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    mA mRNA methylation controls autophagy and adipogenesis by targeting and . Wang Xinxia,Wu Ruifan,Liu Youhua,Zhao Yuanling,Bi Zhen,Yao Yongxi,Liu Qing,Shi Hailing,Wang Fengqin,Wang Yizhen Autophagy N:-methyladenosine (mA), the most abundant internal modification on mRNAs in eukaryotes, play roles in adipogenesis. However, the underlying mechanism remains largely unclear. Here, we show that mA plays a critical role in regulating macroautophagy/autophagy and adipogenesis through targeting and . Mechanistically, knockdown of FTO, a well-known mA demethylase, decreased the expression of ATG5 and ATG7, leading to attenuation of autophagosome formation, thereby inhibiting autophagy and adipogenesis. We proved that FTO directly targeted and transcripts and mediated their expression in an mA-dependent manner. Further study identified that and were the targets of YTHDF2 (YTH N6-methyladenosine RNA binding protein 2). Upon FTO silencing, and transcripts with higher mA levels were captured by YTHDF2, which resulted in mRNA degradation and reduction of protein expression, thus alleviating autophagy and adipogenesis. Furthermore, we generated an adipose-selective knockout mouse and find that FTO deficiency decreased white fat mass and impairs ATG5- and ATG7-dependent autophagy . Together, these findings unveil the functional importance of the mA methylation machinery in autophagy and adipogenesis regulation, which expands our understanding of such interplay that is essential for development of therapeutic strategies in the prevention and treatment of obesity. ABBREVIATIONS:3-MA: 3-methyladenine; ACTB: actin, beta; ATG: autophagy-related; Baf A1: bafilomycin A; CEBPA: CCAAT/enhancer binding protein (C/EBP), alpha; CEBPB: CCAAT/enhancer binding protein (C/EBP), beta; FABP4: fatty acid binding protein 4, adipocyte; FTO: fat mass and obesity associated; HFD: high-fat diet; LC-MS/MS: liquid chromatography-tandem mass spectrometry; MAP1LC3B/LC3: microtubule-associated protein 1 light chain 3 beta; mA: N-methyladenosine; MEFs: mouse embryo fibroblasts; MeRIP-qPCR: methylated RNA immunoprecipitation-qPCR; PPARG: peroxisome proliferator activated receptor gamma; RIP: RNA-immunoprecipitation; SAT: subcutaneous adipose tissue; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; ULK1: unc-51 like kinase 1; VAT: visceral adipose tissue; WAT: white adipose tissue; YTHDF: YTH N6-methyladenosine RNA binding protein. 10.1080/15548627.2019.1659617
    YTHDF3 facilitates translation and decay of N-methyladenosine-modified RNA. Shi Hailing,Wang Xiao,Lu Zhike,Zhao Boxuan S,Ma Honghui,Hsu Phillip J,Liu Chang,He Chuan Cell research N-methyladenosine (mA) is the most abundant internal modification in eukaryotic messenger RNAs (mRNAs), and plays important roles in cell differentiation and tissue development. It regulates multiple steps throughout the RNA life cycle including RNA processing, translation, and decay, via the recognition by selective binding proteins. In the cytoplasm, mA binding protein YTHDF1 facilitates translation of mA-modified mRNAs, and YTHDF2 accelerates the decay of mA-modified transcripts. The biological function of YTHDF3, another cytoplasmic mA binder of the YTH (YT521-B homology) domain family, remains unknown. Here, we report that YTHDF3 promotes protein synthesis in synergy with YTHDF1, and affects methylated mRNA decay mediated through YTHDF2. Cells deficient in all three YTHDF proteins experience the most dramatic accumulation of mA-modified transcripts. These results indicate that together with YTHDF1 and YTHDF2, YTHDF3 plays critical roles to accelerate metabolism of mA-modified mRNAs in the cytoplasm. All three YTHDF proteins may act in an integrated and cooperative manner to impact fundamental biological processes related to mA RNA methylation. 10.1038/cr.2017.15
    A Unified Model for the Function of YTHDF Proteins in Regulating mA-Modified mRNA. Zaccara Sara,Jaffrey Samie R Cell N-methyladenosine (mA) is the most abundant mRNA nucleotide modification and regulates critical aspects of cellular physiology and differentiation. mA is thought to mediate its effects through a complex network of interactions between different mA sites and three functionally distinct cytoplasmic YTHDF mA-binding proteins (DF1, DF2, and DF3). In contrast to the prevailing model, we show that DF proteins bind the same mA-modified mRNAs rather than different mRNAs. Furthermore, we find that DF proteins do not induce translation in HeLa cells. Instead, the DF paralogs act redundantly to mediate mRNA degradation and cellular differentiation. The ability of DF proteins to regulate stability and differentiation becomes evident only when all three DF paralogs are depleted simultaneously. Our study reveals a unified model of mA function in which all mA-modified mRNAs are subjected to the combined action of YTHDF proteins in proportion to the number of mA sites. 10.1016/j.cell.2020.05.012
    mA-binding YTHDF proteins promote stress granule formation. Fu Ye,Zhuang Xiaowei Nature chemical biology Diverse RNAs and RNA-binding proteins form phase-separated, membraneless granules in cells under stress conditions. However, the role of the prevalent mRNA methylation, mA, and its binding proteins in stress granule (SG) assembly remain unclear. Here, we show that mA-modified mRNAs are enriched in SGs, and that mA-binding YTHDF proteins are critical for SG formation. Depletion of YTHDF1/3 inhibits SG formation and recruitment of mRNAs to SGs. Both the N-terminal intrinsically disordered region and the C-terminal mA-binding YTH domain of YTHDF proteins are important for SG formation. Super-resolution imaging further reveals that YTHDF proteins appear to be in a super-saturated state, forming clusters that often reside in the periphery of or at the junctions between SG core clusters, and potentially promote SG formation by reducing the activation energy barrier and critical size for SG condensate formation. Our results suggest a new function of the mA-binding YTHDF proteins in regulating SG formation. 10.1038/s41589-020-0524-y
    The mA epitranscriptome on neural development and degeneration. Yen Ya-Ping,Chen Jun-An Journal of biomedical science N-methyladenosine (mA) is the most prevalent, conserved, and abundant RNA modification of the mRNAs of most eukaryotes, including mammals. Similar to epigenetic DNA modifications, mA has been proposed to function as a critical regulator for gene expression. This modification is installed by mA methylation "writers" (Mettl3/Mettl14 methyltransferase complex), and it can be reversed by demethylase "erasers" (Fto and Alkbh5). Furthermore, mA can be recognized by "readers" (Ythdf and Ythdc families), which may be interpreted to affect mRNA splicing, stability, translation or localization. Levels of mA methylation appear to be highest in the brain, where it plays important functions during embryonic stem cell differentiation, brain development, and neurodevelopmental disorders. Depletion of the mA methylation writer Mettl14 from mouse embryonic nervous systems prolongs cell cycle progression of radial glia and extends cortical neurogenesis into postnatal stages. Recent studies further imply that dysregulated mA methylation may be significantly correlated with neurodegenerative diseases. In this review, we give an overview of mA modifications during neural development and associated disorders, and provide perspectives for studying mA methylation. 10.1186/s12929-021-00734-6
    YTHDF2, a protein repressed by miR-145, regulates proliferation, apoptosis, and migration in ovarian cancer cells. Li Jie,Wu Lei,Pei Meili,Zhang Yun Journal of ovarian research RNA methylation can reverse the methylation modification at the RNA level, which is an extremely important epigenetic modification. The function and mechanism of YTHDF2, as a reader of m6A modification, in epithelial ovarian cancer (EOC) have not been elucidated so far. This study aimed to investigate how YTHDF2 and miR-145 modulated EOC progression through m6A modification. It demonstrated that YTHDF2 was significantly upregulated in EOC tissues compared with normal ovarian tissues. Further functional studies confirmed that YTHDF2 significantly promoted the proliferation and migration of EOC cell lines and reduced the global 6-methyladenine (m6A) mRNA levels. Next, the expression levels of miR-145 and YTHDF2 were found to be inversely correlated in ovarian cancer tissues and cells, and YTHDF2 was the direct target gene of miR-145. A crucial crosstalk occurred between miR-145 and YTHDF2 via a double-negative feedback loop. The overexpression of YTHDF2 rescued miR-145-induced reduction of the proliferation and migration of EOC cells. Hence, YTHDF2 and miR-145, as two crucial m6A regulators, were involved in the progression of EOC by indirectly modulating m6A levels. The findings of this study on YTHDF2 and miR-145 might provide new insights into carcinogenesis and new potential therapeutic targets for EOC. 10.1186/s13048-020-00717-5
    The Role of SMAD2/3 in Human Embryonic Stem Cells. Yang Jie,Jiang Wei Frontiers in cell and developmental biology Human embryonic stem cells (hESCs) possess the potential of long-term self-renewal and three primary germ layers differentiation, and thus hESCs are expected to have broad applications in cell therapy, drug screening and basic research on human early embryonic development. Many efforts have been put to dissect the regulation of pluripotency and direct differentiation of hESCs. TGFβ/Activin/Nodal signal pathway critically regulates pluripotency maintenance and cell differentiation through the main signal transducer SMAD2/3 in hESCs, but the action manners of SMAD2/3 in hESCs are sophisticated and not documented yet. Here we review and discuss the roles of SMAD2/3 in hESC pluripotency maintenance and differentiation initiation separately. We summarize that SMAD2/3 regulates pluripotency and differentiation mainly through four aspects, (1) controlling divergent transcriptional networks of pluripotency and differentiation; (2) interacting with chromatin modifiers to make the chromatin accessible or recruiting METTL3-METTL14-WTAP complex and depositing m6A to the mRNA of pluripotency genes; (3) acting as a transcription factor to activate endoderm-specific genes to thus initiate definitive endoderm differentiation, which happens as cyclin D/CDK4/6 downstream target in later G1 phase as well; (4) interacting with endoderm specific lncRNAs to promote differentiation. 10.3389/fcell.2020.00653
    The RNA mA Reader YTHDF2 Is Essential for the Post-transcriptional Regulation of the Maternal Transcriptome and Oocyte Competence. Ivanova Ivayla,Much Christian,Di Giacomo Monica,Azzi Chiara,Morgan Marcos,Moreira Pedro N,Monahan Jack,Carrieri Claudia,Enright Anton J,O'Carroll Dónal Molecular cell YTHDF2 binds and destabilizes N-methyladenosine (mA)-modified mRNA. The extent to which this branch of mA RNA-regulatory pathway functions in vivo and contributes to mammalian development remains unknown. Here we find that YTHDF2 deficiency is partially permissive in mice and results in female-specific infertility. Using conditional mutagenesis, we demonstrate that YTHDF2 is autonomously required within the germline to produce MII oocytes that are competent to sustain early zygotic development. Oocyte maturation is associated with a wave of maternal RNA degradation, and the resulting relative changes to the MII transcriptome are integral to oocyte quality. The loss of YTHDF2 results in the failure to regulate transcript dosage of a cohort of genes during oocyte maturation, with enrichment observed for the YTHDF2-binding consensus and evidence of mA in these upregulated genes. In summary, the mA-reader YTHDF2 is an intrinsic determinant of mammalian oocyte competence and early zygotic development. 10.1016/j.molcel.2017.08.003
    Nuclear m6A reader YTHDC1 regulates alternative polyadenylation and splicing during mouse oocyte development. Kasowitz Seth D,Ma Jun,Anderson Stephen J,Leu N Adrian,Xu Yang,Gregory Brian D,Schultz Richard M,Wang P Jeremy PLoS genetics The N6-methyladenosine (m6A) modification is the most prevalent internal RNA modification in eukaryotes. The majority of m6A sites are found in the last exon and 3' UTRs. Here we show that the nuclear m6A reader YTHDC1 is essential for embryo viability and germline development in mouse. Specifically, YTHDC1 is required for spermatogonial development in males and for oocyte growth and maturation in females; Ythdc1-deficient oocytes are blocked at the primary follicle stage. Strikingly, loss of YTHDC1 leads to extensive alternative polyadenylation in oocytes, altering 3' UTR length. Furthermore, YTHDC1 deficiency causes massive alternative splicing defects in oocytes. The majority of splicing defects in mutant oocytes are rescued by introducing wild-type, but not m6A-binding-deficient, YTHDC1. YTHDC1 is associated with the pre-mRNA 3' end processing factors CPSF6, SRSF3, and SRSF7. Thus, YTHDC1 plays a critical role in processing of pre-mRNA transcripts in the oocyte nucleus and may have similar non-redundant roles throughout fetal development. 10.1371/journal.pgen.1007412
    METTL3-mediated mA is required for murine oocyte maturation and maternal-to-zygotic transition. Sui Xuesong,Hu Yue,Ren Chao,Cao Qiqi,Zhou Shuai,Cao Yumeng,Li Mingrui,Shu Wenjie,Huo Ran Cell cycle (Georgetown, Tex.) N-methyladenosine (mA) is the most prevalent epigenetic modification of messenger RNA (mRNA) in higher eukaryotes; this modification is mainly catalyzed by a methyltransferase complex including methyltransferase-like 3 (METTL3) as a key factor. Although mA modification has been proven to play an essential role in diverse biological processes, our knowledge of is still limited because mutations are lethal to embryos in both mammals and plants. In this study, we knocked down by microinjection of its specific short interfering RNAs (siRNAs) or morpholino into fully grown germinal vesicle (GV) oocytes. As a result, we demonstrated that knocking down in female germ cells severely inhibited oocyte maturation by decreasing mRNA translation efficiency and led to defects in the maternal-to-zygotic transition, probably due to its interference in disrupting mRNA degradation. The discovery from this study suggests that the reversible mA modification has vital functions in mammalian oocyte maturation and pre-implantation embryonic development processes. 10.1080/15384101.2019.1711324
    YTHDF2 is essential for spermatogenesis and fertility by mediating a wave of transcriptional transition in spermatogenic cells. Zhao Xinxi,Lin Zhen,Fan Yong,Li Wenzhi,Zhang Yujie,Li Fei,Hong Tong,Feng Hua,Tong Minghan,Wang Ningling,Kuang Yanping,Lyu Qifeng Acta biochimica et biophysica Sinica The dynamic and reversible regulation roles of m6A modification and the characterization of m6A readers have provided new insights into spermatogenesis at the post-transcriptional level. YTHDF2, as an m6A reader, has been reported to mediate the m6A-containing transcript decay during the mouse oocyte maturation, embryonic stem cell differentiation, neural development, and zebrafish maternal-to-zygotic transition. However, the roles of YTHDF2 in mammalian spermatogenesis are uncertain. Here, we generated germ cell-specific Ythdf2 mutants (Ythdf2-vKO) at a C57BL/6J background and demonstrated that YTHDF2 is essential for mouse spermatogenesis and fertility. Ythdf2-vKO provides oligoasthenoteratozoospermia phenotype with increased apoptosis in germ cells. High-throughput RNA-seq analysis showed that a group of mRNAs is upregulated in Ythdf2-vKO mouse testis; further analysis and MeRIP-qPCR data showed that most of the upregulated genes in Ythdf2-vKO mouse testis are modified with m6A and are YTHDF2 candidate binding genes. Interestingly, RNA-seq analysis combined with our previous single-cell transcriptomics data of mouse spermatogenesis pointed out the failure of a wave of transcript transition during the spermatogenesis of Ythdf2-vKO mice, which was confirmed by gene expression analysis using qPCR of diplotene spermatocytes and round spermatids obtained through fluorescence-activated cell sorting. Our study demonstrates the fundamental role of YTHDF2 during mouse spermatogenesis and provides a potential candidate for the diagnosis of male infertility with the oligoasthenoteratozoospermia syndrome. 10.1093/abbs/gmab148
    N6-methyladenosine (mA) depletion regulates pluripotency exit by activating signaling pathways in embryonic stem cells. Jin Kang-Xuan,Zuo Rujuan,Anastassiadis Konstantinos,Klungland Arne,Marr Carsten,Filipczyk Adam Proceedings of the National Academy of Sciences of the United States of America N6-methyladenosine (mA) deposition on messenger RNA (mRNA) controls embryonic stem cell (ESC) fate by regulating the mRNA stabilities of pluripotency and lineage transcription factors (TFs) [P. J. Batista et al., 15, 707-719 (2014); Y. Wang et al., 16, 191-198 (2014); and S. Geula et al., 347, 1002-1006 (2015)]. If the mRNAs of these two TF groups become stabilized, it remains unclear how the pluripotency or lineage commitment decision is implemented. We performed noninvasive quantification of Nanog and Oct4 TF protein levels in reporter ESCs to define cell-state dynamics at single-cell resolution. Long-term single-cell tracking shows that immediate mA depletion by Mettl3 knock-down in serum/leukemia inhibitory factor supports both pluripotency maintenance and its departure. This is mediated by differential and opposing signaling pathways. Increased FGF5 mRNA stability activates pErk, leading to Nanog down-regulation. FGF5-mediated coactivation of pAkt reenforces Nanog expression. In formative stem cells poised toward differentiation, mA depletion activates both pErk and pAkt, increasing the propensity for mesendodermal lineage induction. Stable mA depletion by Mettl3 knock-out also promotes pErk activation. Higher pErk counteracts the pluripotency exit delay exhibited by stably mA-depleted cells upon differentiation. At single-cell resolution, we illustrate that decreasing mA abundances activates pErk and pAkt-signaling, regulating pluripotency departure. 10.1073/pnas.2105192118
    Smoke, alcohol and drug addiction and female fertility. de Angelis Cristina,Nardone Antonio,Garifalos Francesco,Pivonello Claudia,Sansone Andrea,Conforti Alessandro,Di Dato Carla,Sirico Felice,Alviggi Carlo,Isidori Andrea,Colao Annamaria,Pivonello Rosario Reproductive biology and endocrinology : RB&E BACKGROUND:Considerable interest has been gathered on the relevant impact of preventable factors, including incorrect lifestyle and unhealthy habits, on female fertility. Smoking, alcohol and addictive drugs consumption represent a major concern, given the broad range of diseases which might be favored or exacerbated by these dependable attitudes. Despite the well-characterized effects of prenatal exposure on pregnancy outcomes and fetus health, a substantial proportion of women of reproductive age is still concerned with these habits. At present, the impact of smoke, alcohol and addictive drugs on women fertility, and, particularly, the specific targets and underlying mechanisms, are still poorly understood or debated, mainly due to the scarcity of well-designed studies, and to numerous biases. OBJECTIVE:The current review will provide a comprehensive overview of clinical and experimental studies in humans and animals addressing the impact of smoke, alcohol and addictive drugs on female fertility, by also embracing effects on ovary, oviduct, and uterus, with particular reference to primary endpoints such as ovarian reserve, steroidogenesis, ovulation and menstrual cycle, oviduct function and uterus receptivity and implantation. A brief focus on polycystic ovary syndrome and endometriosis will be also included. METHODS:A Pubmed literature search was performed with selected keywords; articles were individually retrieved by each author. No limitation was set for publication date. Articles in languages other than English were excluded. Additional articles were retrieved from references list of selected manuscripts. RESULTS AND CONCLUSIONS:Currently, the most consistent evidences of a detrimental effect of smoke, alcohol and addictive drugs on specific domains of the female reproductive function are provided by experimental studies in animals. Overall, clinical studies suggest that smoking is associated to decreased fertility, although causal inference should be further demonstrated. Studies addressing the effect of alcohol consumption on female fertility provide conflicting results, although the majority reported lack of a correlation. Extremely scarce studies investigated the effects of addictive drugs on female fertility, and the specific actions of selected drugs have been difficult to address, due to multidrug consumption. 10.1186/s12958-020-0567-7
    Interplay between oxidative stress, SIRT1, reproductive and metabolic functions. Alam Faiza,Syed Hareem,Amjad Sofia,Baig Mukhtiar,Khan Taseer Ahmed,Rehman Rehana Current research in physiology Silent information Regulators (SIRT1) gene stimulates antioxidants' expression, repairs cells damaged by oxidative stress (OS), and prevents the cells' dysfunction. In particular, the role of different Sirtuins, particularly SIRT1 in reproduction, has been widely studied over the past decade. Decreased SIRT 1 causes mitochondrial dysfunction by increasing Reactive Oxygen Species (ROS), lipid peroxidation, and DNA damage in both male and female gametes (Sperms and Oocytes), leading to infertility. In the female reproductive system, SIRT1 regulates proliferation and apoptosis in granulosa cells (GCs), and its down-regulation is associated with a reduced ovarian reserve. SIRT1 also modulates the stress response to OS in GCs by targeting a transcription factor vital for ovarian functions and maintenance. ROS-mediated damage to spermatozoa's motility and morphology is responsible for 30-80% of men's infertility cases. High levels of ROS can cause damage to deoxyribo nucleic acid (DNA) in the nucleus and mitochondria, lipid peroxidation, apoptosis, inactivation of enzymes, and oxidation of proteins in spermatozoa. SIRT 1 is a cardioprotective molecule that prevents atherosclerosis by modulating various mechanisms such as endothelial injury due to impaired nitric oxide (NO) production, inflammation, OS, and regulation of autophagy. SIRT 1 is abundantly expressed in tubular cells and podocytes. It is also found to be highly expressed in aquaporin 2 positive cells in the distal nephron suggesting its involvement in sodium and water handling. SIRT1 improves insulin resistance by reducing OS and regulating mitochondrial biogenesis and function. It also decreases adiposity and lipogenesis and increases fatty acid oxidation. So, its involvement in the multiple pathways ensures its unique role in reproductive and metabolic derangement mechanisms. 10.1016/j.crphys.2021.03.002
    Impact of Obesity on Anti-Mullerian Hormone (AMH) Levels in Women of Reproductive Age. Oldfield Alexis L,Kazemi Maryam,Lujan Marla E Journal of clinical medicine Obesity negatively impacts reproductive health, including ovarian function. Obesity has been posited to alter Anti-Müllerian hormone (AMH) production. Understanding biological factors that could impact AMH levels is necessary given the increasing use of AMH for predicting reproductive health outcomes in response to controlled ovarian stimulation, diagnosing ovulatory disorders, onset of menopause, and natural conception. In this narrative review, we evaluated the impact of obesity on AMH levels in healthy, regularly cycling reproductive-age women (18-48 years). Thirteen studies ( = 1214 women; (811, non-obese (body mass index; BMI < 30 kg/m); 403, obese (BMI > 30 kg/m))) were included, of which five reported decreased AMH levels with obesity, whereas eight showed comparable AMH levels between groups. Inclusion of women with higher obesity classes (Class 3 versus Class 1) may have been a factor in studies reporting lower AMH levels. Together, studies reporting AMH levels in otherwise healthy women remain limited by small sample sizes, cross-sectional designs, and lack of representation across the entire adiposity spectrum. Ultimately, the degree to which obesity may negatively impact AMH levels, and possibly ovarian reserve, in otherwise healthy women with regular menstrual cycles should be deemed uncertain at this time. This conclusion is prudent considering that the biological basis for an impact of obesity on AMH production is unknown. 10.3390/jcm10143192
    Mitochondria: emerging therapeutic strategies for oocyte rescue. Jiang Zhixin,Shen Huan Reproductive sciences (Thousand Oaks, Calif.) As the vital organelles for cell energy metabolism, mitochondria are essential for oocyte maturation, fertilization, and embryo development. Abnormalities in quantity, quality, and function of mitochondria are closely related to poor fertility and disorders, such as decreased ovarian reserve (DOR), premature ovarian aging (POA), and ovarian aging, as well as maternal mitochondrial genetic disease caused by mitochondrial DNA (mtDNA) mutations or deletions. Mitochondria have begun to become a therapeutic target for infertility caused by factors such as poor oocyte quality, oocyte aging, and maternal mitochondrial genetic diseases. Mitochondrial replacement therapy (MRT) has attempted to use heterologous or autologous mitochondria to rebuild healthy state of oocyte by increasing the amount of mitochondria (e.g., partial ooplasm transfer, autologous mitochondrial transfer), or to stop the transmission of mtDNA diseases by replacing abnormal maternal mitochondria (e.g., pronuclei transfer, spindle transfer, polar body transfer). Among them, autologous mitochondrial transfer is the most promising therapeutic technology as of today which does not involve using a third party, but its clinical efficacy is controversial due to many factors such as the aging phenomenon of germ line cells, the authenticity of the existence of ovarian stem cells (OSC), and secondary damage caused by invasive surgery to patients with poor ovarian function. Therefore, the research of optimal autologous cell type that can be applied in autologous mitochondrial transfer is an area worthy of further exploration. Besides, the quality of germ cells can also be probably improved by the use of compounds that enhance mitochondrial activity (e.g., coenzyme Q10, resveratrol, melatonin), or by innovative gene editing technologies which have shown capability in reducing the risk of mtDNA diseases (e.g., CRISPR/Cas9, TALENTs). Though the current evidences from animal and clinical trials are not sufficient, and some solutions of technical problems are still needed, we believe this review will guide a new direction in the possible clinical applied mitochondrial-related therapeutic strategies in reproductive medicine. 10.1007/s43032-021-00523-4
    Decreased expression of mA demethylase FTO in ovarian aging. Sun Xiaoyan,Zhang Yigan,Hu Yuping,An Junxia,Li Lifei,Wang Yiqing,Zhang Xuehong Archives of gynecology and obstetrics PURPOSE:N6-methyladenosine (mA) and demethylase fat mass and obesity-associated protein (FTO) were reported to be associated with oocyte development and maturation. But the relationship between FTO and ovarian aging was still unclear. This study was aimed at investigating the FTO expression level and the mA content during ovarian aging. METHODS:The expression level of FTO and the content of mA RNA methylation in human follicular fluid (FF), granulosa cells (GCs) and mouse ovary from different age groups were studied by ELISA, WB, qRT-PCR, IHC and mA Colorimetric. RESULTS:Human FF ELISA quantified that the level of FTO protein decreased with age (P = 0.025). QRT-PCR results showed that the relative expression of FTO in human GCs was lower in the elderly group than in the young group (P = 0.012). FTO mRNA and protein expression levels were lower in the ovary of 32-week-old mice than in 3- and 8-week-old mice (P < 0.05). Immunohistochemistry showed FTO was relatively decreased in 32-week-old mice (P < 0.05). The mA content in total RNA from old human GCs and ovary from 32-week-old mice was significantly higher compared with the younger ones. CONCLUSIONS:In human FF, GCs and mouse ovary, the expression of FTO decreased while the content of mA increased with aging. However, the inner mechanism still needs further investigation. 10.1007/s00404-020-05895-7
    Identification and functional annotation of m6A methylation modification in granulosa cells during antral follicle development in pigs. Cao Zubing,Zhang Dandan,Wang Yiqing,Tong Xu,Avalos Lourdes Felicidad Córdova,Khan Ibrar Muhammad,Gao Di,Xu Tengteng,Zhang Ling,G Knott Jason,Zhang Yunhai Animal reproduction science The N-methyladenosine (m6A) derivative has the capacity for ubiquitous epigenetic modification of messenger RNA (mRNA) that regulates gene expression through post-transcriptional mRNA modifications. Findings with mapping of m6A methylomes have indicated there are potential functions of this derivative in different cell types of several species. A profile of m6A methylomes and potential functions in granulosa cells of pigs during antral follicle development, however, has not yet occurred. In the present study, there was profiling of an epitranscriptome-wide map of m6A methylation in granulosa cells of pigs derived from small and large follicles using methylated RNA immunoprecipitation techniques, next-generation sequencing and further annotation of the potential functions of m6A utilizing bioinformatic analyses procedures. The m6A modification is abundant in granulosa cells of pigs, and there are dynamic changes in m6A methylomes during the developmental transition from small (< 3 mm) to large (> 5 mm) sized follicles. In particular, there was a prevalence of 7289 and 6882 m6A in granulosa cells from follicles of two different sizes. There was an increased prevalence of m6A in close proximity to the 5' or 3'-untranslated coding regions and a shared conserved consensus motif. Results from further analysis indicated there was significant enrichment of differentially expressed m6A methylated genes in several signaling pathways associated with steroidogenesis, granulosa cell proliferation and follicular development. When considered as a whole, these results indicate there are differential m6A modifications in granulosa cells of pigs during follicle development that are potentially associated with steroidogenesis and folliculogenesis. 10.1016/j.anireprosci.2020.106510
    Characterization of m6A in mouse ovary and testis. Sun Xiaofeng,Zhang Jiaona,Jia Yong,Shen Wei,Cao Hongguo Clinical and translational medicine 10.1002/ctm2.141
    Profiling of RNA N6-methyladenosine methylation during follicle selection in chicken ovary. Fan Yu,Zhang Chuansheng,Zhu Guiyu Poultry science Ovarian follicle selection is the critical step which determines the oocyte development and ovulation. In avian species, the somatic cells in the follicles decide the process of follicle selection but the precise molecular regulation is not well defined. N6-methyladenosine (m6A) is a ubiquitous reversible epigenetic RNA modification that plays an important role in the gene expression regulation and cell functions. In this study, we profiled transcriptome-wide m6A methylation in chicken follicles during follicular selection process in order to identify key factors involved in the follicle selection. The chicken follicle transcriptome was extensively methylated by m6A and a negative correlation was found between the m6A methylation enrichment and gene expression levels. Interestingly, both the m6A methylation peaks and the m6A modified transcripts increased during follicle selection, which lead to the dynamic expression of many folliculogenesis relevant genes. Functional enrichment analysis indicated that m6A modification of key factors in Wnt pathway could play a major role in regulating follicle selection. This study is the first to comprehensively characterize the m6A patterns in the chicken transcriptome, and provides deep insights into the m6A topology and relevant molecular mechanisms underlying follicle selection. 10.3382/ps/pez277
    -Methyladenosine Level in Silkworm Midgut/Ovary Cell Line Is Associated With Nucleopolyhedrovirus Infection. Zhang Xing,Zhang Yunshan,Dai Kun,Liang Zi,Zhu Min,Pan Jun,Zhang Mingtian,Yan Bingyu,Zhu Hanxue,Zhang Ziyao,Dai Yaping,Cao Manman,Gu Yuchao,Xue Renyu,Cao Guangli,Hu Xiaolong,Gong Chengliang Frontiers in microbiology nucleopolyhedrovirus (BmNPV) is one of the most serious pathogens in sericulture and causes huge economic loss annually. The roles of N6-methyladenosine (m6A) modification in silkworms following BmNPV infection are currently unclear. Here, methylated RNA immunoprecipitation with next-generation sequencing were applied to investigate the m6A profiles in silkworm midgut following BmNPV infection. A total of 9144 and 7384 m6A peaks were identified from the BmNPV-infected (TEST) and uninfected silkworm midguts (CON), respectively, which were distributed predominantly near stop codons. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of common m6A peaks in nuclear genes revealed that these m6A-related transcripts were associated with crucial signaling pathways. Comparative transcriptome analysis showed that 1221 differential expressed m6A peaks were identified between TEST and CON, indicating that m6A modification is regulated following BmNPV infection. GO and KEGG pathway analysis of the differentially expressed m6A peaks showed their association with signal transduction, translation, and degradation. To understand further the effect of the m6A machinery on virus infection, expression levels of m6A-related genes were altered in silencing and overexpression experiments. Expression of viral structural protein VP39 was increased in BmN cells by siRNA-mediated depletion of methyltransferase-like (METTL) enzyme genes (BmMETTL3, BmMETTL14) and cytoplasmic YTH-domain family 3 (BmYTHDF3), while the reverse results were found after overexpression of the m6A-related enzymes in BmN cells. Overall, m6A modification might be a novel epigenetic mechanism that regulation BmNPV infection and interference with this mechanism may provide a novel antiviral strategy for preventing BmNPV disease. 10.3389/fmicb.2019.02988
    Critical roles of mRNA mA modification and YTHDC2 expression for meiotic initiation and progression in female germ cells. Zeng Ming,Dai Xin,Liang Zhibing,Sun Ruliang,Huang Sui,Luo Liangping,Li Zhongxiang Gene Meiotic entry and progression require dynamic regulation of germline gene expression. mA on mRNAs and recognition by YTHDC2 has been known as post-transcriptional regulatory complex, but the roles of this regulator remain unclear for meiotic initiation and progression in female germ cells (FGCs). This study showed that mA modification occurred mainly in FGCs rather than ovarian somatic cells (SOMAs), and mA levels in FGCs increased significantly with meiotic initiation. mA inhibition suppressed expression of the meiotic markers and affected the percent of FGCs at zygotene, pachytene and diplotene stage respectively. YTHDC2 expression also increased in the same pattern with mA. Ythdc2 knockdown decreased the percent of STRA8-positive FGCs and altered the percent of FGCs at zygotene and pachytene stage respectively. Taken together, these results suggest that mRNA mA modification and YTHDC2 expression are essential for meiotic initiation and progression in FGCs. 10.1016/j.gene.2020.144810
    The mA pathway facilitates sex determination in Drosophila. Kan Lijuan,Grozhik Anya V,Vedanayagam Jeffrey,Patil Deepak P,Pang Nan,Lim Kok-Seong,Huang Yi-Chun,Joseph Brian,Lin Ching-Jung,Despic Vladimir,Guo Jian,Yan Dong,Kondo Shu,Deng Wu-Min,Dedon Peter C,Jaffrey Samie R,Lai Eric C Nature communications The conserved modification N-methyladenosine (mA) modulates mRNA processing and activity. Here, we establish the Drosophila system to study the mA pathway. We first apply miCLIP to map mA across embryogenesis, characterize its mA 'writer' complex, validate its YTH 'readers' CG6422 and YT521-B, and generate mutants in five mA factors. While mA factors with additional roles in splicing are lethal, mA-specific mutants are viable but present certain developmental and behavioural defects. Notably, mA facilitates the master female determinant Sxl, since multiple mA components enhance female lethality in Sxl sensitized backgrounds. The mA pathway regulates Sxl processing directly, since miCLIP data reveal Sxl as a major intronic mA target, and female-specific Sxl splicing is compromised in multiple mA pathway mutants. YT521-B is a dominant mA effector for Sxl regulation, and YT521-B overexpression can induce female-specific Sxl splicing. Overall, our transcriptomic and genetic toolkit reveals in vivo biologic function for the Drosophila mA pathway. 10.1038/ncomms15737
    Novel circGFRα1 Promotes Self-Renewal of Female Germline Stem Cells Mediated by mA Writer METTL14. Li Xiaoyong,Tian Geng,Wu Ji Frontiers in cell and developmental biology Circular RNAs (circRNAs) play important roles in the self-renewal of stem cells. However, their significance and regulatory mechanisms in female germline stem cells (FGSCs) are largely unknown. Here, we identified an -methyladenosine (mA)-modified circRNA, circGFRα1, which is highly abundant in mouse ovary and stage-specifically expressed in mouse FGSC development. Knockdown of circGFRα1 in FGSCs significantly reduced their self-renewal. In contrast, overexpression of circGFRα1 enhanced FGSC self-renewal. Mechanistically, circGFRα1 promotes FGSC self-renewal by acting as a competing endogenous RNA (ceRNA) that sponges miR-449, leading to enhanced GFRα1 expression and activation of the glial cell derived neurotrophic factor (GDNF) signaling pathway. Furthermore, circGFRα1 acts as a ceRNA based on METTL14-mediated cytoplasmic export through the GGACU motif. Our study should help to understand the mechanisms regulating germ cell development, add new evidence on the mechanism of action of circRNA, and deepen our understanding of the development of FGSCs. 10.3389/fcell.2021.640402
    Oocyte competence is maintained by mA methyltransferase KIAA1429-mediated RNA metabolism during mouse follicular development. Hu Yue,Ouyang Zhangyi,Sui Xuesong,Qi Meijie,Li Mingrui,He Yuanlin,Cao Yumeng,Cao Qiqi,Lu Qianneng,Zhou Shuai,Liu Lu,Liu Li,Shen Bin,Shu Wenjie,Huo Ran Cell death and differentiation KIAA1429 (also known as vir-like mA methyltransferase-associated protein (VIRMA)), a newly identified component of the RNA mA methyltransferase complex, plays critical roles in guiding region-selective mA deposition. However, in mammals, whether KIAA1429 mediates RNA mA regulatory pathway functions in vivo remains unknown. Here, we show that the Kiaa1429-specific deficiency in oocytes resulted in female infertility with defective follicular development and fully grown germinal vesicle (GV) oocytes failing to undergo germinal vesicle breakdown (GVBD) and consequently losing the ability to resume meiosis. The oocyte growth is accompanied by the accumulation of abundant RNAs and posttranscriptional regulation. We found that the loss of Kiaa1429 could also lead to abnormal RNA metabolism in GV oocytes. RNA-seq profiling revealed that Kiaa1429 deletion altered the expression pattern of the oocyte-derived factors essential for follicular development. In addition, our data show that the conditional depletion of Kiaa1429 decreased the mA levels in oocytes and mainly affected the alternative splicing of genes associated with oogenesis. In summary, the mA methyltransferase KIAA1429-mediated RNA metabolism plays critical roles in folliculogenesis and the maintenance of oocyte competence. 10.1038/s41418-020-0516-1
    Sex-Dependent RNA Editing and -adenosine RNA Methylation Profiling in the Gonads of a Fish, the Olive Flounder (). Wang Lijuan,Wu Zhihao,Zou Congcong,Liang Shaoshuai,Zou Yuxia,Liu Yan,You Feng Frontiers in cell and developmental biology Adenosine-to-inosine (A-to-I) editing and -methyladenosine (m6A) are two of the most abundant RNA modifications. Here, we examined the characteristics of the RNA editing and transcriptome-wide m6A modification profile in the gonads of the olive flounder, , an important maricultured fish in Asia. The gonadal differentiation and development of the flounder are controlled by genetic as well as environmental factors, and the epigenetic mechanism may play an important role. In total, 742 RNA editing events were identified, 459 of which caused A to I conversion. Most A-to-I sites were located in 3'UTRs, while 61 were detected in coding regions (CDs). The number of editing sites in the testis was higher than that in the ovary. Transcriptome-wide analyses showed that more than one-half of the transcribed genes presented an m6A modification in the flounder gonads, and approximately 60% of the differentially expressed genes (DEGs) between the testis and ovary appeared to be negatively correlated with m6A methylation enrichment. Further analyses revealed that the mRNA expression of some sex-related genes (e.g., and ) in the gonads may be regulated by changes in mRNA m6A enrichment. Functional enrichment analysis indicated that the RNA editing and m6A modifications were enriched in several canonical pathways (e.g., Wnt and MAPK signaling pathways) in fish gonads and in some pathways whose roles have not been investigated in relation to fish sex differentiation and gonadal development (e.g., PPAR and RNA degradation pathways). There were 125 genes that were modified by both A-to-I editing and m6A, but the two types of modifications mostly occurred at different sites. Our results suggested that the presence of sex-specific RNA modifications may be involved in the regulation of gonadal development and gametogenesis. 10.3389/fcell.2020.00751
    Increased N6-methyladenosine causes infertility is associated with FTO expression. Ding Chenyue,Zou Qinyan,Ding Jie,Ling Mingfa,Wang Wei,Li Hong,Huang Boxian Journal of cellular physiology The N6-methyladenosine (m6A) modification plays a central role in epigenetic regulation of the mammalian transcriptome. m6A can be demethylated by the fat mass- and obesity-associated (FTO) protein and the α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) protein. Much less is known about that whether m6A content is involved in POI (premature ovarian insufficiency) disease. In this case-controlled study, 69 POI and 53 tubal occlusion patients were recruited from the reproduction centers in our hospital. For the POI animal model experiment, ovarian tissue was obtained from ten POI and nine healthy mice. An m6A test kit was developed to determine the m6A content in the RNA, and qPCR and western blot were used to examine the mRNA and protein expression levels of FTO and ALKBH5. FACS was used to measure the levels of proliferation and apoptosis, and siRNA was used to establish FTO and ALKBH5 knockdown cell lines. Our results showed that the m6A content in the RNA from POI patients and POI mice was significantly higher than control groups and that POI was characterized by the content of m6A. The mRNA and protein expression levels of FTO were significantly lower in the POI patients than control group and were associated with a risk of POI. These data suggest that the decreased mRNA and protein expression levels of FTO may be responsible for the increase in m6A in POI, which may further increase the risk of complications of POI. High m6A should be investigated further as a novel potential biomarker of POI. 10.1002/jcp.26507
    M6 membrane protein plays an essential role in Drosophila oogenesis. Zappia María Paula,Brocco Marcela Adriana,Billi Silvia C,Frasch Alberto C,Ceriani María Fernanda PloS one We had previously shown that the transmembrane glycoprotein M6a, a member of the proteolipid protein (PLP) family, regulates neurite/filopodium outgrowth, hence, M6a might be involved in neuronal remodeling and differentiation. In this work we focused on M6, the only PLP family member present in Drosophila, and ortholog to M6a. Unexpectedly, we found that decreased expression of M6 leads to female sterility. M6 is expressed in the membrane of the follicular epithelium in ovarioles throughout oogenesis. Phenotypes triggered by M6 downregulation in hypomorphic mutants included egg collapse and egg permeability, thus suggesting M6 involvement in eggshell biosynthesis. In addition, RNAi-mediated M6 knockdown targeted specifically to follicle cells induced an arrest of egg chamber development, revealing that M6 is essential in oogenesis. Interestingly, M6-associated phenotypes evidenced abnormal changes of the follicle cell shape and disrupted follicular epithelium in mid- and late-stage egg chambers. Therefore, we propose that M6 plays a role in follicular epithelium maintenance involving membrane cell remodeling during oogenesis in Drosophila. 10.1371/journal.pone.0019715
    Female subfertility. Farquhar Cynthia M,Bhattacharya Siladitya,Repping Sjoerd,Mastenbroek Sebastiaan,Kamath Mohan S,Marjoribanks Jane,Boivin Jacky Nature reviews. Disease primers Subfertility is common and affects one in six couples, half of whom lack an explanation for their delay in conceiving. Developments in the diagnosis and treatment of subfertility over the past 50 years have been truly remarkable. Indeed, current generations of couples with subfertility are more fortunate than previous generations, as they have many more opportunities to become parents. The timely access to effective treatment for subfertility is important as many couples have a narrow window of opportunity before the age-related effects of subfertility limit the likelihood of success. Assisted reproduction can overcome the barriers to fertility caused by tubal disease and low sperm count, but little progress has been made in reducing the effect of increasing age on ovarian function. The next 5-10 years will likely see further increases in birth rates in women with subfertility, a greater awareness of lifestyle factors and a possible refinement of current assisted reproduction techniques and the development of new ones. Such progress will bring challenging questions regarding the potential benefits and harms of treatments involving germ cell manipulation, artificial gametes, genetic screening of embryos and gene editing of embryos. We hope to see a major increase in fertility awareness, access to safe and cost-effective fertility care in low-income countries and a reduction in the current disparity of access to fertility care. 10.1038/s41572-018-0058-8
    Study on the Reparative Effect of PEGylated Growth Hormone on Ovarian Parameters and Mitochondrial Function of Oocytes From Rats With Premature Ovarian Insufficiency. Feng Penghui,Xie Qiu,Liu Zhe,Guo Zaixin,Tang Ruiyi,Yu Qi Frontiers in cell and developmental biology Premature ovarian insufficiency (POI) is a heterogeneous disorder and lacks effective interventions in clinical applications. This research aimed to elucidate the potential effects of recombinant human PEGylated growth hormone (rhGH) on follicular development and mitochondrial function in oocytes as well as ovarian parameters in POI rats induced by the chemotherapeutic agent. The impacts of rhGH on ovarian function before superovulation on follicles, estrous cycle, and sex hormones were evaluated. Oocytes were retrieved to determine oocyte quality and oxidative stress parameters. Single-cell sequencing was applied to investigate the latent regulatory network. This study provides new evidence that a high dosage of rhGH increased the number of retrieved oocytes even though it did not completely restore the disturbed estrous cycle and sex hormones. rhGH attenuated the apoptosis of granulosa cells and oxidative stress response caused by reactive oxygen species (ROS) and mitochondrial superoxide. Additionally, rhGH modulated the energy metabolism of oocytes concerning the mitochondrial membrane potential and ATP content but not mtDNA copy numbers. Based on single-cell transcriptomic analysis, we found that rhGH directly or indirectly promoted the balance of oxidative stress and cellular oxidant detoxification. Four hub genes, Pxmp4, Ehbp1, Mt-cyb, and Enpp6, were identified to be closely related to the repair process in oocytes as potential targets for POI treatment. 10.3389/fcell.2021.649005
    Current Understanding of the Etiology, Symptomatology, and Treatment Options in Premature Ovarian Insufficiency (POI). Ishizuka Bunpei Frontiers in endocrinology Premature ovarian insufficiency (POI) occurs in at least 1% of all women and causes life-long health problems and psychological stress. Infertility caused by POI used to be considered absolute, with infertility treatment having little or no value. Generally, it has been thought that medicine can provide little service to these patients. The etiology of POI has been found to be genetic, chromosomal, and autoimmune. In addition, the increasing numbers of cancer survivors are candidates for iatrogenic POI, along with patients who have undergone ovarian surgery, especially laparoscopic surgery. Over 50 genes are known to be causally related to POI, and the disease course of some cases has been clarified, but in most cases, the genetic background remains unexplained, suggesting that more genes associated with the etiology of POI need to be discovered. Thus, in most cases, the genetic background of POI has not been clarified. Monosomy X is well known to manifest as Turner's syndrome and is associated with primary amenorrhea, but recent studies have shown that some women with numerical abnormalities of the X chromosome can have spontaneous menstruation up to their twenties and thirties, and some even conceive. Hormone replacement therapy (HRT) is recommended for women with POI from many perspectives. It alleviates vasomotor and genitourinary symptoms and prevents bone loss and cardiovascular disease. POI has been reported to reduce quality of life and life expectancy, and HRT may help improve both. Most of the problems that may occur with HRT in postmenopausal women do not apply to women with POI; thus, in POI, HRT should be considered physiological replacement of estrogen (+progesterone). This review describes some new approaches to infertility treatment in POI patients that may lead to new treatments for POI, along with the development of more sensitive markers of secondary/preantral follicles and genetic diagnosis. 10.3389/fendo.2021.626924
    Deficiency Leads to Premature Ovarian Failure. Liu Linlin,Wang Huasong,Xu Guo Liang,Liu Lin Frontiers in cell and developmental biology Tet enzymes participate in DNA demethylation and play critical roles in stem cell pluripotency and differentiation. DNA methylation alters with age. We find that deficiency reduces fertility and leads to accelerated reproductive failure with age. Noticeably, -deficient mice at young age exhibit dramatically reduced follicle reserve and the follicle reserve further decreases with age, phenomenon consistent with premature ovarian failure (POF) syndrome. Consequently, deficient mice become infertile by reproductive middle age, while age matched wild-type mice still robustly reproduce. Moreover, by single cell transcriptome analysis of oocytes, deficiency elevates organelle fission, associated with defects in ubiquitination and declined autophagy, and also upregulates signaling pathways for Alzheimer's diseases, but down-regulates X-chromosome linked genes, such as , which is known to be implicated in POF. Additionally, is aberrantly upregulated and endogenous retroviruses also are altered in deficient oocytes. These molecular changes are consistent with oocyte senescence and follicle atresia and depletion found in premature ovarian failure or insufficiency. Our data suggest that enzyme plays roles in maintaining oocyte quality as well as oocyte number and follicle reserve and its deficiency can lead to POF. 10.3389/fcell.2021.644135
    Urinary trace elements in association with premature ovarian insufficiency and reproductive hormones in a Chinese population. Li Chunming,Ma LinJuan,Qi Tongyun,Pan Wuye,Huang Yizhou,Luo Jie,Ye Xiaoqing,Lan Yibing,Liu Jing,Zhou Wenchao,Ruan Fei,Zhou Jianhong Ecotoxicology and environmental safety Homeostasis disturbance of trace elements has been linked to adverse reproductive consequences, including premature ovarian insufficiency (POI) in women, but limited evidence has been reported so far. This case-control study evaluated the associations between 5 common urinary trace elements [copper (Cu), manganese (Mn), Iron (Fe), Selenium (Se), and zinc (Zn)] and the odds for POI. Urinary concentrations of these 5 metals and serum levels of POI-related reproductive hormones of 169 cases and 209 healthy controls were measured. The urinary levels of Cu and Se in women with POI were significantly higher than those in the controls. The positive associations were observed between Cu levels and the odds of POI [for the medium tertile: odds ratio (OR) = 3.79, 95% CI: 1.98-7.27, p < 0.001; for the highest tertile: OR = 3.85, 95% CI: 2.00-7.41, p < 0.001]. The highest tertile of urinary Se levels was associated with increasing POI risk (for the highest tertile: OR = 2.54, 95% CI: 1.38-4.70, compared with the lowest tertile, p for trend = 0.001). In POI patients, urinary concentrations of Zn and Fe were negatively associated with serum levels of follicle-stimulating hormone (FSH). Our findings suggested that higher exposure levels of Cu and Se might lead to an increased risk of POI. 10.1016/j.ecoenv.2021.112731
    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
    Homozygous variants in cause premature ovarian insufficiency. He Wen-Bin,Tan Chen,Zhang Ya-Xin,Meng Lan-Lan,Gong Fei,Lu Guang-Xiu,Lin Ge,Du Juan,Tan Yue-Qiu Journal of medical genetics BACKGROUND:The genetic causes of the majority of cases of female infertility caused by premature ovarian insufficiency (POI) are unknown. OBJECTIVE:To identify the genetic causes of POI in 110 patients. METHODS:Whole-exome sequencing was performed on 110 patients with POI, and putative disease-causative variants were validated by Sanger sequencing. Bioinformatic and in vitro functional analyses were performed for functional characterisation of the identified candidate disease-causative variants. RESULTS:We identified two homozygous variants (NM_001040274: c.150_151del (p.Ser52Profs*7), c.999A>G (p.Ile333Met)) in in two patients, which had co-segregated with POI in these families. Bioinformatic analysis predicted that the two variants are deleterious, and in vitro functional analysis showed that mutant SYCP2L proteins exhibited mislocalisation and loss of function. CONCLUSIONS: is a novel gene found to be responsible for human POI. Our findings provide a potential molecular marker for POI and improve the understanding of the genetic basis of female infertility. 10.1136/jmedgenet-2019-106789
    Rare deleterious BUB1B variants induce premature ovarian insufficiency and early menopause. Chen Qing,Ke Hanni,Luo Xuezhen,Wang Lingbo,Wu Yanhua,Tang Shuyan,Li Jinsong,Jin Li,Zhang Feng,Qin Yingying,Chen Xiaojun Human molecular genetics Losing of ovarian functions prior to natural menopause age causes female infertility and early menopause. Premature ovarian insufficiency (POI) is defined as the loss of ovarian activity before 40 years of age. Known genetic causes account for 25-30% of POI cases, demonstrating the high genetic heterogeneity of POI and the necessity for further genetic explorations. Here we conducted genetic analyses using whole-exome sequencing in a Chinese non-syndromic POI family with the affected mother and at least four affected daughters. Intriguingly, a rare missense variant of BUB1B c.273A>T (p.Gln91His) was shared by all the cases in this family. Furthermore, our replication study using targeted sequencing revealed a novel stop-gain variant of BUB1B c.1509T>A (p.Cys503*) in one of 200 sporadic POI cases. Both heterozygous BUB1B variants were evaluated to be deleterious by multiple in silico tools. BUB1B encodes BUBR1, a crucial spindle assembly checkpoint component involved in cell division. BUBR1 insufficiency may induce vulnerability to oxidative stress. Therefore, we generated a mouse model with a loss-of-function mutant of Bub1b, and also employed D-galactose-induced aging assays for functional investigations. Notably, Bub1b+/- female mice presented late-onset subfertility, and they were more sensitive to oxidative stress than wild-type female controls, mimicking the clinical phenotypes of POI cases affected by deleterious BUB1B variants. Our findings in human cases and mouse models consistently suggest, for the first time, that heterozygous deleterious variants of BUB1B are involved in late-onset POI and related disorders. 10.1093/hmg/ddaa153
    Low-Intensity Pulsed Ultrasound Promotes Repair of 4-Vinylcyclohexene Diepoxide-Induced Premature Ovarian Insufficiency in SD Rats. The journals of gerontology. Series A, Biological sciences and medical sciences Women with premature ovarian insufficiency (POI) may be more vulnerable to a variety of health risks. To seek a new method to treat the disease, the effects of low-intensity pulsed ultrasound (LIPUS) on promoting repair of ovarian injury in female SD rats induced by 4-vinylcyclohexene diepoxide (VCD) were explored in this research. A total of 24 female SD rats were subjected to intraperitoneal injection of VCD to induce POI. Successful modeling was achieved in 22 rats, which were then randomized into VCD + LIPUS group (n = 13) and VCD group (n = 9). The control group (n = 5) was injected with equal normal saline. Hematoxylin and eosin staining, enzyme-linked immunosorbent assay, Western blot analysis, scanning electron microscope, immunohistochemistry, and terminal deoxynucleotidyl transferase-mediated nick end labeling assay were applied to detect the results. The results indicated that rats in the VCD group showed disorder in the estrous cycle, the number of atresia follicles and apoptosis granulosa cells increased (p < .05). After the LIPUS treatment, the estrous cycle recovered, the number of follicles increased (p < .05), the level of E2 and anti-Müllerian hormone enhanced (p < .05), and the follicle-stimulating hormone decreased (p < .05). The expression of NF-κB p65, TNFα, Bax, ATF4, and caspase-3 in ovarian tissue was significantly decreased (p < .05). These findings showed that LIPUS could promote the repair of the VCD-induced ovarian damage in SD rats, which has the potential to be further applied in the clinic. 10.1093/gerona/glab242
    Pathogenic variants of meiotic double strand break (DSB) formation genes PRDM9 and ANKRD31 in premature ovarian insufficiency. Wang Yiyang,Guo Ting,Ke Hanni,Zhang Qian,Li Shan,Luo Wei,Qin Yingying Genetics in medicine : official journal of the American College of Medical Genetics PURPOSE:The etiology of premature ovarian insufficiency (POI) is heterogeneous, and genetic factors account for 20-25% of the patients. The primordial follicle pool is determined by the meiosis process, which is initiated by programmed DNA double strand breaks (DSB) and homologous recombination. The objective of the study is to explore the role of DSB formation genes in POI pathogenesis. METHODS:Variants in DSB formation genes were analyzed from a database of exome sequencing in 1,030 patients with POI. The pathogenic effects of the potentially causative variants were verified by further functional studies. RESULTS:Three pathogenic heterozygous variants in PRDM9 and two in ANKRD31 were identified in seven patients. Functional studies showed the variants in PRDM9 impaired its methyltransferase activity, and the ANKRD31 variations disturbed its interaction with another DSB formation factor REC114 by haploinsufficiency effect, indicating the pathogenic effects of the two genes on ovarian function were dosage dependent. CONCLUSION:Our study identified pathogenic variants of PRDM9 and ANKRD31 in POI patients, shedding new light on the contribution of meiotic DSB formation genes in ovarian development, further expanding the genetic architecture of POI. 10.1038/s41436-021-01266-y
    Hormone Replacement Therapy Reverses Gut Microbiome and Serum Metabolome Alterations in Premature Ovarian Insufficiency. Jiang Lingling,Fei Haiyi,Tong Jinfei,Zhou Jiena,Zhu Jiajuan,Jin Xiaoying,Shi Zhan,Zhou Yan,Ma Xudong,Yu Hailan,Yang Jianhua,Zhang Songying Frontiers in endocrinology Objective:We explored the gut microbiome and serum metabolome alterations in patients with premature ovarian insufficiency (POI) and the effects of hormone replacement therapy (HRT) with the aim to unravel the pathological mechanism underlying POI. Methods:Fecal and serum samples obtained from healthy females (HC, n = 10) and patients with POI treated with (n = 10) or without (n = 10) HRT were analyzed using 16S rRNA gene sequencing and untargeted metabolomics analysis, respectively. Peripheral blood samples were collected to detect serum hormone and cytokine levels. Spearman's rank correlation was used to evaluate correlations between sex hormones and cytokines and between the gut microbiota and serum metabolites. To further confirm the correlation between and ovarian fibrosis, the mice were inoculated with () through oral gavage. Results:The abundance of genus significantly increased in the fecal samples of patients with POI compared to that observed in the samples of HCs. This increase was reversed in patients with POI treated with HRT. Patients with POI showed significantly altered serum metabolic signatures and increased serum TGF-β1 levels; this increase was reversed by HRT. The abundance of was positively correlated with altered metabolic signatures, which were, in turn, positively correlated with serum TGF-β1 levels in all subjects. Estrogen ameliorated ovarian fibrosis induced by in mice. Conclusions:The interactions between the gut microbiota, serum metabolites, and serum TGF-β1 in patients with POI may play a critical role in the development of POI. HRT not only closely mimicked normal ovarian hormone production in patients with POI but also attenuated gut microbiota dysbiosis and imbalance in the levels of serum metabolites and TGF-β1, which are reportedly associated with fibrosis. The findings of this study may pave the way for the development of preventive and curative therapies for patients with POI. 10.3389/fendo.2021.794496
    Stem Cell Paracrine Signaling for Treatment of Premature Ovarian Insufficiency. Polonio Alba M,García-Velasco Juan A,Herraiz Sonia Frontiers in endocrinology Premature ovarian insufficiency is a common disorder affecting young women and represents the worst-case ovarian scenario due to the substantial impact on the reproductive lifespan of these patients. Due to the complexity of this condition, which is not fully understood, non-effective treatments have yet been established for these patients. Different experimental approaches are being explored and strategies based on stem cells deserve special attention. The regenerative and immunomodulatory properties of stem cells have been successfully tested in different tissues, including ovary. Numerous works point out to the efficacy of stem cells in POI treatment, and a wide range of clinical trials have been developed in order to prove safety and effectiveness of stem cells therapy-in diminished ovarian reserve and POI women. The main purpose of this review is to describe the state of the art of the treatment of POI involving stem cells, especially those that use mobilization of stem cells or paracrine signaling. 10.3389/fendo.2020.626322
    Ovarian Reserve Markers in Premature Ovarian Insufficiency: Within Different Clinical Stages and Different Etiologies. Jiao Xue,Meng Tingting,Zhai Yiwei,Zhao Lijuan,Luo Wei,Liu Peihao,Qin Yingying Frontiers in endocrinology Objective:To characterize the ovarian reserve indicators for premature ovarian insufficiency (POI) at different disease stages and with various etiologies. Methods:According to different FSH levels and menstrual conditions, patients with normal ovarian reserve (NOR with 5 IU/L<FSH<10 IU/L, n=987), precursor stage of POI (pre-POI with 10 IU/L<FSH ≤ 25 IU/L, n=410), early POI (25 IU/L<FSH ≤ 40 IU/L n=147), and premature ovarian failure (POF with FSH>40 IU/L, n=454) were retrospectively screened and their records were abstracted from Reproductive Hospital Affiliated to Shandong University between 2014 and 2019. Based on the known etiologies, POI patients were subdivided into genetic, iatrogenic, autoimmune and idiopathic subsets according to the known etiologies. The phenotypic features were compared within different subgroups, and the predictive value of ovarian reserve markers was analyzed. Results:The ovarian reserve indicators consecutively deteriorated with the progress of ovarian insufficiency, indicated as an increase of FSH and LH but decrease of AMH, inhibin B, AFC, E and T (P<0.01). Most of them changed significantly from NOR to pre-POI while remained relatively stable at a low level or even undetectable at early POI and POF stage. AMH showed the highest predictive value for pre-POI (AUC 0.932, 95% CI 0.918-0.945) and POI (AUC 0.944, 95% CI 0.933-0.954), and the combination of AMH and AFC was highly promising for early prediction. Additionally, significant differences existed in AMH, inhibin B and AFC among women with different etiologies of POI (P<0.05), and the genetic POI presented the worst hormone status. Conclusions:Our study indicated a high heterogeneity of POI in both endocrine hormones and etiological phenotypes. The quantitative changes and cutoff values of AMH and AFC could provide new insights in the prediction and early diagnosis of POI. 10.3389/fendo.2021.601752
    Meiotic Recombination Defects and Premature Ovarian Insufficiency. Huang Chengzi,Guo Ting,Qin Yingying Frontiers in cell and developmental biology Premature ovarian insufficiency (POI) is the depletion of ovarian function before 40 years of age due to insufficient oocyte formation or accelerated follicle atresia. Approximately 1-5% of women below 40 years old are affected by POI. The etiology of POI is heterogeneous, including genetic disorders, autoimmune diseases, infection, iatrogenic factors, and environmental toxins. Genetic factors account for 20-25% of patients. However, more than half of the patients were idiopathic. With the widespread application of next-generation sequencing (NGS), the genetic spectrum of POI has been expanded, especially the latest identification in meiosis and DNA repair-related genes. During meiotic prophase I, the key processes include DNA double-strand break (DSB) formation and subsequent homologous recombination (HR), which are essential for chromosome segregation at the first meiotic division and genome diversity of oocytes. Many animal models with defective meiotic recombination present with meiotic arrest, DSB accumulation, and oocyte apoptosis, which are similar to human POI phenotype. In the article, based on different stages of meiotic recombination, including DSB formation, DSB end processing, single-strand invasion, intermediate processing, recombination, and resolution and essential proteins involved in synaptonemal complex (SC), cohesion complex, and fanconi anemia (FA) pathway, we reviewed the individual gene mutations identified in POI patients and the potential candidate genes for POI pathogenesis, which will shed new light on the genetic architecture of POI and facilitate risk prediction, ovarian protection, and early intervention for POI women. 10.3389/fcell.2021.652407
    Mesenchymal Stem Cells in Premature Ovarian Insufficiency: Mechanisms and Prospects. Li Zhongkang,Zhang Mingle,Tian Yanpeng,Li Qian,Huang Xianghua Frontiers in cell and developmental biology Premature ovarian insufficiency (POI) is a complex endocrine disease that severely affects the physiological and reproductive functions of females. The current conventional clinical treatment methods for POI are characterized by several side effects, and most do not effectively restore the physiological functions of the ovaries. Transplantation of mesenchymal stem cells (MSCs) is a promising regenerative medicine approach, which has received significant attention in the management of POI with high efficacy. Associated pre-clinical and clinical trials are also proceeding orderly. However, the therapeutic mechanisms underlying the MSCs-based treatment are complex and have not been fully elucidated. In brief, proliferation, apoptosis, immunization, autophagy, oxidative stress, and fibrosis of ovarian cells are modulated through paracrine effects after migration of MSCs to the injured ovary. This review summarizes therapeutic mechanisms of MSCs-based treatments in POI and explores their therapeutic potential in clinical practice. Therefore, this review will provide a theoretical basis for further research and clinical application of MSCs in POI. 10.3389/fcell.2021.718192
    CPEB3 deficiency in mice affect ovarian follicle development and causes premature ovarian insufficiency. E Fang,Zhang He,Yin Wanli,Wang Chongyang,Liu Yuanli,Li Yanze,Wang Linlin,Wu Yue,Zhang Runze,Zou Chendan,Song Tianjun,Matunda Cedric,Zou Chaoxia,Gao Xu Cell death & disease Premature ovarian insufficiency (POI) is a heterogeneous and multifactorial disorder. In recent years, there has been an increasing interest in research on the pathogenesis and treatment of POI, owing to the implementation of the second-child policy in China. Cytoplasmic polyadenylation element-binding protein 3 (CPEB3) is an RNA-binding protein that can bind to specific RNA sequences. CPEB3 can bind to and affect the expression, cellular location, and stability of target RNAs. Cpeb3 is highly expressed in the ovary; however, its functions remain unknown. In this study, Cpeb3-mutant mice were used to characterize the physiological functions of CPEB3. Cpeb3-mutant female mice manifested signs of gradual loss of ovarian follicles, ovarian follicle development arrest, increased follicle atresia, and subfertility with a phenotype analogous to POI in women. Further analysis showed that granulosa cell proliferation was inhibited and apoptosis was markedly increased in Cpeb3-mutant ovaries. In addition, the expression of Gdf9, a potential target of CPEB3, was decreased in Cpeb3-mutant ovaries and oocytes. Altogether, these results reveal that CPEB3 is essential for ovarian follicle development and female fertility as it regulates the expression of Gdf9 in oocytes, disruption of which leads to impaired ovarian follicle development and POI. 10.1038/s41419-021-04374-4
    lncRNA participates in premature ovarian insufficiency through regulating and . Li Duan,Xu Weiwei,Wang Xiaoyan,Dang Yujie,Xu Lan,Lu Gang,Chan Wai-Yee,Leung Peter C K,Zhao Shidou,Qin Yingying Molecular therapy. Nucleic acids The list of long non-coding RNAs (lncRNAs) that participate in the function of ovarian granulosa cells (GCs) is rapidly expanding, but the mechanisms through which lncRNAs regulate GC function are not yet fully understood. Here, we recognized a minimally expressed lncRNA (which we named ) in GCs from patients with biochemical premature ovarian insufficiency (bPOI). We further explored the role of lncRNA in GC function and its contribution to the development of bPOI. Mechanistically, silencing downregulated by competitively binding with , and this resulted in significant inhibition of DNA damage repair capacity. In addition, decreased expression of promoted ubiquitin-mediated degradation of Wilms tumor 1 (WT1) protein through interactions with heat shock protein 90 (HSP90), which led to aberrant differentiation of GCs. Moreover, was able to ameliorate the etoposide-induced DNA damage and apoptosis . Taken together, these findings provide new insights into the contribution of lncRNAs in POI pathogenesis. 10.1016/j.omtn.2021.10.015
    Premature Ovarian Insufficiency: Past, Present, and Future. Chon Seung Joo,Umair Zobia,Yoon Mee-Sup Frontiers in cell and developmental biology Premature ovarian insufficiency (POI) is the loss of normal ovarian function before the age of 40 years, a condition that affects approximately 1% of women under 40 years old and 0.1% of women under 30 years old. It is biochemically characterized by amenorrhea with hypoestrogenic and hypergonadotropic conditions, in some cases, causing loss of fertility. Heterogeneity of POI is registered by genetic and non-genetic causes, such as autoimmunity, environmental toxins, and chemicals. The identification of possible causative genes and selection of candidate genes for POI confirmation remain to be elucidated in cases of idiopathic POI. This review discusses the current understanding and future prospects of heterogeneous POI. We focus on the genetic basis of POI and the recent studies on non-coding RNA in POI pathogenesis as well as on animal models of POI pathogenesis, which help unravel POI mechanisms and potential targets. Despite the latest discoveries, the crosstalk among gene regulatory networks and the possible therapies targeting the same needs to explore in near future. 10.3389/fcell.2021.672890
    Premature ovarian insufficiency. Best practice & research. Clinical obstetrics & gynaecology The natural lifespan of the ovary is occasionally interrupted by pathological processes; some are known, but many are unknown. Premature ovarian insufficiency (POI) can be a devastating diagnosis for an adolescent or for someone who has yet to start a family. Common causes of POI include genetic and chromosomal defects, autoimmune damage, and cancer treatments. Knowledge of the pathogenesis of this condition and an awareness of contemporary hormone replacement and fertility options are required to design a multidisciplinary therapeutic approach comprising reproductive medicine, endocrinology, clinical psychology, and assisted fertility expertise. 10.1016/j.bpobgyn.2021.09.011
    Physiological Aspects of Female Fertility: Role of the Environment, Modern Lifestyle, and Genetics. Hart Roger J Physiological reviews Across the Western World there is an increasing trend to postpone childbearing. Consequently, the negative influence of age on oocyte quality may lead to a difficulty in conceiving for many couples. Furthermore, lifestyle factors may exacerbate a couple's difficulty in conceiving due mainly to the metabolic influence of obesity; however, the negative impacts of low peripheral body fat, excessive exercise, the increasing prevalence of sexually transmitted diseases, and smoking all have significant negative effects on fertility. Other factors that impede conception are the perceived increasing prevalence of the polycystic ovary syndrome, which is further exacerbated by obesity, and the presence of uterine fibroids and endometriosis (a progressive pelvic inflammatory disorder) which are more prevalent in older women. A tendency for an earlier sexual debut and to have more sexual partners has led to an increase in sexually transmitted diseases. In addition, there are several genetic influences that may limit the number of oocytes within the ovary; consequently, by postponing attempts at childbearing, a limitation of oocyte number may become evident, whereas in previous generations with earlier conception this potentially reduced reproductive life span did not manifest in infertility. Environmental influences on reproduction are under increasing scrutiny. Although firm evidence is lacking however, dioxin exposure may be linked to endometriosis, phthalate exposure may influence ovarian reserve, and bisphenol A may interfere with oocyte development and maturation. However, chemotherapy or radiotherapy is recognized to lead to ovarian damage and predispose the woman to ovarian failure. 10.1152/physrev.00023.2015
    The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited. Rosenfield Robert L,Ehrmann David A Endocrine reviews Polycystic ovary syndrome (PCOS) was hypothesized to result from functional ovarian hyperandrogenism (FOH) due to dysregulation of androgen secretion in 1989-1995. Subsequent studies have supported and amplified this hypothesis. When defined as otherwise unexplained hyperandrogenic oligoanovulation, two-thirds of PCOS cases have functionally typical FOH, characterized by 17-hydroxyprogesterone hyperresponsiveness to gonadotropin stimulation. Two-thirds of the remaining PCOS have FOH detectable by testosterone elevation after suppression of adrenal androgen production. About 3% of PCOS have a related isolated functional adrenal hyperandrogenism. The remaining PCOS cases are mild and lack evidence of steroid secretory abnormalities; most of these are obese, which we postulate to account for their atypical PCOS. Approximately half of normal women with polycystic ovarian morphology (PCOM) have subclinical FOH-related steroidogenic defects. Theca cells from polycystic ovaries of classic PCOS patients in long-term culture have an intrinsic steroidogenic dysregulation that can account for the steroidogenic abnormalities typical of FOH. These cells overexpress most steroidogenic enzymes, particularly cytochrome P450c17. Overexpression of a protein identified by genome-wide association screening, differentially expressed in normal and neoplastic development 1A.V2, in normal theca cells has reproduced this PCOS phenotype in vitro. A metabolic syndrome of obesity-related and/or intrinsic insulin resistance occurs in about half of PCOS patients, and the compensatory hyperinsulinism has tissue-selective effects, which include aggravation of hyperandrogenism. PCOS seems to arise as a complex trait that results from the interaction of diverse genetic and environmental factors. Heritable factors include PCOM, hyperandrogenemia, insulin resistance, and insulin secretory defects. Environmental factors include prenatal androgen exposure and poor fetal growth, whereas acquired obesity is a major postnatal factor. The variety of pathways involved and lack of a common thread attests to the multifactorial nature and heterogeneity of the syndrome. Further research into the fundamental basis of the disorder will be necessary to optimally correct androgen levels, ovulation, and metabolic homeostasis. 10.1210/er.2015-1104
    Polycystic ovary syndrome. Azziz Ricardo,Carmina Enrico,Chen ZiJiang,Dunaif Andrea,Laven Joop S E,Legro Richard S,Lizneva Daria,Natterson-Horowtiz Barbara,Teede Helena J,Yildiz Bulent O Nature reviews. Disease primers Polycystic ovary syndrome (PCOS) affects 5-20% of women of reproductive age worldwide. The condition is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology (PCOM) - with excessive androgen production by the ovaries being a key feature of PCOS. Metabolic dysfunction characterized by insulin resistance and compensatory hyperinsulinaemia is evident in the vast majority of affected individuals. PCOS increases the risk for type 2 diabetes mellitus, gestational diabetes and other pregnancy-related complications, venous thromboembolism, cerebrovascular and cardiovascular events and endometrial cancer. PCOS is a diagnosis of exclusion, based primarily on the presence of hyperandrogenism, ovulatory dysfunction and PCOM. Treatment should be tailored to the complaints and needs of the patient and involves targeting metabolic abnormalities through lifestyle changes, medication and potentially surgery for the prevention and management of excess weight, androgen suppression and/or blockade, endometrial protection, reproductive therapy and the detection and treatment of psychological features. This Primer summarizes the current state of knowledge regarding the epidemiology, mechanisms and pathophysiology, diagnosis, screening and prevention, management and future investigational directions of the disorder. 10.1038/nrdp.2016.57
    The management of anovulatory infertility in women with polycystic ovary syndrome: an analysis of the evidence to support the development of global WHO guidance. Balen Adam H,Morley Lara C,Misso Marie,Franks Stephen,Legro Richard S,Wijeyaratne Chandrika N,Stener-Victorin Elisabet,Fauser Bart C J M,Norman Robert J,Teede Helena Human reproduction update BACKGROUND:Here we describe the consensus guideline methodology, summarise the evidence-based recommendations we provided to the World Health Organisation (WHO) for their consideration in the development of global guidance and present a narrative review on the management of anovulatory infertility in women with polycystic ovary syndrome (PCOS). OBJECTIVE AND RATIONALE:The aim of this paper was to present an evidence base for the management of anovulatory PCOS. SEARCH METHODS:The evidence to support providing recommendations involved a collaborative process for: (i) identification of priority questions and critical outcomes, (ii) retrieval of up-to-date evidence and exiting guidelines, (iii) assessment and synthesis of the evidence and (iv) the formulation of draft recommendations to be used for reaching consensus with a wide range of global stakeholders. For each draft recommendation, the methodologist evaluated the quality of the supporting evidence that was then graded as very low, low, moderate or high for consideration during consensus. OUTCOMES:Evidence was synthesized and we made recommendations across the definition of PCOS including hyperandrogenism, menstrual cycle regulation and ovarian assessment. Metabolic features and the impact of ethnicity were covered. Management includes lifestyle changes, bariatric surgery, pharmacotherapy (including clomiphene citrate (CC), aromatase inhibitors, metformin and gonadotropins), as well as laparoscopic surgery. In-vitro fertilization (IVF) was considered as were the risks of ovulation induction and of pregnancy in PCOS. Approximately 80% of women who suffer from anovulatory infertility have PCOS. Lifestyle intervention is recommended first in women who are obese largely on the basis of general health benefits. Bariatric surgery can be considered where the body mass index (BMI) is ≥35 kg/m and lifestyle therapy has failed. Carefully conducted and monitored pharmacological ovulation induction can achieve good cumulative pregnancy rates and multiple pregnancy rates can be minimized with adherence to recommended protocols. CC should be first-line pharmacotherapy for ovulation induction and letrozole can also be used as first-line therapy. Metformin alone has limited benefits in improving live birth rates. Gonadotropins and laparoscopic surgery can be used as second-line treatment. There is no clear evidence for efficacy of acupuncture or herbal mixtures in women with PCOS. For women with PCOS who fail lifestyle and ovulation induction therapy or have additional infertility factors, IVF can be used with the safer gonadotropin releasing hormone (GnRH) antagonist protocol. If a GnRH-agonist protocol is used, metformin as an adjunct may reduce the risk of ovarian hyperstimulation syndrome. Patients should be informed of the potential side effects of ovulation induction agents and of IVF on the foetus, and of the risks of multiple pregnancy. Increased risks for the mother during pregnancy and for the child, including the exacerbating impact of obesity on adverse outcomes, should also be discussed. WIDER IMPLICATIONS:This guidance generation and evidence-synthesis analysis has been conducted in a manner to be considered for global applicability for the safe administration of ovulation induction for anovulatory women with PCOS. 10.1093/humupd/dmw025
    Ovarian ageing: the role of mitochondria in oocytes and follicles. May-Panloup Pascale,Boucret Lisa,Chao de la Barca Juan-Manuel,Desquiret-Dumas Valérie,Ferré-L'Hotellier Véronique,Morinière Catherine,Descamps Philippe,Procaccio Vincent,Reynier Pascal Human reproduction update BACKGROUND:There is a great inter-individual variability of ovarian ageing, and almost 20% of patients consulting for infertility show signs of premature ovarian ageing. This feature, taken together with delayed childbearing in modern society, leads to the emergence of age-related ovarian dysfunction concomitantly with the desire for pregnancy. Assisted reproductive technology is frequently inefficacious in cases of ovarian ageing, thus raising the economic, medical and societal costs of the procedures. OBJECTIVE AND RATIONAL:Ovarian ageing is characterized by quantitative and qualitative alteration of the ovarian oocyte reserve. Mitochondria play a central role in follicular atresia and could be the main target of the ooplasmic factors determining oocyte quality adversely affected by ageing. Indeed, the oocyte is the richest cell of the body in mitochondria and depends largely on these organelles to acquire competence for fertilization and early embryonic development. Moreover, the oocyte ensures the uniparental transmission and stability of the mitochondrial genome across the generations. This review focuses on the role played by mitochondria in ovarian ageing and on the possible consequences over the generations. SEARCH METHODS:PubMed was used to search the MEDLINE database for peer-reviewed original articles and reviews concerning mitochondria and ovarian ageing, in animal and human species. Searches were performed using keywords belonging to three groups: 'mitochondria' or 'mitochondrial DNA'; 'ovarian reserve', 'oocyte', 'ovary' or 'cumulus cells'; and 'ageing' or 'ovarian ageing'. These keywords were combined with other search phrases relevant to the topic. References from these articles were used to obtain additional articles. OUTCOMES:There is a close relationship, in mammalian models and humans, between mitochondria and the decline of oocyte quality with ageing. Qualitatively, ageing-related mitochondrial (mt) DNA instability, which leads to the accumulation of mtDNA mutations in the oocyte, plays a key role in the deterioration of oocyte quality in terms of competence and of the risk of transmitting mitochondrial abnormalities to the offspring. In contrast, some mtDNA haplogroups are protective against the decline of ovarian reserve. Quantitatively, mitochondrial biogenesis is crucial during oogenesis for constituting a mitochondrial pool sufficiently large to allow normal early embryonic development and to avoid the untimely activation of mitochondrial biogenesis. Ovarian ageing also seriously affects the dynamic nature of mitochondrial biogenesis in the surrounding granulosa cells that may provide interesting alternative biomarkers of oocyte quality. WIDER IMPLICATIONS:A fuller understanding of the involvement of mitochondria in cases of infertility linked to ovarian ageing would contribute to a better management of the disorder in the future. 10.1093/humupd/dmw028
    Premature Ovarian Insufficiency: New Perspectives on Genetic Cause and Phenotypic Spectrum. Tucker Elena J,Grover Sonia R,Bachelot Anne,Touraine Philippe,Sinclair Andrew H Endocrine reviews Premature ovarian insufficiency (POI) is one form of female infertility, defined by loss of ovarian activity before the age of 40 and characterized by amenorrhea (primary or secondary) with raised gonadotropins and low estradiol. POI affects up to one in 100 females, including one in 1000 before the age of 30. Substantial evidence suggests a genetic basis for POI; however, the majority of cases remain unexplained, indicating that genes likely to be associated with this condition are yet to be discovered. This review discusses the current knowledge of the genetic basis of POI. We highlight genes typically known to cause syndromic POI that can be responsible for isolated POI. The role of mouse models in understanding POI pathogenesis is discussed, and a thorough list of candidate POI genes is provided. Identifying a genetic basis for POI has multiple advantages, such as enabling the identification of presymptomatic family members who can be offered counseling and cryopreservation of eggs before depletion, enabling personalized treatment based on the cause of an individual's condition, and providing better understanding of disease mechanisms that ultimately aid the development of improved treatments. 10.1210/er.2016-1047
    Regulation of Mammalian Oocyte Meiosis by Intercellular Communication Within the Ovarian Follicle. Jaffe Laurinda A,Egbert Jeremy R Annual review of physiology Meiotic progression in mammalian preovulatory follicles is controlled by the granulosa cells around the oocyte. Cyclic GMP (cGMP) generated in the granulosa cells diffuses through gap junctions into the oocyte, maintaining meiotic prophase arrest. Luteinizing hormone then acts on receptors in outer granulosa cells to rapidly decrease cGMP. This occurs by two complementary pathways: cGMP production is decreased by dephosphorylation and inactivation of the NPR2 guanylyl cyclase, and cGMP hydrolysis is increased by activation of the PDE5 phosphodiesterase. The cGMP decrease in the granulosa cells results in rapid cGMP diffusion out of the oocyte, initiating meiotic resumption. Additional, more slowly developing mechanisms involving paracrine signaling by extracellular peptides (C-type natriuretic peptide and EGF receptor ligands) maintain the low level of cGMP in the oocyte. These coordinated signaling pathways ensure a fail-safe system to prepare the oocyte for fertilization and reproductive success. 10.1146/annurev-physiol-022516-034102
    Treatment strategies for women with WHO group II anovulation: systematic review and network meta-analysis. Wang Rui,Kim Bobae V,van Wely Madelon,Johnson Neil P,Costello Michael F,Zhang Hanwang,Ng Ernest Hung Yu,Legro Richard S,Bhattacharya Siladitya,Norman Robert J,Mol Ben Willem J BMJ (Clinical research ed.) OBJECTIVE: To compare the effectiveness of alternative first line treatment options for women with WHO group II anovulation wishing to conceive. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Cochrane Central Register of Controlled Trials, Medline, and Embase, up to 11 April 2016. STUDY SELECTION: Randomised controlled trials comparing eight ovulation induction treatments in women with WHO group II anovulation: clomiphene, letrozole, metformin, clomiphene and metformin combined, tamoxifen, gonadotropins, laparoscopic ovarian drilling, and placebo or no treatment. Study quality was measured on the basis of the methodology and categories described in the Cochrane Collaboration Handbook. Pregnancy, defined preferably as clinical pregnancy, was the primary outcome; live birth, ovulation, miscarriage, and multiple pregnancy were secondary outcomes. RESULTS: Of 2631 titles and abstracts initially identified, 57 trials reporting on 8082 women were included. All pharmacological treatments were superior to placebo or no intervention in terms of pregnancy and ovulation. Compared with clomiphene alone, both letrozole and the combination of clomiphene and metformin showed higher pregnancy rates (odds ratio 1.58, 95% confidence interval 1.25 to 2.00; 1.81, 1.35 to 2.42; respectively) and ovulation rates (1.99, 1.38 to 2.87; 1.55, 1.02 to 2.36; respectively). Letrozole led to higher live birth rates when compared with clomiphene alone (1.67, 1.11 to 2.49). Both letrozole and metformin led to lower multiple pregnancy rates compared with clomiphene alone (0.46, 0.23 to 0.92; 0.22, 0.05 to 0.92; respectively). CONCLUSIONS: In women with WHO group II anovulation, letrozole and the combination of clomiphene and metformin are superior to clomiphene alone in terms of ovulation and pregnancy. Compared with clomiphene alone, letrozole is the only treatment showing a significantly higher rate of live birth. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015027579. 10.1136/bmj.j138
    Sex Differences in Binge Eating: Gonadal Hormone Effects Across Development. Klump Kelly L,Culbert Kristen M,Sisk Cheryl L Annual review of clinical psychology Eating disorders are highly sexually differentiated disorders that exhibit a female predominance in risk. Most theories focus on psychosocial explanations to the exclusion of biological/genetic influences. The purpose of this descriptive review is to evaluate evidence from animal and human studies in support of gonadal hormone effects on sex differences in binge eating. Although research is in its nascent stages, findings suggest that increased prenatal testosterone exposure in males appears to protect against binge eating. Although pubertal testosterone may exert additional protective effects, the prenatal period is likely critical for the decreased risk observed in males. By contrast, studies indicate that, in females, it is the lack of prenatal testosterone coupled with the organizational effects of pubertal ovarian hormones that may lead to increased binge eating. Finally, twin data suggest that changes in genetic risk may underlie these hormone influences on sex differences across development. 10.1146/annurev-clinpsy-032816-045309
    Ovarian hormones and obesity. Leeners Brigitte,Geary Nori,Tobler Philippe N,Asarian Lori Human reproduction update BACKGROUND:Obesity is caused by an imbalance between energy intake, i.e. eating and energy expenditure (EE). Severe obesity is more prevalent in women than men worldwide, and obesity pathophysiology and the resultant obesity-related disease risks differ in women and men. The underlying mechanisms are largely unknown. Pre-clinical and clinical research indicate that ovarian hormones may play a major role. OBJECTIVE AND RATIONALE:We systematically reviewed the clinical and pre-clinical literature on the effects of ovarian hormones on the physiology of adipose tissue (AT) and the regulation of AT mass by energy intake and EE. SEARCH METHODS:Articles in English indexed in PubMed through January 2016 were searched using keywords related to: (i) reproductive hormones, (ii) weight regulation and (iii) central nervous system. We sought to identify emerging research foci with clinical translational potential rather than to provide a comprehensive review. OUTCOMES:We find that estrogens play a leading role in the causes and consequences of female obesity. With respect to adiposity, estrogens synergize with AT genes to increase gluteofemoral subcutaneous AT mass and decrease central AT mass in reproductive-age women, which leads to protective cardiometabolic effects. Loss of estrogens after menopause, independent of aging, increases total AT mass and decreases lean body mass, so that there is little net effect on body weight. Menopause also partially reverses women's protective AT distribution. These effects can be counteracted by estrogen treatment. With respect to eating, increasing estrogen levels progressively decrease eating during the follicular and peri-ovulatory phases of the menstrual cycle. Progestin levels are associated with eating during the luteal phase, but there does not appear to be a causal relationship. Progestins may increase binge eating and eating stimulated by negative emotional states during the luteal phase. Pre-clinical research indicates that one mechanism for the pre-ovulatory decrease in eating is a central action of estrogens to increase the satiating potency of the gastrointestinal hormone cholecystokinin. Another mechanism involves a decrease in the preference for sweet foods during the follicular phase. Genetic defects in brain α-melanocycte-stimulating hormone-melanocortin receptor (melanocortin 4 receptor, MC4R) signaling lead to a syndrome of overeating and obesity that is particularly pronounced in women and in female animals. The syndrome appears around puberty in mice with genetic deletions of MC4R, suggesting a role of ovarian hormones. Emerging functional brain-imaging data indicates that fluctuations in ovarian hormones affect eating by influencing striatal dopaminergic processing of flavor hedonics and lateral prefrontal cortex processing of cognitive inhibitory controls of eating. There is a dearth of research on the neuroendocrine control of eating after menopause. There is also comparatively little research on the effects of ovarian hormones on EE, although changes in ovarian hormone levels during the menstrual cycle do affect resting EE. WIDER IMPLICATIONS:The markedly greater obesity burden in women makes understanding the diverse effects of ovarian hormones on eating, EE and body adiposity urgent research challenges. A variety of research modalities can be used to investigate these effects in women, and most of the mechanisms reviewed are accessible in animal models. Therefore, human and translational research on the roles of ovarian hormones in women's obesity and its causes should be intensified to gain further mechanistic insights that may ultimately be translated into novel anti-obesity therapies and thereby improve women's health. 10.1093/humupd/dmw045
    Ovarian Follicular Theca Cell Recruitment, Differentiation, and Impact on Fertility: 2017 Update. Richards JoAnne S,Ren Yi A,Candelaria Nicholes,Adams Jaye E,Rajkovic Aleksandar Endocrine reviews The major goal of this review is to summarize recent exciting findings that have been published within the past 10 years that, to our knowledge, have not been presented in detail in previous reviews and that may impact altered follicular development in polycystic ovarian syndrome (PCOS) and premature ovarian failure in women. Specifically, we will cover the following: (1) mouse models that have led to discovery of the derivation of two precursor populations of theca cells in the embryonic gonad; (2) the key roles of the oocyte-derived factor growth differentiation factor 9 on the hedgehog (HH) signaling pathway and theca cell functions; and (3) the impact of the HH pathway on both the specification of theca endocrine cells and theca fibroblast and smooth muscle cells in developing follicles. We will also discuss the following: (1) other signaling pathways that impact the differentiation of theca cells, not only luteinizing hormone but also insulinlike 3, bone morphogenic proteins, the circadian clock genes, androgens, and estrogens; and (2) theca-associated vascular, immune, and fibroblast cells, as well as the cytokines and matrix factors that play key roles in follicle growth. Lastly, we will integrate what is known about theca cells from mouse models, human-derived theca cell lines from patients who have PCOS and patients who do not have PCOS, and microarray analyses of human and bovine theca to understand what pathways and factors contribute to follicle growth as well as to the abnormal function of theca. 10.1210/er.2017-00164
    The epidermal growth factor network: role in oocyte growth, maturation and developmental competence. Richani Dulama,Gilchrist Robert B Human reproduction update BACKGROUND:The LH surge induces great physiological changes within the preovulatory follicle, which culminate in the ovulation of a mature oocyte that is capable of supporting embryo and foetal development. However, unlike mural granulosa cells, the oocyte and its surrounding cumulus cells are not directly responsive to LH, indicating that the LH signal is mediated by secondary factors produced by the granulosa cells. The mechanisms by which the oocyte senses the ovulatory LH signal and hence prepares for ovulation has been a subject of considerable controversy for the past four decades. Within the last 15 years several significant insights have been made into the molecular mechanisms orchestrating oocyte development, maturation and ovulation. These findings centre on the epidermal growth factor (EGF) pathway and the role it plays in the complex signalling network that finely regulates oocyte maturation and ovulation. OBJECTIVE AND RATIONALE:This review outlines the role of the EGF network during oocyte development and regulation of the ovulatory cascade, and in particular focuses on the effect of the EGF network on oocyte developmental competence. Application of this new knowledge to advances in ART is examined. SEARCH METHODS:The PubMed database was used to search for peer-reviewed original and review articles concerning the EGF network. Publications offering a comprehensive description of the role of the EGF network in follicle and oocyte development were used. OUTCOMES:It is now clear that acute upregulation of the EGF network is an essential component of the ovulatory cascade as it transmits the LH signal from the periphery of the follicle to the cumulus-oocyte complex (COC). More recent findings have elucidated new roles for the EGF network in the regulation of oocyte development. EGF signalling downregulates the somatic signal 3'5'-cyclic guanine monophosphate that suppresses oocyte meiotic maturation and simultaneously provides meiotic inducing signals. The EGF network also controls translation of maternal transcripts in the quiescent oocyte, a process that is integral to oocyte competence. As a means of restricting the ovulatory signal to the Graffian follicle, most COCs in the ovary are unresponsive to EGF-ligands. Recent studies have revealed that development of a functional EGF signalling network in cumulus cells requires dual endocrine (FSH) and oocyte paracrine cues (growth differentiation factor 9 and bone morphogenetic protein 15), and this occurs progressively in COCs during the last stages of folliculogenesis. Hence, a new concept to emerge is that cumulus cell acquisition of EGF receptor responsiveness represents a developmental hallmark in folliculogenesis, analogous to FSH-induction of LH receptor signalling in mural granulosa cells. Likewise, this event represents a major milestone in the oocyte's developmental progression and acquisition of developmental competence. It is now clear that EGF signalling is perturbed in COCs matured in vitro. This has inspired novel concepts in IVM systems to ameliorate this perturbation, resulting in improved oocyte developmental competence. WIDER IMPLICATIONS:An oocyte of high quality is imperative for fertility. Elucidating the fundamental molecular and cellular mechanims by which the EGF network regulates oocyte maturation and ovulation can be expected to open new opportunities in ART. This knowledge has already led to advances in oocyte IVM in animal models. Translation of such advances into a clinical setting should increase the efficacy of IVM, making it a viable treatment option for a wide range of patients, thereby simplifying fertility treatment and bringing substantial cost and health benefits. 10.1093/humupd/dmx029
    Extracellular Vesicles in Human Reproduction in Health and Disease. Simon Carlos,Greening David W,Bolumar David,Balaguer Nuria,Salamonsen Lois A,Vilella Felipe Endocrine reviews Extensive evidence suggests that the release of membrane-enclosed compartments, more commonly known as extracellular vesicles (EVs), is a potent newly identified mechanism of cell-to-cell communication both in normal physiology and in pathological conditions. This review presents evidence about the formation and release of different EVs, their definitive markers and cargo content in reproductive physiological processes, and their capacity to convey information between cells through the transfer of functional protein and genetic information to alter phenotype and function of recipient cells associated with reproductive biology. In the male reproductive tract, epididymosomes and prostasomes participate in regulating sperm motility activation, capacitation, and acrosome reaction. In the female reproductive tract, follicular fluid, oviduct/tube, and uterine cavity EVs are considered as vehicles to carry information during oocyte maturation, fertilization, and embryo-maternal crosstalk. EVs via their cargo might be also involved in the triggering, maintenance, and progression of reproductive- and obstetric-related pathologies such as endometriosis, polycystic ovarian syndrome, preeclampsia, gestational diabetes, and erectile dysfunction. In this review, we provide current knowledge on the present and future use of EVs not only as biomarkers, but also as therapeutic targeting agents, mainly as vectors for drug or compound delivery into target cells and tissues. 10.1210/er.2017-00229
    Sirtuins in gamete biology and reproductive physiology: emerging roles and therapeutic potential in female and male infertility. Tatone Carla,Di Emidio Giovanna,Barbonetti Arcangelo,Carta Gaspare,Luciano Alberto M,Falone Stefano,Amicarelli Fernanda Human reproduction update BACKGROUND:Sirtuins (SIRT1-7) are a family of NAD+-dependent deacetylases that catalyze post-translational modifications of proteins. Together, they respond to metabolic challenges, inflammatory signals or hypoxic/oxidative stress, and are associated with aging and longevity. The role of Sirtuins in the regulation of fertility emerged in 2003 when a defective reproductive phenotype was observed in SIRT1-null mice. Although studies on Sirtuins in reproductive biology have been increasing in the last years, a recent comprehensive update on this issue is still lacking. OBJECTIVE AND RATIONALE:This review is aimed to provide knowledge on the activation mechanism and cellular role of Sirtuins and to give an update of the rapid development of Sirtuin research in female and male reproduction under physiological and pathological conditions. The final goal is to assess whether strategies aimed to improve Sirtuin expression or activity could have therapeutic potential for infertility associated with polycystic ovarian syndrome (PCOS), endometriosis, diabetes, xenobiotic stress and aging. SEARCH METHODS:The MEDLINE database was examined for peer-reviewed original articles. The following keywords were searched: 'Sirtuin', 'ovary', 'oocyte', 'ovarian follicle', 'embryo', 'endometrium', 'sperm' and 'testis'. These keywords were combined with other search phrases relevant to the topic. OUTCOMES:Our knowledge of Sirtuins in reproductive functions has grown exponentially over the last few years. The majority of the work carried out so far has focused on SIRT1 with a prevalence of studies on female reproduction. Numerous studies have provided evidence that down-regulation of SIRT1 is associated with physiological or pathological reduction of ovarian reserve. SIRT1 has also been shown to regulate proliferation and apoptosis in granulosa cells whereas SIRT3 was found to promote luteinisation. Biochemical modulation of Sirtuin activity has led to discoveries of the roles of SIRT1, SIRT2, SIRT3 and SIRT6 in improving the competence of oocytes grown or matured in vitro in humans and animal models. Recently, SIRT1, SIRT2 and SIRT3 have emerged as protectors of oocyte against postovulatory aging. Transgenic models provide strong evidence that SIRT1 is involved in spermatogenesis by influencing specific functions of male germ cell, Sertoli cells and Leydig cells. When our attention moves to post-fertilization events, maternally derived SIRT3 appears crucial in the protecting early embryos against stress conditions. Finally, increasing SIRT1 activity may have the potential to ameliorate fertility in PCOS, diabetes, endometriosis, xenobiotic stress and aging. Overall, these effects have been ascribed to Sirtuin-mediated regulation of energy homoeostasis, mitochondrial biogenesis, chromatin remodelling and protection against oxidative stress. WIDER IMPLICATIONS:The present review provides challenges and opportunities to stimulate research and exploit Sirtuin-based signalling as diagnostic tools and potential targets for therapeutic applications in reproductive medicine. 10.1093/humupd/dmy003
    Gonadotropins and Their Analogs: Current and Potential Clinical Applications. Anderson Ross C,Newton Claire L,Anderson Richard A,Millar Robert P Endocrine reviews The gonadotropin receptors LH receptor and FSH receptor play a central role in governing reproductive competency/fertility. Gonadotropin hormone analogs have been used clinically for decades in assisted reproductive therapies and in the treatment of various infertility disorders. Though these treatments are effective, the clinical protocols demand multiple injections, and the hormone preparations can lack uniformity and stability. The past two decades have seen a drive to develop chimeric and modified peptide analogs with more desirable pharmacokinetic profiles, with some displaying clinical efficacy, such as corifollitropin alfa, which is now in clinical use. More recently, low-molecular-weight, orally active molecules with activity at gonadotropin receptors have been developed. Some have excellent characteristics in animals and in human studies but have not reached the market-largely as a result of acquisitions by large pharma. Nonetheless, such molecules have the potential to mitigate risks currently associated with gonadotropin-based fertility treatments, such as ovarian hyperstimulation syndrome and the demands of injection-based therapies. There is also scope for novel use beyond the current remit of gonadotropin analogs in fertility treatments, including application as novel contraceptives; in the treatment of polycystic ovary syndrome; in the restoration of function to inactivating mutations of gonadotropin receptors; in the treatment of ovarian and prostate cancers; and in the prevention of bone loss and weight gain in postmenopausal women. Here we review the properties and clinical application of current gonadotropin preparations and their analogs, as well as the development of novel orally active, small-molecule nonpeptide analogs. 10.1210/er.2018-00052
    Insulin-like peptide 3 (INSL3) is a major regulator of female reproductive physiology. Ivell Richard,Anand-Ivell Ravinder Human reproduction update BACKGROUND:Insulin-like peptide 3 (INSL3) is a member of the relaxin family of neohormones which has evolved to address specifically mammalian aspects of reproduction related to viviparity and internal fertilization. It was originally identified as a major product of testicular Leydig cells and has proved to be an important biomarker of Leydig cell functional capacity. However, INSL3 is also produced by theca interna cells of growing antral follicles and is secreted into the bloodstream in phases corresponding to the number and health of the follicles. Moreover, gene silencing experiments have shown that INSL3 is essentially required for androstenedione synthesis, which is the major steroid precursor for the granulosa cells of antral follicles to produce oestrogens. Knockout studies in mice confirm that loss of INSL3 or its receptor in females leads to partial infertility, with reduced follicle numbers, ovulations and litter size. Circulating INSL3 concentration corresponds to the reproductive lifespan, beginning with puberty and declining at the menopause, and thus may contribute to the physiology of other organ systems, particularly those relevant for hormone replacement strategies. SEARCH METHODS:A literature review was carried out by exhaustive searching of literature databases (PubMed and Google Scholar) with the search terms INSL3, RLF, Ley-IL and RXFP2. OBJECTIVE AND RATIONALE:We present the first comprehensive review of INSL3 and its specific receptor RXFP2, and their roles in the context of female reproductive physiology. Moreover, we highlight the potential involvement of INSL3 in female reproductive pathology, such as PCOS, its clinical application as a valuable biomarker of reproductive processes, and its potential for therapeutic interventions. OUTCOMES:In the female mammal, INSL3 is largely produced by the theca interna cells of growing antral follicles during the follicular phase of the menstrual (oestrous) cycle. Within the follicle, INSL3 acts via its G-protein-coupled receptor, RXFP2, in an autocrine/paracrine manner to orchestrate and drive the production of the major steroid precursor androstenedione and its conversion by granulosa cells into oestrogens. These in turn create a positive feedback loop promoting the expression of more theca cell INSL3. This is countered by the follicular production of bone morphogenetic proteins and by the LH surge. Thus, the activity of the theca cell INSL3-RXFP2 system effectively determines the production of estradiol within an antral follicle through the follicular phase. INSL3 is also secreted into the circulation where it acts as a valuable biomarker to monitor the growth of antral follicles; it is consequently increased in PCOS and decreased in women with premature ovarian failure (POF). As an endocrine factor, INSL3 may also influence bone metabolism and kidney function. Additionally, INSL3 or its analogues may prove valuable as an adjunct in hormone replacement therapy or to monitor or influence IVF protocols. WIDER IMPLICATIONS:The INSL3-RXFP2 system represents a new regulatory pathway essential for the proper functioning of growing antral follicles. We still know very little about its involvement in pathologies such as PCOS or POF, and its role as a new biomarker of female function needs to be explored more widely to improve diagnosis and treatment of ovarian dysfunction. We need to examine how INSL3 might be used to improve IVF protocols and outcomes. Opportunities should also be investigated in regard to the systemic application of INSL3 as a rejuvenant therapy, with positive effects on bone or kidney function, and possibly also for fertility regulation. Most research to date has involved animal models; this now needs to be extended to include more human studies. 10.1093/humupd/dmy029
    Demographic and evolutionary trends in ovarian function and aging. Laisk Triin,Tšuiko Olga,Jatsenko Tatjana,Hõrak Peeter,Otala Marjut,Lahdenperä Mirkka,Lummaa Virpi,Tuuri Timo,Salumets Andres,Tapanainen Juha S Human reproduction update BACKGROUND:The human female reproductive lifespan is regulated by the dynamics of ovarian function, which in turn is influenced by several factors: from the basic molecular biological mechanisms governing folliculogenesis, to environmental and lifestyle factors affecting the ovarian reserve between conception and menopause. From a broader point of view, global and regional demographic trends play an additional important role in shaping the female reproductive lifespan, and finally, influences on an evolutionary scale have led to the reproductive senescence that precedes somatic senescence in humans. OBJECTIVE AND RATIONALE:The narrative review covers reproductive medicine, by integrating the molecular mechanisms of ovarian function and aging with short-term demographic and long-term evolutionary trends. SEARCH METHODS:PubMed and Google Scholar searches were performed with relevant keywords (menopause, folliculogenesis, reproductive aging, reproductive lifespan and life history theory). The reviewed articles and their references were restricted to those written in English. OUTCOMES:We discuss and summarize the rapidly accumulating information from large-scale population-based and single-reproductive-cell genomic studies, their constraints and advantages in the context of female reproductive aging as well as their possible evolutionary significance on the life history trajectory from foetal-stage folliculogenesis until cessation of ovarian function in menopause. The relevant environmental and lifestyle factors and demographic trends are also discussed in the framework of predominant evolutionary hypotheses explaining the origin and maintenance of menopause. WIDER IMPLICATIONS:The high speed at which new data are generated has so far raised more questions than it has provided solid answers and has been paralleled by a lack of satisfactory interpretations of the findings in the context of human life history theory. Therefore, the recent flood of data could offer an unprecedented tool for future research to possibly confirm or rewrite human evolutionary reproductive history, at the same time providing novel grounds for patient counselling and family planning strategies. 10.1093/humupd/dmy031
    Ovulation: Parallels With Inflammatory Processes. Duffy Diane M,Ko CheMyong,Jo Misung,Brannstrom Mats,Curry Thomas E Endocrine reviews The midcycle surge of LH sets in motion interconnected networks of signaling cascades to bring about rupture of the follicle and release of the oocyte during ovulation. Many mediators of these LH-induced signaling cascades are associated with inflammation, leading to the postulate that ovulation is similar to an inflammatory response. First responders to the LH surge are granulosa and theca cells, which produce steroids, prostaglandins, chemokines, and cytokines, which are also mediators of inflammatory processes. These mediators, in turn, activate both nonimmune ovarian cells as well as resident immune cells within the ovary; additional immune cells are also attracted to the ovary. Collectively, these cells regulate proteolytic pathways to reorganize the follicular stroma, disrupt the granulosa cell basal lamina, and facilitate invasion of vascular endothelial cells. LH-induced mediators initiate cumulus expansion and cumulus oocyte complex detachment, whereas the follicular apex undergoes extensive extracellular matrix remodeling and a loss of the surface epithelium. The remainder of the follicle undergoes rapid angiogenesis and functional differentiation of granulosa and theca cells. Ultimately, these functional and structural changes culminate in follicular rupture and oocyte release. Throughout the ovulatory process, the importance of inflammatory responses is highlighted by the commonalities and similarities between many of these events associated with ovulation and inflammation. However, ovulation includes processes that are distinct from inflammation, such as regulation of steroid action, oocyte maturation, and the eventual release of the oocyte. This review focuses on the commonalities between inflammatory responses and the process of ovulation. 10.1210/er.2018-00075
    Estrogen, Stress, and Depression: Cognitive and Biological Interactions. Albert Kimberly M,Newhouse Paul A Annual review of clinical psychology This article reviews the interactions of estrogen changes and psychosocial stress in contributing to vulnerability to major depressive disorder (MDD) in women. Estrogen modulates brain networks and processes related to changes in stress response, cognition, and emotional dysregulation that are core characteristics of MDD. Synergistic effects of estrogen on cognitive and emotional function, particularly during psychosocial stress, may underlie the association of ovarian hormone fluctuation and depression in women. We propose a model of estrogen effects on multiple brain systems that interface with stress-related emotional and cognitive processes implicated in MDD and discuss possible mechanisms through which reproductive events and changes in estrogen may contribute to MDD risk in women with other concurrent risk factors. 10.1146/annurev-clinpsy-050718-095557
    Turner syndrome: mechanisms and management. Gravholt Claus H,Viuff Mette H,Brun Sara,Stochholm Kirstine,Andersen Niels H Nature reviews. Endocrinology Turner syndrome is a rare condition in women that is associated with either complete or partial loss of one X chromosome, often in mosaic karyotypes. Turner syndrome is associated with short stature, delayed puberty, ovarian dysgenesis, hypergonadotropic hypogonadism, infertility, congenital malformations of the heart, endocrine disorders such as type 1 and type 2 diabetes mellitus, osteoporosis and autoimmune disorders. Morbidity and mortality are increased in women with Turner syndrome compared with the general population and the involvement of multiple organs through all stages of life necessitates a multidisciplinary approach to care. Despite an often conspicuous phenotype, the diagnostic delay can be substantial and the average age at diagnosis is around 15 years of age. However, numerous important clinical advances have been achieved, covering all specialty fields involved in the care of girls and women with Turner syndrome. Here, we present an updated Review of Turner syndrome, covering advances in genetic and genomic mechanisms of disease, associated disorders and multidisciplinary approaches to patient management, including growth hormone therapy and hormone replacement therapy. 10.1038/s41574-019-0224-4
    Ovarian damage from chemotherapy and current approaches to its protection. Spears N,Lopes F,Stefansdottir A,Rossi V,De Felici M,Anderson R A,Klinger F G Human reproduction update BACKGROUND:Anti-cancer therapy is often a cause of premature ovarian insufficiency and infertility since the ovarian follicle reserve is extremely sensitive to the effects of chemotherapy and radiotherapy. While oocyte, embryo and ovarian cortex cryopreservation can help some women with cancer-induced infertility achieve pregnancy, the development of effective methods to protect ovarian function during chemotherapy would be a significant advantage. OBJECTIVE AND RATIONALE:This paper critically discusses the different damaging effects of the most common chemotherapeutic compounds on the ovary, in particular, the ovarian follicles and the molecular pathways that lead to that damage. The mechanisms through which fertility-protective agents might prevent chemotherapy drug-induced follicle loss are then reviewed. SEARCH METHODS:Articles published in English were searched on PubMed up to March 2019 using the following terms: ovary, fertility preservation, chemotherapy, follicle death, adjuvant therapy, cyclophosphamide, cisplatin, doxorubicin. Inclusion and exclusion criteria were applied to the analysis of the protective agents. OUTCOMES:Recent studies reveal how chemotherapeutic drugs can affect the different cellular components of the ovary, causing rapid depletion of the ovarian follicular reserve. The three most commonly used drugs, cyclophosphamide, cisplatin and doxorubicin, cause premature ovarian insufficiency by inducing death and/or accelerated activation of primordial follicles and increased atresia of growing follicles. They also cause an increase in damage to blood vessels and the stromal compartment and increment inflammation. In the past 20 years, many compounds have been investigated as potential protective agents to counteract these adverse effects. The interactions of recently described fertility-protective agents with these damage pathways are discussed. WIDER IMPLICATIONS:Understanding the mechanisms underlying the action of chemotherapy compounds on the various components of the ovary is essential for the development of efficient and targeted pharmacological therapies that could protect and prolong female fertility. While there are increasing preclinical investigations of potential fertility preserving adjuvants, there remains a lack of approaches that are being developed and tested clinically. 10.1093/humupd/dmz027