Phosphodiesterase 4 inhibitor plus metformin is superior to metformin alone for the treatment of polycystic ovary syndrome: A rat model study

The role of metformin in the management of polycystic ovary syndrome (PCOS) and PCOS-related obesity remains controversial. Recent research on the treatment of PCOS-related obesity investigated novel therapeutic agents with the potential to work synergistically with metformin. The aim of the present study was to determine the synergistic effect of a phosphodiesterase 4 inhibitor (PDE4i) and metformin on weight and hormonal changes in a rat model of PCOS. A total of 40 female Sprague-Dawley rats were randomly divided into 4 groups (n=10/group): Sham; PCOS control (no medication after PCOS induction with dehydroepiandrosterone); metformin (300 mg/kg/day p.o. after PCOS induction); and metformin + PDE4i (300 mg/kg/day p.o. metformin + 0.5 mg/kg/day p.o. PDE4i after PCOS induction). The body weight was measured every 7 days, from day 1 to day 49. Vaginal smears were performed and examined daily via light microscopy for determination of the stage of each rat's estrous cycle. At the end of 21st day and at the end of the study, blood samples were collected from rats and the testosterone and insulin levels were measured. Immunohistochemical staining was performed to quantify phosphorylated cyclic AMP response element-binding protein expression in all groups. At the end of the study, the median body weight differed significantly among the groups (χ(2)=30.581, P<0.001), being the highest in the PCOS control group and the lowest in the metformin + PDE4i group. At the end of the study, the median testosterone level differed significantly among the groups (χ(2)=27.057, P<0.001), being the highest in the PCOS control group and the lowest in the metformin + PDE4i group. The cycle was restored to normal at the end of the study in all the rats in the metformin and metformin + PDE4i groups, whereas an irregular cycle persisted in all the rats in the PCOS control group. In conclusion, PDE4i + metformin was superior to metformin alone in reducing weight gain and decreasing the testosterone levels in a rat model of PCOS.