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      ESHRE guideline: female fertility preservation

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          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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          Most cited references143

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          Ovarian damage from chemotherapy and current approaches to its protection

          Abstract Background Anti-cancer therapy is often a cause of premature ovarian insufficiency and infertility since the ovarian follicle reserve is extremely sensitive to the effects of chemotherapy and radiotherapy. While oocyte, embryo and ovarian cortex cryopreservation can help some women with cancer-induced infertility achieve pregnancy, the development of effective methods to protect ovarian function during chemotherapy would be a significant advantage. Objective and rationale This paper critically discusses the different damaging effects of the most common chemotherapeutic compounds on the ovary, in particular, the ovarian follicles and the molecular pathways that lead to that damage. The mechanisms through which fertility-protective agents might prevent chemotherapy drug-induced follicle loss are then reviewed. Search methods Articles published in English were searched on PubMed up to March 2019 using the following terms: ovary, fertility preservation, chemotherapy, follicle death, adjuvant therapy, cyclophosphamide, cisplatin, doxorubicin. Inclusion and exclusion criteria were applied to the analysis of the protective agents. Outcomes Recent studies reveal how chemotherapeutic drugs can affect the different cellular components of the ovary, causing rapid depletion of the ovarian follicular reserve. The three most commonly used drugs, cyclophosphamide, cisplatin and doxorubicin, cause premature ovarian insufficiency by inducing death and/or accelerated activation of primordial follicles and increased atresia of growing follicles. They also cause an increase in damage to blood vessels and the stromal compartment and increment inflammation. In the past 20 years, many compounds have been investigated as potential protective agents to counteract these adverse effects. The interactions of recently described fertility-protective agents with these damage pathways are discussed. Wider implications Understanding the mechanisms underlying the action of chemotherapy compounds on the various components of the ovary is essential for the development of efficient and targeted pharmacological therapies that could protect and prolong female fertility. While there are increasing preclinical investigations of potential fertility preserving adjuvants, there remains a lack of approaches that are being developed and tested clinically.
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            Oocyte, embryo and blastocyst cryopreservation in ART: systematic review and meta-analysis comparing slow-freezing versus vitrification to produce evidence for the development of global guidance

            Abstract BACKGROUND Successful cryopreservation of oocytes and embryos is essential not only to maximize the safety and efficacy of ovarian stimulation cycles in an IVF treatment, but also to enable fertility preservation. Two cryopreservation methods are routinely used: slow-freezing or vitrification. Slow-freezing allows for freezing to occur at a sufficiently slow rate to permit adequate cellular dehydration while minimizing intracellular ice formation. Vitrification allows the solidification of the cell(s) and of the extracellular milieu into a glass-like state without the formation of ice. OBJECTIVE AND RATIONALE The objective of our study was to provide a systematic review and meta-analysis of clinical outcomes following slow-freezing/thawing versus vitrification/warming of oocytes and embryos and to inform the development of World Health Organization guidance on the most effective cryopreservation method. SEARCH METHODS A Medline search was performed from 1966 to 1 August 2016 using the following search terms: (Oocyte(s) [tiab] OR (Pronuclear[tiab] OR Embryo[tiab] OR Blastocyst[tiab]) AND (vitrification[tiab] OR freezing[tiab] OR freeze[tiab]) AND (pregnancy[tiab] OR birth[tiab] OR clinical[tiab]). Queries were limited to those involving humans. RCTs and cohort studies that were published in full-length were considered eligible. Each reference was reviewed for relevance and only primary evidence and relevant articles from the bibliographies of included articles were considered. References were included if they reported cryosurvival rate, clinical pregnancy rate (CPR), live-birth rate (LBR) or delivery rate for slow-frozen or vitrified human oocytes or embryos. A meta-analysis was performed using a random effects model to calculate relative risk ratios (RR) and 95% CI. OUTCOMES One RCT study comparing slow-freezing versus vitrification of oocytes was included. Vitrification was associated with increased ongoing CPR per cycle (RR = 2.81, 95% CI: 1.05–7.51; P = 0.039; 48 and 30 cycles, respectively, per transfer (RR = 1.81, 95% CI 0.71–4.67; P = 0.214; 47 and 19 transfers) and per warmed/thawed oocyte (RR = 1.14, 95% CI: 1.02–1.28; P = 0.018; 260 and 238 oocytes). One RCT comparing vitrification versus fresh oocytes was analysed. In vitrification and fresh cycles, respectively, no evidence for a difference in ongoing CPR per randomized woman (RR = 1.03, 95% CI: 0.87–1.21; P = 0.744, 300 women in each group), per cycle (RR = 1.01, 95% CI: 0.86–1.18; P = 0.934; 267 versus 259 cycles) and per oocyte utilized (RR = 1.02, 95% CI: 0.82–1.26; P = 0.873; 3286 versus 3185 oocytes) was reported. Findings were consistent with relevant cohort studies. Of the seven RCTs on embryo cryopreservation identified, three met the inclusion criteria (638 warming/thawing cycles at cleavage and blastocyst stage), none of which involved pronuclear-stage embryos. A higher CPR per cycle was noted with embryo vitrification compared with slow-freezing, though this was of borderline statistical significance (RR = 1.89, 95% CI: 1.00–3.59; P = 0.051; three RCTs; I 2 = 71.9%). LBR per cycle was reported by one RCT performed with cleavage-stage embryos and was higher for vitrification (RR = 2.28; 95% CI: 1.17–4.44; P =  0.016; 216 cycles; one RCT). A secondary analysis was performed focusing on embryo cryosurvival rate. Pooled data from seven RCTs (3615 embryos) revealed a significant improvement in embryo cryosurvival following vitrification as compared with slow-freezing (RR = 1.59, 95% CI: 1.30–1.93; P < 0.001; I 2 = 93%). WIDER IMPLICATIONS Data from available RCTs suggest that vitrification/warming is superior to slow-freezing/thawing with regard to clinical outcomes (low quality of the evidence) and cryosurvival rates (moderate quality of the evidence) for oocytes, cleavage-stage embryos and blastocysts. The results were confirmed by cohort studies. The improvements obtained with the introduction of vitrification have several important clinical implications in ART. Based on this evidence, in particular regarding cryosurvival rates, laboratories that continue to use slow-freezing should consider transitioning to the use of vitrification for cryopreservation.
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              Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO Clinical Practice Guidelines†

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                Author and article information

                Journal
                Hum Reprod Open
                Hum Reprod Open
                hropen
                Human Reproduction Open
                Oxford University Press
                2399-3529
                2020
                14 November 2020
                14 November 2020
                : 2020
                : 4
                : hoaa052
                Affiliations
                [h1 ] MRC Centre for Reproductive Health, University of Edinburgh , Edinburgh, UK
                [h2 ] Department of Gynaecological Oncology, Academic Medical Centres Amsterdam , Amsterdam, The Netherlands
                [h3 ] Department of Gynaecology, Antoni van Leeuwenhoek-Netherlands Cancer Institute , Amsterdam, The Netherlands
                [h4 ] Department of Oncology, Catholic University Leuven , Leuven, Belgium
                [h5 ] Department of Obstetrics and Gynaecology, Radboud University Medical Centre , Nijmegen, The Netherlands
                [h6 ] Wales Fertility Institute, Swansea Bay Health Board, University Hospital of Wales, Cardiff University, Cardiff, UK
                [h7 ] Department of Anatomy and Embryology, Leiden University Medical Centre , Leiden, The Netherlands
                [h8 ] Fertility Clinic, CUB-Hôpital Erasme and Research Laboratory on Human Reproduction, Université Libre de Bruxelles , Brussels, Belgium
                [h9 ] Brussels , Belgium
                [h10 ] Institute of Population Health, University of Liverpool , Liverpool, UK
                [h11 ] Department of Medical Oncology, U.O.C Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino , Genova, Italy
                [h12 ] Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova , Genova, Italy
                [h13 ] Cancer Support France , Cahors, France
                [h14 ] Reprodutive Medicine Unit, Unit of Clinical Psychology, Centro Hospitalar e Universitário de Coimbra , Coimbra, Portugal
                [h15 ] University of Coimbra, Center for Research in Neuropsychology and Cognitive and Behavioral Intervention , Coimbra, Portugal
                [h16 ] Laboratory of Reproductive Biology, INOVIE Fertilité Clinique Croix du Sud , Toulouse, France
                [h17 ] Department of Oncology-Pathology, Karolinska Institutet , Stockholm, Sweden
                [h18 ] Division of Gynaecology and Reproduction, Department of Reproductive Medicine, Karolinska University Hospital , Stockholm, Sweden
                [h19 ] European Society of Human Reproduction and Embryology , Central Office, Grimbergen, Belgium
                Author notes
                Correspondence address. University of Edinburgh, MRC Centre for Reproductive Health, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK. E-mail: richard.anderson@ 123456ed.ac.uk ; guidelines@ 123456eshre.eu
                Author information
                http://orcid.org/0000-0002-7495-518X
                http://orcid.org/0000-0003-3866-2803
                http://orcid.org/0000-0002-8506-0699
                http://orcid.org/0000-0003-1797-5296
                http://orcid.org/0000-0001-7542-0497
                http://orcid.org/0000-0003-4378-6181
                http://orcid.org/0000-0001-8046-6799
                Article
                hoaa052
                10.1093/hropen/hoaa052
                7666361
                33225079
                b2ebf33f-addf-4140-a74e-463414d9f54d
                © The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 2 October 2020
                : 2 October 2020
                : 5 October 2020
                Page count
                Pages: 17
                Categories
                ESHRE Pages
                AcademicSubjects/MED00905

                fertility preservation,guideline,evidence-based,oncology,transgender men,age-related fertility loss,oocyte cryopreservation,ovarian tissue cryopreservation,ovarian transposition,pregnancy,organization of care

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