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

Zakerkish F,  Soriano MJ,  Novella-Mestre E,  Brännström M, Diaz-Garcia C
Human Reprod Open. May. 2021 doi: 10.1093/hropen/hoab012
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STUDY QUESTION: Do therapeutic levels of cyclosporine-A and tacrolimus affect ovulation in a rat gonadotrophin-induced ovulation model? SUMMARY ANSWER: Cyclosporine-A, but not tacrolimus, decreases ovulation rate when administered for 5 days before induced ovulation. WHAT IS KNOWN ALREADY: The 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, DURATION: Experimental 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, METHODS: Immature 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 CHANCE: Animals 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 CAUTION: Although 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 FINDINGS: These 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. KEYWORDS: cyclosporine-A, calcineurin, immunosuppression, ovulation, ovary, rat, tacrolimus, transplantation