Sphingosine 1-phosphate protects ovaries from chemotherapy-induced damage in vivo

ObjectiveTo investigate whether sphingosine-1-phosphate (S1P), an apoptosis-inhibitor, would be able to protect ovarian follicles from chemotherapy-induced cell death in vivo.DesignAnimal study.SettingAcademic medical center.Animal(s)Twenty female mice.Intervention(s)Twenty mice were randomly assigned into three groups: in group A (n = 8), each mouse received an injection of low concentration of S1P (A1: 0.5 mM), prepared in a vehicle (PET) into the bursa of one ovary and a high concentration (A2: 2.0 mM S1P) to the contralateral ovary. In group B (n = 8), only PET was injected to both ovaries. Afterwards, both groups received 100 μg Dacarbazine (Medac, Hamburg, Germany) IV. The control group C (n = 4) received no chemotherapy. After 2 weeks, the ovaries from group C and from 4 mice from group A and B were evaluated histologically. The remaining mice from group A and B were allowed 3 mating attempts at 4, 8, and 12 weeks after chemotherapy.Main Outcome Measure(s)Primordial/primary and pre-/antral follicular density, pregnancy rates.ResultsChemotherapy caused a significant reduction in the mean number of primordial follicles of mice treated with only PET or with low concentration of S1P (1.86/field of view [C] vs. 1.17 [B] and 0.98 [A1]; P=.006 and P<.0001, respectively) but not in the ovaries treated with high concentration of S1P (2.05/field of view [A2]; P=.918, not significant). Furthermore, three mice (75%) from group A became pregnant at the first mating attempt, in contrast to group B, in which only one mouse (25%) became pregnant and only after the third mating attempt.Conclusion(s)Local application of S1P protects ovarian follicles from chemotherapy-induced cell death, thereby preserving fertility.