Effects of resveratrol on growth and function of rat ovarian granulosa cells

Abstract

Objective To evaluate the effects of resveratrol on growth and function of granulosa cells. Previously, we have demonstrated that resveratrol exerts profound pro-apoptotic effects on theca-interstitial cells. Design In vitro study. Setting Research laboratory. Animal(s) Immature Sprague-Dawley female rats. Intervention(s) Granulosa cells were cultured in the absence or presence of resveratrol. Main Outcome Measure(s) DNA synthesis was determined by thymidine incorporation assay; apoptosis by activity of caspases 3/7, cell morphology by immunocytochemistry, steroidogenesis by mass spectrometry, anti-Müllerian hormone (AMH) and vascular endothelial growth factor (VEGF) expression by PCR and Western blots. Result(s) Resveratrol induced a biphasic effect on DNA synthesis, whereby a lower concentration stimulated thymidine incorporation, and higher concentrations inhibited it. Additionally, resveratrol slightly increased the cell number and modestly decreased the activity of caspases 3/7 with no effect on cell morphology or progesterone production. However, resveratrol decreased aromatization and VEGF expression, whereas AMH expression remained unaltered. Conclusion(s) Resveratrol, by exerting cytostatic but not cytotoxic effects together with antiangiogenic actions mediated by decreased VEGF in granulosa cells, may alter the ratio of theca-to-granulosa cells and decrease vascular permeability, and hence be of potential therapeutic use in conditions associated with highly vascularized theca-interstitial hyperplasia and abnormal angiogenesis, such as those seen in women with PCOS.

Nutrients as novel therapeutic approaches for metabolic disturbances in polycystic ovary syndrome

“…The antiproliferative actions of resveratrol might be more pronounced among PCOS patients, whose ovarian function is disturbed as a result of excessive T-l cells production (Wong et al, 2010[79]). In contrast with this data, Ortega et al (2012[54]) observed minimal effects of resveratrol on the apoptosis of rat granulosa cells. The authors suggested that the discrepancy observed among their results obtained on granulosa cells, and the previous study which used theca-interstitial cells could be due to the different effects of resveratrol on different type of cells.…”

Resveratrol protects the ovary against chromium-toxicity by enhancing endogenous antioxidant enzymes and inhibiting metabolic clearance of estradiol

“…Previous reports indicated several discrepancies on the effects of RVT on steroid biosynthetic pathways (Supornsilchai et al, 2005; Svechnikov et al, 2009; Morita et al, 2012b; Ortega et al, 2012b; Li et al, 2014; Ortega and Duleba, 2015). A majority of the literature identifies inhibitory effects of RVT on steroidogenesis and/or aromatization of androgens in rat adrenocortical cells (Supornsilchai et al, 2005), Leydig cells (Svechnikov et al, 2009) and theca cells (Ortega et al, 2012b). In contrast, Morita et al (Morita et al, 2012b) reported that RVT increased mRNA levels of Sirt1 , LH receptor , StAR , and P450 aromatase in rat granulosa cells.…”

Effects of resveratrol on ovarian response to controlled ovarian hyperstimulation in ob/ob mice

“…Because in the present study the obese mice treated with resveratrol showed a decrease in plasma insulin levels, this polyphenol might reduce androgen levels through this amelioration of the insulin resistance state. Likewise, it has been demonstrated that resveratrol promotes apoptosis (34) and decreases vascular permeability (53) in cultures of ovarian theca cells, which are the major site of androgen synthesis. Therefore, our results extend those findings to show that this polyphenol reduces androgen levels in vitro (35,54), whereas conversely resveratrol treatment did not seem to exert the same effect in another in vivo study (48).…”

“…However, it has been reported that resveratrol inhibits aromatase production in cultures of rat granulosa cells in vitro (53) and thus reduces the estrogen synthesis that leads to impaired folliculogenesis. In this context, it has been suggested that SIRT1 activation by resveratrol results in a significant increase of LH receptors in granulosa cells (62), and this polyphenol shows higher affinity for estrogen receptor (ER)-b (63) than for ER-a.…”