Endometrial receptivityEndometrial receptivity analysis (ERA) Fresh embryo transfer (ET) Frozen embryo transfer (FET) Personalized embryo transfer (PET) Window of implantation (WOI)

Resveratrol, a natural polyphenol found in grapes, berries, and medicinal plants, exhibits antioxidant and anti-inflammatory activities and has been proposed to be a longevity-prolonging agent. There is also growing evidence that resveratrol has cardioprotective properties and beneficial effects on both glucose and lipid metabolism. Recently, several studies have examined the use of resveratrol as a therapeutic agent to treat numerous pathological and metabolic disorders. Herein, we present insights into the mechanisms of action, biological effects, and current evidence of actions of resveratrol on the ovary. In vitro, resveratrol inhibits proliferation and androgen production by theca-interstitial cells. Resveratrol also exerts a cytostatic, but not cytotoxic, effect on granulosa cells, while decreasing aromatization and vascular endothelial growth factor expression. In vivo, resveratrol treatment reduced the size of adipocytes and improved estrus cyclicity in the previously acyclic rat model of polycystic ovary syndrome (PCOS). In addition, resveratrol increased the ovarian follicular reserve and prolonged the ovarian life span in rats. Taken together, resveratrol emerges as a potential therapeutic agent to treat conditions associated with androgen excess, such as PCOS. The efficacy of resveratrol in the treatment of gynecological conditions requires further investigation.

Polycystic ovary syndrome (PCOS) is characterized by ovarian enlargement, theca-interstitial hyperplasia, and increased androgen production by theca cells. Previously, our group has demonstrated that statins (competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, a rate-limiting step of the mevalonate pathway) reduce proliferation of theca-interstitial cells in vitro and decrease serum androgen levels in women with PCOS. The present study evaluated the effect of simvastatin on rat ovarian theca-interstitial cell steroidogenesis. Because actions of statins may be due to reduced cholesterol availability and/or isoprenylation of proteins, the present study also investigated whether steroidogenesis was affected by cell- and mitochondrion-permeable 22-hydroxycholesterol, isoprenylation substrates (farnesyl-pyrophosphate [FPP] and geranylgeranyl-pyrophosphate [GGPP]), as well as selective inhibitors of farnesyltransferase (FTI) and geranylgeranyltransferase (GGTI). Theca-interstitial cells were cultured for 12, 24, and 48 h with or without simvastatin, GGPP, FPP, FTI, GGTI, and/or 22-hydroxycholesterol. Simvastatin decreased androgen levels in a time- and concentration-dependent fashion. This inhibitory effect correlated with a decrease in mRNA levels of Cyp17a1, the gene encoding the key enzyme regulating androgen biosynthesis. After 48 h, GGPP alone and FPP alone had no effect on Cyp17a1 mRNA expression; however, the inhibitory action of simvastatin was partly abrogated by both GGPP and FPP. The present findings indicate that statin-induced reduction of androgen levels is likely due, at least in part, to the inhibition of isoprenylation, resulting in decreased expression of CYP17A1.

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.