Gonadotrophin-releasing hormone agonists for fertility preservation: unraveling the enigma?

摘要: STUDY QUESTION Can gonadotrophin-releasing hormone agonists (GnRH-a) preserve long-term fertility when administered prior to and concomitantly with chemotherapy? SUMMARY ANSWER GnRH-a display a differential protective effect on fertility, depending upon the specific chemotherapy-induced mechanism of ovarian injury. WHAT IS KNOWN ALREADY The role in preservation has been constantly debated their use is considered experimental due conflicting clinical evidence paucity data regarding for protection. DESIGN, SIZE, DURATION In vivo model: 7-8 weeks old imprinting control region (ICR) mice were injected (Leuprolide-acetate) or saline cyclophosphamide, doxorubicin sacrificed at various time-points longitudinal follow-up; 24 h (n = 36), 1 week 40), month 36) 9 months 66) post chemotherapy treatment. Blood samples drawn Day 0 monthly basis after On day sacrifice, blood ovaries excised processed either immunohistochemistry (IHC), protein RNA extraction. vitro 21-23 days Wistar-derived rats sacrificed, primary granulosa cells (PGC) isolated culture, immunofluorescence (IF) as well MATERIALS, SETTING, METHODS Ovarian reserve was estimated by serial measurements serum anti-mullerian (AMH), quantified AMH Gen II ELISA assay. phosphorylated Akt (pAkt) detected immunoblotting. Vascular endothelial growth factor (VEGF) measured quantitative PCR. GnRH receptor (GnRHR), CD34 visualized IHC, apoptosis evaluated using TdT (terminal deoxynucleotidyl transferase)-mediated dUDP nick-end labeling (TUNEL). MAIN RESULTS AND THE ROLE OF CHANCE Cyclophosphamide-induced injury caused prompt decrease level (P < 0.01) further decline 0.017), indicating damage reserve. Pretreatment diminished AMH-decrease 0.05) maintained long run 0.05). Doxorubicin-exerted ovarian-vascular-injury also displayed an acute increase VEGF sustained 0.001). This followed recovery manifested increased neovascularization. delayed decreased 0.001), thus interfering vascular subsequent doxorubicin-induced damage. LIMITATIONS, REASONS FOR CAUTION To portray each chemotherapy, cyclophosphamide given separately, whereas most protocols include several types chemotherapies. Thus, future study should explore prospective evaluation chemotherapies, combined chemotherapeutic protocols. WIDER IMPLICATIONS FINDINGS Our demonstrates that different agents affect ovary via diverse mechanisms administration concomitantly, could be beneficial subpopulation patients treated cyclophosphamide-based FUNDING/COMPETING INTERESTS work partially supported grant from Israel Science Foundation (ISF) I.B.-A. authors have no conflict interest disclose.