Gonadotropin-Releasing Hormone Agonists for Ovarian Function Preservation in Premenopausal Women Undergoing Chemotherapy for Early-Stage Breast Cancer

Abstract

Importance Chemotherapy may result in a detrimental effect on ovarian function and fertility in premenopausal women undergoing curative treatment for early breast cancer (EBC). For this subgroup of patients, a careful consideration for techniques to minimize this risk should be given and the role of gonadotropin-releasing hormone agonists (GnRHa) for protection of ovarian function is not fully resolved. Objective To determine efficacy of GnRHa administered concurrently with chemotherapy for ovarian function preservation. Data sources The search for studies published between 1975 and March/2015 encompassed PubMed, SCOPUS and Cochrane databases, as well as ASCO Annual Meeting and San Antonio Breast Cancer Symposium abstracts. Study selection Prospective, randomized, controlled trials addressing the role of ovarian suppression with GnRHa in preventing early ovarian dysfunction in premenopausal women undergoing treatment for EBC were selected. Data extraction and synthesis Data extraction was performed independently by two authors. The methodology and the risk of bias were assessment based on the description of randomization method, withdrawals and blinding process. Main Outcomes Measures Rate of resumption of regular menses after a minimal follow-up period of 6 months following chemotherapy was used as surrogate to assess the incidence of ovarian dysfunction. Additional secondary outcomes included hormone levels and number of pregnancies. Risk ratio estimates were calculated based on the number of evaluable patients. Analyses were conducted using a random effect model. Results Seven studies were selected, totaling 1047 randomized patients (856 evaluable patients).. The use of GnRHa was associated with a higher rate of recovery of regular menses after 6 months (OR = 2.41; 95% CI 1.40–4.15; p= 0. 002) and at least 12 months (OR 1.85; 95% CI 1.33–2.59; p = 0.0003) following last chemotherapy cycle. The use of GnRHa was also associated with a higher number of pregnancies (OR 1.85; 95% IC 1.02–3.36; p=0.04), although this outcome was not uniformly reported. Conclusions and Relevance GnRHa given with chemotherapy resulted in increased rates of recovery of regular menses and should be considered an option for ovarian function preservation in young women undergoing treatment for EBC. Additional outcomes related to ovarian function and fertility need to be further investigated.

Adolescent and Young Adult Oncology, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology

“…[123][124][125][126][127][128][129][130][131] Some meta-analyses have shown that GnRH agonist may be beneficial for fertility preservation. [132][133][134] However, the impact of these meta-analyses are limited by flaws such as only examining women with breast cancer and only including trials that were not adequately powered and did not use blinding and/ or a placebo condition. 135,136 Further, results from earlier meta-analyses were inconsistent, with some showing a potential benefit of GnRH to preservation of ovarian function, [137][138][139] while other reviews have been unable to come to this conclusion.…”

“…128,132,134 However, evidence that menstrual suppression with GnRH agonists protects ovarian function is insufficient, so this procedure is not currently recommended as an option for fertility preservation.…”

Gonadotropin‐releasing hormone agonists for ovarian protection during cancer chemotherapy: systematic review and meta‐analysis

“…Furthermore, sample size calculation was not conducted in some studies 24,27,28,32,33 and, when calculated, the required number of participants was not reached in others 23,25,26,29,31,35 . Previous systematic reviews with meta-analysis have addressed the effect of GnRHa on reproductive outcome of women with cancer undergoing chemotherapy, but their inclusion criteria differed from the present review as they included observational studies 12,15 or were restricted to breast cancer [17][18][19][20][54][55][56][57] . The conclusions of these previous reviews ranged from GnRHa having no significant impact on chemotherapy-induced amenorrhea 54 , to an association of GnRHa with lower risk of POI and higher pregnancy rate, suggesting that GnRHa 'might be considered as an option' for ovarian function preservation 57 .…”

“…Despite numerous attempts to synthesize the results in several meta-analyses [9][10][11][12][13][14][15][16][17][18][19][20] , the subject remains controversial. This systematic review and meta-analysis was designed to evaluate the efficacy of GnRHa in ovarian reserve protection before and during cancer chemotherapy in premenopausal women without previous diagnosis of infertility.…”

Optimizing Adjuvant Therapy and Survivorship Care of Stage III Colon Cancer

“…While female patients have the option of embryo/oocyte cryopreservation, another option includes administration gonadotropin-releasing hormones (GnRH) [69]. While there have been mixed results in trials assessing the benefit of these agents, rates of menses resumption is increased with these agents in large meta-analysis, and some studies have suggested a higher rate of pregnancy following use of GnRH agents during pregnancy [70,71]. The most recent meta-analysis by Munhoz et al looking at 856 patients in seven studies suggested that use of a GnRH agonist improved rate of recovery of regular menses (OR: 2.41; 95% CI: 1.40-4.15; p = 0.002) and rates of pregnancy (OR: 1.85; 95% CI: 1.02-3.36; p = 0.04) during adjuvant treatment of breast cancer.…”