"Androgens (testosterone [T] and 5α-dihydrotestosterone [DHT]) control the development, differentiation, and function of male reproductive and accessory sex tissues, such as the seminal vesicle, epididymis, and prostate.
Other organs and tissues, such as skin, skeletal muscle, bone marrow, hair folices, and brain, are also under the influence of androgen.
The principal action of androgen is to regulate gene expression through the androgen receptor (AR), which belongs to the superfamily of nuclear receptors.
Nuclear receptors are ligand-inducible transcription factors that mediate the signals of a broad variety of fat-soluble hormones, including the steroid and vitamin D3 hormones, thyroid hormones retinoids (Evans 1988, Beato 1989, Truss and Beato 1993).
Approximately 70 members of the nuclear receptor superfamily members have been identified (Moras & Gronemeyer 1998). Only some of them are ligand-binding receptors, while others belong to the subfamily of so-called orphan receptors for which specific ligands have not yet been identified or may not even exist (O’malley & Conneely 1992).
AR can modulate gene expression directly by interacting with specific elements in the regulatory regions of target genes (Reigmen et al. 1991) or indirectly by activating various growth factor signalling pathways (Peterziel et al. 1999). "
"The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor[1] which is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone.[2] The androgen receptor is most closely related to the progesterone receptor, and progestins in higher dosages can block the androgen receptor.[3][4]
The main function of the androgen receptor is as a DNA binding transcription factor which regulates gene expression;[5] however, the androgen receptor has other functions as well.[6] Androgen regulated genes are critical for the development and maintenance of the male sexual phenotype."
The primary mechanism of action for androgen receptors is direct regulation of gene transcription. The binding of an androgen to the androgen receptor results in a conformational change in the receptor which in turn causes dissociation of heat shock proteins, transport from the cytosol into the cell nucleus, and dimerization.
The androgen receptor dimer binds to a specific sequence of DNA known as a hormone response element. Androgen receptors interact with other proteins in the nucleus resulting in up or down regulation of specific gene transcription.[10]
Up-regulation or activation of transcription results in increased synthesis of messenger RNA which in turn is transcribed by ribosomes to produce specific proteins.
One of the known target genes of androgen receptor activation is insulin-like growth factor I (IGF-1).[11] Thus, changes in levels of specific proteins in cells is one way that androgen receptors control cell behavior."
i asked about the test for androgen insensitivity and it is way costly but i will do it.
i wrote down all of your suggestions of the other test names and will ask if those are possible too.
thanks again MEW. i will make sure to keep the site updated with the results. i just pray those tests will be normal because if i test positive there is nothing to correct this.
thanks again.it will take around 2 weeks to know the results.
cheers
hi mew,
my lab is called BIOSCIENTIA and it will send the sample by DHL to Addenbrooke’s Hospital
Molecular Genetics Laboratory
Cambridge, United Kingdom
their phone number is (+44) 1223-348866 if you wanna contact them.
the samples will be genital skin sample to test androgen binding plus blood sample to test DNA for Androgen receptor gene mutation.
i asked for the availability of the other test that you suggested its possible names for me and it is not available. are you sure there a test for epigenetic changes?
my doctor excluded the androgen insensitivity syndrome, he said it is congenital anomaly that starts at birth,and there is no evidence whatsoever that finasteride can cause that,but i insisted and said that finasteride shouldn’t do that to me either according to your literature, and it is at least a factor to exclude or include in my situation. so finally he made the request.
will keep you guys updated
That’s great news. Might I also ask why they are not testing for 5AR2 enzyme activity in same tissues to check if 5AR2 is still working post-Fin, or mutation? Is it possible to get 5AR2 activity checked as well?
Also, what is the cost for such testing?
The words I suggested were not tests in of themselves, just ideas to investigate beyond the androgen receptor. I don’t know what the exact names for such tests would be called, an endocrinologist or geneticist would. It was simply to give you some ideas to talk about with your docs, if you wanted to.
This is developing into an excellent thread, many thanks Mew for the superb research and analysis. I would like to contribute by sharing some information as well.
I have been working together with a top male hormone specialist over the past 18 months in an attempt to solve my problem. We have tried just about every hormonal option available including increasing androgens (testosterone and DHT) through various means (testogel, IM testosterone injections, testosterone undecanoate capsules, proviron oral dht, andractim dht gel, etc.). I have been through testosterone ranges from 6 to 60 nmol/l (ref. 12-35), with no positive, but at higher doses, a clearly negative effect. Because of gyno / chest pain problems, we looked into the estrogen side as well (despite low assayed values). I have tried arimidex, aromasin and nolvadex, also in varying doses.
Up to now, NOTHING has provided more than a short benefit. DHT gel (andractim) provided the best relief so far, but unfortunately the positive effect lasted only for a couple of days and was gone for good after about 2 weeks. Following this short period of improvement, even a massively increased dose of DHT gel had no more (positive) effect! Same goes for Testogel. I was actually on the way of recovery about 2 months after the initial “second week crash”. Going onto Testogel at that point took me down a steep ride to hell, a second “crash”.
There is clearly some form of negative “androgen reaction”/desensitization going on here. Doesn’t this ring some bells? Many of us experienced a brief recovery phase, which typically lasted about 2 weeks, after which we “crashed”. What happens in those 2 weeks? My guess is that DHT returns after fin clears out and 5AR starts to function again. Our very own DHT coming back has lead to a “desensitization” of our androgen receptors. Gel converts into DHT much stronger than IM (injections), for example.
Based on the fact that androgen dependant tissue in my body was/is severely impacted (massive muscle wastage, penile tissue loss, some prostate problems), that no form of androgen supplementation has had any positive effect on me, and after researching this forum, my doctor came to the conclusion that I am suffering of some form of dysfunction of the androgen receptor. By then my doctor had a second fin patient, strengthening his belief.
Acting on this hypothesis, we managed to get a research scientist interested in my case. The scope of the first phase of investigation was directed toward checking association and disassociation rates of ligand binding to the androgen receptor as well as various genetic tests. We currently know that ligand binding/dissociation is not the problem and the specialists are suspecting that there possibly may be some form of epigenetic modification of androgen receptor gene expression. Testing this involves cutting edge diagnostic technology (gene expression micro arrays), is very complex to perform and very expensive. I don’t want to get into much more detail here because we obviously don’t want Merck to somehow get into the way of this.
Even though I think we are on the right path to finally prove what happened, I don’t want to get anybody’s hopes up on this leading to a solution anytime soon. Understanding what happened to us will still not tell us anything about how we can reverse it. My doctor told me that research in the area of epigenetics is bleeding edge, an area where science is just beginning to scratch the surface.
There is still a lot which science has not understood yet. We are not Gods and science does not have the answer to everything. This is evidenced by the following quotes and articles:
This article by the brilliant research group Bio-Balance (their site www.bio-balance.com provides excellent reading) clearly states that we don’t have a good understanding about how drugs interact with their target receptors. The equally brilliant article that Mew came up with clearly proves that finasteride is capable of interfering with gene expression in the androgen receptor.
Combine these two facts and I would say that we’ve got a plausible explanation of what happened to us.
Receptor desensitization is a form of epigenetic change of receptor function. This is currently being researched in relationship with a number of diseases. To get a better feeling for this highly complex subject matter you can google it yourself with the search terms “receptor desensitization epigenetic”.
The following quote is from an article dated March 2009 – just to give you an idea of how new this area of research is. Practicing doctors, many of which studied medicine over 20 years ago, possibly have never heard of this before – unless they keep up to date with the latest science developments. Let’s also not forget that medicine is a dauntingly broad field. It’s impossible for doctors to keep up with every development.
In other words: there is more to inheritance than just DNA - this is a very new concept. My doctor told me that epigenetic changes (specifically desensitization) can reverse themselves with time, but doing so often takes years. This could explain why it is taking some of us many YEARS to recover. PSSD (Post-SSRI sexual dysfunction) is also being attributed to receptor desensitization (persistent desensitization of 5HT1A receptors in this case). Same applies here: Some recover quickly, some do so only after years, and some seem to “never” recover.
Working on the assumption that we are dealing with some form of AR dysfunction, that is not strange at all. The prostate is highly dependent on androgen mediated gene expression for good health. If that is not given, cells will start dying off and will get infected.
This is not a contradiction. Mews link clearly shows that finasteride can act directly on gene expression without actually binding to the receptor. Gene expression is what is relevant at the end of the day.
Where did you get this stuff from? You are comparing apples to oranges and deducing from that what a banana looks like. First of all, having an antagonist in your system is fundamentally different to not having an agonist. Secondly we are talking about a different substance (finasteride). You can’t deduce from one what the reaction of another is going to be. According to the guys from Bio-Balance, combining agonists with antagonists can actually avoid desensitization:
A point worth noting with respect to AR antagonists. Based on my bad experience with increasing androgens, one of my doctors voiced the idea of actually combining an antagonist. I haven’t tried this yet but have reduced my TRT levels since. Interesting enough, my condition has improved somewhat.
I hope that this post has given you some appreciation of what epigenetics is all about and that there is a lot more to inheritance across cell generations than just DNA. If your doctor really told you these things, I suggest you give him a copy of this thread as a primer on epigenetics.
mew,in response to your question about testing 5-a-reductase for mutation or gene-silencing, i won’t do that test because i have high DHT. that means there is no problem with 5-a-reductase gene nor enzyme function.the argument of whether my high DHT can be produced by the other isoenzyme 1 which wasn’t inhbited by finasteride makes no sense, since there is no difference between DHT produced by both 5-a-reductase isozymes. and the DHT receptors will recognize it as just DHT,no matter now if it was produced by type 1 or type 2 5-a-reductase.
so,with this high DHT level, the receptors should be occupied with it as a natural ligand,and exert effect,if those receptors were working properly.
Awor,thanks for your enlightening reply. but just to set the record straight,i’m not here to argue, i’m here to understand. you ask me to take this thread to my doctors to “enlighten” them of epigenetic modifications. you said that “if really my doctors told me those things then take this thread to them as a primer” . well,my doctors said "those things " based on what is written in literature (text books and journals). i didn’t talk to any doctor about epigenetic modification,i just talked to my andrologist about androgen insensitivity and he said it is congenital anomaly and there is no documented work that finasteride can cause that. but he finally made a request for testing.
if you have any studies which suggest epigenetic changes that PERSIST after finasteride usage i will be pleased to provide it to my doctors.
second: i like fruit salad, but when i compared finasteride to flutamide i was comparing the possible consequences of both. both can cause androgen receptor downregulation . flutamide ,acting as antagonist, will cause downregulation of AR receptors, and finasteride causes downregulation of AR receptors by inhibiting the formation of natural ligand,DHT. that is what i meant.
i know that we are exceptional cases,and that any trial to analyze our situation by extrapolating from finasteride pharmacology will be in vain,simply because finasteride pharmacology works the same on all fin users. the question is: why did only us ,among all finasteride users ,have this reaction?
i have just a question for you: what is the lab which will test you for epigenetic changes? that will be a great favor of you if you tell me,even in a private message.thank you
speaking with a friend of mine,that is a personal trainer and knows a lot of endocrinologics etc…he said me that first,fina doesn’t affect the receptors,second that a downregulation to dht ,should be to testosterone receptors as well,cause dht and testo receptors are the same … so he said that fina can’t get an AR downregulations…
saying him all my symptoms,he’s focuses on the neurologic aspect,he says it’s strange that i dn’t feel my penis and I have cognitives problems,weak legs,always tired, sleep problems etc…so he’s thinking about a central nervous sistem problem…and maybe that’s why ghb worked for someone and I had benefits too ,it affects the nervous sistem
Now I’m using proviron,I can feel better and hornier ,but still missing something,so next week I 'll start my ghb 1,5 mouth long non stop …
saying all this,I just want to mean that our problem probably is not just hormonally but like a chain it took all our sistem…
Anyway making a test for androgens insensitovity is a good think to prove it is or not our case.
Quick question aisde from all the micromolecular propositioning: How were you granted GHB italy? What doctor decided it was a good prescription, and based on what systems? Thanks.
3PM…I decided to go to a neuro where I went 2 years ago ,at that time I didn’t tell him about propecia cause I was afraid he wouldn’t have believed me and he prescribed me cymbalta;this year I came back to him with all the real story and he prescribed me cymbalta one more time,Inever took that shit but I told him I did cause he said me to call him back after 3 weeks of usage and let him know how Iwas doing;so I told him about this forum and about ghb .Seeing that cymbalta was not good for me,(not true)he prescribed me ghb (alcover) ;he was afraid of his decision so he prescrived me just small amount of ghb,just enough for 10 days …Than I turned to another endo saying all the true story and that I was having results just with ghb,he prescribed me first acth etc…and after decided to give me ghb…(alcover) now I ve some bottles for 1-2 mouths,so I think I’ll start …this is how I did .
Again, you are just making assumptions without proof to back up your thoughts. This is foolish because until you have testing done, you won’t know for sure if what you “think” is true, IS in fact true.
Note what they say about normal or elevated DHT levels; they can still be present in syndromes of 5AR2 deficiency or AR resistance.
The proposed mechanisms of action causing Post-SSRI sexual dysfunction (epigenetic changes) may also be relevant to us, as noted here, considering Finasteride is mentioned:
hi,
sorry for the delayed update,i just had a business trip abroad and just came back.
my Lab results: 1-normal AR binding and dissociation (as tested on genital skin sample)
binding degree:87%
2- test for AR gene mutation (Analysis of the entire coding region: Sequence analysis): Negative
3-test for AR gene deletion (Analysis of the entire coding region: Sequence analysis): Negative
believe me i’m not happy to know those results-not sad either. all what i want is to find what the hell is wrong better than being stuck in no-where.
there must be something wrong, and there must be something done. how come all the tests i have done so far are nearly normal while i’m in deep shit mentally and physically?
this is my third year since i quit and nothing is getting better,and there is no hope out there.
First, sorry to hear you’re not feeling any better. It’s tough, but keep fighting. Years down the line, guys have shown improvement. You never know what is around the corner for you.
Second, I think I’m right in saying that these results are pretty big news. Thanks very much indeed for bringing them to the forum.
Only you and Awor have managed to have these kinds of tests done. It’s really important that you talk to Awor about what you’ve discovered: as he mentions above he is planning further testing with a scientist he’s working with, and these results may help them plan that.
AR binding and dissociation rates were normal. This is in line with what Awor discovered when his scientist tested binding. It seems that the post-finasteride syndrome is not about dysfunctional binding and dissociation rates.
AR gene mutation and deletion were negative. I know that Awor and his team are planning to look at gene expression of the androgen receptor. I don’t know if the test that you have had is the same as the test they want to run. It sounded to me as though Awor’s planned test would be extremely expensive and take many months.
But I don’t know enough about it all. That’s why you definitely should get in touch with Awor, and talk to him and probably to his scientist about the nature of these tests and the results.
These results take us a step forward in learning the true nature of our condition: great work.
As mentioned previously, there can be defects in AR function even with NORMAL binding and dissociation. More investigation is required.
Human minimal androgen insensitivity with normal dihydrotestosterone-binding capacity in cultured genital skin fibroblasts: evidence for an androgen-selective qualitative abnormality of the receptor. pubmedcentral.nih.gov/articl … id=1684524
www3.interscience.wiley.com/jour … 6/abstract
“Appreciable unexplained interexperimental variation of the DHT-binding activities in genital skin fibroblast strains demands that multiple assays be performed on a strain before its receptor status is classified quantitatively. In our experience to date with genital skin fibroblasts, four of 13 propositi with CAI have been receptor-positive.”
See the below screenshot. DNA binding investigation is probably next step.
Did you get 5AR2 activity assessed in the genital skin fibroblast culture? That also needs to be assessed, to see wether DHT is converting correctly locally in those tissues post-Finasteride.
What did your doctor say about the results? You should consider further testing per the attached screenshot.
Interesting stuff in that screenshot about “post receptor defects”.
If I understand it right, the textbook says that this is a mutation in the DNA binding domain of the androgen receptor gene. This mutation means than even though there is normal binding, the androgen receptor cannot exert its effect.
We seem to be seeing normal binding without androgenic effect, so this could be what is happening to us.
Only thing is, Chams said he tested the entire sequence of the androgen receptor gene, and found it was normal. Wouldn’t this include the DNA binding domain?
If not, then we need to test the DNA binding domain of the gene to see if there are changes. Presumably this is possible via the same kind of test that Chams had to analyse the rest of his AR gene. Maybe the lab at Addenbrookes could do it. In which case, I’ll go and give them some of my blood.
It feels as though we are getting somewhere. What we need is a scientist who can answer our questions:
Did Cham’s test include the DNA binding domain?
If not, can we test for mutations of the DNA binding domain?
In the light of Cham’s tests, what else should we be testing for?
Awor is working with such a scientist; the only scientist I’ve heard of who is taking an interest in our condition at this level. They’re interested in investigating epigenetic change of the AR. But we need to take these results to Awor’s scientist and have a discussion. I mean, it’s clear this scientist is interested in this stuff: he’s working closely with Awor. It may be that we are a few blood tests away from serious answers.
i m loosing pieces…so what list/kind of genetic test should a guy have to understand the all situation we need?..if someone can write the list,it ll be easier to someone who need to have them done .
thanks Mew and SM for your replies:
my tests were done on the entire coding region, so i don’t clearly get what MEW posted…but anyways,you can always find lots of possibilities,but the question is about the availability of tests to include or exclude what you suggest.
my Doctor didn’t know about epigenetic changes. i couldn’t find even one lab to do a test for epigenetic changes. i don’t know how you guys came up with that test? i don’t know where Awor is gonna make such test.
MEW if you suggest other tests please name them…5AR can be availabe,and that will be my next step. i have discussed with the doctor if it is possible to take a prostate biopsy and test it ,and i think it is possible.
will keep you guys updated.
Why is that? DNA binding is just another intermediary step in the chain. You just as well can start looking at various known (and unknown!) co-activators and modifiers (which could just as well be the problem*). In other words, this test can turn out normal and you still don’t know what the heck is going on. Just like the receptor testing chams and I had done. We now know that his receptors work and that mine work. Great, but that doesn’t advance us an inch. We can drill another hole into the pipe (=DNA binding) and peek in. Maybe we’ll see something, maybe we won’t. Or we can go to the end of the pipe and look through (=gene expression) and see what’s in there - once and for all. What makes more sense to you?
Guys, let’s get a little focused! We’ve got clear advice from a scientist so far telling us the next step is to test actual gene expression. Gene expression is the end of the chain. In other words, if gene expression turns out normal, then there is no point in looking at anything else “upstream”. If the test turns out negative, then we know that the problem lies somewhere in the nuclear processes downstream. A scientist needs to tell us what to look at after that.
Look mew, it took a lot of effort to find this scientist and get to the information level WE now have. You know that. And you even participated in this effort. Why don’t we just believe what this androgen receptor specialist/scientist says and not try to out-google and out-smart him.
Unfortunately, the lab this scientist works in doesn’t have the (rare) equipment required to test gene expression. Otherwise I would have had the test done and shelled out the cash it takes to do it. We now need to find a lab to perform this gene expression micro array test. It will be expensive but we can get together and pitch in. Perhaps chams can check if his lab has the resources to test this. I will continue searching on my side as well. I’ll keep you guys posted. I am convinced that we will eventually get there if we stay focused.
this statement also originates from the scientist in question
sorry MEW,i didn’t reply to your questions:
first off: my doctor never believed that i have androgen insensitivity syndrome. he said it is congenital defect and there is no evidence whatsoever that finasteride could cause this. he ordered those tests for me because i kept asking for them, and because he has run out of ideas, so to speak.
5AR test will be my next step, i haven’t done it yet.
i have a question for you Mew,or anyone else here: do you have any idea about the mechanism of androgen uptake by human cells? androgen receptors are inside the cells,so androgens have to be uptaken first by the cell in order to bind to receptors. do you have any studies about factors that may affect such uptake process?
