Differential effects of the immunosuppressive calcineurin inhibitors cyclosporine-A and tacrolimus on ovulation in a murine model.

Abstract

STUDY QUESTIONDo therapeutic levels of cyclosporine-A and tacrolimus affect ovulation in a rat gonadotrophin-induced ovulation model?SUMMARY ANSWERCyclosporine-A, but not tacrolimus, decreases ovulation rate when administered for 5 days before induced ovulation.WHAT IS KNOWN ALREADYThe mainstays of immunosuppression in solid organ transplantation, to prevent rejection, are the calcineurin inhibitors cyclosporine-A or tacrolimus. These drugs could potentially affect fertility in transplanted patients. Since ovulation is an inflammation-like process with pivotal roles for several immune cells and modulators, it is possible that the calcineurin inhibitors, with broad effects on the immune system, could interfere with this sensitive, biological process.STUDY DESIGN, SIZE, DURATIONExperimental design at university-based animal facilities. A total of 45 immature Sprague–Dawley rats were used. The study was carried out over 3 months.PARTICIPANTS/MATERIALS, SETTING, METHODSImmature Sprague–Dawley rats (n = 45) were randomly assigned to receive equivalent doses of tacrolimus (0.5 mg/kg/day; TAC), cyclosporine-A (10 mg/kg/day; CyA) or vehicle (Control). Ovarian hyperstimulation was induced with 10 IU of equine chorionic gonadotrophin, and ovulation was triggered with 10 IU of hCG. Oocytes were retrieved from the oviducts and ovulation rates were calculated. Various subpopulations of white blood cells were counted in peripheral blood and ovarian tissue samples.MAIN RESULTS AND THE ROLE OF CHANCEAnimals in the CyA group showed a lower ovulation rate when compared to the TAC and Control groups (CyA: mean 9 oocytes (range 0–22); TAC: 21 oocytes (8–41); Control: 22 oocytes (6–39); P = 0.03). Regarding counts of the white blood cell subpopulations and resident neutrophils in the ovary, no significant differences were observed between the groups.LIMITATIONS, REASONS FOR CAUTIONAlthough the ovulation process is highly conserved within species, the differences between rodents and humans may limit the external translatability of the study.WIDER IMPLICATIONS OF THE FINDINGSThese findings suggest that tacrolimus should be the preferred calcineurin inhibitor of choice in transplanted patients who are aiming for pregnancy.STUDY FUNDING/COMPETING INTEREST(S)Swedish Research Council and ALF of Sahlgrenska Academy, Sweden. Rio Hortega Grant from the Instituto de Salud Carlos III, Spain (CM09/00063). There are no conflicts of interest.