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      Age-related decline in the expression of GDF9 and BMP15 genes in follicle fluid and granulosa cells derived from poor ovarian responders


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          Growth differentiation factor 9 ( GDF9) and bone morphogenetic protein 15 ( BMP15) genes play important roles in folliculogenesis. Altered expression of the two have been found among patients with poor ovarian response (POR). In this prospective cohort study, we have determined the expression of the GDF9 and BMP15 genes in follicle fluid (FF) and granulosa cells (GCs) derived from poor ovarian responders grouped by age, and explored its correlation with the outcome of in vitro fertilization and embryo transfer (IVF-ET) treatment.


          A total of 196 patients with POR were enrolled from a tertiary teaching hospital. The patients were diagnosed by the Bologna criteria and sub-divided into group A (< 35 year old), group B (35–40 year old), and group C (> 40 year old). A GnRH antagonist protocol was conducted for all patients, and FF and GCs were collected after oocyte retrieval. Expression of the GDF9 and BMP15 genes in the FF and GCs was determined with enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting.


          Compared with group C, groups A and B had significantly more two pronuclei (2PN) oocytes and transplantable embryos, in addition with higher rates of implantation and clinical pregnancy ( P <  0.05). The expression level of GDF9 and BMP15 genes in the FF and GCs differed significantly among the three groups ( P <  0.05), showing a trend of decline along with age. The ratio of GDF9/BMP15 mRNA levels were similar among the three groups ( P > 0.05). The relative levels of GDF9 and BMP15 proteins in GCs have correlated with the relative mRNA levels in GCs and protein concentrations in FF ( P <  0.05).


          For poor ovarian responders, in particular those over 40, the expression of GDF9 and BMP15 is declined along with increased age and in accompany with poorer oocyte quality and IVF outcome, whilst the ratio of GDF9/BMP15 mRNA levels remained relatively constant.

          Trial registration

          Chinese Clinical Trial Registry Center ( ChiCTR1800016107). Registered on 11 May 2018.

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          Most cited references41

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          The Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting.

          Many variations in oocyte and embryo grading make inter-laboratory comparisons extremely difficult. This paper reports the proceedings of an international consensus meeting on oocyte and embryo morphology assessment. Background presentations about current practice were given. The expert panel developed a set of consensus points to define the minimum criteria for oocyte and embryo morphology assessment. It is expected that the definition of common terminology and standardization of laboratory practice related to embryo morphology assessment will result in more effective comparisons of treatment outcomes. This document is intended to be referenced as a global consensus to allow standardized reporting of the minimum data set required for the accurate description of embryo development.
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            ESHRE consensus on the definition of 'poor response' to ovarian stimulation for in vitro fertilization: the Bologna criteria.

            The definition presented here represents the first realistic attempt by the scientific community to standardize the definition of poor ovarian response (POR) in a simple and reproducible manner. POR to ovarian stimulation usually indicates a reduction in follicular response, resulting in a reduced number of retrieved oocytes. It has been recognized that, in order to define the poor response in IVF, at least two of the following three features must be present: (i) advanced maternal age or any other risk factor for POR; (ii) a previous POR; and (iii) an abnormal ovarian reserve test (ORT). Two episodes of POR after maximal stimulation are sufficient to define a patient as poor responder in the absence of advanced maternal age or abnormal ORT. By definition, the term POR refers to the ovarian response, and therefore, one stimulated cycle is considered essential for the diagnosis of POR. However, patients of advanced age with an abnormal ORT may be classified as poor responders since both advanced age and an abnormal ORT may indicate reduced ovarian reserve and act as a surrogate of ovarian stimulation cycle outcome. In this case, the patients should be more properly defined as 'expected poor responder'. If this definition of POR is uniformly adapted as the 'minimal' criteria needed to select patients for future clinical trials, more homogeneous populations will be tested for any new protocols. Finally, by reducing bias caused by spurious POR definitions, it will be possible to compare results and to draw reliable conclusions.
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              The nature of aneuploidy with increasing age of the female partner: a review of 15,169 consecutive trophectoderm biopsies evaluated with comprehensive chromosomal screening.

              To determine the relationship between the age of the female partner and the prevalence and nature of human embryonic aneuploidy. Retrospective. Academic. Trophectoderm biopsies. Comprehensive chromosomal screening performed on patients with blastocysts available for biopsy. Evaluation of the impact of maternal age on the prevalence of aneuploidy, the probability of having no euploid embryos within a cohort, the complexity of aneuploidy as gauged by the number of aneuploid chromosomes, and the trisomy/monosomy ratio. Aneuploidy increased predictably after 26 years of age. A slightly increased prevalence was noted at younger ages, with >40% aneuploidy in women 23 years and under. The no euploid embryo rate was lowest (2% to 6%) in women aged 26 to 37, was 33% at age 42, and was 53% at age 44. Among the biopsies with aneuploidy, 64% involved a single chromosome, 20% two chromosomes, and 16% three chromosomes, with the proportion of more complex aneuploidy increasing with age. Finally, the trisomy/monosomy ratio approximated 1 and increased minimally with age. The lowest risk for embryonic aneuploidy was between ages 26 and 30. Both younger and older age groups had higher rates of aneuploidy and an increased risk for more complex aneuploidies. The overall risk did not measurably change after age 43. Trisomies and monosomies are equally prevalent. Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

                Author and article information

                J Ovarian Res
                J Ovarian Res
                Journal of Ovarian Research
                BioMed Central (London )
                4 January 2021
                4 January 2021
                : 14
                : 1
                [1 ]GRID grid.413856.d, ISNI 0000 0004 1799 3643, Reproductive Medicine Center, Sichuan Provincial Women’s and Children’s Hospital, The Affiliated Women’s and Children’s Hospital of Chengdu Medical College, ; 290 Shayan West Second Street, Wuhou District, Chengdu, 610045 Sichuan China
                [2 ]GRID grid.13291.38, ISNI 0000 0001 0807 1581, State Key Laboratory of Biotherapy, West China Hospital, , Sichuan University, ; 37 Guoxuexiang, Wuhou District, Chengdu, 610041 Sichuan China
                [3 ]GRID grid.413856.d, ISNI 0000 0004 1799 3643, Laboratory Medicine Center, Sichuan Provincial Women’s and Children’s Hospital, , The Affiliated Women’s and Children’s Hospital of Chengdu Medical College, ; Chengdu, 610045 Sichuan China
                [4 ]GRID grid.413856.d, ISNI 0000 0004 1799 3643, Department of Genetics, , School of Bioscience and Technology, Chengdu Medical College, ; Chengdu, 610500 Sichuan China
                Author information
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                : 14 May 2020
                : 17 December 2020
                Funded by: the Scientific Research Program of Sichuan Medical Association
                Award ID: S17060
                Award Recipient :
                Funded by: the Technology Innovation Program of Science and Technology Bureau of Chengdu
                Award ID: 2018-YF05-00247-SN
                Award Recipient :
                Funded by: the Science and Technology Innovation Fund of Sichuan Provincial Hospital for Women and Children
                Award ID: 20180205
                Award Recipient :
                Funded by: the Innovation and Entrepreneurship Training Program for College Students of China
                Award ID: 508-2043140
                Award Recipient :
                Funded by: the Scientific Research Project of Sichuan Provincial Health Commission
                Award ID: 20PJ123
                Award Recipient :
                Custom metadata
                © The Author(s) 2021

                Obstetrics & Gynecology
                gdf9 gene,bmp15 gene,poor ovarian response,in vitro fertilization,age
                Obstetrics & Gynecology
                gdf9 gene, bmp15 gene, poor ovarian response, in vitro fertilization, age


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