Immune suppression medications contribute to multiple aspects of endocrine dysfunction including post-transplant\ndiabetes mellitus (PTDM), reproductive dysfunction and fracture. In this paper, we will review the available evidence,\npathophysiology and prevention/treatment strategies for immunosuppression-induced endocrine dysfunction. PTDM\ncan substantially reduce graft and patient survival after kidney transplant. Tacrolimus (TAC), which is among the most\ncommonly used immunosuppression drugs in organ transplantation, can suppress insulin gene expression, decrease\ninsulin release, and may cause islet cell apoptosis. Sirolimus (SIR), which is frequently used in combination with TAC for\nislet transplants, can decrease islet insulin secretion in vitro and may affect insulin action causing an insulin resistance\nstate. Animal studies have shown that short term treatment with TAC or SIR can independently cause hyperglycemia\nwith hyperinsulinemia in normal rats, suggesting insulin resistance, with greater hyperinsulinemia occurring with SIR\nthan with TAC treatment. Together, these agents reduce insulin secretion and increase islet apoptosis. SIR acts by\nbinding to mammalian target of rapamycin, which is a downstream protein in the insulin signal transduction cascade,\nbut how SIR causes insulin resistance is not known. SIR and TAC have been shown to induce islet apoptosis in\nvitro; however, regulation of this process by immunosuppressants has not been studied. While immunosuppressants\ncontribute to PTDM, little is known about whether it can be prevented with any current therapeutic intervention for\ntype 2 diabetes. SIR has been associated with irregular menses and ovarian cysts, and primary hypogonadism posttransplant.\nSIR has been associated with delayed fracture healing, but the effect on bone density is not clear. In\nconclusion, predominant endocrine effects of commonly used immunosuppressive medications appear to be on the\ndevelopment of PTDM and reproductive dysfunction, while also potentially contributing to fractures.
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