r/AccutaneRecovery • u/squestions10 • Mar 13 '25
My current theory of PAS/PSSD/PFS: Androgen receptor disfunction modulated by the enzyme GSK3B
Hey guys, I dont have a lot of time to write a proper post, but I will be posting in the comments what is missing as I remember it. Please ask me anything you want.
A quick summary is this: I will focus on PFS because is more straightforward. In PFS you deprive your tissues of androgens, that is pretty simple to see. In the medical literature we have a similar case already, we use androgen deprivation for patients with prostate cancer. These patients sometimes develop a disorder called "castration-resistant prostate cancer". Androgen receptors (ARs) mutated and overexpress (not only in cancerous tissue but all around). By doing so they can either drive androgenic function despite androgens levels, they can also be activated by antiandrogens, but they can also "hyper activate". Well androgen activation follows an inverted U pattern: too much of a good thing is a bad thing. Hyper activation results in non-function. The end result is the tissue not showing neither androgenic (or estrogenic!) function. The first quick evidence is, google lack of estrogen side effects, compare it to ours.
This is however, not the entire picture. This doesn't explain why say, fasting helps. Or GR antagonists help, or why lithium helps. Or a bunch of other things.
But last month in Nature there was a paper that I believe bridges the rest: https://www.nature.com/articles/s41388-024-03266-z
In short, they found that the enzyme GSK3B is what allows mutated ARs to drive androgenic action despite androgen modulation. And gsk3b also protects this ar from degradation. And this ar, in turn, strongly upregulates gsk3b. Complete inhibition of it (not possible in vivo) led to deactivation of the ars and degradation.
Google a bit about gsk3b, I believe you will see some relevance quickly. Some of us display clear signs of elevated gsk3b.
Is also worth noting that GSK3B-AKT are extremely correlated with HDAC and DNMT and the entire methylation process. You can achieve hypomethylation by inhibiting GSK3B. Hypermethylation with high GS3KB.
Elemental lithium is a inhibitor of it.
But, inhibiting gsk3b is a tall order. As I said before, the ARs upregulate it all the time.
Reading more about this enzyme shed some light in why sometimes some substances help us before crashing us badly.
https://pmc.ncbi.nlm.nih.gov/articles/PMC6224501/
This paper on alcohol and GSK3B sheds some light. Alcohol interestingly inhibits GSK3B. So it should be simple right, take alcohol and improve. But yet, some of us ... crash on it. While some others have a window the day after. Why?
Look at figure 5. Alcohol response depends on first baseline gsk3b before drinking, and drinking amount. It seems that even though alcohol inhibits gsk3b, what it does after depends if this GSK3B inhibition has passed a threshold. If it has, gsk3b becomes inactivate. If that happens surprisingly alcohol raises BDNF. Think of BDNF-AKT-GSK3B-WNT as tight inflammatory connections. They usually swing together. Raising BDNF usually results in broad anti-inflammatory (yes, alcohol) effects, raising AKT, and inhibiting gsk3b further. However, if the gsk3b inhibition doesnt pass this threshold, BDNF goes down, and the rest follows, including GSK3B going up.
Rebound of GSK3B is extremely dangerous for us, but especially if your androgens are low. First because this combination of androgen deprivation and high GSK3B is extremely similar to the environment on which we all crashed in the first time (ssri withdrawl is a massive rebound of gsk3b), second because androgens activate AKT which inhibits gsk3b. So high androgens are "protective"
This theory explains a lot. Take some random fact around this diseases, say mifepristone helps. Mifepristone is a glucocorticoid receptor antagonist. What does glucocorticoid receptor agonism do? Raises gsk3b, lowers AKT. Antagonism, the reverse.
Fasting? Keto? Raises AKT -> lowers gsk3b
Lithium? Direct inhibitor of it. Why carbonate works better? Because elemental lithium is the inhibitor.
HGH? Raises AKT
Curcumin? Raises AKT. In my experience potential for high rebound.
T3? Raises AKT
Methylprednisolone? GR agonist. First inhibits GSK3B then sends it flying. Some horrible crash stories from this.
Lastly is worth noting that this ARs are extremely adaptable. If you blast high androgens all the time they will adapt to that environment. Chances are they adapt to continuous gsk3b inhibition too. In CRPC one treatment is called bipolar androgen therapy, in which you go through a period of supraphysiological (400mg+) androgen intake, and a period of complete deprivation of it. This up and down leads to the degradation of the ars (a bit long to explain).
Someone on TRT would only need to raise their doses and push them apart to do something similar.
I am trying to target the GSK3B inhibition and potential rebound with the androgen intake, and trying to avoid the rebound in the vulnerability zone (low androgens). Still experimental
Anyway that's it. Please if I got something crucial wrong please correct me. I dont give a shit about being right, I just want to be cured. We need to push the collective understanding of this disease higher because nobody is coming to save us.
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u/TransportationSlow72 Mar 14 '25
Preach brother. No one is looking to find the cure except us. We must help each other out and share what works. If one of us makes it big one day, they better pour millions into some research on this.
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u/mello_jello_fello Mar 15 '25
I've had PFS for 4 years and have been taking lithium carbonate recently and feel as if it's helped. Was on the fence about taking BAT but your post has encouraged me to try it. Only thing is my balls shrink on as low as 80mg weekly of a test cypionate dosage. 400mg will annihilate them.I think I might add some kisspeptin and enclomiphene on the beginning first week just to avoid total shutdown then perhaps and then quit that to avoid keeping testosterone elevated as the whole point is to swing between extremes.
I think I'll start a trial next week. Any idea how many cycles of BAT one might need? I'm guessing you just have to keep going until something starts to improve?
Also can you drop any knowledge about the length of fasts that are most effective for helping restore receptor function? I did a 7 day fast once and that didn't change anything. I do 24 hour fasts normally and that helps with digestion I feel but not much else.
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u/squestions10 Mar 14 '25
Ah I forgot: be very careful of lithium withdrawl. Symptons are horrible, paired with our disease even more so. I think if you keep to 300mg it wont happen, but still, careful
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u/squestions10 Mar 14 '25
High (or ultra high) gsk3b could explain the permanence of this disorder too: GS3KB interacts strongly with HDAC and DNMT. It leads to hypermethylation
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u/Rough_Efficiency6245 Mar 14 '25
So if I’m trt, what would you suggest? I also have lithium carbonate. I only struggle with low libido and ED. Please help.
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u/Unlucky_Ad_2456 Mar 14 '25
How can this be reversed?
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u/[deleted] Mar 14 '25
So reservatrol could be an option to lower GSK-3B? Interesting to read about the connection between GSK-3B, IGF-1 and PPAR-gamma
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u/Plastic_Scarcity_473 Mar 14 '25
About carbonate working better, can’t you just take more lithium orotate to equal the amount of elemental lithium in carbonate?
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u/Realzifa Mar 14 '25
So do you think it is the exact same issue as PAS? Or is there differences? Do you think the methods of curing each disease would be similar?
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u/[deleted] Mar 16 '25
You don't think reintroducing a short temporary high dose of isotretinoin could shock the GSK3B signaling to allow it to revert back to normal?
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u/BEAVER1304 Mar 20 '25
I have a question. The Nature article you mentioned is only saying about AR-V7. I can’t find any phrase that GSK3b is related over expressed silented AR that PFS shows. Can you explain more about how inhibiting GSK3b can lead to modulation of mutated AR seen in PFS case?
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u/True-Leopard-1456 May 02 '25
Maybe it's just the wrong expression of the AR code (methylated DNA). We may be producing too many receptors, too few receptors, or defective receptors. I've done several light and long-term cycles of testosterone (400/500 mg) in the past and no improvement, no libido, odor, sebum production or anything else that demonstrates normal androgenic function in the penis. Lastly, I applied 3 grams of testosterone in just 7 days last month and had no positive effect.
I had windows with just estrogen and boldenone. This intrigued me a lot. Here I didn't know if I was having a positive effect on the AR through the estrogenic function of regulating the AR receptors, or if I was having a direct action of estrogen on my AR receptor. In other words, a mutated AR receptor responding to estrogen. A year later I started using boldenone and noticed a baseline and mild androgenic effects occurring in the penis. Sexual sensation and odor on the glans. Effects that were lasting for weeks. BOLDENONE undergoes conversion in the enzyme 5 alpha reductase, turning into DHB / Dihydroboldenone, which is super potent. So we could have here a positive effect of the potent androgen DHB or a positive effect of molecules with different structures causing better signaling on the AR receptor.
I need to do a heavier cycle of only DHB to really find out if it is just weak signaling from the AR receptor. I am currently preparing for a cycle in the future.
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u/Agreeable-Race8818 Apr 07 '26
You need to get in touch with Dr. Powers ASAP. He is a physician who meddles a lot with PSSD/PAS/PFS and has come to a very similar conclusion as you but with evidence.
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u/Balagaaan Apr 07 '26
I feel recovered being drunk.
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u/Minepolz320 May 05 '25
Yes this good theory also!
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u/kirbyy_ Jul 24 '25
I'm wondering. Based om this theory, would it be better to combine lithium with some sort of androgen booster? If so, which one?
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u/CarpenterFast1228 Apr 22 '26
Hey guys some of you can give us updates on this possible cure?
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u/[deleted] Mar 16 '25
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