The Unexpected Downsides of Resveratrol as an Aromatase Inhibitor

When talking about health and wellness, the term ‘resveratrol’ is often held up as a miracle compound. This antioxidant, found in grapes, peanuts, and some berries, is thought to have numerous health benefits including helping reduce inflammation and fighting aging.

However, when it comes to resveratrol’s use as an aromatase inhibitor, not all of the effects are positive. In this blog post, we’ll explore the surprising downsides of resveratrol as an aromatase inhibitor, and discuss why more research needs to be done before we can fully understand its biological effects.

What is an Aromatase Inhibitor?

Testosterone is converted to estradiol by the aromatase enzyme. An excessively high amount of estradiol in the body can lead to multiple negative side effects, including a decrease in testosterone, erectile dysfunction, mental issues, decreased libido, vascular complications, and an increased risk of prostate cancer.

Keeping estradiol within a good range, usually between 20-25pg/ml yields the best benefits, depending on someone’s sensitivity to estrogen of course.

Aromatase inhibitors may help to keep estrogen levels in a healthy range, while simultaneously increasing testosterone production. This is due to the fact that estradiol inhibits the release of luteinizing hormone (LH), which is responsible for stimulating testosterone production.

Is Resveratrol an Effective Aromatase Inhibitor?

This brings us to resveratrol, which some tout as a good aromatase inhibitor. But is it? Here is what the research shows.

In vitro studies:

“The administration of 10 nmol/l testosterone-a substrate of aromatase-produced a 50% increase in the MCF-7aro cell number. This cell proliferation specifically induced by testosterone was significantly reduced by 10 microM resveratrol. In addition, 50 microM resveratrol significantly reduced the CYP19-encoding mRNA abundance in SK-BR-3 cells.” (R)

“Quantitative RT-PCR analysis showed that resveratrol at a concentration of 50 and 100 mM decreased aromatase mRNA expression by 55 and 75%, respectively, and this resulted from decreased transcriptional activity of promoters I.3 and II in the aromatase gene.” (R)

Based on the first in vitro study, they used a resveratrol concentration of 10 microM, which can be achieved by taking 20-25g resveratrol daily (R). The average supplement is 500mg-1g.

Based on the second in vitro study, they used 50 to 100mM concentration, which will be about 100g+ resveratrol daily.

Does this make resveratrol a good aromatase inhibitor? Absolutely not! But wait… there are more (downsides) that I’ll discuss in the next section.

The way resveratrol lowered aromatase activity appears to be via inhibiting COX, an enzyme that regular NSAIDs block to lower inflammation (R). That would mean that regular COX inhibitors, such as aspirin can lower aromatase just as effectively. And yes, aspirin has been shown to increase testosterone and lower excessive aromatase (R, R).

Human study

Unfortunately, resveratrol hasn’t been extensively studied specifically for the purpose of an aromatase inhibitor.

In this pilot study, researchers gave postmenopausal women with a BMI > 25 kg/m3, a daily
dose of 1g of resveratrol for 12 weeks. They experienced no significant changes in estrone or testosterone, but did get a 22.4% increase in estradiol and a 10% increase in SHBG.

On the plus side, resveratrol produced a favorable increase in the concentration of urinary 2-hydroxyestrone (2-OHE1; an estrogen receptor antagonist) and the ratio of 2-OHE1 to 16a-hydroxyestrone (16a-OHE1; a known mitogen) (R).

Related articles:

• How to inhibit the aromatase

The Unexpected Downsides of Resveratrol as an Aromatase Inhibitor

Resveratrol is a phytoestrogen

Like most phytochemicals, resveratrol is a phytoestrogen. Meaning, it has mild estrogenic effects. Plus, resveratrol is structurally strikingly similar to diethylstilbestrol (a carcinogenic synthetic estrogen), which shares the stilbene backbone.

But how estrogenic is it?

Estrogenic compounds are compared to estradiol for affinity to the estrogen receptor (ER). If it has a similar affinity to the ER receptor to estradiol, it’s a very potent estrogen. A step further, once bound to the ER, it initiates/induces estrogenic activity.

Although resveratrol is a weak ER agonist (considerably less potent than estradiol) it produces a maximal level of induction that was 2- to 3-fold greater than that achieved by estradiol, making it a superagonist (R).

This study suggests that the dose necessary to exert estrogenic effects is equivalent to those that are required for its reported anti-inflammatory (R).

Selective estrogenic receptor modulation (SERM) activity of resveratrol

It has been speculated that resveratrol exhibits selective estrogen receptor modulator (SERM) characteristics, displaying both estrogenic activities in peripheral tissues and anti-estrogenic activity in central tissues (R).

Estrogenicity in animal studies

Studies in animals suggest that resveratrol does not have significant estrogenic activity on its own (an ER partial agonist at best (R)), nor does it appear to have anti-estrogenic activity.

• Resveratrol at a dose of 1000 mg/day (equivalent to 20 mg/kg/day) for 6 consecutive days did not antagonize the effects of estradiol (R).
• Resveratrol had no estrogenic activity on its own, and no anti-estrogenic activity in combination with estradiol (R).
• Even high-dose injections didn’t cause estrogenic effects (R).
• “Resveratrol in contrast to E2 did not decrease animal growth, body weight, serum cholesterol and radial bone growth and did not affect uterine indices of growth and differentiation. However, resveratrol did produce small increases in uterine weight at the highest dose and the investigators suggested it possibly exerts a greater effect if higher doses were given. These results indicated resveratrol does not possess sufficient in vivo agonistic properties on ER-expressing tissues.” (R)
• 17β-Estradiol, progesterone, and prolactin concentrations in the serum were not significantly affected by resveratrol or EGCG in rats (R).

Resveratrol inhibits estrogen detoxification

The body detoxes many compounds via the process of glucuronidation and conjugation. Calcium-D-glucarate, a common supplement used for detoxification, promotes glucuronidation.

Resveratrol has been shown to inhibit glucuronidation, thus increasing active estradiol (R).

In terms of conjugation, a group of activating cytochrome P450 enzymes in the liver, mainly CYP1A1/2 and CYP1B1 catalyze the hydroxylation of estrogens to their corresponding catechol derivatives 2-OHE1(E2) and 4- OHE1(E2), respectively.

These catechols are typically conjugated and eliminated, but inhibition of the conjugating
enzymes or deficiency in conjugating precursors increases their conversion to semiquinones and subsequently to quinones, which damage DNA and promote cancer (R). Resveratrol was shown in several studies to inhibit proper estrogen conjugating and detoxification.

Finally, resveratrol has also been shown to inhibit the conversion of estradiol to the weaker estrogen, estriol; via CYP3A4 hydroxylation.

All in all, resveratrol inhibits liver and intestinal detoxification of estrogens. This is likely why, in the study with menopausal women mentioned above, they experienced a 22% increase in estradiol. Impaired inactivation and excretion.

Anti-androgenic effects of resveratrol

To make things even worse, resveratrol isn’t just pro-estrogen, but also anti-androgenic.

Resveratrol on steroidogenic enzymes

The enzymes involved in testosterone synthesis that is inhibited by resveratrol include:

• StAR, thus reducing the influx of cholesterol into the mitochondria used for testosterone production, likely via activation of the ERα (R). ERα isn’t found in human Leydig cells, but it’s found in other tissue that produces androgens such as the skin, muscles and brain.
• 3β-HSD – A dose of 2g or more daily might be enough to start inhibiting this enzyme (R).
• 17,20 lyase activity, which decreased the production of DHEA and testosterone (R).

Resveratrol on steroidogenesis in animals

Rats eating a diet with doses of 50 and 100 mg/kg resveratrol for 2 days lowered serum testosterone levels to approximately half (R). This could be because rats have ERα in their Leydig cells and humans don’t, that’s why we don’t see a drop in testosterone, but only DHEA and androstenedione (study discussed below).

On the flip side, at smaller doses, 20mg/kg/day, rats experienced an increase in LH, FSH and testosterone. This could be because resveratrol could antagonize the ERα in the pituitary (although it has no anti-estrogenic or estrogenic effect in the pituitary) or antagonize the androgen receptor since there is evidence that it blocks the androgen receptor in prostate cells (R).

In rabbits, at a dose of 50mg/day (16.22mg/kg human equivalent dose), resveratrol improved testicular health, and sperm count as well as testosterone (by 51.6%) (R).

Resveratrol inhibits steroidogenesis in humans

At 1g per day, resveratrol lowered the serum level of androstenedione by 24%, DHEA by 41% and DHEAS by 50%. However, prostate size and levels of PSA, testosterone, free testosterone and DHT remained unchanged (R).

High DHEA-S is inversely correlated with mortality and frailty, so lowering it is likely not a good thing.

Anti-thyroid effects of resveratrol

Resveratrol has been shown to act as a thyroid disruptor and a goitrogen by inhibiting the sodium/iodide symporter gene expression and function (R, R). The sodium/iodide symporter transports iodide into the thyroid to be used for thyroid hormone synthesis.

In subclinical hypothyroidism rats, resveratrol treatment downregulated TSH as well as fT4 and fT3 (R). Not good.

Optimal thyroid function is very important for increasing LH, testosterone, testosterone-to-estradiol ratio and especially DHT.

Related articles:

• The easiest way to optimize DHT (thyroid optimation)
• Optimize your testosterone to estradiol ratio with thyroid

Conclusion

No side effects have been reported with short-term doses of resveratrol up to 1.0 g, and long-term clinical trials have demonstrated that it is safe and well-tolerated at doses up to 5 g/day, either taken in a single dose or as part of a multiple-day dosing regimen. (R).

It is important to note that these studies were conducted on healthy individuals, and the results may not be the same in ill patients. Additionally, the effects of resveratrol, including its dose-dependency and administration route, are further complicated due to the fact that orally ingested resveratrol is metabolized by gut microbiota. This makes it difficult to distinguish the effects of resveratrol from those of its metabolites.

For example, the maximal plasma concentration (Cmax) of resveratrol-3-O-sulfate following the oral administration of 0.5 and 1 g of resveratrol in humans was 3.7 and 6.8 lM, respectively. Therefore, this metabolite may flare estrogen-dependent cancers if supplemental doses in excess of 500mg are taken on a chronic basis (R).

In smaller doses, resveratrol might increase testosterone in rats and rabbits, but that’s not been shown to occur in humans.

On the flip side, even though it’s marketed as an aromatase inhibitor, it’s more likely to be estrogenic by inhibiting estrogen clearance.

Resveratrol:

• Is, at the standard supplemental dose (1g), too weak to be an effective aromatase inhibitor.
• Inhibits glucuronidation, thus inhibiting estrogen clearance.
• Inhibits the conjugation of estrogen metabolites, thus promoting the production of cancerous estrogen metabolites.
• Inhibits various steroidogenic enzymes.

From my perspective, the downsides far outweigh any potential benefit for hormonal manipulation.