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      Individualization of FSH Doses in Assisted Reproduction: Facts and Fiction

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          Abstract

          The art of ovarian stimulation for IVF/ICSI treatment using exogenous FSH should be balanced against the relative contribution of other steps of the ART process such as the IVF-lab-phase and the Embryo-Transfer. The aim of ovarian stimulation is to obtain a certain number of oocytes, that will enable the best probability of achieving a live birth. It has been suggested that more oocytes will create a better prospect for pregnancy, but studies on the question whether the retrieval of a few oocytes less or more will make the difference are not clearly supportive for this mantra. Personalization strategies have been the subject of many studies over the past 20 years. Creating the optimal response in a patient in terms of live birth prognosis as well as OHSS risks may be based on information from the Ovarian Reserve testing using the Antral Follicle Count or Anti-Mullerian Hormone, the patient's bodyweight, the ovarian response in a previous cycle, and the dosage level of FSH. Taken together, steering the ovarian response into a supposed optimal range may appear difficult as the interrelation for each of these factors with the egg number is weak. Using OR testing for choosing FSH dosage, compared to a standard normal dosage of 150 IU, has been studied in several trials. Dosage individualization, in general, does not appear to improve the prospects for live birth, but the reduction in OHSS risk may be substantial. This implies that the use of high dosages of FSH in predicted LOW responders lacks any cost-benefit for the patient and may be abandoned, while in predicted HIGH responders, reduction of the usual dosage level of 150 IU may create better safety, provided that in case of an unexpected LOW response cancelation of the cycle is refrained from. In view of recent developments in using GnRH agonist triggering of final oocyte maturation, the trend could be that with the Antagonist co-medication system and a standard dosage of 150 IU of FSH, prior ovarian reserve testing may become futile, as safety can be managed well in actual HIGH responders by replacing the high dose hCG trigger.

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          Association between the number of eggs and live birth in IVF treatment: an analysis of 400 135 treatment cycles.

          While live birth is the principal clinical outcome following in vitro fertilization (IVF) treatment, the number of eggs retrieved following ovarian stimulation is often used as a surrogate outcome in clinical practice and research. The aim of this study was to explore the association between egg number and live birth following IVF treatment and identify the number of eggs that would optimize the IVF outcome. Anonymized data on all IVF cycles performed in the UK from April 1991 to June 2008 were obtained from the Human Fertilization and Embryology Authority (HFEA). We analysed data from 400 135 IVF cycles. A logistic model was fitted to predict live birth using fractional polynomials to handle the number of eggs as a continuous independent variable. The prediction model, which was validated on a separate HFEA data set, allowed the estimation of the probability of live birth for a given number of eggs, stratified by age group. We produced a nomogram to predict the live birth rate (LBR) following IVF based on the number of eggs and the age of the female. The median number of eggs retrieved per cycle was 9 [inter-quartile range (IQR) 6-13]. The overall LBR was 21.3% per fresh IVF cycle. There was a strong association between the number of eggs and LBR; LBR rose with an increasing number of eggs up to ∼15, plateaued between 15 and 20 eggs and steadily declined beyond 20 eggs. During 2006-2007, the predicted LBR for women with 15 eggs retrieved in age groups 18-34, 35-37, 38-39 and 40 years and over was 40, 36, 27 and 16%, respectively. There was a steady increase in the LBR per egg retrieved over time since 1991. The relationship between the number of eggs and live birth, across all female age groups, suggests that the number of eggs in IVF is a robust surrogate outcome for clinical success. The results showed a non-linear relationship between the number of eggs and LBR following IVF treatment. The number of eggs to maximize the LBR is ∼15.
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            Milder ovarian stimulation for in-vitro fertilization reduces aneuploidy in the human preimplantation embryo: a randomized controlled trial.

            To test whether ovarian stimulation for in-vitro fertilization (IVF) affects oocyte quality and thus chromosome segregation behaviour during meiosis and early embryo development, preimplantation genetic screening of embryos was employed in a prospective, randomized controlled trial, comparing two ovarian stimulation regimens. Infertile patients under 38 years of age were randomly assigned to undergo a mild stimulation regimen using gonadotrophin-releasing hormone (GnRH) antagonist co-treatment (67 patients), which does not disrupt secondary follicle recruitment, or a conventional high-dose exogenous gonadotrophin regimen and GnRH agonist co-treatment (44 patients). Following IVF, embryos were biopsied at the eight-cell stage and the copy number of 10 chromosomes was analysed in 1 or 2 blastomeres. The study was terminated prematurely, after an unplanned interim analysis (which included 61% of the planned number of patients) found a lower embryo aneuploidy rate following mild stimulation. Compared with conventional stimulation, significantly fewer oocytes and embryos were obtained following mild stimulation (P < 0.01 and < 0.05, respectively). Consequently, both regimens generated on average a similar number (1.8) of chromosomally normal embryos. Differences in rates of mosaic embryos suggest an effect of ovarian stimulation on mitotic segregation errors. Future ovarian stimulation strategies should avoid maximizing oocyte yield, but aim at generating a sufficient number of chromosomally normal embryos by reduced interference with ovarian physiology.
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              Cumulative live birth rates according to the number of oocytes retrieved after the first ovarian stimulation for in vitro fertilization/intracytoplasmic sperm injection: a multicenter multinational analysis including ∼15,000 women

              To evaluate the association between the number of oocytes retrieved and cumulative live birth rates.
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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
                26 April 2019
                2019
                : 10
                : 181
                Affiliations
                University Medical Center Utrecht , Utrecht, Netherlands
                Author notes

                Edited by: Livio Casarini, University of Modena and Reggio Emilia, Italy

                Reviewed by: Antonio La Marca, University of Modena and Reggio Emilia, Italy; Verena Nordhoff, University of Münster, Germany

                *Correspondence: Frank J. Broekmans f.broekmans@ 123456umcutrecht.nl

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

                Article
                10.3389/fendo.2019.00181
                6497745
                31080437
                a34654f9-a539-494f-a601-b215ffc4617d
                Copyright © 2019 Broekmans.

                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
                : 01 November 2018
                : 04 March 2019
                Page count
                Figures: 3, Tables: 0, Equations: 0, References: 50, Pages: 8, Words: 6493
                Categories
                Endocrinology
                Review

                Endocrinology & Diabetes
                fsh,ovarian response,live birth,safety,ohss,ovarian reserve testing,dosage individualization,ovarian stimulation

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