Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomized study (original) (raw)
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Ovarian Preservation by GnRH Agonists during Chemotherapy: A Meta-Analysis
Journal of Womens Health, 2009
Purpose: Treatment with cyclophosphamide (CYC) confers up to a 40% risk of ovarian failure in women of reproductive age. The use of GnRH agonists (GnRHa) to preserve ovarian function has been investigated in several small studies. We performed a systematic review of studies examining whether a GnRHa administered during chemotherapy is protective of ovarian function and fertility. Methods: We searched the English-language literature (1966( -April 2007 using MEDLINE and meeting abstracts and included studies that reported an association between GnRHa and ovarian preservation in women receiving chemotherapy. Studies without a control group were excluded. Ovarian preservation was defined as the resumption of menstrual cycles and a premenopausal follicle-stimulating hormone (FSH) after chemotherapy. Fertility was determined by a woman's ability to become pregnant. We estimated the summary relative risk (RR) and associated 95% confidence intervals (95% CI) using a random-effects model. Results: Nine studies included 366 women. Three studies included women with autoimmune disease receiving CYC; six included women with hematologic malignancy receiving combination chemotherapy. In total, 178 women were treated with GnRHa during chemotherapy, 93% of whom maintained ovarian function. Of the 188 women not treated with GnRHa, 48% maintained ovarian function. The use of a GnRHa during chemotherapy was associated with a 68% increase in the rate of preserved ovarian function compared with women not receiving a GnRHa (summary RR ¼ 1.68, 95% CI 1.34-2.1). Among the GnRHa-treated women, 22% achieved pregnancy following treatment compared with 14% of women without GnRHa therapy (summary RR ¼ 1.65, CI 1.03-2.6). Conclusions: Based on the available studies, GnRHa appear to improve ovarian function and the ability to achieve pregnancy following chemotherapy. Several randomized trials are underway to define the role and mechanism of GnRHa in ovarian function preservation. In the meantime, premenopausal women facing chemotherapy should be counseled about ovarian preservation options, including the use of GnRHa therapy.
Human Reproduction Update, 2008
BACKGROUND: Cancer survival rates in young women are improving due to progress in treatment. This includes aggressive chemotherapy, a treatment that often poses a threat to fertility. GnRH agonists were proposed as ovarian protectors during gonadotoxic therapies. This study was undertaken in order to determine the clinical evidence concerning this issue. METHODS: The medical literature was searched for studies that reported on ovarian function after the administration of GnRH agonists concomitant with chemotherapy. Twelve studies met the predetermined selection criteria. RESULTS: Data on ovarian function were obtained for 579 women who received chemotherapy. Among 345 women who received GnRH agonist co-treatment, ovarian function was preserved in 91% and 9% had premature ovarian failure. In 234 women who did not receive GnRH agonist co-treatment, ovarian function was preserved in 41% and failed in 59%. Only two of the studies were randomized. The control and the GnRH agonist groups differed in several important characteristics: the follow-up times were not equal, different treatment protocols were utilized and end-points were poorly defined and inconsistent between the studies. CONCLUSIONS: The effectiveness of GnRH agonists as fertility-preserving agents is debatable. A thorough literature search has found insufficient evidence to show that GnRH agonist co-treatment is effective in protecting the ovary from the damage of chemotherapy. A large randomized controlled trial with adequate follow-up is needed.
JAMA Oncology, 2015
IMPORTANCE Chemotherapy may result in a detrimental effect on ovarian function and fertility in premenopausal women undergoing treatment for early-stage breast cancer (EBC). To minimize risk of harm to ovarian function and fertility for patients in this setting, careful considerations should be made. Gonadotropin-releasing hormone agonists (GnRHa) have been suggested as an alternative to prevent the loss of ovarian function due to exposure to cytotoxic agents, but GnRHa use for ovarian protection in EBC patients is not fully resolved. OBJECTIVE To determine the effectiveness of GnRHa administered concurrently with chemotherapy for ovarian function preservation.
Frontiers in women's health, 2017
Background: Patients with cancer must be aware of preventive measures that can be undertaken to preserve their fertility before embarking on gonadotoxic therapy. Different theories have been published on the efficacy and the mechanism of action of gonadotropin releasing hormone agonists (GnRHa) in preventing ovarian failure. We hereof report our experience with the GnRHa, leuprolide (Lupron®), used before chemotherapy to preserve ovarian function concerning resumption of menses and fertility. Objective: To determine whether GnRHa could prevent the early onset of ovarian insufficiency and resume menses in patients with cancer who received chemotherapy. Methods: This is a retrospective case series that included all pre-menopausal women, who attended a tertiary referral center, between December 2010 and December 2015. Patients who are diagnosed with cancer had been referred from the oncology department before receiving chemotherapy. Women were given leuprolide (luteinizing hormone releasing hormone agonist) monthly, which was started before or at first chemotherapy cycle and continued every month until the last cycle of chemotherapy. The GnRHa was started 3-20 days before treatment. The main clinical endpoint was the recovery of menstruation after chemotherapy. The other end point was the rate of successful conception post chemotherapy. Results: Twelve patients were included in the study. Median age was 25.5 years (range 16-48); eleven patients (92%) were less than the age of 40. Most of the patients were single, nine (75%), and only three (25%) were married; two patients had infertility problems (16.7%). Patients received different regimens of chemotherapy, according to their type of cancer. Resumption of menstrual activity after chemotherapy was observed in 10 out of 12 patients (83.3%), and all were less than 40 years. The median time to recovery of menses was 2 to 3 months after cessation of chemotherapy. The paired t-test has shown that there is a statistical significant difference between of FSH serum level before and after administering Leuprolide (P = 0.025). On the other hand, there is moderate significant correlation (r = 0.285) between FSH serum level before and after administering Leuprolide. Conclusion: Current case series, suggests that use of GnRHa given with chemotherapy for cancer patients is successful in preventing chemotherapy-induced amenorrhea. Larger studies are needed to affirm this finding.
Journal of Clinical Oncology, 2012
To assess the efficacy of gonadotropin-releasing hormone agonist (GnRHa) in preventing chemotherapy-induced ovarian failure in patients treated for Hodgkin or non-Hodgkin lymphoma within the setting of a multicenter, randomized, prospective trial. Patients and Methods Patients age 18 to 45 years were randomly assigned to receive either the GnRHa triptorelin plus norethisterone (GnRHa group) or norethisterone alone (control group) concomitantly with alkylating agents containing chemotherapy. The primary end point was the premature ovarian failure (POF) rate (follicle-stimulating hormone [FSH] Ն 40 IU/L) after 1 year of follow-up. Results Eighty-four of 129 randomly assigned patients completed the 1-year follow-up. The mean FSH values were higher in the control group than in the GnRHa group during chemotherapy; however, this difference was no longer observed after 6 months of follow-up. After 1 year, 20% and 19% of patients in the GnRHa and control groups, respectively, exhibited POF (P ϭ 1.00). More than half of patients in each group completely restored their ovarian function (FSH Ͻ 10 IU/L), but the anti-Mü llerian hormone values were higher in the GnRHa group than in the control group (1.4 Ϯ 0.35 v 0.5 Ϯ 0.15 ng/mL, respectively; P ϭ .040). The occurrence of adverse events was similar in both groups with the exception of metrorrhagia, which was more frequently observed in the control group than the GnRHa group (38.4% v 15.6%, respectively; P ϭ .024). Conclusion Approximately 20% of patients in both groups exhibited POF after 1 year of follow-up. Triptorelin was not associated with a significant decreased risk of POF in young patients treated for lymphoma but may provide protection of the ovarian reserve.
Fertility and Sterility, 2011
Objective: To determine whether gonadotropin-releasing hormone (GnRH) analog cotreatment with chemotherapy provides better reproductive outcomes for women at risk of premature ovarian failure (POF) as a side-effect of gonadotoxic chemotherapy. Design: Systematic review and meta-analysis. Setting: University-affiliated research centers. Patient(s): None. Intervention(s): Electronic and manual searches (e.g., MEDLINE, EMBASE, CENTRAL) up to January 2010 were performed to identify randomized controlled trials (RCTs) comparing GnRH cotreatment with chemotherapy alone in premenopausal women. Main Outcome Measure(s): Incidence of POF after treatment, incidence of women with resumption of ovulation, POF after an initial normal cycle, normal cycles but abnormal markers of ovarian reserve, spontaneous occurrence of pregnancy after treatment, and time to reestablishment of menstruation; data also extracted to allow for an intention-to-treat analysis. Result(s): Twenty-eight RCTs were identified, but only six met the inclusion criteria. Data were only available for the incidence of women with new onset of POF, resumption of ovulation, and occurrence of pregnancy. The incidence of POF or resumption of ovulation both demonstrated a statistically significant difference in favor of the GnRH cotreatment. The occurrence of spontaneous pregnancy showed no statistically significant difference between GnRH cotreatment and the control groups. Conclusion(s): Evidence from RCTs suggests a potential benefit of GnRH cotreatment with chemotherapy in premenopausal women, with higher rates of spontaneous resumption of menses and ovulation but not improvement in pregnancy rates. Data relating to study quality and possible bias for the majority of the outcomes in this review were not available, denoting possible selective reporting of trial data. (Fertil Steril Ò 2011;95:906-14. Ó2011 by American Society for Reproductive Medicine.
Controversies over the use of GnRH agonists for reduction of chemotherapy-induced gonadotoxicity
Climacteric : the journal of the International Menopause Society, 2016
The increase in cancer incidence in younger people and the significant improvement in long and permanent remission have brought concern about their reproductive future and quality of life. Up to two-thirds of adult female patients undergoing chemotherapy for malignancies eventually develop premature ovarian failure. This condition is related to many complaints including vasomotor symptoms, osteoporosis, increased risk of cardiovascular diseases, sexual dysfunction, and infertility. Therefore, protection against iatrogenic infertility and loss of endocrine ovarian function caused by chemotherapy is currently of high priority. Several options have been used for preserving ovarian function. Established methods include cryopreservation of embryos and/or ova, and ovarian transposition, while others such as ovarian tissue preservation are new, yet promising treatments for fertility preservation. The administration of gonadotropin releasing hormone (GnRH) agonistic analogs (GnRH-a) is stil...
GnRH-analogues and oral contraceptives for fertility preservation in women during chemotherapy
Human Reproduction Update, 2008
BACKGROUND: For preserving fertility in women during chemotherapy, the character of invasive techniques, such as ovarian cryopreservation and other techniques, await further experience. Meanwhile, non-invasive techniques have attempted to minimize the gonadotoxic effect of chemotherapy, by using gonadotrophin-releasing hormone-analogues (GnRH-a) or oral contraceptives (OC). METHODS: We performed a computerized MEDLINE search to identify articles published on fertility preservation using GnRH-a or OCs. RESULTS: Nine human-controlled studies reported the use of GnRH-a and four reported the use of OCs in parallel to chemotherapy. All nine studies analysing the effect of GnRH-a found lower rates of premature ovarian failure (POF) in patients receiving GnRH-a compared with the controls. Summarizing the studies resulted in 11.1% incidence of POF in patients who received GnRH-a compared with 55.5% incidence in the controls. Evidence using the fertility preserving effect of OC is limited. Two studies showed lower POF rates in OC-treated patients. The summarized data revealed a POF rate of 13.2% in patients who received OCs compared with that of 29.8% in the controls. CONCLUSIONS: The published clinical studies provide evidence, but do not prove statistically, that GnRH-a co-treatment reduces gonadotoxicity. Owing to the retrospective and non-randomized nature of most of the studies, definite conclusions concerning the reduction of POF by GnRH-a can still not be unequivocally drawn. As GnRH-a and OC have no serious side effects and as GnRH-a can even reduce chemotherapy-induced complications, such as severe menometrorrhagia, GnRH-a are considered by many clinicians as a clinically useful co-treatment in chemotherapy. The published clinical studies on OC also suggest a possible effect on the reduction of POF under certain conditions.
Clinical Medicine Insights: Reproductive Health
Chemotherapy-induced premature ovarian insufficiency (POI) is one of the potential drawbacks of chemotherapy use of particular concern for newly diagnosed premenopausal breast cancer patients. Temporary ovarian suppression obtained pharmacologically with the administration of a gonadotropin-releasing hormone agonist (GnRHa) during chemotherapy has been specifically developed as a method to counteract chemotherapy-induced gonadotoxicity with the main goal of diminishing the risk of POI. In recent years, important clinical evidence has become available on the efficacy and safety of this strategy that should now be considered a standard option for ovarian function preservation in premenopausal breast cancer patients, including women who are not interested in conceiving after treatment or that would not be candidates for fertility preservation strategies because of their age. Nevertheless, in women interested in fertility preservation, this is not an alternative to gamete cryopreservati...
Cancer Treatment Reviews, 2014
Background: The role of temporary ovarian suppression with gonadotropin-releasing hormone analogues (GnRHa) in the prevention of chemotherapy-induced premature ovarian failure (POF) is still controversial. We conducted a systematic review and meta-analysis of randomized trials evaluating the efficacy of GnRHa, given before and during chemotherapy, in the prevention of POF in premenopausal cancer patients. Methods: Studies were retrieved by searching PubMed, Web of Knowledge database and the proceedings of major conferences. We calculated Odds Ratios (OR) and 95% confidence intervals (CIs) for POF from each trial and obtained pooled estimates through the random effects model as suggested by DerSimonian and Laird. Results: Nine studies were included in the meta-analysis with 225 events of POF occurring in 765 analyzed patients. The pooled OR estimate indicates a highly significant reduction in the risk of POF (OR = 0.43; 95% CI: 0.22-0.84; p = 0.013) in patients receiving GnRHa. There was statistically significant heterogeneity among studies (I 2 = 55.8%; p = 0.012). There was no evidence of publication bias. Subgroups analyses showed that the protective effect of GnRHa against POF was similar in subgroups of patients defined by age and timing of POF assessment, while it was present in breast cancer but unclear in ovarian cancer and lymphoma patients. Conclusions: Our pooled analysis of randomized studies shows that the temporary ovarian suppression induced by GnRHa significantly reduces the risk of chemotherapy-induced POF in young cancer patients.