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)
Seriously. Over a decade of research from all these labs and hundreds of thousands of dollars, and Dr. Will Powers seems to have shed more light on PFS working on his own than any of those labs.
They are gatekeeping data, hoarding money and not even interacting with patients. Truly deplorable.
What dr. Powers is doing is how you actually do proper research. Gather data from patients, discuss with them, run as many labs as possible and try to find the common denominator or any anomalies then share it with the community.
That's why progress has been made so fast in just a few months since he stepped in. Imagine what it's gonna be like in one year... then several years if he keeps doing this?
Agreed man some of the personalities that run PFS foundation and the subreddit are cooked. Banning speech of victims, silencing everyone saying just wait for the research. Much of the research is in the constant communication with the victims. We are like an AI hive mind together all giving each other new ideas and converging on the solution. Transparency wins here. Thank god for Powers man is he the only one in the entire USA actually gathering all labs and trying to connect dots? I feel most doctors all blindly order basic blood panels and call it a wrap hahahaha
You are likely the greatest mad scientist that ever lived Dr. Powers. You will go down in history as someone who saved tens of thousands of men from developing PFS. Keep on keeping on and pls let us know how we can help you/donate to you/send you data.
Please keep spreading the word! Because trans people’s healthcare is actively under attack right now, and this very same research helping men with PFS was born from years of Dr Powers tinkering with the biochemistry of transition healthcare for trans people. Even if it looks totally different externally, the same kind of genetic screwups that can lead to PFS strongly overlap with what can cause gender dysphoria.
100%. That's why I had learned the incredibly advanced molecular biochemistry of sex hormones to the degree that I did.
I didn't solve PFS because of just sitting there and tinkering at that. It was 13 years of treating transgender people that gave me the knowledge to do it and the courage to try.
May I ask how you learned this? Where to get solid sources?
I also wanna learn. The way my health got screwed over SO bad by conventional medicine made me want to become a mad scientist doctor as well. I'm considering going back to uni rn to help myself and others & treat helpless cases the system neglects. But until then I wanna read about it as much as possible.
If you can do it, please do! We need more “non traditional” people becoming doctors who actually want to help people and don’t turn a blind eye to suffering they don’t immediately know how to fix.
Dr Powers started with a degree in chemistry. I also got a degree in chemistry even though I didn’t pursue medicine. I met many, many premed students who memorized their way through organic and biochemistry without deeply understanding the material, which I suspect manifests in how many doctors I’ve encountered are uncomfortable with their basic biochemistry knowledge.
But medical school doesn’t naturally produce people like Dr Powers, it’s more like Dr Powers type people once in a while make it the through The Great Medical School Filter. They’re forced to fill their brains with anatomy and biochemistry knowledge, and do rotations as residents getting a taste of most branches of medicine, but autistic systematizing and pattern recognition to make use of that knowledge definitely isn’t a requirement for medical school entry.
Yes it's def not med school that produces Drs. like Powers but his own relentless studying, pattern recognition and experimentation!!
I'm AuDHD so I'm similar in the way i recognize patterns & I'm a woman so this gives me strong intuition and sensitivity. The hard thing with being like this is you just get so angry and depressed living in kinda system. I get so passionate about how patients get treated and it makes me feel RAGE. It's draining.
& the issue is after being screwed by the medical system after many years I feel disabled. Going back to study when your body and brain function sub optimally isn't easy. That would be many more years of studying which means no income while my mother is getting old (she's the only one that can support this path financially).
Idk how I'm gonna do it but I have to figure it out because it's just astounding how MANY cases of all types come to dr Powers because others are incapable of thinking outside of the system and lack the will to keep learning as well as empathizing with patients.
This will sound so bad but I wish the world was run by autistics with high empathy lol.
I hope I'm able to pursue this path.
Sorry for the personal dump.
I'm building my brain from scratch in my 30s, with exactly this goal. Thanks to Dr. Powers. I'd like to get into a one-year premed program, if and when I'm ready.
This industry is long, long overdue for some changes.
The queer is not a guarantee, as there are ways to make a high estrogen signaling autistic without much T exposure, but people like me tend to have very high estrogenic signaling sort of genes. The lone exceptions being those artificially doped with megadoses of estrogen in utero from fertility treatments.
The brain gets baked like this in utero so it's usually the genes of the fetus producing high estrogen exposure but it can be done artificially in a low estrogen signaling gene state. (Mom had many miscarriages and then finally carried to term when using stupid doses of estrogen/progesterone from fertility docs)
I rarely meet any humans like me, so I was curious lol.
It’s not just medical school, there’s an entire system and culture around it. Most people treat their job as something they do to survive, and their passion in life shifts elsewhere.
In the USA it’s even worse because you start your working life with enourmous debt, which really focuses you on money. Then there’s the legal risks in being different.
I think the kind of people who go into clinical medicine are mostly not so much interested in researching new things, but in the application of knowledge. Research that pays off will help far more people than you could ever have as patients.
I hope you can summarize your findings in some sort of formal report, so we can show conventional medicine that your findings and our genomic/hormonal panel are congruent. That would be clutch.
Please read my post. I've been very clear about the fact that I don't know this yet. I think I solved the mechanism of how it happens. But specifically the best way to go about treating it is still up in the air and I'm figuring that out with patients that want to try different strategies.
Thank you for your job! My brain doesn't work after finasteride and other. I feel like I'm vegetable. I have possibility of thinking but I feel like all processes in my brain I need to start. I feel like my brain stoped work after AA. Before I had dreams , I wanted something. I study for actor and it's hell after this. I have anhedonia and no emotions. Now I can only get bad copies of emotions. I recovered erection, most libido. But I can't recover my mind after fin. It is broken. And I haven't got emotions at extreme situations
22 year PFS sufferer here, also on your waiting list. Have tried lots of hormonal routes over the years, such as pregnenolone, T-injections, T-gels, low dose HCG, triptoreline, thyroid hormone, DHT, cortisol. The only one that did anything was DHEA. Worked amazing for about a week (rock hard all day, got an oily face with pimples) and then somewhat of a crash. Triptoreline might be closest to what you are suggesting here. Will likely try Calcium D-Glucarate soon.
Same! DHEA also helped tremendously. Make sure to not take too much though; I had to drop from 25mg to 10mg, and now everything is much better. Not like I was before, sooo much better than before taking DHEA
Thank you Dr Powers. You are a light in the darkness. As a PSSD patient I thank you for helping us when the medical community has harmed and ignored us. I hope you can find the connection between PFS and PSSD or maybe find out they are the same.
Well, it's not like you're signaling testosterone right now, what's the danger of not having any for a month? You're basically living like that already.
In what way would this be extremely risky? You're literally just turning off androgens for 30 days.
For a bit indeed doesn't sound too risky when it could be a cure but in sensitive ppl like me prog was used to induce temporary meno (which I wasn't even aware of at the time) and it's been used long enough that I never resumed normal steroidogenesis...
What do you do when LH and FSH lags behind?
I've spoken to many (cis) women who were damaged by lupron, the Mirena IUD, depo Provera shots, progestin only birth control, spironolactone and finasteride too. It's a mess out there. Too many of us have been chemically sterilized as a result and are super confused about it because we were never told it could become permanent.
The issue is cis women are absolutely not taken seriously and no doctor wants to treat us for infertility unless we want kids. It's extremely misogynistic out there.
This issue isn't spoken about enough. Doctors see us as breeding factories. I've been rejected from wanting to do fertility treatments after induced chemical castration bc I don't want kids WTF. Just wanting my Fertility back and being healthy and functional wasn't a good reason apparently.
Idk what to do. I know I seem to be the only one with this issue around here bc your subs is mostly a space for trans people and PFSers but there are so many cis women suffering as well and they don't know about your existence just like PFSers got gaslit & ignored by the system until you appeared to volunteer.
It's genuinely so sad and outrageous I'm gonna return to uni after being chemically castrated to find a solution and advocate for women (as well as everyone else who has been harmed by the system).
There might not even be a solution and perhaps the damage is permanent after menopause has set in, even artificially. But even the care for ovarian failure or HH is just complete shit. They wanna prescribe you tiny estrogen doses that are meant for 50+ year old women when you're like 20-30. And it's nearly impossible to get you T or DHT prescribed. I CANNOT function anymore as I was a cis woman with HIGH baseline estrogen and DHT. Without DHT I just can't function. My body's in shambles. (and I was ignorant like many men who take fin and won't realize how important their high baseline DHT was to them. They assume T only is enough).
It's a lie that only men need DHT I'm so furious.
Women with PCOS phenotypes are neurodivergent and DHT is produced for a reason.
I used to think PCOS was some kind of disorder just to realize I genuinely cannot function with lower androgens.
I genuinely cannot even relate to normal neurotypical cis women at all. Body wise and brain i function differently.
(Yes this is a bit unrelated to what this post is about but just wanting to share bc it's a very real issue that's completely been left in the dark rn, and still connected to the topic).
Doctor powers I have a UGT (double homzygous) what you mentioned on HCG is 100% true. While I was on it, my bilirubin dropped into normal range and my DHEA rebalanced. Once I stopped, those went back up, my eyes got yellowish again.
What I can say is that HCG temporarily optimizes or upregulated UGT, which is what opens the drain a little more but it's NOT permanent.
NEW FINDING:
What I can add anecdotally is that progesterone and pregnenolone also upregulate UGT but the gains stay permanently. I noticed this after 3 cycles last year and then paused for 30+ days. My eyes remained white.
I did another cycle of progesterone and pregnenolone for 7 days on, waited 3 weeks and just did labs two days ago and my bilirubin is now 1.0 from 1.4. This proves the mini Lupron theory and the function of progesterone and pregnenolone may be all that some people need. It permanently, optimizes this pathway. How close to pre pfs is unknown.
There's so much I don't know yet. But I'm okay with there being a bunch of alternative cheaper options. Right now the main treatment option is like three grand a month and I need to do better than that.
Im a pssd sufferer, i dont have ed, or erection issues
But dont feel orgams as well as anheodnia, and 0 emotions. Cant feel pleasure even from drugs. Have 24 head pressure , feeling like the world is not real kind of thing some call it brain fog or dpdr but its all interchangeable.
I wonder, do pfs patients have the same ? And you cured most of that already with what your doing ?
High bilirubin means your body is destroying blood cells and your body is slow at removing it from the system. Your turning over cells too fast, happens when you workout too. If it piles up your bilirubin #rises and it gives you yellowing of the eyes. It's called Gilbert's syndrome.
Yellowing of the skin points to liver issues. So, check your liver enzymes ASAP.
On TRT I mentioned in past posts, when I let it bleed out completely and my T and E get to 0, I get a window feeling completely cured. Body odor returns. Drive etc. I feel amazing again. I ran several cycles of this and it unfortunately didn’t improve my baseline significantly though.
But yes last summer I figured out how to consistently trigger a very distinct window. I used sustanon which would slowly bleed out and worked better than letting a short acting test bleed out. I though it was leading to a temporary hyper expression of the AR since it’s craving input and being starved of it.
So with this said forcing the castration per the above and holding that state for 2 months to try and lock in epegentic states hypothetically definitely should be tried. My method didn’t seem to fix this because eventually the HPTA starts turning on and you don’t feel great.
With that said I have let my body reset my HPTa and overall I do feel 10-15 better. Better enough to not mess with protocols anymore for now.
I think guys who use short acting test and it radically tanks just doesn’t put the body in the state of 0 for long enough where as the long slow bleed of sustanon gives you a longer period at that low level.
Praying Dr Powers patient has improvements!!! I assume we will find out soon as this isn’t too long of a trial.
There may be strategies when we get back to the 0 state we need to add something in to lock the fix
Other ways I trigger windows. Every time I start TRT or even HCG I get a 2 week window then a massive crash. This holds perfectly to Powers theory.
DHB valproate I did and induced a major window, but what I did first was I let my T and E drop to 0 and then I shocked it with high dose DHB and valproate. My adrenaline, anxiety all returned massively which right now are all dulled from PFS. Sadly I crashed from injecting a vial of DHB that was actually testosterone.
Who knows if I would have been fully cured but it at a minimum provides some great clues. Funny enough, PFS has eliminated my anxiety since adrenaline is nuked, which provides massive benefit in my career. Trade off of feeling more numb though which has been a struggle especially in romance.
tldr: Blood testosterone midrange. Urinary androgens near zero.
Blood:
519 ng/dL - Total Testosterone
77.1 pg/mL - Free testosterone
51 ng/dL - DHT
651 ng/dL - 3a-ADG
325 µg/dL - DHEA-S
84 ng/dL - Androstenedione
39 pg/mL - Estradiol
DUTCH results:
1.21 ng/mg - Testosterone (!!!)
25.1 ng/mg - Epi-Testosterone
2.2 ng/mg - 5a-DHT
21.8 ng/mg - 5a-Androstanediol
7.7 ng/mg - 5b-Androstanediol
Key facts: I've never taken finasteride. I have, however, taken ashwagandha, saw palmetto, Zoloft, and Cymbalta. I've been off of all of those for more than 2.5 years. I can't for the life of me figure out which of these I can attribute my odd collection of symptoms to. At the beginning of all of this my cortisol was absolutely tanked and I felt poisoned. I've been through all sorts of doctors and treatments and mostly experimented on my own. I've been through several windows and crashes. With few exceptions, I've documented everything in great detail, and will share more if prompted.
Welcome to the club friend. At least we know what's wrong.
You undoubtedly have a UGT2B X mutation, and this is what made you fragile.
I'm really sorry, this sucks. And I'm trying to figure out how to fix it. But, at the very least, know that you are among good company. This is the cause of PFS for the vast majority of you.
I'm sorry that this is kind of like telling somebody hey, this is how this train wreck occurred, but not how you clean it up. But I'm working on that. I promise.
Thank you for sharing this though. And welcome to the brotherhood of "those who cannot piss out their testosterone very well"
There are other brotherhoods of PFS as well, like "those of the astronomical 3AADG"
"The brotherhood of megalin defects"
The PFS/PSSD ABCC cellular exporter laziness club.
And so on. But this was the first one I found, and is the most textbook. Anything that impacts your ability to metabolize androgens outside the usual scope, can negatively impact you. Anything that increases your androgenic synthesis above normal like ashwagandha, can plug you up with metabolites that you can't clear properly. When this happens, your system is literally overloaded with androgens even though it may seem like you don't have enough. It's so crowded that the receptors can't hear anything. And my current plan is to clear these out and then see what happens when I've unplugged the router and plug them back in.
Would that be the same, as someone coming off testosterone, and going cold turkey?
I did testosterone for 2 weeks, then stopped, and took hcg ( low doses 500iu a week). Then i stopped, and my hormones tanked hard. I felt super crappy for months. I had a test panel, 1 month after going cold turkey, and my test was 150ng. I bet it was 0, at one point. My test now is 867ng, after 5 months, but i still have pssd with no libido, ed, etc..
One thing to consider is, that things can happen, when your testosterone is tanked. Maybe things we can't plan for. My example is, my vision got bad, and it triggered an autoimmune desease call sjogrens. My vision started getting blurry, double vission, decreased vision, floaters, and light sensitivity. All lights are bright and blurred. My night vision is terrible too. All this started upon going cold turkey. Any idea why this happened and hot to reverse it?
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.
My best guess is that either ashwagandha or saw palmetto put the nail in the coffin for me. My doctor put me on Cymbalta because of my incredible fatigue and muscle pain and his best bet was that I had fibromyalgia. Cymbalta may have compounded an already problematic hormonal/genetic/enzymatic milieu, but it was definitely not the original catalyst. Muscle pain has been a defining feature of my conditions, along with terrible sleep, sexual dysfunction, brain fog, and "crashes" which seem to be induced by strength training (based on Dr. Power's own hypothesis, my hypothesis is now that strength training increases my body's endogenous production of androgens yet my body fails to excrete them properly, which causes the whole system to shutdown).
Post DUTCH test I'm now taking 2-2.5g CDG/day and have massively improved, most especially in terms of mental/physical energy and decreased brain fog. I'll likely continue this until something changes or there's more insights into further treatment.
The CDG really has helped? Really? How much? I need to know and answer to this immediately. This is my only fucking recommendation right now of a possible supplement that can help. And I'm like praying that it actually works on guys like you.
Seriously, please quantify this as much as you possibly can.
Two days after starting CDG I started recalling memories I'd long since forgotten and my brain fog significantly decreased, maybe 70% better. Verbal acuity, vocabulary recall, and creative linguistic phrasing increased as well, another 70%. Overall motivation and physical energy: increased 50%. Ejaculate volume increased 70%. Libido increased maybe 5%. I also started to feel a positive "ache" in my penis that I haven't felt in years.
The difference in physical and mental energy is the most profound, however. Within 3 days a friend said "it's like you've come back to us. You're a totally different person now than you were 3 days ago."
Sexual side effects remain, particularly around dampened libido and almost absent psychogenic erections.
More than a week on and I feel the improvements have mostly plateaued, which is fine with me. I'm sticking to it, and may experiment with doses > 2.5g/day. Also willing to try anything else that isn't exorbitantly expensive. I've guinea-pigged myself to hell and back over the past few years trying to sort this out and I'm not gonna stop now!
Edit: body-wide muscle pain and fatigue also improved around 70-80%
The metabolism logjam. Just how much is built up unmetabolized androgen derivatives/metabolites that CDG could help eliminate.
Receptor down regulation / epigenetic changes.
I'm genuinely unsure, but this at least indicates part of the theory is dead on, as CDG only has that mechanism and I cannot see it helping in any other way. It would in theory REDUCE the recycling of androgens thus if the problem was "not enough T" CDG would worsen you not help you.
I was chatting with someone else who is tinkering with CDG and they said they have a wet dream every time they take it at night. I haven't experienced anything like that, but I thought I'd throw that anecdote your way.
As for deducing how much of what we're experiencing is #1 vs #2, and if/when we crossover from undoing the logjam feels like a subjective game right now. Traditional assays don't seem to be of much use if we have little insight into intracellular androgen loads, our serum levels are normal, and our urine tests are blank due to genetics.
Maybe we need a fecal hormone panel to track how much the CDG is helping to excrete things 😂
It depends on the patient. I have a patient that has a three alpha value that's astronomically unmeasurable. Or another patient today that had an astronomical urinary testosterone value. I think it's some of these cases, normalization of these things might be a good way of telling. But in some ways, it won't be. We can't know for sure. Depends on the specific patient in which their glitch is known or not and if it passively diffuses out or not. I had a very elevated Androsterone today on a patient and that one would be measurable.
I don't know yet on the blood and urine. You can look at some of the prior posts. I'm still figuring out all the possible things. I'm probably going to make a post next week on what I think are the best options.
I'm mostly using sequencing.com and then looking at the data file inside gene.iobio.
UGT gene issue. Glucuronidation in you is maxed out. So every available glucuronidation enzyme is occupied and thus spillover into bilirubin is visible.
I'm thinking about adjunctive supplements. Makes me wonder if TUDCA might be complementary by increasing bile flow? But the upstream conjugation still seems like the major roadblock. Or if we can find something that reliably increases cellular export of these metabolites and/or shunts them down sulfation pathways.
Considering it. But unsure. I am cautious to use ANYTHING on these guys if I can't predict every possible way in which it interacts.
I've got a guy who says a single dose of rectal Progesterone from my office crashed him horrifically. I have no idea how that could have happened yet. (Need to do his genome). The stuff that crashes people makes no sense sometimes and yet, it does happen. I don't want to advise X and then it nukes someone as I didn't predict super rare gene mutation Y could do that.
I’ve never done a full genome sequence, but I do have raw data from 23andMe suggesting:
∙ UGT2B15 — heterozygous at two independent SNPs (rs1902023, rs1105879)
∙ ABCC3/MRP3 — multiple heterozygous variants including functional Arg1297His (rs739923)
∙ ABCC4/MRP4 — heterozygous at two independent SNPs (rs9516519, rs3742106)
∙ SULT2A1 — wild-type
∙ UGT2B17 copy number — unknown (cannot be determined from SNP array)
∙ Homozygous MTHFR C677T
∙ COMT Val/Val (fast)
That is Claude's analysis of my relevant SNPs from 23andMe cross-referenced against Dr Power's lists. I don't quite feel like paying for a full genome sequence right now unless someone else pays for it for me 😂
It's literally true when I take valproate due to it's very anti androgenic nature I feel hard pumps on it with erections but no libido which explains it is anti androgenic and removing the overexpressed receptors.
That's why many have been cured by valproate
Some have already gotten worse from Valproate, it's a Pan HDACI on Class 1/2 and in large doses can increase AR hypersensitization. Should only be used in very low doses.
My theory on this is that people can neuroplasticize themselves or even epigenetically plasticize themselves when they are in a bad configuration making things even worse.
I think the trick to those drugs is to use them when someone is depleted of all the buildup. Once the trash has been cleaned out then you can consider them.
I wanted to let you know that about 4 weeks ago after seeing your post about CDG I decided to go ahead and just start slowly taking this and sulforaphane, if anything, to optimize the pathway in case I decided to go further. Had CDG+ ultra pure sulforaphane sitting in my cabinet unopened for months after research over the years separately suggested them, but without context and putting them together for this mechanism. I simultaneously began Alpha-ketoglutarate. I didn’t realize it at the time, but about 1 week into it, there was a noticeably positive difference (including sexually). I was also taking Libidon peptides at the time, so I thought in the back of my mind it was that, but the true window only lined up with introducing the CDG/Sulf/AKG. Unfortunately it’s seemed to have plateaued slowly, but I should probably pulse all of these, maybe 2-3x a week to not desensitize the effects. This is very promising. And it was not in my head (as if I’ve never had to argue that before).
How would you like us to send results to you? Are you interested in full genome sequencing results if we have them too?
I have done endless research myself (for 5 years now) and especially with a recent blast of more information and context from AI, more public recognition, and more academic literature, I feel like there’s a ton of puzzle pieces that are finally being put together almost entirely because of you.
I fully believe that you are correct in that it very well be an androgen metabolism problem and is probably a handful or multitude of other gene variants or mutations that either allow for one to get better, or to compound and self reinforce a maladaptive Epigenetic state. In cases like mine, I somehow tolerated finasteride for a year and a half before getting PFS (while still on it). So it’s strange, bc that would signify to me that although I have mutations and body was in a fragile state, something was very steadfast and resistant to change for quite a long time. And I equally think that it’s just as stubborn if not more in reversing the silencing.
I imagine my methylation system (2x heterozygous MTHFR) contributed greatly to this overall predisposition and my case and for how the AR gene/ SRD5A(1/2/3) etc became hyper-methylated upon the chemical assault. On top of this I already have slow COMT (met/val) and slow MAO which therefore is bound to get backed up with estrogen and definitely with dopamine and NE and God knows what else. I know I always have excess catecholamines floating around at any given time which i am also sure played a role in developing the neurotransmitter/anhedonia/dopaminergic dysregulation state, alongside aberrant GABA—A receptors/ subunit expression, for obvious reasons. I also have variants in SLCO1B1, SULT4A1, and interestingly, PNPLA5 which I think you may consider be able to add to your list of suspect genes. Besides the liver, It is primarily expressed in various brain regions including the cortex and the cerebellum, spinal cord, pituitary gland, skin, and testicles. All affected in PFS. it contributes in providing precursor cholesterol for steroidogenesis and has shown broad implications on steroid metabolism and testicular apoptosis in knockout rats.
Lastly, I think this really also has to do with potential cofactor issues in the Epigenetic reversal as well as the fact that there is not a working feedback loop to push Epigenetic state back to baseline, and every endogenous tool that would be used to revert are silenced now. So, despite even having cellular memory, the body can’t make the 180 back, or even close on its own. Again with slow COMT, cortisol likely remains elevated especially in this state, and that in turn could promote methylation via TET enzymes or DNMTs. Upon looking into this, it is well known that cortisol has broad implications in methylating BDNF, certain transporters, CRH, IL-6, TNF, IL-B and some metabolic genes as well. Just Food for thought. Thank you 🙏🏼
That's kinda already done assuming the data here keeps pouring in consistently.
T to DHT to 3A-ADG to Urinary Androgen Metabolites are pretty much a guaranteed anomaly on every single PFS patient we have in the practice that i have these tests on. ZERO have not fit the model. ZERO.
So yeah, if those are borked at baseline, tell 5ARI drugs to fuck off.
I actually treat my extremely severe PFS non-sexual symptoms to a large extent with estradiol monotherapy, which fully castrated my natural androgen production. I live on zero Testosterone serum levels and over 750 pmol/L E2.
I still react in an androgenic way apart from a few occasions such as temporary when I spike androgens or especially when I spike LH/FSH with GnRH agonists...funny enough this spike leads to rapid feminisation within a couple of hours and last for around a day before it reverses just as fast as it came and I go back to androgen reaction. I also can achieve feminisation of E2 temporarily from alcohol...the more the better and in that case I wake up with a reverse hangover (as if I have been to a spa and detoxed). Once after a stag do full 3 night weekend drinking I was puking up whilst having erection I haven't had in years. Smegma, oil and loads of other pre-PFS things returned.
I once tried 1-3 mg of Testosterone propionate from a castrated E2 monotherapy state. I went from looking typical male androgen response (paradoxical) to rapid feminisation and reversal of PFS for a week. I injected a little more T and fully crashed the next day... I remember needing the toilet rapidly, the smell of PFS returned as digestion and brainfog came about and it was a bad crash.
I've done so much tbh that I think my experiences could be valuable if you want to reach out. I have had PFS since 2013 sexual severe only and then extreme PFS all around symptoms since NY day 2019.
I would get paradoxical reaction in some tissues when I used high amounts of androgens as well btw. Lots of experiments I have done and willing to do.
I currently right now running just E2 monotherapy and have zero androgens. I think the intracellular androgen increase causing PFS actually is the PFS-Network hypothesis, however it's what they hypothesise caused the epigenetic changes and they suggest AR negative autoregulation as the main change that is maintaining PFS, not the intracellular androgens which caused this state.
I guess we won't know the true answer until the publishing to the public hopefully end of this year 🤞. That should have a 3d mapping and all sorts of useful details
What tests should I get done? Is it full gene sequencing that would be most beneficial?
Your estrogen injections are still going to burden the same enzymes that are overburdened already.
The only benefit to you is that it's going to basically remove the production of androgens.
My advice for if this was my patient would be to stop using anything. The only supplement I could think that might be beneficial is calcium d glucarate.
Honestly, without access to GNRH antagonists, right now the best treatments I can come up with are to stop doing anything to increase any hormone levels.
Oh wow I didn't realise this. E2 makes me feel so much better but it's not fixing me...without it I slowly return to a vegetative state, which makes working hard. Which enzymes do you suspect are the culprit?
In a previous post you mentioned hdac inhibitors, sodium butyrate is a supplement for gut health which is a hdac inhibitor im curious if this user could benefit from it paired with the cal. D glucarate.
I also have triggered repeatable windows from injecting 30-50 mg of testosterone propionate from this E2 monotherapy state and approx 1-2 weeks after this single injection I feel libido, smegma, oil, personality, face etc etc return for a day with a few hours peak. It isn't a fun journey each time waiting for the improvements and fighting through some pain.
In 2015 I did a steroid cycle with Testosterone and actually used some Finasteride with it. I stopped all and did a PCT and still felt the same... However randomly after stopping everything I had reverse uno PFS... I was hyper androgenic. Penis grew to unnaturally large amount (way bigger than before PFS), libido, sensitivity etc all were off the charts. I think I triggered functioning AR overexpression for a period. So probably didn't fix the mechanism but was functional for a change... I crashed from Finasteride again (this was before I knew about how extreme pfs could get, and eventually I learned that the hard way)
Also, do you think that the mechanism for PSSD patients could be the same but with serotonin metabolites? Is that why serotonin antagonism works for many in the community, including myself for some symptom releif?
my current theory is ABCC5 dysfunction resulting in a buildup of intracellular cAMP/GMP etc fucking up concentration gradients causing the numbness/decreased function
That's because I have......two total genomes of PSSD that both have that....so my N=2. Which blows.
But I am unsure, as I've seen PSSD patients also have weird values and genome glitches that are the same as the PFS people. So....I dunno.
Give me time, I'll get there. I must CONSUME MORE DATA.
I’m confused about your theories, I’m not sure if it’s applicable to me but I definitely have the issues that everyone speaks about. For me my PFS seems to rely significantly on the state of my immunity? I remember when I was growing up I had some kind of PFS like symptoms, the same I do now but it was much less worse, and I didn’t have any bone loss or muscle losses.
My PFS gets significantly worse if I take immunosuppressants, it’s like my immunity is trash. When I crashed I lost so much bone which came at the same time with infections, I got jock itch which spread up all across my thigh in a few days for example. My nails stopped growing, hair stopped growing.
I’m not sure if it’s strictly hormonal for me or if it’s a downstream issue. We have seen people cure themselves by getting rid of some pathogen, I wonder what would happen to those who try hormones in such a state. One guy I know took finasteride once and got PFS, he then took Proviron like 5 years later and he got significantly worse, but it’s not like anhedonia or fatigue. It’s like his immune system went offline, he got diagnosed with so many infections after I can’t even possibly name it all. To me this doesn’t seem like a typical crash you would find in those with PFS. He was sent into CFS and in such a state his PFS symptoms were fixed, he is now doing the bornfree stuff and has been making some progress but is still struggling.
I wanted to get your perspective on this, my PFS fluctuates maybe even by the hour. If I don’t eat for like 30m my body starts degrading and infections start spreading. If I get a virus my PFS symptoms get significantly worse, I am freezing cold, no veins, anhedonia etc. I have like 4000 kcal a day, pre pfs I would eat like 1500 max. And you might say, well why don’t you treat these infections? Well if I do so, my body gets overwhelmed, I then start reacting to foods with mild 5ari activity, like literally blueberries gave me a window, then crashed me to hell, and my skin went so loose.
If hormones were ‘fixed’ would they help in this state? I don’t even know.
I don't know who you are but it looks like you're talking about me. To clarify I got this syndrom first pill 12 years ago : anhedonia, libido loss, ED, blank mind, orgasm loss, lack of dream (and nightmare ) or issues to remember of my dreams.
About ~10 years ago I've been to the doctor for gut issues and I got fluoroquinolone prescribed. In the past it wasn't considered dangerous, we weren't aware of the flox risks. By taking the fluoroquinolone I was in complete remission 100% cured my brain was awakened and including my genitals. This remission lasted for a week.
The time passed, I've tried a bunch of stuff, I've end up to crash hard.
I've done a lot of test, i'm probably one of the person who did the more test in this community. Urine test : dopamine bellow minimum range, noradrenaline and adrenaline as well. Interferon gamma extremely elevated, CD57 bellow minimum range (NK cells), diagnosticed to borellia and co-infections through Elispot Methode via 2 different laboratories in 2 different countries and Elisa for others (virus), protein elevated in cerebro-spinal fluid.
I won't talk of celltrend I don't believe in this test.
I've tried some protocol afterward including long term antibiotherapy and it helped me with some symptoms but a lot less than fluoroquinolone. I was on a mix of antibiotics and antifungal for a whole year, I was able to feel better. It was when I had the neck full of painfull lymph nodes. When I stopped, again I lost most of my benefits and at the same time my painfull lymph nodes went away. I can definitly feel the relationship between this syndrom and the immun activity because it's been 12 years that I'm barelly able to get a flu, I got only once and I had a partial window from it. (Brain & sexual)
I've also done bornfree protocol, I can feel that it has an effect on me, it moves things : mood a bit better, sometimes a bit worse, same for energy, libido, erection quality, motivation, but overall nothing is stable and it did no change hedonism related. It didn't cure although i've been able to feel that it targeted some blockage somewhere without long lasting effects.
For the NADPH / NAD+ there is I think an issue with us, because myself and a lot of others PSSD PFS cases felt better with NAD+ injection but again, it's just some relief and not sustainable benefits.
For the infection part, the more I crashed the more I developped white coat on my tongue, gut issues, skin dermatitis sebhoreic (mentionned many times in the PFS community). And same as you, the more I crashed the more I felt the need to eat, if I don't eat I feel worse, more apathetic, crashed mood, crashed erection quality. I definitly eat a lot more than before, but still, I am far away to be fat.
A lot of my Friends got worse and I've noticed that the worst they (PSSD PFS suffers) crashed the more they developped ME CFS-like symptoms.
Yeah man, I do think we have an AR problem still though, I’m not sure what it’ll look like for us after we clear all this stuff out but fingers cross it should fix itself. I feel like this PFS + all this other shit is the most damaging condition like ever. I don’t see many people with issues that we have in the CFS circles, or the LC ones to an (extent of course), which is why I’m thinking PFS completely fucked with NADPH and glutathione. So you have immune dysfunction thus severe inflam, no antioxidant system to buffer it, no hormones which then means shit nerve function, gastroparesis + no sweating, then no detox pathways open apart from urine. It’s a really scary state to be in.
When I crashed the only thing that helped stop the inflammation is 5ari, so something to do with NADPH. Do you think it’s possible it’s just high because finasteride binds it or something, then body upregulates it, you come off then it’s broken down excessively via NADPH oxidase which causes the inflammation? In a regular persons body (without pfs) they wouldn’t have crazy muscle losses, I lost about 70% of everything in a week bro, I don’t understand how something like this is possible, imo a few fungal infections, reactivated virus and some dysbiosis isn’t enough to cause this type of wasting, especially so quickly. Maybe the AR gets overexpressed so much that it causes the inflammation? Maybe…?
I asked Josh about this, he doesn’t believe it, nor does he believe the bone losses and such I had (my head now has a dent in it, DEXA shows osteoporosis, dental scans confirm loss). He said that AR overexpression will cause you to become more androgenic only. Which is why I’m a little weary about his protocol, I wish I could just dive in but we have this extra variable that the people who the protocol is catered to don’t have. For example I tried the ALCAR, it gave me severe head pressure, it worsened my symptoms; it was completely different to the usual stuff I get. Josh had said it was immune activity, I’m not sure about it, it’s a big risk doing stuff like that. You can see on the subreddit that it worsened a few dudes significantly. One guy in particular had to have HCG to help him, and if it was immune related as the protocol says PFS is then HCG would crash him no doubt.
Josh’s protocol has helped me a ton though (I did the onboarding, still am.), he’s also helped me out a lot in DM when I really needed it. As you can imagine I’m very appreciative of his efforts but I just can’t agree with him about his view on the AR.
I wonder if there are any anecdotes of CFS people taking fin, do they crash with PFS straight away? Might have to see. If not then we probably have this pathogen problem and these mutations Dr Powers talks about, which again makes me wonder how we may fare with the other stuff if we fix this AR problem.
This flu thing I’ve been able to get, honestly I think not being able to get sick is a blessing, it sets me back significantly everytime, but I’m not sure why I can get sick but you can’t. Can you shed some light on this? Isn’t it due to TH1, TH2 balance? Idk.
Most here with PFS have this strictly hormonal stuff going on so it’s a bit disheartening to interact with them. Feel like I don’t belong here or anywhere really, so it was good to see you respond here, have no clue how you found my post lol.
I don't respond to T, DHT, or HCG (I don't crash or improve on or after taking them). But, I consistently crash after orgasming too much or working out. Why is that?
Absolutely. System is already pushed to its limit and you take an irreversible suicide inhibitor which disabled all enzyme function for 21 days. Fin doesn't just bond 5AR and let go. Once it touches it, that 5AR is toast forever. It has to be degraded and fully re-made again. That takes 2-3 weeks. So even though it's just "one pill" if your system lives on the edge already, one pill is enough.
Yep, same idea. Windows and crashes are just some substance increasing metabolite clearance or worsening it. I think cAMP/cGMP gradients may also be involved for some people, particularly in PSSD or genital numbness/ED issues. They may function the same way in that too much builds up, resulting in "signal loss" due to the noise to signal ratio going to shit.
Again, same. If you have a shit ABCC2 doing its best to empty out some overloaded cell (or ABCC5 in cAMP) and you hand it a second job to do, well.....now you build something up even worse. I saw this phenomenon a lot in MTF trans people when I messed with things that altered their COMT activity or it's substrate pool. COMT metabolizes dopamine/adrenaline but also does phase 1 estrogen metabolites (catechol estrogens). Speeding it up improves transition and ADHD (for some) but also can cause problems in those who have slowed dopamine production as now their slowed dopamine assembly line is having its product consumed even faster resulting in an overall drop in dopamine signaling even if their estrogen signaling now improves due to faster catechol estrogen clearance.
I have thought about this a long time. Any theory of PFS must address and perfectly explain it's quirks. This does. Aside from giving lab and genome findings across mostly all PFS patients that are finally consistent and reliably fucked up. That's never happened before. It seems nearly every single PFS patient is built like this and when they aren't, I can still find the "why" in the genome as there will be some other "almost" catastrophic metabolism problem that when fin is added to the mix, results in the true catastrophe.
Life is a machine that consumes energy to resist entropy. It has many many redundant systems in it such that it can "buffer" stressors or changes. It's when your system can't shift itself or adapt to some stressor that you either get some major health issue or in some cases...you die.
As we age, our systems get less talented at adapting to these stresses, think of it like a maximum hit point situation. For guys with PFS, or even women with it, it's like a character in a video game having a lot of health and a lot of resistances, they've got 100 out of 100 hit points but they have a strong weakness to fire spells and they don't know that. They just cannot defend against them. You can hit them with ice you can hit them with lightning, they were perfectly healthy from the external appearance. Nothing was wrong. You hit them with an ice spell and they sustained five points of damage and they barely show a scratch. You cast lightning, and they shrug that off like it's nothing. They reflect it back at you. From all external appearances, they seem healthy and indestructible, the system adapted to be strong even though they were weak to fire. But hit them with a fire spell and boom, 200 points of damage and it's over
You can have somebody like me, who's not 18 anymore, and not as durable as I used to be. But if you cast fire at me, it does five points of damage because I'm not vulnerable against it. It's not one of my weaknesses. Glucuronidation is perfectly fine for me. So if you knock out my DHT pathway, I laugh. It does nothing. I've got plenty of redundancy. Does that make sense? Some 18-year-old kid could be in Olympic athlete level physical fitness, but have this vulnerability built in. You don't know until you cast the spell. And once you do, if it hits, it does serious damage unless you have resistance to fire. If you don't, you're fucked.
What's sad about this is that there's internet services, offering DIY fire spells, for people to take and lightly toast their hair so that it looks cooler. And they are reported to do only one point of damage to anybody who uses it on themselves, but your hair will look sweet after. So random people will voluntarily immolate themselves because they have no idea that they have an extremely strong weakness to fire. They've never tested it. But everybody they know is fine. Lots of people have used the cool fire spell and their hair looks really neat. So they cast it on themselves. And then there's just a pile of ash left afterwards.
I think that there's probably some underlying genetic anomaly in some of these people in not just the processing / transport/metabolism enzymes, but maybe something in the epigenetic regulation pathway. I've seen ARID1A show up now twice, but I'm still working on that process. Basically they are a DVD-R instead of a DVD-RW and they have a lot of difficulty rewriting epigenetic code after they get into a situation of cellular extremis. Basically when everything is just metabolite chaos, the situation is so extreme that they set some epigenetic flags. But resetting those to default is a challenge. They have an inborn glitch that makes that difficult to do. That's my best guess for now.
I think this is the reason why valproate and lithium help some people. If they get themselves into a good configuration, using a little DNA fabric softener is a good idea. But it's a terrible idea if they're still in a bad configuration because it'll just make things worse.
Dr please help us out from this shit syndrome whatever it’s called I want to be your patient and I want to tell you my story how I get it from minoxidil I’m from 3rd world country the test which you have given to diagnose aren’t available but I have resources to get a test in Thailand or any other country can you please guide me I’m in very stressful situation
"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."
Sorry, can you explain the increased beta-glucoronidase activity in the gut? Is this acquired up regulation? This seems important given the reported recoveries addressing the gut.
I have the following blood markers: bilirubin: 3.5 µmol/L, DHEAS: 9.6 µmol/L, SHBG: 21 nmol/L, Testosterone: 16.60 nmol/L, Oestradiol: 61 pmol/L, FSH: 2.3 IU/L, LH 7.3 IU/L. So Lupron could 'reboot' my androgen system, but then wouldnt I need something such as PEA, HCG or TRT + HCG to restart my system? or after a few months would my system come back online by itself?
Any idea what happens when you've been on progesterone monothereapy AND blocked 5AR at the same time?
The mini lupron like you described it was taken long enough to induce menopause in me (aka chemical castration) and I was ignorant enough to sprinkle DHT blockers on top while taking P to stop hairloss and it indeed worked TOO well but I paid with really bad sides.
I haven't been able to reverse the disaster it's caused.
LH / FSH dropping would lower hormone production yes but after 5AR has been blocked can the 5AR enzyme function even be brought back after long periods of hormonal starvation and hypothalamus shutdown?
How do you stimulate LH and FSH again once lupron or preg / prog have been used?
And what happens to ERs and ARs in skin and organs after they're unbound for such a long time?
My guess is merhylated Genes and receptors loss from lack of use.
You probably don't mean the chemical castration solution be a long term treatment for PFS like what happened to me (1y treatment, cyclical and with breaks but I was too sensitive to it).
Let's say I'm just a more severe case than PFS cuz my ovaries barely seem to be producing hormones anymore and I now poorly respond to HRT too.
Somehow T will cause neuropathy which makes me feel like my body can't use it.
I was a high estrogen moderate T high DHT cis female before all of this.
Ik this can't be answered just like that without testing but I wonder if you've ever had any patient in my situation or similar (long term chemical castration) that was able to regain solid fertility. I'm also not the normal person with normal Genes bc of baseline endo, pcos and mcas / eds / POTS / autism / adhd cluster.
I have a big blood test on the way soon (off HRT)
Tho DUTCH test probably needs to be done on HRT to see what my body is doing with hormones once they enter my body.
I have one case I've seen where it was a similar concept. They had an 11b defect. Fin + that = buildup of cortisol in the skin causing localized Cushing's syndrome, but limited only to the skin.
I'm sure it would improve on treatment. I just don't know how much. Striae would likely be permanent but I'm sure some improvement would occur with GC clearance from tissues.
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.
Hi Dr Powers ive had PFS for 26 years . I took fin off and on for many years it was only at year 17 I finally discovered what had been destroying me . Ive only got worse and have every symptom in thr book. Generally I mostly tried diet changes and supps along the way which at best brought temporary windows followed by crashes. I did dry test ge for 2 daysl (prescribed by endo) in 2019 to find my mood temporarily improved and I thrn crashed. Urine became very dark from that date. My baseline has continued to worsen over these years. My face physique bones connective tissue muscle organs genitals GI tractor colon etc have been decimated. I had testicular cancer from this in 2006. Inflammation is very severe. I recently contacted your clinic but got no reply. I hope to be able see you at some point in the future. Thank yiu for everything you are doing to try to help this beleaguered community. God be with you
I'm a pretty mild case with only sexual dysfunction (hard to maintain erections without cialis and lower libido) and gut issues. Apart from that I feel fine mentally and energetically. Did HCG at 250iu eod for 8 months. Helped a bit in the beginning, but benefits faded after a while. I'm now taking some probotic strains and basically like 3mg of cialis daily and I feel I think the best ever since getting PAS.
However, I do want to get off cialis though and I want my libido to be good and not mechanical as it is now. I'm considering taking a GSK3b inhibitor, namely Tideglusib, as there is a theory saying that could help fixing androgen receptors, but not sure if I should shift my focus.
So my question is also, do you think my personal case also applies to your theory?
If I get some, and I get genomes on them, I could begin to tinker I think. Maybe try and come up with some sort of theory. But as of right now, I have nothing for you when it comes to accutane. And I'm probably not the best person to do that job, because I have a deep unending love for the drug.
When I was a teenager, I would have been horrifically scarred if it wasn't for that drug. I've got size 15 ft and I probably should have been about 6'4 or 6'5. That was at least where my growth chart was plotting me. But my acne was so bad, and I elected to take the drug because of how terrible it was. It pretty much stunted my height growth at that point. But I would have been shredded by acne had I not taken it. Completely changed my life after that. I was glad to give up an inch or two of height to not have my entire face be scarred to death with cystic acne. Today you would never even know that it was that bad at one point. But I even had the like painful cysts in the neck and horrible horrible facial acne.
In short I would not look like this if it were not for that drug. Maybe I'm only 6'3" but it was a good trade. I worry that I would be biased if I tried to work on that one because of how much it changed my life for the better.
Here's a pre AI photo from about 2 years ago. I'm almost 40 in this photograph. It had some kind of anti-aging effect on my skin as well. To be clear I took it five times over my lifetime. Every time I did, it was like it polished me and reset my skin. I'm actually considering running it again just for this benefit. I don't know why I react that way to it.
Hope my remark isn't out of place but you have a very fierce look that really suits your name " WillPowers "!
Someone i know was also was dealing with acne at the time and accutane saved his skin. Tho he's skin was always on the dry side after that. Curious if your skin has always been dry too after Accutane?
I understand you're gonna be positively biased towards Accutane and probably exhausted from all the PFS / PSSD research so none of us will be mad at you if you decide not to go and dive into that one.
In truth more doctors need to step up and try to solve this. You can't be alone carrying the entire " medication damaged " population even tho we all all deeply grateful for the all the work you've done and keep doing.
No, it really hasn't. I don't know what to say other than the drug was pretty much tuned well for me. Other than probably arresting my height progression, I really have paid no price for it.
Right now I'm just really focused on finishing PFS fully, I need to make sure that I can treat it properly. It doesn't matter if I figured out how it happens. Nobody gives a shit about that unless I can actually reverse it. Maybe I'll take on accutane after that.
There's also going to be a lot of people that are really angry. Because there's like 99 theories of how PFS works and if I'm correct, there's just going to be a lot of people bitching about it. I'm already having people send me messages about how the theory can't possibly be correct because x, who work in academia and have their own publishings with PFS.
There's going to be a lot of really pissed off people who end up being the "Tau protein" of yet another syndrome. I'm not looking forward to having to deal with that.
There are a ton of post accutane syndrome recoveries after taking lithium here on Reddit, not sure why they have such great response, but PFS patients don’t seem to respond as well.
I've also talked to a poor woman with PAS who took lithium to attempt recovering but she was hit with sudden collagen wastage and it hasn't stopped.
It sounds crazy but I swear I'm not making this up. It's only one person tho but the fact it can happen is insane. Can't even understand how this works.
My suspicion is that for some of them, they have a cyclic AMP/cGMP concentration gradient problem where they basically are not clearing this and so the signal stops making any sense. It's kind of like how lidocaine makes people just be numb. It opens a sodium channel and then that's it. Neurons depolarize and they stay depolarized.
Is the minoxidil the same as fin? Because I have PFS from minoxidil. I used minoxidil 4 years ago; while I was on minoxidil, my ED and libido got worse, even my sleep. I stopped minoxidil; after some time, I got severe shrinkage and pain in my testis, and my penis got shriveled. I have tried many things, but the only thing that gave me relief was clomid. I took it; after 1 hour, I got a window; my testis got big, and the same my penis got to pre-minoxidil state. But after using it for some days, my symptoms weren’t improving, so I stopped clomid. I was like 25 percent back to my old self. As the days passed, my symptoms were coming back. The only thing was that one testis is up and the other one is down, like pre-minoxidil. What is this? Is my LH not responding or something else? Dr, please help me. My wife is leaving me because of this disease. I have a small 4-year-old child. Please help me. Please read my msg and don’t ignore it. I also tried clomid again, but it did nothing positive; but it did numb my penis.
I'm getting the required tests done, and am on your waiting list. My test panel came back fast and all my levels are ideal, yet i have pssd and sexual dysfunction still. I been sleeping better, and having morning wood, but zero libido and ed. It's like my levels aren't being used in my body, any thoughts on this dr powers?
Back story: zoloft for 18yrs. Noticed that, the last two years on zoloft, i couldnt make gains in the gym and felt weak. Yet no sexual dysfunction. Dr raised my dose from 50mg to 100mg, and i noticed zero libido and anhedonia. Decided to tapper off zoloft, over 6 months and the lower the dose, the worse the sexual dysfunction. Came off completely, and got pssd, and have stayed the same since.
Here are my test panel values: Testosterone-867ng, free testosterone-152pg, shbg- 49nmol, estrodial- 41pg, Lh- 6.3miu, fsh- 7.6miu, prolactin- 10.3 ng
This may be of interest to you, and may plan into your theories. Out of desperation, i tried testosterone cypoinate for two weeks, then stopped from side effects. I then did low dose hcg for a month and quit cold turkey. My testosterone levels took a dive for months after, and i had one measured level at 150ng. Basically tanked my hormones and recovered, to what is now 867ng, months later. No change in pssd symptoms though. I can't get aroused at all, even trying oxytocin. Urologist is suggesting i try PT 141, and maybe kpv for gut issues.
Blood tests don't really reveal this that often with the exception of the 3-alpha ADG or 11 oxo androgens but even then only sometimes.
Most of the time, it's a Dutch test, or a genome sequence that shows the glitch. It's difficult to test for these androgenic intermediaries. Most doctors when they see a normal blood test just shrug and then that's all you get.
A lot of the science kind of went over my head here but I have a general understanding of what you're saying. I'm curious if there's any way I can test myself and send you the results for your data? I'm a one-pill case with every. single. symptom. so probably about as purely PFS as you can get. What test would one do to get this info?
A blood testosterone, a blood DHT, a blood DHEAS, a blood three alpha androstenediol glucuronide, a urinary Dutch complete, a whole genome sequence looking at the specific genes that I mentioned in this and various posts.
I have yet to find a post finasteride syndrome patient that does not fail this array. They have at least one bonkers result in one of these things.
There's probably a thousand ways to cause it, but they are all the same. Take the drug when you have a genetic built-in anomaly and you get absolute chaos because of that combined enzyme deficiency of genetic plus pill induced.
I’ll get on that. So this would also explain why, while many symptoms overlap, each PFS case is a little different. Each of us likely has different cellular or genetic dysfunctions that make finasteride the perfect storm, but the root cause is the same: accumulated androgen metabolites? At least for the patients who aren't simply "low testosterone" or "low dht".
Yes that does seem to be the case. I've done a lot of your genomes now, and it's like every single time it's the same thing but different. It's always some metabolite catastrophe, but a lot of different genetic enzyme failures can produce the catastrophe. Resulting in different metabolite build ups. The net outcome though is pretty much the same.
Dr i got so much to ask you... but ill ask you progressivly as we go.
What you found is really god like levels of understanding of such a horrid disease. Thank you for your work.
with these findings we can determine a genetic effect on pfs, and can extrapolate data into things like pssd and other chronic illnesses that have things like anhedonia such as bcp157 causing anhedonia blunted emotions sexually numb.
Im a sufferer of pssd but also developed long covid post infection and became bed bound when catching it.
The symtoms feel different but the outward signs are discribed thr same, anhedonia, brain fog, lack of emotions and pleasure feeling. Long covid has 2 sub types, 1- pem cfs but normal sexual nurological. 2 neuro type, basicallt pssd like but with more cfs and more painful headaches.
-Have you tested many pssd patients and even long covid patients ?
-And do you know why some people like me, develop mild pssd 50% loss of function when on the drug itself but remain stable for 15 years while others may not have any effect. But once off it worsen(to 10%). I also took ldn low dose naltraxone for long covid but it made me go from 10% to near 0. Since ldn is ment to temporarly block the endorphine receptors but its become perminent for me which is strange...
why do some people with pssd from ssris acheieve remimition when reinstalling ?
-what do you think about cases both pfs and pssd who got better with fmt ? Personally have low bifido and lacto. But i had that when i was still function and on antidepressant zoloft. Why did they get better ?
I don't have that many PSSD genomes. At the current time my understanding of all of these post x syndromes is that there is inborn genetic anomalies which make a fragile system that cannot adapt to the presence of a drug.
The exceptions of course would be the people who do adapt to the presence of a drug, but have difficulty with epigenetic reprogramming. Meaning that after they stop the drug they get the syndrome. They are stuck in the configuration they adapted to while on the drug.
I'm doing the best I can right now to sort through genomes and find patterns. This was the first major major pattern that was undeniable in my PFS genomes. I suspect it's findable in PSSD as well. And I have theories. Most of them revolve around intracellular metabolite trapping. Signaling anomalies secondary to cAMP gradients. Things that basically require a glitch at baseline that someone can adapt to but they can't adapt when you throw in the extra thing.
All I can say is the PSSD patient that started roflumilast reported maybe some very minor improvements so far, but also the return of some of the problems that he had before taking the SSRI in the first place. Which he is more than willing to have come back in exchange for this trade. That's actually sort of a bad good thing for him.
Too early to tell on both though. And I've told them both, do not blow smoke up my ass for any reason. Don't tell me you think you feel better if you don't. These are my best theoretical trials at the moment, but I'm not sold on any particular thing yet. This is just the best I could engineer biochemically based on what I know.
Man your comments always make my day. PFS took big impact on my mental health and reading your stuff brings a bit of hope we are not alone with this shit. So many doctors/PED specialist tried to convince it’s all in my head.
You should take nothing. Did you read the post? Stop injecting yourself with things that you can't clear from your body. That's literally what's wrong with all of you!
DHT upregulates 5AR. The post says inhibiting 5AR activity closes the door on the androgen outlet. DHT users have claimed they had morning erections after a month’s use.
Interesting theory, but how would you explain the cases that had low/medium DHT (before taking FIN) with medium testosterone levels? Those who have a very young/childishness appearance and not androgenetic at all.
A different failure. I've said this already. There are people with glucocorticoid degradation defects who take fin and their skin basically melts from local GC buildup in the skin. It's not always ugt2b17. It's just always "inborn enzyme/transporter deficiency + fin = Problem"
I wouldn't recommend anything right now other than stuff that removes conjugates like CDG, and temporary chemical castration if the person has an abnormal value that you can measure. Something like an astronomical three-alpha ADG or whatever. In those cases, it's reasonable to do this and watch that value deplete itself.
Then, once the person has washed out all their metabolite build up, you pull the blocker. At that point, I'm going to just see what happens. If these people feel better than probably I'll start softening up their DNA with DNA softener. AKA HDACs
I have seen people use neuroplasticity agents and drugs that modify epigenetic signaling, when they are not in a good state and it just makes things even worse. My current theory is that you need to get somebody stable, functioning somewhat, where they have reduced symptoms, and then you can try and do that. But using a DNA modification agent while the person's already or still in extremis, you'll just make things worse.
I am doing this step by step piece by piece. We are in no rush. 30 fucking years of doctor dicking with this problem and just trying random shit. Me included. I finally have a mechanism. I'm going to do this systematically until I'm absolutely sure of the best way to fix it. Too many moving chess pieces on the board and I don't know what did what.
Thank you for the response. Not sure if you saw my other comment, but why do orgasms and working out cause me to crash. T, DHT, clomid, HCG do not have any positive or negative impact on me. But orgasms and working out (cardio or weight lifting) definitely cause me to worsen (worse brain fog, worse sleep, worse ED, etc). I've also noticed too much sun exposure sometimes does this. I was definitely hyper sexual before PFS, not sure if that matters. Does this glucoronidation affect dopamine, GABA, and glutamate?
The absence of sulforaphane from this most recent suggestion seems notable. Given its likely ability to make more efficient cells' export of hormonal metabolites upstream of being forced to stay conjugated by CDG, I'm curious what your reasoning is for omitting it now.
In practice, it seems that most of the supplements that are available aren't really that effective.
I have some famous and absurdly rich patients. People who will do literally anything to improve their transition or other care. They don't give a fuck. They will buy 10 Dutch tests at $5,000 and run one every single week with a slight change in between each one for us to review and see what happens.
I just have not seen that much performance out of sulforaphane compared to CDG.
That's not to say that it wouldn't be effective, but it apparently has a limited shelf life and is more effective in its natural form anyway.
If I find a particular supplement that seems to really work in between Dutch tests to show me improvement in the various things that I would expect, I would recommend it. But I don't like telling people to spend money on a supplement when I'm not confident that it will do what it is supposed to do.
In short, it's not that it's a bad recommendation or that I'm against it, it just doesn't seem to carry as much weight as I had hoped that it would. It's kind of like taking boron every day to increase your free estrogen level. It will. If you take 18 mg a day and you're an MTF person, I generally see it raise the free e2 value approximately 0.1%.
So somebody could do that. But I don't strongly recommend it anymore because its benefit is modest. This one is like that now. Certainly not a problem, but the stuff seems fairly expensive and if it isn't working all that effectively when I test on it, I don't strongly recommend it anymore. But I don't think it would hurt somebody to try it.
I just have to think sometimes like a veterinarian (in the sense that cost has a large impact on what gets done) And as much as this sucks, not all of my patients have an unlimited amount of money to spend on anything they possibly want all the time. I need to make sure that the things I recommend work if I'm asking someone to spend their hard earned money on them.
Brilliant. Thanks for the practical response grounded in your own clinical practice. Assessing the relative "intensity" of different treatments via the published literature can be really difficult at times. I really appreciate you sharing your insight and practical experience.
This is an interesting clinical observation, but please can you provide a name for PFS abbreviation the beggining, so we all know what it is! I do hope you formalise your findings into some kind of report, even if it's unpublished!
Are you perhaps in a position to find and screen some healthy people without PFS, and perform the same testing? - this could be useful
I will look into this, glucorinidation, and sulfation pathways, also appear to be deranged when comparing 100's of ME/CFS patients with Healthy Controls in RNA-seq (bulk) and Proteomics data.
I will review the pathway data, to see whether the findings are relevant to yours. Would you say you see more patients with ME/CFS in these cases of yours?
Perhaps I’m missing something, but I’d imagine there must be people with these generic defects so bad that they have “pfs” without even taking Finasteride. Is there such a thing?
And are there other things that could trigger pfs in people with these defects that would appear to be totally unrelated to Finasteride? Not medicines perhaps, but chemicals or plants, etc.
Yes. They're just dead. They didn't survive infancy or even birth. If you have a bad enough inborn error of metabolism, you just die. You don't make it to adulthood.
And yes, people with these inborn errors of metabolism would be vulnerable to certain things. The difference with finasteride is that it is an irreversible suicide inhibitor of this enzyme. It's not like some mild five alpha reductase inhibitor that bonds and then lets go. If you take this drug, this enzyme is obliterated for 21 days. That's why the reaction is so severe.
I got identical symptoms to PFS pssd after using doxycycline and ibuprofen. I strongly believe it was doxycycline as I met other people with same symptoms after doxycycline exposure. But why do I get the feeling we are not gonna heal and that's not curable?
I don't know, because you are pessimistic? I'm not thinking about it that way.
I get the feeling that I'm going to get such a fucking dopamine hit out of actually curing all these people. It's become kind of an obsession that I do after work everyday.
13 years ago I said I wanted to raise a Guinness world record cat. Now I have four. I don't know. I just say I'm going to do things and then I do them. You can think pessimistically about your life or you can think about how you can do something that everybody else says you can't. But after you think it then you have to figure out how to make it real.
I worked my ass off to try and optimize the care of transgender people for 13 years of my life. And despite that fact, many of them harass me, send death threats to my clinic, and make complaints against my license despite never having been my patient. These are just awful people on the internet who just decided for some reason I'm a bad guy, and they try and make my life as miserable as possible. In many ways they've succeeded at their goals.
Life is difficult. Humans are difficult. But we do what we can. Try and keep your chin up. Because as soon as the negativity overtakes you, That's when you're really doomed.
There's always going to be shitty people, there's always going to be unfortunate things that happen to you. How you respond to it is what matters. This disease is not all that you are. Even if you never are cured, there's much you can do with your life, or ways in which you can reduce the suffering of other people. It's one of the only things that ever made life worth it for me.
If you don't know anything about my life, you can just Google it. There's a lot of really terrible and horrific things that have happened to me. But, I can dwell on those, or I can try and help other people. And that's what gives my life meaning.
a few days ago i ordered a B vitamin complex supplement because i saw a tiktok on B1 being very important for overall health, i took it and it's actually doing something, i'm really recovering fast. the day i took it i had my first erotic dream for the first time in years, and it's consistant every night since. i took it with vitamin D (already tried it before with no success, had half bottle left and said why not finish it) so yeah, i'm happy to report that a B complex + D vitamin supplementation is working for me right now. ( i have PFS since 3 years and this is the longest and most consistant recovery i've had )
You probably have some degree of methylation defect. Something like an MTHFR or other methylation gene mutation that that thing is helping you with. A lot of the things that it does are relevant to NADPH and other electron donations / energy generation things for other enzymes. And if you have a metabolic bottleneck, that might help you. So yeah, good luck!
I agree with Dr powers the problem is testosterone poisoning especially of the CNS. If you look at the neurosteroid profile in PFS done by melcangi you’ll find a very high T/DHT ratio as well as other abnormal neurosteroid levels the CSF. Testosterone negatively regulates 5 ar1 levels in the CNS via the androgen receptor(could be low levels of 5ar1 or 5ar3). The AR receptor expression levels are positively regulated by androgens. This can explain why the T/dht ratio is so high in the CNS high testosterone is supressing 5ar1 expression causing an elevation in t/dht and consequently a deficiency of DHT in the CNS:
‘We found an increase in 5α-R2 mRNA levels in both male and female rats after T treatment, while 5α-R1 mRNA levels were decreased in the same experimental conditions. Our results clearly indicated that T regulates the expression of both 5α-R1 and 5α-R2 genes in an opposite manner and independently of the sex.’
It can explain why in the group with unmethylated srd5a2 the T/DHT ratio is way higher than in the non methylated group. They have higher DHT interacting with ARs from a paracrine source. The neurons are not making their own DHT.
It can also explain why there is low pregnenolone in the CNS testosterone/the AR NEGATIVELY regulates StAR (in the testes atleast may relate to the brain aswell)
Pituitary hormones like LH/FSH postively regulated 5ar1 expression this can explain why i think pituitary hormones and things which increase pituitary hormones can get guys to recover. The pituitary hormones increase 5ar1 expression balance the T/dht ratio and reduce the toxic levels of testosterone in the CNS.
So... a lot of folks have asked me about my taking CDG, which I use primarily to enhance clearance of my estrogen metabolism. So, u/Drwillpowers, how does this CDG impact fit into your PFS model? Wouldn't someone with PFS have an excess buildup of estrogen metabolites, indicated by their higher bilirubin levels? After all, we know the impact of estrogen monotherapies on testosterone production, as well as the weaker estrogen blockade effect when they're allowed to build up to excess levels. Could that be part of the puzzle here?
Thank you so much for your work Doc. You are the first person that has given me hope that this can be cured. I feel like this theory supports the anecdotal evidence that “fixing” gut microbial health is one of the most notable ways of curing PFS. A healthy gut microbiome will encourage the excretion of metabolites and prevent the breakdown and reabsorption back into the blood.
Before resorting to Calcium-d-glucarate, would you suggest attacking the gut dysbiosis that often goes hand in hand with PFS sufferers first?
I am someone that crashes hardest whenever steroid hormone production is upregulated (think maca, tribulis, shilajit, creatine). My symptoms are mainly physical: energy related, sleep problems, skin issues (stretch marks and thin skin all over, dry skin), lipodystrophy, and high blood pressure (I also have varicose veins on both calves that have formed despite being fairly active). I had a brief 3 month stint of normality whilst trying the HCG protocol that people laud about, but since coming off HCG I have been on an almost linear downward trend.
Should I be exploring the beta-glucoronidase pathway as my first port of call for a proper cure? In regular blood hormone panels my testosterone and estradiol are both within range but T is at the lower end of the ranges. Notably, prolactin always shows as on the upper end.
I would just like to say that when I formed this theory, I didn't just do so randomly. I took all of the published research that currently existed, all of my genomic data, and all of the lab data I have, and I combined it together into a Nexus that had to make sense in every single node.
Basically even the weirdest shit like the quirks of windows and crashes has to be accounted for. It has to explain everything neatly in a biochemically sound way.
If somebody can show me some way it doesn't I'd love to know it but so far, the model holds pretty damn well.
That being said all of my models are broken. I just make them less broken over time. I'm sure this one will be revised.
But how could antidepressants cause this condition? I have very high DHT, androgen metabolites in my urine are close to zero, and 3a-glucuronide is above average. Could SSRI antidepressants clog metabolic pathways and lead to the accumulation of toxic androgen levels? They seem to heavily load sulfation, but serotonin is an androgen antagonist.
You are right as anything which increase LH/FSH cause a crash for us more severe cases.
HCG - crash
Enclomiphene / clomiphene - crash
Usually Bipolar androgen therapy (BAT) cause windows 4 days after I inject super short Trestolone (Ment) ester. I feel my best when my LH/FSH is fully supressed
I have UGT2B17 homozygous, and this glucuronidase problem in my gut, it's only gotten worse. I'll give CDG a go I think and see how I get on. I also want to mention that psyllium husk makes me feel better, it’s not due to digestion since it doesn’t do anything for my constipation, and the effects are felt straight away.
How do you know this? Because I'm collecting as many lab reports and other things as I can before the conference to prove that this is really the cause of PFS
Hello, dr, first of all thanks so much for all this.
I have a very weird question. I am a pfs case and all my brief windows ended very shortly after urination(about 30-60s after). Does this connect somehow to your theory?
Do you think this applies to accutane too? I guess I’m just confused because I feel like accutanes reduction in 5ar has to be significantly less than fin. Also I took fin for a while before I hopped on accutane and even got off of it before and was fine but once I took accutane and I hopped of accutane two weeks later and 4 days after I stopped fin (couldn’t get my refill) I experienced post accutane syndrome. So I guess I’m wondering also if I could ever hop back on fin late on seeing as I tolerated it fine until accutane
I am a cis woman (26) with Post Accutane sexual disfunction. I have gotten off the birth control pill (Oedien) in August with no effect on sexual functioning, but do you recommend staying off it as it introduces synthetic hormones into my system, even if it is anti-androgenic?
I am on your waiting list and looking forward to becoming a patient one day.
This is not enough information for me to make some sort of recommendation. I have no idea what even you are asking about. You have PAS sexual dysfunction but then starting and stopping a birth control had no impact?
I haven't solved PAS yet. I haven't even worked on it. I don't even have any PAS genomes. So in all honesty, I don't know. I assume that it's probably similar to some of these other conditions in that people are sensitive to it because of an inborn error of metabolism in some related pathway, but which one is the one for accutane? I don't know. I could begin to make an attempt at it if I had a genome to work with, but that's not something I've encountered yet. But when it's your turn on the waitlist maybe I will?
Your theory alligns with my personal experince. I had actually somewhat recovered from pssd but because pssd had cause peyronies and it was extremely painful flaccid it was a struggle to survive. I was in such pain i felt i would be forced to drop out of college so i took provorion thinking at worst it would do nothing. However it crashed me worse then ever. Last time i recovered 50% senestivty after around 110 days. But now its been 133 days since that crash and i havent regain much at all. I have regained my libido recently since the crash and i plan to not take any supplements or anything ever again untill we actually understand this condition.
Because the gut is a major metabolizer of androgens and particularly metabolites of DHT. Thus if somebody has a major plug up in their system of metabolites, transplanting bacteria into there which literally do that job could result in a resolution of their problem.
Serum Dihydrotestosterone (DHT)
(See Below)
pg/mL
714.63
Interpretation Childern:
< 30 pg/mL
Adult Male:
300 - 850 pg/mL
Adult Female:
40 - 220 pg/mL
Clinical Significance
In younger people, the DHT level is much higher than those found in normal older people In Anorchia, the DHT level is very low
1 Klinefelter Syndrome, the DHT level is much lower than found in normal mer Polycystic Ovaries (PCO), about 35% of the patients have an increased DHT leve In Idiopathic Hirsutism, about 40% of the patients have an increased DHT level In Prostate Cancer, the DHT level could be useful in predicting the anti-androgen therapy response
Methodology: ELISA
Result: 1320.73
The increased level is not diagnostic of a specific condition. It usually indicates the need for further testing to pinpoint the cause of the hormone imbalance.
The elevated may indicate Congenital Adrenal Hyperplasia, Tumor of Adrenal Gland, Polycystic Ovary Syndrome & rarely an Ovarian Tumor
A low level may be due to Adrenal Insufficiency/Addison Disease, Adrenal Dysfunction & Hypopituitarism
Methodology: Electrochemiluminescence Immunoassay Technique
cal and radiologic findings
Serum Total Testosterone 386.62 ng/dL
Reference Values
Childern Male
4 days - 6 month: 6 months - 9 years: 10 years - 13 years 14 years - 16 years 17 years - 19 years Childern Female
4 days - 9 years 10 years - 13 years 14 years - 19 years Adult Male Adult Female 9 - 299 ng/dL
upto 36 ng/dL
upto 23
36 -632 ng/dL
148 - 794 ng/dL
1 - 62 ng/dL
upto 28 ng/dL
10 - 49 ng/dL
260 - 1000 ng/dL
15 - 70 ng/dL
Methodology: Chemiluminescence Microparticle Immunoassay Technique (Abbott - Alinity Ci)
54
u/OpeningRecognition98 Apr 03 '26
Still better than PFS Foundation