Pioglitazone counteracts the tumor necrosis factor-α inhibition of follicle-stimulating hormone-induced follicular development and estradiol production in an in vitro mouse preantral follicle culture system

Background: Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age and is characterized by chronic anovulation. Insulin resistance may be a key component of the pathogenesis of this disorder. Pioglitazone is a thiazolidinedione derivative that acts by improving insulin resistance via the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) pathway. Reportedly, pioglitazone improves the anovulation status in patients with PCOS. In the present study, we examined whether pioglitazone directly affects ovarian follicular development and steroidogenesis using in vitro mouse preantral follicle culture system. Methods: An isolated individual in vitro mouse preantral follicle culture was used to test the effects of pioglitazone on the follicle development and steroidogenesis. Tumor necrosis factor-alpha (TNF-alpha), which plays a role in insulin resistance, has been reported to inhibit the follicle stimulating hormone (FSH)-induced follicular development and steroidogenesis in an in vitro mouse preantral follicle culture system. Therefore, we examined whether pioglitazone counteracts these effects by TNF-alpha. We assessed the follicle diameter and follicle survival and antral-like cavity formation rates, the 17 beta-estradiol (E2) levels in the culture medium, and the ovulation rate using the in vitro preantral follicle culture. Results: Pioglitazone treatment counteracted the inhibition of TNF-alpha in FSH-induced follicle development in a dose-dependent manner. Pioglitazone, at a concentration of 5 mu M, which was the minimum effective concentration, significantly counteracted the inhibition of TNF-alpha in FSH-induced follicle survival (29 versus 56%, P < 0.05), antral-like cavity formation (29 versus 48%, P < 0.05), E2 concentration in the culture medium (mean +/- SEM = 21 +/- 1 versus mean +/- SEM = 27 +/- 1 pg/mL, P < 0.05), and human chorionic gonadotropin-induced ovulation rate (9 versus 28%, P < 0.05). Conclusions: Pioglitazone counteracted the inhibition by TNF-alpha on FSH-induced follicle development and steroidogenesis in the in vitro mouse preantral follicle culture. The results suggest that pioglitazone may directly affect the follicular development and steroidogenesis.