Cellular and molecular mechanisms of pentoxifylline's beneficial effects in experimental polycystic ovary

Abstract

Chronic low-grade inflammation and oxidative stress (OS) appear to be two main pathways involved in the pathogenesis of polycystic ovary (PCO) syndrome. Therefore, targeting these pathways by means of anticytokine and antioxidant agents might be a therapeutic alternative approach to the current treatments of PCO syndrome. In this study, we investigated the protective effects of pentoxifylline (PTX), a drug with antioxidant and anti–tumor necrosis factor alpha (TNF-α) properties, in hyperandrogenism-induced PCO rats. The inflammatory and OS responses and their connections with ovarian functionality in induced PCO rats were investigated through ovarian histopathologic examination and a series of biochemical measurements including serum estradiol, progesterone, testosterone, insulin, and TNF-α, ovarian and serum lipid peroxidation, total antioxidant power, and reactive oxygen species. Experimental PCO was induced in rats by oral administration of letrozole (1 mg/kg body weight) for 21 consecutive days. In a different group, PTX was administrated orally (50 mg/kg/d) for 21 days simultaneous with letrozole to assess its potential protective effects. The letrozole-induced PCOs were characterized by irregular cycles, high incidence of subcapsular ovarian cysts with diminished or scant granulosa cell layers, increased number of atretic preantral and antral follicles, and absence of CL. In addition, the letrozole-induced PCO rats exhibited notable increase in lipid peroxidation and reactive oxygen species of serum and ovary, serum testosterone, insulin, and TNF-α and significant decline in total antioxidant power, serum estradiol, and serum progesterone. Our results indicated that all the identified pathologic parameters and biochemical characteristics in letrozole-induced PCO rats in this study were preserved close to normal levels by simultaneous PTX treatments. Present results demonstrate that there is a direct connection between ovarian dysfunction and increased OS and inflammation in PCO. For the first time, the beneficial effects of PTX as a powerful antioxidant and TNF-α blocker in hyperandrogenism-induced PCO are reported.