Study on the Reparative Effect of PEGylated Growth Hormone on Ovarian Parameters and Mitochondrial Function of Oocytes From Rats With Premature Ovarian Insufficiency.
Feng Penghui,Xie Qiu,Liu Zhe,Guo Zaixin,Tang Ruiyi,Yu Qi
Frontiers in cell and developmental biology
Premature ovarian insufficiency (POI) is a heterogeneous disorder and lacks effective interventions in clinical applications. This research aimed to elucidate the potential effects of recombinant human PEGylated growth hormone (rhGH) on follicular development and mitochondrial function in oocytes as well as ovarian parameters in POI rats induced by the chemotherapeutic agent. The impacts of rhGH on ovarian function before superovulation on follicles, estrous cycle, and sex hormones were evaluated. Oocytes were retrieved to determine oocyte quality and oxidative stress parameters. Single-cell sequencing was applied to investigate the latent regulatory network. This study provides new evidence that a high dosage of rhGH increased the number of retrieved oocytes even though it did not completely restore the disturbed estrous cycle and sex hormones. rhGH attenuated the apoptosis of granulosa cells and oxidative stress response caused by reactive oxygen species (ROS) and mitochondrial superoxide. Additionally, rhGH modulated the energy metabolism of oocytes concerning the mitochondrial membrane potential and ATP content but not mtDNA copy numbers. Based on single-cell transcriptomic analysis, we found that rhGH directly or indirectly promoted the balance of oxidative stress and cellular oxidant detoxification. Four hub genes, Pxmp4, Ehbp1, Mt-cyb, and Enpp6, were identified to be closely related to the repair process in oocytes as potential targets for POI treatment.
Current Understanding of the Etiology, Symptomatology, and Treatment Options in Premature Ovarian Insufficiency (POI).
Frontiers in endocrinology
Premature ovarian insufficiency (POI) occurs in at least 1% of all women and causes life-long health problems and psychological stress. Infertility caused by POI used to be considered absolute, with infertility treatment having little or no value. Generally, it has been thought that medicine can provide little service to these patients. The etiology of POI has been found to be genetic, chromosomal, and autoimmune. In addition, the increasing numbers of cancer survivors are candidates for iatrogenic POI, along with patients who have undergone ovarian surgery, especially laparoscopic surgery. Over 50 genes are known to be causally related to POI, and the disease course of some cases has been clarified, but in most cases, the genetic background remains unexplained, suggesting that more genes associated with the etiology of POI need to be discovered. Thus, in most cases, the genetic background of POI has not been clarified. Monosomy X is well known to manifest as Turner's syndrome and is associated with primary amenorrhea, but recent studies have shown that some women with numerical abnormalities of the X chromosome can have spontaneous menstruation up to their twenties and thirties, and some even conceive. Hormone replacement therapy (HRT) is recommended for women with POI from many perspectives. It alleviates vasomotor and genitourinary symptoms and prevents bone loss and cardiovascular disease. POI has been reported to reduce quality of life and life expectancy, and HRT may help improve both. Most of the problems that may occur with HRT in postmenopausal women do not apply to women with POI; thus, in POI, HRT should be considered physiological replacement of estrogen (+progesterone). This review describes some new approaches to infertility treatment in POI patients that may lead to new treatments for POI, along with the development of more sensitive markers of secondary/preantral follicles and genetic diagnosis.
Deficiency Leads to Premature Ovarian Failure.
Liu Linlin,Wang Huasong,Xu Guo Liang,Liu Lin
Frontiers in cell and developmental biology
Tet enzymes participate in DNA demethylation and play critical roles in stem cell pluripotency and differentiation. DNA methylation alters with age. We find that deficiency reduces fertility and leads to accelerated reproductive failure with age. Noticeably, -deficient mice at young age exhibit dramatically reduced follicle reserve and the follicle reserve further decreases with age, phenomenon consistent with premature ovarian failure (POF) syndrome. Consequently, deficient mice become infertile by reproductive middle age, while age matched wild-type mice still robustly reproduce. Moreover, by single cell transcriptome analysis of oocytes, deficiency elevates organelle fission, associated with defects in ubiquitination and declined autophagy, and also upregulates signaling pathways for Alzheimer's diseases, but down-regulates X-chromosome linked genes, such as , which is known to be implicated in POF. Additionally, is aberrantly upregulated and endogenous retroviruses also are altered in deficient oocytes. These molecular changes are consistent with oocyte senescence and follicle atresia and depletion found in premature ovarian failure or insufficiency. Our data suggest that enzyme plays roles in maintaining oocyte quality as well as oocyte number and follicle reserve and its deficiency can lead to POF.
Urinary trace elements in association with premature ovarian insufficiency and reproductive hormones in a Chinese population.
Li Chunming,Ma LinJuan,Qi Tongyun,Pan Wuye,Huang Yizhou,Luo Jie,Ye Xiaoqing,Lan Yibing,Liu Jing,Zhou Wenchao,Ruan Fei,Zhou Jianhong
Ecotoxicology and environmental safety
Homeostasis disturbance of trace elements has been linked to adverse reproductive consequences, including premature ovarian insufficiency (POI) in women, but limited evidence has been reported so far. This case-control study evaluated the associations between 5 common urinary trace elements [copper (Cu), manganese (Mn), Iron (Fe), Selenium (Se), and zinc (Zn)] and the odds for POI. Urinary concentrations of these 5 metals and serum levels of POI-related reproductive hormones of 169 cases and 209 healthy controls were measured. The urinary levels of Cu and Se in women with POI were significantly higher than those in the controls. The positive associations were observed between Cu levels and the odds of POI [for the medium tertile: odds ratio (OR) = 3.79, 95% CI: 1.98-7.27, p < 0.001; for the highest tertile: OR = 3.85, 95% CI: 2.00-7.41, p < 0.001]. The highest tertile of urinary Se levels was associated with increasing POI risk (for the highest tertile: OR = 2.54, 95% CI: 1.38-4.70, compared with the lowest tertile, p for trend = 0.001). In POI patients, urinary concentrations of Zn and Fe were negatively associated with serum levels of follicle-stimulating hormone (FSH). Our findings suggested that higher exposure levels of Cu and Se might lead to an increased risk of POI.
New theca-cell marker insulin-like factor 3 is associated with premature ovarian insufficiency.
Zhu Chendi,Luo Wei,Li Zhuqing,Zhang Xiruo,Hu Jingmei,Zhao Shidou,Jiao Xue,Qin Yingying
Fertility and sterility
OBJECTIVE:To characterize circulating insulin-like factor 3 (INSL3) in different stages of ovarian insufficiency and its role in the evaluation of premature ovarian insufficiency (POI). DESIGN:Retrospective cohort study. SETTING:University-based center for reproductive medicine. PATIENT(S):A total of 145 women, including 48 patients with POI (25 IU/L < follicle-stimulating hormone [FSH] ≤40 IU/L), 49 with biochemical POI (bPOI) (10 IU/L < FSH ≤25 IU/L) and 48 age-matched control women with normal ovarian reserve (FSH <10 IU/L), retrospectively included from the reproductive hospital affiliated with Shandong University between 2017 and 2019. INTERVENTION(S):Levels of INSL3 in the serum and follicular fluid assayed with a commercial radioimmunoassay. MAIN OUTCOME MEASURE(S):Level of INSL3 in serum and follicular fluid among control women and patients with bPOI and POI, its association with different ovarian reserve markers, and its predictive value for bPOI and POI. RESULT(S):The serum INSL3 level continuously declined with the progress of ovarian insufficiency. It showed strong negative association with FSH (-0.655) and luteinizing hormone (-0.433), but positively correlated with antimüllerian hormone (0.617), inhibin B (0.400), antral follicle count (0.630), and testosterone (0.180). Additionally, the circulating INSL3 served as a good predictor for bPOI and POI. No statistically significant difference of INSL3 levels in follicular fluid was observed between bPOI patients and control women. CONCLUSION(S):For the first time our study has revealed an INSL3 deficiency in women with POI, indicating that circulating INSL3 could serve as a promising theca-cell specific marker for POI. Future research on the role of INSL3 in modulating follicular development, steroidogenesis, and POI pathogenesis is warranted.
Homozygous variants in cause premature ovarian insufficiency.
He Wen-Bin,Tan Chen,Zhang Ya-Xin,Meng Lan-Lan,Gong Fei,Lu Guang-Xiu,Lin Ge,Du Juan,Tan Yue-Qiu
Journal of medical genetics
BACKGROUND:The genetic causes of the majority of cases of female infertility caused by premature ovarian insufficiency (POI) are unknown. OBJECTIVE:To identify the genetic causes of POI in 110 patients. METHODS:Whole-exome sequencing was performed on 110 patients with POI, and putative disease-causative variants were validated by Sanger sequencing. Bioinformatic and in vitro functional analyses were performed for functional characterisation of the identified candidate disease-causative variants. RESULTS:We identified two homozygous variants (NM_001040274: c.150_151del (p.Ser52Profs*7), c.999A>G (p.Ile333Met)) in in two patients, which had co-segregated with POI in these families. Bioinformatic analysis predicted that the two variants are deleterious, and in vitro functional analysis showed that mutant SYCP2L proteins exhibited mislocalisation and loss of function. CONCLUSIONS: is a novel gene found to be responsible for human POI. Our findings provide a potential molecular marker for POI and improve the understanding of the genetic basis of female infertility.
Rare deleterious BUB1B variants induce premature ovarian insufficiency and early menopause.
Chen Qing,Ke Hanni,Luo Xuezhen,Wang Lingbo,Wu Yanhua,Tang Shuyan,Li Jinsong,Jin Li,Zhang Feng,Qin Yingying,Chen Xiaojun
Human molecular genetics
Losing of ovarian functions prior to natural menopause age causes female infertility and early menopause. Premature ovarian insufficiency (POI) is defined as the loss of ovarian activity before 40 years of age. Known genetic causes account for 25-30% of POI cases, demonstrating the high genetic heterogeneity of POI and the necessity for further genetic explorations. Here we conducted genetic analyses using whole-exome sequencing in a Chinese non-syndromic POI family with the affected mother and at least four affected daughters. Intriguingly, a rare missense variant of BUB1B c.273A>T (p.Gln91His) was shared by all the cases in this family. Furthermore, our replication study using targeted sequencing revealed a novel stop-gain variant of BUB1B c.1509T>A (p.Cys503*) in one of 200 sporadic POI cases. Both heterozygous BUB1B variants were evaluated to be deleterious by multiple in silico tools. BUB1B encodes BUBR1, a crucial spindle assembly checkpoint component involved in cell division. BUBR1 insufficiency may induce vulnerability to oxidative stress. Therefore, we generated a mouse model with a loss-of-function mutant of Bub1b, and also employed D-galactose-induced aging assays for functional investigations. Notably, Bub1b+/- female mice presented late-onset subfertility, and they were more sensitive to oxidative stress than wild-type female controls, mimicking the clinical phenotypes of POI cases affected by deleterious BUB1B variants. Our findings in human cases and mouse models consistently suggest, for the first time, that heterozygous deleterious variants of BUB1B are involved in late-onset POI and related disorders.
Low-Intensity Pulsed Ultrasound Promotes Repair of 4-Vinylcyclohexene Diepoxide-Induced Premature Ovarian Insufficiency in SD Rats.
The journals of gerontology. Series A, Biological sciences and medical sciences
Women with premature ovarian insufficiency (POI) may be more vulnerable to a variety of health risks. To seek a new method to treat the disease, the effects of low-intensity pulsed ultrasound (LIPUS) on promoting repair of ovarian injury in female SD rats induced by 4-vinylcyclohexene diepoxide (VCD) were explored in this research. A total of 24 female SD rats were subjected to intraperitoneal injection of VCD to induce POI. Successful modeling was achieved in 22 rats, which were then randomized into VCD + LIPUS group (n = 13) and VCD group (n = 9). The control group (n = 5) was injected with equal normal saline. Hematoxylin and eosin staining, enzyme-linked immunosorbent assay, Western blot analysis, scanning electron microscope, immunohistochemistry, and terminal deoxynucleotidyl transferase-mediated nick end labeling assay were applied to detect the results. The results indicated that rats in the VCD group showed disorder in the estrous cycle, the number of atresia follicles and apoptosis granulosa cells increased (p < .05). After the LIPUS treatment, the estrous cycle recovered, the number of follicles increased (p < .05), the level of E2 and anti-Müllerian hormone enhanced (p < .05), and the follicle-stimulating hormone decreased (p < .05). The expression of NF-κB p65, TNFα, Bax, ATF4, and caspase-3 in ovarian tissue was significantly decreased (p < .05). These findings showed that LIPUS could promote the repair of the VCD-induced ovarian damage in SD rats, which has the potential to be further applied in the clinic.
Pathogenic variants of meiotic double strand break (DSB) formation genes PRDM9 and ANKRD31 in premature ovarian insufficiency.
Genetics in medicine : official journal of the American College of Medical Genetics
PURPOSE:The etiology of premature ovarian insufficiency (POI) is heterogeneous, and genetic factors account for 20-25% of the patients. The primordial follicle pool is determined by the meiosis process, which is initiated by programmed DNA double strand breaks (DSB) and homologous recombination. The objective of the study is to explore the role of DSB formation genes in POI pathogenesis. METHODS:Variants in DSB formation genes were analyzed from a database of exome sequencing in 1,030 patients with POI. The pathogenic effects of the potentially causative variants were verified by further functional studies. RESULTS:Three pathogenic heterozygous variants in PRDM9 and two in ANKRD31 were identified in seven patients. Functional studies showed the variants in PRDM9 impaired its methyltransferase activity, and the ANKRD31 variations disturbed its interaction with another DSB formation factor REC114 by haploinsufficiency effect, indicating the pathogenic effects of the two genes on ovarian function were dosage dependent. CONCLUSION:Our study identified pathogenic variants of PRDM9 and ANKRD31 in POI patients, shedding new light on the contribution of meiotic DSB formation genes in ovarian development, further expanding the genetic architecture of POI.
Hormone Replacement Therapy Reverses Gut Microbiome and Serum Metabolome Alterations in Premature Ovarian Insufficiency.
Jiang Lingling,Fei Haiyi,Tong Jinfei,Zhou Jiena,Zhu Jiajuan,Jin Xiaoying,Shi Zhan,Zhou Yan,Ma Xudong,Yu Hailan,Yang Jianhua,Zhang Songying
Frontiers in endocrinology
Objective:We explored the gut microbiome and serum metabolome alterations in patients with premature ovarian insufficiency (POI) and the effects of hormone replacement therapy (HRT) with the aim to unravel the pathological mechanism underlying POI. Methods:Fecal and serum samples obtained from healthy females (HC, n = 10) and patients with POI treated with (n = 10) or without (n = 10) HRT were analyzed using 16S rRNA gene sequencing and untargeted metabolomics analysis, respectively. Peripheral blood samples were collected to detect serum hormone and cytokine levels. Spearman's rank correlation was used to evaluate correlations between sex hormones and cytokines and between the gut microbiota and serum metabolites. To further confirm the correlation between and ovarian fibrosis, the mice were inoculated with () through oral gavage. Results:The abundance of genus significantly increased in the fecal samples of patients with POI compared to that observed in the samples of HCs. This increase was reversed in patients with POI treated with HRT. Patients with POI showed significantly altered serum metabolic signatures and increased serum TGF-β1 levels; this increase was reversed by HRT. The abundance of was positively correlated with altered metabolic signatures, which were, in turn, positively correlated with serum TGF-β1 levels in all subjects. Estrogen ameliorated ovarian fibrosis induced by in mice. Conclusions:The interactions between the gut microbiota, serum metabolites, and serum TGF-β1 in patients with POI may play a critical role in the development of POI. HRT not only closely mimicked normal ovarian hormone production in patients with POI but also attenuated gut microbiota dysbiosis and imbalance in the levels of serum metabolites and TGF-β1, which are reportedly associated with fibrosis. The findings of this study may pave the way for the development of preventive and curative therapies for patients with POI.
Stem Cell Paracrine Signaling for Treatment of Premature Ovarian Insufficiency.
Polonio Alba M,García-Velasco Juan A,Herraiz Sonia
Frontiers in endocrinology
Premature ovarian insufficiency is a common disorder affecting young women and represents the worst-case ovarian scenario due to the substantial impact on the reproductive lifespan of these patients. Due to the complexity of this condition, which is not fully understood, non-effective treatments have yet been established for these patients. Different experimental approaches are being explored and strategies based on stem cells deserve special attention. The regenerative and immunomodulatory properties of stem cells have been successfully tested in different tissues, including ovary. Numerous works point out to the efficacy of stem cells in POI treatment, and a wide range of clinical trials have been developed in order to prove safety and effectiveness of stem cells therapy-in diminished ovarian reserve and POI women. The main purpose of this review is to describe the state of the art of the treatment of POI involving stem cells, especially those that use mobilization of stem cells or paracrine signaling.
Ovarian Reserve Markers in Premature Ovarian Insufficiency: Within Different Clinical Stages and Different Etiologies.
Jiao Xue,Meng Tingting,Zhai Yiwei,Zhao Lijuan,Luo Wei,Liu Peihao,Qin Yingying
Frontiers in endocrinology
Objective:To characterize the ovarian reserve indicators for premature ovarian insufficiency (POI) at different disease stages and with various etiologies. Methods:According to different FSH levels and menstrual conditions, patients with normal ovarian reserve (NOR with 5 IU/L<FSH<10 IU/L, n=987), precursor stage of POI (pre-POI with 10 IU/L<FSH ≤ 25 IU/L, n=410), early POI (25 IU/L<FSH ≤ 40 IU/L n=147), and premature ovarian failure (POF with FSH>40 IU/L, n=454) were retrospectively screened and their records were abstracted from Reproductive Hospital Affiliated to Shandong University between 2014 and 2019. Based on the known etiologies, POI patients were subdivided into genetic, iatrogenic, autoimmune and idiopathic subsets according to the known etiologies. The phenotypic features were compared within different subgroups, and the predictive value of ovarian reserve markers was analyzed. Results:The ovarian reserve indicators consecutively deteriorated with the progress of ovarian insufficiency, indicated as an increase of FSH and LH but decrease of AMH, inhibin B, AFC, E and T (P<0.01). Most of them changed significantly from NOR to pre-POI while remained relatively stable at a low level or even undetectable at early POI and POF stage. AMH showed the highest predictive value for pre-POI (AUC 0.932, 95% CI 0.918-0.945) and POI (AUC 0.944, 95% CI 0.933-0.954), and the combination of AMH and AFC was highly promising for early prediction. Additionally, significant differences existed in AMH, inhibin B and AFC among women with different etiologies of POI (P<0.05), and the genetic POI presented the worst hormone status. Conclusions:Our study indicated a high heterogeneity of POI in both endocrine hormones and etiological phenotypes. The quantitative changes and cutoff values of AMH and AFC could provide new insights in the prediction and early diagnosis of POI.
Meiotic Recombination Defects and Premature Ovarian Insufficiency.
Huang Chengzi,Guo Ting,Qin Yingying
Frontiers in cell and developmental biology
Premature ovarian insufficiency (POI) is the depletion of ovarian function before 40 years of age due to insufficient oocyte formation or accelerated follicle atresia. Approximately 1-5% of women below 40 years old are affected by POI. The etiology of POI is heterogeneous, including genetic disorders, autoimmune diseases, infection, iatrogenic factors, and environmental toxins. Genetic factors account for 20-25% of patients. However, more than half of the patients were idiopathic. With the widespread application of next-generation sequencing (NGS), the genetic spectrum of POI has been expanded, especially the latest identification in meiosis and DNA repair-related genes. During meiotic prophase I, the key processes include DNA double-strand break (DSB) formation and subsequent homologous recombination (HR), which are essential for chromosome segregation at the first meiotic division and genome diversity of oocytes. Many animal models with defective meiotic recombination present with meiotic arrest, DSB accumulation, and oocyte apoptosis, which are similar to human POI phenotype. In the article, based on different stages of meiotic recombination, including DSB formation, DSB end processing, single-strand invasion, intermediate processing, recombination, and resolution and essential proteins involved in synaptonemal complex (SC), cohesion complex, and fanconi anemia (FA) pathway, we reviewed the individual gene mutations identified in POI patients and the potential candidate genes for POI pathogenesis, which will shed new light on the genetic architecture of POI and facilitate risk prediction, ovarian protection, and early intervention for POI women.
Mesenchymal Stem Cells in Premature Ovarian Insufficiency: Mechanisms and Prospects.
Li Zhongkang,Zhang Mingle,Tian Yanpeng,Li Qian,Huang Xianghua
Frontiers in cell and developmental biology
Premature ovarian insufficiency (POI) is a complex endocrine disease that severely affects the physiological and reproductive functions of females. The current conventional clinical treatment methods for POI are characterized by several side effects, and most do not effectively restore the physiological functions of the ovaries. Transplantation of mesenchymal stem cells (MSCs) is a promising regenerative medicine approach, which has received significant attention in the management of POI with high efficacy. Associated pre-clinical and clinical trials are also proceeding orderly. However, the therapeutic mechanisms underlying the MSCs-based treatment are complex and have not been fully elucidated. In brief, proliferation, apoptosis, immunization, autophagy, oxidative stress, and fibrosis of ovarian cells are modulated through paracrine effects after migration of MSCs to the injured ovary. This review summarizes therapeutic mechanisms of MSCs-based treatments in POI and explores their therapeutic potential in clinical practice. Therefore, this review will provide a theoretical basis for further research and clinical application of MSCs in POI.
CPEB3 deficiency in mice affect ovarian follicle development and causes premature ovarian insufficiency.
E Fang,Zhang He,Yin Wanli,Wang Chongyang,Liu Yuanli,Li Yanze,Wang Linlin,Wu Yue,Zhang Runze,Zou Chendan,Song Tianjun,Matunda Cedric,Zou Chaoxia,Gao Xu
Cell death & disease
Premature ovarian insufficiency (POI) is a heterogeneous and multifactorial disorder. In recent years, there has been an increasing interest in research on the pathogenesis and treatment of POI, owing to the implementation of the second-child policy in China. Cytoplasmic polyadenylation element-binding protein 3 (CPEB3) is an RNA-binding protein that can bind to specific RNA sequences. CPEB3 can bind to and affect the expression, cellular location, and stability of target RNAs. Cpeb3 is highly expressed in the ovary; however, its functions remain unknown. In this study, Cpeb3-mutant mice were used to characterize the physiological functions of CPEB3. Cpeb3-mutant female mice manifested signs of gradual loss of ovarian follicles, ovarian follicle development arrest, increased follicle atresia, and subfertility with a phenotype analogous to POI in women. Further analysis showed that granulosa cell proliferation was inhibited and apoptosis was markedly increased in Cpeb3-mutant ovaries. In addition, the expression of Gdf9, a potential target of CPEB3, was decreased in Cpeb3-mutant ovaries and oocytes. Altogether, these results reveal that CPEB3 is essential for ovarian follicle development and female fertility as it regulates the expression of Gdf9 in oocytes, disruption of which leads to impaired ovarian follicle development and POI.
lncRNA participates in premature ovarian insufficiency through regulating and .
Li Duan,Xu Weiwei,Wang Xiaoyan,Dang Yujie,Xu Lan,Lu Gang,Chan Wai-Yee,Leung Peter C K,Zhao Shidou,Qin Yingying
Molecular therapy. Nucleic acids
The list of long non-coding RNAs (lncRNAs) that participate in the function of ovarian granulosa cells (GCs) is rapidly expanding, but the mechanisms through which lncRNAs regulate GC function are not yet fully understood. Here, we recognized a minimally expressed lncRNA (which we named ) in GCs from patients with biochemical premature ovarian insufficiency (bPOI). We further explored the role of lncRNA in GC function and its contribution to the development of bPOI. Mechanistically, silencing downregulated by competitively binding with , and this resulted in significant inhibition of DNA damage repair capacity. In addition, decreased expression of promoted ubiquitin-mediated degradation of Wilms tumor 1 (WT1) protein through interactions with heat shock protein 90 (HSP90), which led to aberrant differentiation of GCs. Moreover, was able to ameliorate the etoposide-induced DNA damage and apoptosis . Taken together, these findings provide new insights into the contribution of lncRNAs in POI pathogenesis.
Premature Ovarian Insufficiency: Past, Present, and Future.
Chon Seung Joo,Umair Zobia,Yoon Mee-Sup
Frontiers in cell and developmental biology
Premature ovarian insufficiency (POI) is the loss of normal ovarian function before the age of 40 years, a condition that affects approximately 1% of women under 40 years old and 0.1% of women under 30 years old. It is biochemically characterized by amenorrhea with hypoestrogenic and hypergonadotropic conditions, in some cases, causing loss of fertility. Heterogeneity of POI is registered by genetic and non-genetic causes, such as autoimmunity, environmental toxins, and chemicals. The identification of possible causative genes and selection of candidate genes for POI confirmation remain to be elucidated in cases of idiopathic POI. This review discusses the current understanding and future prospects of heterogeneous POI. We focus on the genetic basis of POI and the recent studies on non-coding RNA in POI pathogenesis as well as on animal models of POI pathogenesis, which help unravel POI mechanisms and potential targets. Despite the latest discoveries, the crosstalk among gene regulatory networks and the possible therapies targeting the same needs to explore in near future.
Premature ovarian insufficiency.
Best practice & research. Clinical obstetrics & gynaecology
The natural lifespan of the ovary is occasionally interrupted by pathological processes; some are known, but many are unknown. Premature ovarian insufficiency (POI) can be a devastating diagnosis for an adolescent or for someone who has yet to start a family. Common causes of POI include genetic and chromosomal defects, autoimmune damage, and cancer treatments. Knowledge of the pathogenesis of this condition and an awareness of contemporary hormone replacement and fertility options are required to design a multidisciplinary therapeutic approach comprising reproductive medicine, endocrinology, clinical psychology, and assisted fertility expertise.
improves ovarian function and oocyte quality in aged female mice.
Park Min Jung,Han Si-Eun,Kim Hyeon Jeong,Heo Jeong Doo,Choi Hee-Jung,Ha Ki-Tae,Yang Sun Woo,Lee Kyu Sup,Kim Seung Chul,Kim Chang Woon,Joo Bo Sun
Although ovarian aging is a key cause of decreased ovarian function and oocyte quality, it remains a problem in infertility treatment. Therefore, this study is aimed to investigate whether (PL), a herb improves ovarian function and oocyte quality using aged female mice. C57BL/6 female mice aged 8 months were treated orally every day with PL of 26.5 mg/kg (n=7) and 53 mg/kg (n=7) of body weight for 4 weeks using an oral zoned needle. The control group (n=7) was treated with normal saline. Ovaries and serum were collected for the H&E stain and the evaluation of reactive oxygen species (ROS) levels, respectively. In the second experiment, female mice were orally administered with PL (26.5 mg/kg: n=12, 53 mg/kg: n=12, control: n=12) and then superovulated with PMSG and hCG, and mated with male mice. Zygotes were retrieved and cultured for 4 days. Ovaries were provided for examination of expressions of genes associated with angiogenesis (VEGF and visfatin), anti-aging (Sirt1 and Sirt2), and follicular development (c-Kit, BMP-15, and GDF-9). PL significantly increased numbers of surviving follicles (primordial, primary, secondary, and antral), numbers of zygotes retrieved, embryo development rate, and ovarian expression of VEGF, visfatin, c-Kit, BMP-15, and GDF-9 at both doses. However, ovarian expression of Sirt1 and Sirt2 was increased at 53.0 mg/kg of PL. ROS levels were not affected by PL. These results suggest that PL may possess beneficial effects regarding ovarian function and oocyte quality, possibly by activation of ovarian angiogenesis and follicular development.
Human amnion-derived mesenchymal stem cells improved the reproductive function of age-related diminished ovarian reserve in mice through Ampk/FoxO3a signaling pathway.
Liu Hanwen,Jiang Chunyan,La Boya,Cao Meng,Ning Song,Zhou Jing,Yan Zhengjie,Li Chuyu,Cui Yugui,Ma Xiang,Wang Meilian,Chen Li,Yu Youjia,Chen Feng,Zhang Yuexin,Wu Huimin,Liu Jiayin,Qin Lianju
Stem cell research & therapy
BACKGROUND:Age-related diminished ovarian reserve (AR-DOR) reduced the quality of oocytes, resulting in decreased female fertility. Aging is tightly related to abnormal distribution and function of mitochondria, while mitophagy is a major process to maintain normal quality and quantity of mitochondria in cells, especially in oocytes which containing a large number of mitochondria to meet the demand of energy production during oocyte maturation and subsequent embryonic development. Ampk/FoxO3a signaling is crucial in the regulation of mitophagy. It is reported mesenchymal stem cells (MSCs) can improve ovarian function. Here we aim to explore if human amnion-derived mesenchymal stem cells (hAMSCs) are effective in improving ovarian function in AR-DOR mice and whether Ampk/FoxO3a signaling is involved. METHODS:The AR-DOR model mice were established by 32-week-old mice with 3-8 litters, significantly low serum sex hormone levels and follicle counts. The old mice were divided into 5 treatment groups: normal saline (NS, control), 1% human serum albumin (HSA, resolver), low dose (LD, 5.0 × 10cells/kg), middle dose (MD, 7.5 × 10cells/kg), and high dose (HD, 10.0 × 10cells/kg). The prepared hAMSCs were injected through tail vein. Serum sex hormone level, follicle counts, fertilization rate, gestation rate, little size, apoptosis of granulosa and stromal cells, expression level of Sod2, Ampk, and ratio of phosphorylated FoxO3a to total FoxO3a in ovaries were examined. RESULTS:Our results show that after hAMSC transplantation, the ovarian function in AR-DOR mice was significantly improved, meanwhile the apoptosis of granulosa and stromal cells in the ovaries was significantly repressed, the expression level of Ampk and the ratio of phosphorylated FoxO3a to total FoxO3a both were significantly increased, meanwhile increased Sod2 expression was also observed. CONCLUSION:Our results demonstrate hAMSC transplantation via tail-injection can improve ovarian function of AR-DOR mice through Ampk/FoxO3a signaling pathway.
Human Umbilical Cord Mesenchymal Stem Cells Improve Ovarian Function in Chemotherapy-Induced Premature Ovarian Failure Mice Through Inhibiting Apoptosis and Inflammation via a Paracrine Mechanism.
Deng Taoran,He Jing,Yao Qingyun,Wu Linjing,Xue Liru,Wu Mingfu,Wu Dongcheng,Li Changyong,Li Yufeng
Reproductive sciences (Thousand Oaks, Calif.)
Human umbilical cord mesenchymal stem cell (UC-MSC) application is a promising arising therapy for the treatment of premature ovarian failure (POF). However, little is known about the inflammation regulatory effects of human umbilical cord MSCs (UC-MSCs) on chemotherapy-induced ovarian damage, regardless of in vivo or in vitro. This study was designed to investigate the therapeutic effects of UC-MSC transplantation and underlying mechanisms regarding both apoptosis and inflammation in POF mice. The chemotherapy-induced POF models were induced by intraperitoneal injection of cyclophosphamide. Ovarian function parameters, granulosa cell (GC) apoptosis, and inflammation were examined. Morphological staining showed that UC-MSC treatment increased the ovary size, and the numbers of primary and secondary follicles, but decreased the number of atretic follicles. Estradiol levels in the UC-MSC-treated group were increased while follicle-stimulating hormone levels were reduced compared to those in the POF group. UC-MSCs inhibited cyclophosphamide-induced GC apoptosis and inflammation. Meanwhile, phosphorylation of AKT and P38 was elevated after UC-MSC treatment. Tracking of UC-MSCs in vivo indicated that transplanted UC-MSCs were only located in the interstitium of ovaries rather than in follicles. Importantly, UC-MSC-derived extracellular vesicles protected GCs from alkylating agent-induced apoptosis and inflammation in vitro. Our results suggest that UC-MSC transplantation can reduce ovary injury and improve ovarian function in chemotherapy-induced POF mice through anti-apoptotic and anti-inflammatory effects via a paracrine mechanism.
Effects of Yu Linzhu on ovarian function and oocyte mitochondria in natural aging mice.
Yang Zhen,Wei Mao-Lin,Dong Xiao-Ying
OBJECTIVE:To study the effect of Yu Linzhu on ovarian function and mitochondria in natural aging mice. METHODS:Female BALB/c mice were selected as normal group at 7-8 weeks and natural aging group at 9 months. The natural aging group was divided into Yu Linzhu intervention group and non-intervention group by intragastric administration once a day for 6 weeks. The morphology and blood flow of ovary were observed by ultrasound. Ovarian morphology and follicle were observed by HE staining. Hormone levels were analyzed by ELISA. Serum oxidative stress were detected by radioimmunoassay. The distribution of mitochondria in oocytes was observed by fluorescence staining. The ultrastructure of oocytes and the morphology of mitochondria were observed under electron microscope. The mitochondrial membrane potential was detected by JC-1. RESULTS:Two groups of aging mice had serious disturbance of estrus cycle. The ovarian area of the mice in the aging non-intervention group was smaller than that in the normal group, and the ovarian area of the mice in the aging intervention group recovered. The ovarian blood flow was weak or even disappear in the aging non-intervention group, and the blood flow in the intervention group was improved. The ovarian volume of mice in the non-intervention group was smaller than that in the normal group. Some ovarian tissues were adhered to the surrounding tissues. While in the intervention group, the ovarian volume increased, the degree of adhesion decreased, the infiltration of ovarian interstitial lymphocytes decreased, and the zona pellucida recovered. Granular cell arrangement returned neatly, egg cell shape recover regular and the number also increased. In the non-intervention group, E2 (Estrogen), AMH (Anti-Mullerian hormone) decreased ( = 0.0092 and = 0.0334, respectively), FSH (Follicle stimulating hormone) increased ( < 0.0001). In the intervention group, FSH decreased ( = 0.0002), LH (luteinizing hormone) decreased and E2, AMH increased. In the non-intervention group, GSH-Px (Glutathione peroxidase) decreased ( = 0.0129), SOD (Superoxide dismutase) decreased, ROS (reactive oxidative species), MDA (Malondialdehyde) increased. In the aging intervention group, ROS, MDA decreased and GSH-Px increased. In the non-intervention group, mitochondrial expression was scattered at the concentrated distribution point, the length of mitochondria was mostly long and the average volume increased, the density decreased, the number decreased and some mitochondria fused, and lesions such as swelling, vacuolar degeneration and inclusion body formation, membrane potential decreased ( = 0.0002). In the aging intervention group, mitochondria were evenly distributed, the mitochondria were basically round, the distribution density was moderate, the inner ridge was clear, and the membrane potential of the aging intervention group increased. CONCLUSION:Yu Linzhu can improve the ovarian function of natural aging mice by improving the mitochondrial function of oocytes.
hUMSCs regulate the differentiation of ovarian stromal cells via TGF-β/Smad3 signaling pathway to inhibit ovarian fibrosis to repair ovarian function in POI rats.
Cui Linlu,Bao Hongchu,Liu Zhongfeng,Man Xuejing,Liu Hongyuan,Hou Yun,Luo Qianqian,Wang Siyuan,Fu Qiang,Zhang Hongqin
Stem cell research & therapy
OBJECTIVE:The basic pathological changes of primary ovarian insufficiency (POI) include ovarian tissue fibrosis and follicular development disorders. The human umbilical cord mesenchymal stem cell (hUMSC) transplantation has been shown an effective method to improve the ovarian function in POI rat model; however, the exact mechanisms are still unclear. The purpose of this study is to investigate whether the recovery of ovarian function in POI rats is related to the inhibition of tissue fibrosis following hUMSC transplantation. Furthermore, the transforming growth factor-β (TGF-β) signaling pathway is explored to determine the mechanisms of ovarian function recovery through its inhibition of tissue fibrosis. METHODS:The primary ovarian insufficiency (POI) rat model was established by intraperitoneal injection of chemotherapy drug cisplatin (CDDP) for 7 days. The levels of serum sex hormones were measured using enzyme-linked immunosorbent assay (ELISA). The tissue fibrosis in the ovary was examined using Masson staining and Sirius red staining. The collagen fibers in the ovarian tissues were detected by Western blot analysis. To investigate the mechanisms of ovarian function recovery following hUMSC transplantation, ovarian stromal cells were isolated from the ovarian cortex of immature rats. The expression of Cytochrome P450 17A1 (Cyp17a1) and fibrosis marker of alpha smooth muscle actin (α-SMA) in ovarian stromal cells was examined using immunofluorescence analysis. Also, the protein levels of Cyp17a1 and α-SMA in ovarian stromal cells were examined by Western blot analysis. The expression of TGF-β and Smad3 signals was measured by Western blot and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis. RESULTS:The results show that the function of the ovary in POI rats was significantly improved after hUMSC transplantation. The expression of fibrosis markers (α-SMA) and production of Collagen Type I (Collagen I) and Collagen Type III (Collagen III) in POI rats were significantly inhibited in POI rats following hUMSC transplantation. In the cultured ovarian stromal cells, the decrease of TGF-β and p-Smad3 protein expression was observed in hUMSC-treated POI rats. The treatment with TGF-β inhibitor of SB431542 further confirmed this signal pathway was involved in the process. CONCLUSION:Our study demonstrated that the TGF-β/Smad3 signaling pathway was involved in the inhibition of ovarian tissue fibrosis, which contributed to the restoration of ovarian function in POI rats following hUMSC transplantation.
Effects of single and multiple transplantations of human umbilical cord mesenchymal stem cells on the recovery of ovarian function in the treatment of premature ovarian failure in mice.
Lv Xiaodan,Guan Chunyi,Li Ying,Su Xing,Zhang Lu,Wang Xueqin,Xia Hong-Fei,Ma Xu
Journal of ovarian research
BACKGROUND:Currently, there is no effective treatment for premature ovarian failure (POF), and stem cell therapy is considered the most promising treatment. Human umbilical cord blood mesenchymal stem cells (hUC-MSCs) have shown good regenerative ability in various diseases, including POF; however, their underlying mechanism and dosage for POF treatment remain unclear. This study aimed to compare the effect of single and multiple injections of hUC-MSCs on ovarian function repair in chemotherapy-induced POF. METHODS:Female mice were intraperitoneally injected with 30 mg/kg busulfan and 120 mg/kg cyclophosphamide (CTX) to induce POF. In the single hUC-MSC injection group, hUC-MSCs were transplanted into mice D7 after CTX and busulfan administration, while in the multiple injection group, hUC-MSCs were transplanted on D7, D14, and D21 after CTX and busulfan administration. We evaluated the ovarian morphology, fertility, follicle-stimulating hormone and estradiol concentrations, follicle count, POF model, and cell transplantation results. In addition, real-time polymerase chain reaction, immunohistochemistry, and miRNA and mRNA chips were used to evaluate the effect of the cell therapy. RESULTS:Ovary size, number of follicle at all developmental stages, and fertility were significantly reduced in the POF group compared with the control. Under hUC-MSC treatment, the ovarian morphology and follicle count were significantly restored, and fertility was significantly increased. By comparing the single and multiple hUC-MSC injection groups, we found that the anti-Müllerian hormone and Ki-67 levels were significantly increased in the multiple hUC-MSC group on D60 after chemotherapy. The expression of stimulating hormone receptors, inhibin α, and inhibin β was significantly restored, and the therapeutic effect was superior to that of the single hUC-MSC injection group. CONCLUSION:These results indicate that hUC-MSCs can restore the structure of injured ovarian tissue and its function in chemotherapy-induced POF mice and ameliorate fertility. Multiple hUC-MSC transplantations have a better effect on the recovery of ovarian function than single hUC-MSC transplantation in POF.
The role of Chito-oligosaccharide in regulating ovarian germ stem cells function and restoring ovarian function in chemotherapy mice.
Huang Yaoqi,Ye Haifeng,Zhu Feiyin,Hu Chuan,Zheng Yuehui
Reproductive biology and endocrinology : RB&E
In recent years, the discovery of ovarian germ stem cells (OGSCs) has provided a new research direction for the treatment of female infertility. The ovarian microenvironment affects the proliferation and differentiation of OGSCs, and immune cells and related cytokines are important components of the microenvironment. However, whether improving the ovarian microenvironment can regulate the proliferation of OGSCs and remodel ovarian function has not been reported. In this study, we chelated chito-oligosaccharide (COS) with fluorescein isothiocyanate (FITC) to track the distribution of COS in the body. COS was given to mice through the best route of administration, and the changes in ovarian and immune function were detected using assays of organ index, follicle counting, serum estrogen (E) and anti-Mullerian hormone (AMH) levels, and the expression of IL-2 and TNF-α in the ovaries. We found that COS significantly increased the organ index of the ovary and immune organs, reduced the rate of follicular atresia, increased the levels of E and AMH hormones, and increased the protein expression of IL-2 and TNF-α in the ovary. Then, COS and OGSCs were co-cultured to observe the combination of COS and OGSCs, and measure the survival rate of OGSCs. With increasing time, the fluorescence intensity of cells gradually increased, and the cytokines IL-2 and TNF-α significantly promoted the proliferation of OGSCs. In conclusion, COS could significantly improve the ovarian and immune function of chemotherapy model mice, and improve the survival rate of OGSCs, which provided a preliminary blueprint for further exploring the mechanism of COS in protecting ovarian function.
Fertility preservation for genetic diseases leading to premature ovarian insufficiency (POI).
La Marca Antonio,Mastellari Elisa
Journal of assisted reproduction and genetics
PURPOSE:The current review aims to summarize the data available concerning the applicability of fertility preservation techniques to genetic conditions at risk of premature ovarian insufficiency (POI). METHODS:A literature review through the PubMed Database was carried out. RESULTS:About 10% of cases of POI is related to genetic diseases. The most frequent conditions associated with POI are Turner syndrome and fragile X pre-mutation; mutation of BRCA 1-2 genes and several other mutations and genetic syndromes have recently been highlighted, although they rarely occur. If a diagnosis is issued before POI onset, counseling on currently available fertility preservation techniques is advisable. In case of spontaneous menarche (this can occur variably depending on the mutation) established techniques like embryo or oocyte cryopreservation can be proposed, even if, in some cases, their effectiveness may be reduced by ovarian alterations connected to the mutation. Ovarian tissue cryopreservation has recently been defined as an established medical procedure for fertility preservation in young cancer patients and may be an option for prepubertal patients. However, it is still experimental in special populations with genetic diseases causing POI. New innovative experimental techniques, like in vitro maturation of immature oocytes (IVM) and vitro activation (IVA) of immature follicles on ovarian tissue, have shown limited but encouraging data and they will be probably available in the near future. For a correct risk-benefit evaluation, the following aspects should be considered: actual knowledge about the pathology-specific efficacy of the various techniques, the average age of onset of POI, the possible risks associated with the procedure in relation to the underlying pathology, the probability of spontaneous conception, as well as the health implications of a possible future pregnancy.. CONCLUSIONS:Fertility preservation techniques represent a crucial opportunity for patients with genetic risk of POI. Early diagnosis increases the chances to apply these techniques. No specific recommendations concerning fertility preservation for each genetic pathology are available, and clinicians should first counsel the patient and her relatives about known risks and benefits of the available techniques, both those established and those considered as experimental.
Whole exome sequencing identified a rare WT1 loss-of-function variant in a non-syndromic POI patient.
Molecular genetics & genomic medicine
BACKGROUND:Premature ovarian insufficiency (POI) is a highly heterogeneous disease, and up to 25% of cases can be explained by genetic causes. The transcription factor WT1 has long been reported to play a crucial role in ovary function. Wt1-mutated female mice exhibited POI-like phenotypes. METHODS AND RESULTS:In this study, whole exome sequencing (WES) was applied to find the cause of POI in Han Chinese women. A nonsense variant in the WT1 gene: NM_024426.6:c.1387C>T(p.R463*) was identified in a non-syndromic POI woman. The variant is a heterozygous de novo mutation that is very rare in the human population. The son of the patient inherited the mutation and developed Wilms' tumor and urethral malformation at the age of 7. According to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines, the novel variant is categorized as pathogenic. Western blot analysis further demonstrated that the WT1 variant could produce a truncated WT1 isoform in vitro. CONCLUSIONS:A rare heterozygous nonsense WT1 mutant is associated with non-syndromic POI and Wilms' tumor. Our finding characterized another pathogenic WT1 variant, providing insight into genetic counseling.
Hormone therapy regimens for managing the menopause and premature ovarian insufficiency.
Armeni Eleni,Paschou Stavroula A,Goulis Dimitrios G,Lambrinoudaki Irene
Best practice & research. Clinical endocrinology & metabolism
The transition to menopause is associated with a changing hormonal milieu, leading to bothersome menopausal symptoms in the short-term and chronic health problems in the long-term. Premature ovarian insufficiency (POI) is characterized by the cessation of menses before the age of 40 years. Hormone replacement therapy (HRT) is indicated to restore sex hormones to normal premenopausal levels and prevent chronic diseases, such as osteoporosis and cardiovascular disease. Menopausal hormone therapy (MHT) is indicated in perimenopausal and postmenopausal women over 45 years of age for managing menopausal symptoms, symptoms of vulvovaginal atrophy, and reducing the risk of postmenopausal osteoporosis. Individualization is the key to management, aiming at maximizing efficacy and minimizing clinically relevant risks. This review aimed to present the hormone therapy regimens for women during the transition or after menopause and women with POI and early menopause, as well as advise on: i) the initiation of MHT, ii) steps for monitoring during follow up, iii) weaning and discontinuation of treatment.
A kaleidoscopic view of ovarian genes associated with premature ovarian insufficiency and senescence.
Yang Qingling,Mumusoglu Sezcan,Qin Yingying,Sun Yingpu,Hsueh Aaron J
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Ovarian infertility and subfertility presenting with premature ovarian insufficiency (POI) and diminished ovarian reserve are major issues facing the developed world due to the trend of delaying childbirth. Ovarian senescence and POI represent a continuum of physiological/pathophysiological changes in ovarian follicle functions. Based on advances in whole exome sequencing, evaluation of gene copy variants, together with family-based and genome-wide association studies, we discussed genes responsible for POI and ovarian senescence. We used a gene-centric approach to sort out literature deposited in the Ovarian Kaleidoscope database (http://okdb.appliedbioinfo.net) by sub-categorizing candidate genes as ligand-receptor signaling, meiosis and DNA repair, transcriptional factors, RNA metabolism, enzymes, and others. We discussed individual gene mutations found in POI patients and verification of gene functions in gene-deleted model organisms. Decreased expression of some of the POI genes could be responsible for ovarian senescence, especially those essential for DNA repair, meiosis and mitochondrial functions. We propose to set up a candidate gene panel for targeted sequencing in POI patients together with studies on mitochondria-associated genes in middle-aged subfertile patients.
Role of mTOR Signaling in Female Reproduction.
Guo Zaixin,Yu Qi
Frontiers in endocrinology
Mammalian target of rapamycin (mTOR) is a conserved serine/threonine kinase of the phosphatidylinositol kinase-related kinase family that regulates cell growth, metabolism, and autophagy. Extensive research has linked mTOR to several human diseases including cancer, neurodegenerative disorders, and aging. In this review, recent publications regarding the mechanisms underlying the role of mTOR in female reproduction under physiological and pathological conditions are summarized. Moreover, we assess whether strategies to improve or suppress mTOR expression could have therapeutic potential for reproductive diseases like premature ovarian failure, polycystic ovarian syndrome, and endometriosis.
Ovarian ageing: the role of mitochondria in oocytes and follicles.
May-Panloup Pascale,Boucret Lisa,Chao de la Barca Juan-Manuel,Desquiret-Dumas Valérie,Ferré-L'Hotellier Véronique,Morinière Catherine,Descamps Philippe,Procaccio Vincent,Reynier Pascal
Human reproduction update
BACKGROUND:There is a great inter-individual variability of ovarian ageing, and almost 20% of patients consulting for infertility show signs of premature ovarian ageing. This feature, taken together with delayed childbearing in modern society, leads to the emergence of age-related ovarian dysfunction concomitantly with the desire for pregnancy. Assisted reproductive technology is frequently inefficacious in cases of ovarian ageing, thus raising the economic, medical and societal costs of the procedures. OBJECTIVE AND RATIONAL:Ovarian ageing is characterized by quantitative and qualitative alteration of the ovarian oocyte reserve. Mitochondria play a central role in follicular atresia and could be the main target of the ooplasmic factors determining oocyte quality adversely affected by ageing. Indeed, the oocyte is the richest cell of the body in mitochondria and depends largely on these organelles to acquire competence for fertilization and early embryonic development. Moreover, the oocyte ensures the uniparental transmission and stability of the mitochondrial genome across the generations. This review focuses on the role played by mitochondria in ovarian ageing and on the possible consequences over the generations. SEARCH METHODS:PubMed was used to search the MEDLINE database for peer-reviewed original articles and reviews concerning mitochondria and ovarian ageing, in animal and human species. Searches were performed using keywords belonging to three groups: 'mitochondria' or 'mitochondrial DNA'; 'ovarian reserve', 'oocyte', 'ovary' or 'cumulus cells'; and 'ageing' or 'ovarian ageing'. These keywords were combined with other search phrases relevant to the topic. References from these articles were used to obtain additional articles. OUTCOMES:There is a close relationship, in mammalian models and humans, between mitochondria and the decline of oocyte quality with ageing. Qualitatively, ageing-related mitochondrial (mt) DNA instability, which leads to the accumulation of mtDNA mutations in the oocyte, plays a key role in the deterioration of oocyte quality in terms of competence and of the risk of transmitting mitochondrial abnormalities to the offspring. In contrast, some mtDNA haplogroups are protective against the decline of ovarian reserve. Quantitatively, mitochondrial biogenesis is crucial during oogenesis for constituting a mitochondrial pool sufficiently large to allow normal early embryonic development and to avoid the untimely activation of mitochondrial biogenesis. Ovarian ageing also seriously affects the dynamic nature of mitochondrial biogenesis in the surrounding granulosa cells that may provide interesting alternative biomarkers of oocyte quality. WIDER IMPLICATIONS:A fuller understanding of the involvement of mitochondria in cases of infertility linked to ovarian ageing would contribute to a better management of the disorder in the future.
Metabolic Determinants of Mitochondrial Function in Oocytes.
Seidler Emily A,Moley Kelle H
Seminars in reproductive medicine
Mitochondrial production of cellular energy is essential to oocyte function, zygote development and successful continuation of pregnancy. This review focuses on several key functions of healthy oocyte mitochondria and the effect of pathologic states such as aging, oxidative stress and apoptosis on these functions. The effect of these abnormal conditions is presented in terms of clinical presentations, specifically maternal obesity, diminished ovarian reserve and assisted reproductive technologies.
[Ovarian aging and infertility].
Szafarowska Monika,Jerzak Małgorzata
The biological state of the ovum remains the key element in normal reproduction. Age-related decrease in the number of oocytes, as well as disturbed neuroendocrine function of the ovary and lesions in the uterus, contribute to reduced fertility. Decreasing number of ovarian follicles is accompanied by reduction of their quality including mainly abnormalities of the nucleus (dispersed chromatin, decondensation of chromosomes and abnormalities connected with the spindle apparatus). This results in failed reproduction due to abnormal gametogenesis, fertilization process, early development of the embryo and abnormal implantation. This work describes age-related biochemical mechanisms conditioning molecular changes occurring due to abnormal microenvironment of the ovary; their accumulation leads to aging and to a more rapid apoptosis of the oocyte. There are many theories explaining the causes of oocyte destruction, including abnormal vascularization, oxidative stress, imbalance of free radicals, influence of toxic compounds and genetic changes. Decreased blood perfusion in the microenvironment of a maturating ovum leads to hypoxia and thus to a chain of reactions of oxidative stress. Oxidative imbalance leads to abnormalities of cellular biomolecules. Moreover it is suggested that glycation processes in a cell, leading to the formation of compounds called AGEs (Advanced Glycation End Products), are also responsible for aging of the cells. They contribute directly to protein damage, induce a chain of reactions of oxidative stress, and increase the inflammatory reactions. Recently the role of mitochondria and telomeres in the aging process and loss of reproductive functions has been especially underscored. Moreover this work stresses the prognostic value of clinically used markers evaluating the ovarian reserve. The role of Anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH), estradiol, inhibin B and antral follicle count (AFC) was presented in this paper.
Mitochondrial function in the human oocyte and embryo and their role in developmental competence.
Van Blerkom Jonathan
The role of mitochondria as a nexus of developmental regulation in mammalian oogenesis and early embryogenesis is emerging from basic research in model species and from clinical studies in infertility treatments that require in vitro fertilization and embryo culture. Here, mitochondrial bioenergetic activities and roles in calcium homeostasis, regulation of cytoplasmic redox state, and signal transduction are discussed with respect to outcome in general, and as possible etiologies of chromosomal defects, maturation and fertilization failure in human oocytes, and as causative factors in early human embryo demise. At present, the ability of mitochondria to balance ATP supply and demand is considered the most critical factor with respect to fertilization competence for the oocyte and developmental competence for the embryo. mtDNA copy number, the timing of mtDNA replication during oocyte maturation, and the numerical size of the mitochondrial complement in the oocyte are evaluated with respect to their relative contribution to the establishment of developmental competence. Rather than net cytoplasmic bioenergetic capacity, the notion of functional compartmentalization of mitochondria is presented as a means by which ATP may be differentially supplied and localized within the cytoplasm by virtue of stage-specific changes in mitochondrial density and potential (ΔΨm). Abnormal patterns of calcium release and sequestration detected at fertilization in the human appear to have coincident effects on levels of mitochondrial ATP generation. These aberrations are not uncommon in oocytes obtained after ovarian hyperstimulation for in vitro fertilization. The possibility that defects in mitochondrial calcium regulation or bioenergetic homeostasis could have negative downstream development consequences, including imprinting disorders, is discussed in the context of signaling pathways and cytoplasmic redox state.
Human ovarian aging and mitochondrial DNA deletion.
Suganuma N,Kitagawa T,Nawa A,Tomoda Y
The functions of human ovary change dynamically around the menopausal period. A decrease of the number of primordial follicles and an increase of fibrous tissues are observed histologically in the aged ovary. As endocrinological aspects at menopause, the synthesis and secretion of ovarian steroid hormones such as estrogens and progesterone decrease, followed with the resultant increases of pituitary gonadotropins. However, the mechanism of menopause and ovarian aging is not well understood. Thus, to study the regulatory mechanism of ovarian dysfunction by aging, we analyzed the accumulation of mitochondrial DNA (mtDNA) mutation in the human ovary in women of various ages. The amplification of a 5.5-kb region in mtDNA with polymerase chain reaction revealed a 0.5-kb band in ovarian samples obtained from menopausal and postmenopausal women, which means that the 5.0-kb deletion of mtDNA in ovarian tissue starts at the menopausal period. The close relationship between the occurrence of ovarian mtDNA deletion and the menstrual irregularity was also observed. These observations suggest that the accumulation of the deleted mtDNA may be a regulating factor of dysfunction of the ovary by aging.
Mitochondrial dysfunction and ovarian aging.
Wang Tianren,Zhang Man,Jiang Zongliang,Seli Emre
American journal of reproductive immunology (New York, N.Y. : 1989)
Mitochondria are double-membrane-bound organelles that are responsible for the generation of most of the cell's energy. Mitochondrial dysfunction has been implicated in cellular senescence in general and ovarian aging in particular. Recent studies exploited this association by studying mitochondrial DNA (mtDNA) copy number as a potential biomarker of embryo viability and the use of mitochondrial nutrients and autologous mitochondrial transfer as a potential treatment for poor ovarian function and response.
Mitochondria in oocyte aging: current understanding.
Zhang D,Keilty D,Zhang Z F,Chian R C
Facts, views & vision in ObGyn
The oocyte is the largest cell found in multicellular organisms. Mitochondria, as the energy factories for cells, are found in high numbers in oocytes, as they provide the energy for oocyte maturation, fertilization, and embryo formation via oxidative phosphorylation. Failure of assisted reproduction is mainly attributed to oocyte aging and increased aneuploidy. As the most numerous organelle in the oocyte, the mitochondrion has been confirmed as a crucial player in the process of oocyte aging, which is highly influenced by mitochondrion dysfunction. Every mitochondrion contains one or more mitochondrial DNA (mtDNA) molecule, which, at about 16.5 KD in length, encodes 13 proteins. In this review, we discuss the function of mitochondria and the relationship between mtDNA and oocyte aging. We also discuss technologies that aim to enhance oocyte developmental potential and delay ovarian aging.
[Advances in the study of ovarian dysfunction with aging].
Liu Chuan-Ming,Ding Li-Jun,Li Jia-Yin,Dai Jian-Wu,Sun Hai-Xiang
Yi chuan = Hereditas
Societal changes regarding the role of women have significant impacts on women's willingness and the timing of childbearing. Ovarian reserve in woman typically begins to decline at the age of 35, and it is primarily characterized by a reduction in the number of ovarian follicles and a decline in oocyte quality. The clinical diagnosis of ovarian insufficiency relies on multiple variables including changes of follicle stimulating hormone (FSH), serum anti-Müllerian hormone (AMH), inhibin B, antral follicle count, menstruation and age. It is proven that ovarian cells demonstrate dysfunction associated with aging including mitochondrial dysfunction, telomere shortening, impaired DNA repair, epigenetic changes and metabolic/energetic disorders. In this review, we introduce the clinical diagnosis and management of ovarian insufficiency. We mainly discuss the molecular mechanism and potential interventions. We are optimistic that this information and knowledge will inform the important decisions for women and society regarding childbearing.
Replication Stress at Telomeric and Mitochondrial DNA: Common Origins and Consequences on Ageing.
Billard Pauline,Poncet Delphine A
International journal of molecular sciences
Senescence is defined as a stress-induced durable cell cycle arrest. We herein revisit the origin of two of these stresses, namely mitochondrial metabolic compromise, associated with reactive oxygen species (ROS) production, and replicative senescence, activated by extreme telomere shortening. We discuss how replication stress-induced DNA damage of telomeric DNA (telDNA) and mitochondrial DNA (mtDNA) can be considered a common origin of senescence in vitro, with consequences on ageing in vivo. Unexpectedly, mtDNA and telDNA share common features indicative of a high degree of replicative stress, such as G-quadruplexes, D-loops, RNA:DNA heteroduplexes, epigenetic marks, or supercoiling. To avoid these stresses, both compartments use similar enzymatic strategies involving, for instance, endonucleases, topoisomerases, helicases, or primases. Surprisingly, many of these replication helpers are active at both telDNA and mtDNA (e.g., RNAse H1, FEN1, DNA2, RecQ helicases, Top2α, Top2β, TOP3A, DNMT1/3a/3b, SIRT1). In addition, specialized telomeric proteins, such as TERT (telomerase reverse transcriptase) and TERC (telomerase RNA component), or TIN2 (shelterin complex), shuttle from telomeres to mitochondria, and, by doing so, modulate mitochondrial metabolism and the production of ROS, in a feedback manner. Hence, mitochondria and telomeres use common weapons and cooperate to resist/prevent replication stresses, otherwise producing common consequences, namely senescence and ageing.
The role of mitochondria in the female germline: Implications to fertility and inheritance of mitochondrial diseases.
Chiaratti Marcos Roberto,Garcia Bruna Martins,Carvalho Karen Freire,Machado Thiago Simões,Ribeiro Fernanda Karina da Silva,Macabelli Carolina Habermann
Cell biology international
Mitochondria play a fundamental role during development of the female germline. They are fragmented, round, and small. Despite these characteristics suggesting that they are inactive, there is accumulating evidence that mitochondrial dysfunctions are a major cause of infertility and generation of aneuploidies in humans. In addition, mitochondria and their own genomes (mitochondrial DNA-mtDNA) may become damaged with time, which might be one reason why aging leads to infertility. As a result, mitochondria have been proposed as an important target for evaluating oocyte and embryo quality, and developing treatments for female infertility. On the other hand, mutations in mtDNA may cause mitochondrial dysfunctions, leading to severe diseases that affect 1 in 4,300 people. Moreover, very low levels of mutated mtDNA seem to be present in every person worldwide. These may increase with time and associate with late-onset degenerative diseases such as Parkinson disease, Alzheimer disease, and common cancers. Mutations in mtDNA are transmitted down the maternal lineage, following a poorly understood pattern of inheritance. Recent findings have indicated existence in the female germline of a purifying filter against deleterious mtDNA variants. Although the underlying mechanism of this filter is largely unknown, it has been suggested to rely on autophagic degradation of dysfunctional mitochondria or selective replication/transmission of non-deleterious variants. Thus, understanding the mechanisms regulating mitochondrial inheritance is important both to improve diagnosis and develop therapeutic tools for preventing transmission of mtDNA-encoded diseases.
Mitochondrial DNA Purifying Selection in Mammals and Invertebrates.
Palozzi Jonathan M,Jeedigunta Swathi P,Hurd Thomas R
Journal of molecular biology
Numerous mitochondrial quality control mechanisms exist within cells, but none have been shown to effectively assess and control the quality of mitochondrial DNA (mtDNA). One reason such mechanisms have yet to be elucidated is that they do not appear to be particularly active in most somatic cells, where many studies are conducted. The female germline, the cell lineage that gives rise to eggs, appears to be an exception. In the germline, strong purifying selection pathways act to eliminate deleterious mtDNA. These pathways have apparently evolved to prevent pathogenic mtDNA mutations from accumulating over successive generations and causing a decline of species via Muller's ratchet. Despite their fundamental biological importance, the mechanisms underlying purifying selection remain poorly understood, with no genes involved in this process yet identified. In this review, we discuss recent studies exploring mechanisms of germline mtDNA purifying selection in both mammalian and invertebrate systems. We also discuss the challenges to future major advances. Understanding the molecular basis of purifying selection is not only a fundamental outstanding question in biology, but may also pave the way to controlling selection in somatic tissues, potentially leading to treatments for people suffering from mitochondrial diseases.
Mitochondria as a tool for oocyte rejuvenation.
Labarta Elena,de Los Santos Maria José,Escribá Maria José,Pellicer Antonio,Herraiz Sonia
Fertility and sterility
Ovarian aging leads to a decrease in the quantity and quality of oocytes. Aged oocytes have significantly reduced amounts of mitochondria, the energy factories of cells, leading to lower fertilization rates and poor embryonic development. Various techniques have tried to use heterologous or autologous sources of mitochondria to reestablish oocyte health by providing more energy. However, heterologous sources are no longer used owing to the known risk of heteroplasmy. Although autologous methods have recently been tested in humans, they have not shown a clear improvement in embryo quality. In this review, we describe the techniques that have been tested in recent years to provide a state of the art on oocyte rejuvenation through extra injection of mitochondria.
Mitochondrial unfolded protein response: a stress response with implications for fertility and reproductive aging.
Seli Emre,Wang Tianren,Horvath Tamas L
Fertility and sterility
Mitochondria play a central role in the regulation of energy metabolism in oocytes and preimplantation embryos, where the number and morphology of mitochondria and mitochondrial DNA (mtDNA) content are tightly regulated. A number of mouse models with mitochondrial dysfunction result in infertility, further confirming the key role of mitochondria in female reproductive function. When cells and organisms detect mitochondrial dysfunction they use response mechanisms directed at recovering salvageable mitochondria and eliminating mitochondria that can no longer be rescued. Among these mechanisms, mitochondrial unfolded protein response (UPR) has recently been linked with prevention of aging, as compromised mitochondrial stress response contributes to age-related accumulation of damaged proteins, reduced oxidative phosphorylation, and increased reactive oxygen species (ROS) production. These mechanisms seem to be especially relevant for reproduction, as targeted deletion of the UPR-regulatory gene Clpp results in female infertility, with impaired oocyte maturation and two-cell embryo development, and failure to form blastocysts. In addition, absence of CLPP results in accelerated depletion of follicles, and a phenotype similar to premature reproductive aging. Further studies will provide novel mechanistic insights for physiologic and pathologic control of oocyte and early embryonic mitochondrial function, which can be exploited for the development of novel therapeutic approaches for the promotion of fertility during the aging process.
New Frontiers in IVF: mtDNA and autologous germline mitochondrial energy transfer.
Cozzolino Mauro,Marin Diego,Sisti Giovanni
Reproductive biology and endocrinology : RB&E
Many infertility specialists support the existence of a relationship between the levels of mitochondrial DNA and the quality of the blastocysts. Despite the extensive use of pre-implantation genetic testing for aneuploidy, a significant percentage of euploid embryos do not implant even though the endometrium is normal. Mitochondrial DNA may be used as a new test in evaluating embryonic vitality.Ovarian aging leads to a decrease in the quantity and quality of oocytes and aged oocytes have a reduced number of mitochondria. Mitochondria are the energy factories of the cells and their lacked could leads to lower fertilization rates and poor embryonic development. Various strategies have been tested to increase the mitochondria quantity and thus improve the quality of oocytes used in in vitro fertilization. Results of ovarian rejuvenation techniques such as autologous mitochondrial transplantation have been controversial. In this review, we describe the state of the art concerning the use of mitochondrial DNA and autologous mitochondrial transplantation as new possibilities to increase success in vitro fertilization.
Mitochondria and Female Germline Stem Cells-A Mitochondrial DNA Perspective.
St John Justin C
Mitochondria and mitochondrial DNA have important roles to play in development. In primordial germ cells, they progress from small numbers to populate the maturing oocyte with high numbers to support post-fertilization events. These processes take place under the control of significant changes in DNA methylation and other epigenetic modifiers, as well as changes to the DNA methylation status of the nuclear-encoded mitochondrial DNA replication factors. Consequently, the differentiating germ cell requires significant synchrony between the two genomes in order to ensure that they are fit for purpose. In this review, I examine these processes in the context of female germline stem cells that are isolated from the ovary and those derived from embryonic stem cells and reprogrammed somatic cells. Although our knowledge is limited in this respect, I provide predictions based on other cellular systems of what is expected and provide insight into how these cells could be used in clinical medicine.
Inflamm-Aging: A New Mechanism Affecting Premature Ovarian Insufficiency.
Huang Yaoqi,Hu Chuan,Ye Haifeng,Luo Ruichen,Fu Xinxin,Li Xiaoyan,Huang Jian,Chen Weiyun,Zheng Yuehui
Journal of immunology research
The normal function of ovaries, along with the secretion of sex hormones, is among the most important endocrine factors that maintain the female sexual characteristics and promote follicular development and ovulation. Premature ovarian insufficiency (POI) is a common cause in the etiology of female infertility. It is defined as the loss of ovarian function before the age of 40. The characteristics of POI are menstrual disorders, including amenorrhea and delayed menstruation, accompanied by a raised gonadotrophin level and decreased estradiol level. Inflammatory aging is a new concept in the research field of aging. It refers to a chronic and low-degree proinflammatory state which occurs with increasing age. Inflammatory aging is closely associated with multiple diseases, as excessive inflammation can induce the inflammatory lesions in certain organs of the body. In recent years, studies have shown that inflammatory aging plays a significant role in the pathogenesis of POI. This paper begins with the pathogenesis of inflammatory aging and summarizes the relationship between inflammatory aging and premature ovarian insufficiency in a comprehensive way, as well as discussing the new diagnostic and therapeutic methods of POI.
Advances in the Molecular Pathophysiology, Genetics, and Treatment of Primary Ovarian Insufficiency.
Huhtaniemi Ilpo,Hovatta Outi,La Marca Antonio,Livera Gabriel,Monniaux Danielle,Persani Luca,Heddar Abdelkader,Jarzabek Katarzyna,Laisk-Podar Triin,Salumets Andres,Tapanainen Juha S,Veitia Reiner A,Visser Jenny A,Wieacker Peter,Wolczynski Slawomir,Misrahi Micheline
Trends in endocrinology and metabolism: TEM
Primary ovarian insufficiency (POI) affects ∼1% of women before 40 years of age. The recent leap in genetic knowledge obtained by next generation sequencing (NGS) together with animal models has further elucidated its molecular pathogenesis, identifying novel genes/pathways. Mutations of >60 genes emphasize high genetic heterogeneity. Genome-wide association studies have revealed a shared genetic background between POI and reproductive aging. NGS will provide a genetic diagnosis leading to genetic/therapeutic counseling: first, defects in meiosis or DNA repair genes may predispose to tumors; and second, specific gene defects may predict the risk of rapid loss of a persistent ovarian reserve, an important determinant in fertility preservation. Indeed, a recent innovative treatment of POI by in vitro activation of dormant follicles proved to be successful.