Awor,
if you’ve seen any information on the effects of long-term fasting (food deprivation) on androgen levels (pertaining to one possible way of androgen deprivation), please tell me.
I’ve thought about a long fast before which could help reset the balance, but I’ve not yet executed it. At the same time, I have a feeling that due to my own unrelated health problems, doing such a thing might only improve one area (the prostate, reproductive system, etc.) but not the brain (dopamine).
I’m not sure about the cases mentined being valid for the severe cases of post-propecia syndrome.
‘Troubledfinuser’ never had a problem with erections while ‘dmartinez’ was gradually recovering prior to prolactin reducing treatment, never had chronic ed and tissue changes/shrinkage. ‘Postfinsufferer’ likewise had good T levels and seemingly no bad ed. The user ‘jairus’ had the more typical symptoms and tried similar supraphysiological treatment seemingly without success.
The ‘dustin’ example may prove more reliable with more updates.
I think a big issue is the crash. Many men seem to get into trouble without this (very) brief ‘recovery’ period and perhaps they respond better to treatment. I don’t think JN ‘crashed’ and he at least seemed to get a decent physical if non-sexual response to TRT Something has gone wrong for the others but I don’t know what.
surprisingly, the seemingly unhelpful endocrinologist I saw two weeks ago may have order a test for prolactin levels. If so, it was simply done on a blood sample. I’m wondering if this may show anything.
Yes it is. Like I said in my post I focused my discussion with the scientists on the androgen receptor theory, because I believe that it does the best job at explaining what happened to us. Having said that, we also touched the possibility of 5AR not functioning correctly anymore. At first sight, it seems to be the obvious thing to look at considering that finasteride inhibits 5AR. More on that later.
Unfortunately, all of our theories will remain such until we can prove something in a lab.
You’re right, and I should have stressed that more in my post. Three scientists told me this as well. Our bodies are incredible machines, which can compensate for and repair just about anything. The point I was trying to get across was this: If we are hoping that if everybody chips in 50 bucks and we hire a scientist to solve our problem, we’ll most likely be disappointed.
The power of healing is within us. Deceivingly simple ideas like juicing/diet/herbs/lifestyle etc. can help promote these powers. Believing in ourselves and giving our bodies the time and support they need seems to be a more promising route to me.
This does not mean that we must give up all hope in science. All of the scientists confirmed to me that developments can all of the sudden go very quickly after perhaps years of achieving no results. It’s not a linear business where input leads to continuous output. One of the areas I have been looking into is full genome sequencing. This technology basically lets us analyze the full 3 billion base pairs of the human genome (which includes dna and tons of epigenetic information). This allows for a genetic comparison between “us” and the “other” guys (who don’t have a problem with finasteride), without knowing where to start looking. Once we find out what “sticks out” in our genetic information, scientists could then determine what functions in our body are encoded by these genes - basically attacking the problem from the other end. Currently, such tests cost around $100’000 a pop. This cost is expected to be reduced to under 10K within the next couple of years (< 5 years). We’re in the midst of a molecular tool revolution at the moment.
The answer to this is likely to be quite simple. Even though we are all suffering from the same basic problem, the variation even amongst us is probably still relatively large. In other words, we are not all the same. It is obvious from reading the member stories that we are also not all affected to the same degree. The less affected amongst us are primarily suffering from some degree of ED. I can very well imagine that this group has got sufficient remaining androgen sensitivity to allow for TRT to improve their symptoms. My sensitivity is probably pretty close to zero. But even I sometimes get a little benefit from TRT (sometimes I also get the contrary). In other words, androgen insensitivity has many shades of gray, it’s not all simply black or white, on or off. If you read through the AIS literature, you will notice this as well (Btw. I am NOT saying that we have AIS, this is just an analogy to a remotely similar problem)
I had this testing done as well, except with normal skin tissue, but the results where the same. Let me quickly clarify what we mean by gene expression, receptors, etc. and how it all ties together (hi level):
Ligand (hormone /input) => Receptor (plug) => Signaling Path (machinery) => Gene Expression (output/androgenic action)
Sequencing the genetic code of the androgen receptor, in order to check it for known defects, does NOT tell us anything about what happens at the other end of the machinery. We even know that the receptor is functioning correctly in both cases (chams and me). BUT you can only tell if something is coming out the other end by quantifying the output (gene expression). The scientists are telling me that it is in the machinery (signaling path) that things can easily go wrong (remodeling of signaling paths, etc.). Various mechanisms of gene regulation can play a role here (as described in my last post).
While on the subject, let me use this model to explain why my specialists and myself believe that the problem is somewhere “downstream” from the receptor. Let’s run through what we know about each variable in the equation:
Let’s start with the output: In the most serious cases we’ve got massive penile shrinkage and massive muscle wasting. These are both hallmark androgen dependent tissues. Then we’ve got ED, loss of aggressivity, prostate, etc. Also well know to be androgen dependent. So we are clearly missing out on androgenic action. In other words we are lacking “output” (gene expression).
Ligand/Hormone: Some of us have a lot, some too little. It doesn’t matter. In the best case you can inject an insane amount of Testosterone and get some improvement. In the worst case the same amount won’t do anything. In any case I am still waiting to hear from a guy that has 100% solved the problem through TRT. So it can’t be the hormones.
What about DHT, maybe we’ve got too little or from the wrong enzyme or whatever. Permanent damage to 5AR is actually not a bad theory. But it has a major shortcoming that pretty much rule it out: It doesn’t explain muscle wasting. DHT is not required to build or maintain muscle mass.
This is demonstrated in male pseudohermaphroditism due to congenital 5-AR deficiency. When puberty occurs, the testosterone levels of these individuals raise normally, although their DHT levels remain very low. Despite this, their musculature develops normally like that of other male adults. There are about 3-4 other arguments which further support this and are scientifically backed (joe.endocrinology-journals.org/c … t/170/1/27).
If this is not convincing enough, try supplementing it (I have).
So in my opinion and with current medical knowledge, we can pretty much rule out hormones. But what about all the other hormones? Well, I haven’t found any scientific litterature which explains why androgenic tissue dies because of a dis balance of other (non-androgenic) hormones. Maybe someone can correct me on this. What about hormones that could have a gene silencing effect (regulation) on the androgen receptor? That’s possible. But then we would be talking about something hitting the machinery. Or take a hormone like prolactin. You can explain ED with it, but not muscle wasting. The key is to find a theory which explains everything for everybody. It can’t just work for isolated symptoms or for certain members. In other words, a lot of things can potentially explain ED. If you try combining ED, depression, muscle wasting and penile shrinkage (just to name a few), the number of options gets real small real quick.
Receptor: As stated above, Chams and me had them tested. They work. This for me is sufficient evidence to rule out the receptors.
What we have got left is the machinery. The piece in between that is still partially a scientific mystery. A machine 1000 times more complicated than a missile guidance system. What are the odds?
Just imagine if a scientist finds a solid explanation to our problem one day. All the theories collapse in themselves. What are we going to talk about then in this forum? It’s going to get real boring around here at some point! 
I am hoping to start covering the nutritional side of things with a scientist/doctor in about 1-2 months. I’ll report back on this interesting subject as soon as I find out more.
Keep up hope!
Good luck. Seeing as Doctors are still telling their patients to follow the food pyramid as a healthy way to live, your going to have a tough time finding a Dotor who know’s anything about nutrition.
Scary thing is, even nutrionists have it all wrong.
Looking forward to your results…
My recent urine panel showed high corticosteroids. It turns out that high levels of cortisol cause muscle wastage. It is possible that 5-a-rase is no longer working correctly. As you can see from my test results it is not since I have low 5a-THF/THF ratios, low adiol-G, etc. It is interesting that 5-alpha-reductase also metabolizes cortisol and cortisone into 5a-tetrahydrocortisol and 5a-tetrahydrocortisol. So if cortisol is no longer being metabolized by 5ar, leaving it to circulate it will cause muscle wastage. If you want studies on this I can provide them as I have access to a good medical database that I have been using. Also, check out Cushing’s syndrome if you are interested on the effects of high cortisol.
Yes, I and many others did not experience muscle atrophy while on Finasteride – only after quitting, when our Testosterone levels crashed. It is well known that Testosterone is the primary anabolic agent responsible for muscle mass and tissue growth.
From the study you highlighted, I found the following passage of interest which supports your statement:
Here is what the guy has published: ncbi.nlm.nih.gov/pubmed/advanced (enter Ballmer PE for Author)
I doubt we are talking about the same profile.
First of all, according to scientific litterature, it is the androgen/estrogen balance that regulates the feedback mechanism for gonadotropin production (FSH/LH):
linkinghub.elsevier.com/retrieve … 7798900068
Assuming that the androgen receptor/pathway is not functioning correctly, this would cause the body to think that the estrogen/androgen ratio is higher than it actually is. This would also lead to a down-regulation of LH/FSH production.
In many areas, androgens offset estrogens. This is also clear with the many gyno cases that we are seeing in this forum, despite sometimes normal estrogen levels. I, for example, have normal-low estrogens. Nevertheless, I am developing gyno. That most certainly is because the estrogenic action in the breast cells is not offset by androgenic action any longer. In other words, if the androgen receptors/pathways are not functioning right, you get exactly the same result like if you didn’t have any androgens in your body. Actually, it’s worse. If you you have androgens but the receptors don’t react to them, you still end up with androgens aromatizing to estrogens, giving you all the unwanted estrogenic effects like bloating, gyno, etc. In a situation without androgens, you at least would not have much estrogens floating around either. Having normal estrogen levels without any androgen action to offset them is what is causing me this horrible pain in the breast/nipple area.
Some further research led me to a very interesting study, which was published only two days ago. Here is the punch line:
In other words, without the presence of AR (androgen receptors), FSH does not have the same positive effect on Leydig cell number like it normally does. As we know, Leydig cells are the ones that produce testosterone. If you have less Leydig cells, you logically get less testosterone production. This would also correlate with some guys reporting their balls “shrinking”.
How does that sound?
You can read up some more at: ncbi.nlm.nih.gov/pubmed/1984 … d_RVDocSum
In my opinion, both above cited articles provide strong grounds for explaining why lacking androgen receptor gene expression could lead to a reduction in testosterone production.
In my opinion it is like a cascade, a domino effect.
I believe our main problems are Pituitary suppression + 5arII deficiency. All the other problems/symptoms derive from this.
Example:
5arII deficiency consequences:
Cascade effect:
muscle wastage (caused by excess cortisol)
death of androgen dependent tissues in some men (caused by lack of Androstenadiol Glucoronide combined with low DHT, and low T). So, if one of the three hormones is still somewhat high, your body is able to keep the androgen dependent tissues alive.
We have to remember we will not find an exact pattern on everybody’s symptoms since the drug affects everyone differenttly. So far, the only patterns we found in everybody were a low LH and FSH (which indicate pituitary suppression) and a low 3 adiol G number in everyone who tested it, which indicates 5arII deficiency.
Found this article of interest considering this thread’s topic.
[Size=4]Reprogrammed Role For The Androgen Receptor[/size]
ScienceDaily (July 30, 2009) — The androgen receptor – a protein ignition switch for prostate cancer cell growth and division – is a master of adaptability. When drug therapy deprives the receptor of androgen hormones, thereby halting cell proliferation, the receptor manages to find an alternate growth route. A new study by Dana-Farber Cancer Institute and Ohio State University scientists demonstrates how.
The shift from androgen-dependent to androgen-independent cell growth occurs, in part, because the androgen receptor switches on an entirely different set of genes in the latter group than in the former, the researchers report in the July 24 issue of Cell. In contrast to androgen-dependent prostate tumors, androgen-independent ones experience an uptick in the activity of genes that control cell division, or mitosis. One such gene, called UBE2C, which causes cells to ignore a natural pause in the division process, becomes especially active, the researchers report. This pause, or “checkpoint,” ensures that cell division progresses normally; without it, daughter cells may grow even more aggressively and be harder to stop.
“The evolution of prostate cancer from an androgen-dependent state to an androgen-independent one is a key step in its progression,” says study senior author Myles Brown, MD, of Dana-Farber. “The discovery that the androgen receptor directs a distinct gene pathway in androgen-independent prostate cancers may lead to the identification of genes in that pathway that can be targeted by future therapies.” Prostate cancers whose growth is fed by androgen are commonly treated with androgen-blocking drugs. Such medications can hold the disease in check for a period of time that varies from patient to patient, but the tumor almost invariably gains the ability to grow without external androgen.
One of the ways such cells re-start their growth is by producing their own androgen, scientists have discovered. Another way involves the androgen receptor itself – the “keyhole” in the cell nucleus that androgen molecules fit into – but the actual mechanism by which it operates hasn’t been known.
To find that mechanism, Brown’s team, including co-lead authors Qianben Wang, PhD, now of Ohio State, and Wei Li, PhD, now of Baylor College of Medicine, charted the activity levels, or expression, of genes controlled by the androgen receptor in androgen-dependent and androgen-independent prostate cancer cells. In the androgen-independent cells, they found a group of genes with epigenetic markings – tiny attachments to DNA that switchs genes on and off – that caused them to be especially active. The genes form a completely separate pathway from the one active in androgen-dependent cells.
It’s not known what causes those epigenetic changes to occur, but “we are profiling the genome-wide epigenetic landscape of androgen-dependent and -independent cancers, trying both experimental and computational methods to identify additional regulators,” says study co-senior author X. Shirley Liu, PhD, of Dana-Farber.
“The androgen receptor clearly works by an entirely different program in androgen-dependent and -independent cancers,” says Wang. “Having discovered that program, we’ll be in a better position to understand how it operates and how gene-targeted therapies may shut it down.”
Tbone, from the looks of this study on male twins, it looks like fasting may be of benifit:
propeciahelp.com/forum/viewtopic.php?t=2920
I also have a paper copy of a study showing fasting elevated LH levels significantly.
kazman
Another interesting bit as it relates to androgen receptor CAG repeats mediating androgenic responses in men.
The Role of the CAG Repeat Androgen Receptor Polymorphism in Andrology
content.karger.com/produktedb/pr … 43&typ=pdf
Abstract:
A dysfunctional androgen receptor is able to cause variable phenotypes of androgen insensitivity or androgenicity in humans. In addition, also a polymorphism, the CAG repeat polymorphism in exon 1 of the androgen receptor gene (CAG)n, modulates androgen effects: androgen-induced target activities are attenuated [reduced] corresponding to the length of triplet residues.
Clinically, the Size=4n polymorphism causes marked modulations of androgenicity in eugonadal [normal] men in various tissues and psychological traits and may cause the clinical picture of hypogonadism in the presence of normal testosterone concentrations[/size].
Also pharmacogenetic implications might exist in this regard: there appears to be a significant role of testosterone treatment of hypogonadal men as treatment effects have been demonstrated to be modulated by the number of (CAG)n in retrospective approaches.
Attached screenshot from more complete “book version” of above article.
Clinically, the (CAG)n polymorphism causes marked modulations of androgenicity in eugonadal [normal] men in various tissues and psychological traits and may cause the clinical picture of hypogonadism in the presence of normal testosterone concentrations.
Most of us don’t have normal testosterone concentrations though in terms of numbers, we are very low in range for our ages or even below range.
I read the complete article. It’s gives a good overview of androgen receptor function and some of the genetic aspects that I have discussed in my posts.
Take a look at the breakdown diagram of androgen receptor DNA in Fig.1. There you will see that CAG repeats are encoded on Exon 1 of the AR gene.
What you are proposing can 100% for sure have nothing to do with our problem. The reason why I can claim this is because I had my complete androgen receptor DNA sequenced and additionally CAG repeats checked twice. All three tests showed that both the DNA which encodes my androgen receptor as well as my CAG repeats are perfectly normal. And if it doesn’t explain my case it won’t explain yours either.
Btw, you can easily have CAG repeats checked yourself. The assay is readily available and is tested with serum (no biopsies needed).
.
Yes, most men’s T levels crash post-Fin, but for those who have tried T-boosting protocols or even TRT and felt no different, what does that tell us? The above explanation may provide insights.
As noted here: propeciahelp.com/forum/viewtopic.php?t=1406
… Finasteride affects men differently based on their AR CAG repeats. Perhaps we all share common repeat lengths and as the research notes, were more susceptible to loss of DHT via Finasteride (of course, we did not know this because we hadn’t been tested prior to use of drug, nor had our 5AR2 alleles genotyped, like some researchers now suggest – propeciahelp.com/forum/viewtopic.php?t=1407 ) .
Awor, you are thus far the only person on this forum to have had their CAG repeats measured… although based on your results it seems likely, before stating “if it doesn’t explain my case it won’t explain yours either”, it would be helpful to have additional member test results to compare against.
Finally, I came across this 2009 article, which is of interest since it mentions the potential for androgen signalling pathway remodeling in prostate cancer cells due to loss of DHT via Finasteride and other treatments. This probably isn’t anything new to many, since it is well known that androgen ablation therapy only halts cancer for a certain amount of time – eventually, the androgen receptor signalling changes to allow progression of cancer, despite lack of androgen (ie, by binding with other ligands).
The point is that when under lack of DHT, prostate cancer cells’ androgen signalling pathways can undergo remodeling. Since this thread’s theory relates to androgen receptor gene expression changes/androgen insensitivity due to Finasteride (reduction of DHT), I thought this might be of interest for discussion.
Awor, perhaps you can also share your insights via posting the 2 quoted passages from studies you mentioned to me, regarding “posttranslational control of AR activity appears to be a novel mechanism of negative autoregulation”.
Cheers.
Mew.
Sure. My tests turned out 22 and 25. There seems to be quite a bit of variance. Sequencing is not like reading 1’s and 0’s out of a computer interface. There is enough error involved to require a number of passes. In the case of CAG repeats they then take the average length.
As I said before, a good theory needs to fit 100% of the cases. In other words, one case that doesn’t fit is enough to blow a theory. And I don’t mean everybody has to have the exact same symptoms. But the core mechanism has to fit. Besides, CAG repeats is part of DNA. DNA is very stable and to my knowledge can’t be generally modified by a simple chemical. Modifying DNA is what they are trying to achieve with gene therapy. The main approach here is through vectors (modified viruses).
I first need to put this into context:
I was associating two different bits of information whilst trying to explain how finasteride could have potentially “desensitized” our androgen receptors. The fact that most of us seem to have experienced a brief recovery phase after quitting finasteride led me to the thought of desensitization. The idea here is that DHT could have returned after 5AR starts regenerating after we quit fin. Science has realized that protein level feedback mechanisms exist (a receptor is a form of protein). Nobody knows for sure how it exactly works, but I was guessing that perhaps by lowering DHT, our androgen receptor “set points” somehow got lowered as well. In other words the body starts thinking, after a while, that the reduced DHT levels are normal. After stopping fin, and when DHT presumably starts flooding back, our receptors go into panic mode and shut down.
But for many, the problem actually started whilst on fin (that’s why most of us quit). So how could that fit in? Maybe finasteride is chemically so similar to testosterone that it is actually downregulating the receptor through the same mechanism:
David A. Williams, Thomas L. Lemke, William O. Foye, Foye’s Principles of Medicinal Chemistry, 2002; Page 112
The inhibitory action of finasteride has been attributed both to its similarity in structure to testosterone which allows it to bind to the enzyme … as well as its ability to act as a mechanism based inhibitor, where it can tie up the cofactor NADPH…
books.google.ca/books?hl=en&lr=& … #PPA112,M1
Autoregulation of the Androgenreceptor: (DA Wolf, T Herzinger, H Hermeking, D Blaschke, W Horz, DA Wolf, T Herzinger, H Hermeking, D Blaschke and W Horz, 1993: Molecular Endocrinology, Vol 7, 924-936)
Autoregulation is a control mechanism common to several proteins of the steroid/thyroid hormone receptor superfamily… Inducible reporter constructs demonstrated that prolonged androgen administration to cells results in a progressively impaired sensitivity of the intracellular androgen response mechanism. These results show that prolonged androgen exposure leads, besides its effect on hAR RNA levels, to functional inactivation of the AR. Thus, in vivo, posttranslational control of AR activity appears to be a novel mechanism of negative autoregulation of androgen effects on gene expression.
mend.endojournals.org/cgi/conten … ct/7/7/924 (s. Full Text PDF)
When you read this I think it becomes clear that there are much more powerful mechanisims in there than endocrine axis based regulation such as the HPA. The HPA is actually just the fine tuning. Protein level regulation is where the real action is.
I wish I knew the answer to that. The only conclusion I can draw from what I have read in this forum is to try and sit it out while living as healthy as possible. It seems like you are doing a good job at that. As to the science side of things, we’ll need to give that time as well.
[quote="awor The idea here is that DHT could have returned after 5AR starts regenerating after we quit fin. [/quote]
Has 5AR regenerated? If so, why is my 3 adiol G result 2.40 (range 3.5 - 22.00)?
Here is another recent article that shows that science is starting to realize that “medicine” can cause permanent alterations in gene expression:
sciencedirect.com/science?_o … 2ffe570e2f
I don’t know why your adiol-g is low. Why is my estrogen low despite high testosterone levels (I have numerous pre/post fin values on this). Enzymes are subject to regulation through various cofactors that bind to binding sites on the enzyme. This binding can serve to increase or decrease the enzyme’s activity, providing a means for feedback regulation. In other words, it could just as well be that some cofactors are negatively influencing the throughput of 3a-HSD (maybe even the same cofactors that could be inhibiting AR gene expression). If 5AR (whatever form) would supposedly be damaged, why doesn’t any level of supplementation (Andractim) help? It does help against ED with “normal” men. That’s what it is sold for. Get yourself a tube of Andractim and try it. I’ll even give you one if you arrange for the pickup.
In addition, it is seems to be controversial if adiol-g is even a suitable marker for cutaneous DHT metabolism because the principal site of androgen conjugation to glucuronic acid is the liver. See my post in thread propeciahelp.com/forum/viewtopic.php?t=761
Assuming that your 5AR is defective because your adiol-g is low is jumping to conclusions. Sure, you can theoritize about this, that is what we are all doing around here - but it is not proof of anything. Also, talking about isolated 3-adiol G figures without matching T and DHT serum values is pretty meaningless in my opinion. If you have this kind of data, I would be interested to see it - but in another thread. This thread is about androgen receptor gene expression, let’s keep it focused.
