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      Progestin-primed ovarian stimulation for fertility preservation in women with cancer: A comparative study

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          Abstract

          Background

          In women scheduled for cancer treatment, oocytes cryopreservation is a well-established procedure. Random start protocols have been a substantial improvement in this setting, allowing to prevent delay in the initiation of cancer treatments. However, there is still the need to optimize the regimen of ovarian stimulation, to make treatments more patient-friendly and to reduce costs.

          Methods

          This retrospective study compares two periods (2019 and 2020), corresponding to two different ovarian stimulation regimens. In 2019, women were treated with corifollitropin, recombinant FSH and GnRH antagonists. Ovulation was triggered with GnRH agonists. In 2020, the policy changed, and women were treated with a progestin-primed ovarian stimulation (PPOS) protocol with human menopausal gonadotropin (hMG) and dual trigger (GnRH agonist and low dose hCG) Continuous data are reported as median [Interquartile Range]. To overcome expected changes in baseline characteristics of the women, the primary outcome was the ratio between the number of mature oocytes retrieved and serum anti-mullerian hormone (AMH) in ng/ml.

          Results

          Overall, 124 women were selected, 46 in 2019 and 78 in 2020. The ratio between the number of mature oocytes retrieved and serum AMH in the first and second period was 4.0 [2.3–7.1] and 4.0 [2.7–6.8], respectively (p = 0.80). The number of scans was 3 [3–4] and 3 [2–3], respectively (p<0.001). The total costs of the drugs used for ovarian stimulation were 940 € [774–1,096 €] and 520 € [434–564 €], respectively (p<0.001).

          Conclusions

          Random start PPOS with hMG and dual trigger represents an easy and affordable ovarian stimulation protocol for fertility preservation in women with cancer, showing similar efficacy and being more friendly and economical.

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          Most cited references33

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          Fertility Preservation in Patients With Cancer: ASCO Clinical Practice Guideline Update

          Purpose To provide current recommendations about fertility preservation for adults and children with cancer. Methods A systematic review of the literature published from January 2013 to March 2017 was completed using PubMed and the Cochrane Library. An Update Panel reviewed the identified publications. Results There were 61 publications identified and reviewed. None of these publications prompted a significant change in the 2013 recommendations. Recommendations Health care providers should initiate the discussion on the possibility of infertility with patients with cancer treated during their reproductive years or with parents/guardians of children as early as possible. Providers should be prepared to discuss fertility preservation options and/or to refer all potential patients to appropriate reproductive specialists. Although patients may be focused initially on their cancer diagnosis, providers should advise patients regarding potential threats to fertility as early as possible in the treatment process so as to allow for the widest array of options for fertility preservation. The discussion should be documented. Sperm, oocyte, and embryo cryopreservation are considered standard practice and are widely available. There is conflicting evidence to recommend gonadotrophin-releasing hormone agonists (GnRHa) and other means of ovarian suppression for fertility preservation. The Panel recognizes that, when proven fertility preservation methods are not feasible, and in the setting of young women with breast cancer, GnRHa may be offered to patients in the hope of reducing the likelihood of chemotherapy-induced ovarian insufficiency. GnRHa should not be used in place of proven fertility preservation methods. The panel notes that the field of ovarian tissue cryopreservation is advancing quickly and may evolve to become standard therapy in the future. Additional information is available at www.asco.org/survivorship-guidelines .
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            Fertility preservation in patients undergoing gonadotoxic therapy or gonadectomy: a committee opinion.

            (2019)
            Patients preparing to undergo gonadotoxic medical therapy, radiation therapy, or gonadectomy should be provided with prompt counseling regarding available options for fertility preservation for iatrogenic infertility. Fertility preservation can best be provided by comprehensive programs designed and equipped to confront the unique challenges facing these patients. This document replaces the document with a similar name, last published in 2013.
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              ESHRE guideline: female fertility preservation †

              Abstract STUDY QUESTION What is the recommended management for women and transgender men with regards to fertility preservation (FP), based on the best available evidence in the literature? SUMMARY ANSWER The ESHRE Guideline on Female Fertility Preservation makes 78 recommendations on organization of care, information provision and support, pre-FP assessment, FP interventions and after treatment care. Ongoing developments in FP are also discussed. WHAT IS KNOWN ALREADY The field of FP has grown hugely in the last two decades, driven by the increasing recognition of the importance of potential loss of fertility as a significant effect of the treatment of cancer and other serious diseases, and the development of the enabling technologies of oocyte vitrification and ovarian tissue cryopreservation (OTC) for subsequent autografting. This has led to the widespread, though uneven, provision of FP for young women. STUDY DESIGN, SIZE, DURATION The guideline was developed according to the structured methodology for development of ESHRE guidelines. After formulation of key questions by a group of experts, literature searches and assessments were performed. Papers published up to 1 November 2019 and written in English were included in the review. PARTICIPANTS/MATERIALS, SETTING, METHODS Based on the collected evidence, recommendations were formulated and discussed until consensus was reached within the guideline group. A stakeholder review was organized after finalization of the draft. The final version was approved by the guideline group and the ESHRE Executive Committee. MAIN RESULTS AND THE ROLE OF CHANCE This guideline aims to help providers meet a growing demand for FP options by diverse groups of patients, including those diagnosed with cancer undergoing gonadotoxic treatments, with benign diseases undergoing gonadotoxic treatments or those with a genetic condition predisposing to premature ovarian insufficiency, transgender men (assigned female at birth), and women requesting oocyte cryopreservation for age-related fertility loss. The guideline makes 78 recommendations on information provision and support, pre-FP assessment, FP interventions and after treatment care, including 50 evidence-based recommendations—of which 31 were formulated as strong recommendations and 19 as weak—25 good practice points and 3 research only recommendations. Of the evidence-based recommendations, 1 was supported by high-quality evidence, 3 by moderate-quality evidence, 17 by low-quality evidence and 29 by very low-quality evidence. To support future research in the field of female FP, a list of research recommendations is provided. LIMITATIONS, REASONS FOR CAUTION Most interventions included are not well studied in FP patients. As some interventions, e.g. oocyte and embryo cryopreservation, are well established for treatment of infertility, technical aspects, feasibility and outcomes can be extrapolated. For other interventions, such as OTC and IVM, more evidence is required, specifically pregnancy outcomes after applying these techniques for FP patients. Such future studies may require the current recommendations to be revised. WIDER IMPLICATIONS OF THE FINDINGS The guideline provides clinicians with clear advice on best practice in female FP, based on the best evidence currently available. In addition, a list of research recommendations is provided to stimulate further studies in FP. STUDY FUNDING/COMPETING INTEREST(S) The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the dissemination of the guideline. The guideline group members did not receive payment. R.A.A. reports personal fees and non-financial support from Roche Diagnostics, personal fees from Ferring Pharmaceuticals, IBSA and Merck Serono, outside the submitted work; D.B. reports grants from Merck Serono and Goodlife, outside the submitted work; I.D. reports consulting fees from Roche and speaker’s fees from Novartis; M.L. reports personal fees from Roche, Novartis, Pfizer, Lilly, Takeda, and Theramex, outside the submitted work. The other authors have no conflicts of interest to declare. DISCLAIMER This guideline represents the views of ESHRE, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant ESHRE stakeholders has been obtained. Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgment to each individual presentation, nor variations based on locality and facility type. ESHRE makes no warranty, express or implied, regarding the clinical practice guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose. (Full disclaimer available at  www.eshre.eu/guidelines.) †ESHRE Pages content is not externally peer reviewed. The manuscript has been approved by the Executive Committee of ESHRE.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Writing – original draftRole: Writing – review & editing
                Role: Formal analysisRole: MethodologyRole: Writing – review & editing
                Role: Formal analysisRole: MethodologyRole: Writing – review & editing
                Role: Data curationRole: Writing – review & editing
                Role: Data curationRole: ValidationRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: Writing – review & editing
                Role: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: MethodologyRole: ValidationRole: Writing – original draft
                Role: Editor
                Journal
                PLoS One
                PLoS One
                plos
                PLOS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                28 March 2023
                2023
                : 18
                : 3
                : e0280238
                Affiliations
                [1 ] Infertility Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
                [2 ] Department of Clinical Sciences and Community Health, Università Degli Studi di Milano, Milan, Italy
                [3 ] Environmental and Industrial Toxicology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
                [4 ] Centre for Reproductive Medicine, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
                Nazarbayev University School of Medicine, KAZAKHSTAN
                Author notes

                Competing Interests: The authors of this manuscript have the following competing interests: E.S. received honoraria for presentations at meetings from Gedeon-Richter and Merck-Serono. He is also handling two grants of research from Ferring. None of the remaining authors reported any conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                Author information
                https://orcid.org/0000-0002-0636-2876
                Article
                PONE-D-22-23405
                10.1371/journal.pone.0280238
                10047511
                98810e60-54a3-4878-9e4f-77d623dd2c5b
                © 2023 Filippi et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 21 August 2022
                : 26 December 2022
                Page count
                Figures: 3, Tables: 3, Pages: 13
                Funding
                Funded by: Italian Ministry of Health - Current research IRCCS
                Award Recipient :
                This study was partially funded by Italian Ministry of Health - Current research IRCCS. The funds exclusively consisted in a financial support. No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Germ Cells
                OVA
                Oocytes
                Medicine and Health Sciences
                Oncology
                Cancer Treatment
                Medicine and health sciences
                Pharmacology
                Pharmacologic-based diagnostics
                GnRH stimulation test
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Gynecological Tumors
                Ovarian Cancer
                Biology and Life Sciences
                Biochemistry
                Hormones
                Gonadotropins
                Physical Sciences
                Chemistry
                Chemical Compounds
                Organic Compounds
                Steroids
                Physical Sciences
                Chemistry
                Organic Chemistry
                Organic Compounds
                Steroids
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Follicular Fluid
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Follicular Fluid
                Biology and Life Sciences
                Physiology
                Body Fluids
                Follicular Fluid
                Biology and Life Sciences
                Anatomy
                Reproductive System
                Ovaries
                Follicular Fluid
                Medicine and Health Sciences
                Anatomy
                Reproductive System
                Ovaries
                Follicular Fluid
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Breast Tumors
                Breast Cancer
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                All relevant data are within the manuscript and its Supporting information files.

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