Resveratrol and Joints

I notice the joint pain too, but I have been taking resveratrol for a while and did not notice it previous. I take one 200 mg capsule of Now "Mega Potent" trans-resveratrol before bed. I started drinking more milk as well to increase my calcuium / Vitamin D so maybe that plays an effect.

I don't think the temporary joint pain was due to resveratrol. I had been taking it long before then and never had joint pain and it disappeared a couple weeks ago. It was probably due to something else.

just an FYI on the copper chelation / resv issue:

http://www.imminst.o...&...st&p=324957

We do now have a 4th possibility (aside from bad supplements).

4. Resveratrol lowers estrogen levels.

Vitamin D. D3 or exposure to sun alleviate joint pain in women treated with aromatase inhibitors for breast cancer.

There are also men on TRT taking aromatase inhibitors to control estradiol. Been on 1g of resveratrol for three months now and am experiencing pain/soreness in the tendons of my elbows. Not going to stop taking it, but labs are next week and I may need to adjust some other meds in response. Been taking 2000 IU's of D3 daily for over a year now, so that ain't it.

Oops. I spoke too soon. Doc didn't do D on the last panel but he did this quarter. On 2000IUs of D3 my labs came back at 30 ng/ml (range 32-100). Upping my dose to 8000IUs.

Was just reading about this new study about a negative link between antioxidants and exercise. Haven’t had a chance to read the study yet but it made me wonder if it’s findings had any relevance to the resveratrol-tendon and joint issues that many of us have experienced. Any thoughts?

http://meganmcardle.theatlantic.com/archives/2009/05/exercise_in_futility.php

Was just reading about this new study about a negative link between antioxidants and exercise. Haven't had a chance to read the study yet but it made me wonder if it's findings had any relevance to the resveratrol-tendon and joint issues that many of us have experienced. Any thoughts?

http://meganmcardle.theatlantic.com/archives/2009/05/exercise_in_futility.php

If it turns out that this antioxidant exercise effect is somehow linked to the tendon and joint issues some people experience with resvertrol use, I wonder if abstaining from using resvertrol on days you exercise might be a good idea?

If it turns out that this antioxidant exercise effect is somehow linked to the tendon and joint issues some people experience with resvertrol use, I wonder if abstaining from using resvertrol on days you exercise might be a good idea?

resveratrol works in a similar way that exercise does on the human body, it upregulates the body's endogenous antioxidants. it doesn't work like vitamin c, where it directly intercedes oxidative stress before the body can deal with it naturally.

just an FYI on the copper chelation / resv issue:

http://www.imminst.o...&...st&p=324957

Resveratrol does not chelate copper in a meaningful way, sorry, that's a total myth. I've gone back to the very source paper that everyone cites, and it doesn't work out in vivo. It requires huge amounts of aglycon resveratrol which are literally impossible to gain in vivo and huge amounts of free copper. That is, resveratrol chelation is extremely weak (weak Kd), is abolished the moment resveratrol is modified (requires the aglycon form, so resveratrol cannot remove copper from the body!), and will rapidly be out competed by the biological protein chaperons/chelators you have in your system that bind up copper (you have tons of copper binding proteins, such as metallothionines with their seven cysteines for chelation... sorry, resveratrol is not going to win against your proteins, so it cannot chelate copper in vivo). You don't have much if any free copper floating around your system (hotly debated, but probably so) for resveratrol to bind in the first place. Also, please remember what chelation even means. It simply means one molecule interacting though two (in the case of resveratrol) or more functional groups with another molecule or atom. All resveratrol's got is two hydroxyls available in the aglycon form, with bad geometry.

Chelation does not magically mean something bad, nor does it mean that copper is biologically unavailable if it's chelated. Only if resveratrol had a Kd for copper greater than that of your proteins, so that it could strip copper out of your proteins, would there be a problem. And it doesn't. No friggin way. Compare this to calcium orotate, where the orotate is a chelater of the calcium and INCREASES it's bioavailability to the body! Copper chelation is NOT how resveratrol affects joints, period.

So... enough with that myth. If you want to worry about something that chelates copper biologically, worry about estrogen metabolites that your body naturally produces, oh, and those also damages DNA.

You know, we have discussed so much in this thread, yet everyone seems to have gained amnesia and forgotten what's already here... Aromatase inhibition is the only logical method that resveratrol causes joint pain, and the only method that fits all the evidence, and which is supported by the effects of other aromatase inhibitors that cause the same problems in the same ways; i.e. quercetin and pomegranate juice, and pharmacological aromatase inhibitors.

Anyways, sorry I've been gone so very long, been extremely busy, and still am. So I'll post up a lot more information soonish.. I hope ><.

You know, we have discussed so much in this thread, yet everyone seems to have gained amnesia and forgotten what's already here... Aromatase inhibition is the only logical method that resveratrol causes joint pain, and the only method that fits all the evidence, and which is supported by the effects of other aromatase inhibitors that cause the same problems in the same ways; i.e. quercetin and pomegranate juice, and pharmacological aromatase inhibitors.

Wait a moment, did aromatase inhibition also explain the tendon pain and inflammation that many people had? (I thought it didn't, but I may have missed something.)

I have seen some bloodwork on bodybuilding sites that suggested that resveratrol does not actually inhibit estrogen in vivo too much (although the sample is very small and these individuals did not complain of joint pain, so maybe they were not good examples). For now I am not convinced by the AI argument. But it is also supposedly a SERM, so maybe that also plays a role.

Edited by andre, 29 May 2009 - 05:12 PM.

Wait a moment, did aromatase inhibition also explain the tendon pain and inflammation that many people had? (I thought it didn't, but I may have missed something.)

I have seen some bloodwork on bodybuilding sites that suggested that resveratrol does not actually inhibit estrogen in vivo too much (although the sample is very small and these individuals did not complain of joint pain, so maybe they were not good examples). For now I am not convinced by the AI argument. But it is also supposedly a SERM, so maybe that also plays a role.

Yes, aromatase inhibition does cause tendinitis and inflammation and all that (PMID: 17937464). And we have seen in vivo studies that showed resveratrol lowering estrogen in mice at levels of intake lower than what we typically try to use (PMID: 18656555) (note this required long term resveratrol intake as well).

Moreover, how do you explain that quercetin causes worst joint pain in people who suffer from resveratrol induced joint pain, and pomegranate juice is even more debilitating? The aromatase inhibitor activity of those compounds goes in that order of increasing inhibition. Furthermore, grapefruit juice doesn't cause joint pain in similar anecdotal reports, and it doesn't inhibit aromatase, despite having quercetin in it (some other factor nullifies quercetin's effect in grapefruit juice).

Even slight aromatase inhibition seems to be pretty good at causing joint pain (refer back to first link). This is also something that doesn't happen in the majority of people, though close to, even with the potent pharmacological aromatase inhibitors. Since joint pain with resveratrol is also Very rare, we just have some vocal parties on this board, and has never been seen in actual studies looking for resveratrol's side effects... it seems likely that people who experience joint pain that starts and stops with resveratrol use, happen to be very sensitive to aromatase inhibition. Consequently, they also suffer when taking quercetin, usually, and pomegranate juice, once more solidifying the evidence for this.

Interestingly, 2tender has reported his pain is subsiding, and what season are we going into? Summer. Where there is more sunlight. And sunlight exposure ambiently to the eyes is one method that has been shown to help stop aromatase inhibitor related joint pain.

Edit: Also, I've noticed that the angiogenesis slowing properties of resveratrol, however weak they are, are being brought up again as possibly responsible for the joint pain? You were there earlier in this thread, you've seen that it was proven that isn't the case. Why? Cause condrocytes exist in a hypoxic environment, angiogenesis erodes joints, causes joint pain and arthritis! Inhibiting angiogenesis is one way to treat arthritis and joint pain. So then, do other angiogenesis inhibitors cause joint pain? No, they treat it. Do platelet aggregate inhibitors like asprin, cause joint pain? No.

What's more, is resveratrol has been shown ex vivo in humans to regenerate joints and protects chondrocytes; let alone the in vivo studies done in rabbits showing resveratrol's action to protect against and heal osteoarthritis and in inflammatory arthritis. And then there's in vitro studies on human chondrocytes looking at this in depth. And this isn't even all of the studies.

Ironically, while it's been shown in one case that oral resveratrol with 1% ethanol slowed wound healing, another case showed resveratrol mixed in grape extract topically applied increasing wound healing.

Edited by geddarkstorm, 29 May 2009 - 06:37 PM.

Interestingly, 2tender has reported his pain is subsiding, and what season are we going into?

True, but he also mentioned that he stopped weight training for a month, which confounds things somewhat.

Since joint pain with resveratrol is also Very rare, we just have some vocal parties on this board, and has never been seen in actual studies looking for resveratrol's side effects...

I've heard repeated rumors regarding the outcome of those purported studies for side effects in humans but I have never actually seen one, despite repeated requests on these forums. I am starting to think they are nothing but mythical creatures. Do you have access to any such studies that you could post here? I would love to see an abstract or a table...

Wait a moment, did aromatase inhibition also explain the tendon pain and inflammation that many people had? (I thought it didn't, but I may have missed something.)

Yes, aromatase inhibition does cause tendinitis and inflammation and all that (PMID: 17937464).

You are indeed correct about the AI-tendinopathy connection. See http://www.ncbi.nlm....pubmed/17726034

Notice that this is not just pain, but in various cases actual severe tendinopathy that can cause disability. I think this should be a wake-up call to those who experience tendon issues associated with resveratrol, that the pain that they are experiencing may be a signal of long-term or even permanent damage taking place.

Severe disabling tendinopathy caused by anastrazole.
Martens HA, Schröder CP, van der Eerden PJ, Willemse PH, Posthumus MD.

SIR, Aromatase inhibitors are a group of drugs that are used in the adjuvant treatment of oestrogen receptor-positive breast cancer. Musculoskeletal symptoms are frequently observed during treatment with aromatase inhibitors [1]. Mostly, the complaints consist of arthralgias, muscle-weakness, morning stiffness and bone pain. Also osteoporosis and arthritis may occur. Recently, tenosynovitis occurring during treatment with aromatase inhibitors has been described [2]. In this case report, we describe a patient with severe, disabling tendinopathy during treatment with the aromatase inhibitor anastrozole (Arimidex ).

Case report
A 55-yr-old woman was referred to our Department of Rheumatology for severe, disabling pain and swelling at the wrists. A year before she had started treatment with anastrozole because of oestrogen receptor-positive breast cancer. Since then, she experienced non-severe myalgias and morning stiffness. Pain and swelling at the radial side of the right wrist occurred after 5 months of treatment with anastrozole and had worsened since. In addition, she had pain in the Achilles tendons, but no pain or swelling of joints. She did not use drugs other than anastrozole. Non-steroid anti-inflammatory drugs and splintage had no effect. The week before presentation, pain and swelling also occurred in the left wrist.

At physical examination there was a tender swelling on the radial side of both wrists (Fig. 1A). Resisted extension and abduction of the thumbs was also very painful. Finkelstein’s test was negative. Both Achilles tendons were tender. There were no signs of arthritis, and no further abnormalities at physical examination.

Laboratory tests revealed a normal ESR (2mm in first hour) and CRP (<5 mg/l). Blood count, renal function, liver enzymes and rheumatoid factor were normal. There were no anti-CCP antibodies. Thyroid function was normal. There was no hypercholesterolaemia. Radiographs of hands and wrists showed no abnormalities, neither did skeletal scintigraphy. Ultrasound showed a thickening and irregular aspect of the tendon of the abductor pollicis longus muscle on the right wrist (Fig. 1B). There were no signs of tenosynovitis such as a peri-tendinous fluid collection or swelling. Power Doppler revealed an increased vascularity of the tendon, confirming active inflammation. Based on these findings, the diagnosis of tendinopathy of the tendon of the abductor pollicis longus muscle was made. Treatment with anastrozole was discontinued. After this, the pain in the Achilles tendons resolved completely, but an additional local corticosteroid injection was needed for further improvement of the wrist symptoms.

Discussion
Aromatase inhibitors are increasingly used as adjuvant hormonal therapy in post-menopausal patients with oestrogen-positive breast cancer. These drugs cause a depletion of oestrogen and thereby prevent progression of the disease. Musculoskeletal symptoms, especially arthralgias and myalgias, have been reported in up to 5.4–35.6% of patients during use of aromatase inhibitors [1]. Mostly, these complaints diminished in the first year after start of treatment, but, in some cases, the drugs had to be discontinued because of severe arthralgias [3]. Also carpal-tunnel syndrome has been reported [4]. It has been suggested that aromatase inhibitors inhibit the antinociceptive effects of oestrogen by depleting oestrogen levels, thereby decreasing the threshold for painful stimuli. Furthermore, oestrogen might exert effect on inflammation in the joint [5]. Recently, Morales et al. reported tenosynovitis in 12 patients treated with either letrozole or exemestane [2]. Six of these patients had to discontinue treatment because of disabling pain.

In our patient, a De Quervain’s tenosynovitis appeared to be unlikely because there was no peri-tendinous fluid or swelling at ultrasound, as is often seen in the De Quervain’s tenosynovitis [6]. The involvement of both wrists and the Achilles tendons suggest the presence of a (diffuse) tendinopathy.

Possible causes of tendinopathy were reviewed by Riley in 2004 [7]. Inherited disorders can lead to deficient or abnormal collagen or abnormal fibril structure. Endocrine and metabolic disorders may lead to altered collagen metabolism or deposits between fibrils. Finally, rheumatologic diseases may cause destruction of collagen by inflammation. Also other intrinsic factors, like age and joint laxity and extrinsic factors like occupation and sport may be implicated in chronic tendinopathy. Tendinopathy of the Achilles tendon is often associated with vigorous physical activity or use of drugs like fluoroquinolone antibiotics or steroids [8].

In our patient there were no signs of underlying systemic disease, there was no abnormal physical activity preceding the complaints and she used no other drugs beside anastrozole. Furthermore, the complaints improved after discontinuation of anastrozole. Therefore, the anastrozole is thought to be the cause of the tendinopathy in this patient.

To our knowledge, this is the first case describing a tendinopathy caused by an aromatase inhibitor. As complaints caused by tendinopathy can be severe and aromatase inhibitors are increasingly used in the treatment of breast cancer, one has to be aware of this possible side effect.

See also

http://www.druglib.c...endon_disorder/

Adverse event in 55 year old female receiving Arimidex (Anastrozole)
Reported by a health professional (non-physician/pharmacist) from Netherlands on 2007-10-24
Patient: 55 year old female
Adverse reactions / side effects: Tendon Disorder
Adverse event resulted in: disablity
Suspect drug(s): Arimidex (Anastrozole)

Adverse event in 54 year old female receiving Arimidex (Anastrozole)
Reported by a physician from Canada on 2007-07-10
Patient: 54 year old female
Adverse reactions / side effects: Pain, Deafness, Joint Stiffness, Tendon Pain, Fatigue, Arthralgia, Insomnia, Tendon Disorder, RIB Fracture
Adverse event resulted in: disablity
Suspect drug(s): Arimidex (Anastrozole)
Other drugs received by patient: Tamoxifen

Adverse event in 54 year old female receiving Arimidex (Anastrozole)
Reported by a physician from Canada on 2007-06-07
Patient: 54 year old female
Adverse reactions / side effects: Pain, Deafness, Joint Stiffness, Tendon Pain, Fatigue, Arthralgia, Insomnia, Tendon Disorder, RIB Fracture
Adverse event resulted in: disablity
Suspect drug(s): Arimidex (Anastrozole)

Adverse event in female receiving Arimidex (Anastrozole)
Reported by a physician from Canada on 2007-01-22
Patient: female
Adverse reactions / side effects: Tendon Pain, Fatigue, Arthralgia, Pain, Insomnia, Tendon Disorder, Deafness, Joint Stiffness
Adverse event resulted in: disablity
Suspect drug(s): Arimidex (Anastrozole)

Edited by Michael, 24 July 2009 - 05:15 PM.
Cleanup

Since joint pain with resveratrol is also Very rare, we just have some vocal parties on this board, and has never been seen in actual studies looking for resveratrol's side effects...

I've heard repeated rumors regarding the outcome of those purported studies for side effects in humans but I have never actually seen one, despite repeated requests on these forums. I am starting to think they are nothing but mythical creatures. Do you have access to any such studies that you could post here? I would love to see an abstract or a table...

Only because you aren't paying attention . Here's one safety profile study, PMID: 19194969, which has been previously posted here. Want a table?



List of all reported side effects from the study. Notice that those dosages were taken 6 per day.

Also, have you ever thought that weight training might, just maybe, possibly, cause joint pain and tendinitis on its own, whether you take resveratrol or not? I know, it's a radical idea.

In your case, we already established that it's very unlikely you were intaking a significant amount of resveratrol, since your supplement source was suspended in water, which resveratrol only has a microgram level solubility within! That, and you had tons of other chemicals in your supplement source too. So, I highly doubt resveratrol had anything to do with you, especially since your symptoms persisted months afterwards. Sounds like you just pushed yourself too hard and damaged your body, as hundreds of thousands of people do every day...

Wait a moment, did aromatase inhibition also explain the tendon pain and inflammation that many people had? (I thought it didn't, but I may have missed something.)

Yes, aromatase inhibition does cause tendinitis and inflammation and all that (PMID: 17937464).

You are indeed correct about the AI-tendinopathy connection. See http://www.ncbi.nlm....pubmed/17726034

Notice that this is not just pain, but in various cases actual severe tendinopathy that can cause disability. I think this should be a wake-up call to those who experience tendon issues associated with resveratrol, that the pain that they are experiencing may be a signal of long-term or even permanent damage taking place.

You are amazingly biased. I know you are obsessed with trying to discredit resveratrol, but sometimes you make yourself look a tad rediculous. Oddly, I like you a lot despite that XD.

What is the inhibitory level of that dug? What's its IC50, and pharmacological dosage? Resveratrols effects are Very minor, it only slightly can lower estrogen, enough so only very sensitive people are affected, we already know that, and have said that numerous times. No way it's going to do permanent damage 6_6. Furthermore, all you need is sunlight to undo it in some cases, as has already been shown in studies about aromatase inhibitor pain. Afterall, the issue seems to be about a balance between melatonin and estrogen levels.

You know, there's more potent natural aromatase inhibitors out there, quercetin, pomegranate juice...

Edit: Resveratrol is also an anti-inflammatory, replacing oestrogen there, and heals joints as I posted, and also helps to increase pain threshholds. I don't have time to grab you those studies right now. Resveratrol is a minor estrogen minic, so... It's not like those other drugs that completely deplete estrogen and leave you nothing in its wake.

Edited by Michael, 24 July 2009 - 05:14 PM.
Trim quote

So, I highly doubt resveratrol had anything to do with you, especially since your symptoms persisted months afterwards.

That may or may not be the case for me, but I do think it is a real effect based on others' experience reported here and elsewhere.

Here's one safety profile study, PMID: 19194969, which has been previously posted here. Want a table?



List of all reported side effects from the study. Notice that those dosages were taken 6 per day.

Thank you for the table, but in this study only 13 doses were administered. In other words, resveratrol was given for only two days and a bit, to only ten people! So I find this hardly worth considering. Do you know of any better studies?

You are amazingly biased. I know you are obsessed with trying to discredit resveratrol, but sometimes you make yourself look a tad rediculous. Oddly, I like you a lot despite that XD.

By the way, where did you get that from? This was in response to a post in which I supported your AI hypothesis, in other words, I agreed with you. I am not out to be biased or to malign resveratrol. I am just trying to find a convincing explanation for what seems to be a real effect in some people (even if perhaps not in me). After all, isn't that why you started the thread? Until we know what is really going on, don't you think it is prudent to consider that there might be some damage going on if there is pain?

Edited by andre, 29 May 2009 - 07:38 PM.

Let me jump in here and once again add my voice to the "resv causes joint pain chorus".

As I've mentioned before, on approx 600mg daily (in the afternoon most often) of 98%, vit. prim. resv in yogurt or milk I began experiencing planar fasciitis, Achilles tendon pain, shin pain, shoulder pain, wrist pain, thumb pain and knee pain within 1.5 months! I discontinued use and the various pains started receding. I was not exercising and had not changed any other aspect of my health regimen. Also was taking no other supplements. The only aspect that changed in my life was ridiculous amounts of time stuck in the office... Vit D?

After about 6 months abstaining, the disappearance of all symptoms, and reading this thread I opted to try out the 99% micronized suspended 250mg capsule. I've taken 1 pill in the morning about 4-5 times per week for about 2 months. Now there appears to be minor shoulder pain if days aren't skipped occasionally, all other symptoms have not reappeared. 32 years old, male. I don't notice any other effects, positive or negative.

So, I highly doubt resveratrol had anything to do with you, especially since your symptoms persisted months afterwards.

That may or may not be the case for me, but I do think it is a real effect based on others' experience reported here and elsewhere.

Edited by Shay, 29 May 2009 - 09:00 PM.

You are amazingly biased. I know you are obsessed with trying to discredit resveratrol, but sometimes you make yourself look a tad rediculous. Oddly, I like you a lot despite that XD.

By the way, where did you get that from? This was in response to a post in which I supported your AI hypothesis, in other words, I agreed with you. I am not out to be biased or to malign resveratrol. I am just trying to find a convincing explanation for what seems to be a real effect in some people (even if perhaps not in me). After all, isn't that why you started the thread? Until we know what is really going on, don't you think it is prudent to consider that there might be some damage going on if there is pain?

Because you said this:

"Notice that this is not just pain, but in various cases actual severe tendinopathy that can cause disability. I think this should be a wake-up call to those who experience tendon issues associated with resveratrol, that the pain that they are experiencing may be a signal of long-term or even permanent damage taking place."

Which is both an alarmist and extreme thing to say. We're talking orders of magnitude difference between the resveratrol effect and that of dedicated aromitase inhibitors. Saying such a statement is completely over board. I know it can be easy to get caught up in things, positive or negative, I've been there myself. But, the slightest hint of something negative makes you jump on it to the extreme is a case of bias, which others might try to demean you for. I wasn't trying to sound mean or anything, but bring to your attention how around the bend you suddenly took things.

Yes, that study wasn't long term, and the lowering of estrogen in mice was over a longer period with very low doses. But that study used high doses. And, it wasn't ten people, it was 32, not counting the placebo group. None the less, I wish there were better studies out there (there are others, but I don't have time to scrounge about, yet), but a lot is still hidden since resveratrol is in clinical trials right now, and I'm not privy to such information.

None the less, we know how resveratrol is working, through aromatase. Now, an acute dose would rapidly expose this inhibitory effect and the corresponding results there in. It doesn't matter it was just for two days, the doses were high enough that, if this was a common phenominon, there's a good chane it would have been seen in at least one person (0 out of 8 means it's a less than 1/8 chance to have it happen at that highest dose, let alone the lower ones , at least at this time scale, within the population type they pulled).

The IC50 of resveratrol, the aglycon form only, is 40uM. It's quite hard to get that level of aglycon resveratrol in a human. Even the highest dose in that study only gave a serum concentration AUC of about 1.73uM of resveratrol, so you'd need 40 times their dose there abouts to get to a 50% inhibition level, which would mean you'd need over 4 grams of resveratrol a go. Now, this is still within range to start inhibiting aromatase to an extent (around 3 to 5%), which explains the small drop in mice over time in estrogen, but you aren't going to get even 50% reduction, let alone nearly complete inhibition and loss of estrogen as dedicated aromatase inhibitors do when taking the standard levels people have been.

So, while it explains fully the pain some rare people have experienced, it is not a "OMG you're going to be crippled FOR LIFE!" thing. A single or few EXTREME cases using dedicated, orders of magnitude stronger, aromitase inhibitors does not make for a general result for people taking resveratrol. But those who do experience this now have an answer and possible solutions. Although our proof isn't conclusive, it's heavily supported by all lines of evidence.

Edited by Michael, 24 July 2009 - 03:44 PM.
Trim quotes

Let me jump in here and once again add my voice to the "resv causes joint pain chorus".

As I've mentioned before, on approx 600mg daily (in the afternoon most often) of 98%, vit. prim. resv in yogurt or milk I began experiencing planar fasciitis, Achilles tendon pain, shin pain, shoulder pain, wrist pain, thumb pain and knee pain within 1.5 months! I discontinued use and the various pains started receding. I was not exercising and had not changed any other aspect of my health regimen. Also was taking no other supplements. The only aspect that changed in my life was ridiculous amounts of time stuck in the office... Vit D?

After about 6 months abstaining, the disappearance of all symptoms, and reading this thread I opted to try out the 99% micronized suspended 250mg capsule. I've taken 1 pill in the morning about 4-5 times per week for about 2 months. Now there appears to be minor shoulder pain if days aren't skipped occasionally, all other symptoms have not reappeared. 32 years old, male. I don't notice any other effects, positive or negative.

Vitamin D deficiency itself causes chronic pain, and in people under 18 it's already been shown that a combination of vitamin D deficiency and stress leads to arthralgia and pain. Easy to see how your condition would have lead to the same.

While resveratrol increases the amount of the vitamin D3 receptor (2 fold within serum ranges you should have achieved), consequently increasing vitamin D effectiveness, it may not be enough to compensate for the combination of stress and no sunlight.

Also consider the lack of sunlight will cause your body to make more melatonin, and with your estrogen going down due to resveratrol, if a imbalance between too much melatonin and too little estrogen is how aromatase inhibitors cause pain, then pain as you experienced would be expected as these two independent events work to the same painful conclusion.

Try getting more sunlight exposure, ambiently, to your eyes and see if that helps this minor pain you are reporting. It'll be very helpful to see if it does or not. Otherwise, you may just be too sensitive to take resveratrol -- although your cycling methods seem to be working pretty well at controlling pain.

You are amazingly biased. I know you are obsessed with trying to discredit resveratrol, but sometimes you make yourself look a tad rediculous. Oddly, I like you a lot despite that XD.

By the way, where did you get that from? [...] I am not out to be biased or to malign resveratrol. [...] Until we know what is really going on, don't you think it is prudent to consider that there might be some damage going on if there is pain?

Because you said this:

"Notice that this is not just pain, but in various cases actual severe tendinopathy that can cause disability. I think this should be a wake-up call to those who experience tendon issues associated with resveratrol, that the pain that they are experiencing may be a signal of long-term or even permanent damage taking place."

Which is both an alarmist and extreme thing to say. We're talking orders of magnitude difference between the resveratrol effect and that of dedicated aromitase inhibitors. [...] None the less, we know how resveratrol is working, through aromatase. [...]

So, while it explains fully the pain some rare people have experienced, it is not a "OMG you're going to be crippled FOR LIFE!" thing. A single or few EXTREME cases using dedicated, orders of magnitude stronger, aromitase inhibitors does not make for a general result for people taking resveratrol. But those who do experience this now have an answer and possible solutions. Although our proof isn't conclusive, it's heavily supported by all lines of evidence.

Thanks geddarkstorm, we've missed you.

The above agrees fully with my experience: no tendinitis or joint pain with resveratrol initially even at high (>2 gram) dose, but adding quercetin at 500 or 250 mg, joint pain that ceased on discontinuing quercetin.

I tried luteolin, and thought it was causing pain as had quercetin, but I realize I had added pomegranate juice to my regimen at about the same time. On discontinuing pomegranate, my joint and tendon pain resolved. Currently I am using resveratrol (800 mg) and luteolin (400 mg), once in the morning. (There are reasons I believe they are complementary, beyond boosting resveratrol serum levels by inhibiting sulfonation.) I've had no joint, muscle or tendon pain from this.

Edited by Michael, 24 July 2009 - 03:48 PM.
Trim quotes

Because you said this:

"Notice that this is not just pain, but in various cases actual severe tendinopathy that can cause disability. I think this should be a wake-up call to those who experience tendon issues associated with resveratrol, that the pain that they are experiencing may be a signal of long-term or even permanent damage taking place."

Which is both an alarmist and extreme thing to say. We're talking orders of magnitude difference between the resveratrol effect and that of dedicated aromitase inhibitors. Saying such a statement is completely over board. I know it can be easy to get caught up in things, positive or negative, I've been there myself. But, the slightest hint of something negative makes you jump on it to the extreme is a case of bias, which others might try to demean you for. I wasn't trying to sound mean or anything, but bring to your attention how around the bend you suddenly took things.

I can see how it may sound alarmist to you, but in some cases the pain reportedly associated with resveratrol on this and other threads has been severe and debilitating. What does it matter that it is a weaker AI if the end result is the same? At least a couple of people have had long term tendon problems after stopping resveratrol. If someone has joint or tendon pain, and you tell them not to be alarmed because it is probably nothing serious, they are likely to continue and may do themselves further harm. So without a definitive understanding of the mechanism being available yet, I consider that bad advice. Neither you nor I know for sure if this pain is indicative of damage or toxicity to those individuals. Pain more often than not means damage, and we all know that tendons are a bitch to heal once damaged. Until we know, I think it is irresponsible not to advise, indeed alarm, those individuals into stopping. Someone has to do it.

I have never tried to alarm you or anybody else who does not have pain into stopping.

None the less, we know how resveratrol is working, through aromatase. Now, an acute dose would rapidly expose this inhibitory effect and the corresponding results there in.

Aromatase inhibition is plausible but not definite. But I don't think pain onset with aromatase inhibitors is necessarily rapid. See for example the Arimidex case study I posted where things started happening after five months.

It doesn't matter it was just for two days, the doses were high enough that, if this was a common phenominon, it would have been seen. Furthermore, aren't all the anecdotal reports here claiming near immediate joint pain when taking resveratrol, and at lower doses than that study?

No, several claim gradual onset the first time (sometimes with rapid onset on subsequent times after stopping). So no, a two-day study on 40 people is probably not nearly good enough to show this up.

So, while it explains fully the pain some rare people have experienced, it is not a "OMG you're going to be crippled FOR LIFE!" thing. A single or few EXTREME cases using dedicated, orders of magnitude stronger, aromitase inhibitors does not make for a general result for people taking resveratrol.

Some people get crippling pain from resveratrol, and some from Cipro, just like some do from AIs. This does not imply that the mechanism is the same, even if it could be. At least for Cipro we know it is not. But assuming for the sake of argument that the mechanism is aromatase inhibition, it does not really matter that resveratrol is a weaker AI. Maybe it makes up for that by being a stronger SERM. Whatever the case may be, if it causes the same amount of pain as a dedicated AI, there is quite possibly the same amount of damage.

But those who do experience this now have an answer and possible solutions. Although our proof isn't conclusive, it's heavily supported by all lines of evidence.

I agree that AI is a plausible. I don't think it is yet heavily supported by evidence, though.

Edited by andre, 29 May 2009 - 10:42 PM.

By the way, the fact that several people reported gradual pain onset the first time and then rapid onset on subsequent times, after having stopped resveratrol for a while, suggests that there may be injury that persisted long term even after pain symptoms went away in the meantime.

Edited by andre, 29 May 2009 - 10:31 PM.

I agree that AI is a plausible. I don't think it is yet heavily supported by evidence, though.

I'm going with this one in my case, even though I think it's very much unclear as to the extent that resveratrol suppresses estradiol.

My localized pain in both elbows has gone away in the past quarter. No changes in diet (low glycemic) or exercise (I still do a heavy (for me, at least) 5x5 routine and to hell with cardio). And my vitamin D levels were apparently low the entire time despite 2000 IUs qd. But both my TRT and Resveratrol regimen changed.

I switched from 600mg 50% resveratrol bid to the Tween 80 250mg bid.

For my TRT protocol, no Arimidex, HCG was added (250 IUs eod) and Androgel dosage raised from 7.5 to 10g qd.

Estradiol (Labcorp 004515, range 0-53 pg/mL) went from 21 to 43. (My Doc doesn't like it this high, but I apparently do.)

So estradiol doubled from increased aromatase of the additional testosterone, joint pain went away concurrently (coincidentally?), and the increased dosage of resveratrol failed to inhibit (at least totally) the additional aromatase.

Dunno exactly what to make of all this, but guess I'll stick with it for now.

I can see how it may sound alarmist to you, but in some cases the pain reportedly associated with resveratrol on this and other threads has been severe and debilitating. What does it matter that it is a weaker AI if the end result is the same? At least a couple of people have had long term tendon problems after stopping resveratrol. If someone has joint or tendon pain, and you tell them not to be alarmed because it is probably nothing serious, they are likely to continue and may do themselves further harm. So without a definitive understanding of the mechanism being available yet, I consider that bad advice. Neither you nor I know for sure if this pain is indicative of damage or toxicity to those individuals. Pain more often than not means damage, and we all know that tendons are a bitch to heal once damaged. Until we know, I think it is irresponsible not to advise, indeed alarm, those individuals into stopping. Someone has to do it.

I have never tried to alarm you or anybody else who does not have pain into stopping.

There's a probability we'll get hit by an asteroid tomorrow that'll wipe out all life. There's a higher probability that you'll die in a plane crash, and an even higher probability that you'll be struck dead by lightning. Yet, all these probabilities are extremely low. Being alarmist does /not/ help a situation, mostly because not everyone who reads it will take the time to qualify the situation, although you did do a slight qualification. Never the less, it was consistant with your pattern of behavior from the very first post I've seen you give on this matter to now. Basically, I was trying to temper you down, to keep things logical and rational, and remove pathos from discussion. I am not, and never was, trying to be offensive or anything.

On the other hand, if you've noticed, I've adviced people with such pain to cut back or stop and see what happens. Continuing with something that causes pain is not wise, and should be stopped if a solution is not known. Ideally, we'll find that solution that doesn't require those people to give up resveratrol; and that's the point of this thread, not to be alarmist in any way, shape, nor form.

Aromatase inhibition is plausible but not definite. But I don't think pain onset with aromatase inhibitors is necessarily rapid. See for example the Arimidex case study I posted where things started happening after five months.

No, several claim gradual onset the first time (sometimes with rapid onset on subsequent times after stopping). So no, a two-day study on 40 people is probably not nearly good enough to show this up.

You missed the point. I said /common/ phenomenon. If aromatase inhibition is the method, then acute dosing, which rapidly inhibits aromatase, if it was high enough and severe enough, would have a good probability of causing joint pain, as illustrated with dedicated aromatase inhibitors. This does not mean, in any way, that the pain won't manifest over the long term only, indicative of resveratrol being a weak AI. That is also consistent with the mouse date. However, the point was, that fact /drops/ the probability of it happening at all, especially since almost everyone takes much lower doses than the highest does in that safety study.

Some people get crippling pain from resveratrol, and some from Cipro, just like some do from AIs. This does not imply that the mechanism is the same, even if it could be. At least for Cipro we know it is not. But assuming for the sake of argument that the mechanism is aromatase inhibition, it does not really matter that resveratrol is a weaker AI. Maybe it makes up for that by being a stronger SERM. Whatever the case may be, if it causes the same amount of pain as a dedicated AI, there is quite possibly the same amount of damage.

That brings up another point. Cipro causes pain by being directly toxic to and killing tenocytes. We know for a fact resveratrol isn't doing that, and in fact, has been shown to directly protect and help, even heal, muscle, tendon, and joint cells, as I've already said on this very page and elsewhere. So, it cannot share a mechanism with Cipro. This means, its pain must be through another method. Do you have a more reasonable suggestion that fits the facts?

I agree that AI is a plausible. I don't think it is yet heavily supported by evidence, though.

Oh? What evidence is out of line with it, and what hypothesis do you have that is better supported? I'm a scientist, this is how I think. There isn't a single scrap of evidence inconsistent with this theory. All molecular studies on resveratrol, all in vitro and in vivo studies, and the anecdotal evidence here, all point to the exact same thing. We know resveratrol is an AI inhibitor, and could be inhibiting it at the dosages people commonly take. We know that even low doses can under certain conditions lower estrogen levels. We know that lowered estrogen levels cause joint pain, although the mechanism that happens through is unknown. We know that joint pain caused by lower estrogen is quite different per person and people vary wildly in their sensitivity to this, and the breadth of pain that can be caused covers all anecdotal accounts completely. We know that people who have resveratrol associated joint pain, and who have tested this, are more sensitive to and have greater pain caused by stronger aromatase inhibitors like quercetin and pomegranate juice, including yourself. And we know that this is not caused by tissue damage. We also know that resveratrol protects joint and muscle tissue. We know that all animal studies have never see, even over the life span of the animal, any joint problems caused by resveratrol, again making it similar to aromatase inhibitors who manifested this pain primarily in humans rather than animals.

So then, were does /all/ of this point? To the mysterious, and sometimes incredibly severe though rare pain from aromatase inhibition. Many factors can compound aromatase inhibitor pain, such as low testosterone production, low vitamin D, and too much melatonin; this allows for the huge range of pain in different individuals through slight variations in multiple faucets of their biochemistry. This hypothesis of aromatase inhibition leaves nothing out, is extremely robust, and allows for directly testable experiments to be conducted, thus making it worthy of the moniker "hypothesis".

Is it conclusively proven? No, as I said it isn't. But /all/ evidence, ever last scrap, points to it without any outliers. That's some serious support in science for this hypothesis. Sure, it could turn out wrong, but the probability of that is very low, and we can do direct tests to find out!

If you can come up with a better idea that actually fits the fact, then please share it. I've already shown you how slowing angiogenesis isn't and cannot be the reason for joint pain in any way, shape, nor form, and is used to treat and prevent it; so there goes that hypothesis.

Edited by geddarkstorm, 30 May 2009 - 04:30 PM.

By the way, the fact that several people reported gradual pain onset the first time and then rapid onset on subsequent times, after having stopped resveratrol for a while, suggests that there may be injury that persisted long term even after pain symptoms went away in the meantime.

Not necessarily. There's a chance that's true, but that doesn't mean it is. It could be that their bodies were sensitized to resveratrol after the initial run; which is equally as likely as far as we know. Persistent damage is not needed to explain that, and in fact, makes no sense, as persistent damage would have manifested as pain in other situations and not required resveratrol only!

There is also always the chance that some people are allergic to resveratrol. That would also be consistent with the idea above, were the allergy was worsted by the previous exposure.

I agree that AI is a plausible. I don't think it is yet heavily supported by evidence, though.

I'm going with this one in my case, even though I think it's very much unclear as to the extent that resveratrol suppresses estradiol.

My localized pain in both elbows has gone away in the past quarter. No changes in diet (low glycemic) or exercise (I still do a heavy (for me, at least) 5x5 routine and to hell with cardio). And my vitamin D levels were apparently low the entire time despite 2000 IUs qd. But both my TRT and Resveratrol regimen changed.

I switched from 600mg 50% resveratrol bid to the Tween 80 250mg bid.

For my TRT protocol, no Arimidex, HCG was added (250 IUs eod) and Androgel dosage raised from 7.5 to 10g qd.

Estradiol (Labcorp 004515, range 0-53 pg/mL) went from 21 to 43. (My Doc doesn't like it this high, but I apparently do.)

So estradiol doubled from increased aromatase of the additional testosterone, joint pain went away concurrently (coincidentally?), and the increased dosage of resveratrol failed to inhibit (at least totally) the additional aromatase.

Dunno exactly what to make of all this, but guess I'll stick with it for now.

Very interesting. The fact the pain left as your estrogen went up is consistent with our ideas so far. It's also interesting to note all the other products you are taking and the possible interactions.

There is a trend to simply blame resveratrol immediately for joint pain (or any effects, around this board at times), despite other supplements being taken; when those supplements or the combination of them could be contributing. Some people have been able to rule out everything and pinpoint it down to resveratrol without a doubt, but we still cannot assume every negative result where it's included is directly related to it, just like we cannot assume every positive result is either. Could always be the combination of factors, and that the original resveratrol was 50% was behind it.

Still, the fact the pain left as your estrogen rose points to the problem having been aromatase inhibition or other factors causing a low level of estrogen. Even if resveratrol is inhibiting aromatase, there is still ways to counter that, such as with more testosterone. Furthermore, from what little I know of AI associated pain, more sunlight and vitamin D perhaps, seems to do well to cure it.

So, the issue is still very cloudy, but we have a lot to keep in mind. Thank you very much for your information, and I'm really glad the pain is going away!

Thanks geddarkstorm, we've missed you.

The above agrees fully with my experience: no tendinitis or joint pain with resveratrol initially even at high (>2 gram) dose, but adding quercetin at 500 or 250 mg, joint pain that ceased on discontinuing quercetin.

I tried luteolin, and thought it was causing pain as had quercetin, but I realize I had added pomegranate juice to my regimen at about the same time. On discontinuing pomegranate, my joint and tendon pain resolved. Currently I am using resveratrol (800 mg) and luteolin (400 mg), once in the morning. (There are reasons I believe they are complementary, beyond boosting resveratrol serum levels by inhibiting sulfonation.) I've had no joint, muscle or tendon pain from this.

I've missed being around here. I'm still really busy and am only really here for some of this weekend. I am still working on the reference guide I promised. Just a lot of work, since I'm trying to include every study of resveratrol I can possibly find in an easy to read, categorized approach. It's coming...

Thank you again for this info. It was your work with this that helped give the aromatase inhibition hypothesis life while we were totally at a loss. Sorry you had to go through that pain.

Now that we can explain all the phenomenon, we have a good chance we've found the right explanation. But, who knows if new information will come out that'll flip it on its head, or support it even more.

Sadly though, we still don't have a concrete set of solutions to try.. other than sunlight, bah. There's gotta be something more.

Erm, just to clarify, Andre. I'm really sorry if I came across as harsh or hard on you, that wasn't my intent. Your statement got my panties in a bunch, mostly because the very paper you posted about the aromatase inhibitor tendopathy case showed that there was no permanent damage, and pain disappeared once the person stopped taking the drug (which means it wasn't permanent ). Yet you still made a leap to say resveratrol could be causing permanent damage, when even the dedicated aromatase inhibitor was not being claimed to do so. Again, the person only had disabling pain while on the AI, and once that was discontinued, the pain went away. And the paper you posted also stated similar examples of the same.

It was just quite a leap to me, saying resveratrol could be causing permanent damage when even the dedicated AIs in that paper weren't!

But anyways, I forgot to thank you for that paper. It was very very interesting. That the AIs could cause Achilles' tendon pain was especially interesting, right there with the anecdotal reports. If only we knew for sure the mechanism by which this is occurring, by which AIs cause pain, we could work to prevent and fix it...

Edited by geddarkstorm, 30 May 2009 - 05:27 PM.