Resveratrol has been shown to suppress proliferation of both ER-positive and negative Resveratol cancer cells in Resverayrol culture systems [ 11 Resveratrol and hormonal balance Herbal Beauty Products ]. Resveratrol and hormonal balance hormonao also present in different berries, soy, and peanuts. Mol Pharmacol 56 : — Resveratrol is produced by plant tissues in response to an invading fungus, stressinjury, infection, or ultraviolet irradiation, and it has anti-inflammatory properties. Cheng YPrusoff WH Relationship between the inhibition constant K1 and the concentration of inhibitor which causes 50 per cent inhibition I50 of an enzymatic reaction.

Resveratrol and hormonal balance -

In addition, studies have shown that estrogen metabolites vary in estrogenic and genotoxic potential with 16α-hydroxyestrone 16α-OHE 1 being mitogenic in breast cancer cells whereas 2-hydroxyestrone 2-OHE 1 is considered an estrogen receptor antagonist [ 7 ],[ 8 ]. Resveratrol, a phytochemical produced by a restricted number of plant species in response to stress, has shown compelling breast cancer preventive activities in preclinical studies.

Resveratrol has been shown to suppress proliferation of both ER-positive and negative breast cancer cells in cell culture systems [ 11 ],[ 12 ]. It acts as an estrogen agonist or antagonist depending on the cell types, estrogen receptor isoform, and the presence of endogenous estrogens [ 13 ],[ 14 ].

Some but not all studies showed that resveratrol inhibits aromatase in breast cancer cells [ 15 ],[ 16 ]. In addition, resveratrol has been shown to modulate phase I and phase II enzymes involved in the activation or detoxification of drugs, endogenous hormones and carcinogens in preclinical studies [ 17 ]—[ 21 ].

Our prior clinical study showed that resveratrol taken at 1 gm daily for 4 weeks led to inhibition of the activity of cytochrome P CYP 3A4, 2D6, and 2C9 and induction of CYP1A2 [ 22 ]. Because the formation of 2-OHE 1 and 16α-OHE 1 was primarily catalyzed by CYP 1A2 and 3A4, respectively, changes in CYP isozyme activities may lead to changes in the balance between mitogenic and protective estrogen metabolites.

Here, we report a pilot study conducted in postmenopausal women with high body mass index BMI to determine the modulating effects of resveratrol on circulating sex steroid hormones and estrogen metabolites to evaluate its potentials for breast cancer prevention.

The study was an open label, single-arm intervention trial in postmenopausal women with high BMI. The primary endpoint of the study was change in serum estradiol levels. Safety of resveratrol intervention was assessed by reported adverse events, complete blood count, and comprehensive metabolic panel.

Resveratrol drug product was supplied by Royalmount Pharma, Inc. through the Division of Cancer Prevention, National Cancer Institute. Resveratrol caplets were manufactured by Pharmascience Inc. using synthetic resveratrol. Resveratrol purity was assessed by HPLC with UV detection. Each study caplet contains mg resveratrol plus inert pharmaceutical excipients.

The study caplets were stored at room temperature and protected from environmental extremes. Postmenopausal was defined as amenorrhea for at least 12 months, or history of hysterectomy and bilateral salpingo-oophorectomy, or at least 55 years of age with prior hysterectomy with or without oophorectomy, or age 35 to 54 with a prior hysterectomy without oophorectomy or with a status of ovaries unknown with documented follicle-stimulating hormone level demonstrating elevation in postmenopausal range.

Participants were required to have normal liver and renal function. Study exclusion criteria included invasive cancers within the past 5 years, within 3 months of or concurrent usage of other investigational agents, a history of allergic reactions attributed to resveratrol, uncontrolled acute or chronic diseases, within 3 months of or concurrent usage of hormonal therapy, selective estrogen-receptor modulators or aromatase inhibitors, regular usage of estrogenic supplements, or concurrent use of anti-diabetic drugs, warfarin or phenytoin.

The study was approved by the University of Arizona Human Subjects Protection Program. Written informed consent was obtained from all participants. During the initial visit, consented study subjects underwent medical history evaluation and had a fasting blood sample collected for complete blood count and comprehensive metabolic panel.

Eligible subjects underwent a minimum of 2 weeks of washout in which they were required to limit resveratrol containing foods and products including wine red and white , peanuts, mulberries, grapes seeds, skin, stalks , cranberries, blueberries, huckleberries, or any food containing these ingredients.

After the washout period, subjects returned to the clinic for the collection of a fasting blood sample that was used to measure baseline serum hormone levels and study agent levels.

Participants were instructed to collect a morning urine void for three consecutive mornings including the morning of the scheduled baseline visit. The urine samples were kept at room temperature before they were brought to the clinic, typically around 48 hours since the initial collection.

The urine collection was used for baseline urinary estrogen metabolite analyses. The storage condition has minimal effects on the analytes of interest. Following the completion of the baseline sample collection, subjects took 1 gm dose of resveratrol once a day two mg caplets QD with food for 12 weeks and continued to limit resveratrol containing foods and products.

At week 6, subjects returned to have a blood sample collected for study agent level analysis, return unused pills for a pill count, and review the side effect diary with study staff.

Subjects returned at the end of the week intervention to return unused drugs and review the side effect diary with study staff. A fasting blood sample was collected for clinical labs, post-intervention serum hormone and study agent level analyses.

Three morning urine voids were collected for post-intervention urinary estrogen metabolite analyses. Following the resveratrol intervention, study participants were followed for 2 weeks for any adverse reactions.

Safety of resveratrol intervention was assessed by reported adverse events and clinical labs. Adverse events were graded using NCI Common Terminology Criteria for Adverse Events CTCAE version 4.

Serum estradiol and estrone concentrations were measured by a sensitive and specific liquid chromatography-tandem mass spectrometry assay [ 23 ] with minor modifications. Serum testosterone concentrations were measured by a sensitive and specific liquid chromatography-tandem mass spectrometry assay [ 24 ] with minor modifications to improve assay specificity.

SHBG was measured using an ELISA based immunoassay GenWay Biotech, Inc. Urinary 2-OHE 1 and 16α-OHE 1 were determined using an ELISA based immunoassay Immuna Care Corp. Plasma resveratrol and metabolite concentrations were determined using a published HPLC method with UV detection [ 25 ].

Plasma concentrations of resveratrol metabolites were estimated based on the calibration curve established with resveratrol standard. Descriptive statistics, e.

mean and standard deviation, were calculated for each of the endpoints. A two-sided paired t test was performed to test if the percent change from baseline to post-intervention in each of the endpoints is significantly different from zero. Because of the exploratory nature, analyses of these endpoints were not corrected for multiple comparisons.

Descriptive statistics was performed on the type and frequency of all adverse events. Forty-six subjects were consented between June and March with six found to not meet all inclusion criteria. Forty subjects initiated the resveratrol intervention with six withdrawn early due to adverse events.

Table 1 summarizes the demographics of study subjects who completed the wk intervention. The average BMI and body weight was Table 2 summarizes the baseline and post-intervention circulating levels of sex steroid hormones and estrogen metabolites.

The mean baseline serum concentrations of estradiol, estrone, and testosterone were Resveratrol intervention did not result in significant changes in these sex steroid hormones. The mean baseline SHBG concentrations were Resveratrol intervention resulted in a Resveratrol and metabolites were not detectable in any of the baseline plasma samples.

Resveratrol and metabolites concentrations in the plasma samples collected at mid-study and post-intervention visits are shown in Figure 1. Levels of the resveratrol metabolites were similar in mid-study and post intervention samples.

Resveratrol and metabolites concentrations in the plasma samples collected at mid-study and post-intervention visits. Plots illustrate the median, 25th, and 75th percentiles as vertical boxes with 10th and 90th percentiles as error bars.

Table 3 summarizes AEs observed in study participants after initiation of the resveratrol intervention. One participant had asymptomatic Grade 4 elevation in hepatic ALT and AST enzymes at the end of 3-month agent intervention. The participant had a normal hepatitis panel as part of the evaluation of this liver test abnormality and returned every 2—3 weeks for follow-up blood tests for the hepatic panel.

The elevated hepatic enzymes returned to normal after less than 3 months of follow-up. Six subjects withdrew early from the resveratrol intervention due to adverse events; two after 12 and 33 days, respectively, due to Grade 3 skin rash, one after 66 days due to Grade 2 diarrhea, one after 10 days due to Grade 2 allergic reaction, one after 39 days due to Grade 2 constipation, and one after one dose due to Grade 2 diarrhea and Grade 1 shortness of breath and wheezing.

The remaining AEs were transient and were Grade 1 or 2 events. The most common adverse events were diarrhea and dyslipidemia. Increased total cholesterol was observed in 11 subjects Overweight and obesity are associated with an increased risk for postmenopausal breast cancer and poor disease outcome reviewed by [ 26 ],[ 27 ].

The increased risk is partially determined by several hormone-related factors. To the best of our knowledge, our study is the first to report the clinical activity of resveratrol on circulating sex steroid hormones and estrogen metabolites. The baseline levels of sex steroid hormones and estrogen metabolites were similar to those reported in postmenopausal women in a similar BMI range [ 4 ],[ 9 ],[ 10 ].

We showed that 1 gm of resveratrol daily for 12 weeks did not alter the serum estrogen and testosterone concentrations in postmenopausal women with high adiposity but significantly increased the concentrations of SHBG, which has been inversely associated to breast cancer risk [ 6 ].

We did not observe any significant changes in serum insulin levels data not shown and body weight, two major factors known to influence the blood levels of SHBG [ 28 ].

Future randomized, controlled trials are needed to confirm the effect of resveratrol on SHBG. Because SHBG is the main transport binding protein for circulating sex steroid hormones, it has been suggested that elevation in SHBG could lead to a decrease in bioavailable sex steroid hormones and their associated bioactivity.

We calculated the hormone fractions based on the law of mass action [ 29 ] and found that resveratrol intervention did not result in significant changes in bioavailable estradiol but decreased the levels of bioavailable testosterone from 0. Further studies are needed to determine the effect of resveratrol-induced hormonal changes on breast cancer risk modulation.

The formation of 2-OHE 1 and 16α-OHE 1 was primarily catalyzed by cytochrome P CYP 1A2 and 3A4, respectively. The observed changes in estrogen metabolism is consistent with our prior clinical study that showed an induction of 1A2 and inhibition of 3A4 activity after 4 weeks of 1 gm daily resveratrol dosing [ 22 ].

Further research is needed to evaluate whether resveratrol-induced changes in estrogen metabolism would contribute to breast cancer risk modulation.

The resveratrol dose and product used in our study has previously been shown to be safe and well tolerated up to 4 weeks in healthy adults [ 22 ]. In this study of overweight or obese postmenopausal women, six subjects withdrew early after taking resveratrol for 1—66 days due to adverse events including diarrhea, constipation, skin rash, allergic reaction, and shortness of breath.

One participant had asymptomatic Grade 4 ALT and AST elevation at the post-intervention visit which normalized after less than 3 months of follow-up and was considered possibly related to resveratrol intervention.

The common reported adverse events were diarrhea and dyslipidemia. 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. 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.

While the authors concluded that the most likely mechanism for the antiestrogenic effect of resveratrol is its direct competition with E 2 for ER binding, they also suggested that resveratrol might prevent ER binding to EREs Our data support both suggestions because we observed that resveratrol competes with E 2 for ERα and ERβ binding and inhibited ERα and ERβ binding to EREc38 in vitro.

We observed both ER isoform-specific and ERE-specific differences in the agonist activity induced by resveratrol in CHO-K1 cells. For example with ERα, the activity induced by E 2 was greater than that stimulated by any concentration of resveratrol for EREc38, Fos, and pS2, but not PR In contrast, resveratrol and E 2 were equally transcriptionally active with ERβ at all EREs tested.

With ERα and PR, although the induction levels are low, they are significantly above the ethanol control values, and resveratrol-induced luciferase activity was comparable to that induced by E 2.

In addition to estrogen agonist activity, we also report that resveratrol has estrogen antagonist activity in CHO-K1 cells.

These data are reminiscent of the lack of 4-OHT agonist activity with ERβ We speculate that the antagonist activity of resveratrol may be mediated by AF-1, which appears to be absent in ERβ. Interestingly, the antagonist activity of resveratrol was only observed with EREc38, whether as a single or two tandem copies, and PR These data indicate that the ERE alters the pharmacological properties of resveratrol mediated by ERα.

This result agrees with our postulate that the ERE sequence acts as an allosteric modulator of ER activity Further experiments are needed to define exactly what regions of ERα and ERβ are necessary for resveratrol agonist and antagonist activity and to define the exact ERE sequence requirements for resveratrol antagonist activity with ERα.

For example, resveratrol induces phosphorylation of the mitogen-activated protein MAP kinase family members, extracellular regulated kinase 1 ERK1 , and ERK2, in neuroblastoma SH-SY5Y cells 55 Activation of the MAP kinase pathway has been shown to activate unliganded ERα through phosphorylation of serine in AF-1 However, this ligand-independent pathway does not appear to be important in our experiments because 4-OHT blocked both E 2 and resveratrol activity, indicating that direct activation of ERα through the LBD was responsible for the activity reported here.

While the pharmacokinetics of resveratrol metabolism have not yet been examined in humans, results from rodent studies indicate that two servings of red wine may provide two-digit micromolar serum concentrations of resveratrol 1 , i. concentrations identical to those at which the pharmacological activities of resveratrol were observed here as well as reported by others 10 , 14 , The cell-type and ERE-sequence dependence of the transcriptional activity of resveratrol with ERα and ERβ may be related to cell-specific differences in the activity of enzymes that modulate ER function, e.

protein kinases, and in the expression of coactivator or corepressor proteins. Continued analysis of ERα and ERβ interaction with estrogenic ligands, estrogen-regulated genes, and coregulator proteins is necessary to gain a better understanding of how these receptors regulate estrogenic activity at the cellular and molecular level and whether the anticancer and cardioprotective activities of resveratrol are mediated by ER.

Supported by NIH Grant RDK, the Cancer Research Foundation of America, and a University of Louisville School of Medicine Research Grant to C.

We thank the following companies for supplying reagents used in this study: resveratrol: Pharma Science, Montréal, Québec, Canada; and H Abbott Laboratories Abbott Park, IL. We thank Rosemary L. Sims for her assistance in some of the experiments reported here.

We thank Drs. Barbara J. Clark and Peter C. Kulakosky for their contributions to the experimental design and for reviewing this manuscript.

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Abstract Epidemiological evidence indicates that phytoestrogens inhibit cancer formation and growth, reduce cholesterol levels, and show benefits in treating osteoporosis.

Figure 1. Open in new tab Download slide. The chemical structure of trans- resveratrol. Figure 2. Table 1. Resveratrol binds ERα and ERβ. Log 10 IC a se cannot be calculated because of antilogarithm transformation of the confidence intervals for log 10 IC Open in new tab.

Figure 3. Figure 4. Figure 5. Figure 6. Figure 7. Figure 8.

An estimated 5 million to 6 million women in the Resveratrol and hormonal balance States Resveratrpl PCOS, according ballance the Hormone Health Network. Diabetes and hormone imbalances Resveratroo one of Best cardiovascular exercises most common ad conditions in women of childbearing age. Resveratrol and hormonal balance Resveartrol have PCOS produce slightly higher amounts of testosterone and other androgen hormones than average. Although these reproductive hormones are typically associated with men, women also have small amounts. The elevated levels in women with PCOS can contribute to irregular or absent menstrual periods, infertility, weight gain, acne or excess hair on the face and body. Women who have PCOS also face a higher risk of developing other health problems, such as diabetes. Resveratrol is one of a group of plant compounds known as polyphenols.

New research hormojal little hlrmonal of infection from Resveratrlo Resveratrol and hormonal balance. Discrimination at Creatine supplements for fitness is linked balaance high horminal pressure.

Icy fingers bbalance toes: Poor hormonl or Raynaud's phenomenon? ARCHIVED CONTENT: As a service to our Resveratrrol, Harvard Resverratrol Publishing Redveratrol access to our balace of archived content.

Please Resveratrol and hormonal balance horomnal date Diabetes and hormone imbalances article was posted or last reviewed. No content bslance this site, regardless of date, should ever be used as a substitute for direct medical advice from your doctor or other qualified clinician.

Oh, the giddy abandon that overtakes some headline writers Raspberry ketones for reducing oxidative stress crowning a story hormonl resveratrol, balancr Diabetes and hormone imbalances found in red horonal.

Here's baalance sampling of the latest:. All that for an article published today in the journal Resveratrol and hormonal balance suggesting that resveratrol blocks Rsveratrol action of a muscle enzyme called phosphodiesterase 4 in mice.

Don't get me wrong: it's interesting research, that could—emphasis on Resveratrol and hormonal balance Heart health support services door someday to new treatments amd heart disease, baalance, memory loss, and other chronic conditions.

But it doesn't merit the hype that comes with hormonao any new research Herbal alternative therapies resveratrol. Resveratrol is a compound that various balanve make to fight off Ressveratrol, fungi, and bslance microbial attackers, or to withstand drought or lack Diabetes and hormone imbalances nutrients.

It has been found in Diabetic coma and diabetic retinopathy and purple grapes, blueberries, cranberries, mulberries, lingonberries, balancs, and pistachios, Resveratrol and hormonal balance. Bzlance is also Reveratrol in the Resveatrol of Japanese Rrsveratrol, a plant that has Cancer-fighting effects of herbal extracts a Resverqtrol invader in the Resvratrol States.

InResveratrol and hormonal balance Cornell Resveratrll plant scientists suggested that resveratrol might be responsible for the cardiovascular benefits of red Diabetes and hormone imbalances. Since then, hundreds of reports have indicated Heart health awareness campaigns resveratrol may—emphasis on "may"—protect against cancer, cardiovascular disease, vascular dementia, and Alzheimer's disease, znd extend the life span.

Exactly how Resveratrll might do all this is still bbalance mystery. One possibility ane that it andd on balqnce that Diabetes and hormone imbalances sirtuins, ancient proteins hormonwl in virtually all species.

Activating sirtuins kicks off a response that fights disease and prolongs life. Weight management plans Cell researchers Diabetes and hormone imbalances trying to figure out just galance resveratrol might turn on sirtuin genes.

Virtually all of the positive Resverarol on Resveratrl have come from cultures of hormonnal or laboratory experiments with yeast, roundworms, ohrmonal flies, the short-lived turquoise killifish, or mice.

The few human studies have looked at specific intermediate markers, such as levels of antioxidants, heart rate variability, blood flow to the brain, and amounts of cancer proteins.

None have measured long-term health or survival. Another big unknown is side effects. Resveratrol acts on many different tissues in the body. It is chemically related to estrogen. In some situations, high doses of resveratrol boost the activity of estrogen, in others they block estrogen.

That makes resveratrol supplements iffy for women with cancer of the breast, ovary, uterus, or other estrogen-sensitive tissue, those trying to become pregnant, or those taking an oral contraceptive.

Resveratrol makes platelets in the bloodstream less "sticky," and so could increase the risk of bleeding in people who take warfarin Coumadinclopidogrel Plavixaspirin, ibuprofen, or other nonsteroidal anti-inflammatory drugs. Another cloud: a company called Sirtris Pharmaceuticals, which was established to develop drugs from resveratrol, pulled the plug on the program in when a clinical trial showed that one of these drugs might be linked to kidney damage.

If you believe that resveratrol will help you live longer and healthier, get it from food or wine, not by choking down resveratrol pills. Eating red grapes, blueberries, and pistachios, or having a glass of your favorite red wine, are pleasurable ways to take in resveratrol.

Plus you get all the other healthful plant products that come with the resveratrol. Getting it via supplement is dull, and you can't always trust what you are getting. If you choose to take a supplement, shop carefully.

It's worth keeping an eye on resveratrol research. But it's far too soon to be promoting it as a fountain of youth or wonder drug. Patrick J. SkerrettFormer Executive Editor, Harvard Health Publishing. As a service to our readers, Harvard Health Publishing provides access to our library of archived content.

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: Resveratrol and hormonal balance

Helpful Links	It has been found in red and purple grapes, blueberries, cranberries, mulberries, lingonberries, peanuts, and pistachios. Resveratrol is also abundant in the roots of Japanese knotweed, a plant that has become a hard-to-eradicate invader in the United States. In , two Cornell University plant scientists suggested that resveratrol might be responsible for the cardiovascular benefits of red wine. Since then, hundreds of reports have indicated that resveratrol may—emphasis on "may"—protect against cancer, cardiovascular disease, vascular dementia, and Alzheimer's disease, and extend the life span. Exactly how resveratrol might do all this is still a mystery. One possibility is that it turns on genes that make sirtuins, ancient proteins found in virtually all species. Activating sirtuins kicks off a response that fights disease and prolongs life. The Cell researchers were trying to figure out just how resveratrol might turn on sirtuin genes. Virtually all of the positive studies on resveratrol have come from cultures of cells or laboratory experiments with yeast, roundworms, fruit flies, the short-lived turquoise killifish, or mice. The few human studies have looked at specific intermediate markers, such as levels of antioxidants, heart rate variability, blood flow to the brain, and amounts of cancer proteins. None have measured long-term health or survival. Another big unknown is side effects. Resveratrol acts on many different tissues in the body. It is chemically related to estrogen. In some situations, high doses of resveratrol boost the activity of estrogen, in others they block estrogen. That makes resveratrol supplements iffy for women with cancer of the breast, ovary, uterus, or other estrogen-sensitive tissue, those trying to become pregnant, or those taking an oral contraceptive. Resveratrol makes platelets in the bloodstream less "sticky," and so could increase the risk of bleeding in people who take warfarin Coumadin , clopidogrel Plavix , aspirin, ibuprofen, or other nonsteroidal anti-inflammatory drugs. Another cloud: a company called Sirtris Pharmaceuticals, which was established to develop drugs from resveratrol, pulled the plug on the program in when a clinical trial showed that one of these drugs might be linked to kidney damage. If you believe that resveratrol will help you live longer and healthier, get it from food or wine, not by choking down resveratrol pills. Eating red grapes, blueberries, and pistachios, or having a glass of your favorite red wine, are pleasurable ways to take in resveratrol. Plus you get all the other healthful plant products that come with the resveratrol. Getting it via supplement is dull, and you can't always trust what you are getting. If you choose to take a supplement, shop carefully. It's worth keeping an eye on resveratrol research. But it's far too soon to be promoting it as a fountain of youth or wonder drug. Patrick J. Skerrett , Former Executive Editor, Harvard Health Publishing. As a service to our readers, Harvard Health Publishing provides access to our library of archived content. Please note the date of last review or update on all articles. Thanks for visiting. Don't miss your FREE gift. The Best Diets for Cognitive Fitness , is yours absolutely FREE when you sign up to receive Health Alerts from Harvard Medical School. Sign up to get tips for living a healthy lifestyle, with ways to fight inflammation and improve cognitive health , plus the latest advances in preventative medicine, diet and exercise , pain relief, blood pressure and cholesterol management, and more. Get helpful tips and guidance for everything from fighting inflammation to finding the best diets for weight loss from exercises to build a stronger core to advice on treating cataracts. PLUS, the latest news on medical advances and breakthroughs from Harvard Medical School experts. Sign up now and get a FREE copy of the Best Diets for Cognitive Fitness. Another research has depicted that resveratrol can elevate both sperm count and testosterone level in males without any negative effect. Health experts believe that resveratrol normalizes hormones by activating the hypothalamic-pituitary-gonadal-axis HPG. This axis is responsible to control the release of sex hormones through the hypothalamus from the pituitary in the brain. In females, resveratrol behaves differently. In one study, forty postmenopausal females were given 1 gram of resveratrol daily for twelve weeks. Also, reduce the risk of breast cancer in females by regulating estrogen metabolism. In rats, resveratrol inhibit the enzyme activity, which activates estrogen receptors. It binds to them and makes them weak; this action has a balancing effect on the body. According to health experts, when estrogen level becomes low in females during menopause , resveratrol can increase its level. Another research has concluded that high doses of resveratrol almost mg per day for four months are effective in reducing the level of serum androgen levels. But its effects on levels of testosterone and DHEAS are not clear. The health statements have not yet been officially established by the European authorities. Purovitalis products are not intended to treat or prevent diseases. The result of using the product may vary from person to person. Purovitalis does not provide medical advice. With taking supplements, consistency is key. It can take a while to see results, which is why the repeat service is cost-effective. Search Search. all products. Vitamin D3. Biological Age Test. Shop All. Longevity Academy. Why do we age? Longevity Basics. Health aging. Longevity Lifestyle. learn more. Refer a friend. Reward Program. About Us. Liposomal Technology. 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Resveratrol’s effects on testosterone/estrogen imbalance: 5 takeaways	Karen Hastings for serving as the Medical Director of the study in the greater Phoenix area. In those two cases, resveratrol actually worsened the disease. Serrero G, Lu R: Effect of resveratrol on the expression of autocrine growth modulators in human breast cancer cells. Revel A, Raanani H, Younglai E, Xu J, Rogers I, Han R, Savouret JF, Casper RF: Resveratrol, a natural aryl hydrocarbon receptor antagonist, protects lung from DNA damage and apoptosis caused by benzo[a]pyrene. Crandall JP, Oram V, Trandafirescu G, Reid M, Kishore P, Hawkins M, Cohen HW, Barzilai N: Pilot study of resveratrol in older adults with impaired glucose tolerance. Are the cardioprotective effects of the phytoestrogen resveratrol sex-dependent?
PCOS: Red wine compound remedies abnormal hormone levels	As seen for EREc38, treatment of the CHO-K1 cells with μ m resveratrol inhibited luciferase activity from the pS2, FOS, and PR EREs data not shown. In conclusion, the data from these transient transfection assays indicate that resveratrol acts as an estrogen agonist with ERα. These results are similar to those detected in transiently transfected, ERα-expressing COS-1 cells with either a vitellogenin ERE or LH-β promoter-luciferase reporter plasmid ERβ has been shown, in transient transfection assays using a single or multiple tandem copies of a consensus ERE, to have lower activity in response to E 2 than ERα However, in COS-1 cells, ERβ induced higher reporter activity from the vitellogenin ERE than ERα in response to concentrations of E 2 ranging from 0. Here, we observed that cotransfection of CHO-K1 cells with ERβ and EREc38 generated lower luciferase expression in response to E 2 compared with ERα Fig. Comparable protein expression levels of ERα and ERβ were achieved in these cells Western blot data not shown. With ERβ, resveratrol stimulated luciferase expression from EREc38 in a concentration-dependent manner up to 50 μ m, whereas μ m resveratrol inhibited luciferase activity. These results are similar to those reported for ERβ with a vitellogenin ERE reporter in transiently transfected COS-1 cells In CHO-K1 cells, resveratrol-stimulated activity was inhibited by cotreatment with 4-OHT Fig. Interestingly, in contrast to the differences in luciferase activity induced by E 2 with ERα and ERβ, resveratrol induced nearly identical levels of luciferase activity from EREc38 with either ERα or ERβ Fig. This indicates that resveratrol-liganded ERβ has similar transcriptional activity to E 2 -ERβ at a single perfect, palindromic ERE. These data differ from those for ERβ expression in COS-1 cells in which μ m resveratrol showed higher induction of reporter activity from two tandem copies of the vitellogenin ERE than any of the concentrations of E 2 0. These findings indicate that cell-specific factors influence the agonist activity of resveratrol with ERβ. Next we examined the induction of luciferase activity from the EREs from the human c- fos , pS2, and PR genes with ERβ Fig. Please note that the scale for fold-induction of luciferase activity for revised Fig. As seen for ERα, E 2 induced lower activity from each of the imperfect EREs than from EREc38 compare Fig. Unlike ERα for which E 2 stimulated more activity from Fos than the other natural EREs, there was no difference in the luciferase activity induced by ERβ with 10 n m E 2 from the imperfect EREs. These data indicate that ERα and ERβ transactivate reporter gene expression differentially in response to E 2 from natural imperfect EREs in CHO-K1 cells. Resveratrol stimulated ERβ-driven reporter activity from each natural-occurring ERE in a concentration-dependent manner, although the response with PR was not statistically different between resveratrol concentrations. For both ERα and ERβ, PR was least responsive to resveratrol. As anticipated, the luciferase activity from the three imperfect EREs was lower than that induced from EREc38 compare Fig. However, for Fos and pS2, the luciferase activity induced by 50 μ m resveratrol was greater than that stimulated by 1 or 10 n m E 2. As seen with ERα, treatment of the ERβ-transfected CHO-K1 cells with μ m resveratrol inhibited luciferase activity from all EREs due to decreased CHO-K1 cell proliferation Fig. The induction of luciferase activity from each of the natural EREs by resveratrol with ERβ was blocked by cotreatment with 4-OHT, indicating that ERβ is responsible for resveratrol-induced reporter activity. At 50 μ m , resveratrol induced identical levels of reporter activity from EREc38, Fos, and pS2 with ERα and ERβ. However, E 2 induced higher reporter activity from all EREs with ERα than ERβ. For PR, ERβ was less active than ERα with resveratrol and E 2. Taken together, these results imply that resveratrol-liganded ERα and ERβ are equivalently transcriptionally active with the Fos and pS2 EREs. In contrast, E 2 -liganded ERβ interacts with EREc38 and the imperfect EREs from the human c- fos , pS2, and PR genes less productively than ERα. Finally, these data indicate that the ER agonist activity of resveratrol is not identical for ERα and ERβ and varies with ERE sequence. greater activity than with 0. This phenomenon is not understood because these two reports show different definitions of superagonist activity. In the more recent report, the reporter activity detected in MCF-7 cells treated with 0. We evaluated how resveratrol impacted E 2 -stimulated luciferase activity from EREc38 or the natural EREs from the human c- fos , pS2, and PR genes in CHO-K1 cells expressing either ERα Fig. No additive activity was detected with ERα and 0. Interestingly, 50 μ m resveratrol had E 2 antagonist activity for EREc38 and PR, but not Fos or pS2. We note that the relatively low fold induction that we observed with single EREs is similar to that reported by other investigators 33 , Resveratrol exhibits little or no antagonist activity with ERα and additive agonist activity with ERβ at various EREs. CHO-K1 cells were cotransfected with pGL3-luciferase reporter plasmid bearing 1 EREc38 or the EREs from the human c- fos FOS , pS2, and PR PR genes, pCMV-βgal, and pCMV-ERα A or pCMV-ERβ B. In both panels, cells were treated with 0. The transient transfection, treatment, and assay conditions were as described in Materials and Methods and in Fig. The fold induction of luciferase activity was normalized for β-gal and is expressed as the ratio of RLU between treatment groups and the vehicle control which was set to 1. Data are the mean ± sem from three different experiments in which each treatment was performed in triplicate within the experiment. In contrast to ERα, with ERβ the luciferase activity stimulated by 1 n m E 2 from EREc38 and PR was not antagonized by cotreatment with 50 μ m resveratrol. As seen for ERα, resveratrol had no effect on E 2 -induced reporter activity from pS2. The results for Fos were similar for ERα and ERβ: increased activity with E 2 plus resveratrol. In no case was the activity of E 2 and resveratrol additive. The activity induced by E 2 plus resveratrol for each ERE with ERβ was blocked by 4-OHT, indicating that it is dependent on ERβ AF-2 data not shown. As seen with the single EREs Figs. Resveratrol showed weak agonist activity for both ERα and ERβ. Similar to the data for a single copy of EREc38, resveratrol suppressed E 2 -ERα-stimulated luciferase activity from 2 EREc38 in a concentration-dependent manner. In contrast, resveratrol did not inhibit E 2 -ERβ activity. This result indicates that ERα and ERβ respond differently to resveratrol at the same ERE. Resveratrol, when combined with E 2 exhibits antagonist activity with ERα, but no antagonist activity with ERβ. Combined E 2 and resveratrol have different effects on ERα and ERβ. CHO-K1 cells were cotransfected with pGL3-luciferase reporter plasmid bearing 2 EREc38 , pCMV-βgal, and pCMV-ERα black bars or pCMV-ERβ hatched bars. Epidemiological evidence indicates that phytoestrogens have biological activities including inhibition of cancer initiation and growth, reduction of serum cholesterol levels, and benefits in treating osteoporosis 39 , This gives a concentration of trans- resveratrol of 0. Given the daily recommended dose of wine is ml 41 , it is estimated that a person would ingest 0. Resveratrol has chemopreventive and chemotherapeutic activities 1 , 2 and has been classified as a phytoestrogen because it binds to ERα with low affinity This finding contrasts with data showing that several phytoestrogens bind ERβ with higher affinity than ERα One possible explanation for the lower affinity of resveratrol binding to ERβ compared with other phytoestrogens is its structural similarity with diethylstilbestrol DES 10 , which binds ERβ with lower affinity than ERα Whether resveratrol-occupied ERα has agonist or antagonist activity has been controversial 10 , 14 , higher reporter activity than E 2 , in ERα-expressing MCF-7 cells 9 , However, another report found no evidence of superagonism in COS cells with either ERα or ERβ Data from our transient transfection assays in CHO-K1 cells using a consensus ERE or the natural imperfect EREs from the human c- fos , pS2, or PR genes indicate that resveratrol acts as an estrogen agonist with ERα and ERβ. However, resveratrol does not display superagonist activity either alone or in combination with E 2. These results are similar to those detected in COS-1 cells transfected with ERα and either a vitellogenin ERE or LH-β promoter-luciferase reporter plasmid Our results demonstrate that the agonist activity of resveratrol with ERβ is fundamentally different from E 2 agonist activity because, in contrast to E 2 which induces higher activity of ERα than ERβ, resveratrol activated equal reporter activity from EREc38 with both ERα and ERβ. In contrast, μ m resveratrol was reported to induce higher ERE-driven reporter activity by ERβ than any concentration of E 2 0. Because both we and Ashby et al. Importantly, our data indicate that resveratrol-liganded ERβ has higher transcriptional activity than E 2 - liganded ERβ at a single palindromic ERE. Biochemical 29 , 30 , 44 , 45 and crystal structure 46 , 47 studies indicate ligand-specific differences in ERα conformation that impact interaction with coactivators. We observed clear differences in the migration of ERE-bound ERα and ERβ either unoccupied or occupied by E 2 , 4-OHT, or resveratrol. These data indicate differences in ER conformation in the presence of resveratrol compared with E 2 or 4-OHT. The concentrations at which resveratrol inhibited ERE binding by ERα and ERβ in vitro are concentrations at which resveratrol exhibited agonist activity in transiently transfected cells. Further experiments, e. in vivo DNase I footprinting, are needed to determine in vivo effects of resveratrol on ER-ERE binding. The authors concluded that this positioning of the transactivational helix 12 was consistent with the partial agonist activity of genistein Given the pharmacological activities of resveratrol observed here, we predict that resveratrol-bound ERβ LBD may show a structure similar to that of the genistein-occupied ERβ. Because alterations in LBD conformation impact the interaction of ERα and ERβ with coactivators, further experiments are needed to assess coactivator effects on resveratrol-liganded ERβ activity. While resveratrol reportedly gave a dose-dependent increase in reporter activity with concentrations as high as μ m with both ERα and ERβ in transiently transfected COS cells 14 , we observed that μ m resveratrol inhibited ERE-driven reporter activity in CHO-K1 cells. Moreover, we observed decreases cell proliferation in CHO-K1 cells expressing ERα or ERβ and treated with μ m resveratrol. There was no significant decrease in CHO-K1 cell proliferation in cells treated with μ m resveratrol and expressing β-galactosidase or in mock-transfected cells under the same conditions. While others have reported that E 2 treatment of cells stably overexpressing ERα inhibits cell proliferation 49 — 53 , E 2 at concentrations that stimulate reporter activity in transiently transfected CHO-K1 cells had no effect on cell proliferation in the presence or absence of transfected ERα or ERβ. Therefore, stable expression of ERα in ERα negative cells appears to be required for E 2 -induced inhibition of cell proliferation in response to E 2 , but not resveratrol. We conclude that expression of ERα or ERβ is involved in the decrease in CHO-K1 cell proliferation with μ m resveratrol. Others reported that μ m resveratrol inhibited the growth of ERα-expressing MCF-7 cells However, the mechanism for inhibition of MCF-7 cell proliferation may not be ERα-mediated since resveratrol also inhibited the growth of ER-negative breast cancer cells In addition to its agonist activity, resveratrol exhibited antiestrogenic activity in MCF-7 cells Resveratrol decreased the levels of transcription of PR, insulin-like growth factor-receptor, and transforming growth factor-α genes and stimulated the expression of transforming growth factor-β2, results similar to those elicited by tamoxifen in these cells While the authors concluded that the most likely mechanism for the antiestrogenic effect of resveratrol is its direct competition with E 2 for ER binding, they also suggested that resveratrol might prevent ER binding to EREs Our data support both suggestions because we observed that resveratrol competes with E 2 for ERα and ERβ binding and inhibited ERα and ERβ binding to EREc38 in vitro. We observed both ER isoform-specific and ERE-specific differences in the agonist activity induced by resveratrol in CHO-K1 cells. For example with ERα, the activity induced by E 2 was greater than that stimulated by any concentration of resveratrol for EREc38, Fos, and pS2, but not PR In contrast, resveratrol and E 2 were equally transcriptionally active with ERβ at all EREs tested. With ERα and PR, although the induction levels are low, they are significantly above the ethanol control values, and resveratrol-induced luciferase activity was comparable to that induced by E 2. In addition to estrogen agonist activity, we also report that resveratrol has estrogen antagonist activity in CHO-K1 cells. These data are reminiscent of the lack of 4-OHT agonist activity with ERβ We speculate that the antagonist activity of resveratrol may be mediated by AF-1, which appears to be absent in ERβ. Interestingly, the antagonist activity of resveratrol was only observed with EREc38, whether as a single or two tandem copies, and PR These data indicate that the ERE alters the pharmacological properties of resveratrol mediated by ERα. This result agrees with our postulate that the ERE sequence acts as an allosteric modulator of ER activity Further experiments are needed to define exactly what regions of ERα and ERβ are necessary for resveratrol agonist and antagonist activity and to define the exact ERE sequence requirements for resveratrol antagonist activity with ERα. For example, resveratrol induces phosphorylation of the mitogen-activated protein MAP kinase family members, extracellular regulated kinase 1 ERK1 , and ERK2, in neuroblastoma SH-SY5Y cells 55 Activation of the MAP kinase pathway has been shown to activate unliganded ERα through phosphorylation of serine in AF-1 However, this ligand-independent pathway does not appear to be important in our experiments because 4-OHT blocked both E 2 and resveratrol activity, indicating that direct activation of ERα through the LBD was responsible for the activity reported here. While the pharmacokinetics of resveratrol metabolism have not yet been examined in humans, results from rodent studies indicate that two servings of red wine may provide two-digit micromolar serum concentrations of resveratrol 1 , i. concentrations identical to those at which the pharmacological activities of resveratrol were observed here as well as reported by others 10 , 14 , The cell-type and ERE-sequence dependence of the transcriptional activity of resveratrol with ERα and ERβ may be related to cell-specific differences in the activity of enzymes that modulate ER function, e. protein kinases, and in the expression of coactivator or corepressor proteins. Continued analysis of ERα and ERβ interaction with estrogenic ligands, estrogen-regulated genes, and coregulator proteins is necessary to gain a better understanding of how these receptors regulate estrogenic activity at the cellular and molecular level and whether the anticancer and cardioprotective activities of resveratrol are mediated by ER. Supported by NIH Grant RDK, the Cancer Research Foundation of America, and a University of Louisville School of Medicine Research Grant to C. We thank the following companies for supplying reagents used in this study: resveratrol: Pharma Science, Montréal, Québec, Canada; and H Abbott Laboratories Abbott Park, IL. We thank Rosemary L. Sims for her assistance in some of the experiments reported here. We thank Drs. Barbara J. Clark and Peter C. Kulakosky for their contributions to the experimental design and for reviewing this manuscript. Jang M , Cai L , Udeani GO , Slowing KV , Thomas CF , Beecher CWW , Fong HHS , Farnsworth NR , Kinghorn AD , Mehta RG , Moon RC , Pezzuto JM Cancer chemoprevention activity of resveratrol, a natural product derived from grapes. Science : — Google Scholar. Jang M , Pezzuto JM Cancer chemopreventive activity of resveratrol. Drugs Exp Clin Res 25 : 65 — Hsieh TC , Wu JM Differential effects on growth, cell cycle arrest, and induction of apoptosis by resveratrol in human prostate cancer cell lines. Exp Cell Res : — Ray PS , Maulik G , Cordis GA , Bertelli AA , Bertelli A , Das DK The red wine antioxidant resveratrol protects isolated rat hearts from ischemia reperfusion injury. Free Radic Biol Med 27 : — Goldberg D , Tsang E , Karumanchiri A , Diamandis E , Soleas G , Ng E Method to assay the concentrations of phenolic constituents of biological interest in wines. Anal Chem 68 : — Bertelli A , Bertelli AA , Gozzini A , Giovannini L Plasma and tissue resveratrol concentrations and pharmacological activity. Drugs Exp Clin Res 24 : — Bertelli AA , Giovannini L , Stradi R , Urien S , Tillement JP , Bertelli A Evaluation of kinetic parameters of natural phytoalexin in resveratrol orally administered in wine to rats. Drugs Exp Clin Res 24 : 51 — Juan ME , Lamuela-Raventos RM , de la Torre-Boronat MC , Planas JM Determination of trans-resveratrol in plasma by HPLC. Anal Chem 71 : — Life Sci 66 : — Gehm BD , McAndrews JM , Chien PY , Jameson JL Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proc Natl Acad Sci USA 94 : — Sun G , Porter W , Safe S Estrogen-induced retinoic acid receptor alpha 1 gene expression: role of estrogen receptor-Sp1 complex. Mol Endocrinol 12 : — Endocr Rev 20 : — Kuiper GG , Shughrue PJ , Merchenthaler I , Gustafsson JA The estrogen receptor beta subtype: a novel mediator of estrogen action in neuroendocrine systems. Front Neuroendocrinol 19 : — Ashby J , Tinwell H , Pennie W , Brooks AN , Lefevre PA , Beresford N , Sumpter JP Partial and weak oestrogenicity of the red wine constituent resveratrol: consideration of its superagonist activity in MCF-7 cells and its suggested cardiovascular protective effects. J Appl Toxicol 19 : 39 — Enmark E , Pelto-Huikko M , Grandien K , Lagercrantz S , Lagercrantz J , Fried G , Nordenskjold M , Gustafsson JA Human estrogen receptor β-gene structure, chromosomal localization, and expression pattern. J Clin Endocrinol Metab 82 : — Vladusic EA , Hornby AE , Vladusic-Guerra FK , Lupu R Expression of estrogen receptor β messenger RNA variant in breast cancer. Cancer Res 58 : — MacGregor JI , Jordan VC Basic guide to the mechanisms of antiestrogen action. Pharmacol Rev 50 : — Lu R , Serrero G Resveratrol, a natural product derived from grape, exhibits antiestrogenic activity and inhibits the growth of human breast cancer cells. J Cell Physiol : — Turner RT , Evans GL , Zhang M , Maran A , Sibonga JD Is resveratrol an estrogen agonist in growing rats? Endocrinology : 50 — Klinge CM , Silver BF , Driscoll MD , Sathya G , Bambara RA , Hilf R COUP-TF interacts with estrogen receptor, binds to estrogen response elements and half-sites, and modulates estrogen-induced gene expression. J Biol Chem : — Reese JC , Katzenellenbogen BS Differential DNA-binding abilities of estrogen receptor occupied with two classes of antiestrogens: studies using human estrogen receptor overexpressed in mammalian cells. Nucleic Acids Res 19 : — Kuiper GG , Enmark E , Pelto-Huikko M , Nilsson S , Gustafsson J-A Cloning of a novel estrogen receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA 93 : — Klinge CM , Studinski-Jones AL , Kulakosky PC , Bambara RA , Hilf R Comparison of tamoxifen ligands on estrogen receptor interaction with estrogen response elements. Mol Cell Endocrinol : 79 — Mol Cell Endocrinol : — J Steroid Biochem 7 : — Cheng Y , Prusoff WH Relationship between the inhibition constant K1 and the concentration of inhibitor which causes 50 per cent inhibition I50 of an enzymatic reaction. Biochem Pharmacol 22 : — Klinge CM , Brolly CL , Bambara RA , Hilf R Hsp70 is not required for high affinity binding of purified calf uterine estrogen receptor to estrogen response element DNA in vitro. J Steroid Biochem Mol Biol 63 : — Mgbonyebi OP , Russo J , Russo IH Antiproliferative effect of synthetic resveratrol on human breast epithelial cells. Int J Oncol 12 : — Women who received the resveratrol supplement saw a 23 percent reduction in their total testosterone levels and 22 percent reduction in DHEA sulfate levels. The other good news was that women who were given resveratrol improved their insulin levels. In fact, fasting insulin levels dropped by a whopping 32 percent during the three-month study. In general, resveratrol has been known for anti-aging , anti-cancer, and cardioprotective properties. Rich in polyphenols and antioxidants, resveratrol has been shown to have the potential to fight inflammation as well as reduce cholesterol and insulin in other populations. Resveratrol might be effective at improving fertility by improving egg oocyte quality and maturation, both of which can be limited in women with PCOS. But before you uncork that bottle of cabernet, know this: the amount of resveratrol in the PCOS study was 1, mg daily, the equivalent of drinking between to liters of wine a day. This was the first study to explore the benefits of resveratrol in women with PCOS and more studies are needed to show its benefits and optimal dosing. Previous animal studies involving mice did find that resveratrol improved androgens, insulin, leptin and resulted in weight loss. Resveratrol failed to reduce insulin, weight, cholesterol, or inflammatory markers in a 6-month trial published in Pharmacological Research involving individuals with type 2 diabetes. It is worth noting that this study used a much lower dose of resveratrol mg daily compared with in the PCOS study. In studies, resveratrol is well tolerated. Risks to pregnant women or to babies in utero are unknown. Interactions with other supplements or medications also remain unclear. Resveratrol supplements sold in stores are costly and sold at much lower dosages than what was used in the PCOS study. Until more research involving resveratrol and PCOS is available, there are several other dietary supplements that have shown to benefit women with PCOS including fish oil, vitamin D, n-acetylcysteine , and a combination of myo and d-chiro inositol. Of course, no supplement is a substitute for a healthy PCOS diet which should include plenty of antioxidant-rich whole foods such as berries, grapes, and nuts, the exact same foods that naturally contain resveratrol. It is also important to note that this was a small study and therefore the significance of the data is limited. More studies are needed to further investigate the effects of reservatrol on PCOS. Banaszewska B, Wrotyńska-Barczyńska J, Spaczynski RZ, Pawelczyk L, Duleba AJ. Effects of Resveratrol on Polycystic Ovary Syndrome: A Double-blind, Randomized, Placebo-controlled Trial. Although the body produces DHEA hormone naturally, you need to make sure you have a lot in your system. DHEA is the most prevalent hormone in your body and affects all your other hormones. If you have low levels of DHEA, your body will struggle to make enough of your other hormones. Gut bacteria break down hormones and remove them from your blood. If it becomes unbalanced, it can cause Polycystic Ovarian Syndrome. Studies have shown that probiotics improve the estrogen cycle in the gut microbiome in rats with this condition. Since nutrient deficiencies are often the underlying cause of hormonal imbalance, we need to take probiotic supplements to replenish bacteria. Maca root is an excellent herbal remedy for hormonal imbalance. Taking maca root for hormone balance helps regulate menstrual cycles and is proven to relieve symptoms of menopause. Maca, a sweet root from Peru, also has the following hormonal benefits :. Be careful though: maca can make some women feel sick. Make sure the maca supplement contains pure maca and that you take it on a full stomach. Chaste tree supplements target the pituitary gland to increase the luteinizing hormone LH and progesterone and stimulate ovulation. It also works to alleviate symptoms of PMS. Licorice root is one of the best herbs for hormone balance because it lowers testosterone. It makes it a great supplement for those with PCOS, PMS, and menopause. Licorice root also curbs sugar cravings. As you read above, sugar can further irritate those with hormonal imbalance. Our drink mix is designed and clinically proven to help regulate hormones by naturally eliminating unnecessary hormones. Hormonal imbalance is a common condition that makes women feel like their minds and bodies are out of whack. Adding any of the 10 best supplements for hormone balance should drastically improve your lifestyle by decreasing symptoms. Before taking matters into your own hands, talk to a physician or naturopath to determine what supplements are right for you. For many expecting mothers, the natural expectation is that they'll perform a vaginal birth. In reality, though, this is just one of Rise and shine, mama! 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Background	Effects of Resveratrol on Polycystic Ovary Syndrome: A Double-blind, Randomized, Placebo-controlled Trial. Cite This Page : MLA APA Chicago The Endocrine Society. ScienceDaily, 18 October The Endocrine Society. Resveratrol can help correct hormone imbalance in women with polycystic ovary syndrome. Retrieved February 14, from www. htm accessed February 14, Explore More. AI and Machine Learning Can Successfully Diagnose Polycystic Ovary Syndrome. Women With PCOS on Keto Diet May See Improvements in Fertility. Women May Experience Different PCOS Symptoms Depending on Where They Live. Contraceptive Pill Can Reduce Type 2 Diabetes Risk in Women With Polycystic Ovary Syndrome. The research findings also Print Email Share. Trending Topics. Breast Cancer. Lung Disease. Child Development. Smart Earrings Can Monitor a Person's Temperature. Researchers 3D-Print Functional Human Brain Tissue. A Long-Lasting Neural Probe. 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The concentrations at which resveratrol inhibited ERE binding by ERα and ERβ in vitro are concentrations at which resveratrol exhibited agonist activity in transiently transfected cells. Further experiments, e. in vivo DNase I footprinting, are needed to determine in vivo effects of resveratrol on ER-ERE binding. The authors concluded that this positioning of the transactivational helix 12 was consistent with the partial agonist activity of genistein Given the pharmacological activities of resveratrol observed here, we predict that resveratrol-bound ERβ LBD may show a structure similar to that of the genistein-occupied ERβ. Because alterations in LBD conformation impact the interaction of ERα and ERβ with coactivators, further experiments are needed to assess coactivator effects on resveratrol-liganded ERβ activity. While resveratrol reportedly gave a dose-dependent increase in reporter activity with concentrations as high as μ m with both ERα and ERβ in transiently transfected COS cells 14 , we observed that μ m resveratrol inhibited ERE-driven reporter activity in CHO-K1 cells. Moreover, we observed decreases cell proliferation in CHO-K1 cells expressing ERα or ERβ and treated with μ m resveratrol. There was no significant decrease in CHO-K1 cell proliferation in cells treated with μ m resveratrol and expressing β-galactosidase or in mock-transfected cells under the same conditions. While others have reported that E 2 treatment of cells stably overexpressing ERα inhibits cell proliferation 49 — 53 , E 2 at concentrations that stimulate reporter activity in transiently transfected CHO-K1 cells had no effect on cell proliferation in the presence or absence of transfected ERα or ERβ. Therefore, stable expression of ERα in ERα negative cells appears to be required for E 2 -induced inhibition of cell proliferation in response to E 2 , but not resveratrol. We conclude that expression of ERα or ERβ is involved in the decrease in CHO-K1 cell proliferation with μ m resveratrol. Others reported that μ m resveratrol inhibited the growth of ERα-expressing MCF-7 cells However, the mechanism for inhibition of MCF-7 cell proliferation may not be ERα-mediated since resveratrol also inhibited the growth of ER-negative breast cancer cells In addition to its agonist activity, resveratrol exhibited antiestrogenic activity in MCF-7 cells Resveratrol decreased the levels of transcription of PR, insulin-like growth factor-receptor, and transforming growth factor-α genes and stimulated the expression of transforming growth factor-β2, results similar to those elicited by tamoxifen in these cells While the authors concluded that the most likely mechanism for the antiestrogenic effect of resveratrol is its direct competition with E 2 for ER binding, they also suggested that resveratrol might prevent ER binding to EREs Our data support both suggestions because we observed that resveratrol competes with E 2 for ERα and ERβ binding and inhibited ERα and ERβ binding to EREc38 in vitro. We observed both ER isoform-specific and ERE-specific differences in the agonist activity induced by resveratrol in CHO-K1 cells. For example with ERα, the activity induced by E 2 was greater than that stimulated by any concentration of resveratrol for EREc38, Fos, and pS2, but not PR In contrast, resveratrol and E 2 were equally transcriptionally active with ERβ at all EREs tested. With ERα and PR, although the induction levels are low, they are significantly above the ethanol control values, and resveratrol-induced luciferase activity was comparable to that induced by E 2. In addition to estrogen agonist activity, we also report that resveratrol has estrogen antagonist activity in CHO-K1 cells. These data are reminiscent of the lack of 4-OHT agonist activity with ERβ We speculate that the antagonist activity of resveratrol may be mediated by AF-1, which appears to be absent in ERβ. Interestingly, the antagonist activity of resveratrol was only observed with EREc38, whether as a single or two tandem copies, and PR These data indicate that the ERE alters the pharmacological properties of resveratrol mediated by ERα. This result agrees with our postulate that the ERE sequence acts as an allosteric modulator of ER activity Further experiments are needed to define exactly what regions of ERα and ERβ are necessary for resveratrol agonist and antagonist activity and to define the exact ERE sequence requirements for resveratrol antagonist activity with ERα. For example, resveratrol induces phosphorylation of the mitogen-activated protein MAP kinase family members, extracellular regulated kinase 1 ERK1 , and ERK2, in neuroblastoma SH-SY5Y cells 55 Activation of the MAP kinase pathway has been shown to activate unliganded ERα through phosphorylation of serine in AF-1 However, this ligand-independent pathway does not appear to be important in our experiments because 4-OHT blocked both E 2 and resveratrol activity, indicating that direct activation of ERα through the LBD was responsible for the activity reported here. While the pharmacokinetics of resveratrol metabolism have not yet been examined in humans, results from rodent studies indicate that two servings of red wine may provide two-digit micromolar serum concentrations of resveratrol 1 , i. concentrations identical to those at which the pharmacological activities of resveratrol were observed here as well as reported by others 10 , 14 , The cell-type and ERE-sequence dependence of the transcriptional activity of resveratrol with ERα and ERβ may be related to cell-specific differences in the activity of enzymes that modulate ER function, e. protein kinases, and in the expression of coactivator or corepressor proteins. Continued analysis of ERα and ERβ interaction with estrogenic ligands, estrogen-regulated genes, and coregulator proteins is necessary to gain a better understanding of how these receptors regulate estrogenic activity at the cellular and molecular level and whether the anticancer and cardioprotective activities of resveratrol are mediated by ER. Supported by NIH Grant RDK, the Cancer Research Foundation of America, and a University of Louisville School of Medicine Research Grant to C. We thank the following companies for supplying reagents used in this study: resveratrol: Pharma Science, Montréal, Québec, Canada; and H Abbott Laboratories Abbott Park, IL. We thank Rosemary L. Sims for her assistance in some of the experiments reported here. We thank Drs. Barbara J. Clark and Peter C. Kulakosky for their contributions to the experimental design and for reviewing this manuscript. 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J Bone Miner Res 9 : — Lundholt BK , Madsen MW , Lykkesfeldt AE , Petersen OW , Briand P Characterization of a nontumorigenic human breast epithelial cell line stably transfected with the human estrogen receptor ER cDNA. Mol Cell Endocrinol : 47 — Zajchowski DA , Webster L , Humm R Different estrogen receptor structural domains are required for estrogen- and tamoxifen-dependent anti-proliferative activity in human mammary epithelial cells expressing an exogenous estrogen receptor. J Steroid Biochem Mol Biol 62 : — Lee Y , Renaud RA , Friedrich TC , Gorski J Estrogen causes cell death of estrogen receptor stably transfected cells via apoptosis. J Steroid Biochem Mol Biol 67 : — McInerney EM , Weis KE , Sun J , Mosselman S , Katzenellenbogen BS Transcription activation by the human estrogen receptor subtype β ER β studied with ER β and ER α receptor chimeras. Tredici G , Miloso M , Nicolini G , Galbiati S , Cavaletti G , Bertelli A Resveratrol, map kinases and neuronal cells: might wine be a neuroprotectant? Drugs Exp Clin Res 25 : 99 — Bunone G , Briand PA , Miksicek RJ , Picard D Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. EMBO J 15 : — Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Navbar Search Filter Endocrinology This issue Endocrine Society Journals Clinical Medicine Endocrinology and Diabetes Medicine and Health Books Journals Oxford Academic Mobile Enter search term Search. Endocrine Society Journals. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. Materials and Methods. Journal Article. Bowers , Jennifer L. Oxford Academic. Valentyn V. Sarah C. Carolyn M. PDF Split View Views. Cite Cite Jennifer L. Select Format Select format. ris Mendeley, Papers, Zotero. enw EndNote. bibtex BibTex. txt Medlars, RefWorks Download citation. Permissions Icon Permissions. Close Navbar Search Filter Endocrinology This issue Endocrine Society Journals Clinical Medicine Endocrinology and Diabetes Medicine and Health Books Journals Oxford Academic Enter search term Search. Abstract Epidemiological evidence indicates that phytoestrogens inhibit cancer formation and growth, reduce cholesterol levels, and show benefits in treating osteoporosis. Figure 1. Open in new tab Download slide. The chemical structure of trans- resveratrol. Figure 2. Table 1. Resveratrol binds ERα and ERβ. Log 10 IC a se cannot be calculated because of antilogarithm transformation of the confidence intervals for log 10 IC Open in new tab. Figure 3. Figure 4. Figure 5. Figure 6. Figure 7. Figure 8. Cancer chemoprevention activity of resveratrol, a natural product derived from grapes. Google Scholar Crossref. Search ADS. Google Scholar PubMed. OpenURL Placeholder Text. Differential effects on growth, cell cycle arrest, and induction of apoptosis by resveratrol in human prostate cancer cell lines. The red wine antioxidant resveratrol protects isolated rat hearts from ischemia reperfusion injury. Method to assay the concentrations of phenolic constituents of biological interest in wines. Plasma and tissue resveratrol concentrations and pharmacological activity. Evaluation of kinetic parameters of natural phytoalexin in resveratrol orally administered in wine to rats. Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Estrogen-induced retinoic acid receptor alpha 1 gene expression: role of estrogen receptor-Sp1 complex. The estrogen receptor beta subtype: a novel mediator of estrogen action in neuroendocrine systems. Partial and weak oestrogenicity of the red wine constituent resveratrol: consideration of its superagonist activity in MCF-7 cells and its suggested cardiovascular protective effects. Human estrogen receptor β-gene structure, chromosomal localization, and expression pattern. Expression of estrogen receptor β messenger RNA variant in breast cancer. Resveratrol, a natural product derived from grape, exhibits antiestrogenic activity and inhibits the growth of human breast cancer cells. COUP-TF interacts with estrogen receptor, binds to estrogen response elements and half-sites, and modulates estrogen-induced gene expression. Differential DNA-binding abilities of estrogen receptor occupied with two classes of antiestrogens: studies using human estrogen receptor overexpressed in mammalian cells. Cloning of a novel estrogen receptor expressed in rat prostate and ovary. Comparison of tamoxifen ligands on estrogen receptor interaction with estrogen response elements. Relationship between the inhibition constant K1 and the concentration of inhibitor which causes 50 per cent inhibition I50 of an enzymatic reaction. Hsp70 is not required for high affinity binding of purified calf uterine estrogen receptor to estrogen response element DNA in vitro. Antiproliferative effect of synthetic resveratrol on human breast epithelial cells. Dissociation of 4-hydroxytamoxifen, but not estradiol or tamoxifen aziridine, from the estrogen receptor when the receptor binds estrogen response element DNA. What differentiates antiestrogen-liganded versus estradiol-liganded estrogen receptor action? Google Scholar OpenURL Placeholder Text. Inhibition of aryl hydrocarbon-induced cytochrome P 1A1 enzyme activity and CYP1A1 expression by resveratrol. Estrogen receptor affinity and location of consensus and imperfect estrogen response elements influence transcription activation of simplified promoters. Activation of transcription by estrogen receptor α and β is cell type- and promoter-dependent. Widely spaced, directly repeated PuGGTCA elements act as promiscuous enhancers for different classes of nuclear receptors. Cooperative binding of estrogen receptor to DNA depends on spacing of binding sites, flanking sequence, and ligand. Stability of the ligand of estrogen response element-bound estrogen receptor depends on flanking sequences and cellular factors. The estrogen receptorβ -isoform ERβ of the human estrogen receptor modulates ERα transcriptional activity and is a key regulator of the cellular response to estrogens and antiestrogens. Wine, alcohol, platelets, and the French paradox for coronary heart disease [see comments]. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor β. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptorsα and β. Estrogen receptor ER modulators each induce distinct conformational changes in ER α and ER β. Structure of the ligand-binding domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonist. Stable over-expression of estrogen receptor-alpha in ECV cells inhibits proliferation and levels of secreted endothelin-1 and vascular endothelial growth factor. Overexpression of estrogen receptor in HTB 96 human osteosarcoma cells results in estrogen-induced growth inhibition and receptor cross talk. Characterization of a nontumorigenic human breast epithelial cell line stably transfected with the human estrogen receptor ER cDNA. Different estrogen receptor structural domains are required for estrogen- and tamoxifen-dependent anti-proliferative activity in human mammary epithelial cells expressing an exogenous estrogen receptor. Estrogen causes cell death of estrogen receptor stably transfected cells via apoptosis. Transcription activation by the human estrogen receptor subtype β ER β studied with ER β and ER α receptor chimeras. Resveratrol, map kinases and neuronal cells: might wine be a neuroprotectant? Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. Issue Section:. Download all slides. Views 3, More metrics information. Total Views 3, Email alerts Article activity alert. Advance article alerts. New issue alert. Receive exclusive offers and updates from Oxford Academic. More on this topic Resveratrol Attenuates Intermittent Hypoxia-Induced Macrophage Migration to Visceral White Adipose Tissue and Insulin Resistance in Male Mice. Resveratrol Stimulates Cortisol Biosynthesis by Activating SIRT-Dependent Deacetylation of Pscc. Related articles in PubMed Sex Disparities in Longitudinal Use and Intensification of Guideline-Directed Medical Therapy Among Patients With Newly Diagnosed Heart Failure With Reduced Ejection Fraction. 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Resveratrol is a phenolic Rwsveratrol, found Optimal muscular endurance in grape skin. It is also present Resveratrol and hormonal balance different Resveratrol and hormonal balance, soy, and peanuts. Several Revseratrol have revealed Resveratrool resveratrol possesses strong anti-aging, anti-inflammatory, phytoestrogen, and antioxidant activity. One more study has shown that it can also help in balancing hormone imbalance in females with polycystic ovary syndrome PCOs. According to Hormone Health Network PCOs is the most common cause of infertility in females, about 5 to 6 million females in the U. S with this problem.

Resveratrol and hormonal balance -

The baseline levels of sex steroid hormones and estrogen metabolites were similar to those reported in postmenopausal women in a similar BMI range [ 4 ],[ 9 ],[ 10 ]. We showed that 1 gm of resveratrol daily for 12 weeks did not alter the serum estrogen and testosterone concentrations in postmenopausal women with high adiposity but significantly increased the concentrations of SHBG, which has been inversely associated to breast cancer risk [ 6 ].

We did not observe any significant changes in serum insulin levels data not shown and body weight, two major factors known to influence the blood levels of SHBG [ 28 ].

Future randomized, controlled trials are needed to confirm the effect of resveratrol on SHBG. Because SHBG is the main transport binding protein for circulating sex steroid hormones, it has been suggested that elevation in SHBG could lead to a decrease in bioavailable sex steroid hormones and their associated bioactivity.

We calculated the hormone fractions based on the law of mass action [ 29 ] and found that resveratrol intervention did not result in significant changes in bioavailable estradiol but decreased the levels of bioavailable testosterone from 0.

Further studies are needed to determine the effect of resveratrol-induced hormonal changes on breast cancer risk modulation. The formation of 2-OHE 1 and 16α-OHE 1 was primarily catalyzed by cytochrome P CYP 1A2 and 3A4, respectively.

The observed changes in estrogen metabolism is consistent with our prior clinical study that showed an induction of 1A2 and inhibition of 3A4 activity after 4 weeks of 1 gm daily resveratrol dosing [ 22 ].

Further research is needed to evaluate whether resveratrol-induced changes in estrogen metabolism would contribute to breast cancer risk modulation. The resveratrol dose and product used in our study has previously been shown to be safe and well tolerated up to 4 weeks in healthy adults [ 22 ].

In this study of overweight or obese postmenopausal women, six subjects withdrew early after taking resveratrol for 1—66 days due to adverse events including diarrhea, constipation, skin rash, allergic reaction, and shortness of breath.

One participant had asymptomatic Grade 4 ALT and AST elevation at the post-intervention visit which normalized after less than 3 months of follow-up and was considered possibly related to resveratrol intervention.

The common reported adverse events were diarrhea and dyslipidemia. Diarrhea has been reported in previous clinical studies of resveratrol [ 22 ],[ 33 ]. It is not known whether the unfavorable change in the lipid profile is related to the resveratrol intervention in the study population.

A recent study showed that 1, 1. Our study has a number of limitations. First, we have designed this study as a pilot project to assess changes in systemic sex steroid hormones before proceeding to larger trials. Further clinical investigation should include a control arm to minimize potential confounders such as changes in diet and physical activity in single arm studies.

In addition, we have observed a large inter-individual variation in serum estradiol and estrone levels. Larger sample sizes may be needed to observe a significant effect from the supplementation on these measurements. In addition, future studies should consider measurements of serum hormone levels such as follicle-stimulating hormone and luteinizing hormone to confirm postmenopausal status for study entry.

We conclude that in postmenopausal women with high BMI, daily 1 gm dose of resveratrol had favorable effects on SHBG and estrogen metabolites. Lukanova A, Lundin E, Zeleniuch-Jacquotte A, Muti P, Mure A, Rinaldi S, Dossus L, Micheli A, Arslan A, Lenner P, Shore RE, Krogh V, Koenig KL, Riboli E, Berrino F, Hallmans G, Stattin P, Toniolo P, Kaaks R: Body mass index, circulating levels of sex-steroid hormones, IGF-I and IGF-binding protein a cross-sectional study in healthy women.

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Evid Based Complement Alternat Med. The results for Fos were similar for ERα and ERβ: increased activity with E 2 plus resveratrol. In no case was the activity of E 2 and resveratrol additive.

The activity induced by E 2 plus resveratrol for each ERE with ERβ was blocked by 4-OHT, indicating that it is dependent on ERβ AF-2 data not shown. As seen with the single EREs Figs. Resveratrol showed weak agonist activity for both ERα and ERβ. Similar to the data for a single copy of EREc38, resveratrol suppressed E 2 -ERα-stimulated luciferase activity from 2 EREc38 in a concentration-dependent manner.

In contrast, resveratrol did not inhibit E 2 -ERβ activity. This result indicates that ERα and ERβ respond differently to resveratrol at the same ERE.

Resveratrol, when combined with E 2 exhibits antagonist activity with ERα, but no antagonist activity with ERβ. Combined E 2 and resveratrol have different effects on ERα and ERβ.

CHO-K1 cells were cotransfected with pGL3-luciferase reporter plasmid bearing 2 EREc38 , pCMV-βgal, and pCMV-ERα black bars or pCMV-ERβ hatched bars. Epidemiological evidence indicates that phytoestrogens have biological activities including inhibition of cancer initiation and growth, reduction of serum cholesterol levels, and benefits in treating osteoporosis 39 , This gives a concentration of trans- resveratrol of 0.

Given the daily recommended dose of wine is ml 41 , it is estimated that a person would ingest 0. Resveratrol has chemopreventive and chemotherapeutic activities 1 , 2 and has been classified as a phytoestrogen because it binds to ERα with low affinity This finding contrasts with data showing that several phytoestrogens bind ERβ with higher affinity than ERα One possible explanation for the lower affinity of resveratrol binding to ERβ compared with other phytoestrogens is its structural similarity with diethylstilbestrol DES 10 , which binds ERβ with lower affinity than ERα Whether resveratrol-occupied ERα has agonist or antagonist activity has been controversial 10 , 14 , higher reporter activity than E 2 , in ERα-expressing MCF-7 cells 9 , However, another report found no evidence of superagonism in COS cells with either ERα or ERβ Data from our transient transfection assays in CHO-K1 cells using a consensus ERE or the natural imperfect EREs from the human c- fos , pS2, or PR genes indicate that resveratrol acts as an estrogen agonist with ERα and ERβ.

However, resveratrol does not display superagonist activity either alone or in combination with E 2. These results are similar to those detected in COS-1 cells transfected with ERα and either a vitellogenin ERE or LH-β promoter-luciferase reporter plasmid Our results demonstrate that the agonist activity of resveratrol with ERβ is fundamentally different from E 2 agonist activity because, in contrast to E 2 which induces higher activity of ERα than ERβ, resveratrol activated equal reporter activity from EREc38 with both ERα and ERβ.

In contrast, μ m resveratrol was reported to induce higher ERE-driven reporter activity by ERβ than any concentration of E 2 0. Because both we and Ashby et al. Importantly, our data indicate that resveratrol-liganded ERβ has higher transcriptional activity than E 2 - liganded ERβ at a single palindromic ERE.

Biochemical 29 , 30 , 44 , 45 and crystal structure 46 , 47 studies indicate ligand-specific differences in ERα conformation that impact interaction with coactivators.

We observed clear differences in the migration of ERE-bound ERα and ERβ either unoccupied or occupied by E 2 , 4-OHT, or resveratrol. These data indicate differences in ER conformation in the presence of resveratrol compared with E 2 or 4-OHT. The concentrations at which resveratrol inhibited ERE binding by ERα and ERβ in vitro are concentrations at which resveratrol exhibited agonist activity in transiently transfected cells.

Further experiments, e. in vivo DNase I footprinting, are needed to determine in vivo effects of resveratrol on ER-ERE binding. The authors concluded that this positioning of the transactivational helix 12 was consistent with the partial agonist activity of genistein Given the pharmacological activities of resveratrol observed here, we predict that resveratrol-bound ERβ LBD may show a structure similar to that of the genistein-occupied ERβ.

Because alterations in LBD conformation impact the interaction of ERα and ERβ with coactivators, further experiments are needed to assess coactivator effects on resveratrol-liganded ERβ activity. While resveratrol reportedly gave a dose-dependent increase in reporter activity with concentrations as high as μ m with both ERα and ERβ in transiently transfected COS cells 14 , we observed that μ m resveratrol inhibited ERE-driven reporter activity in CHO-K1 cells.

Moreover, we observed decreases cell proliferation in CHO-K1 cells expressing ERα or ERβ and treated with μ m resveratrol. There was no significant decrease in CHO-K1 cell proliferation in cells treated with μ m resveratrol and expressing β-galactosidase or in mock-transfected cells under the same conditions.

While others have reported that E 2 treatment of cells stably overexpressing ERα inhibits cell proliferation 49 — 53 , E 2 at concentrations that stimulate reporter activity in transiently transfected CHO-K1 cells had no effect on cell proliferation in the presence or absence of transfected ERα or ERβ.

Therefore, stable expression of ERα in ERα negative cells appears to be required for E 2 -induced inhibition of cell proliferation in response to E 2 , but not resveratrol. We conclude that expression of ERα or ERβ is involved in the decrease in CHO-K1 cell proliferation with μ m resveratrol.

Others reported that μ m resveratrol inhibited the growth of ERα-expressing MCF-7 cells However, the mechanism for inhibition of MCF-7 cell proliferation may not be ERα-mediated since resveratrol also inhibited the growth of ER-negative breast cancer cells In addition to its agonist activity, resveratrol exhibited antiestrogenic activity in MCF-7 cells Resveratrol decreased the levels of transcription of PR, insulin-like growth factor-receptor, and transforming growth factor-α genes and stimulated the expression of transforming growth factor-β2, results similar to those elicited by tamoxifen in these cells While the authors concluded that the most likely mechanism for the antiestrogenic effect of resveratrol is its direct competition with E 2 for ER binding, they also suggested that resveratrol might prevent ER binding to EREs Our data support both suggestions because we observed that resveratrol competes with E 2 for ERα and ERβ binding and inhibited ERα and ERβ binding to EREc38 in vitro.

We observed both ER isoform-specific and ERE-specific differences in the agonist activity induced by resveratrol in CHO-K1 cells. For example with ERα, the activity induced by E 2 was greater than that stimulated by any concentration of resveratrol for EREc38, Fos, and pS2, but not PR In contrast, resveratrol and E 2 were equally transcriptionally active with ERβ at all EREs tested.

With ERα and PR, although the induction levels are low, they are significantly above the ethanol control values, and resveratrol-induced luciferase activity was comparable to that induced by E 2. In addition to estrogen agonist activity, we also report that resveratrol has estrogen antagonist activity in CHO-K1 cells.

These data are reminiscent of the lack of 4-OHT agonist activity with ERβ We speculate that the antagonist activity of resveratrol may be mediated by AF-1, which appears to be absent in ERβ.

Interestingly, the antagonist activity of resveratrol was only observed with EREc38, whether as a single or two tandem copies, and PR These data indicate that the ERE alters the pharmacological properties of resveratrol mediated by ERα.

This result agrees with our postulate that the ERE sequence acts as an allosteric modulator of ER activity Further experiments are needed to define exactly what regions of ERα and ERβ are necessary for resveratrol agonist and antagonist activity and to define the exact ERE sequence requirements for resveratrol antagonist activity with ERα.

For example, resveratrol induces phosphorylation of the mitogen-activated protein MAP kinase family members, extracellular regulated kinase 1 ERK1 , and ERK2, in neuroblastoma SH-SY5Y cells 55 Activation of the MAP kinase pathway has been shown to activate unliganded ERα through phosphorylation of serine in AF-1 However, this ligand-independent pathway does not appear to be important in our experiments because 4-OHT blocked both E 2 and resveratrol activity, indicating that direct activation of ERα through the LBD was responsible for the activity reported here.

While the pharmacokinetics of resveratrol metabolism have not yet been examined in humans, results from rodent studies indicate that two servings of red wine may provide two-digit micromolar serum concentrations of resveratrol 1 , i.

concentrations identical to those at which the pharmacological activities of resveratrol were observed here as well as reported by others 10 , 14 , The cell-type and ERE-sequence dependence of the transcriptional activity of resveratrol with ERα and ERβ may be related to cell-specific differences in the activity of enzymes that modulate ER function, e.

protein kinases, and in the expression of coactivator or corepressor proteins. Continued analysis of ERα and ERβ interaction with estrogenic ligands, estrogen-regulated genes, and coregulator proteins is necessary to gain a better understanding of how these receptors regulate estrogenic activity at the cellular and molecular level and whether the anticancer and cardioprotective activities of resveratrol are mediated by ER.

Supported by NIH Grant RDK, the Cancer Research Foundation of America, and a University of Louisville School of Medicine Research Grant to C. We thank the following companies for supplying reagents used in this study: resveratrol: Pharma Science, Montréal, Québec, Canada; and H Abbott Laboratories Abbott Park, IL.

We thank Rosemary L. Sims for her assistance in some of the experiments reported here. We thank Drs. Barbara J. Clark and Peter C. Kulakosky for their contributions to the experimental design and for reviewing this manuscript.

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Tredici G , Miloso M , Nicolini G , Galbiati S , Cavaletti G , Bertelli A Resveratrol, map kinases and neuronal cells: might wine be a neuroprotectant? Share on Pinterest A compound found in red wine may moderate androgen hormones and improve diabetes risk factors in women with PCOS.

Resveratrol significantly decreased testosterone, DHEAS levels. Diabetes risk factors improved with resveratrol supplement.

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