-being and longevity. This summary is a practical toolkit for health-care professionals (HCPs) looking after women with POI.

A workgroup comprising specialists in gynaecology, reproductive medicine, endocrinology, genetics and family medicine reviewed relevant guidelines and literature on POI to establish recom-mendations for the diagnosis and management of POI in Singapore.

A summary to assist HCPs manage POI was produced, outlining: (1) the aetiology and conse-quences of POI; (2) making the diagnosis; (3) hormone therapy (HT) prescribing options including for those with additional medical conditions; (4) counselling women with POI about HT; and (5) long-term management of POI.

Timely diagnosis and management of POI is vital to prevent long-term adverse consequences, except infertility. HT is the mainstay of treatment and there are no alternatives as effective. Contraindications are very few; estrogen-sensitive cancer is the main contraindication, and caution in prescribing may be needed with established coexisting cardiovascular disease. Estrogen dosage is higher than when treating normal menopause, and as a result, the patient might require more progestogen for endometrial protection. Minimising cardiovascular risk factors by following a healthy lifestyle is important. POI is a significant public health issue and it is imperative that women have affordable access to appropriate HT. Large-scale research on POI in Asian women is needed.

Turner syndrome is one of the most common aneuploidies. In vitro fertilization with oocyte donation is the usual method of assisted conception, but spontaneous pregnancy can also occur. Although pregnancies in Turner syndrome are widely accepted to be associated with small for gestational age foetuses, neither the causal role of placental insufficiency nor the contribution of maternal and foetal factors is well understood. Between 2009 and 2023, we followed 75 patients diagnosed with Turner syndrome at our university clinic, and four Turner syndrome patients became pregnant (4/75; 5.3%): ten pregnancies with seven live births (7/10; 70%) were reported. Conception was spontaneous in 6/7 patients (86%), and one patient had in vitro fertilization with oocyte donation. Two Turner syndrome patients with karyotype 45,X and two Turner syndrome patients with mosaicism (45,X/46,XX) were identified. Prenatal transabdominal amniocentesis revealed aneuploidy (45,X) in two foetuses. The most common obstetric complication was placental insufficiency, which presented as intrauterine growth restriction and foetal distress. Four early-term deliveries, one late-term delivery, one preterm delivery, and one extremely premature delivery occurred, and all pregnancies were terminated by caesarean section. No severe maternal complications during pregnancy were reported. Only newborns with Turner syndrome had long-term health problems. In Turner syndrome patients, even if pregnancy is conceived spontaneously, no maternal complications occur, and the foetus also has a normal karyotype, there is still a high prevalence of placental insufficiency and foetal compromise. The presented cases highlight the possible role of inherent maternal factors in Turner syndrome-associated intrauterine growth restriction and emphasize the importance of enhanced obstetric surveillance even in apparently uncomplicated Turner syndrome pregnancies.

Tangier disease (TD) is a rare inherited disorder of lipoprotein metabolism, characterized by the accumulation of cholesterol esters in various tissues, resulting from a marked deficiency or absence of high-density lipoproteins (HDL). There is limited information in the literature regarding the impact of TD on reproduction. We present the case of a 34-year-old female patient who was diagnosed with TD 9 years ago with extremely low concentrations of HDL cholesterol (0.7 mg/dL), low-density lipoprotein cholesterol (5 mg/dL) and apolipoprotein A1 (0.02 mg/dL). Genetic analysis revealed a homozygous c.4218delC (p.Asn1406Lysfs*95) pathogenic variant in the ABCA1 gene causing TD. She presented with a mild clinical course that included gastrointestinal involvement and mild thrombocytopenia. Despite being clinically stable for a long time, the patient, who desired to become pregnant, was diagnosed with premature ovarian insufficiency (POI) according to the hormone profile (follicle stimulating hormone: 58.7 mIU/mL, luteinizing hormone: 37.1 mIU/mL, estradiol: 34.8 pg/mL, anti-Mullerian hormone: 0.08 ng/mL) after experiencing amennorrhea during follow-up.

Ovarian aging is the main cause of reduced reproductive life span, yet its metabolic profiles remain poorly understood. This study aimed to reveal the metabolic homogeneity and heterogeneity between physiological and pathological ovarian aging.

Seventy serum samples from physiological ovarian aging participants, pathological ovarian aging participants (including diminished ovarian reserve (DOR), subclinical premature ovarian insufficiency (scPOI) and premature ovarian insufficiency (POI)), as well as healthy participants were collected and analyzed by untargeted metabolomics.

Five homogeneous differential metabolites (neopterin, menaquinone, sphingomyelin (SM) (d14:1/24:2), SM (d14:0/21:1) and SM (d17:0/25:1)) were found in both physiological and pathological ovarian aging. While five distinct metabolites, including phosphoglyceride (PC) (17:0/18:2), PC (18:2e/17:2), SM (d22:1/14:1), SM (d14:1/20:1) and 4-hydroxyretinoic acid were specific to pathological ovarian aging. Functional annotation of differential metabolites suggested that folate biosynthesis, ubiquinone and other terpenoid-quinone biosynthesis pathways, were mainly involved in the ovarian aging process. Meanwhile, dopaminergic synapses pathway was strongly associated with scPOI, vitamin digestion and absorption and retinol metabolism were associated with POI. Furthermore, testosterone sulfate, SM (d14:0/28:1), PC (18:0e/4:0) and 4-hydroxyretinoic acid, were identified as potential biomarkers for diagnosing physiological ovarian aging, DOR, scPOI, and POI, respectively. Additionally, SM (d14:1/24:2) strongly correlated with both physiological and pathological ovarian aging. 4-hydroxyretinoic acid was strongly correlated with pathological ovarian aging.

Metabolic homogeneity of physiological and pathological ovarian aging was related to disorders of lipid, folate, ubiquinone metabolism, while metabolic heterogeneity between them was related to disorders of lipid, vitamin and retinol metabolism.

Not applicable.

Patients with gynecologic, gastrointestinal, or genitourinary malignancy are at elevated risk of developing premature ovarian insufficiency from the multimodality therapies used to treat their cancers. Premature ovarian insufficiency can result in long-term decrements to all-cause mortality, bone density, cardiovascular health, sexual health, cognitive health, and body mass. Hormone replacement therapy has been demonstrated to reverse these long-term sequalae with the goal of restoring estrogen concentrations to physiological levels. Here, we discuss a practical approach for initiation of hormone replacement therapy as well as challenges to consider.

Global fertility decline has led to increased use of assisted reproductive technology (ART), raising concerns about genetic risks to offspring. This study aimed to investigate cystic fibrosis transmembrane conductance regulator (CFTR) variants in Chinese families and assess their association with pregnancy complications and neonatal outcomes.

This prospective cohort study included 446 Chinese families (148 natural conceptions, 298 ART conceptions) who underwent whole genome sequencing. We analyzed the frequency of pathogenic/likely pathogenic CFTR variants and their association with preterm birth (PTB), pregnancy complications, and neonatal outcomes.

Twelve pathogenic/likely pathogenic CFTR variants were identified, with K464N (c.1392G > T) being the most prevalent (2.9% of cohort). PTB incidence was significantly higher in pregnancies with fetal CFTR variants (43.1%, 22/51) compared to those without (17.5%, 69/395; p < 0.001). Fetuses carrying the CFTR K464N variant exhibited a 3.39-fold increased risk of PTB (95% confidence interval (CI): 1.39-8.23, p = 0.007) after adjusting for confounders. Neither fetal nor maternal CFTR variants were significantly associated with other neonatal outcomes, including neonatal weight, Apgar scores, respiratory distress, or hyperbilirubinemia (p > 0.050).

These findings suggest a potential association between fetal CFTR K464N variant and increased risk of preterm birth in Chinese families, highlighting the importance of considering CFTR genotyping in prenatal care.