The estrogenic activity of resveratrol: a comprehensive review of in vitro and in vivo evidence and the potential for endocrine disruption.

trans-Resveratrol, a polyphenolic stilbene of plant origin is structurally similar to natural and synthetic estrogens and has been classified a phytoestrogen. Direct binding of resveratrol to the nuclear estrogen receptor (ER) and modulation of its genomic activity was among the first of its reported pharmacological actions. Additionally, resveratrol in some investigations interacted with membrane bound ER and modulated non-genomic estrogenic activities. The compound was also reported to interfere in steroidogenesis and estrogen biosynthesis at multiple steps along the pathway. Resveratrol also inhibited hepatic and intestinal metabolism of estrogens and increased circulating levels of sex hormone binding globulin (SHBG). Recent investigations report estrogenic activities for resveratrol metabolites, especially for the predominant sulfate conjugate. The majority of these estrogenic effects have been observed in vitro using micro-molar concentrations. However, the daily consumption of 0.5-1 g of resveratrol supplements is sufficient to furnish plasma levels sufficient to initiate most of these actions. The diverse modes of estrogenic and hormonal activities of resveratrol can produce a progressive shift in the homeostatic balance of estrogens and other steroidal hormones to a new operational set point. While this could represent an opportunity for therapeutic benefit in a variety of endocrine related diseases, it may also pose risk of endocrine disruption following chronic exposure that warrants caution. Herein, a review of the current knowledge of resveratrol's estrogenic activity at the molecular, cellular and whole organism since it was reported two decades ago is provided followed by an assessment of endocrine disruption via an estrogenic mode of action.KEY MESSAGEResveratrol interacts with ER and modulates its genomic and non-genomic activities. It also inhibits several enzymes in steroidogenesis and competes in estrogen metabolism. Commercial supplements reach dosages of 1000 mg per serving and the consumption of 0.5-1 g per day furnishes low micro-molar plasma levels sufficient to start these activities. The pleiotropic hormonal actions of resveratrol open an opportunity for clinical benefit, but also risk endocrine disruption if exposure is chronic or during critical windows of development.