Elliot Bewick Interviews Dr. Jay Bhattychayra head of the NIH
He talks about PSSD
u/Excellent-Push2833 — 8 days ago
u/Excellent-Push2833
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Soft Glans syndrome under the context of the SRD5A2 theory
Everyone. I wont spend much time explaining the theory. Docp still hasn’t gotten a chance to deep dive it. I found something interesting https://pubmed.ncbi.nlm.nih.gov/28713005/.
SRD5A2 is most heavily expressed on the ventral side of the penis. The underside. Under the context of the theory this is the area of the penis that would be most jam packed with metabolite. It explains the phenomenon in which people report getting an erection but the corpus spongiosum does not fill up with blood. The corpora cavernosa do though because they dont express that enzyme as heavily.
Im aware it says during development but i do believe that soft glans presenting as it does is not a coincidence.
u/Excellent-Push2833 — 24 days ago
We may have just set Melcangi’s rats free…
u/Drwillpowers
This is going to be a long one, but we think we've found something genuinely new about how PFS works.
—-
In light of the data collected linking PFS and PSSD via metabolic anomalies and massive GABA-A signaling, I took a trip down memory lane and revisited the studies which established the Melcangi dogma to reinterpret their findings under the ever-growing Powers framework.
The studies were:
Melcangi, 2013: PMID: 23890183
Caruso, 2015: PMID: 24717976
Melcangi, 2017: PMID: 28408350
The most obvious critique of these papers is their lack of coverage. The Melcangi dogma stems from the fact that allopregnanolone is depleted in PFS patients, and that by proxy GABA-A signaling has plummeted causing neuro symptoms as a result. However, this claim doesn’t account for the fact that there are various other positive allosteric modulators of GABA-A derived from androgen and neurosteroid synthesis/metabolism, including but not limited to:
THDOC (tetrahydrodeoxycorticosterone)
Pregnanolone (3α,5β-THP)
Allotetrahydrocortisol (3α,5α-tetrahydrocortisol)
Tetrahydrocorticosterone (3α,5α-THCORT)
3α,5β-Tetrahydrocortisol
Androsterone
Etiocholanolone
Without testing these alongside allo and 3a-diol (the only PAMs that actually were tested), the claim that GABA-A signaling has plummeted in PFS patients cannot be established, which is further driven home by the fact that we’ve gathered clear evidence that the complete opposite is happening.
—
What I’ve said so far has already been largely established, so let me get into the novel theoretical shit that’s been uncovered.
When I was reviewing these studies, the thing I was most curious to analyze was 3a-diol in CSF, but I quickly found that results were inconsistent from study to study, as a matter of fact, most things were inconsistent from study to study.
So, I was there thinking to myself “Damn, this data is junk”, until I realized I had forgotten to use ‘ol’ reliable’: Observing what remains constant throughout the papers.
Doing this uncovered some very meaningful findings.
Let's start with the CSF data:
DHP Low in PFS patients
THP (Allopregnanolone) Low in PFS patients
IMPORTANT DISCLAIMER: In the largest study, CSF allopregnanolone didn't reach significance. The “4.23” value is the spread, and for controls it's twice the average. This can only happen if the group is lopsided. Values can't go below zero, so most controls must be sitting low with a few high ones dragging the average up. The test lines everyone up smallest to largest and asks which group ranks higher. If most controls are down near the patients, the two groups blend together in that lineup and no difference shows up. "Not significant" doesn't mean the groups are the same, but rather that the measurement couldn't tell them apart. PFS values are tight and uniformly low whereas controls are scattered, with the spread running upward.
DHT Low in PFS patients
Testosterone High in PFS patients
——————
Plasma Data:
DHP Low in PFS patients
THP Low in PFS patients
DHT NORMAL in PFS patients
PROG Normal in PFS Patients
Let's start with the CSF findings.
DHP Low
THP Low
DHT Low
T High
A lot of you may immediately realize what these results imply, but if not, allow me to help you.
In the central nervous system, this how de novo synthesis of these various compounds play out:
Progesterone —-(SRD5A1)-----> DHP —---(3a-HSD)-----> THP
Testosterone —-(SRD5A1)-----> DHT
Do you see it now?
SRD5A1 (5-Alpha-Reductase type 1) the primary 5AR isoform in the CNS has had its activity substantially reduced. Note that low THP doesn't require a second cause. THP is made from DHP, so if DHP is low, THP is low by default. Nothing here tells us whether 3a-HSD itself is affected.
At the same time, we can look at plasma DHT and see that there’s no statistically significant difference between PFS patients and controls, indicating that in the periphery, SRD5A2 is seemingly running well.
So, why is this happening? Why is SRD5A1 kaput when finasteride barely touches that isoform?
Well, the first thing you need to understand is that the human body is not a stupid machine, it’s a wonderfully engineered piece of meat. The body doesn’t change something unless it has a good reason to, this isn’t a “BROOO FINASTERIDE BROKE MY 5AR1 FOR NO REASON BRO” situation.
Think about why the brain would intentionally shut off its own production of GABA-A stimulating compounds.
Maybe because it’s getting a massive amount of PAMs from some atypical maladaptive mechanism…? (Cue 4 above range androsterone values in a row. Pick four individuals at random and the odds of that are roughly 1 in 2.5 million, clearly demonstrating the ‘PAM accumulation’ anomaly in this patient population)
Let me help you visualize this. What happens when a man starts using exogenous testosterone?
The brain realizes the body no longer needs to produce its own T, so it stops secreting luteinizing hormone, effectively shutting off endogenous production.
When it comes to an alarming influx of PAMs, we’re likely seeing the brain react in a very similar way, which is by closing off its own production.
When I first thought about this mechanism, I figured it was just a theory, and that speculation would be as far as I’d get. However, I am thrilled to present that that is not the case.
As per this study: https://pmc.ncbi.nlm.nih.gov/articles/PMC2789917/ researchers exposed mice to intoxication levels of ethanol (a positive allosteric modulator of GABA-A) vapor continuously for 72 hours. Now, most alcohol research looks at what happens during withdrawal, which is NOT what we’re modeling here. PFS patients are not in withdrawal by any means. They’re in a saturated state, which is why I especially wanted to see what happens at the 0-hour timepoint, which is right when mice were taken out of the chamber, during which their brains were still absolutely soaked in ethanol. And guess what the research found? Hippocampal 5a-reductase-1 enzyme activity was down 34% in one line and 40% in the other. Srd5a1 mRNA in the hippocampus was down 76%. So, the brain had turned the enzyme down while in chronic exposure. And get this, it wasn’t just the brain, in fact adrenal SRD5A1 expression was down 55% too, with plasma allopregnanolone dropping as a result.
So, two separate measurements, catalytic activity and gene transcript, both point the same direction. Decreased SRD5A1 activity.
(Worth noting): the same group later ran a follow-up using a different technique to map where the gene was being read across brain regions, and that one didn't pick up the change. They report it openly. The activity finding stands either way. In their own data, how much the gene was read and how much work the enzyme actually did didn't always line up. Hold onto that thought! We’re going to come back to it. https://pubmed.ncbi.nlm.nih.gov/21917407/)
So this is no longer speculation about what the brain MIGHT do when it’s drowning in GABA-A potentiation. This is quite literally what biology makes it do. It turns the enzyme down, both centrally and peripherally.
To drive that peripheral point home, look at the plasma data in PFS patients. DHP and THP are low. When you consider that progesterone is normal, there is no substrate limitation that explains why DHP is low, rather the only explanation is an enzymatic one, as the catalysis of progesterone to DHP relies primarily on SRD5A1. (You may notice serum DHT is normal, and that makes sense, since circulating DHT is produced mainly by SRD5A2, a different isoform in different tissues).
Now some of you may bring up the point that Melcangi ran a study checking for methylation of the SRD5A1 and SRD5A2 gene promoter regions in CSF, and this yielded a methylated SRD5A2, and an unmethylated SRD5A1 (here is the study: https://pubmed.ncbi.nlm.nih.gov/31272082/). So, two things I gotta say about that. First and foremost, methylation is a GOOFY data point, a gene can be methylated but you have no idea if that increases or decreases transcription. As a matter of fact, only about half of the PFS patients had a methylated SRD5A2, and when they compared the unmethylated patients to unmethylated controls, those patients STILL showed low DHT, low DHP, and high CSF testosterone (and DHP stayed low in the methylated group too, meaning it's suppressed regardless of SRD5A2 status), which is exactly what you'd expect if the thing driving those values is SRD5A1 and not SRD5A2. Secondly, methylation is only one of several ways to turn a gene down, and it's arguably the least relevant one here. Histone modification is the faster strategy. Acetylation marks turn over in hours to days, they can be dialed like a thermostat rather than flipped like a light switch, and they respond directly to what's happening in the cell (which may be why HDACi’s have had their use here and there in a few recoveries, but still a very messy tool).
And this is where that mouse data comes back. An enzyme's output can drop for reasons that never touch the gene to begin with, such as cofactor supply, protein turnover, or even modifications made AFTER the protein is built. So a clean promoter doesn't mean that the enzyme is spick and span, it’s basically just telling us that methylation isn’t the factor at play.
—--
Summarizing all the findings so far, we see that in response to massive GABA-A signaling SRD5A1 activity is decreased to a notable extent in PFS patients.
But this begs the question, where are all of these PAMs coming from? After all, this entire argument is completely reliant on large quantities of PAMs being sourced from somewhere. So where?
This is where ExcellentPush and I deliberated for DAYS.
Our work has us believing that we’ve created a model that explains how finasteride causes the PFS cascade.
We call it the SRD5A2 Factory Cell Model.
We will first use it to model how PFS is triggered during use.
Let's begin by envisioning a cell that highly expresses SRD5A2 (A prostate cell for example). Under normal conditions, this cell has a flux into the cell of various compounds that matches the flux out of the cell (homeostasis). Coming in, you have testosterone (from gonads) androstenedione, DHEA (from adrenals) and various other substrates. These can act upon the cell, get converted, and get cleared.
What I need you to remember for now is that T enters the cell, becomes DHT via 5AR2, and both cause androgenic signaling (DHT notably more-so). I also need you to keep in mind that adrenal substrates like DHEA and androstenedione are coming in too, but for the sake of simplicity, we won’t model that yet.
Now let's introduce finasteride, Phase 1 (keep in mind that some of the phases/shifts I’m about to present happen simultaneously, I’ve phased it out for the sake of simplicity).
T to DHT conversion is heavily reduced due to 5AR2 inhibition (intended effect of finasteride). This causes two things, both of which are exacerbated by the fact that individuals who develop PFS are reliant on 5AR for metabolism. Firstly, androgenic signaling within the cell drops significantly. Secondly, Testosterone accumulates.
Enter phase 2 and 3, compensation and conversion. In response to the lack of androgenic signaling, the cell upregulates SRD5A2, unleashing more enzymes within the cell in an attempt to restore signaling. At the same time, accumulated testosterone begins converting back and forth into androstenedione en masse.
And this isn't just theory. The PCPT trial, which is the big finasteride prostate cancer prevention study, tracked 286 men taking finasteride and measured their serum androstenedione at baseline and again at year 3. It went up 22%, p<0.0001. So androstenedione does back up behind the blocked step in real humans on finasteride. Keep in mind that they measured serum, and what's happening intracellularly is a different question this study doesn't answer. Though given that serum is largely spillover from tissue, a measurable rise in the blood is consistent with a considerably larger buildup inside the cells.
Enter phase 4, hog and block. The sheer volume of androstenedione from T conversion and adrenals (recall they also supply substrate like DHEA which 3b-HSD converts into androstenedione within cells) begins to crowd out testosterone from the AR, while simultaneously hogging out the 5AR2 enzymes and using them to become 5a-androstanedione, which too crowds out the AR.
In response to this increased loss of signaling, the cell enters phase 5, further compensation, during which the cell further upregulates SRD5A2, allowing more enzymes to flood the cell.
Enter phase 6, factory online. At this point, the 5AR2 enzyme is effectively hogged out by substrates like androstenedione. Massive amounts of androstenedione are then converted into 5a-androstanedione, and are then further converted into androsterone (which can also convert into 3a-diol, I used ADT for the model for the sake of simplicity). This accumulation further crowds out the AR, further upregulating SRD5A2, and triggering a loop that turns this cell into a factory of 3a-diol or androsterone (both of which are PAMs)
Enter phase 7. The PAMs diffuse out of the cell and begin saturating other tissues.
If you’re curious why there are still functional 5AR enzymes within the cell despite finasteride exposure, it’s because finasteride doesn't wipe out SRD5A2, it inhibits what's there at the time. It's a suicide inhibitor, so enzymes have to be replaced by new protein synthesis, but that means a cell cranking out fresh SRD5A2 is constantly putting uninhibited enzyme back into itself. Whether the drug keeps up depends on dose versus how fast that cell is printing. Additionally, the PFS/PFS-susceptible population is not standard in terms of cell dynamics. These individuals were heavily reliant on 5AR to begin with (this is quite literally why they hopped on finasteride to begin with) they start with more enzyme and more demand, so a dose that's plenty for an average man may leave a meaningful fraction of a PFS susceptible individual’s SRD5A2 running.
You may also be wondering how such a small amount of PAMs (considering SRD5A2 dominant tissue is not hugely abundant in the body, and therefore factory volume wouldn’t be huge) could cause the body to become fully saturated. Don’t worry, this will now be explained.
Below is a representation of how the liver processes PAMs like androsterone and 3a-diol. As you can see there is a balance between what’s entering, what’s being processed, and what’s being excreted.
In an individual susceptible to PFS, the same genetic quirks that causes the SRD5A2 factories to establish themselves (i.e. a glucuronidation deficit) makes the liver's margin for error when it comes to processing PAMs much lower.
If the liver can only outflux, let's say 100 units of androsterone or 3a-diol at any given time (units are grossly over simplified for the sake of simplicity), then the liver is safe so long as the influx is <= 100 units of those molecules.
So, when the SRD5A2 factories come online it only takes a slight increase in the influx of androsterone or 3a-diol to get to >100 units, effectively overwhelming clearance which begins the process of accumulation.
When you consider the fact that the liver already has to process a massive input from the adrenals (DHEA -> Androstenedione and Androstenedione on its own to name a few). It’s easy to see how quickly things would back up and saturate the blood stream, which would then enable accumulation in other tissues.
This model would be incomplete if it didn’t address withdrawal cases, so let’s explore that angle too.
Withdrawal cases start off the same way as cases that worsen when using finasteride.
You get Phase 1, during which you lose signaling and accumulate substrate.
You also get an identical phase 2 and 3, during which compensation and conversion occurs.
Here’s where it diverges. Instead of continuously looping itself into a more compromised state, the cell here actually manages to stabilize and achieve homeostasis. This doesn’t mean that the cell is the same as it was when it started, but rather that the cell is stable in its altered state.
Cessation of finasteride occurs. Phase 5.
Enter Phase 6. Here's the thing about the stable state the cell reached: it got there by having a lot more SRD5A2 than it started with. That enzyme was sitting there inhibited. When finasteride clears, the fresh enzyme the cell keeps producing no longer gets inhibited, so the cell rapidly builds up an enormous 5a capacity pointed at the built up substrate pool.
What ensues explains either a crash soon thereafter, or one that takes a little bit longer to set in (the honeymoon phase).
Potential scenario 1, immediate crash: The restored enzyme goes to work on whatever is most abundant, and that's androstenedione, not testosterone. So the flux runs down the 5a-androstanedione branch and straight into androsterone and 3a-diol. Signaling never recovers, the AR stays crowded, the cell upregulates SRD5A2 again, and the factory locks in right away.
Potential scenario 2, honeymoon: This time enough of the flux goes to DHT that signaling punches through the noise. The individual feels great, sometimes better than they did before finasteride. Two weeks of it. But that massive DHT signal downregulates UGT and SULT expression, so clearance capacity drops at the exact moment production is highest. Androsterone and 3a-diol accumulate behind the scenes. And also, I didn’t add this in the diagrams, but DHT itself gets 3a-reduced into 3a-diol (which can convert into androsterone), so even the thing making the individual feel good is feeding the pile. Eventually the accumulated metabolites crowd out signaling, and the individual lands in the exact same factory state, just two weeks later.
One thing heavily worth noting though. The factory forming can be silent, and the PAMs can start to accumulate outside of cells before they become factories (This applies to crashes that occur during use as well as upon withdrawal). The crash a patient feels may not necessarily be the moment the cell flips over, but rather when the liver's margin gets exceeded and PAMs start saturating systemically (especially in the CNS). Which is why some people crash overnight and others describe it creeping up.
Worth noting my own androstenedione came back normal despite androsterone at 81, which is what you'd expect if the factory cell is consuming androstenedione as fast as it arrives. As a matter of fact, high androsterone and normal androstenedione was observed in 3/4 high androsterone patients so far, though I know at least one patient had both elevated, so the pattern isn't uniform. I'm sure the answer as to why is right in front of me and I'm just not seeing it because my brain is kaput from thinking about this for the past week.
Okay, here’s another thing we need to address: How does someone end up with the neuro symptoms but a totally normal dick or no watery semen if these factories come online in those parts of the body.
See, androsterone and 3a-diol are lipophilic, so they diffuse in and out of cells without needing transport. But material leaves the cell only while the cell has more of it than the blood does.
So if the systemic pool is still manageable, the gradient enables the factory to run full tilt while the tissues harboring the factories stay relatively clear. It hasn't left the body though, just gone into circulation, and from there it accumulates in other tissues such as the brain, which is mostly lipid so not only does it attract this stuff, but it simultaneously also actually kind of sucks at exporting it.
The guys who do get the deflated penis are the same physics with a heavier systemic load. Their blood is already saturated, so the concentration gradient forces the cells to heavily accumulate metabolites, causing the material to stay put. End result: Local accumulation -> AR severely crowded -> atrophy.
Therefore, guys with genital atrophy should have higher serum androsterone than the neuro-only guys. If it comes back backwards, this part is wrong.
And for the sake of proving a point, at 81ng/dl androsterone (highest so far), my dick is fried 😂
Also, the neuro-only guys usually still have ED anyway, which is obviously not atrophy, but that could still absolutely implicate a partial drop in local signaling.
—-
Phew! Take a breather now that we're done with that. But get ready cause we still have more.
Here’s where shit gets juicier. We’re going back to the SRD5A1 theory.
Recall the mouse study. The SRD5A1 drop didn't just show up in the brain. It showed up in the adrenals too. And that’s a point of interest, because it suggests that this isn't purely a brain phenomenon. It could potentially be an effect modulated entirely locally.
Now the obvious objection is that the adrenals aren’t independent. They’re part of the HPA axis and respond to the brain, and the mice did have corticosterone 6x normal. So maybe the adrenal SRD5A1 drop was in response to an external signal after all.
Except the numbers don't fit that. Quick bit of context on the study setup: they used two different genetic lines of mice. Both got the same ethanol exposure, and both ended up with corticosterone about six times higher than normal. Same exposure, same stress hormone response.
But the adrenal SRD5A1 drop was notably bigger in one line than the other. If the brain's stress signaling was what turned the enzyme down, you'd expect the enzyme to fall wherever corticosterone rose, since corticosterone rose the same in both. It didn't. The enzyme response followed which genetic line the mouse belonged to, not how much stress signaling it was getting.
This doesn't 100% prove that the adrenals were reacting to the PAMs by downregulating SRD5A1 on their own, but it opens up the possibility.
If we then ASSUME (so now we’re getting really theoretical) that many of the cell types that have GABA-A receptors have a hard coded response mechanism which decreases SRD5A1 when GABA-A signaling passes a certain threshold to avoid signaling more (by decreasing local production of PAMs), then there would potentially be SIGNIFICANT peripheral implications.
So, Dr. P… while every atom of my body respects you immensely, I’m going to have to disagree with you on this comment that you left on my androsterone post: “But really, the magic is happening inside your head not in the periphery” because under this framework, the magic is happening within both.
Symptoms like anhedonia, genital numbness, and whatnot can likely be attributed to the CNS pileup. However, the peripheral decrease of SRD5A1 activity has implications on a wide array of other symptoms.
Let’s look at the skin for example. The primary 5a-reductase isoform expressed in non-genital skin is type 1. If we follow the theoretical framework I’ve crafted, massive GABA-A signaling caused by large amounts of PAMs within non-genital skin cells would have a two pronged effect. #1, it causes androgenicity within the cells to plummet as SRD5A1 crashes. #2, glucocorticoids stack up as 5AR is crucial for glucocorticoid metabolism, if you block it, things like 11DOC struggle to get metabolized out.
The net result is a cell that becomes catabolically dominant. This potentially explains the melty pheno. Personally, I’m inclined to believe it. After all I fall under this pheno (as well as the two others, signaling loss, and neuro), and my comprehensive steroid panel came back normal.
You see, all it takes is for the cell to enter a state that is predominantly catabolic. If you turn SRD5A1 off, you lose the anabolic counterbalance, and under the right genetic/metabolic circumstances you wouldn’t even need glucocorticoids so high they show elevated in the blood to tip the scales and cause weird skin.
I’ve been wondering for a long time why people get dry skin, stretchy skin, and things of that sort when finasteride touches 5AR2 (lightly taps 5AR1) and the cells making up these areas of the body (Sebocytes, Keratinocytes, Dermal fibroblasts, etc) mainly express 5AR1. And well, under this framework it appears to be a downstream effect of the finasteride induced massive secretion/accumulation of PAMs.
Perhaps, other organs can have the same logic applied to them, such as osteoblasts and fibroblasts, which would help explain ligament laxity, and bone density decreases over time. But I haven’t explored this angle too deeply, all I know is that those cells too predominantly express SRD5A1.
You know I will admit, I had absolutely no idea chasing this lead was going to get me as far as potentially explaining a mechanism aggravating skin cells, I thought I was only going to dig into the neuro aspect.
I genuinely had no intention of going this far, but the more I explored the more things opened up.
Anyways, I’m not done yet. There’s a little bit more to cover. I’ll keep this part short and sweet (sort of).
For this section, I’m just going to toss random things around that I still want to address but didn’t above.
- Decreased SRD5A1 in the CNS has serious multi-whammy implications. One of them is the fact that you lose androgenicity in the brain as T -> DHT conversion is decreased. If massive GABA-A signaling wasn’t bad enough for libido and “manliness” this is an additional slap in the face.
- We know that if SRD5A1’s activity has been significantly reduced in the CNS, then the PAM pileup cannot consist of THDOC, because the de novo synthesis of this compound is severely limited without 5ar1. (Recall that the periphery also appears to have taken a hit, meaning those compounds struggle to be made there as well). So, if what I’ve been cooking up here is correct, we should actually expect to see low THDOC in CSF, contrary to current belief.
Additionally, the only pathway the substrate can go down (if SRD5A1 is blocked) that leads to PAMs is AKR1D1 (5b reduction), which is sparsely expressed in the brain.
That leaves these as potential candidates for the PAM pileup.
5α, via peripheral/hepatic 5AR
Androsterone
3α-Androstanediol
5β, via AKR1D1 peripheral/hepatic
Pregnanolone (3α,5β-THP)
Etiocholanolone
Tetrahydrocortisol (3α,5β-THF)
5β-THDOC
5β-THCORT
Under this model, all remaining PAMs come from the periphery and saturate the brain, rather than the brain making them and saturating the periphery.
Additionally, with 5a capacity reduced in the SRD5A1 dominant cells, some flux gets diverted toward 5b-reduction, and that's likely a double whammy in individuals with PFS. These compounds may be harder to clear due to various UGT/SULT/ABCC/SLCO issues, which is probably why the body heavily favored 5a-reduction to begin with. Therefore, the downstream effect of GABA-A signaling significantly lowering SRD5A1 activity is almost mechanistically comparable to the stress a 5AR reliant body endures when using finasteride, as it accumulates these compounds and potentially diffuses them through cell membranes to eventually accumulate all around en masse. Additionally, this accumulation may further crowd out the AR and cause further loss of androgenic signaling within the SRD5A1 dominant cells.
Important note here: If these guys had decent 5b capacity, losing 5a wouldn't have wrecked them. So either they’re bad at making 5b compounds to begin with, or they can make 5b compounds fine but can't clear them well. If it's the former, 5b is a weaker candidate for the pileup and androsterone/3a-diol carry more of the weight. If it's the latter, the 5b arm stays in play.
Different PAMs hit receptors differently. A massive pileup of 3a-diol will potentially have different implications than a massive pileup of androsterone. This may explain why one individual may have one symptom profile while another has a different symptom profile, the fundamental difference and cause may lie in what they’ve specifically piled up. This may also imply that an individual doesn’t need to pile up an absolutely ABSURD amount of PAMs within cells to do something notable, as the right PAM could exert a significant effect at a concentration that's well above its own normal range without being enormous in absolute terms.
To add onto the previous point, no two individuals will react identically to the pileup due to various genetic quirks, even if it's the same exact pileup.
Mile-high-guy, you’re a pioneer, and I will forever admire the balls on you to be the first ever castration trial. Under this framework, I think I can explain why you had remission post castration before eventually having some symptom relapse. Let’s picture the SRD5A2 factory cells and the SRD5A1 dominant cells. Your SRD5A2 Factories are heavily dug in, the looping mechanism is firmly in place, and those cells are churning PAMs like a motherfucker. SRD5A1 cells still face significant consequences from what the SRD5A2 factory cells are doing, but they’re significantly less stuffed in comparison. When you castrated yourself, you were able to clear the SRD5A1 cells by inhibiting a large amount of the SRD5A2 factory cells fuel which was used to make products that aggravated SRD5A1 cells, but you didn’t clear the SRD5A2 factory cells enough to break their loops. For example, you effectively cleared the cells responsible for sebum production, and upon getting off the HPTA suppressors, you saw those areas return to normal until eventually crashing back down. Under this model, this is tell-tale indication that a downstream issue was addressed, but the root cause wasn’t, so eventually the root cause re-introduced the downstream issue. We have a guy on the discord who got his masculine scent back basically instantly on relu. Under this model, these things only make sense if you’re causing the sudden relief of something downstream, not correcting the core problem, because the root cause (under this model) could never be corrected that rapidly.
Your 3a-adg (which may be a poor proxy for your pileup as it’s not direct 3a-diol, nor does it account for the fact that you body may heavily swing towards androsterone production) hovered around 300ng/dl for weeks until you used hydrocortisone, at which point it then crashed down towards 70ng/dl. Considering that the adrenals supply large amounts of androstenedione and DHEA to the SRD5A2 factory cells and liver, you didn’t actually start to really stress the intracrine SRD5A2 factory pileup until you introduced hydrocortisone. That combo of HPTA suppressor + Adrenal suppressor is actually perfect under this model (though I will admit, HC has been hitting individuals hard), theoretically, the HC would need to be run longer alongside a HPTA suppressor to really really stress the loop happening within factory cells. I genuinely think that there’s a certain threshold you can reach where the intracellular SRD5A2 loop breaks, and from there you genuinely don’t have to do anything, the factory goes offline and the system begins to drain, even the brain. The only concern is that upon reboot, the cell might be primed to accidentally catch itself into a loop again (as it’ll be a fairly clean environment, but SRD5A2 will be massively upregulated) so that has to be done cleanly, likely by coming out of a castrated and adrenal suppressed state ONLY with the introduction of androgens so SRD5A2 downregulates.
I'd be very curious what Dr. P makes of running HPTA and HPA suppression concurrently for the full length of a trial (and maybe a shorter/longer trial who knows). Under this framework, it would cause the factory loop to break.
- Also while I’m at it, a lot of people describe a lowered immune response in PFS/PSSD, I have noticed this within myself. Well, immune cells have GABA-A receptors, and GABA signaling is known to dampen some immune responses. So if you flood them with PAMs, it's plausible you'd end up with sluggish immune cells. Makes a lot of sense doesn't it?
—
Of course, the next step is gathering CSFs for much more direct and actionable insights. I figured I’d cook this up while we wait for that to see if I could potentially map out notable aspects of the attractor state.
You may have noticed that I didn’t mention PSSD, I did that on purpose because the data was strictly from PFS studies, not because I don’t think that a lot of these aspects are likely very similar if not identical in PSSD. As a matter of fact, I’ve also modeled how SSRIs cause a similar cascade through the modulation of 3a-HSD, and it holds well (again though, it’s theoretical). If Dr. Powers thinks it’s “go for launch”, I’ll make a post about that too.
Despite having worked on this for basically the entirety of the past week, I have no emotional commitment to this theory, (I suppose this is an advantage of anhedonia) if you find a hole in my work that shatters it into a million pieces, tell me.
Special thanks to u/Excellent-Push2833 for giving me his time over the phone to crunch a lot of this out, as well as providing the studies, and spotting the CSF 5AR anomaly to begin with.
^ his pressure testing of my ideas lead us down the path of uncovering the 5AR2 factory theory. I was about to post this without that entire section.
Who knew two dudes in their early twenties would meta-analyze and theorize this hard.
It wouldn’t have been possible without you Dr. Powers, our entire theoretical foundation lies upon your work.
Thank you Doc 🙏
u/Excellent-Push2833 — 24 days ago
PFS/PSSD Patients: Filing a Medical Board Complaint Finally Got My Prescribing Doctor to Take My Case Seriously
40-year-old PFS patient here. I want to share something that may be useful to other PFS and PSSD sufferers who feel like the medical providers responsible for prescribing their medication have stopped taking their persistent symptoms seriously.
In my case, filing a formal complaint with the Texas Medical Board appears to have made a significant difference in how seriously my prescribing doctor is responding to me.
Earlier this year, I developed persistent sexual symptoms after using 0.75% topical dutasteride. For comparison, the Hims topical dutasteride formulation is 0.1%.
The topical dutasteride was prescribed to me by my hair doctor—the same doctor who had performed my successful hair transplant in October 2025. She was the physician managing my hair-loss treatment and the provider who prescribed the topical dutasteride that I was using when my sexual symptoms began.
I kept this doctor—the doctor who prescribed me the dutasteride—informed of my condition beginning approximately two weeks into my initial crash in March 2026. My symptoms included severe loss of libido, erectile dysfunction, and persistent penile numbness.
For the first three months, she repeatedly assured me that I would return to normal and told me to simply "give it time."
Then, around June 1—roughly three months after my initial crash—the same doctor who prescribed me the topical dutasteride told me that if I hadn't improved by then, dutasteride wasn't the cause to begin with. At one point, she even suggested hypnosis as a possible treatment for what I was experiencing.
Over the following months, I felt that my continued attempts to communicate the seriousness and persistence of my symptoms were not being taken seriously.
That changed after I filed a formal complaint with the Texas Medical Board regarding my prescribing doctor, my dutasteride treatment, and the persistent sexual symptoms I experienced afterward.
I know the Board contacted my doctor because, during our subsequent telehealth appointment, she specifically told me that the Texas Medical Board had contacted her within approximately 24 hours of my filing the complaint. She also discussed the investigation/complaint process and the substantial amount of paperwork she was now required to complete.
Since filing that complaint, something else has changed:
My doctor has started responding to my follow-up emails almost immediately.
We also had a telehealth appointment last Tuesday specifically to discuss my current condition. Even more significantly, the doctor who originally prescribed me the dutasteride is now at least entertaining the possibility of having her practice help reimburse some of the medical expenses I've incurred while seeking treatment for my persistent sexual symptoms.
Those expenses have included specialist appointments, airfare, hotel accommodations, DNA sequencing, a DUTCH hormone test, and extensive bloodwork performed while I've pursued treatment and answers.
There is absolutely no guarantee that her practice will reimburse me, and I don't want to imply otherwise. But simply getting to the point where reimbursement is even being discussed is a major change from where things stood previously.
I'm attaching the email I received today so people can see the response for themselves.
Why am I posting this? Three reasons:
1. Don't be afraid to advocate for yourself.
If you believe you developed persistent symptoms after finasteride, dutasteride, an SSRI/SNRI, or another medication, document what happened.
Keep your emails. Keep your medical records. Keep a timeline showing when you started the medication, when your symptoms appeared, when you discontinued it, which symptoms persisted, and what your providers told you.
Bring your provider legitimate medical literature and pharmacovigilance information regarding persistent adverse effects.
You don't have to quietly disappear just because someone tells you that your symptoms couldn't possibly be related to the medication.
2. If you genuinely believe your care, prescribing, informed consent, or follow-up was inadequate, consider using the formal medical-board complaint process available in your jurisdiction.
In my case, filing with the Texas Medical Board appears to have gotten my prescribing doctor's attention in a way that months of emails did not.
The Board contacted her. She has had to respond to the complaint. And my concerns are now part of a formal process rather than simply another email sitting in someone's inbox.
Medical-board complaints should obviously be truthful, factual, and made in good faith—not used to harass or threaten providers. But patients absolutely have the right to use the regulatory systems that exist specifically to review concerns about medical care.
3. Don't be afraid to ask about reimbursement for expenses you believe resulted from your care.
I originally explored the malpractice route. I contacted approximately 10 local malpractice attorneys, explained my case, and none were interested in taking it.
So I continued documenting everything.
I kept the doctor who prescribed me the dutasteride informed about my symptoms. I explained how profoundly the persistent genital numbness and sexual dysfunction have affected my quality of life. I documented the thousands of dollars I've spent pursuing answers and treatment. And ultimately, I filed a formal complaint with the state medical board.
Now the same doctor who prescribed the dutasteride is at least considering whether her practice will help with those medical expenses.
Again, I have not received compensation, and I don't know whether I ultimately will. I will update everyone if that changes.
But my experience has taught me something important:
PFS AND PSSD PATIENTS: ADVOCATE FOR YOURSELVES.
Document everything.
Communicate with your providers.
Present evidence.
Ask difficult questions.
Request your medical records.
Keep receipts for treatment-related expenses.
And if you sincerely believe there was a problem with your treatment, prescribing, informed consent, or follow-up care, learn how to use the formal complaint process available through your state or country's medical regulator.
For me, filing a complaint with the Texas Medical Board appears to have changed the entire conversation with the doctor who prescribed me dutasteride.
I used the "File a Complaint" process on the Texas Medical Board's website. For those outside Texas, look for the equivalent medical licensing/regulatory authority where your provider practices. That website for me was found at this address:
https://www.tmb.texas.gov/resources/for-the-public/complaint-about-licensee
We can't force providers to agree with us about PFS or PSSD. But we can make sure our experiences are documented, our concerns are heard, and the healthcare system is required to respond through the accountability processes that already exist.
I'll update this post if anything further comes from the Board process or my discussion with my prescribing doctor about reimbursement.
u/Excellent-Push2833 — 1 month ago
Announcement from the largest post drug syndrome group ever made
@everyone Everyone,
I want to make clear here. When you report to the medical board make the report about YOU and YOUR CASE. Not about me or how many other people are suffering. When you email congress make it about US and how were being led by me and use the email template. Also for the med board complaints make the MAIN COMPLAINT. Lack of informed consent ESPECIALLY if you were never told these pills had sexual sides.
I want to make it clear. There is an “impact priority” so to speak here and i want to make sure you all were aware of it. The three things we are doing have different levels of noise/speed they can make an impact. I numbered them in order of noise/speed
- Medical board reports: Were threatening peoples careers here en masse. A lot of you have complained “oh we cant sue so i guess we cant do anything!” Not true. The OPMC
or state equivalent
- will take your complaint seriously and investigate it and your doctor’s career will literally be on the line pending that investigation. I cant emphasize this enough. This is like a bazooka that was buried in the basement that no one knew that we had.
- Emailing congress and the senate with the provided template. If we get ONE representative to take us seriously that is a win I hope you understand. As of right now we have NONE of them backing us.
- Filing FDA reports: Mind you still VERY VERY important just less likely to make an impact in a short amount of time. Think of it as the foundation for the other stuff we are doing. We need that foundation to fall back on. Think of this as stocking up on ammo on the gun we are firing. Not as fun as shooting the gun but just as important.
Next weekend we will be having a mass call in general voice chat to help people report their doctors/ email their reps/ file FDA reports. This will also be a chance to beat out the call that we had that was the LARGEST post drug syndrome call to date where we had a voice chat of 26 members at once.
Here is a link with the time for the call
Join the discord for the time and to join the call https://discord.gg/yCYCs4PVp
This is not legal advice
u/Excellent-Push2833 — 1 month ago
We are mass emailing U.S. Representatives. And I need you to as well.
Below is an announcement I made in my discord linked here: https://discord.gg/yCYCs4PVp I am doxxing myself to the world to make this happen. I need these emails sent out.
u/everyone Please review my video announcement linked here https://drive.google.com/file/d/1t5ui8iTJJrH7Hy1YdqLpWiK0RjtTwsK_/view?usp=sharing
I need these emails sent to your representatives in congress AND the senate you can find who represents you here
https://www.house.gov/representatives/find-your-representative
https://www.senate.gov/senators/
Edit the email wherever there are BRACKETS.
We need to fight to get help.
U.S. Senate: Senators
Dear [name of Senator/Representative]:
I am one of your constituents. I live at [address] I'm emailing to bring an issue to your attention that has been silently ruining the lives of thousands of your constituents for decades. There is a cluster of medical conditions called post-drug syndromes whereby the negative side effects of drugs like finasteride and antidepressants do not cease after the user stops taking them. Examples include Post Finasteride Syndrome and Post SSRI Sexual Dysfunction, often referred to as PFS and PSSD respectively.
Some links for reference:
Dr. Will Powers explains post-drug syndromes: https://www.youtube.com/watch?v=iWFDBRTgT3g
Dr. Josef Witt-Doerring explains PSSD: https://www.youtube.com/watch?v=Tf5EN2JuHHU
Lauren PSSD White House Interview: https://www.c-span.org/clip/public-affairs-event/user-clip-lauren-friedman-discusses-post-ssri-sexual-dysfunction-from-ssris-snris/5200169
YouTube
SIDEfxHUB - PFS & PSSD Patient Organisation
Dr. Will Powers Interview [PFS / PAS / PSSD Summit 2026]
YouTube
Dr. Josef
PSSD (An Explanation For Doctors) #PSSD #psychiatrist #mentalhealth...
Tragically, these conditions are rare, controversial and seriously debilitating. The nation’s medical establishment has yet to officially recognize them. We who suffer from these conditions are often dismissed for seeking help, but we refuse to give up hope. Our group, first organized in May 2026, already counts 400 members and continues its rapid growth under the leadership of USAF Lieutenant David Guerra. He is open to contact and I provided his contact information below.
Linked above, is a video of one of the members of my group that needs help, Lauren; an American woman who went on the white house floor in front of thousands and reluctantly detailed to the world how antidepressants destroyed her life and her sexual function.
To make matters even worse it appears preliminarily that the best way to solve this problem is to chemically castrate yourself for a month to clear androgenic metabolic trash as specified in the linked interview with Dr. Will Powers. One of the most prominent PSSD PFS doctors in the world.
[OFFICIAL NAME], we need your help to get these conditions the attention they deserve so that we may start receiving proper medical care. With no recognized diagnosis and no research funding, patients are left to pursue drastic and speculative interventions on their own, guided by a handful of physicians working outside any institutional support. Many members of our group suffer suicidal ideation as a result of the damage done by these drugs and the desperation of their situation.
[OPTIONAL: As for my personal background…insert PSSD/PFS story here.]
Thank you for your time. If you have any questions, please reach out to me or to Lieutenant Guerra.
[Your name]
[Your email / phone]
2d Lt. David Guerra
davcgue@gmail.com | david.guerra.2@us.af.mil | (631) 455-3499
u/Excellent-Push2833 — 1 month ago
How to Report to the FDA the TUTORIAL
for PFS the term and code are
MEDRA: 10082430
Term: Post 5-alpha-reductase inhibitor syndrome
u/Excellent-Push2833 — 1 month ago
Reminder that PFSN is a nazi organization that limits free speech and to join the largest PFS group ever
374 members and counting
u/Excellent-Push2833 — 2 months ago
▲ 1 r/Antipsychiatry
If you want to take down psychiatry, then the enemy of your enemy is your friend.
Im galvenizing a large group of people harmed by pharmaceuticals. I have 374 I want 1000. I need the people of this subreddit to join so we can actually do something about the harm that was done to us https://discord.gg/jPaN7EEw9
u/Excellent-Push2833 — 2 months ago
Reminder to join the biggest PSSD group ever.
Good Evening everyone,
Here is your reminder to join the biggest and coolest post drug syndrome server ever.
Discord can be easily downloaded from the app store or google play store.
Right now we have 350 members. I want to get to 1000.
The more we band together the more we can get accomplished
u/Excellent-Push2833 — 2 months ago
Members of the Trans community who have used Finasteride and/or SSRIs, please take a moment to read this.
The conversation around Finasteride and SSRIs is alive and well within this subreddit. In the FDA's database, it barely exists. Big Pharma just needs us to stay silent, and so far we've been doing that for them.
The PSSD Network meets with the FDA soon (PFS will be taken to them too). Every report filed before then is evidence in that room. Whatever isn't filed doesn't exist to them.
Not to mention what it'd do for Dr. Powers if researchers started paying closer attention to this. He's been carrying the burden of advancing research alone. Reports are what get other people to look.
So, if these drugs did something to you, whether that be low libido, emotional blunting, or anything else, please file a report. It only takes 5 minutes.
1. Go to https://www.accessdata.fda.gov/scripts/medwatch/
2. Scroll down to "Begin Online Report" and click the middle box — Consumer/Patient (FDA Form 3500B).
3. Fill it out. Name the drug and roughly when you took it (approximate dates are fine.)
4. This part matters the most. In the box where you describe what happened, write the exact term and code that matches you:
PFS: Post 5-alpha-reductase inhibitor syndrome MedDRA 10082430
PSSD: Post-SSRI sexual dysfunction MedDRA 10086208
Then list your symptoms.
5. Complete the rest of the form. Near the end there's a box about sharing your identity with the manufacturer, check it if you don't want the drug company to have your name. Your report counts either way, and FDA is barred by regulation from ever releasing reporter or patient names publicly.
_____________________________________
Thank you to everyone who's already filed. ❤️
Also worth doing: join the SIDEfxHUB registry.
https://registry.sidefxhub.com/
Takes about 2 minutes. It's a patient database researchers pull from when they're recruiting for studies. Signing up means you're on the list when actual research starts happening, and it keeps you in the loop on what's moving.
And if you have questions, come find us.
There are people in there who've filed already and are happy to walk you through it.
u/Excellent-Push2833 — 2 months ago
Enlist in the Post Drug Syndrome Army and post proof of your FDA reports!!!!
Everyone! I have rallied the troops! We have 261 and growing but I WANT YOU for the post drug syndrome army everyone that has reported please post your reports to this subreddit for accountability!
AND JOIN THE POST DRUG ARMY FOR DATA COLLECTION AND FDA REPORT HELP!!!!
JOIN JOIN JOIN JOIN^^^^^^^^^
You can either fight or lay down like a tired defeated dog and take it. Your choice. We choose fight.
u/Excellent-Push2833 — 2 months ago
We are starting a movement. No more waiting around for other people to solve this
Join me https://discord.gg/x9FzVjrud we are growing everyday
In this discord we help for free:
- dig through genomic data
- Gather lab data
- Fill out FDA reports
ANYONE WHO IS CHARGING ANYTHING IN THERE IS NOT ENDORSED BY ME TO DO SO
u/Excellent-Push2833 — 2 months ago
▲ 23 r/PSSD
This issue needs to be politicized to gain traction so that we can get more research and better treatment
In light of recent current events in the USA.Here are all the powerful drugs found in Lindsay Clancy’s system after she strangled her three kids SSRIs are becoming more heavily politicized. We need to use this to our advantage. Why do we not send out a mass email to every single U.S Congressman and Senator explaining to them that people are literally chemically castrating themselves and eating shit (fecal matter transplant) in an attempt to cure themselves of a disease caused by SSRIS of which there is absolutely no help for at all and of which no physician will take us seriously for. Of which we have a subreddit that has 18k weekly members 21k subscribers of sufferers.
Are you telling me that if I email 435 congress people and 100 senators that people are fucking castrating themselves to cure themselves of a disease induced by SSRIS of which a lady has already gone public on the White house floor about that not one of them will take action or reply back of which is RIGHT now in the public eye because of the Lindsey Clancey case. it's the perfect time to strike the nation
u/mobius1014 u/moderator u/pssdnetwork can the pssd network accomplish this. If the answer is no project genome will do it in a probably way less sophisticated way than you guys would. Im not taking no for an answer on this.
u/Excellent-Push2833 — 2 months ago
▲ 4 r/PSSD
To People Who Got PSSD on Withdrawal and then reinstated with the same drug that crashed them what happened
Yes I am well aware that this information is freely available scattered throughout the void. But when a lot of people say reinstatement they do not specify whether or not they went back on the drug that crashed them or a different drug entirely.
The difference matters because each of these drugs inhibit and induce different clearance enzymes. at different rates.
u/Excellent-Push2833 — 2 months ago
▲ 22 r/DrWillPowers
WAR_POWERS PATCHED!
Hey everyone. Turns out there was a massive flaw with the WAR_POWERS program that I put out a month ago. It was missing a bunch of important heterozygous deletions! I put a lot of work into fixing it fast for you all. Here is the finished product!
As always, the program spits out the raw data. I highly encourage you all to read the raw data with a tsv file viewer and not just what the program spits out so that I can continue to improve it. Let me know if you have any questions. I have pushed the new version to the github repository linked here
Also a photo of Doc Powson because "You gotta castrate to uncastrate"
u/Excellent-Push2833 — 2 months ago
▲ 10 r/PSSD
I made a big mistake but i fixed it
https://www.reddit.com/r/PSSD/s/Z0UEAzhrxR
The UGT signal is stronger than I thought. My program was flawed and didnt pick up all heterozygous deletions. I am working on fixing it. But when dr powers said “most of these patients lack glucuronidation in some capacity” well I guess he want kidding
u/Excellent-Push2833 — 2 months ago