Hi all
I would like to give you an update from my interactions with the scientific community.
Looking up and trying to contact scientists around the world has been a pretty intensive and sometimes demoralizing task. Obviously, not all were interested in talking with me (often because they thought that our problem was not relevant to what they were doing). Some were also very surprised to be contacted by some guy from outside of their “circle”. In order to give me a chance of having an intelligent conversation with these people I have spent many months reading all kinds of scientific publications (mainly on pubmed), which I though had relevance to our problem (including many of the excellent links provided by mew and other members of this forum). Each time I came across a term which I didn’t understand, I looked it up. I am currently also following courses on Biochemistry and Molecular Biology at Berkley University (over the Internet). I can strongly recommend this for anyone (with sufficient time) who is interested in getting more background on how we function at the molecular level (which I believe is highly relevant to our problem, I’ll talk about this further on). In addition, a well known cell biology scientist and relative of mine, has been giving me personal guidance during the whole process.
In result I have managed to get into contact with a number of scientists, which are involved in research in the following areas:
- Androgen Insensitivity Syndrome (AIS)
- DNA methylation
- Androgen receptors
- Endocrine disruptors
- Muscle dystrophy
- High end genomic functional studies (including gene expression)
I have had the chance to have some very interesting conversations with these specialists and would like to provide a short summary of the information that I managed to gather.
First of all, the fact that finasteride can cause long lasting symptoms, like the ones described in this forum, was news to all of these people. This clearly confirms that one of the biggest problems this group is currently facing is a complete lack of awareness, even within the scientific community. Our problem is completely off of the map. Hence the first objective that I have been pursuing is to build interest for a case report. Even this has so far proved to be extremely difficult. Androgen receptor related research basically falls into two main categories: Prostate cancer and AIS. We don’t fit either. In order to define a new category, we first need to get this problem onto the map. We can achieve this if someone is willing to do a case report. Only then can we hope for further investigation into our problem.
The other difficulty we are faced with, and one scientist even told me this, is that our problem is not sufficiently dramatic. We have neither a very large affected population nor are the side effects (on average) sufficiently dramatic to catch immediate and widespread attention. Our 1200 members from the forum pale in comparison to the 190’000 new prostate cancer cases each year (alone in the United States). Out of these cases, almost 30’000 die each year. Never mind that for some us it may seem more attractive to die from prostate cancer than to deal with these side effects indefinitely and not having a universally clear diagnosis. Indeed, the most severely affected amongst us are truly in a serious health condition (I consider myself as part of this group).
According to the specialists which have examined me, the severity and duration of my side effects can only be explained by a problem at the molecular level - most likely at the level of the androgen receptor. I fully agree with them and would also say that the more “simple” theories going around on this site, even though easier to understand, just don’t cut it when it comes to explaining side effects such as life threatening depression, extensive damage to penile structure or massive muscle wasting.
Accordingly, my interaction with basic scientists was focused on the androgen receptor theory (including related signaling pathways) and not things like the prostate, pituitary or whatever. I also chose the people I contacted based on what they have published in the fields of the androgen receptor, AIS, prostate cancer, epigenetic and gene regulation mechanisms, 5AR and other closely related fields.
This is what I have learned from talking with these scientists:
- Both the scientist specialized on the androgen receptor and the scientist specialized on endocrine disruptors deemed it to be plausible that our side effects are caused by some form of androgen receptor malfunction.
- The AR specialist told me that the androgen receptor was extremely complex and that over 200 known proteins interact with it, either silencing or enhancing gene expression. Science currently only partially understands how it all plays together.
- We know that mechanisms of self-regulation at the protein level exist, but don’t understand their feedback system. It seems that proteins, such as the androgen receptor, have some mechanism of self-regulation (at the protein level) which are probably based on genetically/epigenetically defined set points. In other words, the receptor has a perception of what the “right” level of gene expression is supposed to be. If this level is exceeded, it shuts down. This regulation happens through various mechanisms of gene regulation (dna methylation, other proteins, post translational modification, etc.).
- One possible explanation of our problem could be, that this set point somehow got messed up by lowering DHT levels. It could also be that our bodies are overproducing some protein involved in gene silencing of the androgen receptor.
- It also seems to be clear that receptor signaling pathways can “permanently” change under hormonal influence (or lack thereof). A good example of this are LNCaP prostate cancer cells. When deprived of androgens through androgen ablation therapy (which notably includes finasteride), the signaling pathways somehow changes to allow the cells to further grow, even with very low levels of androgens. In many ways this is the exact opposite to what seems to have happened to us. Instead of becoming super sensitive, our receptor/pathways have become super insensitive. This analogy was noted by the androgen receptor specialist. Another good example of this is tamoxifen resistance. Estrogen receptors (ERbeta) in breast cells, when treated with tamoxifen, eventually start perceiving tamoxifen as an agonist instead of an antagonist. I personally have experienced this. I have been on tamoxifen since about 2 years now. Initially, this treatment helped to reduce my breast pain. Since about 6 months, tamoxifen actually increases my pain level. In other words, tamoxifen started being perceived as an estrogen at the breast (ER) receptor level.
From talking with these scientists, it is also very clear that our problem is way beyond the current envelope of basic science. Trying to explain what has happened to us is about as daunting as trying to explain the exact mechanism as to why prostate cancer cells become super sensitive to androgens once deprived thereof. Billions of dollars have been invested into this sole question since over 20 years and we still don’t have real answers. Asking for a research solution to our problem is currently like asking for a cure for cancer. We’ll get there someday, but I doubt it will be in a time frame which is still relevant to us. On the other hand, a breakthrough in understanding the underlying mechanisms behind signaling path changes, in prostate cancer cells for example, could also improve the chances of explaining our problem (this was noted by two of the scientists that I have talked with). Molecular tools and diagnostic equipment are advancing at an incredible speed. Discoveries often lead to further discoveries in a snowball fashion. It remains hard to tell, what advances will be possible in what time frames.
Even though a potential cure currently seems out of reach, it is quite realistic that we can actually prove or disprove the androgen receptor theory and what has happened to us. Gene expression studies are becoming increasingly accessible with a unit cost of around 700USD for materials (multiply that by at least 40 individuals and add salaries/time of specialists and we are still talking six digits). Of course, you still need the scientist that can design the test and interpret test results correctly. On the other hand, given the complex nature of protein interaction at the signaling level, it is not said that our problem can be reproduced in a lab environment (in vitro). Also, if our problem is related to some form of post translational modification (chemical modification protein after its translation), a gene expression study isn’t going to reveal this either. But such a scenario is provable as well, although more complex (statement from lab scientist specialized on executing such studies).
The bottom line to all this is: Our problem is likely to be at the molecular level, an area which is still relatively poorly understood by basic science. In order to get our problem onto the map (an get research going), we need to get something published. As far as I can tell, it is not realistic that a cure will be found to our problem within a useful time frame – even once research has started. However, it is realistic that our bodies can heal themselves (at least in some cases). We must support our bodies the best we can in the process. Given the assumption of this problem, it is also not realistic that a simple doctor has any real chance of helping us. A regular doctor (as opposed to a scientist) is governed by the boundaries of basic science. Even worse, he/she is governed by commercialized solutions (i.e. pharma products) resulting from basic science. So if the basic scientists are still trying to figure out what’s going on at the molecular level, we can’t expect a simple doctor to be able to solve this. Most of us that have been to see various “specialists”, without real results to show for, probably have realized this.
To end on a positive note, and I have said this before: Our biggest asset is nature and this forum. We have people trying all kinds of things. Sometimes deceivingly simple things can help. We must condense and build on this knowledge in order to assist our self-healing powers.
In the mean time I am slotted to see another scientist who specializes on nutritional aspects of muscle wasting. I also plan on doing further testing of urine metabolites and will continue to try out various treatments. I will continue to do anything I can to support awareness for our cause in the science community. In particular, I am hoping that we will achieve some form of publication in 2010. I’ll keep you updated on any interesting developments.
Wishing everyone a successful self-healing process.
