THEORY - PAS and PFS - 5-Alpha Reductase Enzyme - Very Plausible/Currently seems to be the most likely cause of PAS

flynn

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The following posts are fairly long, but if you are interested in how PAS arises, then I think they are worth reading. Of all the theories, this one seems to be the most plausible/likely in my opinion.

Another theory of PAS relates to Post Finasteride Syndrome (PFS), this is a recognised syndrome which a subset of men develop after taking the hair loss drug Finasteride (FIN) also known as Propecia. Unfortunately the underlying cause of PFS is still a mystery. However there is strong reason to believe this relates to the inhibition of the 5-alpha reductase (5AR) enzyme by FIN. 5AR is responsible for producing a range of important hormones such as the powerful sex steroid dihydrotestosterone (DHT) and a range of neurosteroids. Studies have also shown that people with PFS have a depletion of neurosteroids which is likely to be related to 5AR inhibition. Note that PFS could be called 5AR inhibition syndrome, as other drugs such as saw palmetto can lead to similar persisting effects.

The symptoms of PFS are surprisingly similar to PAS. Not only do PFS sufferers report sexual dysfunction (sexual anhedonia, loss of libido/arousal/interest in sex), depression and anxiety. They also suffer from a range of mental, physical and cognitive problems which are remarkably similar to reports of people with PAS. Mental and cognitive symptoms include: anhedonia, emotional blunting, loss of drive/motivation/personality, brain fog as well as a loss of interest in hobbies/relationships and activities which they once enjoyed, this could be regarded as a general form of apathy. Not to mention severe memory problems, impaired problem solving and reduced comprehension.

Interestingly, PFS also exhibits a range of physical symptoms found in PAS such as chronically dry skin, decreased oil and sebum production, chronic fatigue, tinnitus, increased fat deposition and reduced HDL cholesterol.

So what is the connection between PFS and PAS?

There are three types of 5AR enzymes: 5AR1, 5AR2 and 5AR3, FIN predominately inhibits the 5AR2 enzyme as its found in the scalp (to prevent hair loss). Its believed that Accutane interferes with the 5AR1 enzyme.

Firstly, Accutane doesn't appear to drastically affect serum (blood) levels of steroid hormones/androgens such as Testosterone and DHT - https://www.ncbi.nlm.nih.gov/pubmed/9298137

Despite this, studies have shown it significantly decreases the levels of several 5 alpha reduced androgens after just 3 months of use. Which indicates that it has a strong effect on peripheral 5AR activity in regions such as the skin - https://www.ncbi.nlm.nih.gov/pubmed/7714084

These findings are backed up by a study which investigated gene expression in the skin cells of patients, who had taken Accutane for 8 weeks. It was found that, the expression of the 5AR1 gene (SRD5A1) was reduced by 2.83 fold alongside a host of other genes. One of which is the gene encoding the 3b-HSD type 1 enzyme (Described in the post below), which is essential for the biosynthesis of all classes hormonal steroids, namely progesterone, glucocorticoids, mineralocorticoids, androgens and estrogens.


Here is the original study looking at gene expression which shows changes in 5AR1 and 3b-HSD expression -
https://www.tandfonline.com/doi/pdf/10.4161/derm.1.3.8258?needAccess=true

The real question is, if Accutane can have such a significant effect on gene expression peripherally in places such as the skin, is it possible it has also altered 5AR and 3b-hsd gene expression in other regions of the body such as the brain?

It's hard to find data on this, but a referenced slide from a research powerpoint indicates that 5AR1 is indeed also found in the brain -
https://www.statusplus.net/issm/saopaulo2014/presentations/083.pdf
Screen Shot 2018-03-10 at 02.35.06.png

More evidence

I have potentially found another line of evidence to suggest there is a sustained reduction of 5AR activity in the brain post-accutane. A study in rats investigated the effect of 5AR inhibition on progesterone induced release of gonadotropins: Luteinising Hormone (LH) and Follicle Stimulating Hormone (FSH). Now here is where things get interesting, when 5AR inhibition was sustained is resulted in a significant inhibition of progesterone-induced FSH but not LH. Essentially, if Accutane has caused sustained reduction of 5AR activity/expression in the brain, PAS people may have lowered levels of FSH.

As mentioned before, of the blood tests I have had, I regarded only DHEA-S as being abnormal, due to it being off the scale. Of all the other hormones, there was only one other which seemed unusually low for a male of my age, that was FSH -

FSH Blood Test - 3.0 IU/L Range 1.5 - 12.4 (certainly on the low end of the scale for a 24 year old male).

More importantly, of all the reports online PAS people seem to consistently report low FSH. Given the role of FSH in spermatogenesis, this would help to explain reports of watery ejaculate and low semen volume.

Why do PAS people seem resistant to Androgens and TRT/Steroids?

Another thing which has always confused me, is the resistance of PAS sufferers to effect of androgens. Many PAS sufferers including myself report normal/high serum androgen levels. Whats more confusing, is the inability of Testosterone replacement therapy/Steroids to alleviate or improve symptoms. There are numerous accounts online of PAS sufferers experimenting with varying levels of steroids, with no effect on symptoms. I have personally experimented with Testosterone Enanthate, dosing between 300-600mg/week over a 8-10 week period.

I was able to make significant strength gains in the gym, building a large amount of new muscle mass but none of my mental symptoms improved. No improvements in sexual function, little change in mood, no increased aggressiveness, no alpha-male feeling which most steroid users report. This seems to be the case with all other PAS people who have tried TRT/steroids. How could this be? In any normal person, TRT/steroids exhibit significant changes in sexual function and/or mood/behaviour.

Firstly, skeletal muscle is unique from other types of androgen receptive tissues in the body. It contains relatively little or no 5AR, DHT isn't usually formed in the muscle and even if it is, it is quickly deactivated by the enyzyme 3alpha hydroxysteroid reductase (3a-HSD). Given this, testosterone is the primary active androgen in muscle. In effect, muscles don't require 5AR activity to gain the beneficial effects of blood testosterone. But other androgen dependent tissues do.

This is evidenced by males suffering from congenital 5-AR deficiency a condition caused by congenital 5-AR deficiency (little or no 5AR enzyme). During Puberty, when their testosterone levels rise. They develop normal musculature like any other adult but have underdeveloped prostate, penis, little to no body/pubic hair and I'll would bet some form of sexual dysfunction -
https://ghr.nlm.nih.gov/condition/5-alpha-reductase-deficiency

In other tissues such as the brain, skin and genitals, the androgen signal is not transmitted by testosterone but by DHT. Given this, it seems to be the case that in androgen dependent tissues excluding for muscle such as the brain


Things to consider

One important question to ask here is, if Accutane does reduces expression of 5AR1, why doesn't 5AR2 activity not supplement the loss of 5AR1 activity and prevent PAS developing. Firstly, we know that with PFS, the sole inhibition of 5AR2 by FIN is sufficient to lead to PFS. Thus its possible that the sole inhibition of 5AR1 is also capable of causing PAS (perhaps the role of the enzymes in the brain is 50/50?).

Another possibility is that Accutane does in fact also affect the expression of 5AR2 in regions of the body such as the brain. Though I can't find many studies investigating the effect of Accutane on 5AR2 gene expression (please enlighten me). However one important difference it seems between PAS and PFS is that PFS people suffer from penile shrinkage and testicle shrinkage due to the location of the 5AR2 in regions such as the genitals. These symptoms don't seem very prevalent in PAS (or am I wrong?). Some PFS people also complain of muscle wastage but it seems likely that this relates to lower serum (blood) levels of testosterone observed in some PFS sufferers.

The important thing to recognise here, is that if Accutane has indeed altered the expression/activity of these enzymes in specific regions of the brain. These changes are likely to take effect irrespective of blood androgen levels. One thing that always confused me was the lack of effect that TRT, steroids and normal healthy androgen levels seem to have for PAS people. This is exactly the same for PFS people. The enzymes seem to crucial in distinct regions for translating the hormonal signals from the blood into the corresponding compounds which elicit dominant effects on brain function and the activation of the neural pathways associated with things like sexual function and reward seeking behaviour.

Which Brain Regions?

In regards to the brain areas to target, at this point, its a guessing game. But according to the following study in mice, the conversion of testosterone to DHT and thus 5AR activity is very high in the pituitary gland and hypothalamus. Other areas with less activity are the cerebral cortex and amygdala -
https://app.dimensions.ai/details/publication/pub.1042917474

Additionally, studies in human males indicate that activation of the bilateral hypothalamus plays a key role in sexual arousal, and activity here was strongly correlated with the sexual response to watching erotic movies. So this is another reason to suggest the hypothalamus may be a suitable target -
https://www.ncbi.nlm.nih.gov/pubmed/18588532


- Flynn
 
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flynn

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Follow up Points for Post Above (exceeded post character limit)

DHT

If you don't think DHT is that significant compared to testosterone, think again. DHT is the most potent endogenous androgen based on several characteristics:

1. The binding affinity of DHT for the Androgen Receptor (AR) is approximately 5 fold higher than Testosterone.

2. The rate of dissociation from the AR is around 3 times slower than testosterone.

3. The binding of DHT to the AR transforms the AR to its DNA-binding state.

4. DHT upregulates AR synthesis and reduces AR turnover

Together, these processes amplify the androgenic effect of DHT compared to testosterone.

Now here are some important points to make about DHT which confuses most people. Firstly, circulating levels of DHT do not correlate with those found in androgen sensitive tissue such as the prostate. This is due to local regulatory mechanisms that tightly control intracellular androgen homeostasis. This is not to say, they have no effect at all but they don't necessarily correlate. This is worth noting, as clinical studies have shown that intracellular concentrations of androgens (particularly in androgen sensitive tissues) are essentially independent of circulating levels.

Now to note, Peripheral 5AR activity accounts for most of the circulating DHT. Supposedly little DHT from prostate and liver enters the circulation due to efficient intracellular mechanisms that metabolise DHT.
One question here, may be to ask. If we have normal levels of DHT in the serum then surely we have normal levels in the brain? Firstly, if accutane has reduced 5AR1 expression, then we still have 5AR2 expression to produce seurm DHT. But even if both 5AR1 and 5AR2 have been down regulated. There is a crucial difference most people miss between the brain and the rest of the body. Neurons in the brain don't divide, as such they remain the same whilst cells in the rest of the body are constantly dividing and changing. Given this, overtime if gene expression has been altered in peripheral cells such as skin cells etc. some of these effects will be reduced over time as the cells divide and change. This is not the case with neurons. If Accutane has altered gene expression in neural cells. These cells will likely remain this way. Hence its possible for 5AR activity in the rest of the body to go back to normal overtime but not 5AR activity in the brain.

All of the above about DHT is referenced from the following paper (sorry about long URL) -
https://watermark.silverchair.com/e..._4grlXCgYu4ZbMoTWsTQXSHYyC9OxqVu51QXJ9369I59M


DHT - The Blood Brain Barrier (BBB)

Given the information above, it makes some sense at to why many PAS people have normal/high serum DHT levels but still suffer all the major symptoms. But there is another thing to consider about serum DHT levels. Even if serum DHT levels are sufficient to effect the desired processes in androgen dependent tissues such as the skin or prostate. We're still forgetting the fact that there is a big difference between normal circulation reaching these kinds of peripheral tissues and circulation in the brain. This is due to the blood brain barrier which is very selective in what it lets in and out of the brain.

Its pretty difficult to find information on DHT and the blood brain barrier but here are some studies which mention it.

According to this study, DHT should be sufficiently lipophilic to passively diffuse into the brain. However, DHT is a known substrate of P-glycoprotein. P-glycoprotein is an efflux transporter in the blood–brain barrier that can extrude a wide variety of lipophilic compounds out of the brain - https://www.sciencedirect.com/science/article/pii/S0969805115000396

Studies in the rhesus monkey show that DHT is far less able to cross the blood-cerebrospinal fluid barrier than testosterone. Its thought this is due to differences in their ability to bind to testosterone binding globulin. As a result, DHT is thought to be an ineffective suppressor of pituitary leutinizing hormone secretion by virtue of its inability to gain entry into the central nervous system – Remember the anterior pituitary which produces LH is protected by the blood brain barrier - https://www.popline.org/node/429036

The only paper to claim is does ( http://ar.iiarjournals.org/content/37/11/6025.full ) claims the following “Moreover, out of the abietane diterpenes extracted from S. miltiorrhiza, DHT most potently penetrates the blood–brain barrier (BBB)”. – I really don’t know what this means. But I will link the study used to reference this below. I had a look but I cant see any mention of DHT, there is only mention of a compound called dihydrotanshinone. So I don’t think this claim is correct, may be a mistake or an assumption (please check this for me if you can) - http://ar.iiarjournals.org/content/37/11/6025.full

Its hard to make assumptions here, as we need more evidence about DHT and the BBB. But studies seem to suggest that DHT isn't particularly apt at crossing the BBB. Which would pose as another reason, why serum levels of DHT are of little significance to conditions such as PAS or PFS.


5AR activity and Acne Flare Ups

Someone linked me to another interesting study. This is fairly unrelated but may give some strong clues as to the mechanism of Accutane action. Most Accutane users report having skin flare ups during Accutane treatment. This is when the acne seems to get much worse before getting better. The study linked below suggests that ATRA (A metabolite of Accutane) acts as a positive regulator of 5-Alpha-Reductase activity in the rat liver. Given this, its plausible that when patients first take Accutane, there is a significant increase in 5AR activity in the skin leading to enhanced sebaceous gland activity and more acne. Overtime however, Accutane is able to downregulate the expression of this enzyme which eventually reduces acne. Its still unclear, whether this is the main reason acne is treated on a long term basis. Or whether genetics changes of the sebaceous gland and sebum production are also involved. But its interesting to note that it is also 5 alpha reductase type 1 which is present in the sebaceous gland. This would provide a plausible theory of why Accutane can make acne worse at first and how Accutane can treat acne on a long term basis.

This may also help to explain why some people experience an increase in libido whilst on Accutane or for periods on Accutane but then go on to crash.

Here is the study - https://www.ncbi.nlm.nih.gov/pubmed/10423178


More Evidence
This is some more info which is kind of implicit, but worth mentioning and noting. I have always stated that PAS must involve some kind of dopaminergic dysfunction. Practically all the major neural pathways associated with the main symptoms of PAS relate to the dopaminergic system, primarily the mesolimbic reward pathway, but also to signalling in regions such as the prefrontal cortex. The primary role of dopaminergic signalling in reward seeking behaviour and pleasure is undeniable, so too is its involvement in sexual function.

Even in conditions such as Post-SSRI Sexual Dysfunction (PSSD), in which sufferers report persisting sexual dysfunction after treatment with Serotonin re-uptake inhibitors (SSRI's/Antidepressants). Its mostly believed to be an issue related to Dopamine function, for example its thought that usage of SSRI's leads to excessive serotonin signalling, which dampens/alters dopaminergic signalling and thus sexual function. It's believed that after stopping treatment, a change in the serotonin system causes persistent dysfunction in serotonin signalling and thus dopamine signalling.

Given this, its important to consider how changes in 5AR activity/expression could affect dopamine.

- In rats the use of Finasteride (which blocks both 5AR1 and 5AR2) was able to reduce the psychotic effects (associated with the dopaminergic mesolimbic pathway) of dopamine agonists Apomorphine and d-amphetamine - This may help to explain some anecdotal reports of changes in the effect of drugs like adderall pre and post-accutane - https://www.nature.com/articles/npp200839

- 5AR activity regulates dopaminergic signalling in brain areas involved in levodopa-induced dyskinesia - https://www.michaeljfox.org/foundation/grant-detail.php?grant_id=1401

- The Medial preoptic area (MPOA) is an important integrative site for male sexual behaviour. Dopamine is released in the MPOA shortly before and during copulation. DHT is required for female induced increase in MPOA dopamine observed during copulation. - https://www.ncbi.nlm.nih.gov/pubmed/15811352

Essentially the metabolites of 5AR activity really do seem to play a significant role in dopamine signalling in the brain. This shows there is some link between 5AR activity and dopaminergic signalling. As such, if there is a problem with 5AR activity, PAS people could have normal serum androgen levels or even experiment with androgen boosting drugs such as steroids but feel few of the mental androgenic effects in the brain as they would feel little dopaminergic activity which relates to androgen activity.



- Flynn
 
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flynn

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Female Sexual Side Effects

Another interesting thing to notice, is that I have seen numerous online reports of female PAS sufferers who have developed some form of sexual dysfunction following Accutane use. Its difficult to find as much information about this online but DHT certainly appears to play a role in female libido. Testosterone therapy has been shown to enhance female libido -
https://pdfs.semanticscholar.org/0fcb/5c4611310c65a75f16e527447ad865af20e6.pdf


Unfortunately there aren't many reports of this online as women don't seem to take 5AR inhibitors as much as men.

Follow up - 3B-HSD

To follow up. The 3B-HSD type 1 enzyme mentioned in the the main post, is responsible for the conversion of pregnenolone, 17a-hydroxyprenenolone, DHEA, androstenediol and androstadienol into their respective hormonal products. Now check this, the expression of this enzyme had been reduced by a staggering 6.19 fold. Which is pretty significant. Also need to give credit for this, to Dubya_B who highlighted the significance of this hormone on his forum - https://www.lastingsides.org/

Another interesting observation here is that of all the basic hormone tests I've had conducted. The only abnormal result was DHEA-S. It was incredibly high.

- D.H.E.A. Sulphate *16.8 umol/L 0.44 - 13.4 - That is way above the top limit of the range. This is pure speculation (likely incorrect), but is it possible that a lack of 3b-HSD type 1 activity has led to a build up of DHEA-S as its not being effectively converted into its product androstenedione by 3b-HSD? Irrespective of this, I doubt 3b-HSD type 1 is the culprit here, from what I can find online. It's expression is limited to the peripheral tissues and placenta (again this could include the brain but it doesn't appear to be the case, I don't know what peripheral tissues is classified here?) - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2755580/

Additional study of interest -
On top of this, Accutane has also been shown to competitively inhibit the 3a-hydroxysteroid enzyme which also plays a role in production/conversion of steroid hormones - However its difficult to gauge whether this is of any real significance -
https://www.sciencedirect.com/science/article/pii/S0006291X03003322




I also want to point out that women also seem to consistently report persistent sexual dysfunction after Accutane. Note that androgens and 5AR also plays a key role in regulating sexual function in women as well -
https://academic.oup.com/humupd/article/10/5/421/769528
 
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tom.math

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never thought about this, makes sense. I feel like I have really low testosterone all the time but blood tests show my levels are fine????

also I read on propecia forum that 3aHSD could be linked to PSSD. some antidepressants upregulate it, just lookd and wikipedia says it converts DHT to allopregnanolone (ALLO).
 

leadbelly

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took me a while to read this but worth it. we need to find researchers who will look into this stuff seriously. how do we find them?
 

paragraf

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Hello I wanted to know how likely it is for isotretinoin to stunt penile growth? I took it when I was 16 and a half years old. I only took 10 mg per day for ~5 months so a very very low dosage. I am now 20 years old and don't recall any significant penis growth since then. (I am 6 inches Non-bone-pressed, bone pressed I am around 6.7-7 inches, and 5.2 inches girth). I want to know if the lack of growth since age 16 is from accutane. I asked on reddit in a subreddit dedicated to men with big dicks https://www.reddit.com/r/bigdickproblems/comments/8fu89z and there were some guys who took it in their young teenage years (13/14 years old) and their dicks still grew well above average. One guy PM'ed me with the following message:
"I took accutane at 14/15 by the time I was 16 I was 7 1/2 and by the time I was 17 I was 81/2 And now 18 I am 9". My dose increased as I got older. I have never put the two together untill I saw your post".
Seems like he thinks that isotretinoin caused his penis to grow even bigger! How could this be? I noticed that some people have very high DHT levels after/during accutane. So could it really get bigger from accutane?

Theories suggest that isotretinoin inhibits 5-AR Type 1 enzyme but there is no evidence for type 2 inhibition, right? 5-ar type 1 is mostly found in skin and not in genitalia. 5-AR type 2 is mostly found in genitalia. So if 5-ar type 2 isnt affected by isotretinoin, there shouldnt be any worries about penile growth, right?

And now to a more general question: How likely is it that the penis of a 16 1/2 year old stopped growing naturally? I was already taller than my dad at this point and was very hairy so I guess I was at the later stages of puberty if not finished already. When did your dicks stop growing?
 

flynn

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Hello I wanted to know how likely it is for isotretinoin to stunt penile growth? I took it when I was 16 and a half years old. I only took 10 mg per day for ~5 months so a very very low dosage. I am now 20 years old and don't recall any significant penis growth since then. (I am 6 inches Non-bone-pressed, bone pressed I am around 6.7-7 inches, and 5.2 inches girth). I want to know if the lack of growth since age 16 is from accutane. I asked on reddit in a subreddit dedicated to men with big dicks https://www.reddit.com/r/bigdickproblems/comments/8fu89z and there were some guys who took it in their young teenage years (13/14 years old) and their dicks still grew well above average. One guy PM'ed me with the following message: Seems like he thinks that isotretinoin caused his penis to grow even bigger! How could this be? I noticed that some people have very high DHT levels after/during accutane. So could it really get bigger from accutane?

Theories suggest that isotretinoin inhibits 5-AR Type 1 enzyme but there is no evidence for type 2 inhibition, right? 5-ar type 1 is mostly found in skin and not in genitalia. 5-AR type 2 is mostly found in genitalia. So if 5-ar type 2 isnt affected by isotretinoin, there shouldnt be any worries about penile growth, right?

And now to a more general question: How likely is it that the penis of a 16 1/2 year old stopped growing naturally? I was already taller than my dad at this point and was very hairy so I guess I was at the later stages of puberty if not finished already. When did your dicks stop growing?

It's impossible to say for certain but I think its pretty unlikely it will have affected your penis growth. Firstly, everyone develops at different ages and rates. It's highly likely your penis had finished growing at 16 years old. As far as I know, penis growth isn't necessarily the same as bone growth for instance, where it growth continues throughout puberty until you are an adult. As far as I know, after several years of puberty your penis is likely to be fully grown and won't grow anymore irrespective of whether your bones (height) continue to grow.

As you say, 5AR2 seems to be associated with penis growth (genitalia), not 5AR1. I haven't found any evidence yet that Isotretinoin affects 5AR2, though its possible. Besides, you are above average, so nothing to worry about in that department. As I mentioned in the acne flare ups section, a metabolite of Accutane called ATRA is thought to increase 5AR activity in the liver, which may also occur with 5AR2 in the genitalia. This could account for the increased penis growth reported by the person online but I think this is highly unlikely and is probably just a coincidence.

As far as I can tell, most people don't report any changes to penis size where as people with post finasteride syndrome (affects 5AR2) do report this problem. This suggests that accutane probably doesn't affect 5AR2 in any significant way.

You are on a fairly low dose. My advice for you is to be very aware of changes to your mental state and side effects. If side effects start to develop which have been reported to persist such as sexual dysfunction, tinnitus, changes in personality, anhedonia, severe fatigue. Seriously consider stopping accutane treatment or tapering off. It's best to be safe with a bit of acne then have clear skin and be full of regret.
 
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paragraf

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Thanks for your reply Flynn. I was worrying so much about this that I contacted Bodo C Melnik (the dermatology professor who did the studies on isotretinoin and FoXO1). I asked him about the possibility of isotretinoin stunting penile growth because of DHT and IGF-1 reduction and he told me that there is nothing to support my theory because there are literally zero reports on this topic. He told me that "Isotretinoin isn't anti-androgenic and has no effect on 5-alpha-reductase" which kinda confused me because there are people like you on the internet who say it is...

Further, he told me that IGF-1 reduction is actually desired to combat the acne. He also told me that IGF-1 reduction should be marginal at doses like 10mg per day. I guess the mild anti-androgenic effect is also desired but has no signifcant effect on sexual maturation (because it seems to only affect 5AR1) or else there would have been reports of delayed or stunted puberty from isotretinoin/retinoids by now but there just are none.

Also, many young kids with neuroblastoma are getting treated with retinoic acids (at much higher doses than for acne) and if it had any significant effect on sexual maturation it would have been noticed by now.. I guess I will just have to accept it all now.

Best of luck to you and your further research. Actually I ended my course and luckily don't have any of the severe side effects you mentioned. I experienced some depression but its gone now since I found a new girlfriend lol :D
 
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flynn

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Thanks for your reply Flynn. I was worrying so much about this that I contacted Bodo C Melnik (the dermatology professor who did the studies on isotretinoin and FoXO1). I asked him about the possibility of isotretinoin stunting penile growth because of DHT and IGF-1 reduction and he told me that there is nothing to support my theory because there are literally zero reports on this topic. He told me that "Isotretinoin isn't anti-androgenic and has no effect on 5-alpha-reductase" which kinda confused me because there are people like you on the internet who say it is...

Further, he told me that IGF-1 reduction is actually desired to combat the acne. He also told me that IGF-1 reduction should be marginal at doses like 10mg per day. I guess the mild anti-androgenic effect is also desired but has no signifcant effect on sexual maturation (because it seems to only affect 5AR1) or else there would have been reports of delayed or stunted puberty from isotretinoin/retinoids by now but there just are none.

Also, many young kids with neuroblastoma are getting treated with retinoic acids (at much higher doses than for acne) and if it had any significant effect on sexual maturation it would have been noticed by now.. I guess I will just have to accept it all now.

Best of luck to you and your further research. Actually I ended my course and luckily don't have any of the severe side effects you mentioned. I experienced some depression but its gone now since I found a new girlfriend lol :D
No worries, thats what this forum is for. To help give people advice/info that isn't easily found online. Yes I would just accept it and wouldn't worry. There is little evidence to suggest it would or could occur. I think we would see far more reports of this, especially from people who clearly have issues with androgens etc.

If you can, perhaps send Bodo C Melnik a link to this page, to see what he thinks. On one of the other posts, I've linked research which talks about FOXO theory and shows the Accutane FOXO-1 connection has been mostly disproven. He is also wrong to say that accutane has no effect on 5AR as the research linked above clearly shows that 5AR1 expression in the skin is reduced several fold following Accutane treatment, which may also occur in other areas of the body such as the brain.
 

paragraf

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No worries, thats what this forum is for. To help give people advice/info that isn't easily found online. Yes I would just accept it and wouldn't worry. There is little evidence to suggest it would or could occur. I think we would see far more reports of this, especially from people who clearly have issues with androgens etc.

If you can, perhaps send Bodo C Melnik a link to this page, to see what he thinks. On one of the other posts, I've linked research which talks about FOXO theory and shows the Accutane FOXO-1 connection has been mostly disproven. He is also wrong to say that accutane has no effect on 5AR as the research linked above clearly shows that 5AR1 expression in the skin is reduced several fold following Accutane treatment, which may also occur in other areas of the body such as the brain.
Yeah very true. As I said. Millions of young teenagers have been treated with isotretinoin and if it really had an effect on puberty/penile growth there would have been reports of stunted puberty by now (after ~35 years). Also, 4 guys who took Isotretinoin at very young ages told me that their dicks still grew much bigger after treatment (On /r/bigdickproblems). I really feel like Isotretinoin only affects 5AR1 because if it had any effect on 5AR2 there wouldn’t be people on acne forums saying that they started to get MPB or thicker beard growth during/after Isotretinoin therapy. What makes you think it has an effect on 5AR2? Also, the suppression of DHT seems to be low, right? All the studies say that significant reduction of DHT was observed but the term "significant" in statistics only means that the reduction is provable but it doesnt say if the reduction was big or very mild. And if it was big, they would have mentioned it, right? I think the 5AR1 expression reduction in skin is desired, this is what actually causes the acne to go away. And honestly it would just make sense that it would affect other parts of the body like the brain... what i don’t understand is, why would this change be permanent? I actually don’t think it is.

Well, Melnik stopped replying when I showed him the studies on androgens (boubou, karadag,..).. really strange.
 
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flynn

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#13
Yeah very true. As I said. Millions of young teenagers have been treated with isotretinoin and if it really had an effect on puberty/penile growth there would have been reports of stunted puberty by now (after ~35 years). Also, 4 guys who took Isotretinoin at very young ages told me that their dicks still grew much bigger after treatment (On /r/bigdickproblems). I really feel like Isotretinoin only affects 5AR1 because if it had any effect on 5AR2 there wouldn’t be people on acne forums saying that they started to get MPB or thicker beard growth during/after Isotretinoin therapy. What makes you think it has an effect on 5AR2? Also, the suppression of DHT seems to be low, right? All the studies say that significant reduction of DHT was observed but the term "significant" in statistics only means that the reduction is provable but it doesnt say if the reduction was big or very mild. And if it was big, they would have mentioned it, right? I think the 5AR1 expression reduction in skin is desired, this is what actually causes the acne to go away. And honestly it would just make sense that it would affect other parts of the body like the brain... what i don’t understand is, why would this change be permanent? I actually don’t think it is.

Well, Melnik stopped replying when I showed him the studies on androgens (boubou, karadag,..).. really strange.
Agreed. Though hair loss on accutane is not likely to be related to DHT and some have reported that they have less beard growth after accutane (again this is all anecdotal and I'm yet to see someone who actually lost beard hair for example, so it may just be imagined).

Its hard to say how significant the changes in hormone levels etc. are, usually the studies will tell you this. As noted however, 5AR1 gene expression in the skin was altered by as much as 2.83 fold which is quite significant in my opinion. Yes this clearly helps with treating acne, as the androgens produced by 5AR1 in the skin certainly contribute to the development of acne. As you say, if it can affect gene expression in the skin, it could surely also affect 5AR1 gene expression in the brain especially given the number of retinoid receptors in the brain and the ability of accutane to pass the blood brain barrier.

Its a good question to ask why these changes would be permanent? Firstly, its possible that the changes in 5AR1 gene expression in the skin are permanent, as acne is cleared on a permanent basis. As such these changes would be permanent in other parts of the body as well. But I think the most important distinction to make, is that our neurons (brain cells) are different to other cells in the body. They are the only cells which don't increase in number as we age. In contrast our skin cells for example are constantly dying and dividing to form new skin cells. This process doesn't really occur in neurons or at least it doesn't occur to the same degree as the rest of the body, meaning our neurons don't continuously divide to form to new neurons, to a large extent you are stuck with the same neurons for life. Thus its possible that if accutane altered gene expression in areas such as the skin, these changes would gradually fade out of the population as new cells are formed however if the changes occur in the brain, these changes are permanent and persist long after finishing treatment.
 
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paragraf

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May 7, 2018
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#14
Agreed. Though hair loss on accutane is not likely to be related to DHT and some have reported that they have less beard growth after accutane (again this is all anecdotal and I'm yet to see someone who actually lost beard hair for example, so it may just be imagined).

Its hard to say how significant the changes in hormone levels etc. are, usually the studies will tell you this. As noted however, 5AR1 gene expression in the skin was altered by as much as 2.83 fold which is quite significant in my opinion. Yes this clearly helps with treating acne, as the androgens produced by 5AR1 in the skin certainly contribute to the development of acne. As you say, if it can affect gene expression in the skin, it could surely also affect 5AR1 gene expression in the brain especially given the number of retinoid receptors in the brain and the ability of accutane to pass the blood brain barrier.

Its a good question to ask why these changes would be permanent? Firstly, its possible that the changes in 5AR1 gene expression in the skin are permanent, as acne is cleared on a permanent basis. As such these changes would be permanent in other parts of the body as well. But I think the most important distinction to make, is that our neurons (brain cells) are different to other cells in the body. They are the only cells which don't increase in number as we age. In contrast our skin cells for example are constantly dying and dividing to form new skin cells. This process doesn't really occur in neurons or at least it doesn't occur to the same degree as the rest of the body, meaning our neurons don't continuously divide to form to new neurons, to a large extent you are stuck with the same neurons for life. Thus its possible that if accutane altered gene expression in areas such as the skin, these changes would gradually fade out of the population as new cells are formed however if the changes occur in the brain, these changes are permanent and persist long after finishing treatment.
Since I can only read the abstract of the studies in most cases, I don't know by how much the DHT levels were altered and I don't want to buy these studies for $$ lol. do you know it? I am looking for actual numbers because 2.83 fold sounds like a big change but then again I have never seen any reports of guys with androgen problems from isotretinoin.
Going back to my concern about penile growth: as long as the DHT levels weren't lower than normal range and the DHT was metabolized without any further problems, there really is no need to worry about penile growth stunt because high DHT levels don't corelate with larger dick growth and as long as the androgen levels were still in range, the penis reached its genetic potential. This would explain why all of the guys on reddit who took it in their teenage years still grew bigger afterwards. Same goes for IGF-1 levels..

I remember reading a study which said that androgen receptor binding capacity was reduced 2.6 fold but the androgen receptor affinity remained unchaged. I think the anti-androgenic effect of isotretinoin is HIGHLY dose dependent and in low doses, the reduction of 5AR1 gene expression or the reduction of androgen receptor binding capacity isn't too big. Actually, everything regarding isotretinoin is dose dependent. I read that in Asia, doctors don't prescribe doses higher than 20mg per day and they have way less problems with side effects there... Its actually seen as a very safe drug in Asia.

This is a really interesting theory and I really think you should contact some of the leading dermatologists in this field.. Look at university professors around you and try to ask them about this theory. In all honesty, I think we still have pretty superficial knowledge about this all and are not considering every factor. That's why I would love if any professional research team could give us an assessment.

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I found this: "Furthermore, male mice with a null mutation in the SRD5A1 virilized normally and appeared to suffer no adverse consequences from loss of this gene. Therefore, a mutation in SRD5A1 is unlikely a cause of androgen resistance in males." (Kenan Qin, in Genetic Diagnosis of Endocrine Disorders, 2010) Seems like if accutane really ONLY inhibits 5AR-1 there is no reason to worry about stunt of penile growth.
 
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flynn

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#15
Since I can only read the abstract of the studies in most cases, I don't know by how much the DHT levels were altered and I don't want to buy these studies for $$ lol. do you know it? I am looking for actual numbers because 2.83 fold sounds like a big change but then again I have never seen any reports of guys with androgen problems from isotretinoin.
Going back to my concern about penile growth: as long as the DHT levels weren't lower than normal range and the DHT was metabolized without any further problems, there really is no need to worry about penile growth stunt because high DHT levels don't corelate with larger dick growth and as long as the androgen levels were still in range, the penis reached its genetic potential. This would explain why all of the guys on reddit who took it in their teenage years still grew bigger afterwards. Same goes for IGF-1 levels..

I remember reading a study which said that androgen receptor binding capacity was reduced 2.6 fold but the androgen receptor affinity remained unchaged. I think the anti-androgenic effect of isotretinoin is HIGHLY dose dependent and in low doses, the reduction of 5AR1 gene expression or the reduction of androgen receptor binding capacity isn't too big. Actually, everything regarding isotretinoin is dose dependent. I read that in Asia, doctors don't prescribe doses higher than 20mg per day and they have way less problems with side effects there... Its actually seen as a very safe drug in Asia.

This is a really interesting theory and I really think you should contact some of the leading dermatologists in this field.. Look at university professors around you and try to ask them about this theory. In all honesty, I think we still have pretty superficial knowledge about this all and are not considering every factor. That's why I would love if any professional research team could give us an assessment.

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I found this: "Furthermore, male mice with a null mutation in the SRD5A1 virilized normally and appeared to suffer no adverse consequences from loss of this gene. Therefore, a mutation in SRD5A1 is unlikely a cause of androgen resistance in males." (Kenan Qin, in Genetic Diagnosis of Endocrine Disorders, 2010) Seems like if accutane really ONLY inhibits 5AR-1 there is no reason to worry about stunt of penile growth.

Yeah the 2.83 fold figure is for 5AR1 not 5AR2. It would only be 5AR2 activity which would affect penile growth, which as you say, if the activity returned to normal after finishing accutane. I'm pretty sure your dick would still grow to its full potential. The study never specified whether acctuane affected 5AR2 expression and so probably doesn't for some reason. The interesting point about this, is that as 5AR1 is expressed in the brain. If accutane does indeed only affect 5AR1 expression. Patients would look and appear completely normal as their 5AR2 is working normally but if the 5AR1 in the brain is insufficient they would suffer from symptoms of androgen deficiency/resistance at the level of the brains such as sexual dysfunction, loss personality, loss of drive, cognitive difficulties etc. all of which, people with PAS suffer from.

If I could find professors who had any interest in researching this or looking into it, I certainly would. However I am unaware of any medical professionals or researches who are studying post accutane syndrome or even acknowledge it exists. Which is a sad state of affairs. Thats why I posted these theories here, so people could discuss them.
 

paragraf

New member
May 7, 2018
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#16
Yeah the 2.83 fold figure is for 5AR1 not 5AR2. It would only be 5AR2 activity which would affect penile growth, which as you say, if the activity returned to normal after finishing accutane. I'm pretty sure your dick would still grow to its full potential. The study never specified whether acctuane affected 5AR2 expression and so probably doesn't for some reason. The interesting point about this, is that as 5AR1 is expressed in the brain. If accutane does indeed only affect 5AR1 expression. Patients would look and appear completely normal as their 5AR2 is working normally but if the 5AR1 in the brain is insufficient they would suffer from symptoms of androgen deficiency/resistance at the level of the brains such as sexual dysfunction, loss personality, loss of drive, cognitive difficulties etc. all of which, people with PAS suffer from.

If I could find professors who had any interest in researching this or looking into it, I certainly would. However I am unaware of any medical professionals or researches who are studying post accutane syndrome or even acknowledge it exists. Which is a sad state of affairs. Thats why I posted these theories here, so people could discuss them.
Man, honestly I don't know about isotretinoin not affecting 5AR2. Now that you mention it... I actually talked to a doctor about isotretinoin and hair loss and he told me that he had patients telling him that their hair "grows better and faster and thicker." during accutane therapy but then again there are many people on the internet saying that they had severe hair loss and developed MPB from accutane. very contradicting statements...

what about this study https://academic.oup.com/jcem/article-abstract/78/5/1064/2650318?redirectedFrom=fulltext again, no specification on where the 5-alpha-reduction inhibition comes from. (type 1, type 2 or even type 3?). The study suggests that isotretinoin also has an effect on 5-alpha-reductase enzyme in the liver but it doesnt say which isoenzyme is affected. 5AR1 and 5AR2 are both expressed highly in the liver...

I also read that Isotretinoin (13 cis retinoic acid) has been used successfully to treat prostate cancer? Do you know more about this? 5AR2 expression in the prostate is way higher than 5AR1 ( https://www.ncbi.nlm.nih.gov/gene/6716 ) so isotretinoin could have an effect on 5AR2 as well after all...?

Yeah your theory about androgen deficiency in the brain sounds quite plausible. I really want an expert to have a look on this... But if isotretinoin really had such a huge effect on both 5AR1 and 5AR2, serum DHT levels would be very low or not? Studies only say that DHT levels dropped significantly but I still dont know by how much exactly and whether or not the levels were still in range..

This whole thing is so annoying and I really hate how we still know so little about the exact mechanism of isotretinoin and that no one seems to care (as long as it gets rid of the acne...) I for myself can only hope that 10mg daily had very little effect on my androgen metabolism and that my dick still grew to its genetic potential once I stopped the medication and the 5AR activity returned back to normal.

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Man wtf is all of this shit! I just found this site and this user named "Max" seems to know everything about isotretinoin. Please have a look at this thread: http://max001.proboards.com/thread/38/1-introduction it says that "Roaccutane is strongly antiandrogen. A 50% suppression of androgen conversion rates have been found in related doses to what is seen in acne-subjects. The 5-alpha reductase is genetic and dependant on androgen receptor polymorphism. Androgen receptors (AR) as well as thyroid receptors (TR) belong to the superfamily of nuclear hormone receptors where also the retinoid receptors belong. The androgen receptor (AR) is a ligand-activated transcription factor that recognises and binds to specific DNA response elements upon activation by the steroids testosterone or dihydrotestosterone"
really? 50% 5AR reduction?! flynn please tell me, did this shit stunt my penile growth? Everything suggests it did... I am like 6 inches non-bone pressed. What if I could have grown bigger man,.. what if!!!! What on earth is this poison? I just read every post on this website and I am honestly in shock. How can this medication still be allowed to be prescribed?!
 
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Mar 27, 2018
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#17
Flynn, you wrote: " If Accutane has altered gene expression in neural cells. These cells will likely remain this way. Hence its possible for 5AR activity in the rest of the body to go back to normal overtime but not 5AR activity in the brain."

So is there no hope?
 

flynn

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Feb 28, 2018
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#18
Flynn, you wrote: " If Accutane has altered gene expression in neural cells. These cells will likely remain this way. Hence its possible for 5AR activity in the rest of the body to go back to normal overtime but not 5AR activity in the brain."

So is there no hope?
No there is always hope as gene expression can potentially be altered in neural cells though it represents a challenge. I have outlined one of the potential cures/treatments that in theory could work. Have a read -

https://pasforum.info/threads/plausible-cure-crispr-cas9-gene-editing.21/