GnRH antagonist-induced ovarian suppression does not protect the ovarian reserve from cyclophosphamide chemotherapy in tumour-bearing mice

Abstract

Gonadotropin-releasing hormone (GnRH) analogues are used clinically to induce ovarian suppression during chemotherapy treatment and are proposed to protect the ovaries from chemotherapy-induced damage, yet their efficacy and underlying mechanisms remain uncertain. While most preclinical and clinical studies have focused on GnRH agonists, far less is known about the effects of GnRH antagonists in this context, despite their more rapid and direct suppression of gonadotrophin signaling. We used the GnRH antagonist degarelix to induce ovarian suppression in an orthotopic tumour-bearing mouse model. We then evaluated whether degarelix protected against cyclophosphamide-induced ovarian damage in reproductively young and aged mice receiving one or two chemotherapy doses. Ovarian function was assessed by quantifying ovarian volume, corpora lutea number (a marker of ovulation), and serum anti-Müllerian hormone (AMH) levels, as well as follicle enumeration and histological assessment of ovarian fibrosis. Degarelix suppressed ovulatory activity, as indicated by reduced corpora lutea number and ovarian volume. However, degarelix was associated with increased ovarian fibrosis in young mice treated with single-dose cyclophosphamide and failed to protect the ovarian reserve following either single or two doses of cyclophosphamide in both age groups. Moreover, degarelix did not prevent reductions in circulating AMH, with all treatment groups displaying reduced AMH levels compared with controls in young mice. Together, our findings do not support a protective effect of GnRH antagonist treatment against cyclophosphamide-induced ovarian damage.