Gonadal impact of target of rapamycin inhibitors (sirolimus and everolimus) in male patients: an overview.

The immunosuppressive agents target of rapamycin inhibitors (TOR-I) (sirolimus, and everolimus) have been widely used in kidney transplantation for >10 years. Up to 40% of men receiving a kidney transplant are younger than 50, and fertility as well as erectile function are major concerns. In this review, we provide a synopsis of past studies focusing on gonadal function in men treated with TOR-I, mainly sirolimus, to establish what impact they have on male gonads, and which pathophysiological pathways are involved. A PubMed search for the years 1990-2006 selected articles that focused on the gonadal impact of TOR-I. Primary outcome measures were testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels. Secondary outcome measures were sexual function, fertility status and sperm parameters. Treatment with TOR-I results in a decrease in testosterone level, and an opposite increase in LH. Moreover, spermatogenesis seems to be disrupted by TOR-I and FSH levels are increased. Sirolimus and everolimus inhibit the activity of mammalian targets of rapamycin, a serine/threonine kinase involved in numerous cell-growth processes. Molecular mechanisms of action of TOR-I on the testis involve inhibition of a stem cell factor/c-kit-dependant process in spermatogonia. Preliminary results appear to show that TOR-I treatment has deleterious actions on the testis and impairs gonadal function after renal transplantation, but the impact of these effects are unknown.