Finasteride caused Androgen Insensitivity or altered Gene Expression?

#1

hey guys
i’m sending this because i’m fully desperate of any solution to our vague and exceptional medical conditions.i have seen so many doctors,some of them are Harvard fellows, and i will tell you the conclusion of all medical opinions which are all backed up by facts that are totally contradictory to our situation:
1-it is strange that finasteride induced my case (and some cases here) of prostatitis. one doctor showed me a study that finasteride is actually used to treat chronic refractory prostatitis with better results! there is a study here on this forum the proves that finasteride plus levofloxacin showed significant difference than levofloxacin alone.

2-an andrologist showed me the data about finasteride in a very famous pharmacology text book called goodman and gilman. finasteride has no affinity for androgen receptors, which contradict with the fact that we became androgen insensitive. even if the androgen receptors downregulated because of lack of DHT, it should reverse again after DHT has come back to system,based on the data obtained from direct androgen antagonists like flutamide and biclutamide which are androgen receptors antagonists that cause downregulation of these receptors ,supposedly in a more intense downregulatory manner than finasteride in that perspective. however more intense downregulation occur, the recovery occurs between 6 to 9 months after discontinuation of those antagonists.

3-talking of gene switch off: a gene is a sequence of DNA base pairs that encode for the production of certain protein. so 5 alpha reductase gene encodes for the production of 5 alpha reductase enzyme.for a drug to switch off the gene it must have an affinity to bind DNA,which isn’t possible for finasteride. the only drug classes that are able to switch off a gene are called antisense drugs. those are inversed gene sequence of certain gene,that is incorporated in DNA base pair instead of that gene causing it to become dysfunctional like a drug called vitrafene. antisense drugs must be an inversed base pairs sequence of the gene and incorporated by biotechnology means into DNA to switch off certain gene.
finasteride is neighter an inversed base-pair sequence of 5 alpha reductase gene nor does it have any affinity to DNA according to mutagenicity studies that are performed routinely prior to drug marketing as a part of safety data.

4-androgen insensitivity is surely one of our problems,but how on earth this was revered temporarily by cipro and cortef?

the whole situation is very complex and vague. it is hard to figure out a treatment. the data about the drug contradict rather than conform with our problems. i find it hard to prove anything to my doctors.

if anyone has certain suggestions of other possible mechanisms please let me know.
thanks :cry:

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#2

We don’t know for sure if that’s the case (androgen insensitivity) since nobody has had tests done at the genetic level to look at AR binding or function, to confirm if this is indeed true. So how can you say that we are all androgen insensitive without such testing having been done?

AR receptors SHOULD do that, yes. Does it mean they DID do that in our cases? Nobody knows because nobody has been tested for that.

Have you had conclusive testing done to confirm your AR expression in those tissues where 5AR2 was inhibited are working correctly?

If not, not sure how you can definitively conclude that our issues DO NOT stem from downregulation of AR (or some other malfunction of AR, or gene expression) thanks to Finasteride, just because other AR antagonist drugs have not had such a documented effect.

Reason I say that is because everything we’ve experienced with regards to side effects persisting after use is currently “undocumented” in the medical field – we are an anomaly in that regard, in the way Finasteride affected us. In other words, we are living proof AGAINST the textbooks examples of what the drug was SUPPOSED to do when it comes to cessation of side effects and mechanisms of action.

Until this drug and our cases have been researched in the lab, I wouldn’t rule anything out. Finasteride wasn’t supposed to cause permanent side effects either, remember? There is a lot that has yet to be discovered about how this drug operates.

For instance, perhaps androgen deprivation via Finasteride caused epigenetic changes or gene silencing DOWNSTREAM beyond the AR, such that even though the AR is functioning & binding with DHT correctly, it is not able to exert its effects beyond that.

We just don’t know, and studies like this should make such investigation even more worthwhile:

propeciahelp.com/forum/viewtopic.php?t=1457

Again, how can you say such things with absolute certainty, without AR testing to backup that you are in fact, androgen insensitive? And what are you referring to when you are talking about reversal due to cipro and cortef?

Yes, exactly my point.

We have had an unusual reaction NOT LISTED IN TEXTBOOKS related to 5AR2, DHT and the various other pathways inhibited via Finasteride, such that discontinuation of the drug did not reverse side effects.

Why? That is the still the million dollar question, and one which needs research in a lab likely at the genetic level.

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#3

Furthermore, although this is in prostate CANCER cells and talks about downregulation of PSA levels and gene expression due to Finasteride, it is interesting to see that Finasteride DID have an effect on AR, which directly effected gene expression of PSA.


Down-regulation of prostate-specific antigen expression by finasteride through inhibition of complex formation between androgen receptor and steroid receptor-binding consensus in the promoter of the PSA gene in LNCaP cells.

FULL TEXT: cancerres.aacrjournals.org/cgi/r … pdf?ck=nck

ABSTRACT:

As a specific competitive inhibitor of 5alpha-reductase, an intracellular enzyme that converts testosterone to dihydrotestosterone, finasteride is being extensively used for the treatment of benign prostatic hyperplasia and in experimental settings for prostate cancer.

In this study, we showed that finasteride markedly inhibited prostate-specific antigen (PSA) secretion and expression. The promoter of the PSA gene contains several well-known cis-regulatory elements. Among them, steroid receptor-binding consensus (SRBC) has been identified as a functional androgen-responsive element.

Our previous study showed that PSA was not only present in conditioned medium of the PSA-positive LNCaP cells but was also detectable in small amounts in PSA-negative cell lines, PC-3 and DU-145 (L. G. Wang et al., Oncol. Rep., 3: 911-917, 1996). A strong correlation between binding of nuclear factors to SRBC and the level of PSA present in the conditioned medium and cell extracts was found in these three cell lines, whereas no such correlation with binding was obtained using Sp1 oligonucleotide as a probe.

Binding of LNCaP cell nuclear proteins to SRBC was diminished when the cells were exposed to 25 microM finasteride, at which concentration 50% of both PSA mRNA and protein were inhibited.

As a major component of DNA-protein complexes, the level of androgen receptor was dramatically decreased in the cells treated with finasteride.

Our data indicate that inhibition of complex formation between SRBC and nuclear proteins [Size=4]due to the remarkable decrease in the level of androgen receptor plays a key role in the down-regulation of PSA gene expression by finasteride in LNCaP cells[/size].

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#4

i remembered asking a doctor about a test for androgen receptor binding and he said it is not available in labs. it is only for research puposes,if i remember his reply right.do you know where can i do that test? has anyone here tested for that?

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#5

Would appreciate if you could provide your thoughts to the questions I asked you in my initial post.


Androgen Insensitivity testing labs:
geneclinics.org/servlet/acce … how_flag=c

5AR2 deficiency or mutation testing lab:
geneclinics.org/servlet/acce … how_flag=c

You would likely need a doctor to refer you for these tests.


Other ways to check:

propeciahelp.com/forum/viewtopic.php?t=1453

propeciahelp.com/forum/viewtopic.php?t=1416

Take the info in those threads, especially the last image here: propeciahelp.com/forum/viewt … 0163#10163

… to your docs, and see if you can get the testing done.

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#6

Here is a study suggesting a form of what I stated above… DHT binds correctly to the receptor, but cannot exert its effects due to a “structural mutation”.

Human minimal androgen insensitivity with normal dihydrotestosterone-binding capacity in cultured genital skin fibroblasts: evidence for an androgen-selective qualitative abnormality of the receptor.

propeciahelp.com/forum/viewtopic.php?t=1260

They also provide a suggestion for treament (anabolic steroids, ie TRT): “Synthetic, nonhepatotoxic androgens, with corrective effects in vitro comparable to those of MT (methyltrienolone), may be therapeutically useful for these subjects.”

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#7

okay,i will ask my doctor to refer me for testing for androgen insensitivity.
concerning 5 alpha reductase deficiency or mutation ,i don’t think so ,because i have HIGH DHT and very normal free and total testosterone,so my 5 alpha reductase is working.

i will post the test results here once done.

then, your last post suggests that androgens can still bind with receptors without exerting biological effect. how can this be tested either? what is the name of that test? i want to make both tests together.

thanks mew for the info,you have really become an expert in that,may be more than many doctors.

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#8

I’m not sure on the exact names but you might suggest words like:

  • testing for epigenetic changes
  • testing for gene silencing
  • testing for genetic or chromosomal mutations
  • testing for decreased gene expression or gene transcription
  • testing for androgen receptor ligand binding & mRNA function

Again this is all just theoretical, and would relate to genetic/DNA effects downstream from the androgen receptor (ie, after DHT binds to it).


herkules.oulu.fi/isbn9514267621/html/x516.html

"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). "


en.wikipedia.org/wiki/Androgen_receptor

"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."

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#9

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

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#10

What exactly is involved with this “androgen insensitivity” test and where will you get it done (genetic lab?)?

How will they test you for this – via genital skin sample, or blood?

Just curious, since you asked your doc about it.

You don’t know that. One step at a time, you are needlessly worrying yourself in the meantime.

Besides, even if there were some problem with the AR, there are treatments involving androgen replacement which can potentially overcome the defect.

First see what comes of such tests, if you can get them.

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#11

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

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#12

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.

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#13

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:

Why Aren’t Drugs Safer? - Is It Because We Need A Fundamental Understanding of the Receptor Response?

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”.

google.ch/search?hl=de&q=rec … rt=40&sa=N

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.

Epigenetic inheritance during the cell cycle

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.

Also, from November 2008!

Epigenetics in the Nervous System

So now back to the original post by chams:

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:

New Agonist/Antagonist Optimal Ratio Combinations as a Potentially Safer Class of Pharmaceutical Drugs

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.

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#14

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

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#15

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.

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#16

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.

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#17

i have found a study that made me shitless ,i think this is directly related to our condition.
you can view the whole study at: content.nejm.org/cgi/content/full/332/21/1393

i will quote some important lines:

could that be what happened to us?

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#18

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 .

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#19

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.

Look at the first screenshot in this thread, particularly the red highlighted text on the RIGHT:
propeciahelp.com/forum/viewtopic.php?t=1400

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:

propeciahelp.com/forum/viewtopic.php?t=1457

That’s not true at all.

Finasteride affects us differently based on CAG repeats in the Androgen Receptor and 5AR2 enzyme variants, as noted by:

propeciahelp.com/forum/viewtopic.php?t=2242
propeciahelp.com/forum/viewtopic.php?t=1406
propeciahelp.com/forum/viewt … genotyping

And any trial to analyze our situation is better than none at all.

Probably as mentioned above (AR CAG repeats, 5AR2 variants): GENETICS and alleles.

I don’t know. As the user “Awor” mentions, testing for such things is at the cutting edge of research. Perhaps Awor can provide more insight.

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#20

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.

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