A Reservatol Study

Say it ain’t so.

Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor.

    * Gehm BD,
    * McAndrews JM,
    * Chien PY,
    * Jameson JL.

Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Medical School, 303 E. Chicago Avenue, Chicago, IL 60611, USA.

The phytochemical resveratrol, which is found in grapes and wine, has been reported to have a variety of anti-inflammatory, anti-platelet, and anti-carcinogenic effects.

Based on its structural similarity to diethylstilbestrol, a synthetic estrogen, we examined whether resveratrol might be a phytoestrogen. At concentrations (approximately 3-10 microM) comparable to those required for its other biological effects, resveratrol inhibited the binding of labeled estradiol to the estrogen receptor and it activated transcription of estrogen-responsive reporter genes transfected into human breast cancer cells.

This transcriptional activation was estrogen receptor-dependent, required an estrogen response element in the reporter gene, and was inhibited by specific estrogen antagonists. In some cell types (e.g., MCF-7 cells), resveratrol functioned as a superagonist (i.e., produced a greater maximal transcriptional response than estradiol) whereas in others it produced activation equal to or less than that of estradiol.

Resveratrol also increased the expression of native estrogen-regulated genes, and it stimulated the proliferation of estrogen-dependent T47D breast cancer cells. We conclude that resveratrol is a phytoestrogen and that it exhibits variable degrees of estrogen receptor agonism in different test systems.

The estrogenic actions of resveratrol broaden the spectrum of its biological actions and may be relevant to the reported cardiovascular benefits of drinking wine.

PMID: 9391166 [PubMed - indexed for MEDLINE]

I’m not going to go so far, especially at this point as research is constantly developing with this compound, to say “it ain’t so in any way” but it’s a very, very common situation to have a given research finding, especially in vitro (Petri dish or test tube, so to speak) or in cell lines, that raises suspicion of problem or offers idea of benefit that practical experience just finds no sign of.

If anything that may be more common than not.

Resveratrol has been around as a supplement quite a while. We’ve used it since way back in the “M” anti-estrogen product of about 6 years ago or so. In addition, a lot of doses of REZ-V have been used, as well as of course products from other companies.

So there’s considerable practical experience: and it seems that no one has ever, once, complained of an estrogenic side effect from resveratrol. If anything the opposite, users finding what they thought to be an anti-estrogenic effect.

As to why the disparity between the study you’ve provided (thank you!) and practical outcomes, I don’t know. However, here is another study that is substantially different in outcome and conclusions and seems more consonant with experiences actual human beings have had with the compound:

[i]Resveratrol Acts as a Mixed Agonist/Antagonist for Estrogen Receptors alpha and beta.

Jennifer L. Bowers, Valentyn V. Tyulmenkov, Sarah C. Jernigan and Carolyn M. Klinge

Epidemiological evidence indicates that phytoestrogens inhibit cancer formation and growth, reduce cholesterol levels, and show benefits in treating osteoporosis. At least some of these activities are mediated through the interaction of phytoestrogens with estrogen receptors alpha and beta. (ER-alpha} and ER-beta). Resveratrol, trans-3,5,4’-trihydroxystilbene, is a phytoestrogen in grapes that is present in red wine. Resveratrol was shown to bind ER in cytosolic extracts from MCF-7 and rat uteri. However, the contribution of ER-alpha vs. ER-beta in this binding is unknown. Here we report that resveratrol binds ER-beta and ER-alpha with comparable affinity, but with 7,000-fold lower affinity than estradiol (E2). Thus, resveratrol differs from other phytoestrogens that bind ER-beta with higher affinity than ER-alpha. Resveratrol acts as an estrogen agonist and stimulates ERE-driven reporter gene activity in CHO-K1 cells expressing either ER-alpha or ER-beta. The estrogen agonist activity of resveratrol depends on the ERE sequence and the type of ER. Resveratrol-liganded ER-beta has higher transcriptional activity than E2-liganded ER-beta at a single palindromic ERE. This indicates that those tissues that uniquely express ER-beta or that express higher levels of ER-beta than ER-alpha may be more sensitive to resveratrol?s estrogen agonist activity. For the natural, imperfect EREs from the human c-fos, pS2, and progesterone receptor (PR) genes, resveratrol shows activity comparable to that induced by E2. We report that resveratrol exhibits E2 antagonist activity for ER-alpha with select EREs. In contrast, resveratrol shows no E2 antagonist activity with ER-beta. These data indicate that resveratrol differentially affects the transcriptional activity of ER-alpha and ER-beta in an ERE sequence-dependent manner.[/i]

Yet another consideration that might be a piece of this puzzle is that with the estrogen receptor it really is not the simple case of either activating or not activating or being an antagonist, but has critically to do with the specific shape the estrogen receptor adopts in response to the ligand. Which isn’t just a matter of ER-beta being different than ER-alpha, but either of them being able to act completely differently to one ligand vs another or vs the same in a different tissue type.

So anyway the upshot is, in practical experience with man, or any in vivo research on man for that matter, is there a trace of evidence that anything undesired of an estrogenic sort occurs with resveratrol?

It’s entirely possible (and seems to be the case) that the answer can be “no” while simultaneously the results of the study you cite can be and probably are true in the context they were studied.

Dr. Roberts,

I know this is slightly off topic, but i was wondering what your opinion was on Calcium D Glucarate, and what you feel is an effective dose of it.

Thank you.

I remember reading somewhere that the problem with some Resveratrol research, other than the obvious in vivo vs in vitro, is the difference between mice and human physiology. Whereas mice breast cancers are estrogen in-sensitive, and human breast cancers are estrogen sensitive.

I’m probably wrong, and don’t know how this shapes the debate, but is something to consider.

Pretty old stuff, but sources no less.

American Institute for Cancer Research. Nutrition and cancer prevention: new insights into the role of phytochemicals. New York: Kluwer Academic/Plenum Publishers, 2001

Gescher, Andreas C., and William Steward. Relationship between Mechanisms, Bioavailibility, and Preclinical Chemopreventive Efficacy of Resveratrol: A Conundrum. Leicester, UK: University of Leicester, Dept of Oncology, 2003.