Re: The Problems with the Theory of Impaired Androgen Signaling caused by Metabolite Accumulation: A Peaceful Challenge to Dr. Powers’ Thesis
u/drwillpowers
r/DrWillPowers2026-09-19T18:28:23Z
Dr Will Powers’ own statements and theorizing
Summary (paraphrased)
Short comment distinguishing two simultaneous processes: peripheral glucuronide buildup ("metabolite crush") and central CNS accumulation of endogenous GABAergic neurosteroids, which he likens to very heavy daily benzodiazepine exposure. He argues studies are "averaging machines" that wash out weak signals from multi-hit disorders and phenotype heterogeneity (androgenic signal loss, melty, neurosteroid excess, neurosteroid depletion). The correct comparison, he says, is counting how many androgen-metabolism genes are disrupted in PFS patients versus healthy finasteride users — looking for one gene fails. He draws an analogy from his transgender genome work: ~200 genomes showed no single "trans gene," but MTF patients (especially those preferring women) overwhelmingly showed failures somewhere in estrogen signaling via ~100 different genetic routes — a "method" to the failure, not one gene. Similarly, there is no PFS gene, only hundreds of risk alleles, and UGT deletions alone are insufficient.
Key points (paraphrased)
- Two-track pathology: peripheral metabolite crush plus central neurosteroid stacking.
- Averaging across heterogeneous phenotypes/multiple hits hides signals; count disrupted genes per patient vs. controls instead of hunting one gene.
- Trans-genome analogy: convergent pathway failure (estrogen signaling) via many different genes.
- Hundreds of PFS risk alleles; UGTs alone insufficient.
Why it’s in the corpus
Powers' methodological manifesto: why conventional single-gene and averaged-cohort studies miss PFS, and his proposed alternative burden-of-disruption comparison. Important framing for how the corpus presents his genetics claims and for evaluating the literature's negative GWAS results.
Context — the post Powers was replying toVerbatim third-party text, shown for context only — not Powers’ statement. Usernames removed.ShowHide
Powers' comment replies to a community member:
There can certainly be debate about the group selected for the study and whether it captures all PFS phenotypes. I don’t disagree with that.
However, my point was more specific: there is a widespread idea, both here and on other forums, that people with PFS have sexual problems because they lack adequate androgenic signaling. That idea is also part of the argument made in your post.
The Basaria study, however, challenges that interpretation. The fact that the PFS group had significant sexual symptoms while showing no evidence of impaired androgenic signaling makes it difficult to attribute those symptoms to reduced peripheral androgenicity, even if such abnormalities may exist in some individuals.
I have some other observations as well, but I’ll wait until you’ve had a chance to comment more thoroughly on the points I raised in the post. In any case, I appreciate your initial comments.
(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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