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The Role of Gonadotropin-Releasing Hormone Agonists

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The Role of Gonadotropin-Releasing Hormone Agonists Review Preserving fertility when choosing chemotherapy regimens -- the role of gonadotropin-releasing 1. Introduction 2. Methods for fertility hormone agonists preservation † Zeev Blumenfeld & Ayelet Evron † 3. GnRH analogues Technion -- Israel Institute of Technology, Department Obstetrics and Gynecology, Rappaport 4. Risks and benefits of the Faculty of Medicine, Reproductive Endocrinology, Rambam Health Care Campus, Haifa, Israel different fertility preservation Introduction: methods The late effects of cancer treatment have recently gained a worldwide ubiquitous interest among reproductive endocrinologists, oncolo- 5. Chemotherapeutic agents gists, and all health care providers. Despite many publications on this subject, 6. GnRHa controversy there are many equivocal issues necessitating summary. The case for and 7. Expert opinion -- suggested against using GnRH-agonist for fertility preservation is summarized with the policy and management rationale that preventing ovarian failure may be better than treating it. Areas covered: We searched Medline in the last 10 years using terms: ‘fertility preservation’, ‘female chemotherapy’, ‘Gonadotropin-releasing hormone (GnRH) analogues’, ‘GnRH agonists’ ‘gonadotoxicity’, and ‘cancer treatment’. We included mainly publications from the past 7 years, but did not exclude previous, commonly referenced publications. Here, we summarize the various methods available for fertility preservation and minimizing chemotherapy induced gonadotoxicity. Expert opinion: Until now, 20 studies (15 retrospective and 5 randomized controlled trial) have reported on 2038 patients treated with GnRH-a in parallel to chemotherapy, showing a significant decrease in premature ovar- For personal use only. ian failure (POF) rate in survivors versus 8 studies reporting on 509 patients, with negative results. Patients treated with GnRH-a in parallel to chemother- apy preserved their cyclic ovarian function in 91% of cases as compared to 41% of controls, with a pregnancy rate of 19 -- 71% in the treated patients. Furthermore, over 10 recent meta-analyses have concluded that GnRH-a are beneficial and may decrease the risk of POF in survivors. Because most of the methods involving ovarian or egg cryopreservation are not yet clinically established and unequivocally successful, these young patients deserve to be informed with all the various modalities to minimize gonadal damage and preserve ovarian function and future fertility. Combining the various modali- ties for a specific patient may increase the odds of preservation of future Expert Opin. Pharmacother. Downloaded from informahealthcare.com by 80.179.114.19 on 03/31/15 fertility. Keywords: fertility preservation, gonadotropin-releasing hormone agonist, gonadotoxicity, premature ovarian failure Expert Opin. Pharmacother. [Early Online] 1. Introduction The increase in cancer incidence in the young age, and the significant increase in the long-term survival have brought about a ubiquitous interest in the attempts to pre- serve fertility in young patients exposed to gonadotoxic chemo- and radiotherapy. Indeed, malignancy is estimated to occur in 1:49 women under the age of 40 in the US [1-3]. About 790,000 new cases of cancer are yearly diagnosed in women in the US, in the last few years and almost one in seven diagnosed female patients 10.1517/14656566.2015.1031654 © 2015 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 1 All rights reserved: reproduction in whole or in part not permitted Z. Blumenfeld & A. Evron iatrogenic infertility caused by chemotherapy gained ubiqui- Article highlights. tous interest in the last decades. The administration of . All the mentioned fertility preservation methods should GnRH-agonistic analogues, in an attempt to decrease the be offered to young women before gonadotoxic gonadotoxic effects of chemotherapy by simulating a prepu- chemotherapy. The decision regarding which of the bertal hormonal milieu, attracts growing attendance [1,5-11].As methods should be used is to be taken by the patient such, the number of publications regarding fertility preserva- after consulting the hematologists/oncologist and reproductive endocrinologist/fertility specialist. tion increased rapidly during the last decade. Unfortunately, . Ovarian cryopreservation and reimplantation bears the none of the suggested methods is ideal and none guarantees possible risk of contamination with malignant cells. future fertility in survivors. Established fertility preservation Every effort should be accomplished to detect such a methods include embryos and/or ova cryopreservation and possibility. Such a risk is high in leukemia but exists even ovarian transposition (oophoropexy), offered to patients in low risk cases such as lymphoma. Nevertheless, ovarian cryopreservation should be offered, since in vitro before pelvic irradiation [1,3]. maturation of primordial follicles may become a reality in the future. 2.1 Cryopreservation of embryos . Despite the controversy, gonadotropin-releasing In Vitro Fertilization (IVF) and embryo cryopreservation, is a hormone agonists bears a beneficial role and may non-investigational, clinically established method, and among decrease the risk of premature ovarian failure (POF) in most female patients exposed to gonadotoxic adult female cancer patients is the most accepted form of fertil- chemotherapy. Prevention of POF is preferable to ity preservation and the most mature technology [1,3-6,8,12]. treating it, following the dictum “An ounce of However, it may necessitate postponing chemotherapy for prevention is worth a pound of cure”. 10 -- 14 days and is frequently not applicable to the very young patient without a partner [1,3-6]. In addition, its cost varies This box summarizes key points contained in the article. among different countries, being almost free of charge to the patient in Israel, but quite expensive in several other counties. are women in the reproductive age [2]. It has been previously No difference was seen between cancer patients and controls estimated, that at present, one in every 250 -- 715 people in with respect to the total units of used gonadotropin, number the adult population will be a cancer survivor [1,3,4]. Therefore, of retrieved ova (12.4 vs 10.9) and number of generated the late effects of cancer treatment have recently gained a embryos (6.6 vs 7.1) [12]. Cumulative pregnancy rate per trans- worldwide interest not only among reproductive endocrinolo- fer for cancer patients compared to controls was 37 versus 43% gists but also among hematologists, oncologists, gynecologists, and cumulative live birth rate per transfer was 30 versus 32% For personal use only. endocrinologists, rheumatologists, family physicians and all [12]. Cancer patients had a higher likelihood of live birth result- healthcare providers [1,3-10]. It is well established that young ing in twins (44 vs 14%; p = 0.035) [12]. In cases where increased women exposed to gonadotoxic chemotherapy face the risk estradiol levels are dangerous, such as in patients with estrogen of suffering premature ovarian failure (POF) and infertility. receptors (ER)-positive breast cancer, the ovarian stimulation The risk of POF ranges from below 10% to over 95% and should include an aromatase inhibitor such as letrozole, to min- is correlated to age, type of chemotherapy and cumulative imize the possible detrimental effect of high estrogen levels on dosage. Among the chemotherapeutic regimens, alkylating the malignant cells [6,13]. Also, to minimize the risk of ovarian agents are the most gonadotoxic agents. Aggressive condition- hyperstimulation syndrome, the advisable controlled ovarian ing chemotherapy, such as used before bone marrow trans- hyperstimulation protocol is the GnRH-antagonist protocol plantation (BMT), especially when combined with using GnRH agonist triggering (such as 0.2 mg Triptorelin) irradiation, bears a very high risk of POF. Thus, a new spe- instead of human chorionic gonadotropin [6,12-16]. Further- Expert Opin. Pharmacother. Downloaded from informahealthcare.com by 80.179.114.19 on 03/31/15 cialization, named ‘oncofertility’ has emerged focusing on more, to minimize the postponement of chemotherapy start, the various aspects of fertility preservation in young women the ovarian stimulation with gonadotropins (controlled ovarian exposed to gonadotoxic chemotherapy [1]. Such methods for hyperstimulation), may be started on any day of the menstrual fertility preservation before chemotherapy include cryopreser- cycle, even in the luteal phase [1,16]. vation of embryos, oocytes, and ovarian tissue, and ovarian suppression using long-acting gonadotropin-releasing 2.2 Cryopreservation of ova hormone (GnRH) agonists from 7 to 14 days before and in For more than 2 years, cryopreservation of oocytes is no lon- parallel to the gonadotoxic chemotherapy. ger considered experimental [1,3,6,14,15]. The big advantage of unfertilized ova cryopreservation is the applicability to young 2. Methods for fertility preservation patients without a partner [3,6,14,15]. Also, in countries where cryopreservation of embryos is not allowed, the vitrification Several options have been put forward for preserving female of ova enables fertility preservation [3,6,14,15]. However, fertility: ovarian transposition, cryopreservation of embryos, although cryopreservation of unfertilized ova has gained unfertilized metaphase-II (M-II) oocytes and ovarian recent popularity and increased success, it also does not tissue [1,3-10]. Due to the high priority, the
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