title: 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.
  
  
  CONCLUSIONS
  In a model of immunosuppressant-induced hyperglycemia, both TAC and SIR induced reproductive abnormalities in adult female rats, likely through different mechanisms.
authors.affiliation: Omaha Veterans Affairs Medical Center, Omaha, NE 68198-3020, USA. vshivaswamy@unmc.edu
authors.forename: Vijay
authors.initials: V
authors.lastname: Shivaswamy
authors.forename: Luann
authors.initials: L
authors.lastname: Ochsner
authors.forename: Dulce
authors.initials: D
authors.lastname: Maroni
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.forename: Joel
authors.initials: J
authors.lastname: Passer
authors.forename: Cara E
authors.initials: CE
authors.lastname: Clure
authors.forename: Frederick G
authors.initials: FG
authors.lastname: Hamel
authors.forename: John S
authors.initials: JS
authors.lastname: Davis
authors.forename: Jennifer
authors.initials: J
authors.lastname: Larsen
mesh_terms: D000818:Animals; D001141:Aromatase / Q000096:biosynthesis; D001786:Blood Glucose / Q000378:metabolism; D004971:Estrus; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000627:therapeutic use; D006943:Hyperglycemia / Q000139:chemically induced; D007166:Immunosuppressive Agents / Q000009:adverse effects; D007333:Insulin Resistance; D010053:Ovary / Q000187:drug effects; D010641:Phenotype; D011085:Polycystic Ovary Syndrome / Q000139:chemically induced; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000009:adverse effects*; D016559:Tacrolimus / Q000009:adverse effects*; D014599:Uterus / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D007166:Immunosuppressive Agents; D001141:Aromatase; D005947:Glucose; D020123:Sirolimus; D016559:Tacrolimus