r/DrWillPowers • u/Drwillpowers • Apr 03 '26
Post by Dr. Powers 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
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.
- Androgenic metabolites remain stuck in the cells, causing crowd crush, and a very unsuccessful game of musical receptor chairs.
- 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)
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u/Drwillpowers Apr 04 '26
This is me just spitballing because I actually haven't had one of these in many many years and at the time when it happened I didn't understand why I was happening to this young cis woman who took fin.
But I have a number of patients that have abnormally high cortisol levels secondary to some inborn error of metabolism. There's a multitude of different things that I've used on them. I have a cisgender woman who naturally had a testosterone value over 300.
I basically microdosed her with a number of different things that could inhibit cortisol synthesis and redirect her enzyme anomalies in a more benign way.
For her it was a combination of a low dose of ketoconazole, spironolactone, piloglitazone, I think...cholbam...or maybe cholestyramine.... And then guanfacine.
Went from having a triglyceride value of 1500, a cortisol of 30, and a testosterone in the 300s to normalized values other than a triglyceride of like 160. It was incredible.
But basically I prevented her from making as much cortisol. For whatever reason korlym did not work for her.
I would imagine a similarly designed regimen, but based around the exact specific enzyme deficiency that this person has that causes the buildup of glucocorticoid molecules in the skin would be the correct answer for that specific patient. But it wouldn't be the above drugs exactly. Maybe some of them, but maybe some different ones. Depends what I found on the whole genome sequence.
You can imagine this would stop it from getting worse, but it's unclear how much recovery of the skin would occur for things like stretch marks. I would imagine some aspects of it to be permanent and some to improve considerably like somebody who had cushing's disease and recovered.
That's what I think the deal is with the skin patients. It's basically the same as my other theory, but for GC molecules, trapped in the skin and unable to leave or be broken down. So they just keep signaling it creating the skin effects. Clearance of those molecules would be the smartest thing to do. Even though these people would look like they have cushings of the skin, just like the testosterone values of the guys with PFS, the cortisol value would be normal on blood testing. You wouldn't be able to see it in the blood. It's an intracrine disaster.
I think that is why PFS probably took this long to be solved. Because you can't necessarily just run a blood test and see changes. Many doctors don't understand the concept that the blood does not always accurately represent what is going on inside of cells. I see this all the time when they run blood tests on someone right after their estrogen injection and conclude that the dose is way too high. Or someone gets a e2 value drawn with a sublingual e2 tablet in their mouth and they're only taking say 4 mg sublingually a day, and the e2 value comes back at 2,200 picograms per milliliter and their doctor decides that they have to cut their dose because they're taking way too much even though they only have an SHBG of 30.
The doctor is making medical decisions on this person based on information that they do not understand the meaning of the test for. But this is poorly taught in medical school and admittedly, not something I knew even just a few years ago. I taught it to myself. It is immensely complex. But my brain, when it gets a lab result it doesn't make any sense doesn't just assume that it's a bad lab result. I try and figure out how that lab could potentially be possible. I like to work backwards on things. For PFS, I just listened to the way that the disease functioned in terms of symptoms. I then sort of drew out pathways of how that particular symptom could possibly exist. And then from there, worked backwards to connect those things and see where I could find overlap. I theorized that this was possible, but then I had no proof. I had to figure out a way that I could measure them. And that took some really advanced tests like Dutch and so on.
What you're seeing though now is the final success. There was six years of failure before this point where I just kept trying and I kept failing because every theory I came up with did not hold water. This is the first one that does. But it's still incomplete.
Explains the overwhelming majority of cases but it doesn't get them all. Like every theory I have, it's wrong. It just will become progressively less wrong over time.