Treatment Of Premature Ovarian Insufficiency Research Articles

Exploring the Mechanism of Yiwei Decoction in the Intervention of a Premature Ovarian Insufficiency Rat Based on Network Pharmacology and the miRNA-mRNA Regulatory Network.

our aim is to explore the mechanism of action of Yiwei decoction (YWD) in addressing premature ovarian insufficiency (POI) through a combination of transcriptomics and network pharmacology. By doing so, we hope to identify important pathways of action, key targets, and active components that contribute to the efficacy of YWD. group A comprised of the model + traditional Chinese medicine group, while group B was the model control group and group C was the normal control group. After gavage, serum AMH and E2 levels were measured by using ELISA. HE staining was used to study the impact of YWD on ovarian follicle recovery in POI rats. Additionally, RNA-seq sequencing technology was employed to analyze the transcription levels of mRNAs and miRNAs in the ovarian tissues of each group, and the resulting data were examined using R. YWD used UPLC-Q-TOF-HRMS to analyze its active ingredients. Upon obtaining the sequencing results, the miRWalk database was utilized to forecast the targets of DEmiRNAs. Network pharmacology was then applied to predict the targets of active ingredients present in YWD, ultimately constructing a regulatory network consisting of active ingredients-mRNA-miRNA. The coexpression relationship between mRNAs and miRNAs was calculated using the Pearson correlation coefficient, and high correlation coefficients between miRNA-mRNA were confirmed through miRanda sequence combination. the application of YWD resulted in improved serum levels of AMH and E2, as well as an increased number of ovarian follicles in rats with POI. However, there was a minimal impact on the infiltration of ovarian lymphocytes. Through GSEA pathway enrichment analysis, we found that YWD may have a regulatory effect on PI3K-Akt, ovarian steroidogenesis, and protein digestion and absorption, which could aid in the treatment of POI. Additionally, our research discovered a total of 6 DEmiRNAs between groups A and B, including 2 new DEmiRNAs. YWD contains 111 active compounds, and our analysis of the active component-mRNA regulatory network revealed 27 active components and 73 mRNAs. Furthermore, the coexpression network included 5 miRNAs and 18 mRNAs. Our verification of MiRanda binding demonstrated that 12 of the sequence binding sites were stable. our research has uncovered the regulatory network mechanism of active ingredients, mRNA, and miRNA in YWD POI treatment. However, further research is needed to determine the effect of the active ingredients on key miRNAs and mRNAs.

Network Pharmacology Analysis and Molecular Docking to Identify the Mechanism of Kuntai Capsules: Brief Research on Its Action in Premature Ovarian Insufficiency

Objective. This study aimed to explore the therapeutic targets and related pathways of Kuntai capsules (KTCs) for premature ovarian insufficiency (POI) using network pharmacology and molecular docking. Methods. The active components and their targets of KTCs were retrieved from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) website, and disease therapeutic targets of POI were downloaded from DisGeNET, GeneCards, and OMIM databases and combined with the disease differential genes of POI microarray dataset from the Gene Expression Omnibus (GEO) database. The intersecting genes of drug potential therapeutic targets and disease therapeutic targets were uploaded to the STRING database to form a protein-protein interaction network. Also, the possible pathway of KTCs in the treatment of POI was explored by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis; through the core therapeutic targets, the corresponding active ingredients of KTCs were found. Finally molecular docking was conducted to verify the accuracy of the drug action. Results. 120 potential therapeutic targets of KTCs for POI were found. The bioinformatics analysis revealed that KTCs may regulate the recruitment, growth, and development of follicles by controlling various pathways such as fluid shear stress, atherosclerosis, PI3K/AKT, and p53 signaling. They can inhibit granulosa cell atrophy and apoptosis, promote follicle maturation, regulate follicle sensitivity to follicle-stimulating hormone, and ultimately impact ovarian function. The core therapeutic targets were TP53, AKT1, and TNF, and the corresponding active ingredients were quercetin, kaempferol, and stigmasterol. The molecular docking results showed that all the root mean square deviations were less than 2. Conclusions. KTCs improve ovarian function probably by acting on regulating the recruitment of follicles, reducing the apoptosis of granulosa cells, promoting their growth and development, reducing oxidative stress damage, and improving the sensitivity of follicles to FSH.

Ningxin-Tongyu-Zishen formula alleviates the senescence of granulosa cells on D-galactose-induced premature ovarian insufficiency mice.

Ningxin-Tongyu-Zishen formula (NTZF) is a clinical experience formula for the treatment of premature ovarian insufficiency (POI) in traditional Chinese medicine (TCM), and the potential mechanism is unknown. For in vivo experiments, POI mouse models (C57BL/6 mice), were constructed by subcutaneous injection of D-galactose (D-gal, 200 mg/kg). After treatment of NTZF (10.14, 20.27, 40.54 g/kg;) or estradiol valerate (0.15 mg/kg), ovarian function, oxidative stress (OS) and protein expression of Sirt1/p53 were evaluated. For in vitro experiments, H2O2 (200 μM) was used to treat KGN to construct ovarian granulosa cells (OGCs) cell senescence model. Pretreatment with NTZF (1.06 mg/mL) or p53 inhibitor (Pifithrin-α, 1 μM) was performed before induction of senescence, and further evaluated the cell senescence, OS, mRNA and protein expression of Sirt1/p53. In vivo, NTZF improved ovarian function, alleviated OS and Sirt1/p53 signaling abnormalities in POI mice. In vitro experiments showed that NTZF reduced the level of OS and alleviated the senescence of H2O2-induced KGN. In addition, NTZF activated the protein expression of Sirt1, inhibited the mRNA transcription and protein expression of p53 and p21. Alleviating OGCs senescence and protecting ovarian function through Sirt1/p53 is one of the potential mechanisms of NTZF in the treatment of POI.

Bibliometric Analysis on Stem Cell Transplantation Treatment for Premature Ovarian Failure

To carry out bibliometric analysis on stem cell transplantations for premature ovarian insufficiency (POI), and quickly grasp the clinical significance and potential of stem cell transplantation in the treatment of POI, the current study used the Web of Science core collection to retrieve relevant literature using keywords “stem cells” and “primary ovarian dysfunction”. VOSviewer was used for network visualization analysis of key words, authors, institutions, and countries. The results showed that, annual publications increased steadily from 2000 to 2023 with some fluctuations. China, Shanghai Jiao Tong University, and “Human Reproduction” are the countries, organizations, and journals with the highest output. The keyword map reflects that fertility preservation and hormone replacement therapy are currently hot topics in the treatment of POI. Mesenchymal stem cells (MSCs) and in vitro activation may have the highest potential to be applied in the future. Based on the current bibliometric analysis, the study on clinical efficacy, prognosis, and mechanism of POI treatment using MSCs and their exosomes is a research hotspot with great potential in this field.

Transcriptome analysis during 4-vinylcyclohexene diepoxide exposure-induced premature ovarian insufficiency in mice.

The occupational chemical 4-Vinylcyclohexene diepoxide (VCD) is a reproductively toxic environmental pollutant that causes follicular failure, leading to premature ovarian insufficiency (POI), which significantly impacts a woman's physical health and fertility. Investigating VCD's pathogenic mechanisms can offer insights for the prevention of ovarian impairment and the treatment of POI. This study established a mouse model of POI through intraperitoneal injection of VCD into female C57BL/6 mice for 15 days. The results were then compared with those of the control group, including a comparison of phenotypic characteristics and transcriptome differences, at two time points: day 15 and day 30. Through a comprehensive analysis of differentially expressed genes (DEGs), key genes were identified and validated some using RT-PCR. The results revealed significant impacts on sex hormone levels, follicle number, and the estrous cycle in VCD-induced POI mice on both day 15 and day 30. The DEGs and enrichment results obtained on day 15 were not as significant as those obtained on day 30. The results of this study provide a preliminary indication that steroid hormone synthesis, DNA damage repair, and impaired oocyte mitosis are pivotal in VCD-mediated ovarian dysfunction. This dysfunction may have been caused by VCD damage to the primordial follicular pool, impairing follicular development and aggravating ovarian damage over time, making it gradually difficult for the ovaries to perform their normal functions.

Kuntai capsule attenuates premature ovarian insufficiency by activating the FOXO3/SIRT5 signaling pathway in mice: A comprehensive study using UHPLC-LTQ-Orbitrap and integrated pharmacology

Ethnopharmacological relevanceClassical prescriptions are not only a primary method of clinical treatment in traditional Chinese medicine (TCM) but also represent breakthroughs in the inheritance and development of this field. Kuntai capsule (KTC), a formulation based on a classical prescription, comprises six TCMs: Rehmanniae Radix Praeparata, Coptidis Rhizoma, Paeoniae Radix Alba, Scutellariae Radix, Asini Corii Colla, and Poria. This formulation possesses various beneficial effects, such as nourishing yin and blood, clearing heat and purging fire, and calming the nerves and relieving annoyance. The investigation of the efficacy and mechanism of KTC in regulating anti-aging factors in the treatment of premature ovarian insufficiency (POI) is not only a prominent topic in classical prescription research but also a crucial issue in the treatment of female reproductive aging using TCM. Aim of the studyTo evaluate the therapeutic effect of KTC on POI and its underlying mechanism. Materials and methodsHealthy and specific pathogen-free (SPF) female Kunming mice aged 6–8 weeks were selected. After acclimatization, the mice were randomly divided into a control, model, and high, middle, and low dose groups of KTC (1.6, 0.8, and 0.4 mg/kg, respectively). Except for the control group, the animals in the other groups were administered a single intraperitoneal injection of 120 mg/kg cyclophosphamide and 30 mg/kg Busulfan to induce the model of POI. After modeling, the mice were treated with the corresponding drugs for 7 days. Serum and ovarian tissues were collected, and the levels of serum follicle-stimulating hormone (FSH), estradiol (E2), and superoxide dismutase 2 (SOD2) were determined using enzyme-linked immunosorbent assay (ELISA). The chemical composition of KTC was characterized and analyzed using ultra-high-pressure liquid chromatography-linear ion trap-Orbitrap tandem mass spectrometry. A “drug-component-target-pathway-disease” network was constructed using network pharmacology research methods to identify the key active components of KTC in treating POI and to elucidate its potential mechanism. The protein expression of the FOXO3/SIRT5 pathway was detected by western blotting. ResultsCompared to the model group, the high-dose group of KTC showed a significant increase in ovarian index, significant increase in levels of E2 and SOD2, and a significant decrease in FSH levels. Through systematic analysis of the chemical constituents of KTC, 69 compounds were identified, including 7 organic acids, 14 alkaloids, 28 flavonoids, 15 terpenoids, 2 lignans, 2 phenylpropanoids, and 1 sugar. Based on network pharmacology research methods, it was determined that KTC exerts its therapeutic effect on POI through multiple components (paeoniflorin and malic acid), multiple targets (FOXO3 and SIRT5), and multiple pathways (prolactin signaling pathway, longevity regulating pathway, and metabolic pathways). The accuracy of the network pharmacology prediction was further validated by detecting the protein expression of SIRT5 and FOXO3a, which showed a significant increase in the middle and high-dose groups of KTC compared to the model group. ConclusionsKTC may effectively treat POI through a multi-component, multi-target, multi-pathway approach, providing an experimental basis for using KTC based on classical prescriptions in the treatment of POI.

A new technology for the treatment of premature ovarian insufficiency: Cell sheet.

Premature ovarian insufficiency (POI) is defined as the development of hypergonadotropic hypogonadism before the age of 40 with definitive treatment being absent. In the current study, we aim to compare the efficacy of the cell sheet method with an intravenous (IV) application of adipose-derived mesenchymal stem cells (AdMSCs) to the POI with an animal model. In the current prospective study, 6-to-8-week-old Sprague Dawley rats were generated four groups: (i) a control group in which only PBS was administered; (ii) an only-POI group generated by cyclophosphamide; (iii) a POI group treated by way of IV AdMSCs; and (iv) a POI group treated by way of the cell sheet method. Twenty-eight days after an oophorectomy was performed, intracardiac blood was taken. Follicle count, immunohistochemical examination for GDF9, BMP15, and TUNEL were conducted, gene expressions of GDF9 and BMP15 were examined, and E2 was measured in the serum samples. With hematoxylin-eosin, in the third group, multi oocytes follicles were the most remarkable finding. In the fourth group, most of the follicles presented normal morphology. GDF9 involvement was similar between the first and fourth groups. BMP-15 immunoreactivity, in contrast to fourth group, was weak in all stages in the second and third groups. The current attempt represents a pioneer study in the literature in which a cell sheet method is used for the first time in a POI model. These results suggest that the cell sheet method may be a feasible and efficient method for the stem cell treatment of models with POI and could be a new treatment approach in POI.

What’s New in The Diagnosis and Treatment of Premature Ovarian Insufficiency (POI)?

What’s New in The Diagnosis and Treatment of Premature Ovarian Insufficiency (POI)?

A Review on Treatment of Premature Ovarian Insufficiency: Characteristics, Limitations, and Challenges of Stem Cell versus ExosomeTherapy.

Premature ovarian insufficiency (POI) is a complex disorder that can result in varying degrees of infertility. Recently, mesenchymal stem cell (MSC) therapy and its derivatives, such as exosomes, have been introduced as novel strategies for the treatment of POI. This review discusses the features, limitations, and challenges of MSC and exosome therapy in the treatment of POI and provides readers with new insights for comparing and selecting chemical agents, optimizing doses, and other factors involved in study design and treatment strategies. MSC therapy has been shown to improve ovarian function in some animals with POI, but it can also have side effects such as high cost, time-consuming processes, limited lifespan and cell sources, loss of original characteristics during in vitro proliferation, dependence on specific culture environments, potential immune reactions, unknown therapeutic mechanisms, etc. However, exosome therapy is a newer therapy that has not been studied as extensively as MSC therapy, but that it has shown some promise in animal studies. The evidence for the effectiveness of MSC and exosome therapy is still limited, and more research is needed to determine whether these therapies are effective and safe for women with POI. This study presents a new perspective for researchers to advance their research in the fields of cell-based and cell-free therapies.

[Consensus of clinical diagnosis and treatment of premature ovarian insufficiency (2023)].

[Consensus of clinical diagnosis and treatment of premature ovarian insufficiency (2023)].

Dissecting the efficacy of the use of acupuncture and Chinese herbal medicine for the treatment of premature ovarian insufficiency (POI): A systematic review and metaanalysis

Premature ovarian insufficiency is a multi-factor gynecological disease that has become a major global health problem. In recent years, several trials have explored the treatment of premature ovarian insufficiency using Chinese herbal medicine and acupuncture, but the efficacy and safety of this combination remains controversial. This systematic review and meta-analysis aimed to comprehensively evaluate the efficacy and safety of combining Chinese herbal medicine with acupuncture to treat premature ovarian insufficiency. From eight different databases, we retrieved randomized controlled trials wherein Chinese herbal medicine and acupuncture had been compared with western medicine in the treatment of premature ovarian insufficiency. The bias risk assessment stipulated by the Cochrane Collaboration's tool was utilized to evaluate the quality of the chosen randomized controlled trials. This meta-analysis was executed with the help of Review Manager 5.3 and Stata 10.0. The quality of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation framework. A total of 10 randomized controlled trials involving 594 premature ovarian insufficiency patients were included in the analysis. Compared with western medicine, co-treatment with acupuncture and Chinese herbal medicine exhibited a significantly higher total effective rate (relative risk: 1.21; 95% confidence interval: 1.12–1.31; P < 0.01, I2 = 0%), but lower levels of luteinizing hormone (standardized mean difference: −0.57; 95% confidence interval: −1.06, −0.08; P < 0.05, I2 = 80%), follicle-stimulating hormone, and Kupperman index score. Moreover, the combined intervention increased estradiol level in the serum. Overall, the data demonstrate that acupuncture plus Chinese herbal medicine is an efficacious and safe treatment option for POI patients. These findings must be verified by conducting large-scale, multicenter, high-quality, and long-term randomized controlled trials.

Appropriateness of premature ovarian insufficiency recommendations provided by ChatGPT.

This study aimed to evaluate the appropriateness of ChatGPT's responses to frequently asked queries regarding the prevention and treatment of premature ovarian insufficiency (POI). A set of 25 questions covering topics related to disease risk factors, screening, symptoms, treatment, and treatment adverse effects were posed to ChatGPT, and the responses were evaluated by two experienced obstetrician/gynecologists. Of the responses given by ChatGPT, 19 of 25 (76%) were deemed appropriate, five (20%) were rated as inappropriate, and the remaining one (4%) was considered unreliable. There was no question that ChatGPT answered completely incorrectly; answers that were considered inappropriate included partially correct information. The study's findings suggest that ChatGPT provides patients with mostly accurate information about the POI but might present significantly inaccurate information. However, it is important to note that further research is needed to validate the use of artificial intelligence chatbots in the context of reproductive health, especially for individuals who may be highly impacted by the emotional and psychological effects of POI. In addition, given the complexity and individuality of medical care, AI chatbots should not be considered a replacement for medical professionals but rather a supplementary tool that can help patients access reliable information and support. Overall, this study contributes to the growing body of research on AI chatbots and their potential use in reproductive health, highlighting both the benefits and limitations of these technologies.

[Qirong Tablets inhibits apoptosis of ovarian granulosa cells via PI3K/Akt/ HIF-1 signaling pathway].

This study aims to observe the effect and explore the mechanism of Qirong Tablets in the treatment of premature ovarian insufficiency(POI) in mice via the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)/hypoxia inducible factor 1(HIF-1) signaling pathway. Sixty SPF female BALB/c mice were randomly divided into normal group, model group, positive control group, Qirong Tablets low-, medium-and high-dose group. The normal group was intraperitoneally injected with the same amount of normal saline, and the other groups were intraperitoneally injected with cyclophosphamide 120 mg·kg~(-1)·d~(-1) once to establish a POI animal model. After the model was successfully established, the low-, medium-and high-dose groups of Qirong Tablets were administered orally with 0.6, 1.2, 2.4 mg·kg~(-1)·d~(-1) respectively. The positive control group was given 0.22 mg·kg~(-1)·d~(-1) Clementine Tablets by intragastric administration, and the normal group and model group were given intragastric administration with the same amount of normal saline, and the treatment was 28 d as a course of treatment. After drug intervention, enzyme-linked immunosorbent assay(ELISA) was employed to measure the levels of estradiol(E_2), follicle-stimulating hormone(FSH), luteinizing hormone(LH), and anti-mullerian hormone(AMH) in peripheral blood, and hematoxylin-eosin(HE) staining to observe the ovarian tissue. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling(TUNEL) assay was used to detect the apoptosis of granulosa cells, and Western blot to determine the expression levels of B-cell lymphoma-2(Bcl-2), Bcl-2-associated X protein(Bax), caspase-3, PI3K, Akt, and HIF-1. Compared with the normal group, the modeling of POI caused loose or destroyed ovarian tissue with vacuolar structures, edema and fibrosis in the ovarian interstitium, disordered or loose arrangement of granulosa cells, and reduced normal follicles. Compared with the model group, drug interventions restored the ovarian tissue and follicles at all the development stages and reduced atretic follicles. Compared with the normal group, the modeling of POI lowered the serum level of E_2 and AMH(P&lt;0.01), and elevated the level of FSH and LH(P&lt;0.01). Compared with the model group, high-dose Qirong Tablets elevated the levels of E_2 and AMH(P&lt;0.05), and lowered the levels of FSH and LH(P&lt;0.05). Compared with the normal group, the modeling of POI up-regulated the protein levels of PI3K, Akt, HIF-1, Bax, and caspase-3 and down-regulated the protein level of Bcl-2 in the ovarian tissue(P&lt;0.01). Compared with the model group, low-, medium-, and high-dose Qirong Tablets down-regulated the protein levels of PI3K, Akt, HIF-1, Bax, and caspase-3 proteins and up-regulated the protein level of Bcl-2 in the ovarian tissue(P&lt;0.05). In conclusion, Qirong Tablets can up-regulate the expression Bcl-2, down-regulate the expression of Bax and caspase-3 in POI mice. Qirong Tablets may inhibit the apoptosis of follicular granulosa cells in mice, thereby delaying ovarian aging, improving reproductive axis function, and strengthening ovarian reserve capacity, which may be associated with the inhibition of PI3K/Akt/HIF-1 pathway.

Dingkun Pill modulate ovarian function in chemotherapy-induced premature ovarian insufficiency mice by regulating PTEN/PI3K/AKT/FOXO3a signaling pathway

Ethnopharmacological relevanceDingkun Pill (DKP) is a traditional Chinese medicine that has been shown to have beneficial effects on reproductive function. However, the specific mechanism underlying its effect on POI is not well understood. Aim of the studyTo investigate the effect of different doses of Dingkun Pill on ovarian function in cyclophosphamide (CTX)-induced premature ovarian insufficiency (POI) mice and to explore its molecular mechanism through PTEN/PI3K/AKT/FOXO3a signaling pathway. This study will provide valuable insights into the potential clinical application of Dingkun Pill for the treatment of POI. Materials and methodsFifty female ICR mice were randomly divided into normal control (NC) group, model control (MC) group, and Dingkun Pill low, medium, high dose (DKP-L, M, H) groups. Mice were injected with CTX to construct the POI model. Mice in the DKP-L, M, and H groups were given 0.9 g/kg, 1.8 g/kg, and 3.6 g/kg of Dingkun Pill suspension for 21 days, respectively. Mice in the NC and MC groups were given the same amount of normal saline by gavage. Changes in body weight, estrous cycle and gonadal index were observed in each group of mice. Serum levels of FSH, LH, E2 and AMH were detected by ELISA. Hematoxylin-eosin (HE) staining observed the changes of ovarian pathological morphology and follicle counts at all levels. qRT-PCR was used to measure the levels of the PTEN and FOXO3a genes in ovarian tissue. The expression of PTEN/PI3K/AKT/FOXO3a signaling pathway related proteins were detected by Western-blot and immunohistochemistry (IHC). ResultsIn POI mice, Dingkun Pill increased body weight, promoted the recovery of estrous cycle, increased ovarian index, and improved pathological morphology of the ovaries. The FSH level decreased in the medium dose group (P < 0.05), the LH level reduced significantly in the medium and high dose groups (P < 0.01), and the E2 level in the high dose group increased (P < 0.05). There was no significant difference in AMH levels across all dose groups. The number of growing follicles improved at all levels in the low and medium dose groups, but declined significantly in the high dose group. However, the number of corpus luteum increased significantly in the high dose group (P < 0.001), and the atretic follicles in the three dose groups decreased. Results from qRT-PCR, Western-blot and IHC showed that the moderate dose of Dingkun Pill suppressed the levels of the p-PI3K and p-AKT proteins by upregulating the expression of PTEN in the ovarian tissues of POI mice, thereby inhibiting the expression of the key protein p-FOXO3a. However, the inhibitory effect of the higher dose may be less than that of the lower and intermediate dose groups. ConclusionsThe Dingkun Pill modulated hormonal levels, promoted follicle growth and induced ovulation in mice with CTX-induced POI, with better results in the low and moderate dose groups. Its mechanism may be related to the regulation of the PTEN/PI3K/AKT/FOXO3a signaling pathway.

Zigui-Yichong-Fang protects against cyclophosphamide-induced premature ovarian insufficiency via the SIRT1/Foxo3a pathway

Ethnopharmacological relevanceZigui-Yichong-Fang (ZGYCF) is a traditional Chinese medicine prescription for the treatment of infertility and premature ovarian insufficiency (POI). It is clinically used to regulate hormone levels, improve ovarian reserve and increase pregnancy rate. However, the exact mechanism of action is not yet clear. Aims of the studyThis study aimed to explore the potential impact and mechanism of ZGYCF on POI, and provide a scientific basis for its clinical application. Materials and methodsUHPLC‒MS/MS was used to identify the main compounds of ZGYCF. Female 8-week-old C57BL/6N mice were randomized into four group containing the vehicle control (Veh) group, the cyclophosphamide (CTX) model group, the low-dose ZGYCF (CTX-ZG-L) group and the high-dose ZGYCF (CTX-ZG-H) group. A mouse POI model was induced with a single intraperitoneal injection of CTX, and the therapeutic effects of different doses of ZGYCF on POI were evaluated according to the ovarian weight coefficient, serum AMH, serum E2, ovarian histomorphology and follicle counts. After the dose screening experiment, the CTX-ZG-L group was renamed the CTX-ZG group and subjected to follow-up experiments. RNA-seq was used to explore the mechanism of POI and the therapeutic mechanism of ZGYCF on POI in Veh group, CTX group and CTX-ZG group. The mechanism of action of ZGYCF on POI were determined by measuring serum hormone level, histomorphology, follicle counts, protein expression and acetylation modification in groups of Veh, CTX, CTX-ZG and CTX-ZG-Nam (SIRT1 inhibitor). ResultsA total of 37 compounds in ZGYCF were identified. ZGYCF attenuated the morphological changes in ovarian tissue in POI model mice, increased serum AMH and E2 levels, reduced the damage to primordial follicles and other follicles at all stages, and protected ovarian reserve. RNA-seq results suggested that the genes expression of the PI3K signaling and apoptosis signaling pathways was increased in POI mice, while ZGYCF upregulated SIRT1 gene and the expression of estradiol, apoptosis inhibition and other signaling pathway genes. Immunohistochemical staining, TUNEL staining, Western blot analysis and immunoprecipitation results showed that in CTX group, SIRT1 expression and Foxo3a nuclei localization were decreased, while Ac-Foxo3a, p-AKT, p-Foxo3a and apoptotic markers were upregulated. After administration of ZGYCF, these conditions were reversed, however, after treatment with the SIRT1 inhibitor, the results were opposite to those of ZGYCF. ConclusionsAcetylated Foxo3a plays an important role in the occurrence of POI. ZGYCF improves the ovarian reserve of CTX-induced POI mice by activating SIRT1-mediated deacetylation of Foxo3a, and played a role in the treatment of POI. SIRT1 may be a novel target for ZGYCF to ameliorate POI.

Long-term follow-up to assess criteria for ovarian tissue cryopreservation for fertility preservation in young women and girls with cancer.

Do the Edinburgh Selection Criteria correctly identify female cancer patients under the age of 18 who are at risk of premature ovarian insufficiency (POI) as candidates for ovarian tissue cryopreservation (OTC)? Patient assessment using these criteria accurately identifies those at risk of POI, who can be offered OTC and future transplantation as a means of fertility preservation. Treatment for childhood cancer can have adverse consequences on future fertility; at the time of diagnosis, fertility risk assessment should be undertaken in order to identify patients to whom fertility preservation should be offered. The Edinburgh selection criteria, based on planned cancer treatment and patient health status, are utilized to identify those at high risk and therefore eligible for OTC. However, this procedure is not without risk and there are few data on the efficacy of the procedure in prepubertal patients. As such, long-term follow-up of reproductive outcomes is necessary, to ensure that OTC is being offered appropriately. Cohort study encompassing all females diagnosed with cancer under the age of 18 in South East Scotland, from 1 January 1996 to 30 April 2020. Patients were followed up for reproductive outcomes to assess for diagnosis of POI. A total of 638 eligible patients were identified; patients under the age of 12 or deceased before the age of 12 were excluded from the study, leaving a study population of 431 patients. Electronic records were reviewed for reproductive function, assessed by current menstruation, pregnancy (in the absence of POI diagnosis), reproductive hormone measurements, pubertal progression, or diagnosis of POI. Patients on hormonal contraception (other than for treatment of POI or panhypopituitarism with no history of gonadatoxic treatment) were excluded from analysis (n = 9). Analysis on remaining 422 patients was carried out using the Kaplan-Meier methods, with POI as the defined event, and Cox proportional hazards model. In the study population of 431 patients, median ages at diagnosis and analysis were 9.8 and 22.2 years, respectively. Reproductive outcomes were unavailable in 142 patients; the assumption was made that these patients did not have POI, but a subanalysis excluding these patients was also performed. Of the 422 patients aged >12 at analysis and not taking hormonal contraception, OTC was offered to 37 patients and successfully performed in 25 patients. Of the 37 patients offered OTC (one at time of relapse), nine (24.3%) developed POI. Of the 386 not offered OTC, 11 (2.9%) developed POI. The probability of developing POI was significantly higher in those offered OTC (hazard ratio [HR] 8.7 [95% CI 3.6-21]; P < 0.0001), even when those patients with unknown outcomes were excluded from the analysis (HR 8.1 [95% CI 3.4-20]; P < 0.001). All patients offered OTC who developed POI did so after treatment for primary disease; in those not offered OTC, five patients (45.5%) developed POI after treatment for disease relapse. A significant number of patients had unknown reproductive outcomes; many of these patients were engaged in ongoing follow-up but did not have documented reproductive assessment. This may have introduced bias to the analysis and highlights the need for reproductive follow-up as part of routine cancer aftercare. In addition, the relatively young age of the patient population and short duration of follow-up in some cases demonstrates the need for ongoing follow-up of this cohort. The prevalence of POI after childhood cancer is low, but the Edinburgh selection criteria remain a robust tool for selecting those at high risk at the time of diagnosis, to offer OTC appropriately. However, disease relapse necessitating more intensive treatments remains a challenge. This study additionally highlights the importance of routine assessment and documentation of reproductive status in haematology/oncology follow-up. K.D. is supported by a CRUK grant (C157/A25193). This work was undertaken in part in the MRC Centre for Reproductive Health, (supported by MRC grant MR/N022556/1). R.A.A. has received consulting fees from Ferring and Roche Diagnostics; payment from Merck and IBSA for educational events; and laboratory materials from Roche Diagnostics. The other authors have no competing interests to declare. N/A.

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.

Potential therapeutic drug targets and pathways prediction for premature ovarian insufficiency —Based on network pharmacologic method

Ethnopharmacological relevanceThe incidence of premature ovarian insufficiency (POI) is gradually increasing, the proportion is rising especially in female infertility patients. The risk of death of POI patients with cardiovascular disease also increases significantly. The cause of POI is complex and unclear, and clinical treatment is still in the exploratory stage, are two major constraints of treating POI. Traditional Chinese medicine (TCM) is widely used in the treatment of POI, and it is a good way to combine the development of modern new drugs with the help of TCM to predict the therapeutic targets. Aim of the studyIn this study, four herbs commonly used in clinical treatment of POI, namely Radix Paeoniae, Polygonatum sibiricum, Rehmannia glutinosa and Eucommia ulmoides were selected to predict their mechanism in the treatment of POI, using network pharmacology methods. Then verify the predicted targets by animal test. Aim to find more effective POI potential core treatment targets and main pathways. Materials and methodsWe screened the active ingredients of drugs from the TCM System Pharmacology Analysis Platform (TCMSP), Performed target prediction of active ingredients from databases such as SwissTargetPrediction and compare and analyze the POI-related targets retrieved from them to obtain potential targets for drug treatment of POI. Used STRING database to construct a protein interaction network, Cytoscape 3.7.2 software to construct an active ingredient-target-pathway network, and DAVID database to conduct the Kyoto Encyclopedia of Genes and Genomes (KEGG) on the intersection targets and gene ontology (GO) enrichment analysis. ResultsThe result is: there were 25 key targets for the treatment of POI with Radix Paeoniae Alba, 31 for the treatment of POI by Eucommia ulmoides, 28 for the treatment of POI by Polygonatum sibiricum, and 8 key targets for the treatment of Rehmannia glutinosa. The intersection targets of four herbs were defined as the core targets, which are CYP19A1, EGF, ESR1, ESR2, MDM2, AR, PCYP17A1, PPARG. Four Chinese herbs treat POI mainly through HIF-1 signaling pathway, PI3K-Akt signaling pathway, FoxO signaling pathway, Estrogen signaling pathway etc. A mouse model of POI was constructed based on the results of network pharmacology to verify the predicted targets. The results showed that the protein expression of the core target changed, and the estrogen level was increased by reducing the expression of peroxisome proliferator-activated receptor gamma (PPARG). ConclusionsThis study predicts the mechanism of multiple herbs in the treatment of POI, screens out more potential therapeutic drug targets and main pathways of POI treatment and provides new ideas for the subsequent development of POI therapeutic drugs.

Mesenchymal stem cells as an adjuvant for the treatment of poi, and as a support in expectant management of placental hematomas and premature rupture of membranes: case report

In Mexico, 17% of women of childbearing age have infertility problems, this alteration may be associated to Premature Ovarian Insufficiency (POI). On the other hand, Premature Rupture of Membranes (PROM) is defined as the rupture of ovular membranes before labor begins. The application of Mesenchymal Stem Cells (MSCs) has been proposed for the treatment of POI, placental abruption and PROM. Objective: Describe a case report of a patient that received MSCs by intravenous injection as an adjuvant for the treatment of POI, and as an aid to reduce placental hematomas that appeared during pregnancy, which resulted in PROM (preterm, and previable), and a preterm baby delivery (alive). Clinical case presentation: A 30-year-old woman with history of primary infertility of 2 years; Anti-Müllerian Hormone (AMH) of 0.2 ng/mL; laparoscopic Bilateral Tubal Obstruction (BTO), endometriosis, diagnostic and surgical laparoscopy for myomatosis, and Factor VII deficiency; as well as 3 IVF, 4 embryo transfers, and 1 IUI unsuccessful. With confirmed POI diagnosis, the application of several doses at different times of MSCS is decided, resulting in pregnancy. Sometime later during pregnancy, placental hematomas and PROM are observed and decided to apply MSCs at different stages of pregnancy, resulting in the live birth of a baby (29.3 Weeks of Gestation) Conclusion: The application of multiple doses of MSCs turns more efficient the placental tissue restoration, allowing hematomas to disappear, and delaying a possible PROM.

Research Progress on the Effect of Traditional Chinese Medicine on Signal Pathway Related to Premature Ovarian Insufficiency.

The occurrence and development of premature ovarian insufficiency involves the abnormality of multiple signal pathways. It is a complex disease. Traditional Chinese medicine affects the relevant factors of the occurrence and development of premature ovarian insufficiency (granulosa cell apoptosis, ovarian blood supply, ovarian reserve, ovarian oxidative damage, gap junction, ovarian fibrosis, follicular development, follicular atresia, and other biological processes) by regulating a variety of signal pathways, thus playing the role in antioxidant stress, prevention and treatment of chemotherapy side effects, protection of ovarian function, control of aging, and improvement of ovarian reserve function. The research shows that the research on the related pathways of traditional Chinese medicine in the treatment of premature ovarian insufficiency has been quite extensive. Based on the search of the domestic and foreign literature, it is found that Yulinzhu and Xianziyizhen capsule and ginsenoside Rg1 can promote the proliferation and differentiation of granulosa cells, inhibit apoptosis, and reduce follicular atresia by affecting the PI3K/Akt/mTOR signal pathway; Guiluo's Anzang decoction, Kuntai capsule, and Yangyin Shugan granule can maintain the balance between pro-apoptotic protein and anti-apoptotic protein through the Bax/cytc/caspase-3 pathway to improve ovarian reserve function; Bushen Jianpi recipe can control cell apoptosis and promote the proliferation and development of ovarian granulosa cells by regulating the MAPK signal pathway; Siwu mixture and Zuo Gui pill can regulate the TGF-β/Smads signaling pathway to promote the recruitment of primordial follicles, promotes follicular development, inhibits follicular atresia, and regulates ovarian function; Erxian decoction, Yiqi Yangrong Fujing formula, and Cistanche deserticola can antagonize the inflammatory symptoms of premature ovarian failure, promote the secretion of relevant vascular growth factors, and enhance the ovarian reserve function through the NF-KB signal pathway; Bushen Culuan decoction can promote damage repair and protect normal ovarian cells through antioxidant stress. The above summary aims at providing reference for the in-depth study of traditional Chinese medicine in the treatment of premature ovarian insufficiency and inspiring new diagnosis and treatment ideas.