Restoring sensitivity to androgens using bicalutamide - a somewhat crazy proposal

Hey guys. I’ve been lurking on the forum for a while now and wanted to chime in on the discussions. I haven’t filled out a symptom chart yet but to give some background I took propecia for a good 3 months and quit due to effects on libido and energy level, which have persisted for 8 years since quitting.

I used to be a prostate cancer researcher and received my PhD in pharmacology and I am hoping I can contribute to and learn more from some of the dialog going on here. After reading a ton of posts about things people have tried, from my perspective it really appears to be an issue of insensitivity to androgens/testosterone (as many of you have noted). This is apparent by the fact that, although there are individuals with dramatically lowered T levels, many of us have normal or only slightly lowered T levels (including myself) yet experience the same side effects. Furthermore, increasing testosterone using gels or drugs which boost T (e.g., clomid) often have a minimal effect or if they do have an effect, the results do not persist.

This leads me to agree with thoughts on here posted by Awor and other members that the cause is primarily an epigenetic one. To summarize, while taking propecia, our T levels skyrocketed to supraphysiological levels and when we stopped taking propecia, our bodies were fully exposed to these levels. As a compensatory mechanism, I am hypothesizing that key genes involved in androgen response were methylated (i.e., shut down) to dampen the response to these super high levels of T as our bodies tried to protect themselves. The problem is that after our bodies equilibrated to the lower levels, the genes remained methylated thereby maintaining this poor response to T despite having physiologically normal levels of testosterone. Thus, all the treatments people have taken to boost their T levels super high would only reinforce this negative feedback loop.

After doing a bit of Pubmed searching, there is unfortunately very literature available on restoring sensitivity to androgens. But, research tells us that DNA methylation is a process that can be reversed and DNA de-methylation occurs quite frequently. My hypothesis is that this would also be possible in our cases, except that we have not had a stimulus strong enough to cause a DNA de-methylation event to occur. In fact, we are only reinforcing the DNA hypermethylation when we keep using T boosting drugs like clomid or testosterone gels.

My “crazy” idea is, what if we were to really lower our T levels dramatically using anti-androgens like bicalutamide (aka Casodex), to virtually non-existent levels for a short period, then slowly SLOWLY bring the levels back up to a normal healthy male level. Theoretically the cells responsive to androgen would note this decrease and demethylate the appropriate androgen response genes, thereby restoring sensitivity to androgen. The hard part would to completely avoid the androgen/testosterone spike that would occur after removing the anti-androgens which would cause the DNA to become methylated again. The good news would be that only a short treatment would likely be necessary because from reading member stories, it seems like many people experienced persistent side effects after using propecia for only a week, so if a reversal happens, it would theoretically happen just as quickly.

The protocol used for shutting down androgen using bicalutamide is pretty hardcore as it also requires combination with an injected LHRH agonist (basically a drug which causes a shutdown in androgen production). I’m not sure if we would need the LHRH agonist as well because we may not need to get androgen levels quite that low. Bicalutamide itself is relatively safe as all it does is bind to androgen receptors on the cell and it doesn’t mess with any enzymes like propecia does. I haven’t had time, but i’m sure there is info out there showing just how low T levels get with bicalutamide by itself. The protocol we use would be to most likely do a super high dose for something like 5 days, then slowly slowly taper it off to avoid exposing ourselves to the spike in T levels while (hopefully) leading to demethylation of the relevant promoters and resensitizing ourselves to T.

info on bicalutamide www1.astrazeneca-us.com/pi/casodex.pdf

Any thoughts? Feel free to shoot me down if this sounds too crazy. There are many possible scientific explanations and possible remedies out there so I just wanted to contribute to the healthy flow of discussions.

Cheers.

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If you haven’t already, you should PM Awor. Let him know that you have a PhD in pharmocology, and that you used to be a prostate cancer researcher.

There may be things you can do to help him coordinate or progress the research that he is pushing. We need guys like you, with a scientific background, on the case.

Your idea to remethylate genes using androgen deprivation is an interesting one. Awor will probably have some thoughts on it.

Thanks, and good luck.

Welcome on board, and thanks for this interesting theory.

Of course it will need brave volunteers, because the process is scary and looks a lot like the one we went through when we took Fin and quit.

However, don’t people who tapered off Fin instead of quitting cold turkey experience PFS too? I thought I had made a big mistake quitting cold turkey (I chose to because I didn’t want to further damage anything in taking the drug), but then I was under the impression that tapering off made little difference, I don’t recall if it was in theory or in practice though. My Doc, however, told me about people (or a person) who took 1mg Fina, experienced problems, then took 0,5 and felt OK. Nobody can tell for sure.

Thats very interesting!!

If T levels skyrocketed we would of known about it, plus using finasteride does not stop T from working. Awor’s theory is that the return of DHT, many times more powerful than T, caused epigenetic changes.

A someone who claims knowledge in this area, dont you find it strange that no experiments involving androgen receptors, or cancer, or real-life experience from men who have undergone androgen ablation for cancer has ever resulted in this problem? Doesnt that suggest that this isnt how the body works? Also, what “negative feedback loop”??

What are you waiting for??

Finasteride has essentially a flat-dose response rate so tapering off and cold turkey are essentially the same.

physics.upenn.edu/facultyinfo/frankel/papers/propeciafda2/

1-Just for information,may I ask where have you worked (hospital, university etc) and what university have you graduated from?
2-Also there are some concerns that finasteride causes some physcial damage to prostate and surrounding areas. what is your expeprience and observation about that? there are some studies on Rats that cells in prostate undergo apoptosis. is it reversible in human case?

3-How many people( just the percentage) have you observed to have permanent sides from using meds (like finasteride and other meds) to treate prostate cancer. Were these sides reversible?

Bicalutamide is an androgen receptor antagonist, not an LH antagonist. It actually leads to a dramatic increase in T according to the wikipedia page:

The rise in estrogen caused by bicalutamide (if it is not used in conjunction with a drug that supresses LH or an anti-estrogen) sounds pretty risky. What are your thoughts on this?

Its not much, but there is at least one study that discusses this:
http://onlinelibrary.wiley.com/doi/10.1111/j.1464-410X.2006.06066.x/full

“In conclusion, most men recover supracastrate TT levels after LTAD (Long Term Androgen Deprivation) and external beam radiotherapy, but the time to recovery of ‘normal’ TT levels is prolonged. Few men recover potency and sexual desire. Patient age and the LH/TT ratio, may be predictive of the time to recovery of both supracastrate and normal serum TT levels.”

Scared Male is right; you should try to contact awor if you haven’t already. He is/was looking for scientists to help with the research effort.

Dubya_B, you must be kidding me, right???

Obviously castration can lead to sexual dysfunction. Its so obvious i didnt think I even had to mention it. Its the most obvious explanation for the sexual symptoms from Finasteride too.

However, the theory goes that all of the other symptoms are caused by androgen ablation. And it is the return of androgens that leads to the ‘crash’ which causes the symptoms to persist.

Well, guess what Dubya_B??? Men undergo FULL androgen ablation (not just 2/3 DHT) - but these other symptoms have NEVER been recorded after stopping. The only reason that it is never recorded must be because it never happens. The ONLY conclusion must be that its because the human body simply does not work that way.

Wow, thanks for the comments guys. A lot of really good points, and corrections too.

Oscar, you are right, it’s DHT, I was being careless and using DHT and T interchangeably. I’m a little rusty on my hormone pathways.

In terms of your questions about it being strange that similar findings have not been observed post androgen ablation, I don’t think so as much. Complete androgen ablation is used relatively rarely, typically only in situations where the prostate cancer has become metastatic. I wouldn’t be suprised if the number of men taking propecia is 100x higher than those who have undergone AA. Thus if the incidence of our symptoms is as low as people think it is, there would be much fewer men who had AA with similar symptoms post AA to even report such symptoms. Furthermore, most men who have stage III-IV prostate cancer and get AA would be in the age range of 60-70, so probably had diminished androgen levels and libido to begin with and honestly libido is the least of their worries.

martinM, thanks for the data, it looks like the doses are not going up linearly and instead in multiples of 5 so i think the curve may look a little more flat and the drop off more drastic then it really it is. I would imagine it would be possible to titrate dose by splitting pills (probably still a challenge though)

spstriken, i would like to answer your quesitons but i’d like to stay more anonymous for now if that’s ok. My dept was pretty small at the university i went to, as well as the research hospital i worked at so it would be pretty easy to triangulate and find me if i said anything. One disclaimer, I haven’t been activiely researching for a good 4 years now, I’ve been working in the pharma industry (not Merck haha) more on the business side (hope this doesn’t invalidate my opinions!).

To answer your second question. I haven’t personally used finasteride in the research setting, but at the doses we are talking about I would be fairly certain that it’s not enough to induce apoptosis. When you block androgen signaling (e.g., DHT) the primary effect is presumed to be on slowing growth and proliferation, not causing cell death. If there were some kind of apoptosis, I would expect it to be reversed and cells to continue growing as normal once you stopped taking the drug.

Dubya. You are absolutely right. You caught a mistake. Thanks. Bical binds to AR and essentially blocks androgen from binding to cells and signaling. What I should say is “what if we were to dramatically lower the level of AR gene activity/signaling using AR antagonists like bicalutimide” Still the same concept.
You are right in pointing out that it cause an increase in T because your system starts pumping out more T in response to the shutdown in androgen activity/signaling by bicalutimide. That is why LHRH agonists are used which then shut down the T production leading to a TOTAL androgen ablation, which I am not sure we would need to go to that extent.

I was also thinking about the rise in estrogen levels which could be risky because it could lead to gyno and that’s a really good point. My initial thought was it may not be as much of an issue since we are talkiing about a really short term use but it still is risky. It would probably be best to use an aromatase inh or some other estrogen blocking molecule. The one thing is, if you are blocking both types of androgen (test & est) it would probably make you feel like complete s*** (esp if you are also using the LHRH agonist). I would want to more research into whether there could be any other side effects we should worry about.

Oscar, in the paper that Dubya was referencing I don’t think they were talking about literal castration, just chemical castration wher eyou temporarily mimic the effects of castration with drugs.

Thanks for all the comments and sorry in advance if I am slow in responding. I have a full-time job as well like the rest of you and I’ve been researching this in my spare time. Keep the comments coming and glad to hear more feedback. I will try to contact Awor and other suggested members when I have more time and after conducting a bit more research.

The median change from baseline for:

5.00 mg = 70% (Proscar)
1.00 mg = 65% (Propecia)
0.05 mg = 50% approximately
0.01 mg = 03% approximately

I think this would require a pill cutter that can accurately determine between 1/100 and 5/100 of a pill. Unfortunately even if we had this the accurate data to determine the required dose between these levels required to wean off doesn’t exist. I’m not sure also, but I’ve seen reports that distribution of the active ingredient inside the filler is not always uniform, which would make this an impossible task without the manufacturer’s help.

I think this is key to the whole arument. Awor is saying andogen deprevation can lead to permanent hypogonadism, even after androgens return. Not just lowered libido/ED.

But androgen deprevation is actually quite well studied under the microscope as well as its effects being well documented in real life. Many $$$ are spent, not only on prostate cancer research, but on the effects of androgen deprevation on ARs in prostate cancer. There are thousands of studies on this very subject, nothing like what you have described has ever been documented.

If AA is x100 rarer than propecia use then you need to find the evidence. But it would also make sense for AA to have a much higher rate of these side effects anyway. My own opinion at the moment is that the 0.01% incident of side effects with propecia (and finasteride alone, not just androgen deprevation) is more in keeping with a hypersensitivity reaction.

Oscar, please read that study again. It was conducted on men who had their last injection of an LHRH agonist at least 6 months prior and the study lasted over 4 years.

“The time to recovery of normal TT levels (>8 nmol/L) from the end of LTAD is shown in Fig. 2A. Defining a normal TT level as ≥ 8.0 nmol/L, the median time to a normal level was 2.3 years (95% CI, 1.9–4.2). At 1.8 years 25% of the men had a normal level, and at 4.2 years 75% had a normal level.”

Only 2 of the 20 men were able to have an erection sufficient for intercourse by the end of the study, and one of the two needed a PDE5 inhibitor. I believe only 11 of the men were able to have intercourse before starting therapy (age ~55-80) though.

I’ll admit that this information by itself is mediocre evidence but it is still a study that demonstrates a side effect continuing long after androgen deprivation in spite of the return of normal testosterone levels.

I think this has already been asked, but how would this be any different than using other agents that reduce AR signaling through reduction of DHT to modulate sensitivity? This has already been attempted without much success.

I dont know alot about this subject matter so maybe someone can enlighten me. I cant see how someone can take a 5AR inhibitor for a couple of days and suffer from the same side effects as someone who has takin it for years, I find it really hard to believe that are prostates are destoryed. I am starting to wounder if are cell have mutated or if something is still binding to the cells themselves, why are some people experience brief recoveries trying different things? Hopefully Awor will be shedding some light on this issue soon.

Dubya_B let me try and spell it out for you:

1.) The effects of androgens on the human body, including at a cellular level is very well studied.

2.) “Lowering androgen levels can cause permanent sexual dysfunction that persists even if androgen levels are restored.” <-- Well known to science.

3.) “Lowering androgen levels can cause permanent hypogondal symptoms (muscle loss, fatigue, anhedonia) that persists even if androgen levels are restored.” <-- Not known to science.

4.) Conclusion: Using finasteride and lowering DHT by 2/3 will not cause the symptoms, apart from the sexual ones. Therefore for some or all of the people here it is not the lowering of androgens that have caused their problems but something else, specific to finasteride.

Oscar and Dubya, you bring up a good counterpoint that there are hypotheses that “androgen deprevation can lead to permanent hypogonadism”. I think this underscores the importance of any of us researching all the risks before trying a new approach, to avoid putting ourselves in a worse position that we started. If you have any other references to studies demonstrating this I’d be interested to see. In terms of the study that Dubya referenced by DR Wilke, I don’t think it is quite analagous to our situation because the subjects studied had long term androgen deprivation/ablation and radiotherapy on top of that, which is quite severe. Nevertheless, it is relevant and can’t be ruled out as a concern.

Oscar when you wrote this:

2.) “Lowering androgen levels can cause permanent sexual dysfunction that persists even if androgen levels are restored.” <-- Well known to science.

Were you referencing a particular study? It was something that I haven’t heard of in my researching on the topic (other than the DR Wilke study which alludes to this)

The theory which some members on this site have and I feel makes sense is that individuals with our symptoms are hypersensitive to high levels of androgen, so that when androgen levels come roaring back after stopping propecia (or androgen ablation) our bodies methylate specific androgen responsive genes to downregulate and desensitize our bodies’ response to androgen. This methylation persists even after androgen levels return to normal.

Dubya, to answer your second question, you are right that using an androgen receptor (AR) antagonist like bicalutimide should have the same net effect of using proscar and other DHT inhibitors. Both approaches have the end goal of blocking AR signaling. The main reason I suggest bicalutamide is that finasteride acts further upstream in the AR signaling pathway and I’m not sure whether it has some off target effects on some other enzymes. Also, I don’t know about you, but I have some serious apprehension (logical or not) about ever taking finasteride again. Bicalutamide just binds straight to the AR. Of course, I have some bias because I’m familiar with using it in the lab in the past and know that it is pretty specific for AR.

The key questions are:

  1. If my theory is true, by what % would we have to inhibit AR signaling (whether by AR antagonists or 5ar inhibitors) to cause a demethylation event to occur and resensitize ourselves to androgen? Would we need total androgen ablation (e.g., bicalutamide with LHRH agonists) or would the 70% reduction in serum DHT using 5mg proscar (finaseteride) be sufficient to get things kick started?

  2. How long would we need to suppress androgen signaling before this theoretical demethylation occurs? (my theory is not that long given how rapidly some members here developed their symptoms)

  3. To what degree does bicalutamide inhibit AR signaling as a single agent, without LHRH agonists? (this one should be searchable in the literature)

  4. What is the proper method of titrating the dose of bicalutamide (or finasteride if one chooses) in order to ensure that a spike in AR signaling does not occur. (Regarding the question about pill splitting, In the lab, we occasionally crush pellets and solubilize them in 70% ethanol, then we could just measure out certain amounts with a pipette or I guess eye dropper for us since we don’t have lab equipment. Would have check whether bicalutamide or fin is soluble in ethanol though)

  5. Lastly, what are the main risks we should be aware of? (e.g., gynecomastia unless aromatase inh are used)

Did anything come of this theory?

You have a good point but you also have to take in consideration that bicalutamide is an HDAC inhibitor and Propecia and Proscar are NO

I dropped some of this stuff about a week ago, maybe an 1/8th of a 50 mg pill (6-7 mg)
It has a 6 day half-life so it is still coming out of my body. I am very prone to gyno so had to use aromatase inhibitors concurrently which I also recommend if anyone try this (raloxifene, celery root(androsterone + luteolin), or arimidex if you can get).

As it is clearing out of my body I notice more and more mental clarity and feeling a return of focus and old pre-Fin mental state. Maybe won’t be cured by this one cycle, but if I drop a larger dose a couple more times, I am almost certain all the brain fog and mental issues could be 100% gone.

It somewhat makes sense that if our receptors were upregulated while being on Fin and then hit hard by the hormonal increase leading them to be permanently downregulated…

Bicalutamide inhibits androgen receptors while keeping hormones high (essentially creating the inverse situation) - this leads to brain sensing low androgen receptors and potentially clearing the epigenetic flag / methylation / whatever which lead to silencing of the AR, making it fully functional again.

It is a dangerous proposition but probably in 3 years of all the things I tried the most promising thing I took for brain fog / overall consciousness / mental clarity since I came off Fin.

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Well, that sounds very very promising!

Best of luck and keep us updated?