T Nation

Resveratrol as Mixed Estrogen Agonist/Antagonist


Looking through the literature, there seems to be many examples of resveratrol being a mixed agonist and antagonist, though I have yet to come across any studies indicating it is only an antagonist.

For those not up to speed, this is not really new to T-Muscle. When introducing Rez-V, Biotest's very own and high-quality resveratrol supplement, TC acknowledged that resveratrol has both agonistic and antagonistic function.

From this, I do wonder in what tissue and ways resveratrol is agonistic, and in what ways is it antagonistic to estrogen.

I would love to invest in some Rez-V, but am paranoid as s#!t about puting anything in my body that may activate estrogen receptors (like soy, parabens, etc.)

What brought Biotest and others to the realization that resveratrol is primarily ant-estrogenic?


I'm curious about this as well. Bill Roberts probably has the asnwer. Let's see if he'll chime in.


Yes, trans-resveratrol has in studies shown mixed agonist/antagonist properties.

If it were a compound never tried in man this would lead to major questions as to exactly what was going to happen.

It needs to be emphasized that some things done by estrogen are good. But there are others that are bad, especially for men.

There is a lot of practical experience with resveratrol and not a single "bad" estrogenic effect has ever been noted so far as I know. It seems to work only to the good.

That said, I don't think it's demonstrated (or if it is, I simply lack the information) that any anti-estrogenic effects are sufficient to deal with serious estrogenic problems such as eliminating risk of gynecomastia when having abnormally high estrogen levels from aromatizating anabolic steroid use.

So I would take it as an interesting pharmacological thing that it has properties falling into this class, but in practice, go with what is observed from it. I think it's reasonably undoubted that it aids health and is a valuable compound.


I just asked TC to chime in with his thoughts, but whether or not there have been studies to determine to what extent it is more anti-estrogenic than estrogenic, it does appear to be highly beneficial in some areas.

However, my interest was peaked upon reading the literature as well as reading a post by an individual taking a resveratrol supplement and experiencing effects related to some aspects of phytoestrogens, including weakened immune system, exaggerated emotions, and a strange affinity for Brittney Spears songs. Ok, admittedly, the last one was made up, but the others DO relate to side effects of phytoestrogen intake when the phytoestrogens are primarily agonistic.

An important note here may be that he was taking a supplement OTHER THAN Rez-V, which may have compromised quality.

Anyway, it is a topic of great interest, being that Rez-V has so many benefits, while baring the dreaded name of "phytoestrogen".


Estrogen receptor agonism in the beta-cells of the pancreas causes their proliferation and accordingly greater insulin secretion. Not all is known about the system's functions though. An interesting story is that women using estrogen supplements in later age were associated with decreased incidence of diabetes. In search of literature regarding this, I came across a new paper from Endocrinology about estrogen's effect to db/db mice. This work would be suggestive that estrogen receptor activation (probably in the pancreas specifically) is likely a good thing if you are planning on releasing a lot of insulin... hence a potential target for resveratrol.

Endocrinology. 2009 May;150(5):2109-17.
Estrogens protect against high-fat diet-induced insulin resistance and glucose intolerance in mice.

Riant E, Waget A, Cogo H, Arnal JF, Burcelin R, Gourdy P.
Institut National de la Sant�?�© et de la Recherche M�?�©dicale Unit�?�© 858, Institut de M�?�©decine Mol�?�©culaire de Rangueil, Boite Postale 84225, 31432 Toulouse Cedex 4, France.
Although corroborating data indicate that estrogens influence glucose metabolism through the activation of the estrogen receptor alpha (ERalpha), it has not been established whether this pathway could represent an effective therapeutic target to fight against metabolic disturbances induced by a high-fat diet (HFD). To this end, we first evaluated the influence of chronic 17beta-estradiol (E2) administration in wild-type ovariectomized mice submitted to either a normal chow diet or a HFD. Whereas only a modest effect was observed in normal chow diet-fed mice, E2 administration exerted a protective effect against HFD-induced glucose intolerance, and this beneficial action was abolished in ERalpha-deficient mice. Furthermore, E2 treatment reduced HFD-induced insulin resistance by 50% during hyperinsulinemic euglycemic clamp studies and improved insulin signaling (Akt phosphorylation) in insulin-stimulated skeletal muscles. Unexpectedly, we found that E2 treatment enhanced cytokine (IL-6, TNF-alpha) and plasminogen activator inhibitor-1 mRNA expression induced by HFD in the liver and visceral adipose tissue. Interestingly, although the proinflammatory effect of E2 was abolished in visceral adipose tissue from chimeric mice grafted with bone marrow cells from ERalpha-deficient mice, the beneficial effect of the hormone on glucose tolerance was not altered, suggesting that the metabolic and inflammatory effects of estrogens can be dissociated. Eventually comparison of sham-operated with ovariectomized HFD-fed mice demonstrated that endogenous estrogens levels are sufficient to exert a full protective effect against insulin resistance and glucose intolerance. In conclusion, the regulation of the ERalpha pathway could represent an effective strategy to reduce the impact of high-fat diet-induced type 2 diabetes.


I believe I fianly found SOMETHING that speaks directly to this issue:

First, to summarize: They treated young growing rats with oral resveratrol, as well as estrodiol for comparison. They found that all of the changes produced by estrodiol were NOT mimicked by resveratrol, and that resveratrol even PREVENTED the effects of serum estrogen, one of which was lowered cholesterol (strangely, this might be seen as a benefit of estrogen by these researchers).

The last sentence in this abstract was certainly the most convincing:

These in vivo [using whole, living organisms] results suggest, in contrast to prior in vitro [using cells in a petri dish] studies, that resveratrol has little or no estrogen agonism on reproductive and nonreproductive estrogen target tissues and may be an estrogen antagonist.

In other words, when applied, it seems resveratrol may just be the estrogen antagonist [anti-estrogen] we all hoped it would be, including being an antogonist on REPRODUCTIVE as well as non reproductive tissue.

Of course, I think there is still more room for human studies.

For the full abstract:
Is Resveratrol an Estrogen Agonist in Growing Rats?1
Russell T. Turner, Glenda L. Evans, Minzhi Zhang, Avudaiappan Maran and Jean D. Sibonga

Departments of Orthopedics, Biochemistry, and Molecular Biology, Mayo Graduate School of Medicine, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Russell T. Turner, Ph.D., Orthopedic Research, Room 3â??69 Medical Science Building, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905.

Trans-3,4,5-trihydroxystilbene (resveratrol), a polyphenolic compound found in juice and wine from dark-skinned grape cultivars, was recently shown to bind to estrogen receptors in vitro, where it activated transcription of estrogen-responsive reporter genes. The purpose of this 6-day study in weanling rats was to determine the dose response (1, 4, 10, 40, and 100 �µg/day) effects of orally administered resveratrol on estrogen target tissues. The solvent (10% ethanol) had no significant effect on any measurement or derived value. 17�?-Estradiol treatment (100 �µg/day) decreased the growth rate, final body weight, serum cholesterol, and radial bone growth (periosteal bone formation and mineral apposition rates) at the tibia-fibula synostosis. In the uterus, 17�?-estradiol treatment increased wet weight, epithelial cell height, and steady state messenger RNA levels for insulin-like growth factor I. In contrast, resveratrol treatment had no significant effect on body weight, serum cholesterol, radial bone growth, epithelial cell height, or messenger RNA levels for insulin-like growth factor I. Resveratrol treatment resulted in slight increases in uterine wet weight, but significance was achieved at the 10-�µg dose only. A second experiment was performed to determine whether a high dose of resveratrol (1000 �µg/day) antagonizes the ability of estrogen to lower serum cholesterol. As was shown for the lower doses, resveratrol had no effect on body weight, uterine wet weight, uterine epithelial cell height, cortical bone histomorphometry, or serum cholesterol. 17�?-Estradiol significantly lowered serum cholesterol, and this response was antagonized by cotreatment with resveratrol. These in vivo results suggest, in contrast to prior in vitro studies, that resveratrol has little or no estrogen agonism on reproductive and nonreproductive estrogen target tissues and may be an estrogen antagonist.


Nice. Anyone know of any in vivo human studies on the topic? I'd like to see similar findings in human and what the dose is.


Hm I looked at that paper and while they state that resveratrol acts as an antagonist to estrogen in reducing serum cholesterol levels, if you examine the only data they present to support this claim (http://endo.endojournals.org/cgi/reprint/140/1/50 figure 4) you will see that combined treatment of resveratrol and estrogen (at the high dose) seem to have a synergistic effect to reduce cholesterol, as the combined treatment had the lowest cholesterol level of all the groups by around 10%.

Perhaps their use of the word antagonize is not correct?

It should mean that resveratrol is reducing the action of estrogen, and I do not see how their data supports this. Does anyone else get it? It would have been wise for them to include a resveratrol + estrogen group in the other studies also I think.