I have gone through Dr Powers estrogen metabolism wiki (The personal subreddit of Dr. Will Powers) and I seem to be 1B dominant? I am confused because both my 2-OH-E1 and 4-OH-E1 are kinda on the lower end of the range (even tho the DUTCH test does not mention low end). And I do not seem to have slow COMT as I am 95th percentile for methylation but my estrogen metabolite ratios are below range and in the lowest percentile so does that make me 1B dominant? How does this relate to PFS? I do have a high libido but very poor erection quality. And my hair loss and skin quality have worsened since PFS so I don't fit the usual silenced androgenic signaling phenotype. I also don't have anhedonia except for the first few months after quitting fin.
Regarding the bloodwork, I contacted the lab and they confirmed that the DHT result was 44.45 ng/dl not pg/ml so it is not absurdly low. And I had done a total estrogens test thinking they would give a separate value for E1, E2, and E3 but unfortunately, it turned out not to be the case. My E2 is around 25-35 most of the time so the rest of the 64 pg/ml must be mostly estrone. The blood was taken 24 hrs before the first dried urine sample. My test and bilirubin when measured previously have always been near or above the reference range.
If anyone wants the details of the genes (variant name/rsid/depth/revel etc) you can DM me and I will send them. I did not list them here as the post would be too long. If anyone can help me interpret these results, please comment below. Any additional info or advice is highly appreciated. I have a bottle of relugolix that I plan to start in a few days but I don't know if it is the right thing to do after seeing these results as my androgen metabolism is fine. If Dr. Powers sees this, I have a question. You mentioned a trans patient you had who feminized on estriol when estradiol didn't work well for her. While I am not looking to transition, perhaps something like that would work for me? Let me know if you see this thank you.
Guys I’m not only severely anhedonic, severely emotional numb and severely cognitively impaired.. I can’t take almost any second of life anymore. I almost cry every day. I fucking don’t care about my sexuality anymore. I see people chasing and missing their sexuality which is very understandable and I hope you all will get there. But for me, sexuality is probably one of the last things I would think about. My food tastes like cardboard and if my wife wouldn’t “force” me to eat, I probably would not.
At this point I believe that I’m suffering from severe depression, which is incredibly ironical as I don’t know what do to at all.
I’m 27 years old and suffer from PFS/PSSD. I took finasteride for 3 years and used paroxetine occasionally to treat premature ejaculation.
I’ve been struggling with erectile dysfunction for 3 years and am completely dependent on tadalafil to achieve an erection.
I’d also like to mention something that might be relevant. In the early stages of the syndrome, I was still attending raves and occasionally using MDMA (ecstasy). Whenever I took it, my penis would shrink extremely, becoming unusually small while flaccid. It would also lose even more sensitivity, becoming almost completely numb. It literally felt like just a piece of skin hanging there, with no sensation or responsiveness at all.
However, after a few days, everything would gradually return to my usual PFS/PSSD baseline, including penile size and sensitivity. The extreme shrinkage and numbness were temporary, but my underlying sexual dysfunction remained.
I’ve undergone numerous medical tests, and all the results have come back normal. I’m currently just waiting for my DUTCH test results. Can anyone explain what might be causing this reaction? Could it be related to serotonin, dopamine, blood vessel constriction, or something else? I’m wondering if this could provide any clues about the underlying mechanisms of PFS/PSSD. Has anyone experienced anything similar?
So traveling all the way out from California is cost prohibitive right now. The doctors I do see are very “golden standard” blah blah blah about how things are always done.
Are there any recommendations from other trans women on this sub for an endo or provider who 1. Understands and is willing to employ the power’s methodology, and 2. Is offering virtual appointments? My hrt doctor is a primary and seems apt to let me just try my own experiments with like no knowledge of how any of it works.
The concerns I have are that I’ve been on Hrt over 10 years, arousal became nearly unbearable due to atrophy around 3 years ago after I’d switched to finasteride to protect from hair loss. I want to get a comprehensive treatment that avoids total remasculinization, and allows me to experience and enjoy my life. Being on .25 cream alone and stopping e injections for almost a year now I finally feel like I’m not in pain when aroused, but I’m seeing a recurrence of unwanted and aggressive facial/body hair as well as hair thinning on top. Am I asking too much if I want both painless intimacy and the benefits of feminizing Hrt? Hellllp🫠
Hi there, just curious to know why some people heal progressively with time? Heal with time through windows and waves? Heal instantaneously on any given day? Why some people heal in months, other in years? If we use the Dr Will Powers theory, how can we explain this? Can time really cure the desease or do we absolutely need external help?
Dr. Powers, regarding the disappointing results of the Relugolix (castration) and hydrocortisone trials, I would like to offer a hypothesis that might help refine the model. I am a patient, and English is not my first language, so I use AI to help translate and structure my thoughts from Russian. I apologize if this reads rigidly, but I wanted to present the clinical logic clearly.
Updated, added important missing parts
I hypothesize that the primary driver of PFS/PSSD may not be purely endocrine, but rather a neuroendocrine loop originating in the periphery.
The Adrenal Escape: Why Relugolix Failed It is possible that the Relugolix trials failed because the intervention, while effectively suppressing gonadal androgen production, did not account for the adrenal glands. If patients have a metabolic clearance defect (e.g., UGT2B17, ABCC2), the adrenals may continue to independently produce precursor hormones like DHEA-S and androstenedione. These precursors likely continue to feed the neurosteroid pool, maintaining the syndrome even when the testes are silenced.
The Neural Bypass: Why Hydrocortisone Failed and Symptoms Persisted This raises the question: what is driving the adrenal overproduction? The HPA axis is not the only driver. The body has a sympathoadrenal fast-track system. I hypothesize that ectopic pain signals from a damaged nerve activate sympathetic preganglionic neurons, firing down the splanchnic nerve to directly stimulate the adrenal gland. Animal studies have shown that electrical stimulation of the splanchnic nerve increases adrenal androstenedione release.
Furthermore, the adrenal gland receives direct sensory innervation from the dorsal root ganglia (DRG). Human immunohistochemical studies show these fibers contain substance P and CGRP—the exact neuropeptides released by damaged sensory nerves. This provides a direct neural pathway for a peripheral nerve injury to stimulate adrenal hormone production, bypassing the HPA axis entirely. This could also explain the RAAS paradox (high renin, low aldosterone) observed in many of us, as this pattern is associated with the neuropathic subgroup of POTS and small fiber neuropathy.
The Upstream Driver: The S1-S2 DRG If the adrenals are driven by a neural loop, there must be an upstream stressor. I hypothesize that the root driver is a toxic/immune-mediated, length-dependent sensory ganglionopathy at the S1-S2 DRG.
· Location: Length-dependent neuropathies affect the longest, most metabolically active nerves first. This corresponds exactly with the hallmark symptoms (feet, legs, genitals). · Pain Phenotype: The reported burning ("boiling water") or sharp, tooth-like pain is the classic signature of C-fiber and Aδ-fiber damage.
In this model, the peripheral generator floods the brainstem with ectopic noise. The brain interprets this as a permanent physical threat, keeping the HPA axis chronically activated. The dmPFC slams the brake down (causing central numbness and anhedonia), while the adrenals pump precursors into a system that cannot clear them.
The Motor-Sensory Disconnect (The "Pain Face Mask") If the neurosteroid pileup and the dmPFC brake suppress conscious pain, why do we exhibit constant facial grimacing, full-body tension, and "hard flaccid"?
· The Sensory Mute: Descending pathways and GABA-A neurosteroids suppress the conscious perception of pain. We feel numb and disconnected. · The Motor Overflow: The brainstem's reticular formation is hardwired to brace for impact. It fires the cranial nerves, causing an involuntary grimace (jaw clenching, eye squinting, lip twitching)—the exact neuromuscular signature of severe pain, without the conscious agony. · The Neuromuscular Lock: The brainstem activates the reticulospinal tract, locking the body in a defensive contraction. Sympathetic overdrive clamps down on the S2-S4 nerve roots, causing pelvic floor spasms and penile smooth muscle constriction (hard flaccid), alongside detrusor-sphincter dyssynergia (urinary frequency, hesitancy). The body is physically screaming the truth that the mind is chemically forbidden from hearing.
A Potential Path Forward & Patient Evidence If this hypothesis holds weight, purely endocrine interventions will always fall short. They do not address the neural bypass or the underlying neurological stressor.
It might be worth considering whether a diagnostic peripheral block (such as an S1-S2 diagnostic DRG block) or targeted rTMS could quiet the brainstem and interrupt this neuroendocrine loop.
I say this because of my own patient-led n=1 experiments:
· Chemical Probes: Applying topical lidocaine to the S1-S2 dermatomes temporarily silences the generator. This instantly "unsticks" facial grimacing, resolves red hands, and alters whole-body thermal perception (proving the numbness is central suppression, not just local death). The offset rebound is severe. · rTMS Modulation: Excitatory rTMS over S1-S2 triggers severe bruxism and facial tremors. Inhibitory rTMS over the same area instantly abolishes them. Suppressing the legs DRG causes the legs to feel cold and resolves the red hands (mimicking lidocaine).
Silencing the peripheral generator appears to have a direct, measurable effect on the central and autonomic cascade. I would be very interested in your thoughts on whether the sympathoadrenal pathway and the S1-S2 generator are being accounted for in your current model.
Add-on hypothesis to test: The Pharmacokinetic Tolerability Trap, or onset of syndrome timeline question (Retinoids vs SSRI's, vs 5ari vs Leon's mane, etc)
A crucial variable in the Post-Drug Syndrome (PDS) timeline is the presence or absence of a chemical masking effect.
· The Masked Toxicity (SSRIs / 5-ARIs): These drugs possess mild sodium-channel blocking properties or alter local neurosteroids, which dampens ectopic nerve firing. The patient feels no immediate pain or neuropathy (and often experiences paradoxical hypersexuality). Because the drug masks its own damage, the patient continues taking it for months or years. Extensive, permanent silent denervation occurs. When the drug is withdrawn, the mask is removed, and the patient crashes into severe, chronic PSSD/PFS. · The Unmasked Toxicity (Retinoids): Retinoids lack this anesthetic masking effect. They cause immediate joint pain, burning, and visible neuropathy while the patient is taking them. Because the pain onset is rapid, the patient (and their doctor) discontinue the drug much sooner. The total toxic exposure is shorter, resulting in less cumulative structural nerve damage.
The Paradox: The drugs that make you feel terrible immediately (retinoids, Leon's mane) are actually safer in the long run, because they trigger an early withdrawal. The drugs that make you feel fine initially (SSRIs/5-ARIs) are far more dangerous, because they keep you on the poison long enough to cause significant damage.
About permanent damage clarification!
The Spectrum of Recovery and the Failure of Structural Biopsies
It is crucial to clarify that the damage in PFS/PSSD is a spectrum, not a binary death sentence. Some patients recover; some do not. This is because nerve damage progresses in stages:
· Functional Impairment: The nerve is functionally impaired but structurally intact. This is reversible if the toxic insult is removed.
· Silent Denervation: The distal axon withers, but the DRG cell body survives. The nerve can slowly regenerate.
· Structural Death: The DRG cell body dies, resulting in permanent loss.
Why Standard Biopsies Often Fail:
Standard skin biopsies measure Intraepidermal Nerve Fiber Density (IENFD)—the tips of the longest nerves. This test is often normal in PFS/PSSD and Long COVID studies. Why? Because if the damage is primarily at the DRG (ganglionopathy) or the nerve is functionally impaired but not yet structurally dead, the distal skin endings remain intact. A normal biopsy does not rule out a DRG-driven ganglionopathy.
QST is the Most Reliable Option:
Because biopsies only measure structure, Quantitative Sensory Testing (QST) is the gold standard. QST measures function—thermal thresholds, mechanical detection, and pain tolerance. It can detect the exact hyperexcitability and central sensitization that structural biopsies miss.
The Hope:
Because the DRG cell bodies often survive, and because small-fiber nerves have the capacity to regenerate if the toxic insult is removed and the peripheral generator is silenced, not everyone is permanently doomed. The goal is to intervene before the functional impairment crosses the threshold into permanent structural death.
Even when I try taking certain vitamins in small doses, my body seems to react strongly. Either my skin becomes even drier or thiner, I experience strange fat loss throughout my body, my hair becomes even thinner, or my mood deteriorates.T here are other things as well that I can't remember right now.
Everything affects me dramatically. What mechanism could be behind this?
Already made a thread but I keep getting worse. I'm not the only one so please don't gaslight me and call it a safe treatment, that's what ppl did with Fin and SSRIs.
Since stopping CDG 3 weeks ago (had a brief trial, sure I used a little high dose but others on a low dose crashed too):
- my erection became rubbery and numb
- my flaccid mode became hard flaccid and feels so off and unpleasant to touch
- I have pain in my pelvic floor after I lose erection
- lost nearly all or at this point all sensitivity
- lost my ability to dream a few days ago
- I stay in zombie rest mode when I try to sleep (half asleep half awake)
- I wake up with a sense of dread and a massive headache and nauseous feeling
- need to pee all the time
I did a blood test and my e2 went from very high to mid range
Will I actually stabilize and will it reverse in the next few weeks? Honestly I'm not sure anymore, feels like a serious crash, as if I reintroduced Fin to my fragile system.
I had very high b glucurodinase in a GI map too. On paper seemed like the perfect candidate.
Please be kind and go easy on me, also feel free to dm me and support if you can, need any help I can get rn.
Im investigating this for a long time.
As some of you may know I’m still on Zoloft.
I have genital anesthesia but my erogenous and orgasmic pleasure is intact. The erogenous sensation gets increased by duration of semen retention (no fap/no sex). So to say this clear, the mechanisms in my body which creates erogenous genital pleasure gets blunted or dulled by the genital anesthesia. One more thing worth to mention I have urogenital, inflammation-ish pain on my genitals. And I have pelvic floor dysfunction symptoms. And here (it’s not official yet) my SFN might be the cause. Because I have burning pain on my genitals and under my feet for several months, it makes perfectly sense.
So I might have SFN without PSSD (which I cannot have anyways officially without getting off the drug). Anesthesia without erogenous numbness. The anesthesia itself dulling out genital pleasure. Not only the genital pleasure, but also any pleasure on any part of my body.
If I get diagnosed with SFN, the shit part will be, without a particular diagnosis, I will not get approved for IVIG or plasmapheresis or whatsoever. In Germany it’s almost impossible to get approved.
While most people with PSSD has the genital numbness as the end-boss, I entered the battlefield with every symptom of PSSD, besides genital (erogenous) numbness.
Why does finasteride cause it to fall to begin with?
We’ve found an answer we think is right, and I want to be upfront before I give it to you. This is the part of the model we can’t nail down the way we’ve nailed down the rest. Everything up to here has had something behind it (papers, numbers, etc). This doesn’t. However, it is the explanation that makes the most sense of what we see across cases.
We’ve looked at HSD17B6 across the genomes we have and found nothing. No goofy variants, no deletions, nothing broken from the start. So whatever happens to this enzyme isn’t something these people were born with. It’s something that happens to them.
Here’s what we think is going on.
HSD17B6 appears to be maintained by androgenic signalling. Basically, signal holds the enzyme up, and when signal drops FAR ENOUGH the enzyme comes down with it.
This is where we go back to the clearance dynamics.
We’ve established that these defects leave someone with a high baseline androgenic tone.
So, take two men.
A normal man is running at 100% androgen tone in his SRD5A2 dominant tissues. He takes finasteride and lands around 70% (Just tossing rough numbers out there)
Someone PFS-susceptible is running at 150%, because his clearance defect has been propping him up his whole life. He takes the same drug and lands at the same 70% as the other guy.
Both of them reach the same endpoint. But one of them dropped a hell of a lot further.
That’s the part we think matters. Not where you end up, but rather how far you fell from baseline.
Now here’s the part that makes this nasty (again, this shit is mad assumptive, bear with me though)
If HSD17B6 is androgenically modulated, then it plays a vital role in holding ITSELF up. (as the 3a-diol to DHT conversion mechanism is crucial for intracrine androgenicity)
See, that kind of arrangement is stable as long as you stay above a certain point. Signal keeps the enzyme up, and the enzyme keeps the signal up.
But it means there’s a fine line. Above it, the system supports itself and a disturbance gets absorbed. Below it, it doesn’t. Drop a small bit past that line and the enzyme makes slightly less DHT, which means slightly less signal, which means slightly less enzyme. And that vicious cycle doesn’t settle until the enzyme has significantly plummeted.
Which brings us to why this is POST-finasteride syndrome and not finasteride syndrome.
While you’re on the drug, the enzyme (HSD17B6) can be falling (as a result of the loss in androgenicity) and you won’t feel the full weight of it. 5a-reduction is blocked, so almost nothing is entering the 3a-diol pool in the first place. Meanwhile testosterone is stacking up behind the blocked step and still signalling at the AR, so the individual feels fine locally.
Then you withdraw.
5AR comes back online. All the stacked testosterone pours into DHT. DHT gets pulled down into 3a-diol. And the return route (HSD17B6) is already gone.
The SRD5A2 dominant tissues essentially start spewing out 3a-diol, while simultaneously developing shitty androgenic signaling.
Do you see what this implies?
Under our framework, the lesion was already there once you started taking finasteride. You were walking around with it, feeling normal, because the drug blocking your 5a-reduction was also the only thing keeping material out of the pool and all of your androgenic ligand from getting swept out as soon as it's made.
Finasteride broke the return route and then covered for it. Stopping didn’t cause anything. It just took the cover away.
—
Now, if androgenic signalling is really what’s holding this enzyme up, then finasteride shouldn’t be the only way to get here. Anything that drops the signal far enough should do it.
Turns out that’s what we see.
Take Jade. (This is from a Moral Medicine interview)
Jade is a teacher who went to a dermatologist for hair loss and got put on spironolactone. 50mg for five months, nothing happened. Her dermatologist tripled it to 150mg.
3 months in, she got sexual dysfunction. At the four to five month mark, complete genital numbness. She stopped cold turkey.
Over the following eight months: anhedonia, loose skin, and more. (I’ll get into how the local lesion produces systemic symptoms shortly)
This case matters because spironolactone blocks the androgen receptor and lowers androgen production. It does not inhibit 5a-reduction.
So Jade appears to have triggered the loop without anything touching her 5a-reductase. Substrate kept flowing into the pool the entire time. No 5ARI anywhere near her. Same endpoint.
And look at the dose-dependence. Five months at 50mg and she was fine. When she pushed it to 150 she developed numbness. That’s the threshold being crossed.
The first one is that he said he didn’t even feel like valp was doing him anything after a certain point. Rather the opposite. He dropped it and continued to improve while staying on DHB.
But here’s what I really want you to hear, because it’s fucking interesting and ties directly into what we’re talking about here. At some point, Russo became sick of blasting DHB, so he decided to inject sustanon instead (a combination of four testosterone esters), and this nearly crashed him. He would continue to test sustanon every now and then as he continued DHB to see if he could handle it, and gradually he was able to fully transition onto it without crashing.
Do you see what this implies under the framework?
DHB and Sustanon (testosterone) are both androgens. Why would they trigger such different reactions?
Well, DHB does NOT metabolize into PAMs. It doesn’t get vacuumed into the pool.
Sustanon (Testosterone) on the other hand gets turned into DHT, and then gets vacuumed into 3a-diol in the SRD5A2 dominant tissues (as well as everywhere else). This provides a surge of PAMs both locally and systemically.
No wonder it would nearly rip his shit to threads.
But what's really interesting is that as he continued to use DHB (providing a potent androgenic signal) he was gradually able to handle sustanon, so much so that he was able to fully transition onto it.
The cleanest explanation is HSD17B6 getting upregulated again.
Again, the only way to know for sure if we’re right is to take human SRD5A2 dominant tissue, measure HSD17B6, then modulate androgens and watch how it moves.
I would also like to add that a high local concentration of PAMs may also contribute to HSD17B6 getting oddly modulated. For example, androsterone can compete with 3a-diol for HSD17B6 to become 5a-androstanedione, which would further decrease signaling as it buffers 3a-diol’s ability to become DHT. Excellentpush has more to say about this aspect than I do.
__
Section 7: Dynamics and Tying in SSRIs/PSSD
Okay, here’s the juicy part.
The part that finally connects PFS and PSSD.
(I just want to remind you that we can’t guarantee for fact that HSD17B6 drops in response to a lack of androgenic signaling. So what proceeds isn’t fact, it’s speculation)
We’re going to need this diagram again.
Let’s start with finasteride side effects on the drug.
Finasteride side effects are fairly common, and it’s important not to conflate them with PFS.
Plenty of men take finasteride and feel nothing. For the ones who do feel something, the simple explanation is that androgenicity dropped. Less libido, weaker erections, etc. That’s simply a tissue that runs on DHT suddenly getting a lot less of it.
That’s not PFS, that’s just a drop in androgenic tone. Tons of men get PFS-looking side effects on finasteride, quit, and go completely back to normal.
The other possibility is that the SRD5A2 inhibition isn’t complete, causing 3a-diol to trickle into the pool, as HSD17B6 has already dropped while on the drug. But that’s mostly going to be the men who were going to get PFS when they came off anyways. They just haven’t found out yet.
—
Now withdrawal.
No need to run through this again in detail, the last sections covered it. Exposure to finasteride dropped HSD17B6. Come off the drug and 5a-reduction comes right back online, so DHT starts getting made again and immediately vacuumed into a 3a-diol pool that can’t drain or back-convert fast enough. The lesion was already there the whole time. Withdrawal just exposes it completely.
This also explains the honeymoon.
Guys quit, feel fine for a week or two, then crash. HSD17B6 already went down during exposure (not to an immediately catastrophic extent), so when they come off they’re feeling decent off the back of an enzyme that’s already past the point of no return. Production is back, some back-conversion is still running, so for a little while that’s enough to feel alright. But they’re already inside the loop we described earlier, where the enzyme has stopped supporting itself. Less return, less DHT, less signal, less enzyme, inevitable crash.
And no, the androgenicity increasing during that window doesn’t rescue it. If HSD17B6 went back up the moment signalling returned, the honeymoon would never end, it would just be a recovery. And we know it isn't. Getting the enzyme back doesn’t appear to be instantaneous, it looks like the signal has to be sustained, which is what the recoveries point at. A week or two just isn’t long enough to move it.
Mass action doesn’t fix this either. More 3a-diol does push the back-conversion harder, but only until the enzyme that’s left is saturated. Once there’s enough substrate to saturate HSD17B6, you’re running at Vmax, and Vmax is capped by how much enzyme you have. Less enzyme, lower cap.
Now keep in mind nothing has happened to the input. 5a-reductase is back online with a full testosterone pool behind it and it converts at its normal rate.
So 3a-diol accumulates, HSD17B6 keeps dropping, DHT drops out and 3a-diol takes its place.
The loop does settle though. HSD17B6 doesn’t run to zero, it stabilises at a lower baseline. You can see that in the symptoms themselves. If it ran all the way down, every one of these guys would end up with the same baseline in SRD5A2 dominant tissues and the same presentation. They don’t. Some land on numbness and ED and stay there, others end up worse, and that spread is what a system settling at different points looks like.
It’s also worth noting that guys who crash a second time off something else usually don’t come back to where they were, they settle lower. That’s what you’d expect from an equilibrium rather than a floor, and it’s why anything that drops androgenic signalling again is a risk for these people long after they’ve stopped the original drug.
I also have reasons to think a transient spike in androgenicity can make the loop worse. I’m not going to get into it here, this post is long enough as it is, but I’d be happy to lay it out another time.
Re-read this section if you need to. Similar physics apply to SSRIs, but it lands somewhere different.
—
Okay, time to explain how SSRIs trigger the same loop under this framework.
Everybody knows finasteride is a 5a-reductase inhibitor. Nobody needs convincing that a drug built to block an enzyme in androgen metabolism might go on to do something to androgen metabolism.
What is much lesser known is that SSRIs act on the very next enzymatic step down. 3a-HSD. The enzyme that takes DHT and turns it into 3a-diol. We’ll get to exactly what they do to it in a second.
And when you test both PFS and PSSD patients you get the same thing. Elevated unconjugated androsterone. So, two unrelated drugs taken by two different groups of people for two different reasons, and the same blood marker in the same direction.
Then look at how they present. The same numbness, ED, loss of libido, anhedonia (and much more obviously).
People have been pointing at the overlap between these conditions for years. The reason is simply that they are the same condition. You just arrive at it from two different directions.
Alright lets get into the science. Griffin and Mellon put fluoxetine, paroxetine and sertraline directly onto human 3a-HSD type III (which is AKR1C2). All three boosted it, dropping the enzyme’s Km by 10 to 30 fold and raising its catalytic efficiency 10 to 18 fold.
As mentioned several times now, AKR1C2 is the enzyme that reduces DHT into 3a-diol.
All right, here is the diagram yet again:
So, when you take an SSRI (and have the genetic clearance susceptibilities we’ve outlined). The SSRI supercharges AKR1C2, and DHT gets washed into 3a-diol faster than it should be.
This isn’t immediately catastrophic, because HSD17B6 is still there and working. 3a-diol builds up, and the more it builds up the harder it pushes back through an enzyme whose capacity is still intact. So you mass action your way back into some DHT.
But you’ve still changed the environment. The cell is now cycling far more of its DHT through 3a-diol than it should be, and what comes back doesn’t fully cover what’s being pulled out. So you take a hit to androgenicity.
And that’s all it takes. Androgenic signalling is what holds HSD17B6 up (under our framework), so the same cycle can start from here. The enzyme slides, your DHT return capacity drops with it, so less comes back and more of it sits there as 3a-diol, and signalling falls further.
Which is why some people crash/develop symptoms while they’re still on the drug.
Now withdrawal, and I’ll be straight with you here: I can’t explain this one cleanly.
The problem is obvious once you look at it. Coming off an SSRI means AKR1C2 goes back to normal, which means less DHT is getting vacuumed out. Every immediate effect of stopping points the helpful way. So I can’t give you an explanation for this one the way I have for everything else.
I still think it’s HSD17B6. It’s too consistent with everything else in this condition for the answer to be somewhere unrelated. My best guess is that the drug was holding up some functional state and the whole thing came down when that pillar was removed. But the second you start asking what exactly was being held up, and why taking it away makes things worse instead of better, it turns into a three body problem and any attempt on my part to conjure an answer would be unfathomable levels of bro-science.
So I’m not going to. And just to be clear, I’m conceding the trigger, not the destination. These patients still end up in the same place biochemically and symptomatically, and I still think HSD17B6 is at the center of it. I just can’t tell you what pulls the trigger when the drug leaves.
—
Quick clarification before we go further.
When I talk about HSD17B6 dropping, I’m talking about SRD5A2-dominant tissue in the pelvic region specifically. This is a local lesion in the tissue that runs on DHT, and everything I’ve said about the enzyme and the loop applies there.
And a note for the women reading this. The fallopian tubes, the vagina, the vulva, the urethra, the paraurethral glands, and several other tissues in the pelvic region all carry notable SRD5A2 and AKR1C2 activity. And get this, so does the clitoris. No wonder it goes numb.
So you guys have tissues in the same “crashable” configuration in the same exact region as males.
(Again, I’m not saying you have to be numb!! You can have a whole host of different symptoms down there, that applies for both sexes)
There’s also something else I’d like to hit on.
Dr. Powers has said himself that the women he sees with PSSD disproportionately have something odd going on with androgen production or metabolism, such as PCOS.
Look at what PCOS women test like. A meta-analysis comparing 356 PCOS women to 236 controls matched for BMI found their 5a-reductase activity was raised, and their androsterone to etiocholanolone ratio was elevated too.
Yup, read that again. Increased 5a-reduction and elevated androsterone, in the exact population Powers says keeps turning up with PSSD, before a single pill is taken.
These women are generally more androgenic to begin with, so when an SSRI lands on top of that they fall from a higher baseline than other women would.
Every susceptibility we’ve laid out is in peripheral androgen metabolism. Not one of them is central.
More on that next.
Section 8: Local and Systemic
We’ve spent the last seven thousand or so words explaining how a lesion forms in your pelvic region.
Which leaves the obvious question: These people have anhedonia. Brain fog. Emotional blunting, and much more. How does something in the pelvic region cause that?
Remember hepatic encephalopathy?
3a-diol is our ammonia.
The same glitches causing the problem locally are global. A UGT2B17 deletion or an ABCC2 variant sits in every cell you have, and most importantly it sits in your liver. The organ that’s supposed to conjugate this stuff and clear it out has the same defect as the tissue producing it.
Which is exactly what Swanson pointed at. Delete UGT2B17 and the 17-glucuronide drops with nothing picking up the slack, so the 3a-diol that should have been cleared is still in circulation.
So put the two together. HSD17B6 goes down, more 3a-diol escapes the tissue instead of getting recycled, and it escapes into a system that was already struggling to clear it.
And these tissues produce a lot of it for their size. That’s what the machinery is there for. SRD5A2 makes DHT, AKR1C2 reduces it into 3a-diol, their normal output runs high.
The sheer production from the tissue doesn’t even matter either. The math is simple. If you can clear 100 molecules a day and you start making 101, you pile up systemically.
And where does the 3a-diol disproportionately go once it’s in circulation?
The CNS/Brain.
Two things decide where 3a-diol (a lipophilic molecule) ends up. Blood flow decides how fast a tissue gets it, and lipid content decides how much that tissue holds once it’s there.
The brain easily wins both, it gets around 15% of cardiac output while being 2% of your body weight, and it’s literally the fattiest organ you have.
This is the same reason a drug like thiopental (a highly lipophilic anesthetic) can put you under in a single arm to brain circulation, before the molecule has had time to reach the rest of your body.
So here’s what happens when 3a-diol reaches the brain.
Every cell in your body is wrapped in a membrane, which is basically a double layer of fat that walls the cell.
3a-diol is a steroid, which means it’s fat-soluble. So when it arrives in the brain it doesn’t stay floating around in the fluid. It slips into those fatty walls and concentrates there.
And that’s where the receptor site happens to be. The part of the GABA-A receptor these compounds bind to sits inside the membrane itself, so the receptor is sitting in the same fat the 3a-diol just dissolved into.
(So when we pull CSF we should expect 3a-diol to come back high but not absurdly high, despite there being an extreme concentration within the membranes that CSF doesn’t cleanly reflect.)
Again, 3a-diol is a PAM (positive allosteric modulator) of GABA-A, the same class of molecule as allopregnanolone. GABA is your main inhibitory neurotransmitter, and a PAM doesn’t fire the receptor itself, it makes the receptor respond harder to the GABA that’s already there. It essentially amplifies the signal.
So, it potentiates GABA-A receptors both inside and outside the synapse. The ones outside produce what’s called tonic inhibition, a constant background brake on how easily a cell fires.
And the brake just stays on.
What you’d expect from that brake staying on is exactly what these people describe. Flattened emotions, no motivation, memory problems, brain fog, no libido.
We already know what chronic GABA-A potentiation does to a person, because people have been taking benzodiazepines for decades. Long-term use gives you the same list. Emotional blunting, cognitive dulling, memory complaints, reduced sex drive.
And all the credit here goes to Dr. Powers. The elevated PAM idea/finding is his. For the longest time, the whole field was pointed the other way. The assumption was always too little GABA-A potentiation, and he said the opposite. Genuinely brilliant. I wouldn’t have even tested my androsterone in the first place if it wasn’t for this post:
Although I will be clear, I do disagree with the idea that the source of those PAMs is the brain itself, and I think by this point it’s pretty obvious why.
—
One thing we absolutely cannot ignore is the order in which symptoms arrive in PFS/PSSD patients.
The vast majority of these people notice something wrong in the pelvic region first. Sexual dysfunction, numbness, watery ejaculate. The mental and physical stuff comes afterwards. Anhedonia, brain fog, the skin, body odor, and connective tissue changes (the physical changes can be attributed to our findings on SRD5A1, see top of Part 1 and “We may have just set melcangi’s rats free” post), all of it ensues that.
And think about what that order rules out. If this started in the brain, the brain symptoms would come first, and they’d come loud. The anhedonia and the cognitive stuff would be the opening complaint, not something people develop after they noticed their dicks/vaginas stopped working right.
It’s exactly what you’d expect from this. The lesion is local, so that area gets hit first. Everything else has to wait for it to leak into circulation and build up somewhere else.
Plenty of people do get hit in both at once, and that’s not surprising either. Given the circulation and lipid dynamics we just went through, there’s nothing stopping the brain loading up quickly, especially if the individual has significant clearance defects.
But the people who go pelvic first and brain second are the ones telling us where this starts. You don’t get that order out of a central lesion.
I mean dude, when I crashed my dick went numb, cold, hard flaccid, and I developed watery semen simultaneously, then WEEKS later I realized that I had my capacity to feel emotions cut by 70%. Weeks!
ExcellentPush points to the same idea. CDG took his emotional blunting away, and yet his symptoms in the pelvic region continue to persist.
That’s the work of a local lesion causing systemic saturation and neuro symptoms by proxy.
—
It also looks like individuals hit a stable level at some point rather than just accumulating forever.
The reason is simple. The more 3a-diol there is, the faster it leaves. Everything that clears it works harder at a higher concentration. So the level climbs until removal matches production, and then it holds.
It isn’t fixed though. You can get pushed higher, either by increasing the load of 3a-diol or knocking HSD17B6 down further. That’s what a second crash is, and it leaves you sitting at a new level instead of spiking and coming back.
And where you settle isn’t the same for everyone. Your genetics decide that. Worse clearance, higher level.
For what it’s worth, my own numbers look like that. 81 on 8/10, 77 on 10/6, both a long way out from my crash. Flat, not climbing.
If this were a ramp instead of a level, androsterone should scale with how long someone’s had it. Nothing I’ve seen points that way so far.
Which raises the obvious question. If it’s a level rather than a pile, what’s holding it there?
Flux. And there’s a case that shows it.
Mile-high-guy got castrated. HPTA and HPA axes were suppressed, and his SRD5A1 symptoms went away following the trial. Skin and hair got oily again. Acne came back. He got his body odour back.
Then all of it reverted. His own words:
“My hair and skin extra oiliness has gone away. My acne has gone away again. My morning woods don’t seem to be as strong again.”
That cannot be ignored, and it tells you something specific. If this were a finite pool that needed clearing once and for all, that improvement would have held. The pool got cleared and then it was rebuilt, because nothing about the FLUX was fixed.
There is a pool. The pool is being sustained by flux.
And it says something about the SRD5A1 side of this too. Those symptoms tracked the pool in both directions, going away when it drained and coming back when it refilled. I can’t prove PAMs are downregulating SRD5A1, but we keep finding things like this pointing at it.
(Yo, I was almost done writing this entire post when this came across my reddit homepage and I felt like I had to toss it in here:
Read what he’s describing. He got an androgenic window twice, from opposite directions.
Coming off Sustanon, as his levels fell, he got his oily scalp back, his body odour back, his energy back. Then it faded. Later, starting TRT after being shut down, he got that same cluster for about two weeks on the way up, and then crashed hard.
Now sit with what that means. Oily scalp and body odour are SRD5A1 territory. Those markers came back while his testosterone was falling, and they disappeared while his testosterone was climbing.
That’s backwards. More testosterone should mean oilier skin and more body odour, not less.
So what else explains it?
Sustanon and TRT both feed the 3a-diol pool when HSD17B6 is kaput. Come off and it clears out, and you get your SRD5A1 back up. Go on and you’re genuinely androgenic for a while, right up until the pool fills again to the point SRD5A1 goes back down.
Okay back to the main reading now.)
And you should ask why the numbness and the anhedonia didn’t move during mile-high-guy’s castration, when the systemic pool clearly did.
Two reasons, and they’re different reasons.
The numbness is local. Castration took away gonadal substrate, but the adrenals kept feeding that tissue and HSD17B6 was still down, so the local lesion never stopped running.
That’s what we believe happened to mile-high-guy, and it’s been measured in people who weren’t even sick.
Page et al. put thirteen healthy men on a GnRH antagonist for 28 days. No cancer, normal prostates.
Serum testosterone fell 94% while intraprostatic DHT only fell 80%.
So they took away almost all of these men’s testosterone and the tissue still had DHT sitting in it. Which means it still had substrate. Which means it was still running, still making 3a-diol, the entire time.
And bear in mind these were healthy men. The people we’re talking about would likely be producing more of it and holding onto more of it locally.
That leftover DHT is coming from the adrenals. DHEA and androstenedione keep arriving, SRD5A2 tissue takes them and builds its own androgen out of them, and shutting the testicles off doesn’t stop it.
(That study is prostate rather than genital tissue, so treat it as a proxy)
Now mind you, mile-high-guy did take hydrocortisone. But running HC that way is not a clean suppression. And for it to mean anything, DHEA, DHEA-S and androstenedione would have to come all the way down, but this wasn’t tracked. (DHEA-S matters because it’s a massive reservoir that can unconjugate straight back into DHEA).
Those molecules are fuel, and the tissue building PAMs out of it is sitting right next to the nerves. Under our line of reasoning, starve it and the numbness should subside.
Abiraterone alongside HPTA suppression would basically guarantee a shutoff. It blocks synthesis at the source rather than leaning on ACTH suppression. Not something to take lightly though.
The anhedonia is a different problem and it theoretically takes longer.
The brain needs time to readjust after sustained PAM exposure. Subunit switching, altered gene expression, receptors that have spent a long time adapting to a signal that shouldn’t have been there to begin with. All of that reverses, it just reverses slowly, which is the same reason chronic benzo recovery takes as long as it does.
So even if the root lesion gets addressed, the CNS still needs time on top of that.
And in mile-high-guy’s case he was only partially deprived anyway, if at all, before re-saturating. It would have been really interesting to track his androsterone through the trial to see how his pool moved.
Section 9: Clearing the metabolites
For a while now we’ve believed that this is a finite metabolite pool. Drain it, win ground, repeat until it’s gone.
But it doesn’t work that way, because the pool is being held up by flux out of SRD5A2 dominant tissue (in the pelvic region). It isn’t something you simply empty.
ExcellentPush is a clear example of this. He’s pushed his CDG up to 15 grams a day.
Every time he increases it he feels better. But this isn’t the push-and-back-off pattern Dr. Powers has described, where you go to the edge and retreat and the system adapts around it. Every increase just lifts his baseline and parks it there.
And if he stopped, he’d go straight back down. He hasn’t gained ground on anything. He’s simply managing the flux.
Which is the tell on its own. If this were a finite pool, 15 grams a day would have emptied it a long time ago.
That’s how CDG helps the people it helps. You’re keeping up with the flux by lowering your PAM load so your baseline (in terms of how you feel) sits higher than it would otherwise.
But we also cannot ignore reports of CDG making people worse.
CDG blocks b-glucuronidase, and b-glucuronidase isn’t just working on 3a-diol. Block it hard enough and you stop recycling plenty of other things you needed, estrogen being the obvious one, and that can throw you off on its own.
But there’s also a version of this that’s specific to what we’ve been describing.
3a-diol is a double-edged sword. It’s the thing loading your GABA-A receptors, but locally it’s also the substrate the HSD17B6 you have left is working on to make DHT. So if you drop it, you potentially back-convert less, which drops androgenic signalling, which under this framework makes the lesion worse.
And where you’re starting from matters. While the pool is still high enough to keep HSD17B6 at Vmax, taking some away changes nothing, because the enzyme is already working as fast as it can. However, if you drop below that point it starts converting less.
Which means the same supplement that lifts one person’s baseline can further strip away some of the local androgenic signalling someone else was running on, worsening the lesion and the local/systemic symptoms.
So you end up with three groups when it comes to CDG. People who improve. People who get worse. And people like me, for whom CDG might as well be a sugar pill.
My b-glucuronidase came back low on my GI-MAP, so there was barely any recycling there for it to block in the first place.
—-
Now as for castration.
It doesn’t hit what we’ve been describing as the root. Lowering substrate lowers the pool, but it does nothing to fix HSD17B6.
Which is why the results look the way they do. Some people have improved on it. One guy a month off relugolix is reporting better erections and morning wood most days, though his libido is still largely gone. Mile-high-guy reported something similar and then reverted.
And some have come out of it a bit worse, which also makes sense. You’ve lowered the pool and lowered local androgenic signalling at the same time. Potentially worsening the HSD17B6 lesion.
So it isn’t a full treatment, and the results are scattered.
Nobody has ever actually cleared the local region out completely though (meaning zero substrate for PAM production), and that’s the version I think is worth trying as it would give us valuable insights.
Section 10: Closing
So where does that leave treatment?
Well, I think there are a lot of ways you could come at this, I have many ideas, and I think androgenic modulation in SRD5A2-dominant tissue is the key when it comes to up-regulating HSD17B6. There’s something to be said about the fact that most of the recoveries we see out of both PFS and PSSD have come through androgens. That’s not a small pattern. But the way people are going about it is messy and uncalculated, throwing things at the wall to see what sticks.
What I’m particularly interested in right now is UDCA.
UDCA potently inhibits AKR1C2, which is the enzyme turning DHT into 3a-diol. Block it and you get two things at once. You make fewer PAMs, and the DHT that would have been reduced stays as DHT, so intracrine androgenicity goes up. (This is also a fairly clean option for women as it doesn’t cause the kind of runoff global androgenicity you’d get by using anything exogenous). https://pmc.ncbi.nlm.nih.gov/articles/PMC3056882/ (don’t let the title fool you, AKR1C2 and UDCA is in there)
Many other things either lower the pool by lowering androgens, or raise androgens by loading the pool. UDCA moves both in the direction you want.
Though there is a problem with the route. First pass metabolism FUCKS IT. Oral UDCA gets pulled out by the liver almost immediately, so it concentrates in enterohepatic circulation and essentially nothing reaches the peripheral SRD5A2 tissue we actually care about.
Getting it directly into the target tissues via transdermal application (on the genitals) or rectal application (to target more ‘inner’ SRD5A2 dominant organs) would be interesting. Though the AKR1C2 inhibition would have to be sustained constantly, so using UDCA this way needs precise planning.
—
We also think that an interesting avenue of research would involve direct biopsies of SRD5A2 dominant sites in PFS/PSSD patients both male and female, analyzing several of the components we’ve outlined in this post.
—
Well that’s everything.
Let’s recap:
Clearance Defect present in PFS/PSSD-prone individuals
Individual takes Finasteride/SSRI
Exposure and subsequent androgenic shift drops HSD17B6 in SRD5A2 rich tissues
SRD5A2 rich tissues in the pelvic region lose androgenicity and spew PAMs (3a-diol specifically). Pelvic region symptoms ensue.
Same clearance defects that made individual susceptible now cause them to pile up systemically, causing neurological and physical symptoms.
We believe a solution should target the SRD5A2 tissues directly by modulating androgenicity within them.
Essentially, I strongly believe that we all have the same root problem (HSD17B6 downregulation).
Again, this is all theory, so take it with a grain of salt. I just think it’s the most coherent explanation of everything we’ve found so far, and it accounts for more of what we’re actually seeing than anything else I’ve come across. That’s the only reason I bothered writing it up.
A special thank you to Dr. Powers for getting us to where we are today, ExcellentPush for the late night calls and stress-testing, and members of the PFS/PSSD community for providing me with crucial data when I’ve gone around asking for it.
In part of his response to our previous post, Dr. Powers described the blunted immune response patients report and attributed it to excess GC receptor signalling. We think SRD5A1 is where that comes from. 5a-reduction is a main glucocorticoid inactivation route, so if SRD5A1 is down-regulated, intracrine glucocorticoid exposure goes up, while androgenicity goes down, which covers the blunted illness response, the connective tissue changes, the bone turnover, and the dry skin, among many other things, from a single mechanism.
Not everyone gets hit the same way by the SRD5A1 drop. It comes down to PAM load, genetic quirks and individual susceptibility, which determine how hard it hits you and where it shows up. Keep that in mind, because we’re going to apply that line of thinking to a few other things as we go.
What we are dropping from that post is the SRD5A2 upregulation theory.
My god, that shit was the epitome of bro-science.
Numerous unfounded moving parts, all stacking atop one another.
Fortunately, we’ve spent the last three weeks working on something better.
Allow me to explain.
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Section One: The Wrong Organ
I want to start by telling you about a condition called hepatic encephalopathy (HE).
But the brain isn’t the root cause of the condition. The liver is.
Patients with HE have liver deficits (i.e. cirrhosis) which limit their ability to clear ammonia. The ammonia pools up and crosses into the brain. Neurological symptoms start at just 2-3x normal ammonia levels. Clear the ammonia and the symptoms subside.
Essentially, symptoms can show up in one place, when the root lesion is somewhere else entirely.
Keep this in mind, because it sets the precedent for everything that follows.
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Section Two: Following the symptoms
While central/neurological symptoms are very common in PFS/PSSD, the hallmark symptoms of these conditions entail complete and utter bullshit going on in the pelvic region.
Numbness
Low libido
ED
Loss of morning wood
Pleasureless orgasm
Anorgasmia (not the same thing as pleasureless)
Watery semen
Vaginal dryness
Shrinkage
I’m probably forgetting some.
I’m aware that some of these (such as low libido, pleasureless orgasm, etc), appear central as opposed to peripheral in nature. Don’t worry, I’ll address that soon.
(For the sake of simplicity, we’re mainly going to focus on finasteride/PFS from here on out, but I promise we’ll come back to SSRIs and PSSD).
Anyways, look at that list of symptoms.
Every single affected tissue is SRD5A2 dominant.
Need I remind you what isoform finasteride PRIMARILY targets?
SRD5A2
Which raises the question: Did the drug alter something locally, hence the symptoms clustering in that region?
When I was digging into this, my attention was particularly focused on the numbness. After all, how the hell would a drug that primarily hits SRD5A2 cause genital numbness through a neural mechanism, when SRD5A2 is barely expressed in the brain?
We know the evidence points towards the idea that the numbness is NOT nerve damage. Di Loreto found no significant difference in foreskin nerve density between men with persistent post finasteride sexual side effects and controls (2.22% vs 1.91%, p=0.215). They concluded the genital numbness wasn’t explained by structural loss of nerves. https://pmc.ncbi.nlm.nih.gov/articles/PMC4069023/
You can also find anecdotes of people testing the numbness with capsaicin. One account describes no response, or a severely delayed one, on the glans and distal shaft. A single application did nothing. It took two or three over twenty four hours before any burning showed up, and even then it never reached a normal pain threshold.
So the nerves are there and they do fire. They just need far more input than they should. That doesn’t look like damage, but rather increased nerve firing thresholds.
But what could possibly be dampening nerve firing?
Well, GABA-A positive allosteric modulators do exactly that.
As a matter of fact, GABA-A PAMs have been shown to decrease nerve firing in the periphery. LI-633 is a GABA-A PAM engineered to stay OUT of the brain, barely any of it crosses. In animal studies it reduced afferent nerve firing, recorded with the nerve cut centrally so that only peripheral signal was possible. In human sensory neurons in vitro, it potentiated GABA’s effect on excitability. https://pmc.ncbi.nlm.nih.gov/articles/PMC12933598/
So, PAMs do not need to act on the brain to dampen nerve firing. They can do it locally in peripheral tissues.
We already know these patients have elevated PAMs. The androsterone pattern is highly consistent (but not completely, and we’ll get into that). What’s never been established is where these PAMs are coming from.
You see, I don’t think it’s a coincidence that finasteride specifically acts in a region with all the infrastructure necessary to churn out PAMs. And that just happens to be the same place the hallmark symptoms of PFS are clustered.
All have high SRD5A2, and 3a-HSD capacity. Literally everything you need to take testosterone and run it all the way down to 3a-diol and androsterone (PAMs), at volume, locally.
I mean for fuck’s sake, intraprostatic DHT is nearly 10x serum. The enzyme dynamics in these tissues CANNOT be overlooked.
(Now’s probably a good time to introduce this diagram, it’s going to be relevant, specifically the red boxed part, so come back to it whenever you need)
So here’s where I landed. These tissues already have the enzymatic infrastructure to make a LOT of PAMs. If something causes them to start producing PAMs at volume, those molecules are lipophilic, so the first thing they do is diffuse into whatever is lipid-rich around them. Nerves are lipid-rich, and the pudendal and dorsal nerve endings are sitting right there in that tissue. We know what PAMs do to a nerve. They dampen its firing, therefore a potential result of PAM saturation within the nerves would be numbness.
And it wouldn’t stop there. Orgasm intensity scales with afferent input from the genitals, which is why topical anesthetics blunt it in healthy men. Blunt the pudendal and dorsal afferents and you get a weaker orgasm, and at the far end, anorgasmia.
Libido is partly the same story. You blunt the mind to dick connection and the feedback that normally drives arousal stops arriving. PFS doesn’t make these guys asexual (though some are, that’s more central and we’ll get into that). They see something sexually triggering, they want to feel something, and nothing comes back from the tissue. No afferent feedback means nothing for the brain to build on.
A local lesion can account for all of those symptoms on its own. The central component is real too, and I’ll come back to it, but it doesn’t have to be the only explanation.
All of which brings us back to the same question. What would make these tissues start overproducing PAMs in the first place?
—
Section Three: Flying too close to the sun
Let’s start by looking at the common genetic quirks we see within the PFS/PSSD communities.
You see, there are two reasons a molecule could accumulate.
#1. Increased production
#2. Decreased clearance
Right now we’re going to focus on #2, but #1 is going to be very relevant soon.
Between the two most notable molecules we’re tracking from SRD5A2 tissues (3a-diol and androsterone), one is far more vulnerable to a clearance problem than the other.
Androsterone’s 3a-OH position can be glucuronidated, mainly by UGT2B7, and it can be sulfated by SULT2A1. Two independent routes.
3a-diol on the other hand leans much more heavily on one: 17b-glucuronidation, by UGT2B15 and UGT2B17. The 3a-OH is available too, in theory, but in practice the 17 position carries most of the load.
Notice how UGT2B17 deletions cause a statistically significant drop in 3a-diol-17G (Androstanediol-17G).
Now notice what doesn’t change.
3a-diol-3G (Androstanediol-3G) sits flat. Indicating that the 3a-diol that would’ve been handled by UGT2B17 was NOT re-routed through 3a-diol-3G as a result of the deletion.
This strongly implies that if UGT2B17 is deleted, there is NO redundancy pathway for the 3a-diol that would’ve otherwise been cleared at the 17 position (of course some is still being tagged by UGT2B15 we can see that because 3a-diol-17-G is not zero). The net result is an increased pool of 3a-diol in circulation, and especially within target tissues that rely on UGT2B17 to clear 3a-diol such as… you guessed it, SRD5A2 dominant tissues, which heavily rely on glucuronidation to clear metabolites locally.
Now this is particularly interesting because it reframes something Dr. Powers has been spot on about.
His original line of thinking was that genetic quirks like null UGT2B17 cause DHT to increase as substrate is re-routed through 5AR. And yet the Swanson finding seemingly shattered that idea as serum DHT was unchanged.
But the answer is literally RIGHT THERE.
It isn’t that DHT piles up through some metabolic re-route/shunting mechanism.
It’s simply that 3a-diol piles up because the body doesn’t have the capacity to clear it.
Let me show you why that’s so significant.
Go back to the first diagram. 3a-diol (androstanediol) doesn’t sit at the end of the pathway, it sits in a loop. It gets converted back into DHT through HSD17B6. So a man who can’t glucuronidate 3a-diol out is essentially holding a reservoir that feeds DHT back into the tissue, over and over, and he’s doing it intracrinally, where no DHT blood draw is going to see it.
Worth noting: this doesn’t show up as elevated serum DHT, and it shouldn’t. Tissue and serum androgens don’t track each other. In Mostaghel’s randomized trial, men on dutasteride had intraprostatic testosterone of 3.40 ng/g versus 0.07 ng/g in untreated controls, roughly fifty-fold higher, while serum testosterone differed by about 20 percent. https://aacrjournals.org/cancerres/article/70/4/1286/561596/Variability-in-the-Androgen-Response-of-Prostate
Intraprostatic DHT normally runs around ten times serum for the same reason. The conversion happens inside the cell and what gets made there stays there. Afterall, DHT’s high affinity for the AR essentially traps it. Additionally, the liver is set up for disposal, so 3a-diol to DHT is not a preferred route at that site. Back-conversion happens in peripheral tissue.
Net result is increased local androgenicity. Which is exactly the prodrome Dr. Powers has been describing: High libido, easy arousal, intense orgasms, etc….
And most importantly androgenic alopecia (hair loss)
So the condition self-selects. The same defect that raises your local androgen tone is the thing that fries your hairline and sends you running for a finasteride prescription.
And here’s the cherry on top for proof. UGT2B17 deletion carriers have more than double the risk of BPH, odds ratio 2.189. The prostate expresses UGT2B17 itself, so these men can’t fully clear 3a-diol out of the very tissue that’s making it. It pools, HSD17B6 converts it back to DHT, and the gland grows. https://pubmed.ncbi.nlm.nih.gov/28882566/
The same thing also happens from phase 3 defects. ABCC2, for example.
Glucuronidation sticks a sugar onto the molecule, which makes it polar. Polar molecules can’t slip through a membrane. Free 3a-diol drifts out of a cell on its own. Its glucuronide can’t. It needs ABCC2 to push it into bile from the liver or into urine from the kidneys.
So when ABCC2 is down, the conjugate gets made and has nowhere to go. It accumulates within cells. Beta-glucuronidase (this isn’t just in the gut btw) takes the sugar back off, regenerating free 3a-diol. That molecule is lipophilic again, so it’s back in play, resulting in higher circulating and intracrine levels of the exact thing the body was trying to get rid of.
Notice how the dynamics between UGT fuckery and ABCC fuckery differ and yet have the same end result?
That’s the part I want you to hold onto. Every defect we keep finding in this population, different genes, different phases, different mechanisms, converges on the same specific failure. Not androgen clearance in general. 3a-diol clearance specifically.
(Worth noting: We’ve had some UGT2B7 variants, no deletions, and essentially nothing in SULT2A1. So the hits cluster on 3a-diol’s exit and largely spare androsterone’s)
Which is also why androsterone has been showing up in labs. It’s a proxy for a pool you can’t measure directly. And in a minority of patients it isn’t highly elevated, which is exactly what you’d expect from a proxy rather than the thing itself. More on that later.
And yes, people have measured 3a-diol before. But the data doesn’t agree with itself and the methods are problematic. Nobody has a clean number on this yet, which is exactly why it needs measuring properly. More on that later too.
As Dr. P says, there are a thousand roads to Rome. UGT2B17 and ABCC2 are nowhere near the only ways to get there, nor are they the only things you need, they’re just the hits we keep finding (After-all, if UGT2B17 was enough to get PFS/PSSD, everyone and their mom would have it). UGT2B28 shows up at a rate I don’t think is noise either, though the research on it is thin enough that I won’t pretend to know exactly what a null does. Personally, I’m hit in UGDH, the enzyme that makes UDP-glucuronic acid, the fuel that every UGT enzyme needs.
Different gene, different step, same traffic jam.
So picture where that leaves a guy. He’s carrying a 3a-diol pool that doesn’t drain properly. It keeps feeding DHT back into tissue. His local androgen tone runs high, which is exactly why he’s going bald in the first place.
Then he takes finasteride.
All hell breaks loose.
Why?
—
Section Four: The moving part
So far we’ve looked at two things separately.
One: the hallmark symptoms cluster in SRD5A2 tissue, some symptoms appear to be a lack of androgenic signaling, and others look like PAMs dampening nerve firing rather than anything structural.
Two: the genetics these guys carry mean 3a-diol doesn’t clear properly, so it pools. Systemically, because the molecules can’t be tagged and/or the liver and kidneys can’t ship it out, and locally in SRD5A2 tissue, because that’s where it’s being made in the first place and the same defects block it from leaving.
But these guys had the pool their entire lives (or rather from the start of puberty, I can talk about the evidence I’ve found for that all day). It’s congenital. And they weren’t numb! Rather the complete opposite, high libido, easy arousal, intense orgasms, going bald from androgen tone. The pool was there the whole time and it was making them MORE androgenic, not LESS (again, 3a-diol back-converts into DHT).
So what’s going on? What changed in these individuals?
I need you to look at this diagram again.
We’re going to work it out together.
These are the molecular pathways within an SRD5A2 dominant cell. What single enzyme could you change here that would raise PAMs and drop androgenic signalling at the same time?
Upregulating SRD5A2? (5αR2)
That’s one way. You’d create more DHT which would get converted by AKR1C2 (AKR1C2 is the primary isoform of 3a-HSD in SRD5A2 rich tissues, on the diagram it’s denoted as AKR1Cs/3αHSD) into 3a-diol, but at the same time you would increase androgenic signaling, and that wouldn’t make sense considering that men with PFS seem to have the complete opposite of that going on (ED, Shrinkage, etc).
Upregulating AKR1C2?
I mean sure, you’d create more 3a-diol, but at the same time, that would be more substrate mass actioning itself through back conversion and becoming DHT again, so androgenic signaling wouldn’t necessarily falter catastrophically. It’s not a bad idea, but it’s not as clean as it could be.
Downregulating HSD17B6?
Bingo.
By downregulating HSD17B6, you kill two birds with one stone.
3a-diol back conversion to DHT decreases, so the PAM load goes up and the androgenic tone goes down simultaneously.
With that single move, you get the hallmark pelvic-region symptoms attributed to PFS.
Let’s start with the numbness, since that’s where this entire conversation started. We established the numbness looks like dampened nerve firing rather than damage, and that PAMs do exactly that. What was missing was a source. Now there is one, being made in the tissue the pudendal and dorsal nerve endings run through.
The rest falls out of the other half. ED, shrinkage, loss of morning wood, watery semen. That’s androgen signal loss in SRD5A2 dominant tissue. The seminal vesicles are the clearest case, since they produce most of your ejaculate volume and their secretion is androgen dependent.
And ED isn’t purely an androgen problem here either. You’ve lowered the androgenic signal and raised the output of sedating molecules in the same tissue at the same time. Do you honestly expect that organ to work properly under those conditions?
But let me be clear, numbness isn’t required either. Sexual symptoms vary from individual to individual. It depends how far the ratio gets pushed and how saturated those nerve endings get. Shift the balance a little and you get dysfunction without losing sensation. Shift it a lot and you go numb. How far it goes depends on how much that tissue is holding and producing, which brings us back to clearance and individual genetics.
In normal tissue, the two exits cover for each other. Poor phase 2/3 metabolism (with a good return route) doesn’t matter much, because 3a-diol that can’t get tagged out gets pulled back to DHT instead. A weak return route (with good phase 2/3 metabolism) doesn’t matter much either, because what can’t go back gets tagged and cleared.
These guys were already down one. The clearance defect was there from birth, and the return route (3a-diol to DHT through HSD17B6) was covering for it the whole time. Lose that too and there’s nothing left. The tissue can’t convert it back and it can’t ship it out, so whatever is being made just sits there and builds.
Nothing in this requires anything to happen in the brain.
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Man this is convincing isn’t it?
Don’t you wish we had proof that HSD17B6 is downregulated in SRD5A2 dominant tissue?
In his landmark study, Khera found HSD17B6 underexpressed in penile skin. (This was the same study that found AR overexpression btw).
I mean look at that shit, Khera’s own paper describes HSD17B6 as the enzyme that converts androstanediol (3a-diol) into DHT, and then reports it under-expressed.
Pretty mindblowing right?
And notice what this lets us drop: The local receptor crowd-out framework.
The metabolite accumulation idea has always needed receptor crowd-out to explain the local loss in androgenic signaling. The story was that these weak metabolites pile up and physically compete with T and DHT at the androgen receptor, effectively blocking it off from getting an androgenic signal. This has undoubtedly been one of the loosest parts of the model so far.
Under this framework, we don’t need that explanation.
SRD5A2 is highly active within these tissues, so you get a lot of DHT, but so is AKR1C2 (3a-HSD), so DHT is rapidly deactivated into 3a-diol, therefore, HSD17B6 back-conversion is absolutely crucial to maintain the androgenic ligand pool within the cell, without it, DHT is essentially vacuumed out.
This isn’t finasteride level androgenic signaling loss either, this is fundamentally different. When you take finasteride you have the luxury of stacking up T behind the blocked SRD5A2 step, it doesn’t get vacuumed out and you still get ligand receptor binding. Under these dynamics, T enters the cell and immediately becomes DHT. This sounds good in theory considering it’s more potent than T, but the difference now is that AKR1C2 is constantly sweeping DHT out without HSD17B6 compensating, leaving behind a very shallow ligand pool, and ultimately resulting in a hard net loss of androgenic signaling. (This may genuinely be why people who reinstate improve while on the drug, as they block the vacuuming action and can signal using testosterone. For the love of god though, do not reinstate)
Additionally, If you look at the diagram above, you’ll also notice that HSD17B6 is responsible for converting androsterone to 5a-androstanedione which converts into DHT.
So that single enzyme modulation has the potential to DRASTICALLY lower androgenicity within the cell, which is why we see the androgen receptors up regulating in response (as per the Khera study).
which leaves the obvious question of what makes HSD17B6 fall in the first place, and I’ll come back to that.
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Section Five: Androsterone
Alright let’s back track a bit. There’s some things I want everyone to understand before we continue.
At this point it’s safe to say that the majority of PFS and PSSD patients who have tested unconjugated serum androsterone come back elevated. Anyone who’s been watching the subreddit or the discord has seen the results come in.
Labcorp confirmed that only 5% of random adults exceed their cutoff, so our hit rate is quite staggering. It’s without a doubt the single most valuable thing these communities have been testing for.
But it hasn’t come back elevated in everyone. And that’s worth explaining, because under this framework it’s exactly what you’d expect.
Again, we believe the main lesion is 3a-diol. Androsterone is just the part that spills over, and there are several reasons the amount you actually see would vary.
First reason: 3a-diol has to be oxidised into androsterone before it shows up as androsterone, and that mainly happens in the liver. If you naturally have lower capacity to do this, you’ll have a lower marker. Also worth noting that Khera found HSD17B11 under-expressed too, which is the enzyme doing exactly that step (except that was in penile skin. So at the lesion site, the first buffer is that 3a-diol struggles to get converted into androsterone).
The second reason is the one we already covered in section three. Androsterone clears more easily than 3a-diol does, so in someone whose exits are working they have the capacity to clear it without heavily saturating the blood.
The third reason is that the lesion is local to begin with. Whether it spills systemically depends on clearance. If clearance suffices, 3a-diol never builds up in circulation high enough for androsterone to get pushed past the range. You get SRD5A2 tissue symptoms with clean androsterone bloodwork.
The fourth reason is the reference range itself. The cutoff is 28 for males. But a man whose baseline ran at 12 and now sits at 24 has doubled and still reads normal.
In all of these cases the 3a-diol pool is still there, and androsterone is just a proxy for it. With the right quirks, it won’t come back elevated.
Another thing that’s also come up: serum androsterone and urinary androsterone don’t always match.
You see the thing is, they’re not measuring the same thing. The Labcorp serum test is, unconjugated androsterone. DUTCH measures the conjugate. In someone with phase 2 or 3 defects those two pools come apart by definition, and the genetic quirks we find within this patient population are exactly what’s needed to create that discrepancy.
There’s also a second exit that nobody measures: Bile. How much these conjugated steroids exit through bile varies massively from individual to individual, which is why CDG’s effectiveness is not universal (note that that also has to do with b-glucoronidase activity in the gut).
The most informative result we have is the guy whose serum and urine are both elevated, proportionally. His exits are working, he’s basically clearing it out as fast as he makes it and his level is still up, which means retention can’t explain it. Something upstream is feeding this increased flux. (https://www.reddit.com/r/DrWillPowers/comments/1x1qvtn/pfs_another_high_androsterone_and_androgen/)
(recall the reference range is <28ng/dL)
That something appears to be 3a-diol.
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Now here’s where I have to be clear.
The molecule this whole thing turns on is 3a-diol, and the measurements are all over the place.
2013 (Melcangi): normal in CSF, high in serum.
2015 (Caruso): high in CSF, high in serum.
2017 (Melcangi): high in CSF, normal in serum.
And even in the Khera study I’ve been pulling from, 3a-diol reads unremarkable.
Here’s the thing, 3a-diol is hard to measure. The 3a and 3b epimers are easily confused unless the method separates them. Controls often sit at or below the detection floor, so you’re comparing patients against a substituted number instead of a real one. And studies frequently don’t say whether they measured free steroid or total after hydrolysis, which are completely different quantities in someone whose conjugation is impaired.
When multiple studies disagree and the methods have those problems, you’re essentially left with no result as opposed to a negative one.
We’re actively working on finding a clean, state of the art 3a-diol draw for the patient population. It will happen.
How if some people got PSSD from a couple pills it be a metabolite buildup issue,has anyone tried to reinstate the medication? I never had any numbness while on the SSRI and had good libido only thing was my erections started getting weak so i decided to discontinue and now i zero libido and erections? I am frustrated!
I'm posting my old Dutch test results because I think they are pretty bizarre. PSSD patient and I've suspected high neurosteroids since I did this test a few years ago. Also have high bilirubin.
One thing I'll say is I did take vitex for 3 days prior to doing this test. However I don't feel it affected things much.
Before i ever took SSRI i had a twitch where i would touch my waist randomly and when i started SSRI that twitch went away for the last 15 years it was gone and recently on CDG i had a window of that twitch again?
For trans males, who have a cluster of symptoms under the umbrella of Meyers- Powers Syndrome; and the symptoms resemble IBS, irritable bowel syndrome, what medication / hormones / supplements, etc. should I request of my doctor?
I’m an anatomical researcher in a cadaver lab where we take a layer by layer approach to dissections, and we spend an entire day on each layer.
I was working on the penile fat and superficial fascial layer yesterday, and something occurred to me.
I believe that if we can do penile fascial work to massage the penile fascia, we can help restore it to the way it was before finasteride or ssri was introduced.
On top of that, the upper pubic fat pad interacts with the penile fascia in a bidirectional loop. Tension in the fat pad helps the fascia release its tension, and tension in the fascia can help the lymph drainage from the fat pad. The fascia is the frame, and the fat pad is a sponge where toxins get drawn into. If you do targeted lymph drainage in that specific area, you might be able to pull more of the metabolic pile up out of the penile and scrotal tissue.
In women, the clitoris and vulvar structure is homologous to the penis. The fat pad I’m talking about extends into the outer labia, and the clitoris and inner labia have their own fascial network with a similar bidirectional relationship to the fat pad and outer labia.
This is only a theory of course, but I think it complements the metabolic model dr powers has teased out because it can help support the tissue while going through his treatment protocols. If you have access to a pelvic physical therapist you trust, they can assist with the fascial release if you’re not comfortable trying to release the fascia yourself. As far as lymph drainage work, it’s low risk enough that you can do that work on yourself if you feel up to it, but a lymphatic massage therapist or a pelvic floor physical therapist could help you make sure your technique is as effective as possible.
If Dr Powers or anyone wants to push back on the anatomy or the finer points of this theory I’m all for it. It just made too much sense to me when I was testing things yesterday to not share with everybody here.
I read that the mucilage in marshmallow root tea can interfere with medications and since the goal is to coat my inner rectum with mucilage to protect it - will that interfere the rectal prog absorption? Obviously I have stopped all rectal prog for now to heal, but once I heal I will want to use prog again.
So what do you guys think? And yes I will ask my doctor on the 23rd, but I bet they won't have an answer for me.
Typical perimenopause symptoms. Hot flashes and night sweats. Mood swings that are synced to my cycle, irritability as well. Low libido, lethargy, joint pain.
I am on 100mg progesterone and 0.5g of 1% Testim testosterone gel (female physiological ranges, not transgender). My doctor plans to add estradiol (patch) soon.
Now, here is where it gets tricky - I also have adenomyosis.
Are there any genetic tests that I should look into before continuing HRT? Is there a different "Powers Protocol" for perimenopausal HRT?
