Development Of Premature Ovarian Failure Research Articles

FGF2 Rescued Cisplatin-Injured Granulosa Cells through the NRF2-Autophagy Pathway.

Premature ovarian failure (POF) is a complicated disorder related to the apoptosis of granulosa cells. The incidence of chemotherapy-associated POF is rising dramatically owing to the increasing proportion of cancer in adolescents. According to previous studies, oxidative stress caused by chemotherapeutic agents plays an important role in the development of POF. However, the exact effects of nuclear factor-erythroid 2-related factor2 (NRF2), a pivotal anti-oxidative factor, are still unknown in chemotherapy-associated POF. Firstly, we manipulated NRF2 expressions on a genetic or pharmaceutical level in cisplatin-injured granulosa cell models. The results indicate that the increasing NRF2 in cisplatin-injured cells was just compensatory and not enough to resist the accumulated stress. Upregulation of NRF2 could protect granulosa cells against cisplatin via elevating autophagic level by using an autophagic activator (rapamycin) and inhibitor (chloroquine). Additionally, exogenous FGF2 exerted a protective role by increasing NRF2 expression and promoting its nuclear translocation. Meanwhile, the results in cisplatin-POF mice models were consistent with what was found in injured cells. In conclusion, our research proved that FGF2 rescued cisplatin-injured granulosa cells through the NRF2-autophagy pathway and might provide a possible alternative treatment choice by targeting NRF2 for POF patients who are intolerant or unsuitable to FGF2.

MicroRNA-144-3p protects against chemotherapy-induced apoptosis of ovarian granulosa cells and activation of primordial follicles by targeting MAP3K9

Premature ovarian failure (POF) is defined by amenorrhea, ovarian atrophy, hypoestrogenism, elevated gonadotropin level, and infertility under the age of 40. POF is frequently induced by chemotherapeutic agents. However, the underlying mechanisms regarding chemotherapy-mediated damage to ovarian function are unclear. In this study, enhanced apoptosis of granulosa cells (GCs) and aberrant activation of primordial follicles were observed in a POF mouse model induced by cisplatin. We subsequently observed significant downregulation of miR-144-3p and upregulation of mitogen-activated protein kinase kinase kinase 9 (MAP3K9) in primary ovarian GCs from POF mice, as revealed by microarrays. Furthermore, MAP3K9 expression was higher in human ovarian granulosa cells (COV434) treated with cisplatin and was identified as a novel target of miR-144-3p. Functional analysis revealed that miR-144-3p attenuated cisplatin induced apoptosis of GCs via silencing MAP3K9 expression, which suppressed the activity of the downstream p38 mitogen activated protein kinase (MAPK) pathway. Meanwhile, miR-144-3p prevented premature primordial follicle depletion in cisplatin-induced POF mice through targeting Map3k9, which led to a decline in the phosphorylation and activation of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase b (AKT) pathway. Taken together, this study revealed the protective effects of miR-144-3p on ovarian function and shed light on the epigenetic regulatory mechanism in the development of POF, which might provide new biomarkers for the ovarian reserve.

Preservation of fertility in patients with testicular germ cell tumors: oncological, legal, and religious aspects

Survival rates for cancer patients continue to steadily increase due to improvement of effectiveness of current treatments. However, despite significant oncological results, one should not forget about the quality of life of this cohort of patients, in particular those who undergo gonadotoxic cancer therapy with development of premature ovarian failure in women and azoospermia in men. Preservation of fertility in both women and men with cancer is currently possible and should be integrated at all levels of cancer care. In this regard, the main purpose of this review is to consider the topic of fertility in men treated for cancer in the context of various aspects of human life.

The Role of Serum Cadmium Levels in the Etiology of Premature Ovarian Failure: A Case-Control Study

Premature ovarian failure (POF) is a clinical syndrome known to affect approximately 1% of women of reproductive age. A number of genetic, autoimmune, metabolic, infectious and environmental causes have been identified in the etiology of POF. Cadmium is a toxic metal which can accumulate in ovaries and causes a significant decrease in the binding of gonadotropins that regulate steroidogenic enzyme activity in granulosa cells. We aimed to investigate the role of cadmium in the etiology of POF. Thirty-five patients with POF were enrolled in group 1 which was the study group. Two control groups were formed from healthy participants. Thirty-fiveparticipants who were age-matched young women with regular menstruation were included in group 2.Thirty-fivehealthy postmenopausal women were included in group 3. Patients' demographic data were recorded. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), thyroid-stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4) and cadmium levels were measured. There was a statistically significant difference between the groups for gravida, parity and living children (p<0.001), but no difference was found for abortion (p=0.430). While there was a statistically significant difference between the groups for serum FSH, LH and E2 levels (p<0.001), no statistically significant difference was found for T3, T4 and TSH. Serum cadmium levels were found to be statistically significantly decreased in group 1 compared to g roups 2 and 3 (p<0.001). This study revealed that cadmium had no direct effect on the development of POF, but it should be kept in mind that the synergistic and antagonistic effects of metals may affect this result.

Epigenetic regulation in premature ovarian failure: A literature review.

Premature ovarian failure (POF), or premature ovarian insufficiency (POI), is a multifactorial and heterogeneous disease characterized by amenorrhea, decreased estrogen levels and increased female gonadotropin levels. The incidence of POF is increasing annually, and POF has become one of the main causes of infertility in women of childbearing age. The etiology and pathogenesis of POF are complex and have not yet been clearly elucidated. In addition to genetic factors, an increasing number of studies have revealed that epigenetic changes play an important role in the occurrence and development of POF. However, we found that very few papers have summarized epigenetic variations in POF, and a systematic analysis of this topic is therefore necessary. In this article, by reviewing and analyzing the most relevant literature in this research field, we expound on the relationship between DNA methylation, histone modification and non-coding RNA expression and the development of POF. We also analyzed how environmental factors affect POF through epigenetic modulation. Additionally, we discuss potential epigenetic biomarkers and epigenetic treatment targets for POF. We anticipate that our paper may provide new therapeutic clues for improving ovarian function and maintaining fertility in POF patients.

MiRNA-190a-5p promotes primordial follicle hyperactivation by targeting PHLPP1 in premature ovarian failure.

We previously screened 6 differentially expressed miRNAs in ovarian tissues of 4-vinylcyclohexene diepoxide (VCD)-treated premature ovarian failure (POF) model in SD rats, including miRNA-190a-5p, miRNA-98-5p, miRNA-29a-3p, miRNA-144-5p, miRNA-27b-3p, miRNA-151-5p. In this study, to investigate the mechanisms causing the onset of POF, we first identified miRNAs with earlier differential expression at consecutive time points in the VCD-treated rat POF model and explored the mechanisms by which the target miRNAs promote POF. The SD rats were injected with VCD for 15days to induce POF. Additionally, we collected rat blood and ovaries at the same time every day for 15 consecutive days, and luteinizing hormone (LH), follicle-stimulating hormone (FSH), Anti-Mullerian hormone (AMH), and estradiol (E2) serum levels were detected by ELISA. Six miRNAs expression were measured in rat ovaries by qRT-PCR. Dual-luciferase reporter gene assays were employed to predict and verify the target gene (PHLPP1) of target miRNAs (miRNA-190a-5p). Western blot was examined to detect the expression levels of PHLPP1, AKT, p-AKT, FOXO3a, p-FOXO3a, and LHR proteins on the target gene PHLPP1 and its participation in the primordial follicular hyperactivation-related pathways (AKT-FOXO3a and AKT-LH/LHR). During the VCD modeling POF rat ovaries, miRNA-190a-5p was the first to show significant differential expression, i.e., 6th of VCD treating, and PHLPP1 was verified to be a direct downstream target of it. Starting from the 6th of VCD treatment, the more significant the up-regulation trend of miRNA-190a-5p expression, the more obvious the down-regulation trend of PHLPP1 and LHR mRNA and protein expression, accompanied by the more severe phosphorylation of AKT and FOXO3a proteins, thus continuously over-activating the rat primordial follicle to promote the development of POF. In conclusion, miRNA-190a-5p may become a potential biomarker for early screening of POF, and it can continuously activate primordial follicles in rats by targeting the expression of PHLPP1 and key proteins in the AKT-FOXO3a and AKT-LH/LHR pathways.

The Role of Inactivated NF-κB in Premature Ovarian Failure

Premature ovarian failure (POF) is defined as deployment of amenorrhea due to the cessation of ovarian function in a woman younger than 40 years old. The pathologic mechanism of POF is not yet well understood, although genetic aberrations, autoimmune damage, and environmental factors have been identified. The current study demonstrated that NF-κB inactivation is closely associated with the development of POF based on the data from literature and cyclophosphamide (Cytoxan)-induced POF mouse model. In the successfully established NF-κB-inactivated mouse model, the results showed the reduced expression of nuclear p65 and the increased expression of IκBα in ovarian granulosa cells; the reduced numbers of antral follicles; the reduction of Ki-67/proliferating cell nuclear antigen-labeled cell proliferation and enhanced Fas/FasL-dependent apoptosis in granulosa cells; the reduced level of E2 and anti-Müllerian hormone; the decreased expression of follicle-stimulating hormone receptor and cytochrome P450 family 19 subfamily A member 1 (CYP19A1) in granulosa cells, which was reversed in the context of blocking NF-κB signaling with BAY 11-7082; and the decreased expressions of glucose-regulated protein 78 (GRP78), activating transcription factor 6, protein kinase R-like endoplasmic reticulum kinase, and inositol-requiring enzyme 1 in granulosa cells. Dual-luciferase reporter assay demonstrated that p50 stimulated the transcription of GRP78, and NF-κB affected the expression of follicle-stimulating hormone receptor and promoted granulosa cell proliferation through GRP78-mediated endoplasmic reticulum stress. Taken together, these data indicate, for the first time, that the inactivation of NF-κB signaling plays an important role in POF.

Inactivation of NF-κB Signaling Facilitates the Occurrence of Premature Ovarian Failure via Accelerating Granulosa Cell Death

Background: Premature ovarian failure (POF) is defined as deployment of amenorrhea because of the cessation of ovarian function prior to woman’s age of 40 years. The POF pathological mechanism has not yet well understood although genetic aberrations, autoimmune damage, and environmental factors have been identified. Methods: In this study, we assume that NF-κB inactivation is closely associated with the development of POF based on the data from previous literatures and CTX-induced POF mouse model. By establishing a NF-κB inactivated mouse model, using histomorphology and molecular biology methods to analyze. Findings: In the successfully established NF-κB-inactivated mouse model, we found the reduced expression of nuclear P65 and the increased expression of IκBα in ovarian granulosa cells; the reduced numbers of antral follicles; the reduction of Ki67/PCNA-labeled cell proliferation and enhanced Fas/FasL-dependent apoptosis in granulosa cells; the increase of phosphorylated H2AX-labelled DNA damage; the elevated level of FSH and declined E2 and AMH; the decreased expressions of FSHR and Cyp19a1 in granulosa cells, which was reversed in the context of blocking NF-κB signaling with Bay 11-7082. Dual-luciferase reporter assay demonstrated that p50 could stimulate the transcription of GRP78. Interpretation: Lack of NF-κB signaling normal response (i.e., inactivation of NF-κB signaling) would increase the incidence of granulosa cell death, which further causes an accelerated antral follicular atresia. Another pathway to initiate the death of granulosa cells might result from the imbalance of ER stress caused by GRP78. Funding Information: This study was supported by NSFC grants (31771331, 31971108) Declaration of Interests: The authors declare that there are no conflict of interests. Ethics Approval Statement: This study was carried out in strict accordance with the recommendations of the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The protocol was approved by the Committee on the Ethics of Animal Experiments of the Jinan University.

Pregnancy in patients with systemic lupus erythematosus after cyclophosphamide therapy.

Systemic lupus erythematosus (SLE) often affects females of reproductive age and Cyclophosphamide, an alkylating agent leading to premature ovarian insufficiency (POF) and labelled category D for pregnancy is used as induction therapy for severe manifestations of lupus. There have been multiple case series reflecting variable outcomes of pregnancies after cyclophosphamide use for cancers and autoimmune diseases. With increasing maternal age, we have an increasing population of lupus patients who may wish to conceive after having received cyclophosphamide therapy. The objective of our study was to improve our understanding of the impact of cyclophosphamide exposure on fertility and pregnancy outcomes in patients with SLE.We retrospectively reviewed the charts of all patients who had received intravenous cyclophosphamide at our academic institute in the time period from 2000-2018 and identified 440 patients which included 157 female patients of reproductive age. There were 37 documented pregnancies after the cyclophosphamide infusion, of which 23 patients had successful outcomes; 4 elective abortion and 10 miscarriages. There were 17 patients who developed POF, of which 7 also had end stage renal disease. The average cumulative dose of cyclophosphamide in the patients who had successful pregnancy was 4080.37 mg compared to 2806.25 mg in those who had a miscarriage (p 0.164) and 5526.47 mg in those who developed POF (p 0.046). Using multiple regressions to evaluate risk factors impacting pregnancy outcomes, when taken as a set, the predictors including race, serological profile, exposure to steroids and Mycophenolate mofetil, age at cyclophosphamide infusion, age at pregnancy, and cumulative cyclophosphamide dose accounted for 46.29% of the variance in outcome of pregnancy (p 0.23) and 39.58% of the variance in development of premature ovarian failure (p 0.008). We noted statistical significance in the impact of maternal age at time of pregnancy (p 0.04) and duration of time between the last infusions to subsequent pregnancy (p 0.02) to pregnancy outcome.Our findings suggest that a longer time interval between the last cyclophosphamide infusion and subsequent pregnancy was favorable for a successful outcome and higher cumulative cyclophosphamide dose is more likely to be associated with premature ovarian failure.

Features of the ovarian reserve of women of reproductive age suffering from autoimmune diseases

The reproductive potential of a woman depends on indicators of the ovarian reserve, such as the anti-Muller hormone (AMH) and the number of antral follicles (NAF). Autoimmune diseases have a significant effect on fertility and contribute to the development of premature ovarian failure.
 Aim.To evaluate the parameters of the ovarian reserve in patients with type 1 diabetes mellitus, carriers of antibodies to the thyroid gland in a state of euthyroidism and compare them with similar parameters in healthy women.
 Materials and methods.In the first block of the study, the level of AMH, follicle-stimulating hormone, luteinizing hormone, NAF was studied among 224 women with diabetes and 230 healthy women in the control group. In block II, the level of the above hormonal indices was studied in 35 carriers of antithyroid antibodies in the state of euthyroidism and 35 healthy women.
 Results.In patients with type 1 diabetes, the level of AMH, NAF was statistically significantly lower when compared with the control group. Among carriers of antithyroid antibodies and healthy women, no difference in AMH and NAF was found.
 Conclusion.The autoimmune processes accompanying diabetes are more influenced by the ovarian reserve indices than autoimmune aggression to the tissues of the thyroid gland.

Current views on the molecular mechanisms of the initial stages of folliculogenesis

The ovary is a unique structure of the female body, which simultaneously presents various morphohistological units-from primordial to dominant follicles. Over the past decades, scientists have focused on studying the mechanisms of folliculogenesis at the gonadotropin-dependent stage. While more complex and lengthy processes that determine the fate of the follicle occur from the moment of their recruitment to the preantral stage of maturity (about 290 days), another 60 days pass before the dominant maturity. Currently, it has been proved that intercellular communication is established within the follicle, which involves a bidirectional exchange of information between the oocyte and its companions granulose and Teka cells through auto-and paracrine interactions using various genes, growth factors and cytokines. The purpose of this review was to study intrafollicular factors that control the early stages of folliculogenesis and other disorders that may ultimately lead to the development of premature ovarian failure.

MicroRNA-146b-5p overexpression attenuates premature ovarian failure in mice by inhibiting the Dab2ip/Ask1/p38-Mapk pathway and γH2A.X phosphorylation.

ObjectiveTo examine the role of high‐fat and high‐sugar (HFHS) diet‐induced oxidative stress, which is a risk factor for various diseases, in premature ovarian failure (POF).Materials and methodsOvarian granulosa cells (OGCs) were isolated from mice and cultured in medium supplemented with HFHS and poly (lactic‐co‐glycolic acid) (PLGA)‐cross‐linked miR‐146b‐5p nanoparticles (miR‐146@PLGA). RNA and protein expression levels were examined using quantitative real‐time polymerase chain reaction and Western blotting, respectively. HFHS diet‐induced POF model mice were administered miR‐146@PLGA.ResultsThe ovarian tissue of mice fed a HFHS diet exhibited the typical pathological characteristics of POF. HFHS supplementation induced oxidative stress injury in the mouse OGCs, activation of the Dab2ip/Ask1/p38‐Mapk signalling pathway and phosphorylation of γH2A.X in vitro and in vivo. The results of the luciferase reporter assay revealed that miR‐146 specifically downregulated p38‐Mapk14 expression. Meanwhile, co‐immunoprecipitation and Western blot analyses revealed that HFHS supplementation upregulated nuclear p38‐Mapk14 expression and consequently enhanced γH2A.X (Ser139) phosphorylation. The HFHS diet‐induced POF mouse model treated with miR‐146@PLGA exhibited downregulated p38‐Mapk14 expression in the OGCs, mitigated OGC ageing and alleviated the symptoms of POF.ConclusionsThis study demonstrated that HFHS supplementation activates the Dab2ip/Ask1/p38‐Mapk signalling pathway and promotes γH2A.X phosphorylation by inhibiting the expression of endogenous miR‐146b‐5p, which results in OGC ageing and POF development.

Association of an APBA3 Missense Variant with Risk of Premature Ovarian Failure in the Korean Female Population.

Premature ovarian failure (POF) is a complex disease of which the etiology is influenced by numerous genetic variations. Several POF candidate genes have been reported. However, no causal genes with high odds ratio (OR) have yet been discovered. This study included 564 females of Korean ethnicity, comprising 60 patients with POF and 182 controls in the discovery set and 105 patients with POF and 217 controls in the replication set. We conducted genome-wide association analysis to search for novel candidate genes predicted to influence POF development using Axiom Precision Medicine Research Arrays and additive model logistic regression analysis. One statistically significant single nucleotide polymorphism (SNP), rs55941146, which encodes a missense alteration (Val > Gly) in the APBA3 gene, was identified with OR values for association with POF of 13.33 and 4.628 in the discovery and replication sets, respectively. No rs55941146 minor allele homozygotes were present in either cases or controls. The APBA3 protein binds FIH-1 that inhibits hypoxia inducible factor-1α (HIF-1α). HIF-1α contributes to granulosa cell proliferation, which is crucial for ovarian follicle growth, by regulating cell proliferation factors and follicle stimulating hormone-mediated autophagy. Our data demonstrate that APBA3 is a candidate novel causal gene for POF.

Clinical characteristics and relationship between myasthenia gravis and premature ovarian failure: report of two cases

Myasthenia gravis (MG) and premature ovarian failure (POF) are rare. MF and POF greatly affect patients’ health. Combined occurrence of MF and POF in young women can have serious consequences. We report two cases of MG with POF. Case 1 was a 20-year-old woman who presented with myasthenic crisis and menopause in September 2015 and November 2015, respectively. The patient’s estradiol and follicle-stimulating hormone levels were abnormal. She was administered plasmapheresis and methylprednisolone pulse therapy. She improved and was discharged with normal restoration of menstruation after 3 months. Case 2 was a 21-year-old woman who had right eyelid droop and double vision in June 2014. She presented with menstrual disorder and menopause in August 2014 and September 2014, respectively. Estradiol and follicle-stimulating hormone levels were abnormal. She underwent progesterone therapy. She was admitted to hospital again in March 2016 with a myasthenic crisis. She received methylprednisolone pulse therapy and underwent thymectomy, but menstruation was not restored. In conclusion, there is comorbidity of POF in MG, and there is a close relationship between these two diseases. MG may subsequently lead to development of POF, and timely immunotherapy for MG may normalize POF.

MiR-15b induces premature ovarian failure in mice via inhibition of α-Klotho expression in ovarian granulosa cells

A thorough understanding of epigenetics regulatory mechanisms of premature ovarian failure (POF) is still lacking. Here, we found that cyclophosphamide induced significantly decrease in α-Klotho (Kl) expression in mouse ovarian granulosa cells (mOGCs), suggesting that cyclophosphamide inhibited Kl expression. Cyclophosphamide also significantly accelerated ageing and led to a decline in the pregnancy rate of C. elegans. We subsequently noted that the pathological condition exhibited by Kl−/- mice was similar to that observed in cyclophosphamide-induced POF mice. Furthermore, the mOGCs in both types of mice showed significant signs of oxidative stress damage, including decreased SOD and ATP, increased ROS levels. Detailed analyses revealed that the decreased Kl expression led to the reduced expression of autophagy-related proteins in mOGCs, which resulted in decreased autophagy activity. Finally, we found that cyclophosphamide attenuated the autophagy function of mOGCs via upregulating microRNA-15b expression, which silenced the endogenous Kl mRNA expression and stimulated the activity of the downstream TGFβ1/Smad pathway. Therefore, we demonstrated that Kl was one of the key inhibitory factors in the development of POF. It elucidated the underlying epigenetic regulatory mechanism, whereby cyclophosphamide-dependent microRNA-15b inhibited Kl expression, leading to the reduced ability of mOGCs to induce autophagy and ROS scavenging, ultimately causing POF.

Analysis on the level of IL-6, IL-21, AMH in patients with auto-immunity premature ovarian failure and study of correlation.

Expression of interleukin-6 (IL-6), interleukin-21 (IL-21) and anti-müllerian hormone (AMH) in premature ovarian failure (POF) patients were observed to explore the correlation of each indicator and its significance in POF. One hundred and forty-two patients diagnosed with POF in Binzhou City Center Hospital from June 2014 to December 2015 were selected as the observation group. At the same time, another 140 healthy women were selected as the control group. The serum levels of IL-6, IL-2l, AMH, follicle stimulating hormone (FSH) and luteinizing hormone (LH), estradiol (E2), testosterone (T) and basal antral follicle count (AFC), and mean ovarian volume (MOV) were determined and compared; correlation analysis of IL-6, IL-2l and AMH with other indicators was performed. Compared to the control group, the serum levels of IL-6, IL-21, FSH and LH in the observation group were significantly higher (P<0.05), while E2, T, AMH levels in the serum, AFC and MOV were significantly lower (P<0.05). Spearman's correlation analysis showed that IL-6, IL-21 was positively correlated with FSH and LH (P<0.05), but negatively correlated with E2, T and MOV (P<0.05). AMH was negatively correlated with FSH and LH, but positively correlated with E2, T and MOV. Our results showed that the expression of IL-6, IL-21 and AMH were related to the occurrence and development of POF, IL-6, IL-21 and AMH can be used as the primary screening indexes for POF patients.

Клеточно-тканевые и молекулярные аспекты формирования преждевременного истощения яичников при аутоиммунном оофорите

Клеточно-тканевые и молекулярные аспекты формирования преждевременного истощения яичников при аутоиммунном оофорите

Preservation of gonadal function in women undergoing chemotherapy: a systematic review and meta-analysis of the potential role for gonadotropin-releasing hormone agonists.

To evaluate the available randomized controlled trials (RCTs) in the literature investigating the use of gonadotropin-releasing hormone agonist (GnRHa) co-treatment for ovarian preservation in women receiving chemotherapy. A systematic review of the literature was performed from 1960 through 2017 to identify relevant RCTs. Included patients had lymphoma, ovarian cancer, or breast cancer. The primary outcome was the proportion of women who retained ovarian function after chemotherapy. Extracted data points included study design, patient characteristics, and proportion of women who developed premature ovarian failure (POF). A risk of bias assessment was performed according to the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions. The pooled odds ratio was calculated, and outcomes of individual studies were compared using the random-effects model with the inverse-variance method and the DerSimonian-Laird estimator. Twenty-nine RCTs were identified, and 10 met criteria for inclusion in the meta-analysis. An analysis of patients who did not develop POF after chemotherapy revealed eight studies supporting the use of GnRHa (OR 1.83; 95% CI 1.34-2.49). The duration of benefit of GnRHa is unclear. An analysis of three studies with outcome data at 2years revealed a non-significant OR of 0.53 (95% CI 0.22-1.30) for the preservation of ovarian function with GnRHa treatment. GnRHa may have a protective effect against the development of POF after gonadotoxic chemotherapy; however, the duration of benefit is unclear and requires further study.

Telocytes as potential targets in a cyclophosphamide-induced animal model of premature ovarian failure.

Premature ovarian failure (POF) refers to the presence of ovarian atrophic permanent amenorrhea in women under the age of 40. The pathogenesis of POF remains to be fully elucidated. Telocytes are a group of specialized cells with a small cell volume and very long cytoplasmic prolongations with dichotomous branching. Previous studies have indicated that telocytes function to support the trachea and serve as stem cell niches. Although it has been confirmed that telocytes are present in numerous organs in mammals, it remains to be determined whether they are present in ovarian tissues and whether they are involved in the development of POF. The present study used a cyclophosphamide-induced mouse model of POF. Hematoxylin and eosin staining and an enzyme-linked immunosorbent assay revealed that cyclophosphamide induced edema and apoptosis of ovarian stromal and granulosa cells and increased atretic follicles. In addition, cyclophosphamide induced abnormal peripheral blood FSH and E2 levels in mice. Transmission electron microscopy revealed a small number of telocyte-like cell structures in the ovarian stroma of wild-type mice. In addition, flow cytometry and immunohistochemical staining results suggested that the number of cluster of differentiation (CD)34/platelet-derived growth factor receptor (PDGFR)α, CD34/PDGFRβ and CD34/vimentin double-positive cells in the ovaries of POF mice was significantly decreased compared with wild-type mice. In conclusion, mouse ovarian tissues appear to contain telocytes, and cyclophosphamide treatment significantly reduced the number of ovarian telocytes. Therefore, telocytes may serve as a potential novel marker of POF induced by cyclophosphamide.

Association between premature ovarian failure, polymorphisms in MTHFR and MTRR genes and serum homocysteine concentration

This study investigated the association between premature ovarian failure (POF), MTHFR C677T/A1298C and MTRR A66G genotypes and serum homocysteine (Hcy) concentration. A prospective study was conducted in Chinese women, which included POF patients (n = 180) and controls (n = 195). Peripheral blood samples were used to determine MTHFR C677T/A1298C and MTRR A66G genotypes, and serum Hcy and sex hormone concentrations. Results showed that serum Hcy concentrations of POF patients were significantly higher than those of controls (P < 0.0001). In POF patients, serum Hcy concentrations were significantly correlated with oestradiol and FSH concentrations (r = −0.174, P = 0.037 and r = +0.238, P = 0.006, respectively). There were no significant differences in the distributions of MTHFR C677T/A1298C or MTRR A66G genotypes between the two groups. However, these genetic variants influenced serum Hcy concentrations in POF patients, especially for MTRR 66 AA/AG/GG genotypes, which were significantly correlated with the patients' Hcy concentrations (τ = 0.166, P = 0.033). These results suggest that serum Hcy concentrations in Chinese POF patients are increased and correlated with serum oestradiol/FSH concentrations. In conclusion, MTHFR C667T/A1298C and MTRR A66G genotypes are not associated with POF development, but they affect the patients' serum Hcy concentrations.