There are several apoptotic pathways, including the sphingomyeline pathway that triggers apoptosis of ovarian follicles.  In the sphingomyeline pathway sphingomyeline is degraded to ceramide which has pro-apoptotic effects.  Ceramide is subsequently degraded to sphingosine and then sphingosine-1-phosphate (S1P) through hydrolysis.  Sphingosine-1-phosphate regulates proliferative cellular processes including cell growth and cell differentiation and inhibits apoptosis [25].  In vivo mice studies of ovarian tissue xenografts treated with S1P show increased vascular density and angiogenesis with reduced follicular apoptosis.  However, in mice treated with S1P pre-chemotherapy, the evidence is inconclusive, with some studies showing a protective effect in the presence of Dacarbazine [25] and others showing no effect in the presence of cyclophosphamide [26].  Conversely, S1P treatment prior to radiation has been shown to be effective in a dose-dependent manner with preservation of both primordial and primary follicles in rats, primates and xenografted ovarian tissue [26-28]. Male mice who received local treatment with S1P prior to radiation were also shown to have protection of early stages of spermatogenesis [29].  Limitations of S1P are that it cannot be administered systemically and must be injected into tissue, thus limiting its clinical usefulness.  However, a benefit of this targeted treatment is that it may minimize interference with cancer therapy efficacy in other tissues.  This has not been adequately studied, however.  Lastly, consistent with concerns with other fertoprotective agents, inhibition of follicular apoptosis with S1P may result in transmission of genetically damaged DNA.  Studies of offspring in mice and primates treated with S1P prior to radiation showed no propagation of DNA damage and no abnormalities in the offspring [30].

 

 

References