Androgen stimulates transcription and replication of XMRV

omerbasket

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Found the following study, which was published, as I understand it, in this month:
http://www.prohealth.com/library/showarticle.cfm?LIBID=15127&UTM_CAMPAIGN=Feed

[Note: Androgens are compounds/hormones that stimulate male characteristics. Testosterone is the primary androgen, and in turn produces another androgen - dihydrotestosterone (DHT) - which has been associated with prostate cancer.]

Xenotropic murine leukemia virus-related virus (XMRV) is a gammaretrovirus originally identified in a subset of prostate cancer patients. Because androgens stimulate prostate tumors and some retroviruses, we investigated the effects of dihydrotestosterone (DHT) on XMRV transcription and replication.

Transcription from the XMRV U3 region was stimulated up to 2-fold by DHT, but only in cells containing a functional androgen receptor.

Mutations in the glucocorticoid response element (GRE) of XMRV impaired basal transcription and androgen responsiveness.

Furthermore, DHT stimulated XMRV replication 3-fold, whereas androgen inhibitors (casodex and flutamide) suppressed viral growth up to 3-fold.

Findings suggest that integration of the XMRV long terminal repeat (LTR) into host DNA could impart androgen stimulation on cellular genes.

Source: Journal of Virology, Feb 2010;84(3):1648-51. PMID: 19906923, by Dong B, Silverman RH. Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA. [E-mail: silverr@ccf.org]
I would be happy if the people here who have knowledge in science would tell us what exactly does this study says - about us and also about prostate cancer patients (or patients of any other disease).

In addition, I would like to ask: Are the two mdicines described there - casodex and flutamide - can possibly be a good treatment for us and/or for prostate cancer patients?

Thanks in advance!
Omer.
 

julius

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I'd be interested in hearing some analysis of this as well.

Also, does anyone have any thoughts on Saw Palmetto extract for this. From Wiki on Saw Palmetto extract,

"Saw palmetto extract is the most popular herbal preparation taken for benign prostatic hyperplasia...."

"...proposals for mechanisms of action include interfering with dihydrotestosterone binding to the androgen receptor"
 
G

Gerwyn

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Found the following study, which was published, as I understand it, in this month:
http://www.prohealth.com/library/showarticle.cfm?LIBID=15127&UTM_CAMPAIGN=Feed



I would be happy if the people here who have knowledge in science would tell us what exactly does this study says - about us and also about prostate cancer patients (or patients of any other disease).

In addition, I would like to ask: Are the two mdicines described there - casodex and flutamide - can possibly be a good treatment for us and/or for prostate cancer patients?

Thanks in advance!
Omer.
XMRV has a "tail" with a repetitive base sequence where it integrates and seperates from the host DNA U3-R-U5-Gag .The U3 region promotes replication and can be stimulated by androgens in cells that have the receptor needed for androgens to enter.This means that XMRV replicates in these cells much more than normal.the drugs mentioned block androgen sensitivity at the U3 region probably at a certain base sequence GRE.Both drugs are used to treat prostate cancer in combination but can produce life threatening side effects.They shouldn,t have any effect on replication of xmrv in other cells
 

omerbasket

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Thanks Gerwin.
If XMRV's replication is related to androgen - perhaps it's realted to androgen also in other cells (not related to the prostate)? and if so - are there drugs that can inhibit androgens in these cells?
Thanks in advance, one again...
 
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Gerwyn

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Thanks Gerwin.
If XMRV's replication is related to androgen - perhaps it's realted to androgen also in other cells (not related to the prostate)? and if so - are there drugs that can inhibit androgens in these cells?
Thanks in advance, one again...
My worry is that there is a preponderance of women that suffer from Me while they produce androgens would the levels be high enough to explain the increased replication rate of xmrv.unless progesterone does the same but better.The drugs we mentioned are for males only and would produce unacceptable side effects in women
 

omerbasket

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Ok... But, as you know, we males also deserve to live... :)
So, can these drugs be good for us? And also - might they help prostate cancer patients (I ask because I know someone who has prostate cancer)?
 
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Gerwyn

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Ok... But, as you know, we males also deserve to live... :)
So, can these drugs be good for us? And also - might they help prostate cancer patients (I ask because I know someone who has prostate cancer)?
For prostate cancer they are useful treatments to prevent spread for ME blocking u3 and gre should inhinit propagation. I dont know whether xmrv does more damage whilst integrated into the dna via TGF -beta one and glutathionine depletion.As its such a simple retrovirus it doesnt code for immunosuppressive proteind like AIDS but infection does affect the cell mediated immune system ----How- it must be something to do with its integration sites--what I have no idea.keeping it integrtated might not be such a good idea.
 

omerbasket

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So, excuse me because it's hard for me to understand the science here - in the bottom line - do you say that you tend to believe that using such drugs as the drugs mentioned (or even other drugs to inhibit androgen) would not help, at least not significantly, ME/CFS patients? And what about prostate cancer pateints?
 
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No, tentatively they are not a viable option to inhibit XMRV outside of the prostate. These drugs can already be used in prostate cancer.
 
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Gerwyn

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But would it help prostate cancer patients eliminate at least some of their XMRV infection?

it should slow down the rare of xmrv replication so reduce the number of virus particles so there would not be so many to infect other cells so if used early and assuming xmrv is causative yes
 

Cort

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I don't understand the androgen, cortisol, progesterone connection in XMRV; all of these stimulate XMRV replication but ME/CFS patients typically have low levels of these hormones and some patients benefit from cortisol, testosterone, etc. supplementation. Dr. Mikovits talked of maybe lowering these levels but they already appear to be too low (???). Its a conundrum for me.
 
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Cort, I have been wondering the same thing. To be clear, though, on progesterone, for women, her recommendation was to level out the progesterone, reducing the spikes and valleys. For women, our progesterone can go up, but it also falls very low in the cycle. And as women approach menopause, their spikes and valleys can become erratic.

Given men have low levels of progesterone, maybe they need to look at reducing other triggers for their treatment.

I also notice I feel worse CFs symptoms, when my progesterone is at its lowest in my monthly cycle. Of course, since the immune system has a three-day delay, it could be my symptoms are the result of the progesterone spike I had a few days earlier. So the feeling bad is the cytokines and inflammation from the viral load (both XMRV and latent) from the increase replication rate that happened three to seven days earlier, when the progesterone was high.

But it does seem counter intuitive that when my progesterone is its lowest, three days before my period starts to two days after, that I feel the worse.

But, this was an in vitro study. therefore, we know the virus does reduce replication when androgens are missing. So overall, that can give us some direction.

Cortisol being low, as most CFSers have, including me, with the XMRV being activated by high cortisol, well, I don't know. Could it be that when inflammation or high cytokines are released, the adrenal gland is told to stop producing cortisol so that you will be forced to rest, needed so your immune system can fight infections? So if we are in chronic inflammation mode because XMRV has reduced NK cells and their function, causing latent virus activation, then the body is constantly in the mode of keeping the adrenals in low output so person can heal.

I love talking theories. But I love concrete information more. I have a feeling Mikovitz understands all of this and it all actually makes sense. The problem is with us. Hopefully she will keep giving speeches, Reno mushrooms, and someone will ask her these questions.

Or, maybe Dr. Donnica? Hey, are you there? Help us out here since you are a doctor and speaks for WPI, so Mikovitz can keep doing here laboratory work. HELP US.

I also wonder if it makes sense to reduce inflammation since that is the human's normal response to cause NK Cells to attack viruses, such as latent EBV, the enterroviruses, etc.

Seems to me, the key is to stop XMRV replication and stimulate fresh Nk cell birth so we have healthy ones to replace the infected ones.

Tina
 
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Gerwyn

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I don't understand the androgen, cortisol, progesterone connection in XMRV; all of these stimulate XMRV replication but ME/CFS patients typically have low levels of these hormones and some patients benefit from cortisol, testosterone, etc. supplementation. Dr. Mikovits talked of maybe lowering these levels but they already appear to be too low (???). Its a conundrum for me.
this could be consistent with the idea that XMRV does the most "damage" during its latent phase low androgen low rep more symptoms just a thought. something is causing our thf-beta i to drop cellular competition immuno suppression in the aids mode is impossible because of its simplicity-so how is it doing it?
 

julius

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Is it possible that once the hormone binds with the receptor of an infected cell, it remains bound longer than it would with a healthy cell. Or maybe that it remains permanently bound?

If that were the case, then that could explain why tests for levels of these hormones show low levels. There is just as much hormone present in the body, but since it is bound up with receptors, isn't being detected.

I have had just about every testosterone test available, and all are normal, except for extremely low free-T. This, according to my specialist, show that I am producing plenty of T but it is 'bound up' (his words) somehow. He thought it was probably bound with albumin.
 

SunnyGal

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Some random thoughts

I don't understand the androgen, cortisol, progesterone connection in XMRV; all of these stimulate XMRV replication but ME/CFS patients typically have low levels of these hormones and some patients benefit from cortisol, testosterone, etc. supplementation. Dr. Mikovits talked of maybe lowering these levels but they already appear to be too low (???). Its a conundrum for me.
Does XMRV need these things to become activated but once the immune system is crippled by it (and other viruses that cause their own host of problems have jumped on board), maybe XMRV doesn't need high levels of these hormones to stay active? Just throwing out an idea. No idea if it makes any sense.

When I first got sick it was when I got pregnant the first time. Progesterone goes up 10 fold, I think I read somewhere, during pregnancy. I got more sick each time I got pregnant after that.

When I got extremely sick a couple of years after that it was due to extreme stress with high evening levels of cortisol. Morning levels were extremely low but evening levels were high. During my 10+ years of illness I've never had across the board low cortisol levels as I know so many do. I seem to fit well with what Dr. Mikovits has explained so far. I tested positive for XMRV in both PCR and culture.

Perhaps people with low cortisol levels for years have something else that activates XMRV, such as monthly progesterone spikes? Or maybe there is something else that activates XMRV that we don't know about yet?

Sunny
 
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Gerwyn

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Does XMRV need these things to become activated but once the immune system is crippled by it (and other viruses that cause their own host of problems have jumped on board), maybe XMRV doesn't need high levels of these hormones to stay active? Just throwing out an idea. No idea if it makes any sense.

When I first got sick it was when I got pregnant the first time. Progesterone goes up 10 fold, I think I read somewhere, during pregnancy. I got more sick each time I got pregnant after that.

When I got extremely sick a couple of years after that it was due to extreme stress with high evening levels of cortisol. Morning levels were extremely low but evening levels were high. During my 10+ years of illness I've never had across the board low cortisol levels as I know so many do. I seem to fit well with what Dr. Mikovits has explained so far. I tested positive for XMRV in both PCR and culture.

Perhaps people with low cortisol levels for years have something else that activates XMRV, such as monthly progesterone spikes? Or maybe there is something else that activates XMRV that we don't know about yet?

Sunny
I find the association of HERVs with MS fascinating .These vestigal viruses seem capable of doing damage in their latent----for millions of years---phase usually because of mutations and deletions.I wonder if XMRV is more dangerous inserted
 

ukxmrv

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I found a sort of "androgen for dummies" and women type article here

http://www.infertilityphysician.com/androgen/intro.html

Years ago when I was being examined for infertility I was told that I was PCOS like and that my ovaries showed signs of PCOS. However, there was something that didn't add up in my blood-work that stopped the diagnosis of PCOS being made. I'm going to have to dig out those very old test results and see if I can make sense of it.

Certainly I fit the pattern described in that article for too much androgen in women (hair, body shape etc).

I've got low cortisol, low cholesterol.

XMRV+
 

ukxmrv

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This is from the same website above but another page. I don't have excess cortisol but it is the part about the body trying to produce the cortisol and producing the adrenal androgen

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The problem is basically the inability of the adrenal gland to make the hormones your body requires - principally cortisol- in proper amounts. Cortisol is not only necessary for every day life, it is one of the body's main hormones in times of stress - both physical and emotional. Many people will notice that acne worsens in times of emotional stress. Women will notice that their facial hair growth is worse in times of stress. Menstrual irregularities may be worsened in times of stress and the over production of cortisol by the adrenal gland is one of the mechanisms for this.

In times of stress, the adrenal produces increased amounts of cortisol. If the adrenal has to work overtime to produce the necessary amount of cortisol, it produces even greater amounts of androgen.

It is impossible to fix the underlying adrenal abnormality although gene therapy is already a theoretical possibility. It may prove to be an actual therapeutic tool within the not too distant future.

In the meantime, since the adrenal cannot be fixed and since the problem is to make sure that the body has a proper amount of cortisol, the solution is simply to give your body what it needs in terms of cortisol. By giving you cortisol or a hormone derived from cortisol, your body's daily needs are supplied and the overproduction of adrenal androgen is eliminated.

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Maybe that explains the supplementation paradox? i.e. if we supplement with cortisol (as ours is low) then the production of excess adrenal androgen ceases?
 

Dr. Yes

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Androgen stimulates XMRV Transcription & Replication

ETA - Okay I just realized the abstract to this HAD been posted (of course) here:

http://www.forums.aboutmecfs.org/sh...of-XMRV&highlight=androgen+xmrv+transcription

...and if there is a way to delete threads I forgot how. If any mod/admin reads this, could you please delete this thread?
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Androgen Stimulates Transcription and Replication of Xenotropic Murine Leukemia Virus-Related Virus

Beihua Dong and Robert H. Silverman*
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195
Received 20 August 2009/Accepted 4 November 2009

Xenotropic murine leukemia virus-related virus (XMRV) is a gammaretrovirus originally identified in a subset of prostate cancer patients. Because androgens stimulate prostate tumors and some retroviruses, we investigated the effects of dihydrotestosterone (DHT) on XMRV transcription and replication. Transcription from the XMRV U3 region was stimulated up to 2-fold by DHT, but only in cells containing a functional androgen receptor. Mutations in the glucocorticoid response element (GRE) of XMRV impaired basal transcription and androgen responsiveness. Furthermore, DHT stimulated XMRV replication 3-fold, whereas androgen inhibitors (casodex and flutamide) suppressed viral growth up to 3-fold. Findings suggest that integration of the XMRV long terminal repeat (LTR) into host DNA could impart androgen stimulation on cellular genes.