Bioactive sphingolipid ceramide-1-phophate (C1P) protects against age-related ovarian dysfunction/decline in female mice

SCOTTI LEOPOLDINA; PASCUALI NATALIA; DI PIETRO MARIANA; OUBIÑA ALEJANDRO; COHEN DEBORA; ABRAMOVICH DALHIA; PARBORELL FERNANDA

Congreso; 17th world congress of human reproduction; 2017

Context: As many women postponechildbearing over 38 years a large portion ofaged female becomes infertile. Ovarian aging is dominated by theprogressive loss of primordial follicles and a decline in oocyte quality. Activationof ovarian angiogenesis has emerged as a new strategy to halt age-relateddecline of ovarian response. Bioactive sphingolipids such as C1P, aproangiogenic and antiapoptotic factor, are key regulators of cell homeostasis.Objective: To study whether C1P can improve the ovarian responseand angiogenesis in aged female mice.Methods: Aged female mice (26-31 weeks) received C1P(10µl/ovary; 50µM) under the bursa of one ovary and vehicle on the other, andwere sacrificed 48h later. Young mice (6-9 weeks) were used as control. Ovarieswere isolated.Main Outcome Measure(s): Histological and immunohistochemical analysis (VW and α-SMA; endothelialand periendothelial cell markers, respectively), radioimmunoassay (E2 and P4concentrations) and western blot (pFoxo3a/Foxo3a and AMH; ovarian reservemarkers) were performed. Results: The % of primary (PF), preantral (PrF) and antralfollicles (AF) in aged mice were lower than in young mice (p<0.05). C1Ptreatment increased the % of PrF and AF in aged mice (p<0.05). The % ofatretic follicles (AtrF) in aged mice was higher than in young mice (p<0.01)and C1P decreased the % of AtrF (p<0.05) in aged mice. C1P increased theconcentration of ovarian E2 and P4 (p<0.05) and AMH levels in aged mice,while decreasing pFoxo3a/Foxo3a ratio (p<0.05). The endothelial andperiendothelial cell areas increased in ovaries from aged mice treated with C1P(p<0.05).  Conclusion: C1P administration in aged mice improves the ovarianresponse, possibly by preserving the ovarian reserve and increasing the ovarianangiogenesis. These results may have potential clinical implications in thetreatment of age-related infertility.