title: Sirolimus-associated testicular toxicity:  detrimental but reversible.
abstract: BACKGROUND
  Mammalian target of rapamycin (mTOR) inhibition has been associated with gonadal dysfunction. The aim of this study was to characterize the effect of sirolimus (SRL) on male gonadal function in an experimental model.
  
  
  METHODS
  Male Wistar rats were treated with intraperitoneal administration of vehicle or SRL. Vehicle group was treated for 12 weeks. Rats treated with SRL were killed at 4, 8, and 12 weeks. A group of rats was treated with SRL for 4 weeks and then observed during 8 weeks to analyze the possible reversibility of the effect of mTOR inhibition. Body and testicular weight, testosterone, follicle-stimulating hormone level, and luteinizing hormone level were measured and testicular histology was analyzed including proliferation and apoptosis analysis.
  
  
  RESULTS
  Testicular weight was significantly lower in all SRL groups. After SRL withdrawal testicular weight had partially recovered. The expression of steroidogenic acute regulatory protein decreased during SRL treatment, which could explain the reduction of testosterone levels, because steroidogenic acute regulatory protein is crucial for testosterone synthesis. Spermatogenesis was blocked on the spermatogonial level by SRL treatment. Withdrawal of SRL treatment led to complete recovery.
  
  
  CONCLUSIONS
  mTOR inhibition in healthy animals produces sexual hormone dysfunction, seminiferous tubule dystrophy and spermatogenesis blockade. Furthermore, the spermatogenesis blockade produced by SRL is reversible.
authors.affiliation: Laboratori Experimental de Nefrologia I Trasplantament, Department of Nephrology and Renal Transplantation, Hospital Clínic de Barcelona, IDIBAPS, Barcelona, Spain. jrovira1@clinic.ub.es
authors.forename: Jordi
authors.initials: J
authors.lastname: Rovira
authors.forename: Fritz
authors.initials: F
authors.lastname: Diekmann
authors.forename: María José
authors.initials: MJ
authors.lastname: Ramírez-Bajo
authors.forename: Elisenda
authors.initials: E
authors.lastname: Bañón-Maneus
authors.forename: Daniel
authors.initials: D
authors.lastname: Moya-Rull
authors.forename: Josep M
authors.initials: JM
authors.lastname: Campistol
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005500:Follow-Up Studies; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000633:toxicity; D007274:Injections, Intraperitoneal; D008297:Male; D009929:Organ Size; D010750:Phosphoproteins / Q000096:biosynthesis / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus / Q000008:administration & dosage / Q000633:toxicity*; D013091:Spermatogenesis / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013733:Testicular Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D013737:Testis / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013739:Testosterone / Q000096:biosynthesis; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D007166:Immunosuppressive Agents; D010750:Phosphoproteins; D000098682:Steroidogenic Acute Regulatory Protein; D013739:Testosterone; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus