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      Ovarian Reserve Markers to Identify Poor Responders in the Context of Poseidon Classification

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          Abstract

          It is well-known that poor ovarian reserve is a cause of infertility, poor response to gonadotrophin stimulation and poor success rate after in vitro fertilization (IVF) cycles. Some years ago a consensus was elaborated on precise criteria which can lead to a correct identification of poor responders (the Bologna criteria). More recently, the POSEIDON group has proposed a new stratified classification of patients with low prognosis, also with the aim of providing clinical indications for the management of these patients. A literature search was carried out for studies that investigated the ability of ovarian reserve markers, in particular AMH and AFC, to predict poor ovarian response in IVF cycles; secondly, studies regarding the Bologna criteria and their prognostic value were analyzed and available literature on POSEIDON classification was reported. The most recent markers of ovarian reserve (serum AMH and ultrasound AFC) have shown to provide a direct and accurate measurement of ovarian follicle pool. These markers have generally shown comparable predictive power for ovarian response and a number of retrieved oocytes in IVF cycles. “Abnormal ovarian reserve test” is a very important parameter both in the Bologna criteria and in the POSEIDON classification. Several studies have already been published about the reproductive outcome of patients defined as poor responders according to the ESHRE Bologna criteria: all of them agree on the poor IVF outcome and low pregnancy rate of these patients. Instead, being the POSEIDON classification of very recent publication, the efficacy of the POSEIDON approach in improving management and outcomes of POR patients has yet to be tested and validated with future prospective clinical trials. Prediction of poor response may help clinicians choose the stimulation protocol with the aim of gaining patient compliance and cost reduction, and many efforts have been made by researchers in this sense, including the formulation of the Bologna criteria and of the POSEIDON classification, in which the ovarian reserve markers (AMH and AFC) play a fundamental role.

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          Most cited references66

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          GnRH antagonist versus long agonist protocols in IVF: a systematic review and meta-analysis accounting for patient type.

          Most reviews of IVF ovarian stimulation protocols have insufficiently accounted for various patient populations, such as ovulatory women, women with polycystic ovary syndrome (PCOS) or women with poor ovarian response, and have included studies in which the agonist or antagonist was not the only variable between the compared study arms.
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            Which follicles make the most anti-Mullerian hormone in humans? Evidence for an abrupt decline in AMH production at the time of follicle selection.

            Anti-Müllerian hormone (AMH) is exclusively produced by granulosa cells (GC) of the developing pre-antral and antral follicles, and AMH is increasingly used to assess ovarian function. It is unclear which size follicles make the most AMH (total content) and are the main contributors to circulating AMH concentrations. To determine AMH gene expression in GC (q-RT-PCR) and follicular AMH production (Elisa and RIA) in relation to follicular development, 87 follicles (3-13 mm diameter) including both GC and the corresponding follicular fluid (FF) were collected in connection with fertility preservation of human ovaries. Further, follicle number and diameter, graded in 1 mm increments, were determined by 3D ultrasound in 113 women in their natural menstrual cycle to determine follicle number and diameter in relation to circulating AMH levels. This study demonstrates for the first time a positive association between AMH gene expression in human and both total follicular fluid AMH (P < 0.02) and follicular fluid AMH concentration (P < 0.01). AMH gene expression and total AMH protein increased until a follicular diameter of 8 mm, after which a sharp decline occurred. In vivo modelling confirmed that 5-8 mm follicles make the greatest contribution to serum AMH, estimated for the first time in human to be 60% of the circulating concentration. Significant positive associations between gene expression of AMH and FSHR, AR and AMHR2 expression (P < 0.00001 for all three) and significant negative association between follicular fluid AMH concentration and CYP19a1 expression were found (P < 0.0001). Both AMH gene expression (P < 0.02) and follicular fluid concentration of AMH (P < 0.00001) correlated negatively with estradiol concentration.
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              Assessing ovarian response: antral follicle count versus anti-Müllerian hormone.

              Oocyte number and quality decline with age; however, fertility varies significantly even among women of the same age. Various measures have been developed to predict response to ovarian stimulation and reproductive potential. Evaluation of ovarian reserve can identify patients who may experience poor response or hyper-response to exogenous gonadotrophins and can aid in the personalization of treatment to achieve good response and minimize risks. In recent years, two key methods, antral follicle count (AFC), an ultrasound biomarker of follicle number, and the concentration of serum anti-Müllerian hormone (AMH), a hormone biomarker of follicle number, have emerged as preferred methods for assessing ovarian reserve. In this review, a live debate held at the American Society for Reproductive Medicine 2013 Annual Meeting is expanded upon to compare the predictive values, merits, and disadvantages of AFC and AMH level. An ovarian reserve measure without limitations has not yet been discovered, although both AFC and AMH have good predictive value. Published evidence, however, as well as the objectivity and potential standardization of AMH level and the convenience of testing any time throughout the menstrual cycle, leans towards AMH level becoming the gold-standard biomarker to evaluate ovarian reserve and predict ovarian response to stimulation.
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                Author and article information

                Contributors
                Journal
                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                1664-2392
                08 May 2019
                2019
                : 10
                : 281
                Affiliations
                Section of Obstetrics and Gynecology, Mother-Infant Department, University of Modena and Reggio Emilia , Modena, Italy
                Author notes

                Edited by: Peter Humaidan, Aarhus University, Denmark

                Reviewed by: Carlo Alviggi, University of Naples Federico II, Italy; Andreas Norbert Schüring, University Hospital Münster, Germany; Jung Ryeol Lee, Seoul National University College of Medicine, South Korea

                *Correspondence: Antonio La Marca antlamarca@ 123456libero.it

                This article was submitted to Reproduction, a section of the journal Frontiers in Endocrinology

                Article
                10.3389/fendo.2019.00281
                6517840
                31139145
                6cb6a61e-fba8-4d73-a9a5-4ba431e099db
                Copyright © 2019 Grisendi, Mastellari and La Marca.

                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
                : 21 May 2018
                : 16 April 2019
                Page count
                Figures: 0, Tables: 2, Equations: 0, References: 77, Pages: 8, Words: 7599
                Categories
                Endocrinology
                Mini Review

                Endocrinology & Diabetes
                ivf,poor response,ovarian reserve markers,amh,afc,bologna criteria,live birth rate,poseidon classification

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