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Not medical advice. A living research archive of historical and continually changing sources, for research and personal reference only. Summaries are paraphrases — verify against the originals. Full disclaimer
Not medical advice. A living research archive of historical and continually changing sources, for research and personal reference only. Summaries are paraphrases — verify against the originals. Full disclaimer
supportedsuggestedunstudiedconflicting
The single best-evidenced PFS mechanism (three independent CSF cohorts). The PSSD link rests on one 2026 review plus preclinical data — plausible but thinner.
CSF LC-MS/MS in PFS patients shows persistently decreased tetrahydroprogesterone, isopregnanolone, DHT and related neurosteroids with elevated testosterone/estradiol after discontinuation.
Xie 2026 review identifies allopregnanolone depletion via 5α-reductase inhibition as a PSSD mechanism; paroxetine disrupts neurosteroidogenesis in rats with incomplete reversal on withdrawal — no human CSF studies in corpus.
No corpus evidence on isotretinoin and neurosteroids.
Single-investigator hypothesis (Reddit post + interview); unpublished, untested. Flagged as speculation — but it is Powers' current model and must be represented.
Powers 2026 proposes the anhedonia/low-libido subtype is driven by EXCESS of GABA-A-active neurosteroids (THDOC, androsterone) causing network remodeling — directly contradicting his 2020 deficiency model and Melcangi depletion data; he reconciles via subtypes.
Powers extends the excess model to an anhedonic PSSD subtype via a shared GABAergic mechanism, while Xie 2026 maintains the depletion model for PSSD.
No corpus evidence.
PFS evidence converges from three independent angles (transcriptomics, review model, clinical theorizing) but the key primary study is preliminary.
Baylor penile-skin microarray found significant AR overexpression among 3,700+ differentially expressed genes (preliminary, conference-level); Traish 2020 proposes AR upregulation as part of the epigenetic model; Powers' intracrine model centers on upregulated AR crowded by weak metabolites.
Included in Rege's shared-mechanism framing and the Giatti 2024 bridge; no PSSD-specific AR expression data in corpus.
No corpus evidence.
The strongest human genetic-susceptibility finding in the corpus, from two studies by one Trieste group whose PFS cohorts (69 and 66) may overlap (SIDE-011, PFS-007); a US study of 25 men found no explanatory AR or SRD5A variants (SIDE-010). PFS-only; needs independent replication.
Cauci 2017 (n=66 PFS patients): (CAG)n and (GGN)n repeat lengths associated with different symptom patterns (libido, genital sensitivity, muscle, skin), U-shaped for some symptoms.
Peleg 2022 lists genetic predisposition as a PSSD risk factor; Rege cites glutamatergic (not AR) polymorphisms — no AR-specific PSSD data in corpus.
No corpus evidence.
The best-supported SHARED mechanism — the leading candidate for why effects outlast drug exposure across syndromes.
Traish 2018/2020 drug-induced epigenetics model; Melcangi-team CSF gene-promoter methylation finding (via Rege); Powers reports recurrent ARID1A/CHD8/HDAC10 glitches in PFS genomes.
Csoka/Szyf 2009 pharmacoepigenetics hypothesis; Xie 2026 epigenetic silencing of dopaminergic reward circuits; persistent transcriptomic changes after paroxetine withdrawal in rats (PSSD-012); Rege mechanism 4.
No PRSD-specific epigenetic data in corpus; Healy cross-drug grouping hypothesizes a shared downstream pathway but provides no retinoid epigenetic evidence.
Human PFS data is preliminary; PSSD data is preclinical. Both point the same direction but neither is definitive.
Baylor 2021 microarray: 1,446 genes over-expressed / 2,318 under-expressed in PFS penile skin vs controls — flagged preliminary (conference report, journal publication unconfirmed).
Giatti 2024: whole-transcriptome changes in rat hypothalamus/nucleus accumbens after paroxetine, some persisting after withdrawal — preclinical only.
No corpus evidence.
The most PSSD-specific mechanism in the matrix — the one place PSSD evidence outruns PFS evidence.
Giatti 2024 bridge includes serotonin/dopamine/catecholamine signaling; Rege shared mechanisms 1–2 (testosterone→dopamine via nitric oxide synthase; serotonergic inhibition of dopamine) — no PFS-primary data.
Bala 2018 and Xie 2026 reviews: 5-HT1A desensitization and serotonergic inhibition of nucleus accumbens dopamine as core PSSD pathophysiology (emotional blunting + sexual dysfunction).
No corpus evidence.
Convergent but early: a review-level claim for PFS, one preclinical study for PSSD. Powers separately implicates gut beta-glucuronidase in androgen excretion (DWP-002).
Giatti 2024 bridge lists gut microbiota; Rege PFS mechanism 5: finasteride reduces gut microbiome diversity — review/video level.
Diviccaro 2022 (PSSD-011): paroxetine altered colonic steroidogenesis and microbiota in rats — preclinical; Rege PSSD mechanism 6.
No corpus evidence.
Symptom-level evidence is strong for both. Large-fibre nerve tests were abnormal in a minority of PFS patients (DISC-013) and normal in most PSSD patients tested (CUR-003); small fibres have been looked at only by corneal microscopy in tiny mixed series, and no skin-biopsy study exists.
Melcangi 2017 (DISC-013, n=16): abnormal pudendal somatosensory evoked potentials in 4 of 16, the men with severe erectile dysfunction — the first objective neuropathy evidence in PFS.
Genital anesthesia is the hallmark PSSD symptom, independent of depression (Ben-Sheetrit 2015; Healy 2022 criteria). Objective testing now exists: at Queen Square all 9 PSSD patients had genital sensory loss on examination, but pelvic neurophysiology (pudendal, dermatomal and tibial SEPs) was normal in 8, which the authors read as a central mechanism (CUR-003); a 43-patient chart review used quantitative sensory testing (LIT-033); corneal confocal microscopy in small mixed post-drug series suggests small-fibre involvement (LIT-040, SIDE-002).
No corpus evidence.
Thin on both sides; mostly clinical observation and review-level claims. Notably, routine HPG labs are often normal in these patients — which is itself informative.
Powers clinical observations: rectal-progesterone suppression of LH/FSH (2019 lecture), HPTA-shutdown 'window then crash' patient reports — no formal HPG study in corpus.
Rege PSSD mechanism 3: decreased gonadotropins/testosterone with elevated prolactin (dopamine–prolactin inverse relationship) — review/video level.
No corpus evidence.
The newest and least-tested mechanism in the matrix — Powers' signature contribution. Testable via the SIDEfxHUB three-test battery; treat as hypothesis.
Powers 2026 only: WGS implicates UGT/ABCC variants; >50% of his PFS patients show near-zero urinary androgens on DUTCH; 3α-androstanediol glucuronide assays 'maxing out' — unpublished, single-investigator.
Powers describes PSSD as 'same but different... just which metabolite problem, which gene' — no PSSD-specific data.
No corpus evidence.
Intriguing because it is one of very few mechanisms attributed to BOTH drug classes by the same source — but it appears only in a YouTube explainer, not in the peer-reviewed corpus. Verify before citing.
Rege video only: finasteride inhibits phenylethanolamine N-methyltransferase (noradrenaline→adrenaline); excess noradrenaline favors flaccid state. Single video source.
Rege video only: paroxetine likewise inhibits PNMT — presented as a shared mechanism. Single video source.
No corpus evidence.