Vasoactive intestinal peptide (vip) as an ovarian protector: prevention against premature ovarian failure during chemotherapy

Abstract

The ovary, in addition to its endocrine and intraovarian control, is regulated by direct neural inputs of peptidergic nature. Vasoactive intestinal peptide (VIP) was originally isolated from the small intestine and lung tissues and plays an important role in ovarian function. Previous studies have found VIP immunoreactivity in ovarian follicles. The objective of this study was to determine the effect of VIP on ovarian function in a doxorubicin (DX) induced-Premature Ovarian Failure (POF) murine model.To induce POF, DX 10mg/kg, i.p. was applied in F1 mice (C57XBalbC 8 weeks old) on day 1. Control and DX mice underwent sham surgery and received an intrabursal injection of saline solution on both ovaries, while DX + VIP groups received either 1μl or 10µl VIP 1µM 1 h prior to DX administration. Sacrifices were made at day 15. The ovaries were isolated for histological analysis and protein extraction for Western Blot assays. For all data analysis ANOVA followed by Tukey test were performed. An ovarian morphological analysis showed that DX decreased the % of primary (PriF), preantral (PF) and early antral follicles (EAF), and increased the % of atretic follicles (AtrF) (p<0.05). VIP (1 µl) increased the % of EAF and decreased the % AtrF. However, the highest dose of VIP (10 µl) increased the % of PriF, PF and EAF, and decreased the % of AtrF compared to DX (p<0.05). These results were corroborated by IHC for Anti-Müllerian Hormone (AMH), where it was found that DX reduced the % of follicles expressing AMH, while VIP (both doses) increased it (p<0.001). DX increased the apoptotic index (cleaved caspase-3-positive follicles/total follicles) in follicles, compared to control (P<0.01). VIP (both doses) protected follicles from this increment.In conclusion, VIP might be a promising strategy to protect female fertility in cancer patients. Further studies on VIP effects on female reproduction in chemotherapy-induced POF and on the safety of use of this peptide are required.