Pathogenesis Of Premature Ovarian Insufficiency Research Articles

A Glimpse of Research Trends and Frontiers in the Etiology of Premature Ovarian Insufficiency via Bibliometric Analysis.

Premature Ovarian Insufficiency (POI) is the most common reproductive aging disorder in women of reproductive age, which is characterized by decreased ovarian function in women before the age of 40. Etiology research of POI has garnered interest and attention from scholars worldwide over the past decades. However, to the best of our knowledge, no comprehensive survey with bibliometric analysis has been conducted yet on the research trends of POI etiology. This article aimed to analyze current scientific findings on the etiology of POI, offering innovative ideas for further research. Research articles on the etiology of POI from 1994 to 2023 were collected from the Web of Science Core Collection. A total of 456 research articles were included, and the total number of publications increased annually. We used VOSviewer and bibliometric.com to analyze the keywords, terms, institution, publication country/region, author name, publication journal, and the sum of times the articles have been cited. This study has shown that a research hotspot is the genetic etiology of POI; however, there is still a lack of research on the impact of epigenetic alterations, iatrogenic injuries, environmental pollution, social stress, and unhealthy lifestyles on the pathogenesis of POI. The factors illustrated here represent potential future directions for POI etiology research and warrant more attention from researchers.

The crucial role of HFM1 in regulating FUS ubiquitination and localization for oocyte meiosis prophase I progression in mice

BackgroundHelicase for meiosis 1 (HFM1), a putative DNA helicase expressed in germ-line cells, has been reported to be closely associated with premature ovarian insufficiency (POI). However, the underlying molecular mechanism has not been clearly elucidated. The aim of this study was to investigate the function of HFM1 in the first meiotic prophase of mouse oocytes.ResultsThe results suggested that the deficiency of HFM1 resulting in increased apoptosis and depletion of oocytes in mice, while the oocytes were arrested in the pachytene stage of the first meiotic prophase. In addition, impaired DNA double-strand break repair and disrupted synapsis were observed in the absence of HFM1. Further investigation revealed that knockout of HFM1 promoted ubiquitination and degradation of FUS protein mediated by FBXW11. Additionally, the depletion of HFM1 altered the intranuclear localization of FUS and regulated meiotic- and oocyte development-related genes in oocytes by modulating the expression of BRCA1.ConclusionsThese findings elaborated that the critical role of HFM1 in orchestrating the regulation of DNA double-strand break repair and synapsis to ensure meiosis procession and primordial follicle formation. This study provided insights into the pathogenesis of POI and highlighted the importance of HFM1 in maintaining proper meiotic function in mouse oocytes.

Bioinformatic analysis of the role of immune checkpoint genes and immune infiltration in the pathogenesis and development of premature ovarian insufficiency

PurposeWith advances in immunology, increasing evidence suggests that immunity is involved in premature ovarian insufficiency (POI) pathogenesis. This study investigated the roles of immune checkpoint genes and immune cell infiltration in POI pathogenesis and development.MethodsThe GSE39501 dataset and immune checkpoint genes were obtained from the Gene Expression Omnibus database and related literature. The two datasets were intersected to obtain immune checkpoint-related differentially expressed genes (ICRDEGs), which were analyzed using Gene Ontology and Kyoto Encyclopedia of Gene and Genomes enrichment analysis, weighted correlation network analysis, protein–protein interaction and related microRNAs, transcription factors, and RNA binding proteins. The immune cell infiltration of ICRDEGs was explored, and receiver operating characteristic curves were used to validate the diagnostic value of ICRDEGs in POI.ResultsWe performed ICRDEG functional enrichment analysis and found that these genes were closely related to immune processes, such as T cell activation. Specifically, they are enriched in various biological processes and pathways, such as cell adhesion molecule and T cell receptor signaling pathways. Weighted correlation network analysis identified seven hub genes: Cd200, Cd274, Cd28, neurociliary protein-1, Cd276, Cd40lg, and Cd47. Furthermore, we identified 112 microRNAs, 17 RNA-binding proteins, and 101 transcription factors. Finally, immune infiltration analysis showed a clear positive correlation between hub genes and multiple immune cell types.ConclusionBioinformatic analysis identified seven potential ICRDEGs associated with POI, among which the immune checkpoint molecules CD200 and neurociliary protein-1 may be involved in the pathogenesis of POI.

Advanced oxidation protein products attenuate the autophagy-lysosome pathway in ovarian granulosa cells by modulating the ROS-dependent mTOR-TFEB pathway

Oxidative stress dysfunction has recently been found to be involved in the pathogenesis of premature ovarian insufficiency (POI). Previously, we found that advanced oxidation protein products (AOPPs) in plasma were elevated in women with POI and had an adverse effect on granulosa cell proliferation. However, the mechanism underlying the effects of AOPPs on autophagy-lysosome pathway regulation in granulosa cells remains unclear. In this study, the effect of AOPPs on autophagy and lysosomal biogenesis and the underlying mechanisms were explored by a series of in vitro experiments in KGN and COV434 cell lines. AOPP-treated rat models were employed to determine the negative effect of AOPPs on the autophagy-lysosome systems in vivo. We found that increased AOPP levels activated the mammalian target of rapamycin (mTOR) pathway, and inhibited the autophagic response and lysosomal biogenesis in KGN and COV434 cells. Furthermore, scavenging of reactive oxygen species (ROS) with N-acetylcysteine and blockade of the mTOR pathway with rapamycin or via starvation alleviated the AOPP-induced inhibitory effects on autophagy and lysosomal biogenesis, suggesting that these effects of AOPPs are ROS-mTOR dependent. The protein expression and nuclear translocation of transcription factor EB (TFEB), the key regulator of lysosomal and autophagic function, were also impaired by the AOPP-activated ROS-mTOR pathway. In addition, TFEB overexpression attenuated the AOPP-induced impairment of autophagic flux and lysosomal biogenesis in KGN and COV434 cells. Chronic AOPP stimulation in vivo also impaired autophagy and lysosomal biogenesis in granulosa cells of rat ovaries. The results highlight that AOPPs lead to impairment of autophagic flux and lysosomal biogenesis via ROS-mTOR-TFEB signaling in granulosa cells and participate in the pathogenesis of POI.

Integrated metabolomics and transcriptomics to reveal biomarkers and mitochondrial metabolic dysregulation of premature ovarian insufficiency.

The metabolic characteristics of premature ovarian insufficiency (POI), a reproductive endocrine disease characterized by abnormal sex hormone metabolism and follicle depletion, remain unclear. Metabolomics is a powerful tool for exploring disease phenotypes and biomarkers. This study aims to identify metabolic markers and construct diagnostic models, and elucidate the underlying pathological mechanisms for POI. Non-targeted metabolomics was utilized to characterize the plasma metabolic profile of 40 patients. The metabolic markers were identified through bioinformatics and machine learning, and constructed an optimal diagnostic model by classified multi-model analysis. Enzyme-linked immunosorbent assay (ELISA) was used to verify antioxidant indexes, mitochondrial enzyme complexes, and ATP levels. Finally, integrated transcriptomics and metabolomics were used to reveal the dysregulated pathways and molecular regulatory mechanisms of POI. The study identified eight metabolic markers significantly correlated with ovarian reserve function. The XGBoost diagnostic model was developed based on six machine learning models, demonstrating its robust diagnostic performance and clinical applicability through the evaluation of receiver operating characteristic (ROC) curve, decision curve analysis (DCA), calibration curve, and precise recall (PR) curve. Multi-omics analysis showed that mitochondrial respiratory chain electron carrier (CoQ10) and enzyme complex subunits were down-regulated in POI. ELISA validation revealed an elevation in oxidative stress markers and a reduction in the activities of antioxidant enzymes, CoQ10, and mitochondrial enzyme complexes in POI. Our findings highlight that mitochondrial dysfunction and energy metabolism disorders are closely related to the pathogenesis of POI. The identification of metabolic markers and predictive models holds significant implications for the diagnosis, treatment, and monitoring of POI.

Homozygous missense variant in MEIOSIN causes premature ovarian insufficiency.

Are variants of genes involved in meiosis initiation responsible for premature ovarian insufficiency (POI)? A MEIOSIN variant participates in the pathogenesis of human POI by impairing meiosis due to insufficient transcriptional activation of essential meiotic genes. Meiosis is the key event for the establishment of the ovarian reserve, and several gene defects impairing meiotic homologous recombination have been found to contribute to the pathogenesis of POI. Although STRA8 and MEIOISN variants have been found to associate with POI in a recent study, the condition of other meiosis initiation genes is unknown and direct evidence of variants participating in the pathogenesis of POI is still lacking. This was a retrospective genetic study. An in-house whole exome sequencing (WES) database of 1030 idiopathic POI patients was screened for variations of meiosis initiation genes. Homozygous or compound heterozygous variations of genes involved in meiosis initiation were screened in the in-house WES database. The pathogenicity of the variation was verified by in vitro experiments, including protein structure prediction and dual-luciferase reporter assay. The effect of the variant on ovarian function and meiosis was demonstrated through histological analyses in a point mutation mouse model. One homozygous variant in MEIOSIN (c.1735C>T, p.R579W) and one in STRA8 (c.258 + 1G>A), which initiates meiosis via the retinoic acid-dependent pathway, were identified in a patient with idiopathic POI respectively. The STRA8 variation has been reported in the recently published work. For the MEIOSIN variation, the dual-luciferase reporter assay revealed that the variant adversely affected the transcriptional function of MEIOSIN in upregulating meiotic genes. Furthermore, knock-in mice with the homologous mutation confirmed that the variation impacted the meiotic prophase I program and accelerated oocyte depletion. Moreover, the variant p.R579W localizing in the high-mobility group (HMG) box domain disrupted the nuclear localization of the MEIOSIN protein but was dispensable for the cell-cycle switch of oocytes, suggesting a unique role of the MEIOSIN HMG box domain in meiosis initiation. Further studies are needed to explore the role of other meiosis initiation genes in the pathogenesis of POI. The MEIOSIN variant was verified to cause POI by impaired transcriptional regulation of meiotic genes and was inherited by a recessive mode. The function of HMG box domain in MEIOSIN protein was also expanded by this study. Although causative variations in meiotic initiation genes are rare in POI, our study confirmed the pathogenicity of a MEIOSIN variant and elucidated another mechanism of human infertility. This work was supported by the National Key Research & Developmental Program of China (2022YFC2703800, 2022YFC2703000), National Natural Science Foundation for Distinguished Young Scholars (82125014), National Natural Science Foundation of China (32070847, 32170867, 82071609), Basic Science Center Program of NSFC (31988101), Natural Science Foundation of Shandong Province for Grand Basic Projects (ZR2021ZD33), Natural Science Foundation of Shandong Province for Excellent Young Scholars (ZR2022YQ69), Taishan Scholars Program for Young Experts of Shandong Province (tsqn202211371), and Qilu Young Scholars Program of Shandong University. The authors declare no conflict of interest. N/A.

Identification of transcriptome characteristics of granulosa cells and the possible role of UBE2C in the pathogenesis of premature ovarian insufficiency

BackgroundPremature ovarian insufficiency (POI) is an important cause of infertility characterized by the functional decline of the ovary. Granulosa cells (GCs) around oocytes are critical for folliculogenesis, and GC dysfunction is one of the important etiologies of POI. The aim of this study was to explore the potential biomarkers of POI by identifying hub genes and analyze the correlation of biomarkers with immune infiltration in POI using RNA profiling and bioinformatics analysis.MethodsRNA sequencing was performed on GCs from biochemical POI (bPOI) patients and controls. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were used to explore the candidate genes. qRT‒PCR was performed to verify the expression of hub genes. Western blot, Cell Counting Kit-8, 5‐ethynyl‐2’‐deoxyuridine (EdU) assays, TUNEL (TdT-mediated dUTP Nick-End Labeling) and flow cytometry analysis were used to validate the possible role of ubiquitin-conjugating enzyme 2C (UBE2C) in POI. CIBERSORT was adopted to explore immune cell infiltration and the correlation between UBE2C and immune cells in bPOI.ResultsThrough analysis of differentially expressed genes (DEGs) and WGCNA, we obtained 143 candidate genes. After construction of the protein‒protein interaction (PPI) network and analysis with Cytoscape, 10 hub genes, including UBE2C, PBK, BUB1, CDC20, NUSAP1, CENPA, CCNB2, TOP2A, AURKB, and FOXM1, were identified and verified by qRT‒PCR. Subsequently, UBE2C was chosen as a possible biomarker of POI because knockdown of UBE2C could inhibit the proliferation and promote the apoptosis of GCs. Immune infiltration analysis indicated that monocytes and M1 macrophages may be associated with the pathogenesis of POI. In addition, UBE2C was negatively correlated with monocytes and M1 macrophages in POI.ConclusionsThis study identified a hub gene in GCs that might be important in the pathogenesis of POI and revealed the key role of UBE2C in driving POI. Immune infiltration may be highly related with the onset and etiology of POI.

P-705 Homozygous missense variant in MEIOSIN causes premature ovarian insufficiency

Abstract Study question Are the gene variants involved in meiosis initiation responsible for premature ovarian insufficiency (POI)? Summary answer MEIOSIN variant participates in the pathogenesis of human POI by impairing meiosis due to insufficient transcriptional activation of essential meiotic genes. What is known already Meiosis is the key event for the establishment of the ovarian reserve, and several gene defects impairing meiotic homologous recombination have been found to contribute to the pathogenesis of POI. However, the genes involved in meiosis initiation have not been associated with POI. Study design, size, duration Retrospective genetic study. An in-house whole exome sequencing (WES) database of 1,030 idiopathic POI patients was screened for variations of meiosis initiation genes. Participants/materials, setting, methods Gene variations involved in meiosis initiation were screened in the in-house WES database of 1,030 POI cases. The pathogenicity of the variation was verified by in vitro experiments, including protein structure prediction and dual-luciferase reporter assay. The effect of the variant on ovarian function and meiosis was demonstrated through histological analyses in a point mutation mouse model. Main results and the role of chance A homozygous variant of MEIOSIN that initiates meiosis via the retinoic acid dependent pathway was identified in a patient with idiopathic POI. The dual-luciferase reporter assay revealed that the variant adversely affected the transcriptional function of MEIOSIN in upregulating meiotic genes. Further knock-in mice with the homologous mutation confirmed that the variation impacted the meiotic prophase I program and accelerated oocyte depletion. Limitations, reasons for caution Further studies are needed to explore the role of other meiosis initiation genes in the pathogenesis of POI. Wider implications of the findings The present study firstly identified pathogenic MEIOSIN variants in patients with POI. Although the causative variation in meiotic initiation genes is rare in POI, our study expanded the spectrum of causative genes and elucidated the different mechanisms in human infertility. Trial registration number Not available

Pathogenic bi-allelic variants of meiotic ZMM complex gene SPO16 in premature ovarian insufficiency.

Premature ovarian insufficiency (POI) is a heterogeneous disease affecting the physical and mental health of millions of women worldwide. The contribution of genetic factors in the pathogenesis of POI has increased, with quite a few of causative genes involved in meiosis. ZMM proteins are a group of conserved proteins participating in meiotic synapsis and crossover maturation. Here, by screening the variations of ZMM genes in our in-house WES database of 1030 idiopathic POI patients, one novel homozygous variation in SPO16 (c.160 + 8A > G) was firstly identified in one patient. The variation was verified to disturb mRNA splicing by minigene assay, produced a non-functional SPO16 protein, and was classified as pathogenetic according to American College of Medical Genetics guideline. During meiotic prophase I, SHOC1 binds to branched DNA and recruits SPO16 and other ZMM proteins to facilitate crossover formation. Together with our recent identified bi-allelic variations of SHOC1 in a published work, this study highlighted the essential roles of ZMM genes in the maintenance of ovarian function and expanded the POI gene spectrum.

Ningxin Tongyu Zishen Tang in Treatment of Premature Ovarian Insufficiency: A Retrospective Control Study

Premature ovarian insufficiency (POI) is a common refractory disease in gynecology, and its etiology and pathogenesis are complex. Psychological stress exerts an impact on women's physical and mental health, and in turn affects the ovarian reserve function, which is one of the important etiologies and pathogenesis of POI. The compound formula Ningxin Tongyu Zishen Tang (NTZT) is composed of Chinese herbal medicines which can nourish heart and tranquilize mind, tonify kidney and supplement essence. By comparing the menstrual symptoms, traditional Chinese medicine (TCM) symptoms and the levels of serum sex hormone before and after treatment, the NTZT is clarified for its curative effect and advantages in patients with POI. The study aimed to observe the effects of NTZT on menstrual symptoms, TCM symptoms and the levels of serum sex hormone in POI patients. 60 POI patients were divided into two groups, namely observation group and control group, with 30 patients each. The patients in both groups were treated by hormone replacement therapy (HRT). The observation and control groups received treatment with NTZT and Liuwei Dihuang Wan (LDW), respectively. Both groups of patients were treated for 3 months continuously. The menstrual symptoms, TCM symptoms and the levels of serum sex hormone of the two groups were investigated before and after treatment. It was found that the menstrual symptoms, TCM symptoms and the levels of serum sex hormone improved dramatically after treatment in the observation group (P < 0.01). By comparison, the menstrual symptoms and the levels of serum sex hormone improved significantly (P < 0.01), but no obvious improvement in TCM symptoms (P > 0.05) in the control group was observed. Compared with the control group, the observation group showed significant improvement in TCM symptoms and the levels of serum sex hormone (P < 0.01), but no significant difference was observed in the menstrual symptoms (P > 0.05). In addition, no any adverse events such as gastrointestinal dysfunction and drug allergy were observed in both groups, indicating the safety of the two TCM formulas. The study found that NTZT could restore menstruation and improve the levels of sex hormone in patients with POI. It was also found that NTZT could eliminate the feelings of vexation, insomnia and dreamfulness, as well as tidal fever and sweating, aching pain of loins, and vaginal dryness significantly. It can be proved that NTZT is effective in treating patients with POI owing to its effects of nourishing heart and tranquilizing mind, tonifying kidney and supplementing essence together, leading to elimination of psychological stress, which further promotes the development of the ovaries.

TP63 gain-of-function mutations cause premature ovarian insufficiency by inducing oocyte apoptosis.

The transcription factor p63 guards genome integrity in the female germline, and its mutations have been reported in patients with premature ovarian insufficiency (POI). However, the precise contribution of the TP63 gene to the pathogenesis of POI needs to be further determined. Here, in 1,030 Chinese patients with POI, we identified 6 heterozygous mutations of the TP63 gene that impaired the C-terminal transactivation-inhibitory domain (TID) of the TAp63α protein and resulted in tetramer formation and constitutive activation of the mutant proteins. The mutant proteins induced cell apoptosis by increasing the expression of apoptosis-inducing factors in vitro. We next introduced a premature stop codon and selectively deleted the TID of TAp63α in mice and observed rapid depletion of the p63+/ΔTID mouse oocytes through apoptosis after birth. Finally, to further verify the pathogenicity of the mutation p.R647C in the TID that was present in 3 patients, we generated p63+/R647C mice and also found accelerated oocyte loss, but to a lesser degree than in the p63+/ΔTID mice. Together, these findings show that TID-related variants causing constitutive activation of TAp63α lead to POI by inducing oocyte apoptosis, which will facilitate the genetic diagnosis of POI in patients and provide a potential therapeutic target for extending female fertility.

BCAA insufficiency leads to premature ovarian insufficiency via ceramide-induced elevation of ROS.

Premature ovarian insufficiency (POI) is a disease featured by early menopause before 40 years of age, accompanied by an elevation of follicle-stimulating hormone. Though POI affects many aspects of women's health, its major causes remain unknown. Many clinical studies have shown that POI patients are generally underweight, indicating a potential correlation between POI and metabolic disorders. To understand the pathogenesis of POI, we performed metabolomics analysis on serum and identified branch-chain amino acid (BCAA) insufficiency-related metabolic disorders in two independent cohorts from two clinics. A low BCAA diet phenotypically reproduced the metabolic, endocrine, ovarian, and reproductive changes of POI in young C57BL/6J mice. A mechanism study revealed that the BCAA insufficiency-induced POI is associated with abnormal activation of the ceramide-reactive oxygen species (ROS) axis and consequent impairment of ovarian granulosa cell function. Significantly, the dietary supplement of BCAA prevented the development of ROS-induced POI in female mice. The results of this pathogenic study will lead to the development of specific therapies for POI.

Pathogenic variants in TSC2 might cause premature ovarian insufficiency through activated mTOR induced hyperactivation of primordial follicles

To investigate the role of tuberous sclerosis complex (TSC) genes, including TSC1 and TSC2, in the pathogenesis of human premature ovarian insufficiency (POI). Genetic and functional study. University-based reproductive medical center. Six patients from a cohort of 1,030 cases with idiopathic POI. Variants in TSC1 and TSC2 were screened through the largest in-house database of whole exome sequencing performed in 1,030 patients with idiopathic POI. The pathogenic effects of the variants were further verified by functional studies. TSC1 or TSC2 variant and functional characteristics. Five pathogenic heterozygous variants in TSC2 were identified in 6 patients with POI. Functional studies showed these variants impaired the repressive effect of TSC2 on mammalian target of rapamycin (mTOR) pathway by disrupting the formation of TSC complex or its GTPase-activating protein activity. Furthermore, invitro ovarian culture assay showed that TSC2 p.R98Q led to hyperactivation of mTOR pathway thereby triggering primordial follicle activation. The present study identified pathogenic variants of TSC2 in patients with POI, firstly suggested defective TSC/mTOR pathway mediated hyperactivation of primordial follicle participating in the pathogenesis of POI, giving insights into new targets of genetic counseling and clinical prevention for POI. Considering the pivotal role of TSC2 variants in diagnosis of TSC syndrome, the present study also highlighted the importance of history collection and long-term follow-up for the TSC2 variants carriers.

Advances in the cellular immunological pathogenesis and related treatment of primary ovarian insufficiency.

To describe the immunological mechanism in the pathogenesis of premature ovarian insufficiency (POI), summarize the alternations in humoral immunity and cellular immunity in patients with POI, and review some associated treatment methods based on these immunological changes. Symptoms of patients with POI are similar to that of menopause, such as amenorrhea, anovulation, early depletion of the ovarian reserve, decreased estrogen, and elevated follicle-stimulating hormone (FSH) levels. Therefore, most previous research has focused on finding ovary-related antibodies. In recent years, advances in the field of immunology have increased our understanding of the pathogenic mechanism of POI, which includes changed levels of cytokines and immunological cells especially Tregs cells and Th17 cells. Based on these advances, many associatedtreatment methods including DHEA supplementation, Traditional Chinese Medicine, adoptive transfer of Treg cells and stem cell transplantation have become research hotspots. This review focuses on the current literature regarding alterations in cellular immunity in patients with POI, as well as the role in the pathogenesis of POI, and summarizes treatment methods based on these immunological alternations, which have a great application potential in the clinical practice.

Melatonin protects against excessive autophagy-induced mitochondrial and ovarian reserve function deficiency though ERK signaling pathway in Chinese hamster ovary (CHO) cells

Excessive autophagy-induced follicular atresia of ovarian granulosa cells might be one of the pathogenesis of Premature Ovarian Insufficiency (POI), and melatonin (MT) exerted many beneficial effects on mitochondria. However, there was little report regarding the beneficial effects of MT on excessive autophagy-induced mitochondrial and ovarian reserve function deficiency, and the mechanisms have not been clearly identified. Autophagy played a protective role in cells survival, however, high level of autophagy could lead to cell death. In this report, firstly, Chinese hamster ovary cell damage model stably expressing EGFP-LC3 was established. Next, we systematically investigated the protective effects of MT on mitochondrial and ovarian reserve function and molecular mechanisms using this cell damage model. Our results revealed that 10-9 M MT not only protected against the decline of anti-mullerian hormone (AMH) expression induced by excessive autophagy, but also rescued excessive autophagy-induced impairment of mitochondrial expression and mitochondrial membrane potential. Furthermore, MT protected against excessive autophagy-induced decrease of nucleus-encoded proteins including SDHA and mitofilin, and mitochondrial dynamic-related proteins including OPA1, MFN2, and DRP1. MT also decreased mitochondrial oxidative stress, increased antioxidant enzyme superoxide dismutase 2 (SOD2) expression and ameliorated the G2/M cell cycle arrest induced by excessive autophagy. Finally, MT inhibited excessive autophagy-induced activation of extracellular signal regulated kinase (ERK) signaling pathway. In conclusion, our study showed that MT rescued impairment of mitochondrial and ovarian reserve function, and production of mitochondrial ROS and cell cycle arrest induced by excessive autophagy through down-regulated ERK pathway, implying the potential therapeutic drug target for POI.

INHIBITION OF SHP2 DISRUPTS FSH-STIMULATED SYNTHESIS OF ESTROGEN IN GRANULOSA CELLS

Dysfunction of granulosa cells is a major cause of premature ovarian insufficiency (POI), a serious event for women that leads to infertility with unknown etiology. SHP2 is a tyrosine phosphatase that regulates multiple signaling cascades, including G-protein-coupled receptors signaling that plays a significant role in FSH-stimulated steroid synthesis signaling pathway. However, the function of SHP2 in the production of estrogen in granulosa cells and the pathogenesis of POI remains unknown.

Autologous transplantation of thecal stem cells restores ovarian function in nonhuman primates

Premature ovarian insufficiency (POI) is defined as the loss of ovarian activity under the age of 40. Theca cells (TCs) play a vital role during folliculogenesis and TCs dysfunction participate in the pathogenesis of POI. Therefore, transplantation of thecal stem cells (TSCs), which are capable of self-renewal and differentiation into mature TCs, may provide a new strategy for treating POI. To investigate the feasibility, safety, and efficacy of TSCs transplantation in clinically relevant non-human primate (NHP) models, we isolate TSCs from cynomolgus monkeys, and these cells are confirmed to expand continuously and show potential to differentiate into mature TCs. In addition, engraftment of autologous TSCs into POI monkeys significantly improves hormone levels, rescues the follicle development, promotes the quality of oocytes and boosts oocyte maturation/fertilization rate. Taken together, these results for the first time suggest that autologous TSCs can ameliorate POI symptoms in primate models and shed new light on developing stem cell therapy for POI.

The Role of Noncoding RNA in the Pathophysiology and Treatment of Premature Ovarian Insufficiency.

Premature ovarian insufficiency (POI) is defined as a loss of ovarian function before the age of 40 years, with a prevalence rate estimated at approximately 1%. It causes infertility and is related to serious long-term health consequences, including reduced life expectancy, increased cardiovascular risk, decreased bone mineral density and neurological disorders. There is currently no effective therapy for POI that is widely available in clinical practice; therefore, the treatment of patients with POI is based on hormone replacement therapy. One of the recent advances in the understanding of the pathophysiology of POI has been the role of microRNAs (miRNAs) and other noncoding RNAs (ncRNAs) in the disease. Moreover, intensive research on human folliculogenesis and reproductive biology has led to the development of novel promising therapeutic strategies with the use of exosomal miRNAs derived from mesenchymal stem cells to restore ovarian function in POI patients. This narrative review focuses on the new studies concerning the role of ncRNAs in the pathogenesis of POI, together with their potential as biomarkers of the disease and targets for therapy.

Treg deficiency-mediated TH 1 response causes human premature ovarian insufficiency through apoptosis and steroidogenesis dysfunction of granulosa cells.

Immune dysregulation has long been proposed as a component of premature ovarian insufficiency (POI), but the underlying mediators and mechanisms remain largely unknown. Here we showed that patients with POI had augmented T helper 1 (TH1) responses and regulatory T (Treg) cell deficiency in both the periphery and the ovary compared to the control women. The increased ratio of TH1:Treg cells was strongly correlated with the severity of POI. In mouse models of POI, the increased infiltration of TH1 cells in the ovary resulted in follicle atresia and ovarian insufficiency, which could be prevented and reversed by Treg cells. Importantly, interferon (IFN) ‐γ and tumor necrosis factor (TNF) ‐α cooperatively promoted the apoptosis of granulosa cells and suppressed their steroidogenesis by modulating CTGF and CYP19A1. We have thus revealed a previously unrecognized Treg cell deficiency‐mediated TH1 response in the pathogenesis of POI, which should have implications for therapeutic interventions in patients with POI.

Premature Ovarian Insufficiency: Past, Present, and Future.

Premature ovarian insufficiency (POI) is the loss of normal ovarian function before the age of 40 years, a condition that affects approximately 1% of women under 40 years old and 0.1% of women under 30 years old. It is biochemically characterized by amenorrhea with hypoestrogenic and hypergonadotropic conditions, in some cases, causing loss of fertility. Heterogeneity of POI is registered by genetic and non-genetic causes, such as autoimmunity, environmental toxins, and chemicals. The identification of possible causative genes and selection of candidate genes for POI confirmation remain to be elucidated in cases of idiopathic POI. This review discusses the current understanding and future prospects of heterogeneous POI. We focus on the genetic basis of POI and the recent studies on non-coding RNA in POI pathogenesis as well as on animal models of POI pathogenesis, which help unravel POI mechanisms and potential targets. Despite the latest discoveries, the crosstalk among gene regulatory networks and the possible therapies targeting the same needs to explore in near future.