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      Premature Ovarian Insufficiency: Past, Present, and Future

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          Abstract

          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.

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          Most cited references127

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          The transcriptional landscape of the mammalian genome.

          This study describes comprehensive polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome. We identify the 5' and 3' boundaries of 181,047 transcripts with extensive variation in transcripts arising from alternative promoter usage, splicing, and polyadenylation. There are 16,247 new mouse protein-coding transcripts, including 5154 encoding previously unidentified proteins. Genomic mapping of the transcriptome reveals transcriptional forests, with overlapping transcription on both strands, separated by deserts in which few transcripts are observed. The data provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development.
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            Landscape of transcription in human cells

            Summary Eukaryotic cells make many types of primary and processed RNAs that are found either in specific sub-cellular compartments or throughout the cells. A complete catalogue of these RNAs is not yet available and their characteristic sub-cellular localizations are also poorly understood. Since RNA represents the direct output of the genetic information encoded by genomes and a significant proportion of a cell’s regulatory capabilities are focused on its synthesis, processing, transport, modifications and translation, the generation of such a catalogue is crucial for understanding genome function. Here we report evidence that three quarters of the human genome is capable of being transcribed, as well as observations about the range and levels of expression, localization, processing fates, regulatory regions and modifications of almost all currently annotated and thousands of previously unannotated RNAs. These observations taken together prompt to a redefinition of the concept of a gene.
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              Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment.

              Primary ovarian insufficiency (POI) and polycystic ovarian syndrome are ovarian diseases causing infertility. Although there is no effective treatment for POI, therapies for polycystic ovarian syndrome include ovarian wedge resection or laser drilling to induce follicle growth. Underlying mechanisms for these disruptive procedures are unclear. Here, we explored the role of the conserved Hippo signaling pathway that serves to maintain optimal size across organs and species. We found that fragmentation of murine ovaries promoted actin polymerization and disrupted ovarian Hippo signaling, leading to increased expression of downstream growth factors, promotion of follicle growth, and the generation of mature oocytes. In addition to elucidating mechanisms underlying follicle growth elicited by ovarian damage, we further demonstrated additive follicle growth when ovarian fragmentation was combined with Akt stimulator treatments. We then extended results to treatment of infertility in POI patients via disruption of Hippo signaling by fragmenting ovaries followed by Akt stimulator treatment and autografting. We successfully promoted follicle growth, retrieved mature oocytes, and performed in vitro fertilization. Following embryo transfer, a healthy baby was delivered. The ovarian fragmentation-in vitro activation approach is not only valuable for treating infertility of POI patients but could also be useful for middle-aged infertile women, cancer patients undergoing sterilizing treatments, and other conditions of diminished ovarian reserve.
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                Author and article information

                Contributors
                Journal
                Front Cell Dev Biol
                Front Cell Dev Biol
                Front. Cell Dev. Biol.
                Frontiers in Cell and Developmental Biology
                Frontiers Media S.A.
                2296-634X
                10 May 2021
                2021
                : 9
                : 672890
                Affiliations
                [1] 1Department of Obstetrics and Gynecology, Gachon University Gil Medical Center, College of Medicine, Gachon University , Incheon, South Korea
                [2] 2Department of Molecular Medicine, College of Medicine, Gachon University , Incheon, South Korea
                [3] 3Lee Gil Ya Cancer and Diabetes Institute , Incheon, South Korea
                [4] 4Department of Health Sciences and Technology, GAIHST, Gachon University , Incheon, South Korea
                Author notes

                Edited by: Marcela Alejandra Michaut, CONICET Mario H. Burgos Institute of Histology and Embryology (IHEM), Argentina

                Reviewed by: So-Youn Kim, University of Nebraska Medical Center, United States; April K. Binder, Central Washington University, United States

                *Correspondence: Zobia Umair, zobiamughal@ 123456gmail.com

                This article was submitted to Molecular and Cellular Reproduction, a section of the journal Frontiers in Cell and Developmental Biology

                Article
                10.3389/fcell.2021.672890
                8141617
                34041247
                02f8bc1f-cb6b-4a25-aec7-07facd9b2623
                Copyright © 2021 Chon, Umair and Yoon.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 26 February 2021
                : 09 April 2021
                Page count
                Figures: 1, Tables: 5, Equations: 0, References: 127, Pages: 13, Words: 0
                Funding
                Funded by: National Research Foundation of Korea 10.13039/501100003725
                Award ID: NRF-2020R1C1C1009913
                Funded by: Gil Medical Center, Gachon University 10.13039/501100006107
                Award ID: FRD2019-03
                Categories
                Cell and Developmental Biology
                Review

                premature ovarian insufficiency,premature ovarian failure,early menopause,ovarian aging,ovary

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