title: Gonadal impact of target of rapamycin inhibitors (sirolimus and everolimus) in male patients: an overview.
abstract: 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.
authors.affiliation: Department of Urology and Andrology, CHU Rangueil, Toulouse, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Huyghe
authors.forename: Anas
authors.initials: A
authors.lastname: Zairi
authors.forename: Joe
authors.initials: J
authors.lastname: Nohra
authors.forename: Nassim
authors.initials: N
authors.lastname: Kamar
authors.forename: Pierre
authors.initials: P
authors.lastname: Plante
authors.forename: Lionel
authors.initials: L
authors.lastname: Rostaing
mesh_terms: D000328:Adult; D007172:Erectile Dysfunction / Q000139:chemically induced; D000068338:Everolimus; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007248:Infertility, Male / Q000139:chemically induced; D016030:Kidney Transplantation; D008297:Male; D011494:Protein Kinases / Q000187:drug effects; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D013091:Spermatogenesis / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases; D013739:Testosterone / Q000037:antagonists & inhibitors
chemical_list: D007166:Immunosuppressive Agents; D013739:Testosterone; D000068338:Everolimus; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus