Treatment Of Primary Ovarian Insufficiency Research Articles

Assessment of bidirectional relationships between autoimmune diseases and primary ovarian insufficiency: insights from a bidirectional two-sample Mendelian randomization analysis.

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

Research on liposomal hydrogels loaded with "Liu Zi Tang" compound Chinese medicine for the treatment of primary ovarian insufficiency

IntroductionPrimary ovarian insufficiency (POI) is marked by reduced estrogen production and irregular ovulation, often resulting in lowered fertility or infertility. The traditional Chinese medicine "Liu Zi Tang" (LZT) has displayed promising outcomes in treating POI. Yet, conventional oral LZT administration poses challenges, including gastrointestinal irritation and the liver's first-pass effect. Thus, a novel drug delivery approach is imperative. MethodThis research incorporated the extracts of traditional Chinese medicine LZT into a novel liposome type, leading to the creation of LZT-glycerol plasmid/chitosan hydrogel (LZT-Gly-Lip/CS Gel) drug-carrier patches for achieving transdermal gradual-release drug delivery. The POI model was established in rats through intraperitoneal injection of vinylcyclohexene dioxide (VCD). A total of twenty-four 4-week-old female SD rats were distributed randomly among four groups: negative control (NC), vinylcyclohexene dioxide model (VCD), LZT/chitosan hydrogel treatment (VCD+LZT/CS Gel), and LZT glycerol liposome/chitosan hydrogel treatment (VCD+LZT-Gly-Lip/CS Gel). The therapeutic efficacy was evaluated by observing and analyzing the rats' body weight, diverse organ indices, serum hormone levels, and histopathological sections. ResultRats treated with LZT-Gly-Lip/CS Gel manifested significant enhancements in body weight (243.0 ± 11.0 g), serum estradiol concentration (64.362 ± 6.461 pg/mL), and uterus index (0.34 ± 0.05 %), demonstrating outcomes approaching normal levels (245.3 ± 12.0 g, 74.280 ± 8.903 pg/mL, 0.32 ± 0.10 %, respectively). DiscussionThese results confirm the effectiveness of LZT-Gly-Lip/CS Gel as a promising transdermal drug delivery system for addressing POI.

Bioinformatics and integrated pharmacology network to identify the therapeutic targets and potential molecular mechanism of alpha-lipoic acid on primary ovarian insufficiency.

Women experiencing primary ovarian insufficiency (POI) are more likely to experience infertility, and its incidence is increasing worldwide annually. Recently, the role of alpha-lipoic acid (ALA) in the treatment of POI has been reported. However, details of the potential pharmacological targets and related molecular pathways of ALA remain unclear and need to be elucidated. Thus, this study aims to elucidate the potential therapeutic target and related molecular mechanism of ALA on POI. First, the potential targets of POI and ALA-related targets were downloaded from online public databases. Subsequently, the overlapped target genes between POI and ALA were acquired, and gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG) analysis, protein-protein interaction (PPI) networks were performed and constructed. Finally, molecular docking was performed to verify protein-to-protein effect. A total of 152 potential therapeutic targets were identified. The biological processes of the intersecting targets were mainly involved in the cellular response to peptides, response to xenobiotic stimuli, and response to peptide hormones. The highly enriched pathways were the cAMP, PI3K/AKT, estrogen, progesterone mediated oocyte maturation, and apoptosis signaling pathways. The top 10 hub targets for ALA in the treatment of POI were STAT3, STAT1, CASP3, MTOR, PTGS2, CASP8, HSP90AA1, PIK3CA, MAPK1, and ESR1. The binding between ALA and all top hub targets were verified using the molecular docking analysis. In summary, using the systematic integrated pharmacology network and bioinformatics analysis, this study illustrated that ALA participates in the treatment of POI via multiple targets and multiple pathways mechanisms.

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.

WANG Yin¢s experience in treatment of primary ovarian insufficiency

The clinical experience of professor WANG Yin in the treatment of primary ovarian insufficiency are summarized. Regarding acupoints selection, the sancai, named "heaven-earth-human being" method is adopted, focusing on the regulation of the middle jiao and shen (mind/spirit). Regarding needling technique, the elongated needle is used in preference. Besides, the bloodletting and cupping method with filiform-fire needle are innovated to achieve both the reinforcing and the reducing purposes as well as to eliminate stasis. The periodic therapy is applied to comply with the changes in the physiological cycle of gynecology. Acupuncture, Chinese herbal medicine, or the combination of them is selected in consideration of the concrete individual cases of primary ovarian insufficiency.

A stem cell-derived ovarian regenerative patch restores ovarian function and rescues fertility in rats with primary ovarian insufficiency.

Rationale: Primary ovarian insufficiency (POI) normally occurs before age 40 and is associated with infertility. Hormone replacement therapy is often prescribed to treat vasomotor symptom, but it cannot restore ovarian function or fertility. Stem cell therapy has been studied for the treatment of POI. However, the application of live stem cells has suffered from drawbacks, such as low cell retention/engraftment rate, risks for tumorigenicity and immunogenicity, and lack of off-the-shelf feasibility.Methods: We developed a therapeutic ovarian regenerative patch (ORP) that composed of clinically relevant hydrolysable scaffolds and synthetic mesenchymal stem cells (synMSCs), which are microparticles encapsulating the secretome from MSCs. The therapeutic potency of ORP was tested in rats with cisplatin induced POI injury.Results:In vitro studies revealed that ORP stimulated proliferation of ovarian somatic cells (OSCs) and inhibited apoptosis under injury stress. In a rat model of POI, implantation of ORP rescued fertility by restoring sexual hormone secretion, estrus cycle duration, and follicle development.Conclusion: ORP represents a cell-free, off-the-shelf, and clinically feasible treatment for POI.

Safety of Intraovarian Injection of Human Mesenchymal Stem Cells in a Premature Ovarian Insufficiency Mouse Model

Primary ovarian insufficiency (POI), a condition in which there is a loss of ovarian function before the age of 40 years, leads to amenorrhea and infertility. In our previously published studies, we demonstrated recovery of POI, correction of serum sex hormone levels, increase in the granulosa cell population, and restoration of fertility in a chemotherapy-induced POI mouse model after intraovarian transplantation of human bone marrow-derived mesenchymal stem cells (hBM-MSCs). While hBM-MSC may be a promising cell source for treatment of POI, there are few reports on the safety of stem cell-based therapy for POI. For future clinical applications, the safety of allogenic hBM-MSCs for the treatment of POI through intraovarian engraftment needs to be addressed and verified in appropriate preclinical models. In this study, we induced POI in C57/BL6 mice using chemotherapy, then treated the mice with hBM-MSCs (500,000 cells/ovary) by intraovarian injection. After hBM-MSC treatment, we analyzed the migration of engrafted cells by genomic DNA polymerase chain reaction (PCR) using a human-specific ALU repeat and by whole-body sectioning on a cryo-imaging system. We examined the possibility of transfer of human DNA from the hBM-MSCs to the resulting offspring, and compared the growth rate of offspring to that of normal mice and hBM-MSC-treated mice. We found that engrafted hBM-MSCs were detected only in mouse ovaries and did not migrate into any other major organs including the heart, lungs, and liver. Further, we found that no human DNA was transferred into the fetus. Interestingly, the engrafted cells gradually decreased in number and had mostly disappeared after 4 weeks. Our study demonstrates that intraovarian transplantation of hBM-MSCs could be a safe stem cell-based therapy to restore fertility in POI patients.

Mini Review; Differentiation of Human Pluripotent Stem Cells into Oocytes.

Primary Ovarian Insufficiency (POI) is one of the main diseases causing female infertility that occurs in about 1% of women between 30-40 years of age. There are few effective methods for the treatment of women with POI. In the past few years, stem cell-based therapy as one of the most highly investigated new therapies has emerged as a promising strategy for the treatment of POI. Human pluripotent stem cells (hPSCs) can self-renew indefinitely and differentiate into any type of cell. Human Embryonic Stem Cells (hESCs) as a type of pluripotent stem cells are the most powerful candidate for the treatment of POI. Human-induced Pluripotent Stem Cells (hiPSCs) are derived from adult somatic cells by the treatment with exogenous defined factors to create an embryonic-like pluripotent state. Both hiPSCs and hESCs can proliferate and give rise to ectodermal, mesodermal, endodermal, and germ cell lineages. After ovarian stimulation, the number of available oocytes is limited and the yield of total oocytes with high quality is low. Therefore, a robust and reproducible in-vitro culture system that supports the differentiation of human oocytes from PSCs is necessary. Very few studies have focused on the derivation of oocyte-like cells from hiPSCs and the details of hPSCs differentiation into oocytes have not been fully investigated. Therefore, in this review, we focus on the differentiation potential of hPSCs into human oocyte-like cells.

Transcriptional profiling of long noncoding RNAs and their target transcripts in ovarian cortical tissues from women with normal menstrual cycles and primary ovarian insufficiency.

Previous studies have shown that long noncoding RNAs (lncRNAs) show a highly tissue- and disease-specific expression pattern and that they regulate the expression of neighboring genes. Because lncRNAs have been shown to be secreted into the general circulation, they may be used as diagnostic tools for some diseases. Primary ovarian insufficiency (POI) is a disease in which women have menstrual cessation before the age of 40, accompanied by elevated follicle stimulating hormone and decreased estrogen levels. In this study, ovarian cortical tissues from five women with normal menstrual cycles and from five POI patients were used for next-generation RNA sequencing. We found 20 differentially expressed lncRNAs with 12 upregulated and eight downregulated lncRNAs in cortical tissues of POI ovaries, compared with normal controls (fold change ≥ 2 and false discovery rate[FDR] ≤ 0.05). We also found 52 differentially expressed messenger RNA transcripts, with 33 upregulated and 19 downregulated ones (foldchange ≥ 2 and FDR ≤ 0.05). Functional annotation showed that these differentially expressed transcripts were associated with follicular development and granulosa cell function. Thirteen differentially expressed lncRNAs and their targeted neighboring transcripts were coregulated in ovarian cortical tissues, including lnc-ADAMTS1-1:1/ADAMTS1, lnc-PHLDA3-3:2/CSRP1, lnc-COL1A1-5:1/COL1A1, lnc-SAMD14-5:3/COL1A1, and lnc-GULP1-2:1/COL3A1. Furthermore, serum levels of these lncRNAs in POI patients were significantly different from those in normal patients ( p < 0.05), and expression differences were consistent with those in ovarian cortical tissues. This study showed that key lncRNAs were differentially expressed in both ovarian cortical tissues and serum samples between women with normal menstrual cycles and POI patients. Further studies on the regulation of ovarian lncRNAs during follicular development are critical in understanding the etiologies of POI. Analyses of lncRNA expression in serum samples might provide a basis for early diagnosis and treatment of POI.

Management of Primary Ovarian Insufficiency Symptoms in Survivors of Childhood and Adolescent Cancer.

Cancer treatments can damage the ovaries, causing primary ovarian insufficiency (POI), a condition associated with numerous sequelae that impact long-term quality of life. This article systematically reviews the literature on the prevalence, surveillance, and treatment of POI in survivors of pediatric and adolescent and young adult (AYA) cancers. A systematic review of the literature was conducted in January 2018 through a search of Medline, Embase, Web of Science, and SCOPUS, alongside the screening of relevant reference lists. An initial search identified 746 potentially relevant studies. A total of 36 studies were included in the final review. Studies were categorized into one of the following categories: incidence/prevalence of POI, measurement of ovarian reserve, and other. Depending on patient characteristics, cancer diagnosis, and treatment, the prevalence of POI ranged from 2.1% to 82.2%. Risk factors for POI included exposure to alkylating agents and abdominal/pelvic radiation. POI may be associated with a number of complications, including low bone mineral density and poor cardiovascular health. Radiotherapy and chemotherapy are known to cause gonadal damage in female survivors of pediatric and AYA cancers. Acute or chronic effects depend on the dose of treatment, age of the individual, radiotherapy field, and ovarian reserve of the individual. Some women experience short-term loss of reproductive function and then may resume menstrual cycles, months or even years later. Although protecting fertility through banking of mature eggs, embryos, and tissue samples has become standard of care, additional steps need to be taken to ensure that patients have adequate hormone levels to maintain whole-body health, including life expectancy, bone health, cardiovascular health, quality of life, sexual and genitourinary function, and neurologic function. Surveillance and management of each of these comorbidities is critically important to survivor health.

Cryopreservation of Ovarian Tissue: Opportunities Beyond Fertility Preservation and a Positive View Into the Future.

In current years, ovarian tissue cryopreservation (OTC) and transplantation is gaining ground as a successful method of preserving fertility in young women with primarily cancer diseases, hereby giving them a chance of becoming biological mothers later on. However, OTC preserves more than just the reproductive potential; it restores the ovarian endocrine function and thus the entire female reproductive cycle with natural levels of essential hormones. In a female population with an increased prevalence in the loss of ovarian function due to induced primary ovarian insufficiency (POI) and aging, there is now, a need to develop new treatments and provide new opportunities to utilize the enormous surplus of follicles that most females are born with and overcome major health issues associated with the lack of ovarian hormones. Cell/tissue-based hormone replacement therapy (cHRT) by the use of stored ovarian tissue could be one such option comprising both induction of puberty in prepubertal POI girls, treatment of POI and premature menopause, and as primary prevention at the onset of menopause. In the current review, we explore known and entirely new applications for the potential utilization of OTC including cHRT, social freezing, culture of immature oocytes, and a modern ovarian resection for women with polycystic ovaries, and discuss the indications hereof.

Determination of Follicular Localization in Human Ovarian Cortex for Vitrification.

To determine the optimal follicle localization for ovarian vitrification in adolescent and young adult (AYA)-aged (between 15 and 39 years of age) patients with cancer or primary ovarian insufficiency (POI). In total, ovaries from 24 women were included in our study. These include women who received ovariectomy for fertility preservation before gonadotoxic treatments for cancer (n = 4), or for the treatment of POI by the in vitro activation method (n = 8), and other women and infants (0-3 years of age) whose ovaries were autopsied (n = 12). Before cryopreservation, a portion of the ovary sampled from cancer and POI patients was used for histological analysis. Depths of follicles from the surface of ovarian cortices were then measured by using digital imaging software. The locations of the follicles at different developmental stages in the ovarian cortex were noted. The mean depth at which the primordial and primary follicles were located was 271 μm in infants. This was deeper in women in their twenties, thirties, and forties (501, 462, and 493 μm, respectively). The majority of secondary follicles were located <1000 μm from the ovarian surface (mean depth, 639 μm). In regard to patients with POI, the mean depth of primordial and primary follicles was 566 μm, whereas 70% of secondary follicles were located >1000 μm deep. These findings suggest that <1 mm is a potential optimum thickness of normal ovarian tissue for vitrification and a requirement that thicker ovarian cortices include secondary follicles in POI patients.

Role of inflammation and oxidative stress in the etiology of primary ovarian insufficiency.

Objective:The aim of this study was to elucidate the etiology and treatment of primary ovarian insufficiency, which is of unknown cause in 95% of the cases.Materials and Methods:Thirty patients aged 18-40 years who presented to Dicle University Faculty of Medicine Clinic of Obstetrics and Gynecology between June 2012 and January 2014 and were diagnosed as having primary ovarian insufficiency based on their clinical and endocrinologic data, and 30 healthy controls were included in this study.Results:No significant differences were found between patients with primary ovarian insufficiency and control subjects in demographic data and lipid profile levels, thyroid- stimulating hormone, prolactin, and glucose. However, the neutrophil to lymphocyte ratio and levels of follicle-stimulating hormone, luteinizing hormone, total antioxidant status, total oxidant status, and oxidative stress index were significantly higher in patients with primary ovarian insufficiency than in control subjects. In the correlation analysis, follicle-stimulating hormone exhibited a positive correlation with total oxidant status, oxidative stress index, and the neutrophil to lymphocyte ratio (r=0.573** p<0.001, r=0.584** p<0.001, r=0.541 p<0.001, respectively) and correlated negatively with total antioxidant status (r=-0.437** p<0.001).Conclusion:The neutrophil to lymphocyte ratio, total oxidant status, and oxidative stress index levels are elevated in primary ovarian insufficiency. Therefore, anti-oxidative and anti-inflammatory treatment might be administered to patients in the early stage of primary ovarian insufficiency. However, larger studies are needed to clarify whether these elevated levels are a cause or a consequence of primary ovarian insufficiency.

In Vitro Activation: A Possible New Frontier for Treatment of Primary Ovarian Insufficiency.

In vitro activation (IVA) represents a new frontier in the treatment of women with primary ovarian insufficiency as well as patients with cancer desiring fertility preservation. Here, we review the biological basis of IVA and the recent translation of IVA to humans by targeting Hippo and Akt-signaling pathways. We then provide a new integrated viewpoint on IVA, highlighting basic science research on the aspects of follicular development and ovarian tissue transplantation which may potentially optimize future translational research on IVA. Specific topics discussed include cryopreservation techniques, additional IVA pathway targets, the roles of actin polymerization, paracrine and endocrine factors, and the role of mechanical signaling and associated tissue rigidity in controlling ovarian follicular activation. Further research and improved understanding is needed to optimize success of IVA.

Hyaluronic acid prevents immunosuppressive drug-induced ovarian damage via up-regulating PGRMC1 expression.

Chemotherapy treatment in women can frequently cause damage to the ovaries, which may lead to primary ovarian insufficiency (POI). In this study, we assessed the preventative effects of hyaluronic acid (HA) in immunosuppressive drug-induced POI-like rat models and investigated the possible mechanisms. We found that HA, which was reduced in primary and immunosuppressant-induced POI patients, could protect the immunosuppressant-induced damage to granulosa cells (GCs) in vitro. Then we found that HA blocked the tripterygium glycosides (TG) induced POI-like presentations in rats, including delayed or irregular estrous cycles, reduced 17 beta-estradiol(E2) concentration, decreased number of follicles, destruction of follicle structure, and damage of reproductive ability. Furthermore, we investigated the mechanisms of HA prevention effects on POI, which was associated with promotion of GC proliferation and PGRMC1 expression. In conclusion, HA prevents chemotherapy-induced ovarian damage by promoting PGRMC1 in GCs. This study may provide a new strategy for prevention and treatment of POI.

Hyaluronic acid promotes the expression of progesterone receptor membrane component 1 via epigenetic silencing of miR-139-5p in human and rat granulosa cells.

Primary ovarian insufficiency (POI) is a serious reproductive dysfunction in which the follicle pool is reduced and depleted. Abnormal apoptosis of ovarian granulosa cells (GCs) is believed to result in follicle loss. Progesterone receptor membrane component 1 (PGRMC1), which is critical for GC survival, was reported to be reduced in POI patients, but the mechanism is unknown. In the present study, we found that PGRMC1 expression was correlated with the level of hyaluronic acid (HA) in POI patients. HA up-regulated PGRMC1 expression in GCs via suppression of miR-139-5p, which was proven by Western blotting and luciferase reporter assays to target PGRMC1. Consistent with these findings, levels of miR-139-5p were significantly increased and presented an inverse correlation with PGRMC1 in POI patients. Noticeably, HA inhibited CD44-mediated miR-139-5p expression but had no effect on luciferase activity after insertion of miR-139 promoter into luciferase plasmid. Interestingly, miR-139-5p was significantly up-regulated in KGN cells (GC tumor cell line) by the histone deacetylase inhibitor trichostatin A, indicating that HA down-regulated miR-139-5p expression via histone deacetylation. Taken together, we report an unrecognized mechanism of HA in the promotion of PGRMC1 expression, suggesting that HA may be a potential molecule for the prevention and treatment of POI.