Tacrolimus and Sirolimus Induce Reproductive Abnormalities in Female Rats

Abstract

Background Immunosuppression medications contribute to posttransplant diabetes mellitus in patients and can cause insulin resistance in male rats. Tacrolimus (TAC)-sirolimus (SIR) immunosuppression is also associated with appearance of ovarian cysts in transplant patients. Because insulin resistance is observed in patients with polycystic ovary syndrome, we hypothesized that TAC or SIR may induce reproductive abnormalities. Methods We monitored estrus cycles of adult female rats treated daily with TAC, SIR, and combination of TAC-SIR, or diluent (control) for 4 weeks. Animals were then challenged with oral glucose to determine their glucose and insulin responses, killed, and their blood and tissues, including ovaries and uteri harvested. Results TAC and TAC-SIR treatments increased mean random glucose concentrations (P<0.05). TAC, SIR, and TAC-SIR treatments also increased the glucose response to oral glucose challenge (P<0.05). The insulin response to glucose was significantly higher in rats treated with SIR compared with TAC (P<0.05). TAC, SIR and TAC-SIR treatments reduced number of estrus cycles (P<0.05). The ovaries were smaller after SIR and TAC-SIR treatment compared with controls. The TAC and TAC-SIR treatment groups had fewer preovulatory follicles. Corpora lutea were present in all groups. Ovarian aromatase expression was reduced in the SIR and TAC-SIR treatment groups. A significant (P<0.05) reduction in uterine size was observed in all treatment groups when compared with controls. Conclusion In a model of immunosuppressant-induced hyperglycemia, both TAC and SIR induced reproductive abnormalities in adult female rats, likely through different mechanisms.

Uterine rejection after allogeneic uterus transplantation in the rat is effectively suppressed by tacrolimus

“…Interestingly, there was also a small reduction in uterine size in the Sham-TAC group. A similar finding was observed in an animal study investigating the effect of tacrolimus on reproductive function in the rat, which also showed decreased estrogen receptor levels within the uteri of tacrolimus-treated animals (38).…”

Post-Transplant Diabetes Mellitus: Causes, Treatment, and Impact on Outcomes

“…Whereas amenorrhea often improves after transplant, many women in particular may still have menstrual irregularities after transplant (200), and recent evidence suggests that both tacrolimus and sirolimus may impact reproductive function (201).…”

The metabolic and toxicological considerations for immunosuppressive drugs used during pancreas transplantation

“…Sirolimus withdrawal was associated with a reduction in cyst size and resolution of cysts in 80% of subjects. In rodents, sirolimus and FK were related to reduced number of estrus, smaller ovaries, fewer preovulatory follicules, reduced ovarian aromatase expression, and reduced uterine size [122].…”