I-19: The Selective Vitamin D Receptor Agonist Elocalcitol Reduces Development of Endometriosis and Formation of Peritoneal Adhesion in A Mouse Model

Background: Endometriosis is a chronic disorder characterized by the presence of endometrial tissue outside the uterus. Endometrial cells from retrograde menstruation implant on peritoneal surfaces and elicit an inflammatory response, associated with angiogenesis, fibrosis, neuronal infiltration, and anatomical distortion. Affecting an estimated 176 million women worldwide, the condition is still an unmet clinical need since an optimal drug that allows for pain management and continued attempts to conceive does not exist. An ideal treatment should not only eradicate lesions but also prevent post-surgical recurrences and eliminate peritoneal adhesions Since both eutopic and ectopic endometrium express the vitamin D receptor (VDR), and VDR agonists are endowed with anti-proliferative, anti-inflammatory, and anti-fibrotic properties, we evaluated the effect of elocalcitol, a VDR agonist with low calcemic liability, in a mouse model of experimentally induced endometriosis. Materials and Methods: Endometriosis was induced by injection of syngeneic endometrial tissue fragments into adult Balb/c female mice. Mice were administered with elocalcitol (100 μg/kg) or vehicle orally, once a day, starting at different times after disease induction, and sacrificed at day 15 or 21. Peritoneal lesions and adhesions were evaluated by an operator blind to the experiment. Lesion extent was evaluated by weighting of dried lesions. Adhesion extent was evaluated by taking into account the number and the extent of adhesion sites. Cell adhesion assaye were performed on ECMcoated plates. Peritoneal macrophages were isolated and analysed for cytokine secretion by specific ELISA assays. Differences between groups were compared by Student’s paired t test or the Kruskal-Wallis test as appropriate. Probability <0.05 was considered as statistically significant. Results: Mice with induced endometriosis were administered with elocalcitol (100 μg/kg) or vehicle orally, once a day, for different times. In this model, elocalcitol reduced total lesion weight up to 70% upon treatment for one week before and two weeks after disease induction. Peritoneal adhesions were not detected in elocalcitoltreated mice. Interestingly, a therapeutic effect was also observed on already established lesions. Elocalcitol was shown to reduce the capacity of mouse endometrial cells to adhere to collagen. In addition, a decreased state of peritoneal inflammation in treated mice was demonstrated by the inhibition of macrophage recruitment and inflammatory cytokine secretion. Conclusion: The VDR agonist elocalcitol inhibits lesion development in a validated mouse model of endometriosis, and exerts a protective effect on both the implantation and organization of transferred endometrial tissue. The realistic objective to suppress, rather than eliminate implant growth, can be achieved with an antiinflammatory drug such as elocalcitol that may represent a safe treatment in limiting the growth of pre-existing lesions and treat recurrences. Further experiments using primate models as well as clinical trials will be helpful in evaluating the therapeutic potential of elocalcitol in women with endometriosis. Based on the results of this study, a possible translation into the clinical setting would be to administer elocalcitol during the perimenstrual and menstrual phase of the cycle. In this phase, all the potential activities of the compound (inhibition of inflammation, inhibition of endometrial cell adhesion, inhibition of lesion organization) could be exerted with the maximal efficacy.