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    Novel STAG3 variant associated with primary ovarian insufficiency and non-obstructive azoospermia in an Iranian consanguineous family. Akbari Arvand,Zoha Tabatabaei Seyedeh,Salehi Najmeh,Padidar Kimiya,Almadani Navid,Ali Sadighi Gilani Mohammad,Mashayekhi Mehri,Motevaseli Elahe,Totonchi Mehdi Gene Non-obstructive azoospermia (NOA) and primary ovarian insufficiency (POI) present the most severe forms of male and female infertility. In the last decade, the increasing use of whole exome sequencing (WES) in genomics studies of these conditions has led to the introduction of a number of novel genes and variants especially in meiotic genes with restricted expression to gonads. In this study, exome sequencing of a consanguineous Iranian family with one POI and two NOA cases in three siblings showed that all three patients were double homozygous for a novel in-frame deletion and a novel missense variant in STAG3 (NM_001282717.1:c.1942G > A: p.Ala648Thr; NM_001282717.1:c.1951_1953del: p. Leu652del). Both variants occur within a short proximity of each other affecting the relatively conserved armadillo-type fold superfamily feature. STAG3 is a specific meiotic cohesin complex component that interacts with the α-kleisin subunit through this feature. Protein homology modeling indicated that the in-frame deletion destabilizes kleisin biding by STAG3. Although the missense variant did not seem to affect the binding significantly, protein homology modeling suggests that it further destabilizes kleisin binding when in double homozygous state with the deletion. Our findings are in line with several other studies having associated deleterious variants affecting this region with male and female infertility in humans and mouse models. This is the first report associating an in-frame STAG3 variant with NOA and POI in a single family. SUMMARY SENTENCE: A patient with primary ovarian failure and her two brothers with non-obstructive azoospermia were double homozygous for a novel in-frame deletion and a novel missense variant in STAG3 that potentially disrupt the protein's meiotic functions. 10.1016/j.gene.2022.146281
    A novel POF1B variant in a Chinese patient is associated with premature ovarian failure. Yuan Zhuang-Zhuang,Wang Chen-Yu,Jin Jie-Yuan,Sheng Yue,Zhao Mei-Fang,Fan Liang-Liang,Zhang Ai-Qian Clinical genetics A novel mutation of POF1B was identified in a patient with premature ovarian failure. 10.1111/cge.14048
    Update about the disrupting-effects of phthalates on the human reproductive system. Mesquita Inês,Lorigo Margarida,Cairrao Elisa Molecular reproduction and development Phthalate esters are synthetic chemicals used in the plastic industry as plasticizers and consumable products. According to United Nations, about 400 million tons of plastic are produced every year. In parallel with increased production, the concerns about its effects on human health have increased because phthalates are endocrine-disrupting compounds. Humans are continuously exposed to phthalates through different routes of exposure. Experimental data have associated the phthalates exposure to adverse effects on development and reproduction in women (e.g., earlier puberty, primary ovarian insufficiency, endometriosis, preterm birth, or in vitro fertilization) and men (e.g., anogenital distance, cryptorchidism, hypospadias, and changes in adult reproductive function) although there is no consensus. Therefore, one question arises: could the increase in infertility be related to phthalates exposure? To answer this question, we aimed to assess the disrupting-effects of phthalates on the human reproductive system. For this, we reviewed the current literature based on epidemiological and experimental data and experimental studies in humans. The phthalate effects were discussed in a separate mode for female and male reproductive systems. In summary, phthalates induce toxicity in the reproductive system and human development. The increased plastic production may be related to the increase in human infertility. 10.1002/mrd.23541
    LncRNA DLEU1 is overexpressed in premature ovarian failure and sponges miR-146b-5p to increase granulosa cell apoptosis. Zheng Caihong,Liu Shiwei,Qin Zhihong,Zhang Xiaoqian,Song Yubao Journal of ovarian research BACKGROUND:miR-146b-5p has been reported to participate in premature ovarian failure (POF) in mice. However, its role in POF patients is unclear. We predicted that miR-146b-5p might interact with lncRNA DLEU1, a crucial player in ovarian cancer. We then explored the interaction between DLEU1 and miR-146b-5p. METHODS:Expression of DLEU1 and miR-146b-5p in POF and control ovary tissues was determined by RT-qPCR. The subcellular location of DLEU1 in human KGN cells was analyzed using subcellular fractionation assays. The direct interaction between DLEU1 and miR-146b-5p was analyzed using RNA pull-down assays. The role of DLEU1 in miR-146a expression was analyzed using overexpression assay. Cell proliferation was analyzed using cell apoptosis assay. RESULTS:Increased DLEU1 expression and decreased miR-146b-5p expression were observed in POF. DLEU1 directly interacted with MiR-146b-5p and was expressed in both nuclear and cytoplasm samples of KGN cells. In KGN cells, DLEU1 and miR-146b-5p failed to regulate the expression of each other. However, DLEU1 promoted cell apoptosis and reduced the inhibitory effects of miR-146b-5p on cell apoptosis. CONCLUSIONS:DLEU1 is overexpressed in POF and sponges miR-146b-5p to increase KGN cell apoptosis. 10.1186/s13048-021-00905-x
    Pathogenic Variations of Homologous Recombination Gene Identified in Sporadic Patients With Premature Ovarian Insufficiency. Li Shan,Xu Weiwei,Xu Bingying,Gao Shuchang,Zhang Qian,Qin Yingying,Guo Ting Frontiers in cell and developmental biology Premature ovarian insufficiency (POI) is defined as depletion of ovarian function before 40 years of age, which affects 3.7% of women in reproductive age. The etiology of POI is heterogeneous. Recently, with the widespread use of whole-exome sequencing (WES), the DNA repair genes, especially for those involved in meiosis progress, were enriched in the causative gene spectrum of POI. In this study, through the largest in-house WES database of 1,030 patients with sporadic POI, we identified two novel homozygous variations in (c.382T>C, p.C128R; c.557T>C, p.L186P). An functional study revealed that both variations impaired the nuclear location of HSF2BP and affected its DNA repair capacity. Our studies highlighted the essential role of meiotic homologous recombination genes in the pathogenesis of sporadic POI. 10.3389/fcell.2021.768123
    Causal and Candidate Gene Variants in a Large Cohort of Women With Primary Ovarian Insufficiency. The Journal of clinical endocrinology and metabolism CONTEXT:A genetic etiology likely accounts for the majority of unexplained primary ovarian insufficiency (POI). OBJECTIVE:We hypothesized that heterozygous rare variants and variants in enhanced categories are associated with POI. DESIGN:The study was an observational study. SETTING:Subjects were recruited at academic institutions. PATIENTS:Subjects from Boston (n = 98), the National Institutes of Health and Washington University (n = 98), Pittsburgh (n = 20), Italy (n = 43), and France (n = 32) were diagnosed with POI (amenorrhea with an elevated follicle-stimulating hormone level). Controls were recruited for health in old age or were from the 1000 Genomes Project (total n = 233). INTERVENTION:We performed whole exome sequencing (WES), and data were analyzed using a rare variant scoring method and a Bayes factor-based framework for identifying genes harboring pathogenic variants. We performed functional studies on identified genes that were not previously implicated in POI in a D. melanogaster model. MAIN OUTCOME:Genes with rare pathogenic variants and gene sets with increased burden of deleterious variants were identified. RESULTS:Candidate heterozygous variants were identified in known genes and genes with functional evidence. Gene sets with increased burden of deleterious alleles included the categories transcription and translation, DNA damage and repair, meiosis and cell division. Variants were found in novel genes from the enhanced categories. Functional evidence supported 7 new risk genes for POI (USP36, VCP, WDR33, PIWIL3, NPM2, LLGL1, and BOD1L1). CONCLUSIONS:Candidate causative variants were identified through WES in women with POI. Aggregating clinical data and genetic risk with a categorical approach may expand the genetic architecture of heterozygous rare gene variants causing risk for POI. 10.1210/clinem/dgab775
    Pathogenic variants in the human m6A reader YTHDC2 are associated with primary ovarian insufficiency. JCI insight Primary ovarian insufficiency (POI) affects 1% of women and carries significant medical and psychosocial sequelae. Approximately 10% of POI has a defined genetic cause, with most implicated genes relating to biological processes involved in early fetal ovary development and function. Recently, Ythdc2, an RNA helicase and N6-methyladenosine reader, has emerged as a regulator of meiosis in mice. Here, we describe homozygous pathogenic variants in YTHDC2 in 3 women with early-onset POI from 2 families: c. 2567C>G, p.P856R in the helicase-associated (HA2) domain and c.1129G>T, p.E377*. We demonstrated that YTHDC2 is expressed in the developing human fetal ovary and is upregulated in meiotic germ cells, together with related meiosis-associated factors. The p.P856R variant resulted in a less flexible protein that likely disrupted downstream conformational kinetics of the HA2 domain, whereas the p.E377* variant truncated the helicase core. Taken together, our results reveal that YTHDC2 is a key regulator of meiosis in humans and pathogenic variants within this gene are associated with POI. 10.1172/jci.insight.154671
    Variations of C14ORF39 and SYCE1 Identified in Idiopathic Premature Ovarian Insufficiency and Nonobstructive Azoospermia. Hou Dong,Yao Chencheng,Xu Bingying,Luo Wei,Ke Hanni,Li Zheng,Qin Yingying,Guo Ting The Journal of clinical endocrinology and metabolism CONTEXT:Premature ovarian insufficiency (POI) and nonobstructive azoospermia (NOA) are the most severe diseases causing irreversible infertility in females and males, respectively. The contribution of synaptonemal complex (SC) gene variations in the pathogenesis of sporadic patients with POI and NOA has not been systematically illustrated. OBJECTIVE:To investigate the role of SC genes in the pathogenesis of sporadic POI and NOA. DESIGN:Genetic and functional study. SETTING:University-based reproductive medicine center. PATIENT(S):A total of 1030 patients with sporadic POI and 400 patients with sporadic NOA. INTERVENTION(S):The variations of SC genes were filtered in the in-house database of whole exome sequencing performed in 1030 patients with sporadic POI and 400 patients with sporadic NOA. The pathogenic or likely pathogenic variations following recessive inheritance mode were selected according to American College of Medical Genetics and Genomics (ACMG) guidelines and confirmed by Sanger sequencing. The pathogenic effects of the variations were verified by functional studies. MAIN OUTCOME MEASURE(S):ACMG classification and functional characteristics. RESULT(S):Two homozygous variations of C14ORF39 and 2 recessive variations of SYCE1 were first identified in sporadic patients with POI and NOA, respectively. Functional studies showed the C14ORF39 variations significantly accelerated the protein degradation and the variations in SYCE1 disrupted its interaction with SYCP1 or C14ORF39, both of which affected SC assembly and meiosis. CONCLUSION(S):Our study identified novel pathogenic variations of C14ORF39 and SYCE1 in sporadic patients with POI or NOA, highlighting the essential role of SC genes in the maintenance of ovarian and testicular function. 10.1210/clinem/dgab777
    Meiotic genes in premature ovarian insufficiency: variants in HROB and REC8 as likely genetic causes. European journal of human genetics : EJHG Premature ovarian insufficiency (POI), affecting 1 in 100 women, is characterised by loss of ovarian function associated with elevated gonadotropin, before the age of 40. In addition to infertility, patients face increased risk of comorbidities such as heart disease, osteoporosis, cancer and/or early mortality. We used whole exome sequencing to identify the genetic cause of POI in seven women. Each had biallelic candidate variants in genes with a primary role in DNA damage repair and/or meiosis. This includes two genes, REC8 and HROB, not previously associated with autosomal recessive POI. REC8 encodes a component of the cohesin complex and HROB encodes a factor that recruits MCM8/9 for DNA damage repair. In silico analyses, combined with concordant mouse model phenotypes support these as new genetic causes of POI. We also identified novel variants in MCM8, NUP107, STAG3 and HFM1 and a known variant in POF1B. Our study highlights the pivotal role of meiosis in ovarian function. We identify novel variants, consolidate the pathogenicity of variants previously considered of unknown significance, and propose HROB and REC8 variants as new genetic causes while exploring their link to pathogenesis. 10.1038/s41431-021-00977-9
    Outdoor air pollution and diminished ovarian reserve among infertile Korean women. Kim Hannah,Choe Seung-Ah,Kim Ok-Jin,Kim Sun-Young,Kim Seulgi,Im Changmin,Kim You Shin,Yoon Tae Ki Environmental health and preventive medicine BACKGROUND:Mounting evidence implicates an association between ambient air pollution and impaired reproductive potential of human. Our study aimed to assess the association between air pollution and ovarian reserve in young, infertile women. METHODS:Our study included 2276 Korean women who attended a single fertility center in 2016-2018. Women's exposure to air pollution was assessed using concentrations of particulate matter (PM and PM), nitrogen dioxide (NO), carbon monoxide (CO), sulfur dioxide (SO), and ozone (O) that had been collected at 269 air quality monitoring sites. Exposure estimates were computed for 1, 3, 6, and 12 months prior to the ovarian reserve tests. Anti-Müllerian hormone (AMH) ratio (defined as an observed-to-expected AMH based on age) and low AMH (defined as < 0.5 ng/mL) were employed as indicators of ovarian reserve. We included a clustering effect of 177 districts in generalized estimating equations approach. A secondary analysis was conducted restricting the analyses to Seoul residents to examine the association in highly urbanized setting. RESULTS:The mean age was 36.6 ± 4.2 years and AMH level was 3.3 ± 3.1 ng/mL in the study population. Average AMH ratio was 0.8 ± 0.7 and low AMH was observed in 10.3% of women (n=235). The average concentration of six air pollutants was not different between the normal ovarian reserve and low AMH groups for all averaging periods. In multivariable models, an interquartile range (IQR)-increase in 1 month-average PM was associated with decrease in AMH ratio among total population (β= -0.06, 95% confidence interval: -0.11, 0.00). When we restrict our analysis to those living in Seoul, IQR-increases in 1 and 12 month-average PM were associated with 3% (95% CI: -0.07, 0.00) and 10% (95% CI: -0.18, -0.01) decrease in AMH ratio. The ORs per IQR increase in the six air pollutants were close to null in total population and Seoul residents. CONCLUSIONS:In a cohort of infertile Korean women, there was a suggestive evidence of the negative association between ambient PM concentration and ovarian reserve, highlighting the potential adverse impact of air pollution on women's fertility. 10.1186/s12199-021-00942-4
    Intrauterine exposure to diesel exhaust diminishes adult ovarian reserve. Ogliari Karolyn Sassi,Lichtenfels Ana Julia de Faria Coimbra,de Marchi Mary Rosa Rodrigues,Ferreira Alice Teixeira,Dolhnikoff Marisa,Saldiva Paulo Hilario Nascimento Fertility and sterility OBJECTIVE:To analyze ovarian and uterine morphologic changes resulting from intrauterine and postnatal exposure to diesel exhaust. DESIGN:Crossover study. Experimental groups: intrauterine and postnatal clean air exposure; intrauterine exposure to diesel only; postnatal exposure to diesel only; and intrauterine and postnatal exposure to diesel. SETTING:Laboratory of Experimental Air Pollution. ANIMAL(S):Swiss mice. INTERVENTION(S):Mice exposed to diesel exhaust with doses that correspond to the daily average PM₂.₅ levels (fine particles in the ambient air 2.5 μm or less in size) reported by the World Health Organization. MAIN OUTCOME MEASURE(S):Morphometric analyses of the ovaries and uterus were performed to define the relative area occupied by follicles, corpus luteum, and stroma and the proportionate area of glands, epithelial layer, and stroma within the uterine endometrium. RESULT(S):A significant reduction in the proportion of primordial follicles was observed in intrauterine-exposed animals, those exposed during the postnatal period, and in animals exposed during both phases. Primary follicle proportion was reduced in animals exposed during pregnancy. No significant changes were detected in uterine morphology. CONCLUSION(S):Intrauterine exposure to acceptable levels of diesel exhaust compromises the reproductive potential of female mice, diminishing ovarian reserve when sexual maturity is achieved. This effect could increase the risk of premature menopause. The findings raise concern about current environmental guidelines for diesel exposure, warranting more careful examination of this issue in humans by regulatory authorities. 10.1016/j.fertnstert.2013.01.103
    A cross-sectional national questionnaire survey assessing the clinical attitudes of members of the British Menopause Society to the management of women with premature ovarian insufficiency. Mittal Monica,Savvas Michael,Narvekar Nitish,Panay Nick,Hamoda Haitham Post reproductive health OBJECTIVE:To explore the current clinical attitudes of members of the British Menopause Society to the management of premature ovarian insufficiency. DESIGN:An electronic cross-sectional questionnaire survey. SETTING:Members of the British Menopause Society. POPULATION:All members of the British Menopause Society with a valid email address. METHOD:Completion of an electronic survey. MAIN OUTCOME MEASURES:Investigations and treatment options and preferences for the management of women with premature ovarian insufficiency. RESULTS:A total of 130 questionnaires were returned and analysed. The majority of responses were from Hospital Consultants (n = 55/130; 42.3%). A total of 53/124 (42.7%) clinicians routinely performed a bone density scan. A total of 73/130 (56.2%) clinicians would prescribe hormone replacement therapy in preference to combined ethinyl estradiol and progesterone (COC; 27/130, 20.8%). A total of 44/108 (40.7%) routinely prescribed oral estradiol in preference to transdermal administration (62/108, 57.4%). A total of 26/128 (20.3%) prescribed oral micronised progesterone, 31/128 (24.2%) oral progestogens, while 42/128 (32.8%) preferred the intra-uterine system. Fertility concerns remain an important aspect of care, with 33.9% (n = 39/115) of clinicians indicating that more than 50% of their patients had a concern regarding their fertility. CONCLUSION:The majority of clinicians indicated a preference for hormone replacement therapy instead of the COC as their choice of hormone replacement in women with premature ovarian insufficiency. However, there was a significant variation in practices. This information can be useful in counselling women and in guiding clinical practitioners. The results highlight the need for further research to determine the optimal regimens for the management of women with premature ovarian insufficiency. 10.1177/2053369114540883
    Analysis of NR5A1 in 142 patients with premature ovarian insufficiency, diminished ovarian reserve, or unexplained infertility. Jaillard Sylvie,Sreenivasan Rajini,Beaumont Marion,Robevska Gorjana,Dubourg Christèle,Knarston Ingrid M,Akloul Linda,van den Bergen Jocelyn,Odent Sylvie,Croft Brittany,Jouve Guilhem,Grover Sonia R,Duros Solène,Pimentel Céline,Belaud-Rotureau Marc-Antoine,Ayers Katie L,Ravel Célia,Tucker Elena J,Sinclair Andrew H Maturitas Ovarian deficiency, including diminished ovarian reserve and premature ovarian insufficiency, represents one of the main causes of female infertility. Little is known of the genetic basis of diminished ovarian reserve, while premature ovarian insufficiency often has a genetic basis, with genes affecting various processes. NR5A1 is a key gene required for gonadal function, and variants are associated with a wide phenotypic spectrum of disorders of sexual development, and are found in 0.26-8% of patients with premature ovarian insufficiency. As there is some debate about the extent of involvement of NR5A1 in the pathogenesis of ovarian deficiency, we performed an in-depth analysis of NR5A1 variants detected in a cohort of 142 patients with premature ovarian insufficiency, diminished ovarian reserve, or unexplained infertility associated with normal ovarian function. We identified rare non-synonymous protein-altering variants in 2.8 % of women with ovarian deficiency and no such variants in our small cohort of women with infertility but normal ovarian function. We observed previously reported variants associated with premature ovarian insufficiency in patients with diminished ovarian reserve, highlighting a genetic relationship between these conditions. We confirmed functional impairment resulting from a p.Val15Met variant, detected for the first time in a patient with premature ovarian insufficiency. The remaining variants were associated with preserved transcriptional activity and localization of NR5A1, indicating that rare NR5A1 variants may be incorrectly curated if functional studies are not undertaken, and/or that NR5A1 variants may have only a subtle impact on protein function and/or confer risk of ovarian deficiency via oligogenic inheritance. 10.1016/j.maturitas.2019.10.011
    The effect of ovarian reserve and receptor signalling on granulosa cell apoptosis during human follicle development. Regan Sheena L P,Knight Phil G,Yovich John L,Stanger James D,Leung Yee,Arfuso Frank,Almahbobi Ghanim,Dharmarajan Arun Molecular and cellular endocrinology The poor oocyte quality in older women has previously been linked to the depletion of the ovarian reserve of primordial follicles and an increase in granulosal apoptosis. Granulosa cells were collected from 198 follicles and individually analysed by flow cytometry. In the young IVF patients, the level of apoptosis was inversely proportional to the expression of bone morphogenetic protein (BMPR1B) and follicle stimulating hormone (FSH) receptors. Conversely, in the older patients this relationship became dysregulated. In the older patients, at the time of preovulatory maturation, the reduced apoptosis reflects the poor mitogenic growth turnover rate of healthy follicles rather than the death rate in an atretic follicle. Restoring an optimum receptor density and down-regulation of receptors may improve oocyte quality and the pregnancy rate in older women. 10.1016/j.mce.2017.11.002
    Menstrual cycle characteristics of young females with occult primary ovarian insufficiency at initial diagnosis and one-year follow-up with serum amh level and antral follicle count. Guzel Yilmaz,Aba Yilda Arzu,Yakin Kayhan,Oktem Ozgur PloS one Occult primary ovarian insufficiency (also known as incipient ovarian failure or diminished ovarian reserve) is defined as serum AMH level ≤1.1ng/mL in women under age 30. Limited data is available regarding the prevalence of occult POI, the preceding menstrual characteristics and its natural course in otherwise healthy young females. We aimed in this prospective observational study to determine the prevalence of occult POI in young females (< age 30) screened with serum AMH measurement; and analyze the patterns of change in their menstruation at initial assessment and one-year follow-up in relation to the changes in ovarian reserve quantitatively assessed with AMH and AFC. 963 young female college students under age 30 voluntarily participated in this study. 43 of them (4.4%) were diagnosed with occult POI as their AMH levels were ≤ 1.1ng/mL. Thirty-eight (83.4%) of them have regular cycles and denied any menstrual irregularity in the last 12 months. This rate was not statistically different from 7.3% of those with AMH>1.1ng/mL who reported at least one abnormal menstrual cycle in the last year (p = 0.36). Cycle length was significantly shorter in females with AMH ≤ 1.1ng/mL compared to those with AMH>1.1ng/mL (25.1±3.2 vs. 31.2±2.8 respectively, p<0.001). Karyotype, FMR-1 mutation analyses and auto-antibody screening returned normal in all. At one-year follow-up AMH, AFC and mean cycle length were further reduced compared to their values at initial assessment. Now, a greater proportion of the participants with occult POI were menstruating regularly at every 21 days compared to the initial evaluation one year ago (39.5% vs. 13.9% respectively, p = 0.013). Twenty-five underwent oocyte cryopreservation. These findings underscore the importance of screening young females with AMH for possible occult POI. It also emphasizes that young females with critically diminished ovarian reserve may continue to menstruate regularly without any characteristic menstrual abnormality other than shortening of cycle length. 10.1371/journal.pone.0188334
    Evaluation of safety, feasibility and efficacy of intra-ovarian transplantation of autologous adipose derived mesenchymal stromal cells in idiopathic premature ovarian failure patients: non-randomized clinical trial, phase I, first in human. Mashayekhi M,Mirzadeh E,Chekini Z,Ahmadi F,Eftekhari-Yazdi P,Vesali S,Madani T,Aghdami N Journal of ovarian research BACKGROUND:Premature ovarian failure (POF) is characterized by the loss of ovarian activity before the age of 40 years. Stem cell therapy has the capability to create a regenerative microenvironment and is a proposed treatment for POF-related infertility due to the presence of renewal folliculogenesis and germ cells in the adult ovaries. In this study, we assessed the safety, feasibility, efficacy and dose adjustment of autologous adipose-derived stromal cells (ADSCs) and their ability to improve ovarian function in POF patients. METHODS:This study was a non-randomized clinical trial, phase I. Nine women with a definitive diagnosis of POF were divided into three groups (n = 3 per group) that received either 5 × 10, 10 × 10, or 15 × 10 autologous ADSCs suspension transplanted in the one ovary. Participants were followed-up at 24 h after the transplantation, and at 1 and 2 weeks, and 1, 2, 3, 6, and 12 months after the transplantation. The primary objective was to evaluate the safety of ADSCs transplantation. Secondary objectives included the effects of ADSCs transplantation on the resumption of menstruation, hormones level (Follicle-stimulating hormone (FSH) and anti-Müllerian hormone), ovarian function (Antral follicle count and ovary volume by ultrasonography evaluation) as well as dose escalation. RESULTS:Participants had not shown any early-onset possible side effects and secondary complications during follow-up. The menstruation resumption was observed in four patients which established for several months. In the 15 × 10 group, two POF patients had a return of menstruation second months after the intervention. Two other POF patients in 5 × 10 and 10 × 10 cell groups reported menstruation resumption at 1 month after the intervention. We observed decreased serum FSH levels of less than 25 IU/l in four patients. In two patients in 5 × 10 and 10 × 10 cell groups, serum FSH showed an inconsistent decline during a 1 year follow up after ADSCs transplantation. The ovarian volume, AMH, and AFC were variable during the follow-up and no significant differences between cell groups (p > 0.05). CONCLUSIONS:We showed the intra-ovarian embedding of ADSCs is safe and feasible and is associated with an inconsistent decline in serum FSH. This should be further investigated with a large RCT. TRIAL REGISTRATION:NCT02603744 , Registered 13 November 2015 - Retrospectively registered, http://www.Clinicaltrials.gov. 10.1186/s13048-020-00743-3
    Resumption of ovarian function and pregnancies in 358 patients with premature ovarian failure. Bidet Maud,Bachelot Anne,Bissauge Estelle,Golmard Jean Louis,Gricourt Solenne,Dulon Jérôme,Coussieu Christiane,Badachi Yasmina,Touraine Philippe The Journal of clinical endocrinology and metabolism CONTEXT:Resumption of ovarian activity and spontaneous pregnancies are described in patients with premature ovarian failure (POF), but there is a lack of data concerning the prevalence of and predictive factors for these phenomena. OBJECTIVE:The aim of the study was to determine both the prevalence of and predictive factors for spontaneous resumption of ovarian function in POF patients. DESIGN AND SETTING:A mixed retrospective and prospective study was performed at a referral center for reproductive endocrinology. PATIENTS:A total of 358 consecutive POF patients were followed from 1997 to 2010 in our center. MAIN OUTCOMES MEASURES:The cumulative incidence of resumption of ovarian function was determined, and predictive factors were identified by univariate and multivariate analysis. RESULTS:Of 358 patients with idiopathic POF, 86 (24%) patients presented features indicating resumption of ovarian function, and in 77 cases (88%) within 1 yr of diagnosis. Twenty-one spontaneous pregnancies (16 births, five miscarriages) occurred in 15 (4.4%) patients. Multivariate analysis (Cox model) showed that a familial history of POF, secondary amenorrhea, presence of follicles at ultrasound, and inhibin B and estradiol levels were significantly predictive of resumption of ovarian function (P < 0.01), whereas association with an autoimmune disease, anti-mullerian hormone level, the presence of follicles on biopsy, and/or genetic abnormalities did not appear predictive. We created a predictive score for resumption of ovarian function comprising age at diagnosis, presence of follicles at ultrasound, and inhibin B level. CONCLUSION:Intermittent ovarian activity in patients with POF is not a rare phenomenon. The predictive score described in this study may help us to identify POF patients most likely to recover intermittent ovarian function. 10.1210/jc.2011-1038
    Telomere Shortening and Fusions: A Link to Aneuploidy in Early Human Embryo Development. Obstetrical & gynecological survey IMPORTANCE:It is known that oocytes undergo aging that is caused by exposure to an aged ovarian microenvironment. Telomere length in mouse and bovine oocytes declines with age, and age-associated telomere shortening in oocytes is considered a sign of poor development competency. Women with advanced age undergoing assisted reproductive technologies have poor outcomes because of increasing aneuploidy rates with age. Research has shown that aneuploidy is associated with DNA damage, reactive oxygen species, and telomere dysfunction. OBJECTIVE:In this review, we focus on the possible relationship between telomere dysfunction and aneuploidy in human early embryo development and several reproductive and perinatal outcomes, discussing the mechanism of aneuploidy caused by telomere shortening and fusion in human embryos. EVIDENCE ACQUISITION:We reviewed the current literature evidence concerning telomere dysfunction and aneuploidy in early human embryo development. RESULTS:Shorter telomeres in oocytes, leukocytes, and granulosa cells, related to aging in women, were associated with recurrent miscarriage, trisomy 21, ovarian insufficiency, and decreasing chance of in vitro fertilization success. Telomere length and telomerase activity in embryos have been related to the common genomic instability at the cleavage stage of human development. Complications of assisted reproductive technology pregnancies, such as miscarriage, birth defects, preterm births, and intrauterine growth restriction, also might result from telomere shortening as observed in oocytes, polar body, granulosa cells, and embryos. CONCLUSIONS AND RELEVANCE:Telomere length clearly plays an important role in the development of the embryo and fetus, and the abnormal shortening of telomeres is likely involved in embryo loss during early human development. However, telomere fusion studies have yet to be performed in early human development. 10.1097/OGX.0000000000000907
    Forecasting early onset diminished ovarian reserve for young reproductive age women. McCallie Blair R,Haywood Mary,Denomme Michelle M,Makloski Rachel,Parks Jason C,Griffin Darren K,Schoolcraft William B,Katz-Jaffe Mandy G Journal of assisted reproduction and genetics PURPOSE:To investigate the biological networks associated with DOR in young women and the subsequent molecular impact on preimplantation embryos. METHODS:Whole peripheral blood was collected from patients: young women presenting with diminished ovarian reserve (DOR) and age-matched young women with normal ovarian reserve. Maternal exome sequencing was performed on the NovaSEQ 6000 and sequencing validation was completed using Taqman® SNP Genotyping Assays. Blastocyst global methylome and transcriptome sequencing were also analyzed. RESULTS:Exome sequencing revealed 730 significant DNA variants observed exclusively in the young DOR patients. Bioinformatic analysis revealed a significant impact to the Glucocorticoid receptor (GR) signaling pathway and each young DOR female had an average of 6.2 deleterious DNA variants within this pathway. Additional stratification based on patient age resulted in a cut-off at 31 years for young DOR discrimination. Embryonic global methylome sequencing resulted in only a very small number of total CpG sites with methylation alterations (1,775; 0.015% of total) in the DOR group. Additionally, there was no co-localization between these limited number of altered CpG sites and significant variants, genes, or pathways. RNA sequencing also resulted in no biologically significant transcription changes between DOR blastocysts and controls. CONCLUSION:GR signaling DNA variants were observed in women with early-onset DOR potentially compromising oocyte production and quality. However, no significant downstream effects on biological processes appear to impact the resulting blastocyst. The ability to forecast premature DOR for young women may allow for earlier identification and clinical intervention for this patient population. 10.1007/s10815-021-02155-8
    Aberrant and constitutive expression of FOXL2 impairs ovarian development and functions in mice. Nicol Barbara,Rodriguez Karina,Yao Humphrey H-C Biology of reproduction Development and functions of the ovary rely on appropriate signaling and communication between various ovarian cell types. FOXL2, a transcription factor that plays a key role at different stages of ovarian development, is associated with primary ovarian insufficiency and ovarian cancer as a result of its loss-of-function or mutations. In this study, we investigated the impact of aberrant, constitutive expression of FOXL2 in somatic cells of the ovary. Overexpression of FOXL2 that started during fetal life resulted in defects in nest breakdown and consequent formation of polyovular follicles. Granulosa cell differentiation was impaired and recruitment and differentiation of steroidogenic theca cells was compromised. As a consequence, adult ovaries overexpressing FOXL2 exhibited defects in compartmentalization of granulosa and theca cells, significant decreased steroidogenesis and lack of ovulation. These findings demonstrate that fine-tuned expression of FOXL2 is required for proper folliculogenesis and fertility. 10.1093/biolre/ioaa146
    Ameliorative effect of recombinant human lactoferrin on the premature ovarian failure in rats after cyclophosphamide treatments. Li Shubin,Liu Mengnan,Ma Hongmeng,Jin Qin,Ma Yuzhen,Wang Chunyu,Ren Jingyu,Liu Gang,Dai Yanfeng Journal of ovarian research This study investigated the effect of recombinant human lactoferrin (rhLF) on the premature ovarian failure (POF) of rats. After cyclophosphamide treatments, the POF rats were divided into the following groups: normal control group (NC), low-dose group (LD), medium-dose group (MD) and high-dose group (HD) of rhLF. After drug administrations, the ovarian indexes and hormonal levels were detected. After follicle number count, the proliferation and apoptosis were analyzed with the expressions of genes related with oogenesis, reactive oxygen species (ROS) production and apoptosis detected, followed by the calculation of oxidative stress and protein expressions. After 4-hydroperoxy cyclophosphamide (4-HC) treatments, the effect of rhLF on the proliferation, ROS production and gene expressions of primary rat granulosa cells (GCs) cultured in vitro were detected. After mating, the fertilities of POF rats were recorded. The result showed that the rhLF administrations up-regulated the ovarian index with the number of developing follicles increased and the decreases of hormonal levels conferred. The Ki-67 intensities of the MD and HD groups were up-regulated with the Tunnel intensities decreased. The rhLF treatments significantly promoted the expression of oogenesis, antioxidant and anti-apoptosis related genes. The expression of Bax and Caspase 3 were decreased with the expression of Bcl-2 up-regulated after rhLF administrations. The in vitro treatments of rhLF effectively conferred the toxicity of 4-HC on primary rat GCs. The fertility assessment showed the rhLF treatments up-regulated the offspring's' folliculogenesis, which confirmed the ameliorative role of rhLF on the POF damages via the inhibition of ROS production in GCs. 10.1186/s13048-020-00763-z
    The Therapeutic Effect of Stem Cells on Chemotherapy-Induced Premature Ovarian Failure. Chen Haoran,Liu Chi,Zhu Shaomi,Li Shaowei,Zhang Qinxiu,Song Linjiang,Liang Xin Current molecular medicine Premature ovarian failure (POF) refers to ovarian dysfunction in women under 40 years old. It is characterized by low estrogen, high gonadotropin, amenorrhea, and infertility, which seriously affect physical and mental health of women. The pathogenic factors of POF include iatrogenic factors, autoimmune factors, genetic factors, oxidative stress, infection, thyroid dysfunction, and adrenal diseases. Chemotherapy is a common cause of POF and is gaining increasing attention. With the development of modern medicine and advances in understanding cancer, women's cancer survival rates have been significantly increased. Currently, the main treatment options for POF are hormone supplement and in vitro activation (IVA), but there is still no specific treatment for POF. Stem cells, known as undifferentiated cells of multicellular organisms, exhibit characteristics of self-renewal, directional differentiation into different cells, and low immunogenicity. Thus, they have potential in regenerative medicine and provide a promising direction for POF treatment. In this review, we summarize the latest research progress of various stem cells in chemotherapy-induced POF models to provide a theoretical basis for further research and treatment. 10.2174/1566524020666200905113907
    Galactosaemia occurring in association with primary ovarian insufficiency, Addison's disease and chronic myeloid leukaemia. Khoury Brandon,Shakir Mohamed Km,Hoang Thanh Duc BMJ case reports Classic galactosaemia is the most severe type, inherited in an autosomal recessive fashion and normally detected on newborn screening. It is caused by an inability to digest galactose due to a deficiency of galactose-1-phosphate uridyltransferase (GALT), resulting in an intolerance of feeds in the neonatal period, failure to thrive, hypoglycaemia, jaundice, cataracts, hepatomegaly, vomiting, diarrhoea, developmental delay and an increased risk of sepsis. The long-term sequelae of this disorder include cognitive impairment, neurological symptoms, such as ataxia, nutritional deficiencies, such as calcium and vitamin D, and gonadal dysfunction. We report here a case of a 34-year-old woman with classic galactosaemia diagnosed in adulthood, developing primary ovarian insufficiency and osteoporosis as well as primary adrenal insufficiency and chronic myeloid leukaemia, which are two associations not seen in current literature. Further studies are needed to determine if an association exists between these diseases. 10.1136/bcr-2021-244788
    Association Between Human Papillomavirus Vaccination and Primary Ovarian Insufficiency in a Nationwide Cohort. Hviid Anders,Myrup Thiesson Emilia JAMA network open Importance:Anecdotal case reports have suggested an association between human papillomavirus (HPV) vaccination and primary ovarian insufficiency, but observational studies of HPV and primary ovarian insufficiency are rare, and their findings do not support an association. However, available studies have been limited by statistical power, and concerns about infertility after vaccination are associated with lower levels of uptake of the cancer-preventing vaccine in many countries. Objective:To evaluate the risk of primary ovarian insufficiency after quadrivalent human papillomavirus (4HPV) vaccination. Design, Setting, and Participants:This retrospective cohort study with follow-up from 2007 to 2016 used nationwide data for 996 300 Danish-born girls and women aged 11 to 34 years. Cox proportional hazards regression was used to estimate hazard ratios (HRs) of primary ovarian insufficiency diagnoses by 4HPV vaccination status with adjustment for age, calendar period, and a propensity score summarizing health care use. Data were analyzed from October 2020 to January 2021. Exposures:Receiving 4HPV vaccination compared with receiving no vaccination. Main Outcomes and Measures:The main outcome was hospital contacts for primary ovarian insufficiency, and the main outcome measures were HRs comparing rates of primary ovarian insufficiency among vaccinated and unvaccinated individuals. Results:During 6 781 166 person-years of follow-up among 996 300 girls and women aged 11 to 34 years (505 829 vaccinated individuals [50.8%] and 490 471 unvaccinated individuals [49.2%]), 144 individuals were diagnosed with primary ovarian insufficiency, including 54 individuals diagnosed after 4HPV vaccination. The median (interquartile range) age of primary ovarian insufficiency diagnosis was 26.94 (12.68) years. The adjusted HR of primary ovarian insufficiency comparing 4HPV vaccination to no vaccination was 0.96 (95% CI, 0.55-1.68). Conclusions and Relevance:This study found no association between HPV vaccination and primary ovarian insufficiency. However, given the rarity of the outcome in this study, the presence of a clinically relevant increase in rate of diagnosis cannot be excluded. 10.1001/jamanetworkopen.2021.20391
    Proteomic profile of the effects of low-dose bisphenol A on zebrafish ovaries. Molina Ana M,Abril Nieves,Lora Antonio J,Huertas-Abril Paula V,Ayala Nahum,Blanco Carmen,Moyano M Rosario Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association Human exposure to bisphenol-A (BPA) is largely unavoidable because BPA is an environmental contaminant found in soil, water, food and indoor dust. The safety of authorized BPA amounts in consumer products is under question because new studies have reported adverse effects of BPA at doses far below that previously established by the NOAEL (50 μg/kg per day). To protect public health, the consequences of low-dose BPA exposure in different organs and organismal functions must be further studied to generate relevant data. This study attempted to investigate the effects and potential molecular mechanisms of short-term exposure to 1 μg/L BPA on zebrafish ovarian follicular development. We observed only minor changes at the histopathological level with a small (3 %) increase in follicular atresia. However, a shotgun proteomics approach indicated deep alterations in BPA-exposed ovarian cells, including induction of the oxidative stress response, metabolic shifts and degradome perturbations, which could drive oocytes towards premature maturation. Based on these results, it could be suggested that inadvertent exposure to small concentrations of BPA on a continuous basis causes alteration in biological processes that are essential for healthy reproduction. 10.1016/j.fct.2021.112435
    Identification of a unique epigenetic profile in women with diminished ovarian reserve. Olsen Kristina W,Castillo-Fernandez Juan,Chan Andrew Cho,la Cour Freiesleben Nina,Zedeler Anne,Bungum Mona,Cardona Alexia,Perry John R B,Skouby Sven O,Hoffmann Eva R,Kelsey Gavin,Grøndahl Marie Louise Fertility and sterility OBJECTIVE:To investigate whether epigenetic profiles of mural granulosa cells (MGC) and leukocytes from women with diminished ovarian reserve (DOR) differ from those of women with normal or high ovarian reserve. DESIGN:Prospectively collected material from a multicenter cohort of women undergoing fertility treatment. SETTING:Private and university-based facilities for clinical services and research. PATIENT(S):One hundred and nineteen women of various ages and ovarian reserve status (antimüllerian hormone level) who provided blood samples and MGC. INTERVENTION(S):None. MAIN OUTCOME MEASURE(S):Measures of epigenetic aging rates from whole-genome methylation array data: DNA methylation variability, age acceleration, DNA methylation telomere length estimator (DNAmTL), and accumulation of epimutations. RESULT(S):Comparison of DOR or high ovarian reserve samples to controls (normal ovarian reserve) showed differential methylation variability between DOR and normal samples at 4,199 CpGs in MGC, and 447 between high and normal (false-discovery rate < 0.05). Variable sites in MGC from DOR were enriched in regions marked with the repressive histone modification H3K27me3, and also included genes involved in folliculogenesis, such as insulin growth factor 2 (IGF2) and antimüllerian hormone (AMH). Regardless of ovarian reserve, very few signals were detected in leukocytes, and no overlaps with those in MGC were found. Furthermore, we found a higher number of epimutations in MGC from women with DOR (Kruskal-Wallis test, difference in mean = 3,485). CONCLUSION(S):The somatic cells of human ovarian follicles have a distinctive epigenetic profile in women with DOR. A high frequency of epimutations suggests premature aging. Ovarian reserve status was not reflected in the leukocyte epigenetic profile. 10.1016/j.fertnstert.2020.09.009
    A systematic review and meta-analysis of the association between vitamin D and ovarian reserve. Karimi Elham,Arab Arman,Rafiee Masoumeh,Amani Reza Scientific reports It is hypothesized that vitamin D deficiency could be related to ovarian reserve. This systematic review and meta-analysis was undertaken to analyze the possible association between vitamin D and ovarian reserve among adolescent and adult women. All eligible studies identified through the ISI Web of Science, PubMed, and Scopus were included up to May 2021. A random-effects meta-analysis model was implemented and a weighted mean difference (WMD) and 95% confidence interval (CI) were calculated. A total of 38 papers covering 8608 individuals were enrolled in this systematic review and meta-analysis. Antral follicle count (AFC) was significantly lower among Asians (WMD - 0.65; 95% CI - 1.28 to - 0.01; P = 0.04; I = 0.0%) and luteinizing hormone (LH) levels were higher in non-Asians (WMD 2.16 IU/L; 95% CI 0.20 to 4.12; P = 0.031; I = 9.3%) with vitamin D insufficiency/deficiency. Also, there was a negative correlation between vitamin D and LH/FSH ratio in women with normal body mass index (BMI) (Fisher's Z: - 0.18; 95% CI - 0.37 to - 0.008; P = 0.041; I = 51.5%). Although there were no significant associations between serum vitamin D levels and any of the intended ovarian reserve markers, subgroup analyses have found significant findings regarding AFC, LH, and LH/FSH ratio. In order to understand the underlying mechanisms of vitamin D in female reproduction, further attempts are needed. 10.1038/s41598-021-95481-x
    The cyto-protective effects of LH on ovarian reserve and female fertility during exposure to gonadotoxic alkylating agents in an adult mouse model. Del Castillo L M,Buigues A,Rossi V,Soriano M J,Martinez J,De Felici M,Lamsira H K,Di Rella F,Klinger F G,Pellicer A,Herraiz S Human reproduction (Oxford, England) STUDY QUESTION:Does LH protect mouse oocytes and female fertility from alkylating chemotherapy? SUMMARY ANSWER:LH treatment before and during chemotherapy prevents detrimental effects on follicles and reproductive lifespan. WHAT IS KNOWN ALREADY:Chemotherapies can damage the ovary, resulting in premature ovarian failure and reduced fertility in cancer survivors. LH was recently suggested to protect prepubertal mouse follicles from chemotoxic effects of cisplatin treatment. STUDY DESIGN, SIZE, DURATION:This experimental study investigated LH effects on primordial follicles exposed to chemotherapy. Seven-week-old CD-1 female mice were randomly allocated to four experimental groups: Control (n = 13), chemotherapy (ChT, n = 15), ChT+LH-1x (n = 15), and ChT+LH-5x (n = 8). To induce primary ovarian insufficiency (POI), animals in the ChT and ChT+LH groups were intraperitoneally injected with 120 mg/kg of cyclophosphamide and 12 mg/kg of busulfan, while control mice received vehicle. For LH treatment, the ChT+LH-1x and ChT+LH-5x animals received a 1 or 5 IU LH dose, respectively, before chemotherapy, then a second LH injection administered with chemotherapy 24 h later. Then, two animals/group were euthanized at 12 and 24 h to investigate the early ovarian response to LH, while remaining mice were housed for 30 days to evaluate short- and long-term reproductive outcomes. The effects of LH and chemotherapy on growing-stage follicles were analyzed in a parallel experiment. Seven-week-old NOD-SCID female mice were allocated to control (n = 5), ChT (n = 5), and ChT+LH-1x (n = 6) groups. Animals were treated as described above, but maintained for 7 days before reproductive assessment. PARTICIPANTS/MATERIALS, SETTING, METHODS:In the first experiment, follicular damage (phosphorylated H2AX histone (γH2AX) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay), apoptotic biomarkers (western blot), and DNA repair pathways (western blot and RT-qPCR) were assessed in ovaries collected at 12 and 24 h to determine early ovarian responses to LH. Thirty days after treatments, remaining mice were stimulated (10 IU of pregnant mare serum gonadotropin (PMSG) and 10 IU of hCG) and mated to collect ovaries, oocytes, and embryos. Histological analysis was performed on ovarian samples to investigate follicular populations and stromal status, and meiotic spindle and chromosome alignment was measured in oocytes by confocal microscopy. Long-term effects were monitored by assessing pregnancy rate and litter size during six consecutive breeding attempts. In the second experiment, mice were stimulated and mated 7 days after treatments and ovaries, oocytes, and embryos were collected. Follicular numbers, follicular protection (DNA damage and apoptosis by H2AX staining and TUNEL assay, respectively), and ovarian stroma were assessed. Oocyte quality was determined by confocal analysis. MAIN RESULTS AND THE ROLE OF CHANCE:LH treatment was sufficient to preserve ovarian reserve and follicular development, avoid atresia, and restore ovulation and meiotic spindle configuration in mature oocytes exposed at the primordial stage. LH improved the cumulative pregnancy rate and litter size in six consecutive breeding rounds, confirming the potential of LH treatment to preserve fertility. This protective effect appeared to be mediated by an enhanced early DNA repair response, via homologous recombination, and generation of anti-apoptotic signals in the ovary a few hours after injury with chemotherapy. This response ameliorated the chemotherapy-induced increase in DNA-damaged oocytes and apoptotic granulosa cells. LH treatment also protected growing follicles from chemotherapy. LH reversed the chemotherapy-induced depletion of primordial and primary follicular subpopulations, reduced oocyte DNA damage and granulosa cell apoptosis, restored mature oocyte cohort size, and improved meiotic spindle properties. LARGE SCALE DATA:N/A. LIMITATIONS, REASONS FOR CAUTION:This was a preliminary study performed with mouse ovarian samples. Therefore, preclinical research with human samples is required for validation. WIDER IMPLICATIONS OF THE FINDINGS:The current study tested if LH could protect the adult mouse ovarian reserve and reproductive lifespan from alkylating chemotherapy. These findings highlight the therapeutic potential of LH as a complementary non-surgical strategy for preserving fertility in female cancer patients. STUDY FUNDING/COMPETING INTEREST(S):This study was supported by grants from the Regional Valencian Ministry of Education (PROMETEO/2018/137), the Spanish Ministry of Science and Innovation (CP19/00141), and the Spanish Ministry of Education, Culture and Sports (FPU16/05264). The authors declare no conflict of interest. 10.1093/humrep/deab165
    Depletion of GPSM1 enhances ovarian granulosa cell apoptosis via cAMP-PKA-CREB pathway in vitro. Cai Xuzi,Fu Huijiao,Wang Yan,Liu Qiwen,Wang Xuefeng Journal of ovarian research BACKGROUND:Genetic causes of premature ovarian insufficiency (POI) account for approximately 20 ~ 25% of patients. So far, only a few genes have been identified. RESULTS:Here, we first identified the c.1840C > A on G-protein signaling modulator 1 (GPSM1) as a susceptibility locus for POI in 10 sporadic POI patients by whole-exome sequencing. The frequency of GPSM1 c.1840C > A was then verified as 3/20 in a POI sample of 20 patients (including the above 10 patients) by Sanger sequencing. RT-PCR and western blot analysis showed the expression of GPSM1 in rat ovaries was increased in the large antral follicle stage compared to the primordial follicle stage (P < 0.01). The cell proliferation assay (CCK8) and flow cytometry suggested that the small-interfering RNA-induced silencing of Gpsm1 significantly increased apoptosis and decreased proliferation of rat ovarian granulosa cells (GCs) (P < 0.01). Furthermore, suppression of Gpsm1 in GCs reduced levels of cAMP, PKAc, p-CREB as well as the ratio of Bcl-2/Bax, and increased the expression of Caspase-3 and Cleaved Caspase-3 (P < 0.01). CONCLUSIONS:In summary, this study identified a susceptibility variant GPSM1 c.1840C > A of POI for the first time. Gpsm1 was related to rat follicle development, and silencing of Gpsm1 increased apoptosis and decreased proliferation in rat GCs, possibly through inhibition of the cAMP-PKA-CREB pathway. 10.1186/s13048-020-00740-6
    Homozygous mutations in C14orf39/SIX6OS1 cause non-obstructive azoospermia and premature ovarian insufficiency in humans. Fan Suixing,Jiao Yuying,Khan Ranjha,Jiang Xiaohua,Javed Abdul Rafay,Ali Asim,Zhang Huan,Zhou Jianteng,Naeem Muhammad,Murtaza Ghulam,Li Yang,Yang Gang,Zaman Qumar,Zubair Muhammad,Guan Haiyang,Zhang Xingxia,Ma Hui,Jiang Hanwei,Ali Haider,Dil Sobia,Shah Wasim,Ahmad Niaz,Zhang Yuanwei,Shi Qinghua American journal of human genetics Human infertility is a multifactorial disease that affects 8%-12% of reproductive-aged couples worldwide. However, the genetic causes of human infertility are still poorly understood. Synaptonemal complex (SC) is a conserved tripartite structure that holds homologous chromosomes together and plays an indispensable role in the meiotic progression. Here, we identified three homozygous mutations in the SC coding gene C14orf39/SIX6OS1 in infertile individuals from different ethnic populations by whole-exome sequencing (WES). These mutations include a frameshift mutation (c.204_205del [p.His68Glnfs2]) from a consanguineous Pakistani family with two males suffering from non-obstructive azoospermia (NOA) and one female diagnosed with premature ovarian insufficiency (POI) as well as a nonsense mutation (c.958G>T [p.Glu320]) and a splicing mutation (c.1180-3C>G) in two unrelated Chinese men (individual P3907 and individual P6032, respectively) with meiotic arrest. Mutations in C14orf39 resulted in truncated proteins that retained SYCE1 binding but exhibited impaired polycomplex formation between C14ORF39 and SYCE1. Further cytological analyses of meiosis in germ cells revealed that the affected familial males with the C14orf39 frameshift mutation displayed complete asynapsis between homologous chromosomes, while the affected Chinese men carrying the nonsense or splicing mutation showed incomplete synapsis. The phenotypes of NOA and POI in affected individuals were well recapitulated by Six6os1 mutant mice carrying an analogous mutation. Collectively, our findings in humans and mice highlight the conserved role of C14ORF39/SIX6OS1 in SC assembly and indicate that the homozygous mutations in C14orf39/SIX6OS1 described here are responsible for infertility of these affected individuals, thus expanding our understanding of the genetic basis of human infertility. 10.1016/j.ajhg.2021.01.010
    Qilin Pill Exerts Therapeutic Effect on Resection-Induced Premature Ovarian Insufficiency Rats by Inhibiting the MAPK and PI3K-AKT Signaling Pathways. Drug design, development and therapy BACKGROUND:The Qilin pill (QLP) is a traditional Chinese compound prescription comprising 15 herbs that has demonstrated significant therapeutic effects on premature ovarian insufficiency (POI) in recent years. However, a pharmacological evaluation of QLP on ovarian function remains to be conducted, and the key mechanism of QLP treatment on POI is unclear. METHODS:Premature ovarian insufficiency rats were established by bilateral partial ovariectomy. The model rats were administrated with low (QLP-L), medium (QLP-M) and high (QLP-H) doses of QLP for 4 weeks to evaluate the ovarian function in terms of estrous cycle, hormone level, and follicle count. The mechanism of QLP in the treatment of POI was systematically explored by network pharmacology, and expression levels of the MAPK and PI3K-AKT signaling pathways were verified by Western blotting and molecular docking. RESULTS:The rat model of resection-induced POI was successfully established, and QLP could significantly recover the estrous cycle, decrease serum FSH levels, and decelerate follicle depletion after 4 weeks of administration. The optimal dose of QLP in the experiment was preliminarily determined to be 0.9 g/kg. Based on the network pharmacology methods, we constructed the compound-target network and protein protein interaction (PPI) network of QLP for the treatment of POI. The experimental verification of the enrichment analysis showed that QLP inhibited the MAPK and PI3K-AKT signaling pathways, and the key compounds and key targets involved were verified by molecular docking. CONCLUSION:QLP exerted significant therapeutic effects on resection-induced POI rats, and this was achieved by the inhibition of the MAPK and PI3K-AKT signaling pathways. This study is the first to systematically investigate the effects and mechanism of QLP on POI rats, which will provide valuable guidance in clinic. 10.2147/DDDT.S321010
    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. 10.1096/fj.202100756R
    Protective effects of human umbilical cord mesenchymal stem cell-derived conditioned medium on ovarian damage. Hong Liming,Yan Long,Xin Zhimin,Hao Jie,Liu Wenjing,Wang Shuyu,Liao Shujie,Wang Hongmei,Yang Xiaokui Journal of molecular cell biology Chemotherapeutic agents are extensively used to treat malignancies. However, chemotherapy-induced ovarian damage and reduced fertility are severe side effects. Recently, stem cell transplantation has been reported to be an effective strategy for premature ovarian insufficiency (POI) treatment, but safety can still be an issue in stem cell-based therapy. Here, we show the protective effects of human umbilical cord mesenchymal stem cell-derived conditioned medium (hUCMSC-CM) on a cisplatin (Cs)-induced ovarian injury model. hUCMSC-CM can relieve Cs-induced depletion of follicles and preserve fertility. In addition, hUCMSC-CM can decrease apoptosis of oocytes and granulosa cells induced by Cs. RNA sequencing analysis reveals the differentially expressed genes of ovaries after Cs and hUCMSC-CM treatments, including genes involved in cell apoptosis. Furthermore, we show that the granulocyte colony-stimulating factor (G-CSF)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway plays an important role in protecting granulosa cells from Cs-induced apoptosis. Together, we confirm the protective effects of hUCMSC-CM on ovarian reserve and fertility in mice treated with Cs, highlighting the remarkable therapeutic effects of hUCMSC-CM. 10.1093/jmcb/mjz105
    Extracellular Vesicles Derived from Mesenchymal Stem Cells Recover Fertility of Premature Ovarian Insufficiency Mice and the Effects on their Offspring. Liu Conghui,Yin Huiqun,Jiang Hong,Du Xin,Wang Cunli,Liu Yingchun,Li Yu,Yang Ziling Cell transplantation It has been reported that extracellular vesicles (EVs) derived from human umbilical cord mesenchymal stem cells (HUCMSCs) can promote the proliferative and secretive functions of granulosa cells. In vivo study further demonstrated that EVs derived from HUCMSCs can not only promote the angiogenesis of ovarian tissue but also restore the function of an ovary of chemically induced premature ovarian insufficiency (POI) mice. However, no study investigates the effects of HUCMSCs derived EVs on fertility recovery of POI mice and evaluating their offspring. This study investigates the effects of HUCMSCs derived EVs on fertility recovery and the cognitive function of their offspring. A POI model was established by intraperitoneal injection of cyclophosphamide (CTX) and busulfan (BUS), and randomly divided into EVs-transplantation group (a single injection of 150 µg EVs proteins which suspended in 0.1 ml phosphate buffer saline [PBS] via tail vein), POI group (a single injection of 0.1 ml PBS via tail vein), and normal control group (a single injection of 0.1 ml PBS via tail vein without intraperitoneal injection of CTX and BUS). After EVs treatment, not only the ovarian function of POI mice recovered but also the fertility increased with less time to get pregnant, evaluating by fertilization and mating test. Cognitive behaviors of the offspring were similar among the three groups through the Y-maze test and novel object recognition task. An anti-apoptotic effect was identified through immunohistochemistry, real-time polymerase chain reaction and western blot. These findings indicate that HUCMSCs derived EVs can improve the fertility of POI mice without adverse effects on the cognitive behavior of their offspring, highlighting the potential value of EVs to be a cell-free therapy for patients suffering from POI. 10.1177/0963689720923575
    First pregnancy in China after ovarian tissue transplantation to prevent premature ovarian insufficiency. Ruan X,Du J,Lu D,Duan W,Jin F,Kong W,Wu Y,Dai Y,Yan S,Yin C,Li Y,Cheng J,Jia C,Liu X,Wu Q,Gu M,Ju R,Xu X,Yang Y,Jin J,Korell M,Montag M,Liebenthron J,Mueck A O Climacteric : the journal of the International Menopause Society OBJECTIVE:This article reports the first case of pregnancy after frozen-thawed ovarian tissue transplantation to prevent iatrogenic premature ovarian insufficiency in China. METHODS:Ovarian tissue cryopreservation was performed in a patient with myelodysplastic syndrome (MDS) before multi-agent chemotherapy and hematopoietic stem cell transplantation. Two years later, she showed complete remission from MDS, and six frozen-thawed ovarian tissue strips were transplanted into the peritoneal pocket. RESULTS:The patient's ovarian activity was restored 3 months after transplantation, and pregnancy occurred spontaneously 27 months after grafting. Until now, the pregnancy has progressed for 30 weeks, and the repeated ultrasound showed normal fetal development. CONCLUSION:This is the first pregnancy resulting from ovarian tissue cryopreservation and transplantation in China. 10.1080/13697137.2021.1956453
    Attitude and knowledge for menopause management among health professionals in mainland China. Lin L,Feng P,Yu Q Climacteric : the journal of the International Menopause Society OBJECTIVE:This study aims to understand the attitude of health-care professionals (HPs) in mainland China toward menopause management (MM) as well as the knowledge they have received regarding MM during training. METHODS:An anonymous survey recruited 3709 medical workers nationwide (including physicians, orthopedists, obstetricians and gynecologists, and general practitioners) through online surveys and on-site interviews at professional meetings. RESULTS:Of the 3709 questionnaires completed, 3426 questionnaires met the inclusion criteria. Of the participants, 1532 HPs had not received menopause management training (MMT) in nearly 1 year. Among the residents and physician assistants, 103 reported they were not familiar with MM. Satisfyingly, 98.3% of HPs considered it very important or essential to accept MM. Although most interviewees replied some correct menopausal knowledge, nearly half of them could not correctly identify the contraindications for menopause hormone therapy (MHT). Additionally, 73.1% of HPs would advise patients with premature ovarian insufficiency to receive hormone replacement therapy at least until the average age of menopause. CONCLUSION:This survey indicated that HPs have some knowledge regarding MM, but a gap remains to master the basic theory of MHT. In order to manage the growing menopausal population in China, creating more in-depth educational MMT programs for HPs is necessary. 10.1080/13697137.2020.1775809
    Ovarian tissue cryopreservation and transplantation prevents iatrogenic premature ovarian insufficiency: first 10 cases in China. Ruan X,Cheng J,Korell M,Du J,Kong W,Lu D,Wu Y,Li Y,Jin F,Gu M,Duan W,Dai Y,Yin C,Yan S,Mueck A O Climacteric : the journal of the International Menopause Society OBJECTIVE:The aim of this study was to report on the first 10 cases of ovarian tissue cryopreservation (OTC) and retransplantation (OTCT) in China. METHODS:A retrospective descriptive study was performed of 10 Chinese women with different diseases undergoing OTC/OTCT in the first specialized center in China. Patients' ovarian function and fertility were followed up. RESULTS:The 10 cases included five cases of cervical cancer and one case each of endometrial cancer, breast cancer, rectal cancer, myelodysplastic syndrome, and aplastic anemia, respectively. The average age at OTC was 33.70 years; the time from OTC to OTCT was 15 months. The average number of transplanted ovarian tissue pieces was 4.9, with 9.5 pieces remaining cryopreserved. The OTCT position for nine cases was in a right-sided peritoneal pocket of ovarian fossa, and for one patient was in bilateral pockets. The average time from OTCT to restoration of ovarian function was 3.4 months. One year after OTCT, all ovaries were still functioning normally. In the first case, the function now remains preserved for more than 3 years. So far, the woman who wishes to conceive has no pregnancy. CONCLUSION:Regarding ovarian function, OTC and OTCT were successful and reliable in China's first cryobank. We expect to perform more retransplantations in the near future, which will add to the global data. 10.1080/13697137.2020.1767569
    Prevention of chemotherapy-induced premature ovarian insufficiency in mice by scaffold-based local delivery of human embryonic stem cell-derived mesenchymal progenitor cells. Shin Eun-Young,Kim Da-Seul,Lee Min Ji,Lee Ah Reum,Shim Sung Han,Baek Seung Woon,Han Dong Keun,Lee Dong Ryul Stem cell research & therapy BACKGROUND:Premature ovarian insufficiency (POI) is one of the most serious side effects of chemotherapy in young cancer survivors. It may not only reduce fecundity but also affect lifelong health. There is no standard therapy for preserving ovarian health after chemotherapy. Recently, administration of embryonic stem cell-derived mesenchymal progenitor cells (ESC-MPCs) has been considered a new therapeutic option for preventing POI. However, the previous method of directly injecting cells into the veins of patients exhibits low efficacy and safety. This study aimed to develop safe and effective local delivery methods for the prevention of POI using two types of bioinspired scaffolds. METHODS:Female mice received intraperitoneal cisplatin for 10 days. On day 11, human ESC-MPCs were delivered through systemic administration using intravenous injection or local administration using intradermal injection and intradermal transplantation with a PLGA/MH sponge or hyaluronic acid (HA) gel (GEL) type of scaffold. PBS was injected intravenously as a negative control. Ovarian function and fertility were evaluated 4 weeks after transplantation. Follicle development was observed using hematoxylin and eosin staining. The plasma levels of sex hormones were measured using ELISA. Expression levels of anti-Müllerian hormone (AMH) and ki-67 were detected using immunostaining, and the quality of oocytes and embryos was evaluated after in vitro fertilization. The estrous cycles were observed at 2 months after transplantation. RESULTS:The local administration of human ESC-MPCs using the bioinspired scaffold to the backs of mice effectively prolonged the cell survival rate in vivo. The HA GEL group exhibited the best recovered ovarian functions, including a significantly increased number of ovarian reserves, estrogen levels, and AMH levels and decreased apoptotic levels. Furthermore, the HA GEL group showed improved quality of oocytes and embryos and estrous cycle regularity. CONCLUSIONS:HA GEL scaffolds can be used as new delivery platforms for ESC-MPC therapy, and this method may provide a novel option for the clinical treatment of chemotherapy-induced POI. 10.1186/s13287-021-02479-3
    Emerging follicular activation strategies to treat women with poor ovarian response and primary ovarian insufficiency. Reig Andres,Herraiz Sonia,Pellicer Antonio,Seli Emre Current opinion in obstetrics & gynecology PURPOSE OF THE REVIEW:Female reproductive aging remains one of the key unsolved challenges in the field of reproductive medicine. This article reviews three of the most recent and cutting-edge strategies that are currently being investigated to address the issues of poor ovarian response (POR) and primary ovarian insufficiency (POI). RECENT FINDINGS:Publications revealing the mechanism of mechanical disruption of the Hippo signaling pathway paved the way to studies on its potential application for fertility treatments. This, in combination with Akt stimulation, resulted in live births and ongoing pregnancies in women with POI. Building on previous reports on the effects of bone marrow transplants on fertility after chemotherapy, another approach involved autologous stem cell ovarian transplantation (ASCOT). The method proved effective in achieving live births in women previously diagnosed with POR. A third approach, intraovarian injection of autologous platelet-rich plasma, resulted in live births and ongoing pregnancies both spontaneously and via in vitro fertilization (IVF) in women with POI and POR. SUMMARY:New paths are being charted to address the issues of POI and POR. Although these are preliminary studies that should be interpreted with caution, they represent great promise for the women affected by these conditions and the physicians treating them. 10.1097/GCO.0000000000000703
    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. 10.1016/j.fertnstert.2020.08.005
    Advanced Oxidation Protein Products Induce G1/G0-Phase Arrest in Ovarian Granulosa Cells via the ROS-JNK/p38 MAPK-p21 Pathway in Premature Ovarian Insufficiency. Zhou Xing-Yu,Zhang Jun,Li Ying,Chen Ying-Xue,Wu Xiao-Min,Li Xin,Zhang Xiao-Fei,Ma Lin-Zi,Yang Yi-Zhen,Zheng Ke-Ming,Liu Yu-Dong,Wang Zhe,Chen Shi-Ling Oxidative medicine and cellular longevity The mechanism underlying the role of oxidative stress and advanced oxidation protein products (AOPPs) in the aetiology of premature ovarian insufficiency (POI) is poorly understood. Here, we investigated the plasma AOPP level in POI patients and the effects of AOPPs on granulosa cells both in vitro and in vivo. KGN cells were treated with different AOPP doses, and cell cycle distribution, intracellular reactive oxygen species (ROS), and protein expression levels were measured. Sprague-Dawley (SD) rats were treated daily with PBS, rat serum albumin, AOPP, or AOPP+ N-acetylcysteine (NAC) for 12 weeks to explore the effect of AOPPs on ovarian function. Plasma AOPP concentrations were significantly higher in both POI and biochemical POI patients than in controls and negatively correlated with anti-Müllerian hormone and the antral follicle count. KGN cells treated with AOPP exhibited G1/G0-phase arrest. AOPP induced G1/G0-phase arrest in KGN cells by activating the ROS-c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK)-p21 pathway. Pretreatment with NAC, SP600125, SB203580, and si-p21 blocked AOPP-induced G1/G0-phase arrest. In SD rats, AOPP treatment increased the proportion of atretic follicles, and NAC attenuated the adverse effects of AOPPs in the ovary. In conclusion, we provide mechanistic evidence that AOPPs may induce cell cycle arrest in granulosa cells via the ROS-JNK/p38 MAPK-p21 pathway and thus may be a novel biomarker of POI. 10.1155/2021/6634718
    The different doses of radiation therapy-induced damage to the ovarian environment in rats. Onder Gozde Ozge,Balcioglu Esra,Baran Munevver,Ceyhan Ayse,Cengiz Ozge,Suna Pinar Alisan,Yıldız Oguz Galip,Yay Arzu International journal of radiation biology PURPOSE:The sequelae of premature loss of ovarian function can undoubtedly have undesirable effects for a woman although radiotherapy is one of the most relevant treatment modalities for various types of malignancies. The aim of this study was to determine the effect of different doses of radiation on ovarian folliculogenesis, inflammation, and apoptotic markers. MATERIALS AND METHODS:For this purpose, 40 healthy Wistar albino female rats divided into four groups: 1) Control group; 2) those that were exposed to total body 1 Gy of gamma rays; 3) those that were exposed to the total body 5 Gy of gamma rays, and 4) those that were exposed to total body 10 Gy of gamma rays. External irradiation to the total body was given with gamma irradiation delivered by the Co60 teletherapy machine. The day after radiation application the rats were sacrificed and the ovaries were removed in all groups. Histopathologic examination, follicle counting, and classification were performed in the ovarian tissues. The expression of AMH, TNF-α, IL1-β, Bax, and Bcl-2 was detected. The stained sections were examined for caspase 3 positive apoptotic cell numbers. RESULTS:The recorded results revealed that increased radiation dose induced obvious ovarian injuries that were indicated by histopathological, and immunohistochemical alterations, including elevation of ovarian injury markers. A significantly lower number of total and primordial follicles was detected with increasing radiation dose compared with the control group. According to our immunohistochemical results, 10 Gy of gamma rays group had the lowest AMH expression levels, while had the highest TNF-α, IL1-β expression level compared to the control group. When the groups were evaluated in terms of apoptosis, it was seen that the number of caspase 3 positive cells and Bax immunoreactivity intensity increased with radiation dose. In contrast, Bcl-2 immunoreactivity intensity decreased with increasing radiation dose compared with the control group. CONCLUSIONS:We demonstrate here that dose rate plays an important role when estimating the relation between exposure to an increased dose of ionizing radiation and the risk of ovarian disease. According to these results, certain factors have to be optimized before introducing them into clinics. 10.1080/09553002.2021.1864497
    The Interconnections Between Somatic and Ovarian Aging in Murine Models. Schneider Augusto,Saccon Tatiana D,Garcia Driele N,Zanini Bianka M,Isola José V V,Hense Jéssica D,Alvarado-Rincón Joao A,Cavalcante Marcelo B,Mason Jeffrey B,Stout Michael B,Bartke Andrzej,Masternak Michal M The journals of gerontology. Series A, Biological sciences and medical sciences The mammalian female is born with a limited ovarian reserve of primordial follicles. These primordial follicles are slowly activated throughout the reproductive lifecycle, thereby determining lifecycle length. Once primordial follicles are exhausted, women undergo menopause, which is associated with several metabolic perturbations and a higher mortality risk. Long before exhaustion of the reserve, females experience severe declines in fertility and health. As such, significant efforts have been made to unravel the mechanisms that promote ovarian aging and insufficiency. In this review, we explain how long-living murine models can provide insights in the regulation of ovarian aging. There is now overwhelming evidence that most life-span-extending strategies, and long-living mutant models simultaneously delay ovarian aging. Therefore, it appears that the same mechanisms that regulate somatic aging may also be modulating ovarian aging and germ cell exhaustion. We explore several potential contributing mechanisms including insulin resistance, inflammation, and DNA damage-all of which are hallmarks of cellular aging throughout the body including the ovary. These findings are in alignment with the disposable soma theory of aging, which dictates a trade-off between growth, reproduction, and DNA repair. Therefore, delaying ovarian aging will not only increase the fertility window of middle age females, but may also actively prevent menopausal-related decline in systemic health parameters, compressing the period of morbidity in mid-to-late life in females. 10.1093/gerona/glaa258
    Si-Wu-Tang facilitates ovarian function through improving ovarian microenvironment and angiogenesis in a mouse model of premature ovarian failure. Zhou Fanru,Song Yufan,Liu Xia,Zhang Chu,Li Fan,Hu Runan,Huang Yanjing,Ma Wenwen,Song Kunkun,Zhang Mingmin Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Premature ovarian failure (POF) is a severe illness, characterized by premature menopause with a markedly decrease in ovarian function, which leads to infertility. Si-Wu-Tang (SWT), also called "the first prescription of gynecology" by medical experts in China, is widely used as the basic formula in regulating the menstrual cycle and treating infertility. However, the potential effect and underlying mechanisms of action of SWT on the treatment of POF have not yet been elucidated. PURPOSE:This study aimed to explore the therapeutic effect and underlying molecular mechanism of action of SWT on the treatment of POF in C57BL/6 mice. MATERIALS AND METHODS:The main compounds of SWT were identified by high-performance liquid chromatography (HPLC). POF model groups were established by a single intraperitoneal injection of cyclophosphamide (Cy, 100 mg/kg). SWT or dehydroepiandrosterone (DHEA) were administered via oral gavage for 28 consecutive days. Ovarian function and pathological changes were evaluated by hormone levels, follicular development, and changes in angiogenesis. Furthermore, statistical analyses of fertility were also performed. RESULTS:Treatment with SWT significantly improved estrogen levels, the number of follicles, antioxidant defense, and microvascular formation in POF mice. Moreover, SWT significantly activated the Nrf2/HO-1 and STAT3/HIF-1α/VEGF signaling pathways to promote angiogenesis, resulting in a better fertility outcome when compared to the model group. CONCLUSIONS:Our findings indicated that SWT protected ovarian function of Cy-induced POF mice by improving the antioxidant ability and promoting ovarian angiogenesis, thereby providing scientific evidence for the treatment of POF using SWT. 10.1016/j.jep.2021.114431
    Protective effect of Huyang Yangkun Formula on ovarian function in premature ovarian insufficiency rats based on apoptotic mechanism. Wang Lingdi,Li Meifang,Liu Jian,Nie Guangning,Li Yang,Yang Hongyan Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Huyang Yangkun Formula(HYF) is a traditional Chinese medicine formula based on the traditional theory of Yin and Yang. It could consolidate the Qi of Yin and Yang, adjust the balance of Qi and blood. It has shown clinical efficacy for patients with Premature Ovarian Insufficiency(POI). AIM OF THE STUDY:Aim to access the effect of Huyang Yangkun formula (HYF) on premature ovarian insufficiency rat model and explores the mechanism related to aquaporins(AQPs) and apoptosis. MATERIALS AND METHODS:Female SD rats were injected with 4-vinylcyclonhexenediepoxide(VCD, 160 mg/kg/day) for 15 days. Then, HYF (0.297 g/kg)/estradiol valerate (0.1 mg/kg) was administered for 105 days in the HYF/estradiol valerate treatment(EVT) group. Serum AMH, FSH and E were detected by ELISA, and the developing follicles were counted in each group.The TUNEL assay was used to detect positive apoptotic signals. IHC and western blots were used to verify differentially expressed AQPs and apoptosis-related regulators potentially associated with HYF. RESULTS:Total follicles were increased significantly in the HYF group. Serum AMH was increased in the HYF group compared with MOD group. Serum FSH and E showed no obvious difference between HYF group and MOD group. Apoptosis occurred in POI model was proved by TUNEL and Caspase3/9 and HYF could rescue this apoptosis, besides the anti-apoptotic effect may be better than EVT. Distribution of AQPs in rat ovaries based on developmental stages of follicle was observed, and AQP8 was obviously expressed in the developing follicles and corpus luteum, particularly in granulosa cells. Upregulation of AQP8 in the MOD group and downregulation by HYF were observed. BCL-XL was significantly upregulated in the HYF group and EVT group; BCL-2 was upregulated in the HYF group with no statistical difference; MCL-1 was downregulated in the HYF group. BAX and BIM were significantly upregulated in the MOD group. The ratio of BCL-2/BAX and BCL-XL/BAX were decreased in the MOD group, and BCL-XL/BAX was increased in the HYF group and EVT group. CONCLUSION:This study evaluated the treatment effect of HYF on POI in rats. It showed that HYF could promote the follicles development by regulating AQP8/Bcl-2 family-related mitochondrial apoptosis, which provides basic evidence for TCM as an alternative therapy for POI. 10.1016/j.jep.2021.114477
    Transplantation of human umbilical cord mesenchymal stem cells to treat premature ovarian failure. Shareghi-Oskoue Oldouz,Aghebati-Maleki Leili,Yousefi Mehdi Stem cell research & therapy As one of the problems and diseases for women before 40 years, premature ovarian failure (POF) could be characterized by amenorrhea, low estrogen levels, infertility, high gonadotropin levels, and lack of mature follicles. Causes of the disease involve some genetic disorders, autoimmunity diseases, and environmental factors. Various approaches have been employed to treat POF, however with limited success. Today, stem cells are used to treat POF, since they have the potential to self-repair and regenerate, and are effective in treating ovarian failure and infertility. As mesenchymal stem cell (MSC) could simultaneously activate several mechanisms, many researchers consider MSC transplantation to be the best and most effective approach in cell therapy. A good source for mesenchymal stem cells is human umbilical cord (HUCMSC). Animal models with cyclophosphamide are required for stem cell treatment and performance of HUCMSC transplantation. Stem cell therapy could indicate the levels of ovarian markers and follicle-stimulating hormone receptor. It also increases ovarian weight, plasma E2 levels, and the amount of standard follicles. Herein, the causes of POF, effective treatment strategies, and the effect of HUCMSC transplantation for the treatment of premature ovarian failure are reviewed. Many studies have been conducted in this field, and the results have shown that stem cell treatment is an effective approach to treat infertility. 10.1186/s13287-021-02529-w
    Anti-müllerian hormone levels and antral follicle count in women with a BRCA1 or BRCA2 germline pathogenic variant: A retrospective cohort study. Denis-Laroque Laurie,Drouet Youenn,Plotton Ingrid,Chopin Nicolas,Bonadona Valérie,Lornage Jacqueline,Salle Bruno,Lasset Christine,Rousset-Jablonski Christine Breast (Edinburgh, Scotland) BACKGROUND:Some studies suggested a decreased ovarian reserve among BRCA1/2 pathogenic variant carriers, with conflicting results. METHODS:We conducted a retrospective single-center observational study of ovarian reserve and spontaneous fertility comparing BRCA1/2 pathogenic variant carriers to controls (women who attended consultations to discuss fertility preservation before gonadotoxic treatment). Measures of associations between plasma AMH concentration, AFC and BRCA1/2 status were modelled by nonlinear generalized additive regression models and logistic regressions adjusted for age at plasma storage, oral contraceptive use, body mass index, cigarette smoking, and the AMH assay technique. RESULTS:The whole population comprised 119 BRCA1/2 pathogenic variant carriers and 92 controls. A total of 110 women (42 carriers, among whom 30 were cancer-free, and 68 controls) underwent an ovarian reserve evaluation. Spontaneous fertility analysis included all women who previously attempted to become pregnant (134 women). We observed a tendency towards a premature decrease in ovarian reserve in BRCA1/2 pathogenic variant carriers, but no difference in mean AMH or AFC levels was found between BRCA1/2 pathogenic variant carriers and controls. An analysis of the extreme levels of AMH (≤5 pmol/l) and AFC (≤7 follicles) by logistic regression suggested a higher risk of low ovarian reserve among BRCA1/2 pathogenic variant carriers (adjusted odds ratio (OR) = 3.57, 95% CI = 1.00-12.8, p = 0.05; and adjusted OR = 4.99, 95% CI = 1.10-22.62, p = 0.04, respectively). DISCUSSION:Attention should be paid to BRCA1/2 pathogenic variant carriers' ovarian reserve, considering this potential risk of premature alteration. 10.1016/j.breast.2021.07.010
    Energy sensors and reproductive hypothalamo-pituitary ovarian axis (HPO) in female mammals: Role of mTOR (mammalian target of rapamycin), AMPK (AMP-activated protein kinase) and SIRT1 (Sirtuin 1). Estienne Anthony,Bongrani Alice,Ramé Christelle,Kurowska Patrycja,Błaszczyk Klaudia,Rak Agnieszka,Ducluzeau Pierre-Henri,Froment Pascal,Dupont Joëlle Molecular and cellular endocrinology In female, energy metabolism influences reproductive function by modulating the Hypothalamic Pituitary Ovarian axis including the hypothalamic GnRH neuronal network, the pituitary gonadotropin secretion and the ovarian follicle growth and steroidogenesis. Several hormones and neuropeptides or metabolites are important signals between energy balance and reproduction. These energy sensors mediate their action on reproductive cells through specific kinases or signaling pathways. This review focuses on the role of three main enzymes-specifically, mTOR, AMPK, and SIRT1 at the hypothalamic pituitary and ovarian axis in normal female fertility and then we discuss their possible involvement in some women reproductive disorders known to be associated with metabolic complications, such as polycystic ovary syndrome (PCOS) and premature ovarian failure (POF). 10.1016/j.mce.2020.111113
    Genetic insights into biological mechanisms governing human ovarian ageing. Ruth Katherine S,Day Felix R,Hussain Jazib,Martínez-Marchal Ana,Aiken Catherine E,Azad Ajuna,Thompson Deborah J,Knoblochova Lucie,Abe Hironori,Tarry-Adkins Jane L,Gonzalez Javier Martin,Fontanillas Pierre,Claringbould Annique,Bakker Olivier B,Sulem Patrick,Walters Robin G,Terao Chikashi,Turon Sandra,Horikoshi Momoko,Lin Kuang,Onland-Moret N Charlotte,Sankar Aditya,Hertz Emil Peter Thrane,Timshel Pascal N,Shukla Vallari,Borup Rehannah,Olsen Kristina W,Aguilera Paula,Ferrer-Roda Mònica,Huang Yan,Stankovic Stasa,Timmers Paul R H J,Ahearn Thomas U,Alizadeh Behrooz Z,Naderi Elnaz,Andrulis Irene L,Arnold Alice M,Aronson Kristan J,Augustinsson Annelie,Bandinelli Stefania,Barbieri Caterina M,Beaumont Robin N,Becher Heiko,Beckmann Matthias W,Benonisdottir Stefania,Bergmann Sven,Bochud Murielle,Boerwinkle Eric,Bojesen Stig E,Bolla Manjeet K,Boomsma Dorret I,Bowker Nicholas,Brody Jennifer A,Broer Linda,Buring Julie E,Campbell Archie,Campbell Harry,Castelao Jose E,Catamo Eulalia,Chanock Stephen J,Chenevix-Trench Georgia,Ciullo Marina,Corre Tanguy,Couch Fergus J,Cox Angela,Crisponi Laura,Cross Simon S,Cucca Francesco,Czene Kamila,Smith George Davey,de Geus Eco J C N,de Mutsert Renée,De Vivo Immaculata,Demerath Ellen W,Dennis Joe,Dunning Alison M,Dwek Miriam,Eriksson Mikael,Esko Tõnu,Fasching Peter A,Faul Jessica D,Ferrucci Luigi,Franceschini Nora,Frayling Timothy M,Gago-Dominguez Manuela,Mezzavilla Massimo,García-Closas Montserrat,Gieger Christian,Giles Graham G,Grallert Harald,Gudbjartsson Daniel F,Gudnason Vilmundur,Guénel Pascal,Haiman Christopher A,Håkansson Niclas,Hall Per,Hayward Caroline,He Chunyan,He Wei,Heiss Gerardo,Høffding Miya K,Hopper John L,Hottenga Jouke J,Hu Frank,Hunter David,Ikram Mohammad A,Jackson Rebecca D,Joaquim Micaella D R,John Esther M,Joshi Peter K,Karasik David,Kardia Sharon L R,Kartsonaki Christiana,Karlsson Robert,Kitahara Cari M,Kolcic Ivana,Kooperberg Charles,Kraft Peter,Kurian Allison W,Kutalik Zoltan,La Bianca Martina,LaChance Genevieve,Langenberg Claudia,Launer Lenore J,Laven Joop S E,Lawlor Deborah A,Le Marchand Loic,Li Jingmei,Lindblom Annika,Lindstrom Sara,Lindstrom Tricia,Linet Martha,Liu YongMei,Liu Simin,Luan Jian'an,Mägi Reedik,Magnusson Patrik K E,Mangino Massimo,Mannermaa Arto,Marco Brumat,Marten Jonathan,Martin Nicholas G,Mbarek Hamdi,McKnight Barbara,Medland Sarah E,Meisinger Christa,Meitinger Thomas,Menni Cristina,Metspalu Andres,Milani Lili,Milne Roger L,Montgomery Grant W,Mook-Kanamori Dennis O,Mulas Antonella,Mulligan Anna M,Murray Alison,Nalls Mike A,Newman Anne,Noordam Raymond,Nutile Teresa,Nyholt Dale R,Olshan Andrew F,Olsson Håkan,Painter Jodie N,Patel Alpa V,Pedersen Nancy L,Perjakova Natalia,Peters Annette,Peters Ulrike,Pharoah Paul D P,Polasek Ozren,Porcu Eleonora,Psaty Bruce M,Rahman Iffat,Rennert Gad,Rennert Hedy S,Ridker Paul M,Ring Susan M,Robino Antonietta,Rose Lynda M,Rosendaal Frits R,Rossouw Jacques,Rudan Igor,Rueedi Rico,Ruggiero Daniela,Sala Cinzia F,Saloustros Emmanouil,Sandler Dale P,Sanna Serena,Sawyer Elinor J,Sarnowski Chloé,Schlessinger David,Schmidt Marjanka K,Schoemaker Minouk J,Schraut Katharina E,Scott Christopher,Shekari Saleh,Shrikhande Amruta,Smith Albert V,Smith Blair H,Smith Jennifer A,Sorice Rossella,Southey Melissa C,Spector Tim D,Spinelli John J,Stampfer Meir,Stöckl Doris,van Meurs Joyce B J,Strauch Konstantin,Styrkarsdottir Unnur,Swerdlow Anthony J,Tanaka Toshiko,Teras Lauren R,Teumer Alexander,Þorsteinsdottir Unnur,Timpson Nicholas J,Toniolo Daniela,Traglia Michela,Troester Melissa A,Truong Thérèse,Tyrrell Jessica,Uitterlinden André G,Ulivi Sheila,Vachon Celine M,Vitart Veronique,Völker Uwe,Vollenweider Peter,Völzke Henry,Wang Qin,Wareham Nicholas J,Weinberg Clarice R,Weir David R,Wilcox Amber N,van Dijk Ko Willems,Willemsen Gonneke,Wilson James F,Wolffenbuttel Bruce H R,Wolk Alicja,Wood Andrew R,Zhao Wei,Zygmunt Marek, , , , , , , , ,Chen Zhengming,Li Liming,Franke Lude,Burgess Stephen,Deelen Patrick,Pers Tune H,Grøndahl Marie Louise,Andersen Claus Yding,Pujol Anna,Lopez-Contreras Andres J,Daniel Jeremy A,Stefansson Kari,Chang-Claude Jenny,van der Schouw Yvonne T,Lunetta Kathryn L,Chasman Daniel I,Easton Douglas F,Visser Jenny A,Ozanne Susan E,Namekawa Satoshi H,Solc Petr,Murabito Joanne M,Ong Ken K,Hoffmann Eva R,Murray Anna,Roig Ignasi,Perry John R B Nature Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease. 10.1038/s41586-021-03779-7
    ZSWIM7 Is Associated With Human Female Meiosis and Familial Primary Ovarian Insufficiency. McGlacken-Byrne Sinéad M,Le Quesne Stabej Polona,Del Valle Ignacio,Ocaka Louise,Gagunashvili Andrey,Crespo Berta,Moreno Nadjeda,James Chela,Bacchelli Chiara,Dattani Mehul T,Williams Hywel J,Kelberman Dan,Achermann John C,Conway Gerard S The Journal of clinical endocrinology and metabolism BACKGROUND:Primary ovarian insufficiency (POI) affects 1% of women and is associated with significant medical consequences. A genetic cause for POI can be found in up to 30% of women, elucidating key roles for these genes in human ovary development. OBJECTIVE:We aimed to identify the genetic mechanism underlying early-onset POI in 2 sisters from a consanguineous pedigree. METHODS:Genome sequencing and variant filtering using an autosomal recessive model was performed in the 2 affected sisters and their unaffected family members. Quantitative reverse transcriptase PCR (qRT-PCR) and RNA sequencing were used to study the expression of key genes at critical stages of human fetal gonad development (Carnegie Stage 22/23, 9 weeks post conception (wpc), 11 wpc, 15/16 wpc, 19/20 wpc) and in adult tissue. RESULTS:Only 1 homozygous variant cosegregating with the POI phenotype was found: a single nucleotide substitution in zinc finger SWIM-type containing 7 (ZSWIM7), NM_001042697.2: c.173C > G; resulting in predicted loss-of-function p.(Ser58*). qRT-PCR demonstrated higher expression of ZSWIM7 in the 15/16 wpc ovary compared with testis, corresponding to peak meiosis in the fetal ovary. RNA sequencing of fetal gonad samples showed that ZSWIM7 has a similar temporal expression profile in the developing ovary to other homologous recombination genes. MAIN CONCLUSIONS:Disruption of ZSWIM7 is associated with POI in humans. ZSWIM7 is likely to be important for human homologous recombination; these findings expand the range of genes associated with POI in women. 10.1210/clinem/dgab597
    Network Pharmacology Approach for Predicting Targets of Zishen Yutai Pills on Premature Ovarian Insufficiency. Evidence-based complementary and alternative medicine : eCAM METHODS:A comprehensive strategy based on several Chinese herb databases and chemical compound databases was established to screen active compounds of ZSYTP and predict target genes. For network pharmacological analysis, network construction and gene enrichment analysis were conducted and further verified by molecular docking. RESULTS:A total of 476 target genes of ZSYTP were obtained from 205 active compounds. 13 herbs of ZSYTP overlapped on 8 active compounds based on the compound-target-disease network (C-T network). 20 biological processes and 9 pathways were strongly connected to the targets of ZSYTP in treating POI, including negative regulation of gene expression, mRNA metabolic process, hypoxia-inducible factor 1 (HIF-1) signaling pathway, and gluconeogenesis. Finally, molecular docking was visualized. CONCLUSION:Intriguingly, the signal pathways and biological processes uncovered in this study implicate inflamm-aging and glucose metabolism as potential pathological mechanisms of POI. The therapeutic effect of ZSYTP could be mediated by regulating glucose metabolism and HIF-1 signal pathway. Collectively, this study sheds light on the therapeutic potential of ZSYTP on POI. 10.1155/2021/8215454
    Premature ovarian insufficiency: A hormonal treatment approach. Benetti-Pinto Cristina Laguna,Soares Júnior José Maria,Maciel Gustavo Arantes,Nácul Andrea Prestes,Yela Daniela Angerame,Silva Ana Carolina Japur Sá Rosa E Revista brasileira de ginecologia e obstetricia : revista da Federacao Brasileira das Sociedades de Ginecologia e Obstetricia 10.1055/s-0040-1716929
    Matrigel/Umbilical Cord-Derived Mesenchymal Stem Cells Promote Granulosa Cell Proliferation and Ovarian Vascularization in a Mouse Model of Premature Ovarian Failure. Zhou Yao,Zhou Jinhua,Xu Xi,Du Fangzhou,Nie Mengting,Hu Lvzhong,Ma Yuhao,Liu Mengmeng,Yu Shuang,Zhang Jingzhong,Chen Youguo Stem cells and development In women of reproductive age, severe injuries to the ovary are often accompanied by premature ovarian failure (POF), which can result in amenorrhea or infertility. Hormone replacement therapy has been used to treat POF; however, it has limited therapeutic efficiency and may cause several side effects. In this study, we aimed to fabricate a Matrigel scaffold loaded with human umbilical cord-derived mesenchymal stem cells (MSCs) and explore its potential to restore ovarian function and repair ovarian structures in vitro and in vivo. POF mouse models were established by injecting mice with cyclophosphamide for 15 consecutive days. Then, MSC/Matrigel was transplanted into the ovaries of the mice. Five weeks later, the morphology of the ovaries and follicles was observed by hematoxylin/eosin staining, and the tissue fibrosis ratio was measured using Masson's trichrome staining. The number of blood vessels was evaluated by α-smooth muscle actin and CD31 immunofluorescence, and Ki67 expression was used to determine the proliferation of granulosa cells. The expression of vascular endothelial growth factor (VEGF)-A was assessed by western blotting. The Matrigel scaffold regulated the expression of VEGF-A in vitro. Moreover, it promoted MSC survival and proliferation and prevented MSC apoptosis in vivo. After the transplantation of the MSC/Matrigel, the number of follicles was significantly increased in the mice with POF, and the tissue fibrosis ratio was reduced. Furthermore, the MSC/Matrigel significantly improved the proliferation rate of granulosa cells, increased the number of blood vessels, and upregulated the expression of VEGF-A. These findings demonstrate that MSC/Matrigel may support follicular development and help restore ovarian structures in vivo. 10.1089/scd.2021.0005
    Effects of Intraovarian Injection of Autologous Platelet-Rich Plasma on Ovarian Rejuvenation in Poor Responders and Women with Primary Ovarian Insufficiency. Aflatoonian Abbas,Lotfi Marzieh,Saeed Lida,Tabibnejad Nasim Reproductive sciences (Thousand Oaks, Calif.) Injection of intraovarian platelet-rich plasma (PRP) was recently presented in terms of improvement ovarian function in women with a poor ovarian response (POR) or primary ovarian insufficiency (POI). In a before and after study, 17 poor responder women and 9 women with the diagnosis of POI were recruited. The multifocal intramedullary infusion of 1.5 ml activated PRP was performed into each ovary. The majority of women in both groups received the second PRP injection with the twofold increase in the dosage to 3ml, 3 months after the first injection. Evaluation of serum anti-mullerian hormone ( AMH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) was performed. In addition, all women were followed with regard to pregnancy outcome up to delivery. In the POI group, menstrual restoration was monitored. The significant difference was not detected regarding the hormonal profile between the three time points in both groups. With regard to pregnancy outcome, 8/17 (47%) of PORs had spontaneous pregnancy in response to PRP injection. Of those, three women (37.55%) had abortions, whereas 4 pregnancies (50%) led to healthy live births, and one woman (12.5%) was in the 24 week of her pregnancy. Menstruation recovery occurred among 22.2% of women with POI after the second PRP injection, but no one became pregnant. Intraovarian injection of autologous PRP might be considered an alternative treatment in poor responders. As for women with POI, it is questionable whether PRP could induce menstrual recovery. 10.1007/s43032-021-00483-9
    The effect of selenium and vitamin E supplementation on anti-Mullerian hormone and antral follicle count in infertile women with occult premature ovarian insufficiency: A randomized controlled clinical trial. Safiyeh Farhadi Dizaji,Mojgan Mirghafourvand,Parviz Shahabi,Sakineh Mohammad Alizadeh,Behnaz Sadeghzadeh Oskouei Complementary therapies in medicine OBJECTIVE:Increased accumulation of reactive oxygen species (ROS) in the process of oogenesis is one of the most well known causes of ovarian insufficiency and decreased ovarian reserve. Selenium and vitamin E as cofactors of glutathione peroxidase plays an important role in the removal of ROS in the ovary. We evaluated the effects of selenium and vitamin E supplementation on anti-Mullerian hormone (AMH) index and antral follicle count (AFC) (primary outcomes) and mean ovarian volume (MOV) and side effects of these supplements (secondary outcome) in infertile women with occult premature ovarian insufficiency (OPOI). METHODS:70 patients were allocated into the control and treatment groups through block randomization method. 35 women in the treatment group received 200 ng selenium and 400IU vitamin E and 35 women in the control group received placebo for a total of 90 days. AMH index, AFC and mean ovarian volume (MOV) were investigated in both groups after 12 months of study. RESULT:There was no significant difference between groups before intervention in AMH (Mean difference: -0.08; 95% CI: -0.20 to.08; p=0.33), AFC (-0.71; 95%CI: -1.44 to -0.01; p=0.05) and MOV (-0.55; 95% CI: -0.85 to -0.24; p=0.001). There was a significant increase in AMH (mean difference: 0.59; 95% CI: 0.48 to 0.71; p<0.001), AFC (5.08; 95% CI: 4.36 to 5.08; p<0.001) and MOV (2.17; 95% CI: 1.87 to 2.47; p<0.001) in selenium + vitamin E group compared to placebo group 12 months after intervention. These supplements had no side effects. CONCLUSION:Supplementation with selenium and vitamin E can increase AMH, AFC and MOV in women with OPOI. 10.1016/j.ctim.2020.102533
    Controlling chronic low-grade inflammation to improve follicle development and survival. Yang Ziwei,Tang Zijuan,Cao Xiuping,Xie Qi,Hu Chuan,Zhong Zhisheng,Tan Jun,Zheng Yuehui American journal of reproductive immunology (New York, N.Y. : 1989) Chronic low-grade inflammation is one cause of follicle development disturbance. Chronic inflammation exists in pathological conditions such as premature ovarian failure, physiological aging of the ovaries, and polycystic ovary syndrome. Inflammation of the whole body can affect oocytes via the follicle microenvironment, oxidative stress, and GM-CSF. Many substances without toxic side-effects extracted from natural organisms have gradually gained researchers' attention. Recently, chitosan oligosaccharide, resveratrol, anthocyanin, and melatonin have been found to contribute to an improvement in inflammation. This review discusses the interrelationships between chronic low-grade inflammation and follicle development, the underlying mechanisms, and methods that may improve follicle development by controlling the level of chronic low-grade inflammation. 10.1111/aji.13265
    Constitutive expression of Steroidogenic factor-1 (NR5A1) disrupts ovarian functions, fertility, and metabolic homeostasis in female mice. Rotgers Emmi,Nicol Barbara,Rodriguez Karina,Rattan Saniya,Flaws Jodi A,Yao Humphrey Hung-Chang FASEB journal : official publication of the Federation of American Societies for Experimental Biology Steroid hormones regulate various aspects of physiology, from reproductive functions to metabolic homeostasis. Steroidogenic factor-1 (NR5A1) plays a central role in the development of steroidogenic tissues and their ability to produce steroid hormones. Inactivation of Nr5a1 in the mouse results in a complete gonadal and adrenal agenesis, absence of gonadotropes in the pituitary and impaired development of ventromedial hypothalamus, which controls glucose and energy metabolism. In this study, we set out to examine the consequences of NR5A1 overexpression (NR5A1+) in the NR5A1-positive cell populations in female mice. Ovaries of NR5A1+ females presented defects such as multi-oocyte follicles and an accumulation of corpora lutea. These females were hyperandrogenic, had irregular estrous cycles with persistent metestrus and became prematurely infertile. Furthermore, the decline in fertility coincided with weight gain, increased adiposity, hypertriglyceridemia, hyperinsulinemia, and impaired glucose tolerance, indicating defects in metabolic functions. In summary, excess NR5A1 expression causes hyperandrogenism, disruption of ovarian functions, premature infertility, and disorders of metabolic homeostasis. This NR5A1 overexpression mouse provides a novel model for studying not only the molecular actions of NR5A1, but also the crosstalk between endocrine, reproductive, and metabolic systems. 10.1096/fj.202100304R
    Primate-specific POTE-actin gene could play a role in human folliculogenesis by controlling the proliferation of granulosa cells. Kasahara Yukiyo,Osuka Satoko,Takasaki Nobuyoshi,Bayasula ,Koya Yoshihiro,Nakanishi Natsuki,Murase Tomohiko,Nakamura Tomoko,Goto Maki,Iwase Akira,Kajiyama Hiroaki Cell death discovery Patients with primary ovarian insufficiency (POI) often have a high prevalence of autoimmune disorders. To identify antigenic molecules associated with ovarian autoimmunity, we performed immunoprecipitation (IP) screening using serum from patients with POI and the established human granulosa cell line (HGrC1). POTE ankyrin domain family member E (POTEE) and POTE ankyrin domain family member F (POTEF), proteins specific to primates, were identified as candidate antigens. Using immunohistochemistry (IHC) with human ovarian tissue, POTEE or POTEF was weakly seen in the granulosa cells (GCs) of primordial follicles and primary follicles, and strongly in large antral follicles and luteal cells. Interestingly, no signals were detected in growing GCs in secondary, preantral, and small antral follicles. Thus, to explore the function of POTEE and POTEF in human folliculogenesis, we established HGrC1 cell lines with drug-inducible expression of POTEF. Expression of POTEF significantly suppressed cell proliferation in HGrC1 cells. Furthermore, chaperonin containing TCP-1 complex (CCT) components, which affect folding proteins required for cell proliferation, was bound to the actin domain of POTEF protein. Although CCT is normally localized only around the Golgi apparatus, TCP-1α, a component of CCT, co-migrated closer to the cell membrane when POTEF expression was induced. These data suggest that the interaction between POTEF and CCT components impairs the usual function of CCT during cell growth. In addition, over-accumulation of POTEF in HGrC1 cells leads to autophagic failure. It was recently reported that knockout of an autophagic gene in mice leads to a phenotype similar to human POI. These results suggested that a proper amount of POTEF is required for the maintenance of GCs in follicle pools, whereas POTEF overaccumulation might be involved in follicle atresia and the development of POI. We also showed the possibility that POTEF could be an antigen involved in ovarian autoimmunity. 10.1038/s41420-021-00566-1
    Pathways coordinating oocyte attrition and abundance during mammalian ovarian reserve establishment. Grive Kathryn J Molecular reproduction and development The mammalian ovarian reserve is comprised of a finite pool of primordial follicles, representing the lifetime reproductive capacity of females. In most mammals, the reserve is produced during embryonic and early postnatal development with oocyte numbers peaking during mid-to-late gestation, and then experiencing a dramatic decline continuing until shortly after birth. Oocytes remaining after the bulk of this attrition are subsequently surrounded by a layer of somatic pre-granulosa cells with these units then referred to as "primordial follicles." The complex and varied cell death mechanisms intrinsic to this process are not only characteristic of, but also essential for, the proper formation of this pool of follicles, and as a result must be immaculately balanced to ensure long-term fertility and reproductive health. Too few follicles can lead to Primary Ovarian Insufficiency, resulting in fertility loss and other features of aging, such as an overall shorter lifespan. On the other hand, whereas an excess of follicles might extend reproductive lifespan, this might also be the underlying etiology of other ovarian pathologies. The last decade, in particular, has vastly expanded our understanding of oocyte attrition and determinants of ovarian reserve abundance. By continuing to decipher the intricacies underlying the cell death processes and development of the initial primordial follicle pool, we may be in a much better position to understand idiopathic cases of premature follicle depletion and improve ovarian health in reproductive-age women. 10.1002/mrd.23401