Pioglitazone Improves Tacrolimus Induced Reproductive Dysfunction

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 561-585-Ovarian & Uterine Function II
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-571
Vijay Shivaswamy*1, Brendan Ottemann2, Frederick G Hamel3, Robert Gerard Bennett4, Jennifer L Larsen5 and John S Davis6
1University of Nebraska Med Ctr, Omaha, NE, 2UNMC, 3Omaha VA Med Ctr, Omaha, NE, 4VA Med Ctr, Omaha, NE, 5Univ of Nebraska Med Ctr, Omaha, NE, 6UNMC, Omaha, NE
Reproductive dysfunction is a significant problem after kidney transplantation (KTX). We have shown that commonly used immunosuppressants for KTX, tacrolimus (TAC) and sirolimus (SIR) induce hyperglycemia and reproductive abnormalities in normal female rats. So we hypothesized that pioglitazone can reduce hyperglycemia and prevent the reproductive abnormalities induced by TAC and SIR. Eight groups (n=3) of normal female Sprague-Dawley rats were studied: Four groups received daily oral gavage of water (vehicle) and subcutaneous injections of TAC, SIR, TAC+SIR or Control (CTRL) for 14 days. Four other groups of rats received daily oral gavage of pioglitazone (PIO) (10mg/kg) and subcutaneous injections of TAC, SIR, TAC+SIR or CTRL for 14 days. Daily glucoses and weights were measured. Vaginal swabs were obtained daily to estimate the stage of estrus cycles in rats. All rats were administered an oral glucose challenge on day 15 and tail blood was collected for glucose and insulin at each time point. On day 16 rats were sacrifice by cardiac puncture and liver, pancreas, fat, muscle, uteri and ovaries were harvested. Ovarian and uterine weight weights quantified.  Progesterone concentrations were measured by RIA. TAC+SIR increased random blood glucoses compared to CTRL and PIO treatment significantly reduced the random blood glucoses in TAC+SIR group. TAC, SIR and TAC+SIR reduced weight gain compared to CTRL group, and PIO did not significantly improve weight gain in any of the groups. SIR, TAC and TAC+SIR increased glucose response to oral glucose challenge and PIO did not improve glucose responses in any of the treatment groups. Insulin response to oral glucose challenge was higher in SIR compared to control and PIO did not affect the insulin levels in SIR. TAC and TAC+SIR induced longer and fewer estrus cycles.  SIR alone induced irregular estrus cycles. PIO treatment dramatically improved the number of estrus cycles in TAC treated rats only. Ovarian and uterine weights were lower than CTRL in TAC+SIR group and PIO appeared to improve the ovarian and uterine weights in TAC+SIR group, but did not reach significance. Progesterone levels were significantly lower in TAC+SIR group than CTRL and PIO did not affect it. In conclusion, despite having minimal effects on hyperglycemia induced by TAC, PIO treatment showed a significant impact on TAC induced disruption of estrus cycles. Future studies of effects of TAC and SIR fertility in normal female rats are planned, with PIO and metformin as a preventive treatment for immunosuppressant effects on reproductive function.

Nothing to Disclose: VS, BO, FGH, RGB, JLL, JSD

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