Can you explain specifically why AR gene expression theory is not a plausible theory? “At best (for the theory) there is mild AR acquired” <This doesn’t make any sense.
There are documented studies which show that pharmaceuticals alter gene expression. In fact, persistent sexual dysfunction from SSRI’s is thought to be a result of gene expression changes.
It’s just really loose theory at this point, i suppose. MOST of the sufferers have messed up hormone levels which can cause all sorts of diffs with neurotranmitters and brain function. I just think that this covers a good 90% of people’s PFS problems.
What i meant way - so some people acquire complete AR (relatively speaking) overnight (concidentally concurrent with a hormonal crash, may i add!) whilst others slowly and surely find it creep up on them? Does this fit into the mechanics of the theory?
Isn’t a messed up endocrine system enough for you people?
I, like many, wish it was a simple hormonal imbalance. But not acknowledging other possibilities simply because i don’t want it to be true is not going to change anything.
I am no expert, but gene expression is complex. I am sure there are variations between individuals in how finasteride has effected their bodies at the cellular level as there are individual variations in symptoms and blood work. This could also translate to how their bodies cope with Fin, some crash, some slowly get worse and stay that way.
Whilst i agree that it may not explain every case, for guys who have been off fin for several years with little to no improvement in symptoms i believe it is the most plausible explanation.
I’m not totally dismissing it but i think alot of guys underestimate the chain reactions that occur with such endocrine shocks that fin causes (going on it, taking it, and going off it, namely) in terms of hormones and the brain function.
Little to no improvement generally = ineffective treatment for one reason or the other. Obviously this is owed to the complexity but also due to resources and expertise of endos.
Hello.
Yes. If you listen to the recorded radio show on that link you’ll find that Dr John does mention Finasteride. He clearly states men have normal hormonal profiles and all the symptoms of hypogonadism. Despite the subject of the radio show being about preg he does not mention that as a therapy. In fact you could hardly of posted a WORSE link to support your claims 
.
I see in your past couple of posts you have now stopped going on about ‘preg/prog/cortisol production lines’ or ‘cortsol therapy’ or ‘DHT metabolism’, but just for the record; members here have been (and still are) treated by Dr John and Dr Hertogue and have NEVER been prescribed such a treatment. Because its BLLCKS.
Im sure in different circumstances we could be the best of friends, but all I care about now is getting better. So no offence but, this is a very different forum from hairllosstalk and the crap you have come up with is just filling the forum with misleading unverified rubbish.
If you have normal T, DHT, SHBG and Oestradiol levels and ratios (as 95% of the people here do) what hormonal balance could cause these symptoms? Read what Luckfax said:
If it was a hormonal inbalance Colin a lot more people would be posting in the recoveries section over the last 3.5yrs (even without your help! )
Heres the root of the problem with you Colin, your posting unverified rubbish. You dont know if that post is true or false and you have not included a source to verify the claim. You deserve to get shot down for such posts. (This is the Theory section and I have posted a Theory. I dont know how much truth is in it - so Im not claiming I have all the answers, whatsoever.)
But isnt it obvious that if you have something scientific to add to the discussion that it MUST be supported by science (text book, opinion, research paper) or otherwise stated as a theory with the appropriate science and reasoning to support that theory. This is also true if you want to crititise someone elses theory or ideas. If these rules are not upheld we are not taking part in an intelligent and constructive debate but an extremely tedious and repetitive, and quite frankly stupid, discussion that will lead nowhere.
Ok, i can’t really fault that post.
I simply think you’ve misinterpreted many of my posts. I mean, im not presenting anything as fact or trying to mislead. I wasn’t trying to gain any credit or anything. I’m simply trying to help people by offering an additional avenue that is somewhat overlooked on here. I have no doubt this CPL has merit because a few people have reported good experiences including JR. It’s all going to be “theory” to some degree given the mess that PFS really is. People are free to reject it or try it.
Same as you though - all i care about is getting better, too. Let’s not forget we’re both wasting our time on this forum that reason. My FSH is 1.6 FFS.
Excuse me gentlemen, but I take the opportunity of the debate to ask something I could never find out, no matter how I searched:
Where the hell are Dr Crisler’s or Shippen’s or Hertogue’s or Jacobs’ or whoever Post-Fin doc patients who actually recovered ?
These patients are exactly like aliens: everybody knows someone who heared about many reports, but nobody actually saw them.
As you’re all aware I prescribe to the androgen insensitivity idea which is very variable in each of us. Some of us will display androgenic properties in parts and not others. Some will have loss of all functions.
If you have lets say an insensitive prostate then by increasing Testosterone by TRT or other means will not reactivate it but will drive the other pathways in places still sensitive so increased hair loss, acne etc… I experienced this whilst on Tribulus. Did it help me overall - no. Did it show signs of increased androgenic use - yes.
As my hormones have all been good I doubt changing them would help and having been on this forum have seen very few long term improvements on ANY hormone and the ones that did help only had them in pulses like Dury and ScaredinMD.
I have seen no happy Dr crisler patient on this forum and have to say do not trust the man mainly because he is not evidence based and makes you sign a form that means he takes no responsibility for anything that happens and basically has full reign. Not very trustworthy if you ask me.
That last part is utterly unfair (yet it explains the who rarity of good reports - i hope!!) because that is a basic medical requirement especially with the more “experimental” treatment that PFS really requires.
Well something has to give. I mean alot of people come on here, report sides and disappear after a while never to come back.
So either they cured themselves (NB - time being the biggest healer), topped themselves, are the same but avoid this board for some reason or have been cured professionally and put this behind them.
Surely atleast some fit into the latter category and even if not, not everyone uses the internet for such matters.
I do agree though, it’s not ideal or wholly reassuring but it is what it is. I have to take Dr C’s word that he has cured people in the past - atleast to appreciable levels!
Something I don’t understand is, why, if the PFS has many recoveries outside the board, the posters we regularly see on the board never come some day to say to us “hey, I recovered!”. People on the board go on and on posting about their suffering, and seem to be the living proof of the persistance of side effects.
What I meant by my alien analogy is that the recovering and recovered people are always outside of the board.
Damn, I would like to talk to one of them!
In my opinion, the only advantage of these doctors is that they believe in PFS, so when you see them, you’re not battling the additional problem of diagnosis; instead the focus is on treatment.
I must agree, for all the accolades these doctors get, I haven’t seen many of their patients who have returned to normal.
While the PFS docs are trying to help many of us, I think they fail to try to identify the specific cause of all of our problems which is most certainly low 5-AR-2. I have mentioned this numerous times to the 3 doctors I’ve seen including one of the PFS doc’s and they always seem to ignore my statements about the cause being low 5-AR-2.
I am in the process of getting my 3-adiol-G tested by Dr. Jacobs, which I believe will most likely come back low. Maybe he will then discuss the 5-AR-2 issue with me. However I am still at wits end as to what if any method there is for increasing this enzyme.
I used to have bad acne cysts on the back of my neck… all through my teens and up until I used finasteride. On Finasteride this cleared up quickly, and came back briefly for a week after quitting finasteride (as did my sense of mental well being)… then a few days later back in early Jan. 2011. My mood went down, the acne stopped developing and I was sweating less in the gym. Just like being on finasteride, except that my erections and libido disappeared.
What do the two states have in common? Being on finasteride, I had low 5-AR-2, now off I am still having the same effects… the 5-AR-2 must be having a cascade effect on all our hormones… testosterone, adrenals…
What I am having a hard time wrapping my head around are two issues,
why I was I able to have pretty good erections (only about 50% libido thou) while on finasteride but being off… it went to Sh*t.
Why was there the brief recovery, right after coming off the fina, but then my body reverse regulated itself, to state less than that of being on the fina even.
My brain-fog has improved somewhat since being off, my sleep somewhat as well. Thou I have been taking a ton of stuff, some prescribed, some OTC.
My erections are better while taking DHEA… 100 mg twice a day.
Thats what we are trying to figure out. It makes no sense. But 5aR seems to be the most obvious place to start.
If you follow this theory the hepatic enzymes which are repressed by finasteride (thus properly preventing its metabolism) can lead to a state of hypogonadism when actually over-expressed (which may happen for some reason when finasteride usage ends).
{I have also notice that one test for this theory is by measuring the ratio of deactivated 6beta-hydroxycortisol/cortisol ratio (see cebp.aacrjournals.org/content/1/7/567.full.pdf) This possibly opens up the door to a range of other symptoms of cortisol deficiency if the ratio of deactivated cortisol is off, although the fact CYP3A4 is also responsible for cortisol homeostasis is not prominently mentioned in the literature.}
Hello again.
If you have been following this thread you will know that I have been trying to work on the theory (that has actually been around in one form or another since the forum started) that the liver is involved. The reason that this theory exists at all is that the liver also plays a strong role in the homeostasis (metabolism/deactivation) of testosterone.
The Theory basically goes like this: Finasteride causes side effects related to those seen in androgen deprevation, this may occur in some due to Finasteride inhibiting its own metabolism. The same enzymes involved in metabolism can also deactivate testosterone, and prehaps when some people ‘crash’ or do not get better its because the liver is now hyperactive.
One problem that remained was that that blood test results showed normal testosterone levels and DHT levels, therefore it simply does not matter about anything the liver does if this all remains OK. I attempted to make an explanation for this by stating that there was something called ‘Phantom DHT’ which is the product of deactivated-testosterone and 5aR. However, it turns out i need not of tried to reinvent the wheel!
Phase 1 metabolism of testosterone occurs by hydroxylation by CYP3As - this leads to deactivation of testosterone. Phase 2 metabolism (which can just occur instead of phase 1) is Sulfoconjugation where testosterone is made unable to bind to androgen receptors in preperation for excretion with urine. Both of these processes are controlled by the Pregnane X Receptor.
I had ignored this phase 2 metabolism because I didnt understand it, it didnt fit in with my theory and I hadnt read the full papers my own theory had relied upon. I now have. It turns out phase 2 metabolism is much moe important than i knew.
[Size=4]Pregnane X Receptor As A Therapeutic Target To Inhibit Androgen Activity[/size] Zhang et al
[b]Another major pathway to inhibit androgen activity is hormone metabolism, which includes the sulfotransferase (SULT)-mediated sulfoconjugation and cytochrome P450 (CYP)-mediated hydroxylation…
…Sulfonation plays an important role in steroid hormone deactivation, because sulfonated hormones often fail to bind to and activate their cognate receptors and thus lose their hormonal activities…
…Changes in hepatic hydroxysteroid sulfotransferase (SULT2A1)expression can result in alterations in androgen hormonal activity and responsiveness. Androgen sensitivity of the rat liver was inversely correlated with the hepatic expression of SULT2A1…
In addition to SULT2A1, the CYP3A enzymes also contribute to androgen deprivation through their oxidative deactivation of testosterone…
PXR has been established as a master regulator that controls the expression of drug-metabolizing enzymes and transporters. The PXR target genes include CYP3As and SULT2A1…
…We propose that PXR-mediated SULT2A1and CYP3As gene activation represents a novel mechanism to lower androgen activity.
Activation of PXR in mice inhibited androgen-dependent prostate regeneration…
Activation of PXR induced the expression of CYP3As and SULT2A1/2A9, hydroxytestosterone and testosterone sulfate failed to activate AR, and a forced expression of CYP3A11 or SULT2A1 was sufficient to deactivate androgens…
6β-hydroxytestosterone and testosterone sulfate are the primary testosterone metabolites upon CYP3As and SULT2A1 metabolism, respectively. We used transient transfection to determine whether 6β-hydroxytestosterone and testosterone sulfate are indeed hormonally inactive…
…treatment with T induced the reporter gene activities, whereas the activation of reporter gene was not observed in
6β-OH-T or T-Sulfate treated cells.
…forced expression of either CYP3A11 or SULT2A1 inhibited T and DHT-induced reporter gene activation.
It is believed that most of the androgen actions are mediated through AR, whose activation stimulates a cascade of events that are required for the initiation and progression prostate cancer (26). As such, the most effective endocrine therapy for prostate cancer has been the androgen ablation (27). Other than castration and the use of anti-androgens, an important pathway to deactivate androgens is through the enzyme-mediated metabolic inactivation. In this study, we revealed a novel PXR-controlled and SULT2A1- and CYP3As-mediated pathway of lowering androgen activity.
We propose that the PXR-SULT2A1 and -CYP3As pathways represent a novel mechanism to lower androgen activity.[/b]
Regulation of a xenobiotic sulfonation cascade by nuclear pregnane X receptor (PXR) pnas.org/content/99/21/13801.full
PXR: a xenobiotic receptor of diverse function implicated in pharmacogenetics http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2593625/
Mutual repression between steroid and xenobiotic receptor and NF-kappaB signaling pathways links xenobiotic metabolism and inflammation. ncbi.nlm.nih.gov/pubmed/16841097
Xenobiotic- and Vitamin D-responsive Induction of the Steroid/bile acid-sulfotransferase Sult2A1 in Young and Old Mice http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1888572/
Ok Oscar you’ve made your theory now put it to the test!
Either get a metabolite tested - hydroxy-testosterone - testosterone ratio - contact Rhein labs and see what they can do
Or take something that will keep the pregnane X receptor busy whilst testosterone is able to do its thing.
Just to clarify are you saying that if you increase your DHT via say direct hormone replacement this will in effect cause more deactivated DHT to be produced therefore acting as a competitor. The ratio will stay somewhat similar. This upscaling of metabolism could explain the lag when first starting TRT - as some people get benefits at first - then it wears off. However, if you were take a mega dose of TRT the body would not be able to compensate.
You said:
Fin Inhibition of 5bR+PXR
Decreased CYP3A4 - leading to decreased xenobiotic (Fin) and testosterone metabolism.
Over-expression of 5bR+PXR (after stopping Fin)
Increased CYP3A4 - leading to increased testosterone metabolism/deactivation
Increased CYP24 - leading to low levels of Vitamin D
Makes sense.
It’s definitely a possibility. I strongly urge you to explore it further and look for ways to determine if there is merit in it - tests or treatments. And get that test or treatment done!! Good science in just one of us who suffers could give the answer for everyone.
Increased metabolism or epigenetic based resistance or epigenetic based increased metabolism - one of these is the answer. I’ve explored the resistance issue as much as i can. I will look into this one a bit further.
Yeah Im just about out of ideas. I dont know how much of what I have said is true or false and theres not much point second-guessing myself.
The test for this would be to measure the ratios of 6beta-hydroxytestosterone or 6beta-hydroxycortisol.
I CANNOT get this tested for in England. I have contacted private pathology labs directly and I have spoken to NHS endos (who have no clue what I am on about!).
I’l keep on trying as its a worth while avenue to persue - this much I know for certain. It CAN be tested for in the USA by Quest labs (see link posted previously) and I encourage anyone in america reading this to get tested.
Also, one thing I cannot fit into any theory: why some people get ‘brain fog’ using fin that simply continues upon quitting. I only experienced brain fog (that I noticed) when I crashed, so my ideas fit my experience the best.
Assuming the same thing is involved for everyone I cannot even imagine any way it could happen for some people one way and for me and others only upon quitting. Unless there is an entirely different process involved (ie neurotoxicity from the added chemicals in generic finasteride building up in the brain - or some are just more suseptable to inhibition of neurosteroids) . So basically I am back to square one.
Ocar, try to speak to Professor Bouloux from London he seems to have an active interest in this stuff.