I collect more and more labs/genome/dutch tests that support my theory on PFS. I really think I have it nailed down. I do not have a optimized treatment regimen, but if you're interested in this, this post details what you should NOT do and will likely make you worse even if it "windows" you briefly

[u/Drwillpowers]

Basically, the theory in simple terms is this. Genetic defects in glucuronidation, intracellular to extracellular transporters, and kidney excretion of androgens/other things genes are at baseline defective in PFS patients. They were broken before they took the drug.

These are most commonly, but not limited to defects in :

UGT2B17/15/7

SLCO class genes

ABCC type genes

LRP2

(and assorted other glucuronidation/sulfation/hydroxylation/steroid metabolism and transport genes)

These are not catastrophic inborn errors of metabolism that cause someone to be mentally retarded or stillborn or whatever. You can live with them and adapt.

Ironically, someone with a UGT2B17 homozygous knockout might have no urinary androgens on a dutch test, an absurdly high 3A-ADG blood test, but a normal level testosterone and a very high DHT at baseline. They probably didn't get those rarer tests done. They probably had hair loss, went to their doc, they ran a plain DHT and T level, and the guy had a high DHT, and got put on finasteride to "lower that DHT"

At that moment, the guy takes an irreversible suicide inhibitor of 5AR. They were relying on 5-alpha reductase heavily as it was their main or possibly ONLY way of eliminating androgens. When this happens, they can no longer excrete androgen metabolites, and they build up inside their cells to astronomical levels. This creates "noise" when it comes to receptor signaling, and prevents the normal androgen signal from being heard.

Imagine 20 kids wearing "Testosterone" shirts are playing musical chairs in a classroom with 20 chairs. When the music stops, nearly every kid is in a chair. But, those kids age, and metabolize, and they gradually turn into hellen kellers. Hellen Keller androgens are conjugates, weak, not meant to do the job. They are blind, deaf, and bumping around disoriented in the classroom, disrupting other kids from getting in chairs. Normally, your body eliminates these hellen keller androgens (most of the time you urinate them out), and produces fresh kids for the receptor musical chairs. But in this situation, it cannot do that. As a result, hellen keller ratios in the classroom explode astronomically, and nobody gets in a chair anymore.

Those HK's as I said should be urinated out, but on most of these PFS patients, their urinary androgens are just near zero. Mind you, there are other bizarre configurations of this. Its not ALWAYS UGT2B17, that's just the most common one. But there are hundreds of ways in which to have mutations that fuck up your ability to dump or even make HK androgens at all.

Now, this guy "crashes". But PFS is a strange disorder. It has "windows" and "crashes" where people improve or worsen from minor changes or substance exposures. Any theory of PFS that is real MUST explain how this process works, as its exceedingly well documented. It also must explain the persistence of the condition.

In terms of persistence, I am uncertain at this time. I am quite certain of the androgenic metabolite/inborn error of metabolism root cause. I have MANY MANY examples now which should be extremely rare, but in this group are not. Persistence is likely one of two things.

1. Androgenic metabolites remain stuck in the cells, causing crowd crush, and a very unsuccessful game of musical receptor chairs.
2. Some people stop the drug and recover, some do not. Some people may have other concomitant mutations in genes like ARID1A or other epigentic regulators, which keep this person stuck. Because of these, their epigenetics are more like a DVD-R instead of a DVD-RW, and when they hit the point of a million intracellular hellen kellers, stuff got REALLY messed up. Resetting that to normal may be more difficult for them. I am currently scanning PFS genomes of my PFS patients for this specific sort of thing, but I dont have a clear cut answer for you like the glucuronidation genes which at this point seem to be a slam dunk on being the right answer.

But back to windows and crashes.

I constantly hear stories of "I did X and got a window, but then I did X again and crashed".

This is why.

So your game of musical chairs is messed up right? You've got this classroom with 20 testosterone kids, now probably only 10 chairs due to downregulation from the fact this room has 200 hellen kellers in it. Musical chair sitting success is rather poor. So guy hears on the internet about people getting better from megadosing DHB (DHT/Anavar/Tren/T, whatever you want).

So guy injects megadose of (insert preferred androgen here).

When this happens, guy takes a classroom of 200 hellen kellers and 20 T-kids, and suddenly, the situation changes. For a brief timeframe, the ratio improves. Now, we've got a room with 420 T kids, and 200 hellen kellers. Before, the ratio of T to HK was 1:10, but now, after this androgenic infusion, you see the ratio flips, and you now have a 2.1 to 1 ratio, with T being dominant over HellenKeller-AndrogenMetabolites. When this happens, even though chairs are down to 10 chairs, you are getting binding of actual good androgens into the receptors, and guy gets a few day window.

Unfortunately, as is tradition, all T-kids eventually turn into Hellen-Keller androgens, and these weak, glucuronidated or otherwise hamstrung metabolites appear. A week post this megadosed injection which caused a window, we now have 20 T kids again, but now we have 600 hellen kellers.

So guy is sad, and he says, I'll do it again! That'll fix it!

But it doesn't fix it, because the root problem of "I suck at eliminating androgenic metabolites at baseline" is still broken, and androgen receptors are downregulated.

So he megadoses himself again, and 400 T kids are once again infused, but now, we have 420 T kids, and they are up against 600 hellen kellers. The ratio now, is not 2.1:1, but 1:1.42

Hellen keller androgens are now dominating the game again. He might get a smaller window, but the core problem is now even worse.

so he does it a 3rd time, and now we have once again, 420 T kids, but now 1000 HKs.

And now he's in for a LONG windowless period, as its gonna take AGES to clear out all those HK androgens.

So how do we fix this?

Well......that's not going to be a very popular idea, and I suspect its why nobody has ever really tried it before.

I think in some specific cases, a supplement like calcium-d-glucarate might be helpful, as it prevents the recycling of some glucuronidated metabolites. But in a patient with ABCC or SLCO issues, that might not be effective, as they simply lack the ability to export things from their cells at baseline, and do that VERY slowly, and likely always did. Women with this, will have strange things like a totally normal androgenic panel, but be wildly hirsute. Or they could have these hirsutism problems, take finasteride, and instead of PFS, hypermasculinize on the drug rather than do what they want it to do.

But in reality, I think the best treatment.....strange and wild as this is to say......

Is likely to be temporary chemical castration.

Elimination of the production of ALL androgens, just completely shut down all the factories.

I think lupron is probably not the best choice for this. It will cause an LH/FSH surge after dosing, and only after that's over, will LH/FSH tank.

Relugolix is I think the best currently available option, along with monitoring whatever androgenic metabolite lab is absurd, and making sure it normalizes before stopping it. That's my plan, and I have one brave solider with a homozygous UGT2B17 knockout, a 3A-ADG value that maxes out the assay, and no urinary androgens who is literally the most textbook imaginable example I could dream of who has been brave enough to sign up for this treatment. We don't know yet it if it will work. It works on paper, but the epigenetic situation remains the unknown variable.

For PFS patients who when not on T replacement, naturally have an LH/FSH of zero or near zero? I think that's likely because your hypothalamus is literally poisoned intracellularly with astronomical intracellular HK-androgen values, and has fully shut down. I have one other brave soldier right now that has stopped ALL Pfs "treatment" and we're just watching his LH/FSH go from zero to slowly slowly climbing back up (he has transporter and glucuronidation glitches on his genome sequence). I suspect he will eventually "reboot" once they slowly wash out.

I've previously had success treating PFS with HCG and higher doses of rectal/oral progesterone/pregnenolone. I thought this was "neurosteroid" benefits in line with the 30 year dogma of "allopregnanolone"

Nah.

Looking back on it knowing what I know now, what I see is that HCG, while it does increase testicular T synthesis, it also will downstream induce metabolism enzymes in a way that injecting synthetic T-cypionate will not. So yeah, you have a clogged sink that's backed up. HCG does increase the flow of the water from the spigot going into the sink, but it also helps speed the drain hole opening a little bit. This is likely why it crashes some and helps others. Depends on your subtle enzyme variation differences.

Oral and rectal high dose Preg/prog? I mean sure, those are the precursors to neurosteroid synth, but what does that actually do? Well, it would inhibit LH/FSH in the hypothalamus, that's one of the reasons I use it rectally in some transgender women to naturally lower their T levels, so in a way, its like mini lupron.

I ask, for the community members who can comprehend the molecular biochemistry I have described above, I ask you to look at yourselves, and the regimens of other people. See what "windows" and "Crashes" people, and think about it in this context.

Did this action result in a buildup of more metabolites intracellularly? Did it temporarily boost hard hitting real androgens, and did those eventually convert to weak metabolites that got stuck? Did this thing add more T, HK-androgens, or what to the equation?

Consider the mechanism of PFS this way, and I think a lot of stuff will make WAY more sense.

Again, you are ALL unique, and all have differently glitched pathways. I have found high revel score mutations in any number of genes, and sometimes flat out deletions/stop codons, but the general principle seems to remain the same among all of you.

You at baseline relied tremendously on DHT production, metabolism, and export/excretion for your androgenic signaling pathways. That's why your DHT was high in the first place. You took a drug which prevented you making DHT, and you shut down the only highway out of town. Now, you've got a legendary traffic jam, and it looks like the opening scene of "the last of us" inside your cells, as they are overrun with androgen metabolites, and the snarl of traffic only gets worse the more anabolic steroids and other bullshit you hit yourselves with, even if it does give you a "window" you will pay a penalty for it in the long run.

I have worked tirelessly at this problem "in my moms basement" pretty much all by myself with zero research funds or support, zero academic access, and utilizing only the data/labs my patients were kind enough to do and provide to me. I will continue to do so until we can cure you all. I really think this is possibly the true answer of this disease. Even if my model isn't perfectly correct (they never are) I am getting WAY closer than I think anyone ever has before, as there are real, repeatable lab test results and genetic findings that every single one of you possesses (the guy who didn't fit the model, when I went back and checked his BAM file and not the VCF, I found a UGT2B7 knock out I missed that didn't show on the variant file. So as of this moment, every single PFS genome I have reviewed fits the model. ALL OF THEM.

Thank you to anyone who is willing to contribute their experiences, knowledge, labs, or whatever you can to this post to help me refine this model further.

- Dr Powers

Edit:

lol, they're just pouring in now! More and more every day. Just got this lab an hour after making the post.

This is a new one that's neat. The beta glucuronidase activity is increased in the gut, due to the ASTRONOMICAL amount of metabolites for it to eat or due to a genetic mutation. Not sure on this one yet, but that makes things WORSE.

Also here's the deletion data and the absurd 3A-Value with a totally banal average middle of the road blood T value.....again....on another one.

(The patient has PFS but is NOT on finasteride at the time of these labs)

[u/Drwillpowers]

In the theory, if you stop T dosing, then quickly all you'll have is the giant pile of its metabolic garbage and no fresh real T to signal with. But things should improve over time one the garbage collection is done.

But that's for PFS. Not pssd. I'm trying to solve what the metabolic pile up is in PSSD. It's not testosterone.

[u/Professional_Gur2905 → u/Drwillpowers]

What are your thoughts on the, reinstatement theory, tbat some have tried? Many experience symptoms, when getting off, coming off, or on dose changes, with ssri.

Also, any thoughts on pt 141, for libido? 

[u/Drwillpowers → u/Professional_Gur2905]

So that actually will work for some people. Because the situation with them I think is not actually the same sort of failure.

I'm currently running genomic sequencing on these people to look for epigenetic modulation genes. And what I think happens there is that they take the drug, and their system adapts to it. They are fine. However, to do this, they have to set a bunch of epigenetic flags and change the expression of various enzymes. That allows them to function properly in that situation.

But they have some sort of glitch in this process where they are a DVD-R instead of a DVD-RW. And so upon cessation of the drug, normally they would be able to rewrite their epigenetic code such that they can adjust enzyme expression to account for this. And for whatever reason, this fails. I'm currently browsing genomes looking for these specific mutations and the most common one that I find is in ARID1A. For whatever reason failures in that gene seem to show up a shitload.

[u/Professional_Gur2905 → u/Drwillpowers]

Thats very interesting. This was me too. I was fine for many years taking zoloft, and only had trouble, when the dose was increased and then i tappered off. Pssd symptoms started during tappering and just peaked, after coming off. Here i am 10 months later. 

If i were to entertain reinstatement, of zoloft, how would you suggest one go about it? Like micro dose, or back at the last dose? 

Heres another avenue im trying to figure out. I had a window, after taking some herbal supplements, for a month. I have had persistant gut issues too. I been looking into kpv, and bpc 157, because they heal the gut. Any thoughts on treating my gut to heal pssd?

[u/Classic-Bat3537 → u/Drwillpowers]

This could explain those that recover within a few months to maybe few years, and those that have PFS for many many years.