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Fertility benefit of gonadotropin-releasing hormone agonists remains unclear
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Women treated with gonadotropin-releasing hormone agonists while undergoing chemotherapy for early-stage breast cancer experienced increased recovery of regular menstrual periods, according to the results of a systemic review and meta-analysis.
However, the researchers did not have sufficient evidence to evaluate outcomes related to gonadotropin-releasing hormone agonists (GnRHa) and ovarian function and fertility.
Chemotherapy can damage ovarian function and fertility in premenopausal women undergoing treatment for early-stage breast cancer. Some studies have suggested luteinizing hormone-releasing hormone analogues and GnRHa can prevent the loss of ovarian function due to cytotoxic agent exposure.
Thus, Rodrigo Ribeiro Munhoz, MD, medical oncologist at Hospital Sírio Libanês in Sao Paulo, and colleagues sought to determine the efficacy of GnRHa administered concurrently with chemotherapy for the purpose of ovarian function preservation.
Munhoz and colleagues conducted a systemic review and meta-analysis by searching PubMed, SCOPUS and Cochrane databases for studies published between January 1975 and March 2015. Further, they searched ASCO Annual Meeting abstracts between 1995 and 2014, as well as San Antonio Breast Cancer Symposium abstracts between 2009 and 2014.
The researchers selected prospective randomized controlled trials that addressed the role of ovarian suppression with GnRHa in preventing premature ovarian dysfunction in women receiving chemotherapy for early-stage breast cancer.
The rate of resumption of regular menses after a 6-month minimum post-chemotherapy follow-up acted as a surrogate for ovarian dysfunction and served as the primary endpoint. Secondary endpoints included hormone levels and number of pregnancies.
The analysis included data from seven studies, comprising 856 evaluable patients. The use of GnRHa appeared associated with a higher rate of recovery of regular menses after 6 months (OR = 2.41; 95% CI, 1.4-4.15) and 12 or more months (OR = 1.85; 95% CI, 1.33-2.59) following chemotherapy cessation.
Further, GnRHa appeared associated with a higher number of pregnancies (OR = 1.85; 95% CI, 1.02-3.36). However, the researchers acknowledged that fertility or rate of pregnancy did not serve as the primary endpoint for any trial, and that pregnancy outcomes were not uniformly reported.
The researchers acknowledged the small number of studies and patients included in the final analysis as study limitations. Further, they noted that nearly half (44%) of patient data came from two studies, and that survival data were lacking in most studies.
Kutluk Oktay
“Currently available guidelines consider the use of GnRHa as experimental,” Munhoz and colleagues wrote. “Evidence is not sufficient to assess the effect of GnRHa on fertility or pregnancy rates. Additional outcomes related to ovarian function and fertility need to be further investigated.”
Lingering concerns surrounding the long-term health effects of GnRHa — in addition to the potential for selection bias involved in a meta-analysis — should be considered when determining appropriate treatment, Kutluk Oktay, MD, PhD, and Volkan Turan, MD, both of the division of reproductive medicine and laboratory of molecular reproduction and fertility preservation at New York Medical College, wrote in an accompanying editorial.
“It is not surprising that Munhoz and colleagues did not find a fertility preservation benefit from the utility of GnRHa co-treatments,” Oktay and Turan wrote. “The seeming benefit on menstruation also disappears when all randomized studies are considered, regardless of the cancer type. The few studies that reported benefit on menstrual redemption likely reflect the inaccuracy of using a nonquantitative surrogate (eg, menstruation) in a nonblinded and non–placebo-controlled fashion. … Given the cost and potential irreversible bone loss with the long-term use of GnRHa, and given that ‘just in case,’ may result in the underuse of proven methods such as embryo and oocyte cryopreservation, GnRHa suppression should not be considered an effective method of fertility preservation during chemotherapy.” – by Cameron Kelsall
Disclosure: Munhoz reports no relevant financial disclosures. One study researcher reports remuneration, funding support and advisory payments from AstraZeneca. Oktay and Turan report no relevant financial disclosures.
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