Re: The Problems with the Theory of Impaired Androgen Signaling caused by Metabolite Accumulation: A Peaceful Challenge to Dr. Powers’ Thesis
u/drwillpowers
r/DrWillPowers2026-09-19T16:47:22Z
Dr Will Powers’ own statements and theorizing
Mentions treatments or doses — not guidance
Summary (paraphrased)
First half of a two-part reply in the same critique thread. Powers reports clinical observations — PFS patients regrowing hair while on treatment, and multiple cases of osteopenia/osteoporosis suggesting failed androgenic or estrogenic signaling. He says UGT2B17 was merely the first statistically anomalous finding; the broader pattern is disruption across many pathways (e.g., ABCC-family stop codons, inability to synthesize glucuronide). He argues PFS is polygenic — "a thousand roads to Rome" — using eye color as an analogy: with ~100 different genes able to produce one phenotype, GWAS-style single-gene hunting fails, which is why PFS GWAS shows nothing. He then describes his THDOC hypothesis: excessive GABA-A positive allosteric modulation by neurosteroids acting like massive chronic endogenous Xanax exposure, with downstream network adaptation. At a PSSD patient's suggestion he trialed indomethacin (an NSAID, imperfect THDOC-synthesis blocker); in the first week two patients had ER-level panic attacks resembling benzodiazepine withdrawal, followed by minor improvements in libido and genital sensation. He reframes treatment as managing an addiction-like dependence on endogenously overproduced neurosteroids requiring slow tapering, and says he has since lowered the dose for new trial patients.
Key points (paraphrased)
- Polygenic model: no single PFS gene; many distinct inborn disruptions converge on the same phenotype, explaining negative GWAS results.
- Clinical signals: hair regrowth on treatment, osteopenia/osteoporosis indicating signaling failure.
- THDOC neurosteroid-excess hypothesis: chronic GABA-A positive modulation → network remodeling, analogous to chronic benzodiazepine exposure.
- Indomethacin probe: severe anxiety/panic on initiation (interpreted as benzo-like withdrawal), then modest libido/sensation gains.
- Treatment reframed as slow adjustment of an endogenous "addiction," not a single corrective dose.
Why it’s in the corpus
Core statement of the neurosteroid-excess/THDOC arm of Powers' model and his main pharmacological probe (indomethacin), plus his clearest articulation of the polygenic "no single gene" defense against negative GWAS findings — directly relevant to both the pharmacology and genetics axes of the corpus.
Context — the post Powers was replying toVerbatim third-party text, shown for context only — not Powers’ statement. Usernames removed.ShowHide
Powers' comment replies to the original post "The Problems with the Theory of Impaired Androgen Signaling caused by Metabolite Accumulation: A Peaceful Challenge to Dr. Powers’ Thesis" by [username removed]:
Yesterday, while commenting on [username removed] post (a very good post, btw), I ended up starting a discussion about the thesis proposed there and some of the problems I have with both it and Dr. Powers' original thesis more broadly. I spent some time thinking about whether I should make a post about this, mainly because I am aware of the multitude of things the doctor has had to deal with lately. However, since he himself seems to encourage people to challenge his theories (and I personally think that this only contributes to refining them), I decided to write this.
I anticipate that this will probably be a long post, and that my goal here is not to attack him or anyone else here. I simply want to peacefully reflect on some aspects of his ideas that seem flawed (or not very plausible) to me.
- The UGT2B17 deletion problem
I think the vast majority of people here are already quite familiar with the theory developed by Dr. Powers in this subreddit over the past few months. Therefore, I will not bother describing it again in all its details, and will only revisit some of its main points so that I can discuss them throughout this post.
In short, we know that Dr. Powers' propositions are based on the idea that PFS patients tend to have, at baseline, glucuronidation problems that make them susceptible to “metabolic catastrophes” when exposed to finasteride. The best example of this, although it does not seem to be limited to it and apparently depends on a number of other […]
(Parent context recovered from the r.genit.al mirror on 2026-10-07; Powers' comment text itself is from John's user-provided export.)
Some fields on this page come from the release’s Markdown edition, which carries text the JSON edition omits.
Related records
- Powers · Reddit post
Untitled long-form research update — new model of PFS/PSSD/post-drug syndromes (Sept 2026)
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Re: The Problems with the Theory of Impaired Androgen Signaling caused by Metabolite Accumulation: A Peaceful Challenge to Dr. Powers’ Thesis
u/drwillpowers · r/DrWillPowers
Long reply to a community member's critique of his impaired-androgen-signaling theory. Powers concedes his earlier strong claim — that androgens must exit through DHT when UGTs are impaired — was overstated: testosterone can route through oxidation…
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