5 replies to this topic

[smift]

Hi all,

This is my first post here, though I've spent the last few days reading a large chunk of the info on this forum, and have found it very useful for getting to up speed on resveratrol. I've been mostly trying to find out about possible side effects. It seems to me that the main one to be concerned about, apart from some gastrointestinal upset, is the effect on testosterone and estrogen.

The evidence on this seems to be complicated. I've compiled all the relevant papers I could find at the bottom of this post. The overall message seems to be that resveratrol has some effect on testosterone, but it's quite dose-dependent. It's hard to know how this translates into humans. I can't find any data for humans other than anecdotal reports, which generally do seem to indicate an increase in testosterone.

Some questions that perhaps some people on this forum might have some info on:

1) Does anyone know of any reports on the mechanism for resveratrol's effect on testosterone/estrogen levels? Is it SIRT1 mediated, or is it via some other mechanism. It seems there would be less to worry about if it was SIRT1 mediated.

2) Does anyone have personal before/after blood testosterone data? I couldn't find any published studies with this data in humans.

3) Anecdotal reports from a number of people on this forum (xanadu, fearfrost, bixbyte, velopismo) mention increased aggression as a side effect (I understand that the role of testosterone in aggression is debated, so this may be unrelated).
For the people who reported this side effect, what kind of doses were you taking? Is this something that is generally experienced by everyone?

I have no idea how much weight I should give to this side effect. I would be rather cautious about taking any kind of supplement that might mess with my hormonal balance (and hence possibly behaviour, brian function, etc). However, I really know almost nothing about the effects of altered testosterone level.

I'm currently trying to decide whether or not to take resveratrol or recommend it to my parents. I'm a 25 year old male in good health. My parents are nearing 60, and are also generally in good health, but have a few warning signs such as high cholesterol, some elevated prostate-related signals, and some issues such as small amounts of osteoarthritis. I'm fairly comfortable recommending resveratrol to them, given that the potential benefits are large, and a ten-year-wait-and-see approach is not realistic. Regarding hormonal effects, I would be less concerned given that some offsetting of age-related decline may even be beneficial. My current recommendation to them is 500g of 99% resv daily, taken in the morning.

On the other hand, I am less certain if I want to take resveratrol myself. Are there any younger people on the forum who can offer some experience on the hormone issue?

Anyway, thanks everyone for a useful forum. I really appreciate the fact that statements here are backed up with links to research papers.

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Papers on the topic.
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Arch Pharm Res. 2008 Jan;31(1):83-7.Links
trans-Resveratrol relaxes the corpus cavernosum ex vivo and enhances testosterone levels and sperm quality in vivo.
Shin S, Jeon JH, Park D, Jang MJ, Choi JH, Choi BH, Joo SS, Nahm SS, Kim JC, Kim YB.
College of Veterinary Medicine, Chungbuk National University, Heungdeok-gu, Cheongju, Chungbuk 361-763, Korea.

"resveratrol did elicit an increase in blood testosterone concentration, testicular sperm counts and epididymal sperm motility by 51.6%, (smift notes: study in rabbits, Dosage 50mg/kg) 15.8% and 23.3%, respectively, without influence on sperm deformity. In conclusion, we propose that resveratrol has a positive effect on male reproductive function by triggering a penile erection, as well as enhancing blood testosterone levels, testicular sperm counts, and epididymal sperm motility.

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trans-Resveratrol, a natural antioxidant from grapes, increases sperm output in healthy rats.
Juan ME, González-Pons E, Munuera T, Ballester J, Rodríguez-Gil JE, Planas JM.
Departament de Fisiologia, Facultat de Farmàcia, Universitat de Barcelona, E-08028 Barcelona, Spain.

"...Moreover, sperm counts were significantly greater in the resveratrol-treated rats (24.8 +/- 3.30 x 10(7)) than in the control group (14.1 +/- 0.80 x 10(7)), but sperm quality did not differ. Serum concentrations of gonadotrophins and testosterone were significantly higher in the resveratrol-treated group.

Dosage: 20 mg/(kg d) for 28 d

Testosterone, nmol/L
Control Group: 12.51 +/- 1.35
Treatment Group: 33.25 +/- 9.85
=======================

EFFECT OF RESVERATROL ON THE TESTOSTERONE PRODUCTION OF MOUSE PRIMARY LEYDIG CELL CULTURE
1Forgács, Zs, 2Somosy, Z, 2Telbisz, Á, 3Massányi, P, 3Lukác, N
1 National Institute of Chemical Safety, Budapest, Hungary
2 National "Frederic Joliot-Curie" Research Institute for Radiobiology and Radiohygiene, Budapest, Hungary
3 Slovak University of Agriculture, Nitra, Slovak Republic

Resveratrol (Res) is a phytoestrogen and antioxydant of the red grape, which translocates and presents into the red wine. This compound is a known modulator of the balance of different sex hormones and founded to be an agonist of estrogen and androgen receptors. In our experiments primary cultures of mouse Leydig cells were exposed to resveratrol at the concentration range of 1.56 - 200 μM for 48 hours. Testosterone (T) content of the culture media was measured by enzyme linked immunosorbent assay (ELISA). The effect of Res on the T production was studied also in the presence of maximally stimulating amounts of human chorionic gonadotropin (1 IU/ml hCG) or dibutyryl cyclic adenosine monophosphate (1 mM db-cAMP). Res did not reduce the basal T production of Leydig cells up to 100 μM concentration. Moreover, interestingly Res stimulated the basal T production in the 12.5-50 μM concentration range. Whereas hCG (an LH receptor agonist) stimulated T production was decreased at 25 μM concentration of Res, while the db-cAMP (an effector of post-receptor signaling route) stimulated T response diminished even at 12.5 μM of Res. Res had also an additive effect on hCG stimulated T response at 3.12 μM concentration.
Our data suggest that Res may influence the testosterone production via direct or indirect modulation of LH-receptor mediated signals (at the receptor or secondary messenger cAMP level). Another possible mechanism of the effect of resveratol is a cross-talk effect between androgen and estrogen receptors.

 testosterone_vs_resveratrol_in_animal_cells.PNG   73.3KB   71 downloads

(Smift notes: There seems to be little effect on testosterone below 1.5uM. I understand typical concentrations in humans after 500mg does are on the order of 0.3uM)
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Resveratrol suppresses prostate cancer progression in transgenic mice.
Harper CE, Patel BB, Wang J, Arabshahi A, Eltoum IA, Lamartiniere CA.
Department of Pharmacology and Toxicology, University of Alabama at Birmingham, 1670 University Boulevard, Birmingham, AL 35294-0019, USA.

Serum total testosterone, free testosterone, estradiol, dihydrotestosterone and sex hormone-binding globulin (SHBG) concentrations and Simian Virus-40 large T antigen expression in the prostate were not altered in resveratrol-treated mice. Total resveratrol concentration in the blood serum of 12-week-old mice treated for 3 weeks with 625 mg resveratrol per kg diet was 52 +/- 18 nM.

(Smift notes: Serum concentraions here are low. For 500mg dose in humans, reported serum concentration ~300nM)
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Inhibits aromatase at high concentrations:

The Red Wine Polyphenol Resveratrol Displays Bilevel Inhibition on Aromatase in Breast Cancer Cells
Authors: Wang, Yun; Lee, Kai Woo; Chan, Franky L.; Chen, Shiuan; Leung, Lai K.

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Resveratrol Inhibits the Expression and Function of the Androgen Receptor in LNCaP Prostate Cancer Cells1
Susan H. Mitchell, Wen Zhu, and Charles Y. F. Young2
Departments of Urology [S. H. M., C. Y. F. Y.] and Biochemistry and Molecular Biology [W. Z.], Mayo Graduate School, Mayo Foundation, Rochester, Minnesota 55905

(Smift notes: I don't know enought to interpret this. Increased circulating testosterone may be offset by modulation of androgen receptors? On the other hand testosterone is aromatized to estradiol, so increased T may still have effect via that route?)

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Anecdotal reports:

One report of possible increased testosterone on yahoo resveratrol-users group.
http://health.groups...ers/message/555

One similar report elsewhere in this forum:
http://www.imminst.o...showtopic=15333

Four users on this forum note increased aggression.

Testosterone increase reported by supplement manufacturer Patrick Arnold (possible vested interest)
"one of our guys had an increase of 1100% in total test after 4 weeks while taking 1000mg res / 1000mg quercetin combination. one guy was around 70% the other one closer to 200%."

No reported change from user on leanbulk forum
http://www.leanbulk....stosterone.html
"one full month on 1000mg/day 98% resveratrol(transmax).testosterone in the 800's.exactly as usual for me."

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Background info: Testosterone levels versus age in healthy subjects:

 testosterone_vs_age.PNG   18.79KB   72 downloads

[balance]

Very interesting post. I too have been wondering about this. My own conclusion:

The research showing an increase in testosterone has almost exclusively been in cases where very high doses are used (1000mg or much more). In my opinion this is not a realistic resveratrol dose, but I understand many people here take doses even higher. I personally wouldn't go beyond 250-500mg. In that aspect I don't see much reason for concern if you give your parents 250-500mg. I have read that resveratrol is an aromatase inhibitor, yet this too seems to be dose related, with the most potent effects at very high doses. The only thing I personally find problematic (depending on your goals) is the significant decrease in IGF-1. It seems the mice with deficiencies of IGF-1 live the longest. That said, DHEA is also anti-aging and is said to increase IGF-1 back to youthful levels... Also, for any kind of weight resistance training program you will want to have high levels of IGF-1 for muscle growth. Basically the word isn't entirely out on IGF-1 yet. We know it can be powerful fuel for cancer, yet if you don't have/get cancer, IGF-1 can be great. I don't know.. I guess for general anti-aging a lack of IGF-1 can be great, but for general wound repair, muscle growth/repair, immune system function you benefit from IGF-1...
In some ways IGF-1 and testosterone are connected, whereby lowering one will lower the other. That was sort of the reason I responded to your post. I think resveratrol might possibly lower testosterone or have no effect at all. I wouldn't worry about it in your parents' case, since they are probably just interested in not dying. In your case, if you're a gym beast, maybe stick with a low dose, if not and you are interested in anti aging, resveratrol is the way to go.

[smift]

Thanks piet3r. I'd also come to the conclusion that taking resveratrol and trying to build muscle was not likely to be winning combination (despite the interest in bodybuilding forums). My big sport is cycling though, and for aerobic sports it seems resveratrol is all positive.

[balance]

Hey Smift,

Indeed for aerobic exercise there seems a boost, but I don't know how it compares to something like green tea for that purpose.
Something I forgot to add in my previous post in this thread was that a dose of resveratrol between 113mg to 565mg increased endothelial nitric oxide levels by 76.2% and 90.3% and decreased artery-constricting levels of angiotensin II by 12.4% and 15.3%. Nitric oxide has an important role in the testosterone and erection process. That said, there's many NO boosters. Carnosine even though is claimed to be one, doesn't do anything noticeable.. Taking lots of cocoa polyphenols however will achieve clear results! Same goes for high dose pomegranate, but I feel cocoa does a better job.

[TianZi]

A couple of things from my perspective as a layman:

1. You seem to regard higher levels of testosterone in the body as necessarily a bad thing. It's not, although it can be.

Testosterone is something the body produces less of as we age. It is for this reason that injections of testosterone have been administered by some physicians, with significant anti-aging effects.

The American Association of Clinical Endocrinologists says "Hypogonadism is defined as a free testosterone level that is below the lower limit of normal for young adult control subjects. Previously, age-related decreases in free testosterone were once accepted as normal. Currently, they are not considered normal....Patients with low-normal to subnormal range testosterone levels warrant a clinical trial of testosterone."

For persons who are middle-aged or elderly, restoring a youthful hormonal balance is generally a positive thing. We know that exogenous testosterone supplementation can be dangerous if the amount delivered is excessive; this form of supplementation requires the close supervision of a physician.

However, I'm unaware of any study showing that triggering the body itself to produce more testosterone is necessarily harmful, just as no studies have shown that triggering the body to produce higher levels of HGH is harmful.

Keep in mind that there have been no significant negative effects attributed to resveratrol in the many animal studies, and ongoing human studies, to date.

2. Regarding a "realistic dosage" of resveratrol, why one poster above considers 1 gram or above an "unrealistic" dose, but that 250/500 mg is not, is unclear to me. It seems an arbitrary conclusion. There isn't any evidence that a daily dose of 250/500 mg is any safer than a daily dose of 1 gram. Indeed, there isn't any evidence that taking resveratrol in doses equivalent to 10+ grams for a 150 pound human is harmful.

The dosage being used by Sirtris in its human clinical trials is many times greater than 1 gram t-res per day.

Edited by TianZi, 23 April 2008 - 04:44 AM.

[krillin]

Keep in mind that there have been no significant negative effects attributed to resveratrol in the many animal studies, and ongoing human studies, to date.

Toxicol Sci. 2004 Dec;82(2):614-9. Epub 2004 Aug 25.
Resveratrol-associated renal toxicity.
Crowell JA, Korytko PJ, Morrissey RL, Booth TD, Levine BS.
Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland 20892-7322, USA. jc94h@nih.gov

Resveratrol, (3,5,4'-trihydoxystilbene) a compound found in grapes, mulberries, and peanuts, has antimycotic, antiviral, and beneficial cardiovascular and cancer preventive activities. It is being developed for several clinical indications. To evaluate the potential toxicity of resveratrol, rats were administered by gavage 0, 300, 1000, and 3000 mg trans-resveratrol per kilogram body weight per day for 4 weeks. Most of the adverse events occurred in the rats administered 3000 mg per kilogram body weight per day. These included increased clinical signs of toxicity; reduced final body weights and food consumption; elevated BUN, creatinine, alkaline phosphatase, alanine aminotransferase, total bilirubin, and albumin; reduced hemoglobin, hematocrit, and red cell counts; and increased white cell counts. Increases in kidney weights and clinically significant renal lesions, including an increased incidence and severity of nephropathy, were observed. Diffuse epithelial hyperplasia in the bladder was considered, equivocal and of limited biological significance. No histological effects on the liver were observed, despite the clinical chemistry changes and increased liver weights in the females. Effects seen in the group administered 1000 mg resveratrol per kilogram body weight per day included reduced body weight gain (females only) and elevated white blood cell count (males only). Plasma resveratrol concentrations in blood collected 1 h after dose administration during week 4 were dose related but were relatively low given the high dosage levels; conjugates were not measured. Under the conditions of this study, the no observed adverse effect level was 300 mg resveratrol per kilogram body weight per day in rats.

PMID: 15329443