Re: The Problems with the Theory of Impaired Androgen Signaling caused by Metabolite Accumulation: A Peaceful Challenge to Dr. Powers’ Thesis
u/drwillpowers
r/DrWillPowers2026-09-20T19:15:54Z
Dr Will Powers’ own statements and theorizing
Mentions treatments or doses — not guidance
Summary (paraphrased)
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, aromatization, and 5-beta pathways, and experimental data show UGT2B17 deletion alone does not force elevated DHT, though it changes steroid end-fates and enzyme expression and can combine with other glitches to worsen outcomes. He revises UGT2BXX deletions to "risk modifier, not a direct level-change mutation." He warns that four distinct measures get conflated — unconjugated 3α-androstanediol, the 3-glucuronide, the 17-glucuronide, and the clinical aggregate "3A-ADG" — and that serum lab values don't reflect intracellular metabolite content, which is the core of his theory. He engages the Basaria study (agrees it rules out generalized global androgen deprivation but not tissue-local dysregulation) and the Baylor penile-tissue study (AR overexpression with differential gene expression despite normal circulating metabolites — a "compartment mismatch" he takes as supporting evidence). He names five PFS phenotype categories — high flux, retention, pre-conjugation, globally low 5α, and central-only/neurosteroid — and admits the weakest part of his theory is proving direct metabolite competition at the androgen receptor, which he infers indirectly (e.g., very high 3A-ADG with very low DHT). He notes indomethacin also strongly inhibits AKR1C3 and COXs, so he may have the treatment right but the mechanism wrong, and closes by saying he will amend the model and that a funded research study is being scoped.
Key points (paraphrased)
- Retraction/refinement: UGT2BXX deletions act as a risk modifier in an already disrupted metabolism, not as mutations that reliably raise DHT or any specific steroid.
- Four lab measures (unconjugated 3α-diol, 3-glucuronide, 17-glucuronide, aggregate serum 3A-ADG) are not interchangeable; labs don't capture intracellular content.
- Basaria study rules out global androgen deprivation/hypogonadism/receptor insensitivity but cannot exclude tissue-specific dysregulation.
- Baylor study: normal circulating metabolites + AR overexpression and altered gene expression in penile skin = compartment mismatch.
- Five phenotype bins: high flux, retention, pre-conjugation, low-5α-global, central-only neurosteroid phenotype.
- Direct AR metabolite competition is unproven — inferred indirectly; alternative framing is elimination/retention defects driving compensatory receptor and chromatin remodeling.
Why it’s in the corpus
A major self-correcting statement in which Powers narrows his UGT claim from causal to risk-modifier status — essential for tracking how his model evolved and for avoiding overstatement of the genetics claims in the corpus. It also lays out his five-phenotype framework and his standards of evidence (indirect inference vs. direct proof), which matter for the corpus's methodology thread.
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.
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