How Accutane can cause similar effects if it is not an 5AR inhibitor?

accutane
isotretinoin

#1

These articles show no significant change in 5ar enzymes in men after Accutane treatment. Yet, many people experience the same hormonal crash as propecia users. How this can be possible? Isn’t that Accutane inhibits 5AR type-1 but not the 5AR type 2?
5ar only found in skin cells, isn’t it? And 5ar type 2 is in the prostate… So how the hell we experience the similar symptoms…


#2

Presumably the Androgen Receptor is affected similarly.


#3

Well, i read a positive post for me at least. Because i used Accutane, it seems Accutane have no effect on penile tissue but prostate… i was worried for my pelvic muscles, also i have very mild peyronies disease. I thought this all caused from accutane. But accutane inhibist only the 5AR type 1 and 5ar type 1 is only on skin, hair and prostate. Maybe it damaged my prostate but my muscle tissue is healthy? Is it possible? I don’t understand why i developed hourglass flaccid penis years after the usage tho. And many people experience the same crash with penile shrinkage, peyronies disease etc. on Accutane… so everything looks contradictory and im so lost in my mind…

Here is the info from the article:
The inhibitors of the 5-alpha-reductase (5ARI), enzyme that catalyzes the conversion of Testosterone to Dihydrotestosterone (DHT) [1], have been widely used for more than 20 years, especially in the treatment of androgenetic alopecia and benign prostatic hyperplasia. There are 2 types of 5-alpha-reductase (5AR): type 1 (5AR-1) and type 2 (5AR-2). 5AR-1 is predominantly localized in hair follicles and sebaceous glands, non-genital skin, as well as in the liver, prostate and kidneys, contributing to one third of the circulating DHT2. 5AR-2 is predominantly localized in the prostate, seminal vesicles, epididymis, hair follicles, genital skin and liver, contributing to the remaining two thirds of the circulating DHT [[3] While dutasteride is a dual inhibitor of the 5AR, finasteride only inhibits 5AR-2.

Note: So it does contribute DHT2 to circulate… maybe this is the cause?


#4

Yours is a key question, which deserves to be discussed in more detail.

Our syndrome (PFS, PAS, whatever you want to call it) can result from any substances with anti-androgenic properties. Inhibiting 5ar is only one possible such mechanism. Various papers have found isotretinoin to have such anti-androgenic properties through the downregulation of AR expression:

Exposure of primary lacrimal acinar cells in culture to 10(-10)-10(-6)M all-trans retinoic acid for 4-24hr causes an approximately 50% decrease in AR mRNA expression.

A pharmacologic dose of retinoic acid inhibits AR expression in lacrimal gland acinar cells in vivo, as well as in vitro.

Even much earlier, the following paper found:

significant decreases in 5 alpha-dihydrotestosterone [DHT]

induce a 2.6-fold decrease in its binding capacity constant [of AR]

The decrease in skin androgen receptor levels (this study) and the recently reported suppression of skin 5 alpha-dihydrotestosterone production by isotretinoin treatment appeared consistent with the involvement of androgen receptor and 5 alpha-dihydrotestosterone in the pathogenesis of acne.

One year earlier, this paper found

a highly significant decrease in 5 alpha-dihydrotestosterone formation by skin biopsies;

Taken together, the above listed publications clearly demonstrate the potent anti-androgenic effect of 13-cis-retinoic acid (isotretinoin, Accutane) through downregulation of AR and downregulation of DHT. Even though neither of these papers discuss the mechanism by which 13-cis-RA downregulates DHT, it is likely because 5ar is under AR (androgen receptor) control, as is outlined in the following publication:

We found that androgen regulates the mRNA level of 5α-reductase isoenzymes in a cell type-specific manner, that such regulation occurs at the transcriptional level, and that AR is necessary for this regulation.

Through this evidence, it becomes abundantly clear that “PFS” is a syndrome which is a result of anti-androgenic action, and not limited to substances which inhibit 5ar. As we will hopefully demonstrate in the near future through our upcoming survey, other substances such as Leuprorelin (Lupron) and anti-depressants can also cause “PFS” through their respective anti-androgenic properties, even though they have nothing to do with 5ar.

It is for this reason that I am of the opinion, that research which only focuses on finasteride and 5alpha reductase, is not very useful. There is a lot that we can learn by looking at the bigger picture.


Single Accutane pill and ED
Literature or at least sound theoretical basis for connection with PSSD and PAS?
#5

Awor do you feel that any of the studies currently or of the past address this as a whole? Is the Baylor study addressing a broad or specific scope?


#6

Unfortunately not. They are all only focused on finasteride. What needs to happen first, is that the common denominator must at least be accepted as a hypothesis. Once that happens, existing studies could then be repeated on isotretinoin, leuprorelin, pssd etc. patients, to see if those groups produce the same results.

Alternative approaches could be:

  • Produce a real animal model (i.e. genetically engineered), but for this we need to know the genetic drivers
  • Get enough 23andme genomes from all groups and demonstrate that we all have a similar underlying genetic predisposition via GWAS (we’re slowly getting there for finasteride, but seriously lacking with regards to all other groups)

If someone could produce “big picture” pilot data along the lines of what I described above, I am pretty sure that this would be our ticket for heavy duty government funding. From that point onward, life hopefully would be much easier for us.

In my opinion, the safest way of getting the most powerful pilot data possible, would be to repeat the Baylor full genome gene expression study with all groups. I would actually repeat the finasteride part as well, thereby putting Baylor under pressure to deliver their results, and make sure that they will not tamper with them, like BWH presumably did. I would clearly perform this study outside the United States, because our experience of doing studies there so far has not been good (BWH because they basically stole our money, and Baylor because of the timeline). I might even consider to at least partially contracting this work to a commercial lab, as to cut out any university style nonsense with regards to the timeline and deviation from protocol, and to have more control.

My estimate is that we need about USD 400K to get this done. So if anyone has a good idea on how we can get this kind of cash together, let me know.

It would be a nice Christmas present to us all, in any case.

PS: Under the assumption that our syndrome is not drug specific, but rather the result of anti-androgenic action, we’re going to need a non-substance specific term for this syndrome at some point.


#7

Maybe some kind of collaboration with them would be possible: https://rxisk.org/prize/ ?


#8

Hi @awor, for those of us who are relatively new on the forum, can you tell us what happened with the BWH study?


#9

Thanks for the responses, with what you just said, you don’t necessarily believe this is the only route for success correct? Obviously seems to be the most ideal, but the studies currently ongoing are beneficial to an extent in your mind right? I understand you are asked about Baylor a lot as you are the face of this forum who many go to in search of help, so if you don’t want to address it anymore I understand. In your opinion is the timeline so dragged on bc of a) extensive amounts of information and study (best case) b) taking the study not as serious or c) political tampering so to speak? Thank you


#10

You have spoken about this before - about the dangers of anti-androgens of any type for potentially worsening our condition (nothing to speak of causing it). Is there a lot of evidence that people who already have pretty bad PFS can get even worse after taking anti-androgens? I know that @axolotl recently had such an unfortunate experience. (it would be nice if axolotl can talk about this as well).

I am asking about zinc in particular - because I am considering re-starting zinc after having been off it for 6 months. I never knew how bad my PFS was while I was on zinc. Now that I am off it I am worse than ever. I know zinc is supposed to mirror the function of finasteride in reducing DHT and that sounds awful as an intended effect but if I can go back to my previous baseline, I would - while other possible treatments are being investigated. I am afraid of the risks however. The way I got PFS was after I restarted finasteride after I had discontinued it for 6 months. I don’t want the same thing to happen again with zinc but I really can’t go on with my current state any longer so I might have to take the risk. How much worse can it get? My libido is already at 0…


#11

No disrespect, but there are people here whose smallest concern is low or no libido. If libido is your main/only issue, things can get much worse. How about emotional numbness, insomnia, crippling anxiety, severe derealization where you experience life like peeking through a looking glas and stumble over your own feet? Low libido and the effects on relationships etc. suck. But there is large universe of equally if not worse side effects out there. There have been people before you who thought they had nothing loose and found out that they were mistaken. There are a lot of things that you only realize you’ve had when they are gone.


#12

I am talking about this study:

They basically did not stick to the agreed protocol, took a huge amount of money, and produced a very Merck friendly paper. Merck is a major sponsor of many universities, and pays the top dogs in the field nice “consulting” fees. Go figure what happened.

This conclusion

expression levels of AR-dependent genes in skin did not differ among groups

is absolutely not possible given what the Di Loreto paper had already found (namely overexpressed AR).

Something is seriously fishy about this study. I don’t want to go on further about this in public and risk facing retaliation of some sort. Just want to say, I don’t want a repeat of this disaster.


#13

Tbh, I am a little confused about the evidence. Cases with broad and strong symptoms are susceptible to get worse from taking further anti-androgens. This includes Axo and myself. Others seem to do well on Zinc for example. I don’t think anyone will benefit long term from taking stronger AA’s such as dutasteride, etc.


#14

I think you are severely underestimating the importance of libido for the normal psychological functioning of human beings, which is a mistake people without PFS usually make. I have all of the emotional and mental side effects you mention and much worse (I also have the standard physical side effects). Let me just say that my side effects are bad enough to be absolutely life-threatening, nothing to speak of life-destroying. And I can tell you with 100% certainty that they are all caused by severe depression which in turn is caused by lack of libido (and everything that entails). In other words, if I can recover my libido, I will recover the psychological symptoms as well. I am sure we can debate this without reaching an agreement.


#15

That’s for sure. I am not even considering finasteride or dutasteride. But how similar to those is zinc’s effect on suppressing DHT? I harbor no illusions that lowering DHT to any extent again can only make things worse in the long term by further upregulating the androgen receptors or alternatively from preventing downregulation. Still, I feel that I need a short-term measure to get me through the worst of this, even at the expense of long-term harm.


#16

Hopefully people will not become discouraged to fund because of this. It’s horrible and hopefully Baylor is not as corrupt as BHW. But unfortunatelly we have no other choices. My biggest concern is that something like this may happen again, and therefore it would be great if someone like Awor and a non corrupt doctor get the right/access to supervise the process of the research.


#17

I think you severely overestimate the role of libido. And yes, I am sure we can debate this without reaching an agreement. But that does not mean it is not a debate worth having. So, please provide the evidence that made you 100% certain that all psychological side effects are caused by decreased libido. How do you know it is not the other way around?


#18

@Sibelio and @Northern_Star: Could we please keep this on topic? :slight_smile:


#19

I may be one of the few here who has taken both…Accutane as a teenager which stopped my cystic acne and I had blood tests they monitor your liver on Accutane…I stopped treatment early.

Then generic Finasteride in 2014 which didnt do anything but make my hair loss worse fast…

1mg Propecia in 2015 for 6 months gave me horrible symptoms then after stopping the following months I began a journey of health loss like I would have never thought possible…


#20

I could be wrong but the study where they found overexpression of the AR was localized in the skin of the penis and in the BWH study they don’t say where the skin samples were taken from. Maybe it’s different depending on where the skin is taken from? Just thoughts