madman
Super Moderator
The estrogenic activity of resveratrol: a comprehensive review of in vitro and in vivo evidence and the potential for endocrine disruption
ABSTRACT
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 the 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 a 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 MESSAGE
Resveratrol 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.
3. Effects of resveratrol on ER biology
3.1. Effects on genomic ER signaling
3.1.1. Evidence from in vitro assays
3.1.1.1. Competitive receptor binding and ligand displacement
3.1.1.2. Functional transactivation of a reporter gene construct
3.1.1.3. Functional transactivation of endogenous estrogen-responsive genes
3.1.1.4. Cellular proliferation assay (E-screen assay).
3.1.2. Evidence from in vivo assays
3.1.2.1. Uterotrophic assay in rodents. T
3.2. Effects on non-genomic ER signaling
3.3. Effects on ER expression
3.4. Effects on steroidogenesis and estrogen biosynthesis
3.5. Effects on estrogen metabolism
3.6. Effects on plasma levels of sex hormone-binding globulin (SHBG)
4. Experimental evidence in animals that resveratrol induces endocrine disruption via an estrogenic mode of action
4.1. Prenatal exposure
4.2. Neonatal exposure
4.3. Prepubertal exposure
4.4. Adult exposure
4.5. Short term and sub-chronic repeated dosing toxicity studies
5. Evidence of estrogenic and hormonal activities of resveratrol in therapeutic applications
5.1. Preclinical studies
5.2. Clinical studies
6. Discussion
7. Summary
Literature evidence suggests that the hormonal effects of resveratrol are subtle, require time to manifest, and are likely to go unnoticed or masked by acute or progressive toxicity to specific organ systems in acute and sub-chronic toxicity studies. Resveratrol modulates estrogenic activity via multiple mechanisms. The compound directly interacts with ER and functions as a mixed agonist/antagonist. It also interferes in the intestinal and hepatic metabolism of estrogens, which increases their levels and potentially intensifies their central and peripheral actions. Resveratrol also inhibits critical enzymes in steroidogenesis which alters the plasma levels of steroids and their precursors. The short term consumption of dietary supplements may not produce endocrine-related abnormalities, but chronic exposure to pharmacological doses of the compound potentially shifts the homeostatic balance of estrogens and other steroid hormones to a new operational set point. This outcome opens a window for therapeutic benefit in some endocrine diseases, but also predisposes to detrimental effects on reproductive organ development and function, socio-sexual behavior and endocrine-related pathologies such as hormonal dependent cancers. Therefore, there is a need to determine the long term effects of resveratrol on steroid hormone homeostasis in future preclinical and clinical trials, especially with pharmacological doses in excess of 0.5 g. Until sufficient data is available, the consumption of high-strength resveratrol supplements for general health benefits on a long-term basis or during critical windows of development or by specific consumer subpopulations warrants caution.
ABSTRACT
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 the 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 a 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 MESSAGE
Resveratrol 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.
3. Effects of resveratrol on ER biology
3.1. Effects on genomic ER signaling
3.1.1. Evidence from in vitro assays
3.1.1.1. Competitive receptor binding and ligand displacement
3.1.1.2. Functional transactivation of a reporter gene construct
3.1.1.3. Functional transactivation of endogenous estrogen-responsive genes
3.1.1.4. Cellular proliferation assay (E-screen assay).
3.1.2. Evidence from in vivo assays
3.1.2.1. Uterotrophic assay in rodents. T
3.2. Effects on non-genomic ER signaling
3.3. Effects on ER expression
3.4. Effects on steroidogenesis and estrogen biosynthesis
3.5. Effects on estrogen metabolism
3.6. Effects on plasma levels of sex hormone-binding globulin (SHBG)
4. Experimental evidence in animals that resveratrol induces endocrine disruption via an estrogenic mode of action
4.1. Prenatal exposure
4.2. Neonatal exposure
4.3. Prepubertal exposure
4.4. Adult exposure
4.5. Short term and sub-chronic repeated dosing toxicity studies
5. Evidence of estrogenic and hormonal activities of resveratrol in therapeutic applications
5.1. Preclinical studies
5.2. Clinical studies
6. Discussion
7. Summary
Literature evidence suggests that the hormonal effects of resveratrol are subtle, require time to manifest, and are likely to go unnoticed or masked by acute or progressive toxicity to specific organ systems in acute and sub-chronic toxicity studies. Resveratrol modulates estrogenic activity via multiple mechanisms. The compound directly interacts with ER and functions as a mixed agonist/antagonist. It also interferes in the intestinal and hepatic metabolism of estrogens, which increases their levels and potentially intensifies their central and peripheral actions. Resveratrol also inhibits critical enzymes in steroidogenesis which alters the plasma levels of steroids and their precursors. The short term consumption of dietary supplements may not produce endocrine-related abnormalities, but chronic exposure to pharmacological doses of the compound potentially shifts the homeostatic balance of estrogens and other steroid hormones to a new operational set point. This outcome opens a window for therapeutic benefit in some endocrine diseases, but also predisposes to detrimental effects on reproductive organ development and function, socio-sexual behavior and endocrine-related pathologies such as hormonal dependent cancers. Therefore, there is a need to determine the long term effects of resveratrol on steroid hormone homeostasis in future preclinical and clinical trials, especially with pharmacological doses in excess of 0.5 g. Until sufficient data is available, the consumption of high-strength resveratrol supplements for general health benefits on a long-term basis or during critical windows of development or by specific consumer subpopulations warrants caution.
