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      Use of Growth Hormone in the IVF Treatment of Women With Poor Ovarian Reserve

      review-article
      1 , 2 , *
      Frontiers in Endocrinology
      Frontiers Media S.A.
      growth hormone, IVF, ovarian reserve, poor responder, embryo quality

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          Abstract

          Growth hormone (GH) has been used as an adjunct in the field of female infertility treatment for more than 25 years, although, apart from treating women with GH deficiency its role has not yet been clarified. Contributing to this lack of clarity is that several underpowered studies have been performed on women undergoing IVF treatment, with a previous “poor response” to ovarian stimulation, which have suggested a favorable outcome. Meta-analysis of randomized controlled trials has demonstrated a benefit for the use of the adjunct growth hormone, in comparison to placebo; with reductions in the duration of ovarian stimulation required prior to oocyte retrieval, with a greater number of oocytes collected, and improvements in many of the early clinical parameters with the use of GH. However, no benefit of an increased chance of a live birth with the use of growth hormone for the “poor responding” patient has been determined. Consequently the role of GH to treat a woman with a poor response to ovarian stimulation cannot be supported on the basis of the available evidence. However, the place for GH in the treatment of women undergoing IVF may yet still be determined, as it is also used, without firm evidence of benefit; for women with poor embryonic development, poor endometrial development and for women who do not conceive despite multiple embryo transfers (recurrent implantation failure).

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          Most cited references43

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          How to improve the probability of pregnancy in poor responders undergoing in vitro fertilization: a systematic review and meta-analysis.

          To systematically review the literature to identify randomized controlled trials, which evaluate interventions aiming to improve the probability of pregnancy in poor responders undergoing in vitro fertilization (IVF). Systematic review and meta-analysis. University-based hospital. None. Pregnancy rate. Twenty-two eligible randomized controlled trials were identified that evaluated in total 15 interventions to increase pregnancy rates in poor responders. Based on limited evidence, the only interventions that appear to increase the probability of pregnancy were the addition of GH to ovarian stimulation (odds ratio for live birth: 5.22, confidence interval: 95% 1.09-24.99) and the performance of embryo transfer on day 2 compared with day 3 (ongoing pregnancy rate: 27.7% vs. 16.3%, respectively; difference: +11.4, 95% confidence interval: +1.6 to +21.0). Insufficient evidence exists to recommend most of the treatments proposed to improve pregnancy rates in poor responders. Currently, there is some evidence to suggest that addition of GH, as well as performing embryo transfer on day 2 versus day 3, appear to improve the probability of pregnancy.
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            Effects of an Igf1 gene null mutation on mouse reproduction.

            Both sexes of adult mice homozygous for a targeted mutation of the Igf1 gene, encoding insulin-like growth factor 1, are infertile dwarfs (approximately 30% of normal size). The testes are reduced in size less than expected from the degree of dwarfism but sustain spermatogenesis only at 18% of the normal level. The epididymides are overall nearly allometric to the reduced body weight, but the distal regions of the duct, vas deferens, seminal vesicles, and prostate are vestigial. Despite the mutational impact on the epididymis, capacitated sperm are able to fertilize wild type eggs in vitro. It is hypothesized that the infertility of male mutants is caused by failure of androgenization resulting in absence of mating behavior, due to drastically reduced levels of serum testosterone (18% of normal). This hormonal deficiency was correlated with an ultrastructural analysis of mutant Leydig cells revealing a significant developmental delay, while assays in organ culture showed that the basal and LH-stimulated production of testosterone by testicular parenchyma is reduced in comparison with wild type controls. The female mutants fail to ovulate even after administration of gonadotropins, which is apparently the primary cause of their infertility, and possess an infantile uterus that exhibits a dramatic hypoplasia especially in the myometrium. The phenotypic manifestations of the mutation were correlated with the localization of transcripts for insulin-like growth factor I and its cognate receptor in wild type reproductive tissues by in situ hybridization.
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              Addition of growth hormone to gonadotrophins in ovarian stimulation of poor responders treated by in-vitro fertilization: a systematic review and meta-analysis.

              Whether the addition of growth hormone (GH) can improve the probability of pregnancy in poor responders undergoing ovarian stimulation for in-vitro fertilization (IVF) has been examined to date by several underpowered studies, which have not provided solid conclusions. A computerized literature search in MEDLINE, EMBASE, CENTRAL and randomized controlled trial (RCT) registries was performed independently by two reviewers, aiming to identify RCTs that evaluated the following research question: does GH addition increase the probability of pregnancy in poor responders undergoing ovarian stimulation with gonadotrophin releasing hormone (GnRH) analogues and gonadotrophins for IVF? Six relevant RCTs were identified, including a total of 169 patients. GH addition significantly increased clinical pregnancy (rate difference: +16%, 95% CI: +4 to +28; fixed effects model) (number-needed-to-treat (NNT) = 6, 95% CI: 4-25) and live birth rates (rate difference: +17%, 95% CI: +5 to +30; fixed effects model) (NNT = 6; 95% CI: 3-20). Furthermore, GH addition was associated with a significantly higher proportion of patients reaching embryo transfer (rate difference: +22%, 95% CI: +7 to +36; fixed effects model). The present meta-analysis provides evidence that GH addition increases the probability of clinical pregnancy and live birth in poor responders undergoing ovarian stimulation with GnRH analogues and gonadotrophins for IVF. However, the total number of patients analyzed is small and thus further RCTs are warranted to prove or disprove this finding.
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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
                24 July 2019
                2019
                : 10
                : 500
                Affiliations
                [1] 1Division of Obstetrics and Gynaecology, University of Western Australia , Perth, WA, Australia
                [2] 2Fertility Specialists of Western Australia, Bethesda Hospital , Claremont, WA, Australia
                Author notes

                Edited by: Tom Kelsey, University of St. Andrews, United Kingdom

                Reviewed by: Kannamannadiar Jayaprakasan, University of Nottingham, United Kingdom; Rong Yuan, Southern Illinois University Carbondale, United States

                *Correspondence: Roger J. Hart roger.hart@ 123456uwa.edu.au

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

                Article
                10.3389/fendo.2019.00500
                6667844
                31396160
                99232f17-f396-4beb-b58a-6ec115cb667e
                Copyright © 2019 Hart.

                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
                : 16 April 2019
                : 09 July 2019
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 45, Pages: 7, Words: 4591
                Categories
                Endocrinology
                Mini Review

                Endocrinology & Diabetes
                growth hormone,ivf,ovarian reserve,poor responder,embryo quality
                Endocrinology & Diabetes
                growth hormone, ivf, ovarian reserve, poor responder, embryo quality

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