Prevention Of Chemotherapy-induced Ovarian Damage Research Articles

Gonadotropin-releasing hormone agonists for ovarian protection during breast cancer chemotherapy: a systematic review and meta-analysis.

ImportanceThe increasing trend of delaying childbirth means that more women are being diagnosed with breast cancer before having given birth to their desired number of children. Although chemotherapy can significantly improve the prognosis of this population, it also causes ovarian damage, including premature ovarian insufficiency and infertility. Gonadotropin-releasing hormone agonists (GnRHa) have shown promising fertility protective activity in premenopausal women, but their clinical usage remains controversial.ObjectiveHere, we conducted a meta-analysis to assess the efficacy of GnRHa when administered concurrently with chemotherapy that included cyclophosphamide in the prevention of chemotherapy-induced ovarian damage in premenopausal women.Evidence ReviewAn extensive literature search was performed using the PubMed, Embase, and Cochrane databases. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were determined.FindingsEleven randomized controlled trials with a total of 1,219 participants were included in the analyses. A significantly higher number of women treated with GnRHa experienced the resumption of ovarian function after chemotherapy than those who did not receive this treatment (OR, 3.04; 95% CI, 1.87‐4.94; P < 0.001). Regarding spontaneous pregnancy, a statistically significant difference was observed only in hormone receptor-negative participants (OR, 2.06; 95% CI, 1.03‐4.11; P = 0.04).Conclusions and RelevanceWhen treating premenopausal women with breast cancer, the administration of GnRHa concurrently with chemotherapy appeared to improve the resumption rate of ovarian function; however, the spontaneous pregnancy rate only improved in hormone receptor-negative patients. Thus, the use of GnRHa during chemotherapy may represent a feasible strategy for preserving ovarian function in women with breast cancer.

Utility of gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage in premenopausal women with breast cancer: a systematic review and meta-analysis.

BackgroundPremature ovarian failure and infertility following chemotherapy are major concerns for premenopausal women with breast cancer. A potential ovarian function preservation strategy is administration of gonadotropin-releasing hormone (GnRH) agonists during adjuvant chemotherapy; however, studies of the clinical efficacy of GnRH agonists to protect chemotherapy-induced ovarian damage have shown mixed results.ObjectiveThis meta-analysis study was designed to estimate the efficacy of GnRH agonists administered concurrently with chemotherapy to prevent chemotherapy-induced ovarian damage in premenopausal women with breast cancer.MethodsElectronic literature databases (PubMed, EMBASE, MEDLINE, Cochrane Library databases searching, China National Knowledge Infrastructure, Web of Science, and the Wanfang Data) were searched for relevant randomized controlled trials (RCTs) published until September 2015. Only RCTs that examined the effect of GnRH agonists for chemotherapy-induced ovarian failure in premenopausal women with breast cancer were selected. The rate of spontaneous resumption of menses and spontaneous pregnancy were collected. All data were analyzed by RevMan 5.3 (Cochrane Collaboration, Copenhagen, Denmark) and Stata 12.0 (StataCorp, College Station, TX, USA).ResultsEleven RCTs with a total of 1,062 participants (GnRH agonists administered concurrently with chemotherapy, n=541; chemotherapy alone, n=521) were included in the meta-analysis. A significantly greater number of women treated with GnRH agonist experienced spontaneous resumption of menses after the adjuvant chemotherapy, yielding a pooled odds ratio of 2.57 (versus chemotherapy alone, 95% confidence interval (CI)=1.65, 4.01; P<0.0001). A subgroup analysis showed that addition of GnRH agonists significantly improved the resumption of menses rate in patients who were hormone-insensitive. However, the two treatment groups experienced similar spontaneous pregnancy (odds ratio =0.177; 95% CI=0.92, 1.40; P=0.09).ConclusionGnRH agonists cotreatment with chemotherapy in premenopausal women with breast cancer plays a beneficial role in resumption of ovarian function, with a higher rate of resumption of menses. However, treatment with GnRH agonists does not appear to exhibit its protective effects in fertility.

Prevention of chemotherapy-induced ovarian damage: possible roles for hormonal and non-hormonal attenuating agents.

Current options for female fertility preservation in the face of cytotoxic treatments include embryo, oocyte and ovarian tissue cryopreservation. However these methods are limited by the patient age, status or available timeframe before treatment and they necessitate invasive procedures. Agents which can prevent or attenuate the ovotoxic effects of treatment would provide significant advantages over the existing fertility preservation techniques, and would allow patients to retain their natural fertility without the necessity for costly, invasive and risky procedures. Recent studies have contributed to our understanding of the mechanisms involved in cytotoxicity-induced ovarian follicle loss and highlight a number of agents that may be able to prevent or reduce this loss. This paper reviews the relevant literature (research articles published in English up to December 2013) on the mechanisms of cytotoxic-induced ovarian damage and the implications for fertility preservation. We present a comprehensive discussion of the potential agents that have been shown to preserve the ovarian follicle reserve in the face of cytotoxic treatments, including an analysis of their respective advantages and risks, and mechanisms of action. Multiple molecular pathways are involved in the cellular response to cytotoxic treatments, and specific cellular reactions depend on variables including the drug class and dose, cell type, and cell stage. A number of agents acting on different elements of these pathways have demonstrated potential for preventing or reducing ovarian follicle loss, although in most cases, the studies are still very preliminary. Advances in our understanding of the mechanisms and pathways involved in both cytotoxic ovarian damage and follicle growth and development have opened up new directions for fertility preservation. In order to bring these agents from the lab to the clinic, it will be vital to accurately evaluate the efficacy of each agent and additionally to demonstrate that co-treatment with these agents will not interfere with the anti-cancer activity of the chemotherapy drugs, or produce genetically comprised embryos.

Influence of gonadotropin-releasing hormone agonist on the effect of chemotherapy upon ovarian cancer and the prevention of chemotherapy-induced ovarian damage: an experimental study with nu/nu athymic mice

Gonadotropin-releasing hormone (GnRH) plays an important role in the regulation of ovarian function and ovarian cancer cell growth. In this study, we determined whether administration of the GnRH agonist (GnRHa), triporelin, prior to cisplatin treatment affects cisplatin and/or prevents cisplatin-induced ovarian damage. nu/nu mice were injected with ovarian cancer OVCAR-3 cells intraperitoneally. After two weeks, the mice were treated with saline (control), cisplatin, GnRHa, or cisplatin plus GnRHa for four weeks. At the end of the experimental protocol, blood, tumor, ovary, and uterine tissues were resected for hematoxylin and eosin (H&E) staining, immunohistochemical analyses of Ki67, nuclear factor-κB (NF-κB), and caspase-3, transmission electron microscopy of apoptosis, or enzyme-linked immunosorbent assay (ELISA) analyses of anti-Mullerian hormone (AMH). Cisplatin treatment effectively inhibited tumor growth in mice treated with human ovarian cancer cells; however the treatment also induced considerable toxicity. Immunohistochemical analyses showed that Ki67 expression was reduced in cisplatin-treated mice compared to control (P<0.05), but there was no statistically significant differences between cisplatin-treated mice and cisplatin plus GnRHa-treated mice (P>0.05), while expressions of NF-κB and caspase-3 were reduced and induced, respectively, in cisplatin-treated mice and cisplatin plus GnRHa-treated mice. Apoptosis occurred in the GnRHa, cisplatin, and cisplatin plus GnRHa-treated mice, but not in control mice. Ovaries exposed to GnRHa in both GnRHa mice and cisplatin-treated mice (combination group) had significantly more primordial and growth follicles and serum levels of AMH than those in the control mice and cisplatin-treated mice (P<0.05). Administration of GnRHa to mice significantly decreased the extent of ovarian damage induced by cisplatin, but did not affect the anti-tumor activity of cisplatin.

Recognition and Handling of Discordant Negative Human Epidermal Growth Factor Receptor 2 Classification by Oncotype DX in Patients With Breast Cancer

REFERENCES 1. Blumenfeld Z: Gonadotropin-releasing hormone agonist for preservation of ovarian function during (neo)adjuvant chemotherapy for breast cancer. J Clin Oncol 30:3310, 2012 2. Tomao F, Benedetti Panici P, Tomao S: Gonadotropin-releasing hormone agonists for the preservation of ovarian function during chemotherapy. J Clin Oncol 30:3310, 2012 3. Munster PN, Moore AP, Ismail-Khan R, et al: Randomized trial using gonadotropinreleasing hormone agonist triptorelin for the preservation of ovarian function during (neo)adjuvant chemotherapy for breast cancer. J Clin Oncol 30:533-538, 2012 4. Badawy A, Elnashar A, El-Ashry M, et al: Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: Prospective randomized study. Fertil Steril 91:694-697, 2009 5. Del Mastro L, Boni L, Michelotti A, et al: Effect of the gonadotropinreleasing hormone analogue triptorelin on the occurrence of chemotherapyinduced early menopause in premenopausal women with breast cancer: A randomized trial. JAMA 306:269-276, 2011 6. Gerber B, von Minckwitz G, Stehle H, et al: Effect of luteinizing hormone– releasing hormone agonist on ovarian function after modern adjuvant breast cancer chemotherapy: The GBG 37 ZORO study. J Clin Oncol 29:2334-2341, 2011 7. Leonard RC, Adamson D, Anderson R, et al: The OPTION trial of adjuvant ovarian protection by goserelin in adjuvant chemotherapy for early breast cancer. J Clin Oncol 28:89s, 2010 (abstr 590) 8. Sukumvanich P, Case LD, Van Zee K, et al: Incidence and time course of bleeding after long-term amenorrhea after breast cancer treatment: A prospective study. Cancer 116:3102-3111, 2010 9. Fornier MN, Modi S, Panageas KS, et al: Incidence of chemotherapyinduced, long-term amenorrhea in patients with breast carcinoma age 40 years and younger after adjuvant anthracycline and taxane. Cancer 104:1575-1579, 2005

Effect of the gonadotropin-releasing hormone antagonist cetrorelix on the prevention of chemotherapy-induced ovarian damage in women with hematological malignancy

Gonadotropin-releasing hormone (GnRH) agonists are the most commonly used pharmaceutical treatment for ovarian protection during chemotherapy [1,2]. A recent study showed that a combination of GnRH agonists and antagonists induced a long-lasting suppression of gonadotropins but did not completely prevent flare-up of follicle stimulating hormone [3]. The aim of the present study was to evaluate the use of cetrorelix, a GnRH antagonist, for prevention of ovarian damage during chemotherapy in patients with a hematologic malignancy, such as Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), and acute leukemia (AL). The study included 24 women (mean age at diagnosis, 23.3± 6.4 years) who had been diagnosed with a hematologic malignancy (15 HL, 4 NHL, and 5 AL). All patients received chemotherapy with various cytotoxic agents, including cyclophosphamide, and 3 mg of cetrorelix subcutaneously every second day. Data were compared retrospectively with 31 women (mean age, 26.4±6.2 years) who had been diagnosed with a hematologic cancer (18 HL, 12 NHL, and 3 AL) and received the same chemotherapy, but without cetrorelix. The study was approved by the Institutional Review Board. Pb0.05 was considered significant at statistical analysis. Among the 23 evaluable women (1 died) who received cetrorelix, the incidence of secondary amenorrhea 6 months after cessation of treatment was significantly lower compared with the women who did not receive cetrorelix (4.3% vs 27.3%, P=0.036; Table 1). No significant differences were observed between the 2 groups in the mean serum levels of follicle-stimulating hormone, estradiol, and anti-Mullerian hormone after completion of chemotherapy (P>0.05; Table 1), suggesting a degree of ovarian damage despite cetrorelix administration.

Combination of gonadotropin-releasing hormone (GnRH) agonists with GnRH antagonists before chemotherapy reduce but does not completely prevent a follicle-stimulating hormone flare-up

Increasing evidence supports GnRH agonists to be an effective treatment to preserve ovarian function during chemotherapy, but the initial flare-up of FSH during the first week after GnRH agonist application still limits its use. The combination of GnRH agonists with GnRH antagonists might solve this problem to some extent as the addition of GnRH antagonists at least significantly reduces the FSH flare-up.

Efficacy and safety of ovarian stimulation before chemotherapy in 205 cases

Ovarian stimulation and cryopreservation of fertilized oocytes before cancer therapy is the best established and efficient fertility preservation technique and should still be considered before chemotherapy. Within a short time frame of 2 weeks, between 8.6 (18-25 y) and 5.1 (36-40 y) fertilized oocytes can be cryopreserved.

O21 Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: Prospective randomized study

International Journal of Gynecology & ObstetricsVolume 107, Issue S2 p. S99-S99 Free communication (oral) presentations O21 Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: Prospective randomized study B. Ahmed, B. AhmedSearch for more papers by this author B. Ahmed, B. AhmedSearch for more papers by this author First published: 20 November 2009 https://doi.org/10.1016/S0020-7292(09)60393-3AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume107, IssueS2Abstracts of XIX FIGO World Congress of Gynecology and ObstetricsOctober 2009Pages S99-S99 RelatedInformation

RETRACTED: Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomized study

To determine whether GnRHa administration before and during combination chemotherapy for breast cancer could preserve posttreatment ovarian function in young women or not. Prospective randomized controlled study. Department of Obstetrics and Gynecology, Mansura University Hospital, Mansura, Egypt. Eighty patients with unilateral adenocarcinoma of the breast and with no metastasis who had undergone modified radical mastectomy or breast-conserving surgery plus full axillary lymph node dissection were included in the study. Patients were assigned randomly to receive combined GnRHa and chemotherapy or chemotherapy alone. One woman in each group dropped out. Return of spontaneous menstruation and ovulation. Hormonal changes (FSH, LH, E(2), P) during and after the course of treatment. In the study group, 89.6% resumed menses and 69.2% resumed spontaneous ovulation within 3-8 months of termination of the GnRHa/chemotherapy cotreatment; 11.4% experienced hypergonadotrophic amenorrhoea and ovarian failure 8 months after treatment. In the control group (chemotherapy without GnRHa), 33.3% resumed menses and 25.6% resumed normal ovarian activity. The median FSH and LH concentrations, 6 months after completion of the GnRHa/chemotherapy cotreatment group, were significantly less than the control group. During the GnRHa/chemotherapy cotreatment the concentrations of FSH, LH, and P decreased to almost prepubertal levels. However, within 1-3 months after the last GnRHa injection, an increase in LH and FSH concentrations was detected, followed several weeks later in by an increase in P concentrations to within normal levels. GnRHa administration before and during combination chemotherapy for breast cancer may preserve posttreatment ovarian function in women <40 years. Long-term studies are required.