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. Conclusion. In a model of immunosuppressant-induced hyperglycemia, both TAC and SIR induced reproductive abnormalities in adult female rats, likely through different mechanisms.

Original languageEnglish (US)
Pages (from-to)1333-1339
Number of pages7
JournalTransplantation
Volume91
Issue number12
DOIs
StatePublished - Jun 27 2011

Fingerprint

Tacrolimus
Sirolimus
Glucose
Estrus
Immunosuppression
Therapeutics
Insulin Resistance
Ovary
Insulin
Ovarian Cysts
Aromatase
Polycystic Ovary Syndrome
Corpus Luteum
Immunosuppressive Agents
Hyperglycemia
Uterus

Keywords

  • Corpus luteum
  • Immunosuppressants
  • Insulin resistance
  • Ovary
  • Polycystic ovary syndrome

ASJC Scopus subject areas

  • Transplantation

Cite this

Tacrolimus and sirolimus induce reproductive abnormalities in female rats. / Shivaswamy, Vijay; Ochsner, Luann; Maroni, Dulce; Wang, Cheng; Passer, Joel; Clure, Cara E.; Hamel, Frederick G; Davis, John S; Larsen, Jennifer Lynn.

In: Transplantation, Vol. 91, No. 12, 27.06.2011, p. 1333-1339.

Research output: Contribution to journalArticle

Shivaswamy, Vijay ; Ochsner, Luann ; Maroni, Dulce ; Wang, Cheng ; Passer, Joel ; Clure, Cara E. ; Hamel, Frederick G ; Davis, John S ; Larsen, Jennifer Lynn. / Tacrolimus and sirolimus induce reproductive abnormalities in female rats. In: Transplantation. 2011 ; Vol. 91, No. 12. pp. 1333-1339.
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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. Conclusion. In a model of immunosuppressant-induced hyperglycemia, both TAC and SIR induced reproductive abnormalities in adult female rats, likely through different mechanisms.",
keywords = "Corpus luteum, Immunosuppressants, Insulin resistance, Ovary, Polycystic ovary syndrome",
author = "Vijay Shivaswamy and Luann Ochsner and Dulce Maroni and Cheng Wang and Joel Passer and Clure, {Cara E.} and Hamel, {Frederick G} and Davis, {John S} and Larsen, {Jennifer Lynn}",
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T1 - Tacrolimus and sirolimus induce reproductive abnormalities in female rats

AU - Shivaswamy, Vijay

AU - Ochsner, Luann

AU - Maroni, Dulce

AU - Wang, Cheng

AU - Passer, Joel

AU - Clure, Cara E.

AU - Hamel, Frederick G

AU - Davis, John S

AU - Larsen, Jennifer Lynn

PY - 2011/6/27

Y1 - 2011/6/27

N2 - 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. Conclusion. In a model of immunosuppressant-induced hyperglycemia, both TAC and SIR induced reproductive abnormalities in adult female rats, likely through different mechanisms.

AB - 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. Conclusion. In a model of immunosuppressant-induced hyperglycemia, both TAC and SIR induced reproductive abnormalities in adult female rats, likely through different mechanisms.

KW - Corpus luteum

KW - Immunosuppressants

KW - Insulin resistance

KW - Ovary

KW - Polycystic ovary syndrome

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