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Turan V, Oktay K. Developments in pharmacotherapy for the preservation of ovarian function during cancer treatment. Expert Opin Pharmacother 2025; 26:897-907. [PMID: 40271805 DOI: 10.1080/14656566.2025.2495090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Revised: 04/14/2025] [Accepted: 04/15/2025] [Indexed: 04/25/2025]
Abstract
INTRODUCTION Cancer is one of the major causes of human death, and anti-cancer therapy often results in premature ovarian failure and infertility, depending on factors such as age, initial ovarian reserve, and chemotherapy type and dose. Fertility preservation procedures, such as oocyte, embryo, and ovarian cortex cryopreservation, can help women achieve pregnancy after cancer treatment. However, the development of pharmacological therapies to protect ovarian function during chemotherapy would represent a significant advancement. AREAS COVERED We searched the published articles in PubMed up to December 2024, containing key words '"chemotherapy",' 'cancer,' '"ovarian protection",' '"pharmacological therapy",' '"ovarian reserve"' and '"fertility".' Chemotherapeutic agents act via various mechanisms in the human ovary, including direct DNA damage leading to oocyte apoptosis, as well as damage to ovarian stroma and microvascular architecture. In recent years, numerous protective agents have emerged, showing promise in protecting ovaries from chemotherapy-induced damage. However, most studies have relied on animal models, and only a limited number have directly tested these agents in human ovarian tissue. At present, no pharmacological treatment has been conclusively proven effective for preserving fertility. EXPERT OPINION A comprehensive understanding of the mechanisms underlying chemotherapy-induced ovarian damage is critical for the development of efficient and targeted pharmacological therapies.
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Affiliation(s)
- Volkan Turan
- Department of Obstetrics, Health and Technology University School of Medicine, Istanbul, Turkey
- Innovation Institute for Fertility Preservation, Newyork, CT, USA
| | - Kutluk Oktay
- Innovation Institute for Fertility Preservation, Newyork, CT, USA
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
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Annibali O, Castellino A, Cenfra N, Ciccarone M, Rotondo F, Minoia C, Petrucci L, Gini G, Rusconi C, Bozzoli V, Nicolosi M, Margiotta G, Meli E, Cocito F, Bigliardi S, Ciavarella S, Tesei C, Zaja F. Fertility preservation in lymphoma patients treated with immunochemotherapy regimens with or without radiotherapy: results of a retrospective multicenter Italian study (Ferty care). Leuk Lymphoma 2024; 65:1448-1455. [PMID: 38847543 DOI: 10.1080/10428194.2024.2361358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 05/05/2024] [Accepted: 05/24/2024] [Indexed: 10/02/2024]
Abstract
This is a retrospective, multicentric study, aimed to describe the real-life application of fertility preservation methods during treatment in female lymphoma patients, aged 18-40 years old, diagnosed between Oct 1st/2010 and May 31st/2018. Among 414 women included, median age was 28 years old, histologies were: HL 74%, PMBCL 13%, DLBCL 10%, others 3%. First line treatments were: ABVD in 295 (71%), R-CHOP like in 102 (25%), higher intensity regimens in 17 (4%) cases. Fertility preservation strategies were: GnRHa in 315 (78%), Oral Contraceptive in 41 (10%), oocytes and ovarian tissue cryopreservation in 55 and 42 patients, respectively. After therapy, we observed a restored regular period in 293 (70%) and premature ovarian failure (POF) in 33 (8%), Furthermore we recorded 43 pregnancies, all spontaneous with 5 years median follow-up. Median age at diagnosis and number of lines of treatment correlate with higher rate of amenorrhea, risk of POF and menopause (p < 0.001).
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Affiliation(s)
- Ombretta Annibali
- Unit of Hematology, Stem cell Transplantation, Fondazione Policlinico Universitario Campus Bio Medico, Roma, Italy
| | | | - Natalia Cenfra
- Unit of Hematology, Santa Maria Goretti Hospital, Latina, Italy
| | - Mariavita Ciccarone
- Gemme Dormienti Onlus Association, Roma, Italy
- San Carlo di Nancy Hospital, Rome, Italy
| | | | - Carla Minoia
- IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy
| | - Luigi Petrucci
- Policlinico Umberto I Hospital and University, Roma, Italy
| | - Guido Gini
- Ospedali Riuniti, Università Politecnica delle Marche Hospital and University, Ancona, Italy
| | - Chiara Rusconi
- Fondazione IRCCS Istituto nazionale dei tumori, Milano, Italy
| | | | - Maura Nicolosi
- Hospital and University Maggiore della Carità, Novara, Italy
| | | | - Erika Meli
- ASSt Grande Niguarda Hospital, Milano, Italy
| | | | - Sara Bigliardi
- UOSD di oncologia Area Sud sede di Sassuolo, AUSL Modena Osedale di Sassuolo, Modena, Italy
| | | | - Cristiano Tesei
- Department of Hematology, University of Rome Tor Vergata, Rome, Italy
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Szymanska KJ, Tan X, Oktay K. Unraveling the mechanisms of chemotherapy-induced damage to human primordial follicle reserve: road to developing therapeutics for fertility preservation and reversing ovarian aging. Mol Hum Reprod 2021; 26:553-566. [PMID: 32514568 DOI: 10.1093/molehr/gaaa043] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 05/24/2020] [Indexed: 12/16/2022] Open
Abstract
Among the investigated mechanisms of chemotherapy-induced damage to human primordial follicle reserve are induction of DNA double-strand breaks (DSBs) and resultant apoptotic death, stromal-microvascular damage and follicle activation. Accumulating basic and translational evidence suggests that acute exposure to gonadotoxic chemotherapeutics, such as cyclophosphamide or doxorubicin, induces DNA DSBs and triggers apoptotic death of primordial follicle oocytes within 12-24 h, resulting in the massive loss of ovarian reserve. Evidence also indicates that chemotherapeutic agents can cause microvascular and stromal damage, induce hypoxia and indirectly affect ovarian reserve. While it is possible that the acute reduction of the primordial follicle reserve by massive apoptotic losses may result in delayed activation of some primordial follicles, this is unlikely to be a predominant mechanism of loss in humans. Here, we review these mechanisms of chemotherapy-induced ovarian reserve depletion and the potential reasons for the discrepancies among the studies. Based on the current literature, we propose an integrated hypothesis that explains both the acute and delayed chemotherapy-induced loss of primordial follicle reserve in the human ovary.
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Affiliation(s)
- Katarzyna J Szymanska
- Laboratory of Molecular Reproduction and Fertility Preservation, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA
| | - Xiujuan Tan
- Laboratory of Molecular Reproduction and Fertility Preservation, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA
| | - Kutluk Oktay
- Laboratory of Molecular Reproduction and Fertility Preservation, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA
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Lee JH, Choi YS. The role of gonadotropin-releasing hormone agonists in female fertility preservation. Clin Exp Reprod Med 2021; 48:11-26. [PMID: 33648041 PMCID: PMC7943347 DOI: 10.5653/cerm.2020.04049] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 10/13/2020] [Indexed: 11/19/2022] Open
Abstract
Advances in anticancer treatments have resulted in increasing survival rates among cancer patients. Accordingly, the quality of life after treatment, particularly the preservation of fertility, has gradually emerged as an essential consideration. Cryopreservation of embryos or unfertilized oocytes has been considered as the standard method of fertility preservation among young women facing gonadotoxic chemotherapy. Other methods, including ovarian suppression and ovarian tissue cryopreservation, have been considered experimental. Recent large-scale randomized controlled trials have demonstrated that temporary ovarian suppression using gonadotropin-releasing hormone agonists (GnRHa) during chemotherapy is beneficial for preventing chemotherapy-induced premature ovarian insufficiency in breast cancer patients. It should also be emphasized that GnRHa use during chemotherapy does not replace established fertility preservation methods. All young women facing gonadotoxic chemotherapy should be counseled about and offered various options for fertility preservation, including both GnRHa use and cryopreservation of embryos, oocytes, and/or ovarian tissue.
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Affiliation(s)
- Jae Hoon Lee
- Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.,Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Young Sik Choi
- Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea.,Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
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Dolmans MM, Taylor HS, Rodriguez-Wallberg KA, Blumenfeld Z, Lambertini M, von Wolff M, Donnez J. Utility of gonadotropin-releasing hormone agonists for fertility preservation in women receiving chemotherapy: pros and cons. Fertil Steril 2020; 114:725-738. [PMID: 33040981 DOI: 10.1016/j.fertnstert.2020.08.011] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 08/06/2020] [Indexed: 12/11/2022]
Affiliation(s)
- Marie-Madeleine Dolmans
- Pôle de Gynécologie, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium; Gynecology Department, Cliniques Universitaires Saint Luc, Brussels, Belgium
| | - Hugh S Taylor
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
| | - Kenny A Rodriguez-Wallberg
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Department of Reproductive Medicine, Division of Gynecology and Reproduction, Karolinska University Hospital, Stockholm, Sweden
| | - Zeev Blumenfeld
- Department of Reproductive Endocrinology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Matteo Lambertini
- Department of Medical Oncology, U.O.C. Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy; Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, Genova, Italy
| | | | - Jacques Donnez
- Société de Recherche pour l'Infertilité, Brussels, Belgium; Catholic University of Louvain, Brussels, Belgium.
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Mandelbaum RS, Klar M, Takiuchi T, Bainvoll L, Matsuzaki S, Paulson RJ, Matsuo K. Fertility-sparing treatment for early-stage epithelial ovarian cancer: Contemporary oncologic, reproductive and endocrinologic perspectives. J Obstet Gynaecol Res 2020; 46:1263-1281. [PMID: 32500605 DOI: 10.1111/jog.14302] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 04/21/2020] [Accepted: 04/30/2020] [Indexed: 12/11/2022]
Abstract
AIM Epithelial ovarian cancer (EOC) can be a devastating diagnosis in women of reproductive age who desire future fertility. However, in early-stage disease, fertility-sparing surgery (FSS) can be considered in appropriately selected patients. METHODS This is a narrative descriptive review of the recent literature on FSS for EOC from oncologic, reproductive and endocrinologic perspectives. RESULTS The recurrence rate following FSS performed for stage I EOC in published retrospective studies collectively is 13% but ranges from 5 to 29%, while mortality ranges from 0 to 18%. Five-year disease-free survival following FSS is over 90% but decreases with higher stage and grade. Recurrences following FSS are more likely to be localized with a more favorable prognosis compared to recurrences following radical surgery. Adjuvant chemotherapy is recommended in women with high-risk disease, and strategies to minimize gonadotoxicity during chemotherapy such as gonadotropin-releasing hormone (GnRH) agonists may be considered. Oocyte, embryo and/or ovarian cryopreservation can also be offered to patients desiring future biologic children. Reproductive outcomes following FSS, including pregnancy and miscarriage rates, resemble those of the general population, with a chance of successful pregnancy of nearly 80%. CONCLUSION In retrospective data, FSS appears to be oncologically safe in stage IA and IC grade 1-2 non-clear cell EOC. In patients with grade 3 tumors or clear cell histology, treatment can be individualized, weighing a slightly higher risk of recurrence with fertility goals. A multidisciplinary approach with oncology and reproductive endocrinology may be of utility to help these patients achieve their fertility goals.
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Affiliation(s)
- Rachel S Mandelbaum
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California, USA.,Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California, USA
| | - Maximilian Klar
- Department of Obstetrics and Gynecology, University of Freiburg, Freiburg, Germany
| | - Tsuyoshi Takiuchi
- Department of Obstetrics and Gynecology, Osaka University, Osaka, Japan
| | - Liat Bainvoll
- Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Shinya Matsuzaki
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California, USA
| | - Richard J Paulson
- Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California, USA
| | - Koji Matsuo
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California, USA.,Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA
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Bangalore Krishna K, Fuqua JS, Rogol AD, Klein KO, Popovic J, Houk CP, Charmandari E, Lee PA, Freire AV, Ropelato MG, Yazid Jalaludin M, Mbogo J, Kanaka-Gantenbein C, Luo X, Eugster EA, Klein KO, Vogiatzi MG, Reifschneider K, Bamba V, Garcia Rudaz C, Kaplowitz P, Backeljauw P, Allen DB, Palmert MR, Harrington J, Guerra-Junior G, Stanley T, Torres Tamayo M, Miranda Lora AL, Bajpai A, Silverman LA, Miller BS, Dayal A, Horikawa R, Oberfield S, Rogol AD, Tajima T, Popovic J, Witchel SF, Rosenthal SM, Finlayson C, Hannema SE, Castilla-Peon MF, Mericq V, Medina Bravo PG. Use of Gonadotropin-Releasing Hormone Analogs in Children: Update by an International Consortium. Horm Res Paediatr 2020; 91:357-372. [PMID: 31319416 DOI: 10.1159/000501336] [Citation(s) in RCA: 171] [Impact Index Per Article: 34.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 06/04/2019] [Indexed: 11/19/2022] Open
Abstract
This update, written by authors designated by multiple pediatric endocrinology societies (see List of Participating Societies) from around the globe, concisely addresses topics related to changes in GnRHa usage in children and adolescents over the last decade. Topics related to the use of GnRHa in precocious puberty include diagnostic criteria, globally available formulations, considerations of benefit of treatment, monitoring of therapy, adverse events, and long-term outcome data. Additional sections review use in transgender individuals and other pediatric endocrine related conditions. Although there have been many significant changes in GnRHa usage, there is a definite paucity of evidence-based publications to support them. Therefore, this paper is explicitly not intended to evaluate what is recommended in terms of the best use of GnRHa, based on evidence and expert opinion, but rather to describe how these drugs are used, irrespective of any qualitative evaluation. Thus, this paper should be considered a narrative review on GnRHa utilization in precocious puberty and other clinical situations. These changes are reviewed not only to point out deficiencies in the literature but also to stimulate future studies and publications in this area.
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Affiliation(s)
- Kanthi Bangalore Krishna
- Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, Penn State Hershey Medical Center, Hershey, Pennsylvania, USA,
| | - John S Fuqua
- Department of Pediatrics, Indiana University School of Medicine and Riley Hospital for Children, Indianapolis, Indiana, USA
| | - Alan D Rogol
- Department of Pediatrics, University of Virginia, Charlottesville, Virginia, USA
| | - Karen O Klein
- University of California, San Diego and Rady Children's Hospital, San Diego, California, USA
| | - Jadranka Popovic
- Division of Pediatric Endocrinology, Pediatric Alliance, Pittsburgh, Pennsylvania, USA
| | - Christopher P Houk
- Department of Pediatrics, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
| | - Evangelia Charmandari
- Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, Athens, Greece
| | - Peter A Lee
- Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, Penn State Hershey Medical Center, Hershey, Pennsylvania, USA
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Hampe ME, Rhoton-Vlasak AS. Fertility preservation in breast cancer with case-based examples for guidance. J Assist Reprod Genet 2020; 37:717-729. [PMID: 32008180 PMCID: PMC7125269 DOI: 10.1007/s10815-019-01665-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 12/12/2019] [Indexed: 12/12/2022] Open
Abstract
With more young breast cancer survivors, a trend toward having children later in life, and improvements in assisted reproductive technology (ART), fertility preserving techniques are of growing importance prior to initiation of gonadotoxic treatments. The American Society for Clinical Oncology (ASCO) updated their Fertility Preservation in Patients with Cancer guidelines in April of 2018. ASCO continues to recognize oocyte and embryo cryopreservation as standard practice for women interested in preserving fertility and sperm cryopreservation as standard practice for men. ASCO has clarified their statement on ovarian suppression during chemotherapy as an option when standard methods are unavailable but should not be used as the sole method of fertility preservation (FP) due to conflicting evidence. ASCO also updated their statement on ovarian tissue cryopreservation, which is still labeled experimental but ASCO acknowledges that it can restore global ovarian function and could be of use in specific patients. The NCCN's Version 1.2018 Clinical Practice Guidelines® for treatment of breast cancer include fertility counseling as part of their work-up in all types of breast cancer for premenopausal women.The purpose of this review is to explain the indications and evidence for the different methods of FP for young breast cancer patients in accordance with ASCO and NCCN guidelines. The guidance will then be applied to three theoretical clinical cases in order to highlight actual use in clinical practice.
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Affiliation(s)
- Mary E Hampe
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville, FL, USA
| | - Alice S Rhoton-Vlasak
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville, FL, USA.
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9
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Blumenfeld Z. Fertility Preservation Using GnRH Agonists: Rationale, Possible Mechanisms, and Explanation of Controversy. CLINICAL MEDICINE INSIGHTS. REPRODUCTIVE HEALTH 2019; 13:1179558119870163. [PMID: 31488958 PMCID: PMC6710670 DOI: 10.1177/1179558119870163] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Accepted: 07/18/2019] [Indexed: 12/15/2022]
Abstract
The only clinically accepted method of fertility preservation in young women facing gonadotoxic chemo- and/or radiotherapy for malignant or autoimmune diseases is cryopreservation of embryos or unfertilized ova, whereas cryopreservation of ovarian tissue for future reimplantation, or in vitro maturation of follicles, and the use of gonadotropin-releasing hormone agonists (GnRHa) are still considered investigational, by several authorities. Whereas previous publications have raised the fear of GnRHa's possible detrimental effects in patients with hormone receptor-positive breast cancers, recent randomized controlled trials (RCTs) have shown that it either improves or does not affect disease-free survival (DFS) in such patients. This review summarizes the pros and cons of GnRHa co-treatment for fertility preservation, suggesting 5 theoretical mechanisms for GnRHa action: (1) simulating the prepubertal hypogonadotropic milieu, (2) direct effect on GnRH receptors, (3) decreased ovarian perfusion, (4) upregulation of an ovarian-protecting molecule such as sphingosine-1-phosphate, and (5) protecting a possible germinative stem cell. We try to explain the reasons for the discrepancy between most publications that support the use of GnRHa for fertility preservation and the minority of publications that did not support its efficiency.
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Affiliation(s)
- Zeev Blumenfeld
- Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
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10
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EUropean REcommendations for female FERtility preservation (EU-REFER): A joint collaboration between oncologists and fertility specialists. Crit Rev Oncol Hematol 2019; 138:233-240. [DOI: 10.1016/j.critrevonc.2019.03.010] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 10/25/2018] [Accepted: 03/20/2019] [Indexed: 11/17/2022] Open
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Fertility preservation for adolescent and young adult cancer patients in Japan. Obstet Gynecol Sci 2018; 61:443-452. [PMID: 30018898 PMCID: PMC6046357 DOI: 10.5468/ogs.2018.61.4.443] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Revised: 11/24/2017] [Accepted: 12/12/2017] [Indexed: 12/27/2022] Open
Abstract
Adolescent and young adult (AYA) patients are generally defined as being from 15 to 39 years old. For preservation of fertility in AYA cancer patients, the best-known guideline in this field was released by the American Society of Clinical Oncology (ASCO) in 2006. However, the ASCO guideline is not necessarily applicable to Japanese cancer patients. The Japan Society for Fertility Preservation (JSFP) was formed in 2012, and a system and guideline for fertility preservation in Japanese AYA cancer patients plus children was released in July 2017. According to this guideline, patients should receive psychological and social support from health care providers such as doctors, nurses, psychologists, pharmacists, and social workers. In 2013, the American Society for Reproductive Medicine stated that freezing oocytes is a method that has passed beyond the research stage. However, freezing ovarian tissue is still a research procedure. While slow freezing of ovarian tissue is generally performed, rapid freezing (vitrification) is more popular in Japan. We have developed a new closed technique for ovarian tissue cryopreservation. It has been suggested that optical coherence tomography might be applied clinically to measure the true ovarian reserve and localize follicles in patients undergoing ovarian tissue transplantation. Combining gonadotropin-releasing hormone agonist therapy with anticancer agents might be useful for ovarian protection and it is expected that discussion of such combined treatment will continue in the future. This article outlines practical methods of fertility preservation using assisted reproductive techniques for AYA cancer patients in Japan.
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Leonard RCF, Adamson DJA, Bertelli G, Mansi J, Yellowlees A, Dunlop J, Thomas GA, Coleman RE, Anderson RA. GnRH agonist for protection against ovarian toxicity during chemotherapy for early breast cancer: the Anglo Celtic Group OPTION trial. Ann Oncol 2018; 28:1811-1816. [PMID: 28472240 DOI: 10.1093/annonc/mdx184] [Citation(s) in RCA: 110] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Background Chemotherapy-induced premature ovarian insufficiency (POI) impacts fertility and other aspects of women's health. The OPTION trial tested whether administration of a gonadotropin-releasing hormone agonist during chemotherapy for early breast cancer reduced the risk of POI. Patients and methods This was a prospective, randomized, parallel group study of the gonadotropin-releasing hormone agonist goserelin administered before and during chemotherapy for breast cancer with stage I-IIIB disease. The primary outcome was amenorrhoea between 12 and 24 months after randomization, supported by elevated follicle stimulating hormone concentrations to give an additional analysis as rate of POI. Results A total of 227 patients were randomized and the primary analysis was conducted on 202 patients. Goserelin reduced the prevalence of amenorrhoea between 12 and 24 months to 22% versus 38% in the control group (P = 0.015) and the prevalence of POI to 18.5% versus 34.8% in the control group (P = 0.048). Follicle stimulating hormone concentrations were also lower in all women treated with goserelin at both 12 and 24 months (P = 0.027, P = 0.001, respectively). The effect of goserelin was not statistically significant in women >40 years. Assessment of the ovarian reserve using anti-Müllerian hormone showed a marked fall in both groups during treatment to median values of 5% of pretreatment levels in the control group and 7% in the goserelin group, which were not significantly different between groups. Conclusion This study shows that goserelin reduced the risk of POI in women treated with chemotherapy for early breast cancer, with particular efficacy in women aged ≤40 years old. The degree of ovarian protection also seems limited and the clinical significance for fertility and longer term prevention of estrogen deficiency-related outcomes needs to be determined.
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Affiliation(s)
- R C F Leonard
- Department of Surgery and Oncology, Imperial College, London
| | | | - G Bertelli
- Department of Oncology, Singleton Hospital, Swansea
| | - J Mansi
- Department of Oncology, NHS Foundation Trust, Guy's and St Thomas' NHS Foundation Trust and Biomedical Research Centre, King's College, London
| | | | - J Dunlop
- Scottish Clinical Trials Research Unit, Information Services Division, NHS National Services Scotland, Edinburgh
| | - G A Thomas
- Department of Surgery and Oncology, Imperial College, London
| | - R E Coleman
- Department of Oncology, Sheffield University, Sheffield
| | - R A Anderson
- MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK
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Del Mastro L, Lambertini M. Gonadotropin-releasing hormone analogs for ovarian function protection during chemotherapy in young early breast cancer patients: the last piece of the puzzle? Ann Oncol 2018; 28:1683-1685. [PMID: 28838207 DOI: 10.1093/annonc/mdx277] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Affiliation(s)
- L Del Mastro
- Department of Medical Oncology, U.O. Sviluppo Terapie Innovative, Ospedale Policlinico San Martino, Genova, Italy
| | - M Lambertini
- Department of Medical Oncology and Breast Cancer Translational Research Laboratory, Institut Jules Bordet and Université Libre de Bruxelles (U.L.B.), Brussels, Belgium
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Anti-Müllerian hormone (AMH) levels in premenopausal breast cancer patients treated with taxane-based adjuvant chemotherapy - A translational research project of the SUCCESS A study. Breast 2017; 35:130-135. [PMID: 28732324 DOI: 10.1016/j.breast.2017.07.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 07/11/2017] [Accepted: 07/12/2017] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Premenopausal women undergoing chemotherapy are at high risk for premature ovarian failure and its long-term consequences. Data on potential markers to evaluate ovarian reserve pre- and posttreatment are limited. Anti-Müllerian hormone (AMH) known for ovarian reserve in reproductive medicine could be a surrogate marker and was assessed in premenopausal breast cancer patients of the SUCCESS A study (EUDRA-CT no. 2005-000490-21). METHODS We identified 170 premenopausal patients, age ≤ 40 years at trial entry, who received FEC-Doc as taxane-anthracylince based chemotherapy. Blood samples were taken at three time points: Before, four weeks after and two years after adjuvant chemotherapy. Serum AMH-levels were evaluated in a central laboratory by a quantitative immunoassay AMH Gen II ELISA (Beckman Coulter, Brea, USA). RESULTS Median age was 36 years (21-40 years). Median serum AMH-level before chemotherapy was 1.37 ng/ml (range < 0.1-11.3 ng/ml). Four weeks after chemotherapy AMH-levels dropped in 98.6% of the patients to <0.1 ng/ml (range < 0.1-0.21 ng/ml). After two years, 73.3% (n = 101) showed no evidence of ovarian function recovery (AMH <0.1 ng/ml, range < 0.1-3.9 ng/ml). Permanent chemotherapy induced amenorrhea occurred only in 50.6% of the patients. CONCLUSIONS In this analysis, premenopausal patients showed a high rate of ovarian impairment reflected by low AMH-levels after chemotherapy.
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Taylan E, Oktay KH. Current state and controversies in fertility preservation in women with breast cancer. World J Clin Oncol 2017; 8:241-248. [PMID: 28638793 PMCID: PMC5465013 DOI: 10.5306/wjco.v8.i3.241] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 05/04/2017] [Accepted: 05/15/2017] [Indexed: 02/06/2023] Open
Abstract
On average, over 25000 women are diagnosed with breast cancer under the age of 45 annually in the United States. Because an increasing number of young women delay childbearing to later life for various reasons, a growing population of women experience breast cancer before completing childbearing. In this context, preservation of fertility potential of breast cancer survivors has become an essential concept in modern cancer care. In this review, we will outline the currently available fertility preservation options for women with breast cancer of reproductive age, discuss the controversy behind hormonal suppression for gonadal protection against chemotherapy and highlight the importance of timely referral by cancer care providers.
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Oktay K, Turan V, Bedoschi G. Reply to M. Lambertini et al. J Clin Oncol 2016; 35:807-809. [PMID: 27893322 DOI: 10.1200/jco.2016.70.6101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Affiliation(s)
- Kutluk Oktay
- Kutluk Oktay, Volkan Turan, and Giuliano Bedoschi, New York Medical College and Innovation Institute for Fertility Preservation, New York, NY
| | - Volkan Turan
- Kutluk Oktay, Volkan Turan, and Giuliano Bedoschi, New York Medical College and Innovation Institute for Fertility Preservation, New York, NY
| | - Giuliano Bedoschi
- Kutluk Oktay, Volkan Turan, and Giuliano Bedoschi, New York Medical College and Innovation Institute for Fertility Preservation, New York, NY
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Demeestere I, Brice P, Peccatori FA, Kentos A, Dupuis J, Zachee P, Casasnovas O, Van Den Neste E, Dechene J, De Maertelaer V, Bron D, Englert Y. No Evidence for the Benefit of Gonadotropin-Releasing Hormone Agonist in Preserving Ovarian Function and Fertility in Lymphoma Survivors Treated With Chemotherapy: Final Long-Term Report of a Prospective Randomized Trial. J Clin Oncol 2016; 34:2568-74. [PMID: 27217453 DOI: 10.1200/jco.2015.65.8864] [Citation(s) in RCA: 147] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
PURPOSE We have reported previously that after 1-year follow up, gonadotropin-releasing hormone agonist (GnRHa) did not prevent chemotherapy-induced premature ovarian failure (POF) in patients with lymphoma, but may provide protection of the ovarian reserve. Here, we report the final analysis of the cohort after 5 years of follow up. PATIENTS AND METHODS A total of 129 patients with lymphoma were randomly assigned to receive either triptorelin plus norethisterone (GnRHa group) or norethisterone alone (control group) during chemotherapy. Ovarian function and fertility were reported after 2, 3, 4, and 5 to 7 years of follow up. The primary end point was POF, defined as at least one follicle-stimulating hormone value of > 40 IU/L after 2 years of follow up. RESULTS Sixty-seven patients 26.21 ± 0.64 years of age had available data after a median follow-up time of 5.33 years in the GnRHa group and 5.58 years in the control group (P = .452). Multivariate logistic regression analysis showed a significantly increased risk of POF in patients according to age (P = .047), the conditioning regimen for hematopoietic stem cell transplant (P = .002), and the cumulative dose of cyclophosphamide > 5 g/m(2) (P = .019), but not to the coadministration of GnRHa during chemotherapy (odds ratio, 0.702; P = .651). The ovarian reserve, evaluated using anti-Müllerian hormone and follicle-stimulating hormone levels, was similar in both groups. Fifty-three percent and 43% achieved pregnancy in the GnRHa and control groups, respectively (P = .467). CONCLUSION To the best of our knowledge, this is the first long-term analysis confirming that GnRHa is not efficient in preventing chemotherapy-induced POF in young patients with lymphoma and did not influence future pregnancy rate. These results reopen the debate about the drug's benefit in that it should not be recommended as standard for fertility preservation in patients with lymphoma.
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Affiliation(s)
- Isabelle Demeestere
- Isabelle Demeestere, Julie Dechene, Yvon Englert, and Viviane De Maertelaer, Université Libre de Bruxelles; Alain Kentos and Yvon Englert, Erasme Hospital; Eric Van Den Neste, Cliniques Universitaires UCL Saint-Luc; Dominique Bron, J. Bordet Institute, Brussels; Pierre Zachee, Algemeen Ziekenhuis Stuivenberg, Antwerpen, Belgium; Pauline Brice, St Louis Hospital, APHP; Jehan Dupuis, Hôpital Henri Mondor, Paris; Olivier Casasnovas, CHU de Dijon, Dijon, France; and Fedro A. Peccatori, Istituto Europeo di Oncologia, Milano, Italy.
| | - Pauline Brice
- Isabelle Demeestere, Julie Dechene, Yvon Englert, and Viviane De Maertelaer, Université Libre de Bruxelles; Alain Kentos and Yvon Englert, Erasme Hospital; Eric Van Den Neste, Cliniques Universitaires UCL Saint-Luc; Dominique Bron, J. Bordet Institute, Brussels; Pierre Zachee, Algemeen Ziekenhuis Stuivenberg, Antwerpen, Belgium; Pauline Brice, St Louis Hospital, APHP; Jehan Dupuis, Hôpital Henri Mondor, Paris; Olivier Casasnovas, CHU de Dijon, Dijon, France; and Fedro A. Peccatori, Istituto Europeo di Oncologia, Milano, Italy
| | - Fedro A Peccatori
- Isabelle Demeestere, Julie Dechene, Yvon Englert, and Viviane De Maertelaer, Université Libre de Bruxelles; Alain Kentos and Yvon Englert, Erasme Hospital; Eric Van Den Neste, Cliniques Universitaires UCL Saint-Luc; Dominique Bron, J. Bordet Institute, Brussels; Pierre Zachee, Algemeen Ziekenhuis Stuivenberg, Antwerpen, Belgium; Pauline Brice, St Louis Hospital, APHP; Jehan Dupuis, Hôpital Henri Mondor, Paris; Olivier Casasnovas, CHU de Dijon, Dijon, France; and Fedro A. Peccatori, Istituto Europeo di Oncologia, Milano, Italy
| | - Alain Kentos
- Isabelle Demeestere, Julie Dechene, Yvon Englert, and Viviane De Maertelaer, Université Libre de Bruxelles; Alain Kentos and Yvon Englert, Erasme Hospital; Eric Van Den Neste, Cliniques Universitaires UCL Saint-Luc; Dominique Bron, J. Bordet Institute, Brussels; Pierre Zachee, Algemeen Ziekenhuis Stuivenberg, Antwerpen, Belgium; Pauline Brice, St Louis Hospital, APHP; Jehan Dupuis, Hôpital Henri Mondor, Paris; Olivier Casasnovas, CHU de Dijon, Dijon, France; and Fedro A. Peccatori, Istituto Europeo di Oncologia, Milano, Italy
| | - Jehan Dupuis
- Isabelle Demeestere, Julie Dechene, Yvon Englert, and Viviane De Maertelaer, Université Libre de Bruxelles; Alain Kentos and Yvon Englert, Erasme Hospital; Eric Van Den Neste, Cliniques Universitaires UCL Saint-Luc; Dominique Bron, J. Bordet Institute, Brussels; Pierre Zachee, Algemeen Ziekenhuis Stuivenberg, Antwerpen, Belgium; Pauline Brice, St Louis Hospital, APHP; Jehan Dupuis, Hôpital Henri Mondor, Paris; Olivier Casasnovas, CHU de Dijon, Dijon, France; and Fedro A. Peccatori, Istituto Europeo di Oncologia, Milano, Italy
| | - Pierre Zachee
- Isabelle Demeestere, Julie Dechene, Yvon Englert, and Viviane De Maertelaer, Université Libre de Bruxelles; Alain Kentos and Yvon Englert, Erasme Hospital; Eric Van Den Neste, Cliniques Universitaires UCL Saint-Luc; Dominique Bron, J. Bordet Institute, Brussels; Pierre Zachee, Algemeen Ziekenhuis Stuivenberg, Antwerpen, Belgium; Pauline Brice, St Louis Hospital, APHP; Jehan Dupuis, Hôpital Henri Mondor, Paris; Olivier Casasnovas, CHU de Dijon, Dijon, France; and Fedro A. Peccatori, Istituto Europeo di Oncologia, Milano, Italy
| | - Olivier Casasnovas
- Isabelle Demeestere, Julie Dechene, Yvon Englert, and Viviane De Maertelaer, Université Libre de Bruxelles; Alain Kentos and Yvon Englert, Erasme Hospital; Eric Van Den Neste, Cliniques Universitaires UCL Saint-Luc; Dominique Bron, J. Bordet Institute, Brussels; Pierre Zachee, Algemeen Ziekenhuis Stuivenberg, Antwerpen, Belgium; Pauline Brice, St Louis Hospital, APHP; Jehan Dupuis, Hôpital Henri Mondor, Paris; Olivier Casasnovas, CHU de Dijon, Dijon, France; and Fedro A. Peccatori, Istituto Europeo di Oncologia, Milano, Italy
| | - Eric Van Den Neste
- Isabelle Demeestere, Julie Dechene, Yvon Englert, and Viviane De Maertelaer, Université Libre de Bruxelles; Alain Kentos and Yvon Englert, Erasme Hospital; Eric Van Den Neste, Cliniques Universitaires UCL Saint-Luc; Dominique Bron, J. Bordet Institute, Brussels; Pierre Zachee, Algemeen Ziekenhuis Stuivenberg, Antwerpen, Belgium; Pauline Brice, St Louis Hospital, APHP; Jehan Dupuis, Hôpital Henri Mondor, Paris; Olivier Casasnovas, CHU de Dijon, Dijon, France; and Fedro A. Peccatori, Istituto Europeo di Oncologia, Milano, Italy
| | - Julie Dechene
- Isabelle Demeestere, Julie Dechene, Yvon Englert, and Viviane De Maertelaer, Université Libre de Bruxelles; Alain Kentos and Yvon Englert, Erasme Hospital; Eric Van Den Neste, Cliniques Universitaires UCL Saint-Luc; Dominique Bron, J. Bordet Institute, Brussels; Pierre Zachee, Algemeen Ziekenhuis Stuivenberg, Antwerpen, Belgium; Pauline Brice, St Louis Hospital, APHP; Jehan Dupuis, Hôpital Henri Mondor, Paris; Olivier Casasnovas, CHU de Dijon, Dijon, France; and Fedro A. Peccatori, Istituto Europeo di Oncologia, Milano, Italy
| | - Viviane De Maertelaer
- Isabelle Demeestere, Julie Dechene, Yvon Englert, and Viviane De Maertelaer, Université Libre de Bruxelles; Alain Kentos and Yvon Englert, Erasme Hospital; Eric Van Den Neste, Cliniques Universitaires UCL Saint-Luc; Dominique Bron, J. Bordet Institute, Brussels; Pierre Zachee, Algemeen Ziekenhuis Stuivenberg, Antwerpen, Belgium; Pauline Brice, St Louis Hospital, APHP; Jehan Dupuis, Hôpital Henri Mondor, Paris; Olivier Casasnovas, CHU de Dijon, Dijon, France; and Fedro A. Peccatori, Istituto Europeo di Oncologia, Milano, Italy
| | - Dominique Bron
- Isabelle Demeestere, Julie Dechene, Yvon Englert, and Viviane De Maertelaer, Université Libre de Bruxelles; Alain Kentos and Yvon Englert, Erasme Hospital; Eric Van Den Neste, Cliniques Universitaires UCL Saint-Luc; Dominique Bron, J. Bordet Institute, Brussels; Pierre Zachee, Algemeen Ziekenhuis Stuivenberg, Antwerpen, Belgium; Pauline Brice, St Louis Hospital, APHP; Jehan Dupuis, Hôpital Henri Mondor, Paris; Olivier Casasnovas, CHU de Dijon, Dijon, France; and Fedro A. Peccatori, Istituto Europeo di Oncologia, Milano, Italy
| | - Yvon Englert
- Isabelle Demeestere, Julie Dechene, Yvon Englert, and Viviane De Maertelaer, Université Libre de Bruxelles; Alain Kentos and Yvon Englert, Erasme Hospital; Eric Van Den Neste, Cliniques Universitaires UCL Saint-Luc; Dominique Bron, J. Bordet Institute, Brussels; Pierre Zachee, Algemeen Ziekenhuis Stuivenberg, Antwerpen, Belgium; Pauline Brice, St Louis Hospital, APHP; Jehan Dupuis, Hôpital Henri Mondor, Paris; Olivier Casasnovas, CHU de Dijon, Dijon, France; and Fedro A. Peccatori, Istituto Europeo di Oncologia, Milano, Italy
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Oktay K, Bedoschi G. Appraising the Biological Evidence for and Against the Utility of GnRHa for Preservation of Fertility in Patients With Cancer. J Clin Oncol 2016; 34:2563-5. [PMID: 27217452 DOI: 10.1200/jco.2016.67.1693] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Affiliation(s)
- Kutluk Oktay
- New York Medical College and Innovation Institute for Fertility Preservation, New York, NY
| | - Giuliano Bedoschi
- New York Medical College and Innovation Institute for Fertility Preservation, New York, NY
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Lambertini M, Del Mastro L. Fertility preservation in BRCA-mutated breast cancer patients. BREAST CANCER MANAGEMENT 2016. [DOI: 10.2217/bmt-2016-0009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
A possible side effect of anticancer treatments in premenopausal women is the occurrence of premature ovarian failure and subsequent infertility. The inheritance of a deleterious genetic mutation in the BRCA1 or 2 genes generates the hereditary breast and ovarian cancer syndrome. Additional fertility counseling for breast cancer patients with BRCA mutations is warranted to educate them about the available fertility preservation options in the context of their unique concerns (i.e., prophylactic gynecologic surgery, pre-implantation genetic diagnosis and risk of developing long-term treatment-related premature ovarian failure). In this report we discuss the available options for fertility preservation in women with breast cancer, with a particular focus on the specific issues in breast cancer patients with BRCA mutations.
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Affiliation(s)
- Matteo Lambertini
- Department of Medical Oncology, U.O. Oncologia Medica 2, IRCCS AOU San Martino-IST, Largo Rosanna Benzi 10, 16132, Genova, Italy
- BrEAST Data Centre, Department of Medicine, Institut Jules Bordet, & l'Université Libre de Bruxelles (U.L.B), Brussels, Belgium
| | - Lucia Del Mastro
- Department of Medical Oncology, U.O. Sviluppo Terapie Innovative, IRCCS AOU San Martino-IST, Genova, Italy
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Rodriguez-Wallberg K, Turan V, Munster P, Oktay K. Can ovarian suppression with gonadotropin-releasing hormone analogs (GnRHa) preserve fertility in cancer patients? Ann Oncol 2015; 27:357. [PMID: 26609009 DOI: 10.1093/annonc/mdv554] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- K Rodriguez-Wallberg
- Department of Oncology-Pathology, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
| | - V Turan
- Department of Obstetrics and Gynecology, New York Medical College, Valhalla Innovation Institute for Fertility Preservation and IVF, New York
| | - P Munster
- Helen Diller Cancer Center, University of California, San Francisco
| | - K Oktay
- Innovation Institute for Fertility Preservation and IVF, New York Laboratory of Molecular Reproduction and Fertility Preservation, Division of Reproductive Medicine, Department of Obstetrics and Gynecology, New York Medical College, Valhalla, USA
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