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      The novel POSEIDON stratification of ‘Low prognosis patients in Assisted Reproductive Technology’ and its proposed marker of successful outcome

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          Abstract

          In reproductive medicine little progress has been achieved regarding the clinical management of patients with a reduced ovarian reserve or poor ovarian response (POR) to stimulation with exogenous gonadotropins -a frustrating experience for clinicians as well as patients. Despite the efforts to optimize the definition of this subgroup of patients, the existing POR criteria unfortunately comprise a heterogeneous population and, importantly, do not offer any recommendations for clinical handling. Recently, the POSEIDON group ( Patient- Oriented Strategies Encompassing Individualize D Oocyte Number) proposed a new stratification of assisted reproductive technology (ART) in patients with a reduced ovarian reserve or unexpected inappropriate ovarian response to exogenous gonadotropins. In brief, four subgroups have been suggested based on quantitative and qualitative parameters, namely, i. Age and the expected aneuploidy rate; ii. Ovarian biomarkers (i.e. antral follicle count [AFC] and anti-Müllerian hormone [AMH]), and iii. Ovarian response - provided a previous stimulation cycle was performed. The new classification introduces a more nuanced picture of the “low prognosis patient” in ART, using clinically relevant criteria to guide the physician to most optimally manage this group of patients. The POSEIDON group also introduced a new measure for successful ART treatment, namely, the ability to retrieve the number of oocytes needed for the specific patient to obtain at least one euploid embryo for transfer. This feature represents a pragmatic endpoint to clinicians and enables the development of prediction models aiming to reduce the time-to-pregnancy (TTP). Consequently, the POSEIDON stratification should not be applied for retrospective analyses having live birth rate (LBR) as endpoint. Such an approach would fail as the attribution of patients to each Poseidon group is related to specific requirements and could only be made prospectively. On the other hand, any prospective approach (i.e. RCT) should be performed separately in each specific group.

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          Bivalent separation into univalents precedes age-related meiosis I errors in oocytes

          The frequency of chromosome segregation errors during meiosis I (MI) in oocytes increases with age. The two-hit model suggests that errors are caused by the combination of a first hit that creates susceptible crossover configurations and a second hit comprising an age-related reduction in chromosome cohesion. This model predicts an age-related increase in univalents, but direct evidence of this phenomenon as a major cause of segregation errors has been lacking. Here, we provide the first live analysis of single chromosomes undergoing segregation errors during MI in the oocytes of naturally aged mice. Chromosome tracking reveals that 80% of the errors are preceded by bivalent separation into univalents. The set of the univalents is biased towards balanced and unbalanced predivision of sister chromatids during MI. Moreover, we find univalents predisposed to predivision in human oocytes. This study defines premature bivalent separation into univalents as the primary defect responsible for age-related aneuploidy.
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            Androgens (dehydroepiandrosterone or testosterone) for women undergoing assisted reproduction.

            Infertility is a condition affecting 10% to 15% of couples of reproductive age. It is generally defined as "the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse". The treatment of infertility may involve manipulation of gametes or of the embryos themselves. These techniques are together known as assisted reproductive technology (ART). Practitioners are constantly seeking alternative or adjunct treatments, or both, in the hope that they may improve the outcome of assisted reproductive techniques. This Cochrane review focusses on the adjunct use of synthetic versions of two naturally-produced hormones, dehydroepiandrosterone (DHEA) and testosterone (T), in assisted reproduction.DHEA and its derivative testosterone are steroid hormones proposed to increase conception rates by positively affecting follicular response to gonadotrophin stimulation, leading to greater oocyte yields and, in turn, increased chance of pregnancy.
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              Array CGH analysis shows that aneuploidy is not related to the number of embryos generated.

              This study retrospectively analysed array comparative genomic hybridization (CGH) results of 7753 embryos from 990 patients to determine the frequency of embryonic euploidy and its relationship with the cohort size (i.e. the number of embryos available for biopsy and array CGH analysis). Linear regression analysis was performed to assess the effect of cohort size on euploidy rate adjusted for the effect of female age. While increasing female age was associated with a significant decrease in euploidy rate of day-3 and day-5 embryos (P<0.001 for both groups), cohort size was not significantly associated with euploidy rate. Logistic regression analysis was performed to assess the effect of cohort size, adjusted for maternal age, on the likelihood of having at least one euploid embryo available for transfer. The odds of having at least one euploid embryo in an assisted cycle was significantly decreased by increasing female age (P<0.01 for both day-3 and day-5 embryos) and was significantly increased by every additional embryo available for analysis (P<0.001 for both day-3 and day-5 embryos). Copyright © 2012 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                F1000Res
                F1000Res
                F1000Research
                F1000Research
                F1000Research (London, UK )
                2046-1402
                23 December 2016
                2016
                : 5
                : 2911
                Affiliations
                [1 ]Fertility Clinic, Skive Regional Hospital, Skive, Denmark
                [2 ]Faculty of Health, Aarhus University, Skive, Denmark
                [3 ]Department of Neuroscience, Reproductive Science and Odontostomatology, University of Naples Federico II, Naples, Italy
                [4 ]Fertility Center Hamburg, Hamburg, Germany
                [5 ]ANDROFERT, Andrology & Human Reproduction Clinic, Campinas, Brazil
                [1 ]ARIES Consulting, Geneva, Switzerland
                [1 ]IVF Unit, Department of Obstetrics and Gynecology, Edith Wolfson Medical Center, Holon and Sackler Faculty of Medicine, Tel Aviv University (TAU), Tel Aviv, Israel
                [2 ]Reproductive Medicine Unit, Department of Obstetrics and Gynecology, Poriya Medical Center, Israel Faculty of Medicine, Bar-Ilan University, Tiberias, Galilee, 15208, Israel
                [1 ]Division of Reproductive Medicine,Department of Gynecology and Obstetrics, University of São Paulo (USP) , São Paulo, Brazil
                Author notes

                All authors contributed equally to the preparation and revision of the draft manuscript and have agreed to the final content.

                Competing interests: PH, CA, RF, and SE are members of the POSEIDON group.

                Competing interests: No competing interests were disclosed.

                Competing interests: No competing interests were disclosed.

                Competing interests: No competing interests were disclosed.

                Author information
                http://orcid.org/0000-0002-1313-9680
                Article
                10.12688/f1000research.10382.1
                5302217
                28232864
                d058c790-ad34-4afe-adc9-20c2fe317031
                Copyright: © 2016 Humaidan P et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 19 December 2016
                Funding
                This work is supported by institutional funding of Androfert Center to the Poseidon group.
                Categories
                Opinion Article
                Articles
                Female Fertility Regulation
                Pregnancy, Labor, Delivery & Postpartum Care

                assisted reproductive technology,diagnosis,gonadotropins,group poseidon,ovarian stimulation,embryo aneuploidy,poor ovarian response,prognosis.

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