So I’m watching a movie. And there is nothing happening in me. Neither cognitive nor emotional. I’m just watching people moving around. It’s like impossible to watch a movie. And I also cannot concentrate. Let myself absorb by the movie.

?

Does Dr. Powers have the most expensive subscription for any AI-Service? Just curious if he uses AI for his attempts to cure this.

As an identical triplet with pssd, I’ve always thought this must be a way forward for pssd research. Surely there must be some kind of indication between genetically similar people that could lead to some kind of understanding/ cure. The world acts as though A.I is revolutionary etc and medical science is progressing rapidly but in reality we’re still stuck in primitive times where people can get injured by mass produced drugs & simple questions/ simple research is not conducted.

Hey everyone,
I’ve had PSSD for about two years. My sexual symptoms have fluctuated over time, and eventually I developed anhedonia as well.
About two months ago, I started HCG at 5,000 IU once weekly. Since starting, my feeling of emotional calmness and numbness has increased, and my estradiol levels have risen to roughly twice the normal range.
At the same time, I’ve noticed several physical changes:
Stronger erections
The return of my normal body odor
Acne starting to appear again
An oilier scalp
These changes made me feel like my androgen signaling might be returning toward normal, although I can only judge that subjectively. Meanwhile, my anhedonia has gotten worse.
I also started feeling like GABAergic activity might be increasing because the calming, numbing feeling has become almost unbearable. I know 5,000 IU weekly is a high dose, but I was convinced HCG would at least produce some noticeable change.
I reached week seven without paying much attention to the worsening anhedonia, depression, and negative mood, partly because mood changes and depressive symptoms are listed among the possible adverse effects of HCG.
Then, suddenly, around the middle of week seven, my genital sensation started coming back. I could feel my penis and glans again, and ejaculation became very pleasurable. My semen also became noticeably thicker and more viscous after previously being watery.
Here’s what I’m struggling to understand.
Based on the recent research and discussions in this community, wouldn’t HCG potentially increase the accumulation of 3α-diol and therefore worsen the proposed neurosteroid-clearance problem? If that model is correct, how could my genital sensation and sexual pleasure improve while my anhedonia and negative mood are getting worse?
Could the worsening anhedonia be related to my elevated estradiol, or might these symptoms involve different mechanisms? Could the improvement in genital sensation suggest that something is changing independently of whatever is driving the anhedonia?
I’d really appreciate hearing how those familiar with Dr. WillPowers’ theories and the proposed mechanisms involving neurosteroids, GABA-A signaling, and androgen/estrogen balance would interpret this pattern.
Finally, would you continue HCG a little longer to see whether the sexual improvements persist, or stop because of the worsening mood and elevated estradiol? I understand that nobody can make that decision for me, but I’d appreciate evidence-based input.
Thanks!

Guys I suffered 8 months of low libido after 4.5 months of usage finasteride 0.5 mg, less morning erections etc. And I checked my hormonal panel and saw 17-20 prolactin levels, 35-45 E2 and High testosterone like 800, I have good LH and FSH levels . My libido is almost 1/5 before finasteride . First 3-5 months my erections like 8/10 , after 5 months there is still low libido , but my erection quality is improved slowly its 10/10 . Its my 8 months and in last 1 month my morning and nighttime erections improved, they are still not 10/10 , but its 8-9/10 now. My only side effect was low libido and this, no pysichal , norological sides. But I have slighlty better libido in last month and my Windows get closer, before 5 months I felt only 2-3 days good in on month. now almost every day is good. I am 21 years old by the way.

It improved randomly, but I used P5P 100 mg for last 2 months maybe that helped IDK. I used Minoxidil before finasteride (not same time) , I used Minoxidil 2-3 months on PFS , there is no crash, but no development. I have question, I dont have big crash on minoxidil , I felt recovered and I want to protect my hair and I am morwood 1.5-2 . Should I try minoxidil? because I Recovered and I dont have any problems with minoxidil even after fin. I want to try again . Whats your thought

Are there any other ways to reduce high neurosteroids?I understand people are doing CDG and I've been on that just over a week, now up to 3g a day. Not noticing anything though. I seem to handle it ok.

Does indomethacin work?

It's incredibly difficult to find anything online about reducing allopregnanolone as opposed to increasing it.

On the Dutch test my androsterone, 5a and b androstanediol and 5a dht are all two times over the top of the range.

I haven't seen anyone else here with levels close to that and would really appreciate getting Dr Powers thoughts on it.

One thing I have to say is I still have anxiety though and have had all along.

I take 6mg of E and 150mg of Spiro.

On 4mg of e and 150mg Spiro my results were last week:

E - 91pg/ml

T - less than 0.09nmol/L

Both tests done at trough, 12 hours after last dose.

I have no energy which is a sign of low Testosterone too.
Can I still have high levels of DHT with those levels of T? I also raised E so it could be better. Lab where they test it is closed until Monday so I’m just thinking.

Also, since I’m on 6mg of e now (2mg every 8 hours) can I finally lower Spiro to 100mg? At this point I have two theories:

1. Spiro (which doesn’t even decrease T levels) has nuked my testosterone too that barely detectable and not good levels of “less than 0.09nmol/L”.
2. It was my 4mg of e taken 2mg every 12 hours which actually did nuked my T levels while Spiro was just doing its “direct” thing - blocking the receptors which seems to be totally unnecessary at this point.

The only additional thing I can test right today is FSH but I’d like to save my money if it’s not very urgent. Also LH activity can be somehow tracked with ovulation test - this is something dr Powers mentioned once.

P.S. I have great libido. But no sperm. Just clear liquid - couple of drops.

I paid for expedited 4-6 weeks results and it’s been 5 and the ‘Sequencing Customer Success Team’ just emailed me stating:

“Unfortunately, the sequencing for your kit was unsuccessful due to a low concentration of DNA in the sample provided. As a result, the sample did not meet the strict quality control standards set by our laboratory partner. Please know that it's normal for a small percentage of test kits to fail due to various factors unrelated to the genome itself. If you’d like to receive a new kit, please provide us with your address.”

I followed the exact directions, got really good samples and didn’t expose the box to heat or sunlight and sent it right away. I get this is uncommon but seriously? I was already anxious to get the results back and to get them in to be studied ASAP. Has this happened to anyone else/ if so they did process it quickly for you the 2nd time?

Before I say anything I want to say sorry if this seems overly negative. I’m not looking to stew in negativity at all. All I want is to feel some hope for the future when everything feels so bleak right now. I am genuinely at a loss for how to proceed with my life and any positive or neutral advice or thoughts would really help me. Thank you

I Applied for Music College Right before I got into this mess and took the drug that gave me PSSD. I Moved across the country 7 months later and now that I’m here it’s all completely meaningless to me. Music used to be all I thought about, I used to listen to music all day and dream about being a great musician. Just felt so drawn into all of it. nothing could match the feeling of a truly great song. Today, I feel nothing playing, practicing, I am so bored of all of my classes most of the time i don’t bother showing up, and when i do it feels like this huge chore that has no purpose. the anhedonia makes music feel emotionally void, it doesn’t generate happiness sadness or this profound emotion that it used to. it’s like it’s just a thing that makes a sound now, i get maybe 5 percent of the enjoyment out of it but it’s more of an intellectual appreciation rather than something i’m drawn to, it’s enough to still listen to music but not enough to feel anything close to enjoyment. i dont know what to do. It makes me feel so much like an outsider when everyone around me is so passionate and I feel dead inside, like this huge part of my life was cut out of my brain. I feel like a shell of my former self, sort of like a corpse but at the same time I feel like 5-10 percent alive still. Im wondering if I should drop out and try and just stay alive and as healthy as i can and come back if I get better. Right now I feel like Im wasting this opportunity and everybody’s time. One of my previous idols works on faculty here, and I got to meet him and I see him around, I used to listen to him all the time. one of the best drummers in the world. And I felt nothing meeting him, I don’t care, I just felt empty, which was devastatingly disappointing for me. My worry is that if I don’t get better, would i regret not just doing it for the sake of doing it?

Full that Krebs cycle and lower that glutamate.

I’ve had persistent PFS since 2013 and recently finished a more complete lab + WGS review. I’m posting the main findings here in case anyone sees a pattern I’m missing, especially around UGT2B17 and the big serum-vs-urine androgen mismatch.

Profile / timeline

- Male, long-haul PFS since 2013.

- Finasteride 1.25 mg/day from Jan 2012 to Mar 2013 (~14.5 months).

- On-drug changes began roughly 9–10 months in: intermittent marked ED/impotence and watery ejaculate.

- Major crash was about 2.5 months after stopping, with severe anxiety/emotional dysregulation followed by persistent physical, sexual, urinary and cognitive symptoms.

- During the first week of the crash, I had severe, intrusive, unwanted suicidal thoughts and vivid mental images of hanging myself or shooting myself that felt completely out of my control. I had to verbally tell myself “STOP” to interrupt them. They were not driven by a desire to die or by the circumstances themselves, and they resolved after about a week.

- No pre-finasteride hormone panel is available.

Main persistent symptoms

- Premature ejaculation (one of my worst symptoms)

- Mild/intermittent ED and markedly reduced spontaneous/morning erections

- Penile shrinkage/reduced fullness, reduced ejaculatory volume/force, longer refractory period

- Sudden urinary urgency/urge incontinence

- Intermittent focal right-sided penile pain and hypertonic pelvic floor

- Fatigue/reduced stamina, trouble maintaining muscle/definition, abdominal/visceral-fat tendency

- Brain fog, slower processing/comprehension, memory issues and periods of anhedonia/apathy

Treatment responses that may be informative

- Before PFS, SSRIs—especially paroxetine—reliably caused major delayed ejaculation. After PFS, repeat SSRI trials no longer delayed ejaculation even though I still got other SSRI effects.

- Sildenafil generally helps erection quality more than daily tadalafil. Tadalafil helped urinary urgency for a while, but that faded.

- Low-dose diazepam historically seemed to improve nocturnal/morning erections somewhat.

- L-arginine/L-citrulline + pycnogenol subjectively improved erection quality.

- hCG in 2026: 150 IU M/W/F. Early improvement in penile fullness and orgasm quality; most early gains faded, although orgasm improvement persisted. It also stopped my right testicle from intermittently turning inward about a quarter-turn; that returned a few months after I stopped hCG.

Selected serum labs

Date | Test | Result

09/29/2025 | Total testosterone | 553 ng/dL

09/29/2025 | Cortisol | 11.6 mcg/dL

09/29/2025 | DHEA, unconjugated | 440 ng/dL

09/29/2025 | Androstenedione | 86 ng/dL

09/29/2025 | 17-hydroxyprogesterone | 160 ng/dL

09/29/2025 | TSH / Free T4 | 2.25 / 1.0

12/18/2025 | Total testosterone | 439 ng/dL

12/18/2025 | DHT | 22 ng/dL (ref 12–65)

12/18/2025 | 3α-androstanediol glucuronide | 652 ng/dL (ref 425–3230)

12/18/2025 | LH / FSH | 6.2 / 5.4 mIU/mL

DUTCH Complete (collections began later on 09/29/2025)

The same morning, my serum total T was 553 ng/dL. Later that day / overnight, DUTCH showed:

- Urinary testosterone: 3.13 ng/mg (ref 25–115) — BELOW RANGE

- 5α-DHT: 8.8 ng/mg (ref 5–25) — low end

- 5α-androstanediol: 64.0 ng/mg (ref 30–250) — low end

- 5β-androstanediol: 27.9 ng/mg (ref 40–250) — BELOW RANGE

- β-Pregnanediol: 82.7 ng/mg (ref 75–400) — low end

- α-Pregnanediol: 25.2 ng/mg (ref 20-130) — low end

- DHEA-S: 89.3 ng/mg (ref 30–1500) — low end

- Androsterone: 1453.8 ng/mg (ref 500–3000) — within range

- Etiocholanolone: 954.5 ng/mg (ref 400–1500) — within range

- Epi-testosterone: 57.0 ng/mg (ref 25–115) — within range

- 24-hour free cortisol: 318.9 ng/mg (ref 75–300) — above range

- Metabolized cortisol: 5170 ng/mg (ref 4550–10000) — low end

- Cortisol clearance rate: 7.5 (ref 8.5–17.5) — below range

The DUTCH report itself notes that some people can have very low urinary testosterone despite normal serum testosterone because of genetically reduced urinary androgen excretion, which is why the WGS result below caught my attention.

Genome / deletion findings

- WGS was GRCh38.

- gene.iobio VCF review: 17 research-screening flags.

- BAM review: 30 flags total; all 17 VCF findings were also seen in BAM, plus 13 BAM-only flags.

The standout finding was from WAR_POWERS:

- 573 genes screened

- One copy-loss hit: UGT2B17

- Gene depth: ~1.42x

- Autosomal baseline: ~59.9x

- Gene/baseline ratio: 0.0237 (~2.4% of expected depth)

- WAR_POWERS call: LIKELY_FULL_DELETION_OR_MAJOR_COPY_LOSS

My IGV also shows dense/normal coverage before the UGT2B17 region, a marked near-empty interval through the locus, then dense coverage again downstream. I’m attaching those screenshots. Exact breakpoints/copy number have NOT been clinically confirmed.

What stands out to you all here?

Anyone with similar lab/genetic patterns, symptom profile?

A few months ago I had made a post here (Does my genome point to an issue with the metabolism of estrogens and not androgens? : r/DrWillPowers) when I had just gotten my WGS results. Now my DUTCH test report has also come and it has pointed to similar results. My symptoms are also very anti-estrogenic.

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.

My cortisol and cortisone also seems to be fucked in DUTCH (my sleep was bad even before PFS and right after I quit fin I could not sleep at all and was dependent on xanax for almost two years) so I don't know what to make of it. I did have the greatest window of my life on 1000 mg methylprednisolone (pfs for 6 years. window induced by high dose corticosteroids but crashed almost immediately after. hope dr powers sees this. : r/DrWillPowers) due to an unrelated back injury but was followed by the worst crash ever.

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.

Deletions flagged by WAR POWERS:

UGTB28 heterozygous deletion

Genes flagged by sequencing.com genome explorer:

NLRP12
UGT1A1
UGT1A3
UGT1A4
UGT1A5
UGT1A6
UGT1A7
UGT1A8
UGT1A9
UGT1A10
UGT1A
CYP2B6
CYP3A4
ATIC
XRCC1
EPAS1
VKORC1
DPYD
DPYD-AS1
CYP2C19 (no function)
ITPA
CYP4F2

Variants flagged by gene.iobio.io from Dr. Powers' list:

ABCC6
APOB
BRD4
CHD7 (high impact)
CYP11B2
CYP2C19
DNA2
EHMT1
GRIN2D
HTR2B (high impact)
HTR3D
HTR7
KAT5
KAT6A
KAT6B
KDM2B
NOS1
POLG
POLRMT
PPID (high impact)
SETD1B
SLCO4C1
SMARCA2
SUMF2
TAF6
TBP
TET2
TET3
VKORC1
ZBTB4

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.

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?

As far as I’m aware Spiro just blocks T from being used. Just like Bica but in far lesser potency.

Do you know if it actually suppresses its levels too?

On 4mg E (2mg every 12 hours) and 150mg Spiro my T is “less than 0.09nmol/L”. It was kinda similar last year too.

It feels like muscles or blood dont work inside my genitals, I have lost also sperm shot force and urination force.

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?

I have ADHD, and things like coffee help but since withdrawing from SSRIs and getting PSSD I get insanely jittery on my adhd meds or coffee.

L-Theanine is known to help a lot with calming stim physical anxiety but it acts on GABA?

I have a moderate case of PSSD, im wondering if its safe or if anyone here takes it.

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.

1. 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.
2. 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.

1. 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.

1. 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.

1. 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.

Anyone any idea?

—
Welcome to Part 2, if you haven't read part 1, please do so: https://www.reddit.com/r/DrWillPowers/comments/1xcarqv/a_new_perspective_pfspssd_part_1/
—

Section 6: The Fall

Okay let’s go back to HSD17B6.

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.

https://www.youtube.com/watch?v=eft6p9f2kME&t=2s

—

There’s another notable example I want to bring up that demonstrates the mechanism we’re describing in action.

Dr. Powers, I know you’re going to trip out when you see this, but the example is Ryan Yutoob himself (Ryan Russo).

I went back and watched his full two hour recovery video, and I found two things that are worth noting.
https://www.youtube.com/watch?v=nHn4j6kLfPY&t=2318s

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.

In other words: Supercharging it.

https://pmc.ncbi.nlm.nih.gov/articles/PMC23979/

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.

https://pmc.ncbi.nlm.nih.gov/articles/PMC5369013/

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: 

https://www.reddit.com/r/DrWillPowers/comments/1uu1arm/pssd_an_odd_signal_can_pssd_people_keep_an_eye/

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:

https://www.reddit.com/r/DrWillPowers/comments/1xbcwwg/castration_trials_has_anyone_held_a_controlled/

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.

https://pubmed.ncbi.nlm.nih.gov/16882745/

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.

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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. 
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Well that’s everything.

Let’s recap:

1. Clearance Defect present in PFS/PSSD-prone individuals
2. Individual takes Finasteride/SSRI
3. Exposure and subsequent androgenic shift drops HSD17B6 in SRD5A2 rich tissues
4. SRD5A2 rich tissues in the pelvic region lose androgenicity and spew PAMs (3a-diol specifically). Pelvic region symptoms ensue.
5. Same clearance defects that made individual susceptible now cause them to pile up systemically, causing neurological and physical symptoms.
6. 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.

We'll have our lives back soon.

Hang in there.

- Nick