Dr Will Powers archive

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…

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…

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…

Second half of the two-part reply, on scientific openness and testability. Powers says he welcomes challenges and is certainly wrong about parts of his model, describing himself as a clinician learning biochemistry and genetics on the fly; chemical castration…

Reply to a poster reporting strong mental benefits from finasteride plus progesterone. Powers theorizes that PFS/PSSD may involve neurosteroid excess rather than deficiency — the traditional deficiency theory, he says, was pushed for 20 years with essentially…

Answer to why calcium D-glucarate causes anxiety. Powers explains it downstream of his core model: buildup of two identified neurosteroids produces chronic GABA-A positive allosteric modulation — like constant endogenous Xanax — forcing downstream systems…

Reply in a thread about a community gene list for gene.iobio analysis (the export also appends some unrelated Powers replies about subreddit scope and a DUTCH repost). Powers describes three PFS phenotypes with overlap driven by each patient's specific gene…

Powers names his three most common PFS subtypes: (1) androgenic signal loss, a metabolite pileup problem; (2) "melty," a glucocorticoid-related (rarely mineralocorticoid) metabolite buildup; (3) neurosteroid disruption — the traditional theory, which he…

Powers' current theory of anhedonic substance blockage: dopaminergic signaling breaks down because efflux pump/transporter defects let substances accumulate intra- or extracellularly, destroying concentration gradients and effectively silencing signaling…

On a proposed cAMP/concentration-gradient theory for PSSD, Powers reports having tried cyproheptadine: it can create temporary windows but doesn't solve the problem — much as bicalutamide doesn't cure PFS — because, in his view, it's not about the receptor…

Reply (partly in Spanish, with complaints about Reddit's auto-translation) to a question about anti-androgens and PFS. Powers confirms that androgenic trapping in skin — secondary to transporter defects and differential enzyme/transporter expression in skin…

Reply to a community member's glucuronidation-theory thought about sulfation labs. Powers notes the discussed factor interacts with androgen production and ABCC-family transporters (he believes ABCB1 specifically, with the caveat that he read it long ago)…

Reply to someone anxious about SNP-array results. Powers says the SNPs flagged by consumer tools are well-known common glitches carried by many healthy people with good outcomes; the variants that matter don't appear on SNP arrays at all. His example: a PFS…

Reply in his post-PFS-congress update thread addressing heritability. Powers distinguishes susceptibility from the syndrome itself: the androgen-metabolism glitches (e.g., a homozygous UGT2B17 deletion) can be passed on, but PFS itself cannot be inherited…

Brief reply in a thread on genome results from a dual PFS/PSSD case (the export concatenates several of Powers' replies, including unrelated remarks on prenatal hormone exposure and transgender genome findings). The genetics-relevant content: Powers expresses…

Comment in a thread on emerging trends in PSSD genomes involving the DBH gene. Powers notes that several PSSD patients have volunteered for the temporary chemical-castration trial if his other PSSD approaches don't work. He says he's increasingly convinced of…

Powers lists his diagnostic array for PFS: blood testosterone, blood DHT, blood DHEAS, blood 3α-androstanediol glucuronide, a urinary DUTCH complete panel, and whole-genome sequencing reviewed against the gene list from his posts. He claims he has yet to find…

Follow-up in the same labs/genome/DUTCH thread. Powers states the T → DHT → 3A-ADG → urinary androgen metabolites pathway is a near-guaranteed anomaly in every PFS patient in his practice on whom he has these tests — zero exceptions. His practical conclusion…

A multi-part comment (the export concatenates several of Powers' replies, including remarks on a post-anastrozole castration-trial image post and the "melty" phenotype). The core diagnostic content: the castration trial's purpose is to test whether the blood…

Brief reply in the glucuronidation-theory thread. Powers proposes a selection bias: men who seek out finasteride do so because DHT is their predominant — possibly their only — metabolism pathway. High baseline DHT may therefore indicate underlying…

Powers reported that relugolix (temporary chemical castration) at least temporarily fully restores normal androgenic signaling, with patients typically noticing improvement within days — return of acne, body odor, and related signs — persisting for weeks…

Powers gave what he called an honest take on the castration trials: temporary chemical castration improves androgenic signaling for patients with androgenic signal loss, but does nearly nothing for brain symptoms such as low libido or anhedonia. He said the…

Powers explained his use of indomethacin as the only available "hammer" for lowering THDOC, while noting he lacks good alternatives — one patient with a single kidney cannot take NSAIDs, diazepam inhibits THDOC synthesis but is itself a GABA-A agonist…

Powers reduced calcium D-glucarate's (CDG) action to a single mechanism — inhibition of bacterial beta-glucuronidase — arguing it only matters for patients who actually have substantial beta-glucuronidase activity, using a house-fire/shed-fire analogy. He…

Powers gave a deliberately simple account of calcium D-glucarate: as a beta-glucuronidase inhibitor it causes glucuronidated compounds and catechols to be dumped into the gut and lost rather than reabsorbed, leaving COMT (catechol-O-methyltransferase) with…

Powers said his progesterone/pregnenolone use is now phenotype-specific: he reserves it for patients with an apparent low-neurosteroid-production picture — chronic anxiety, tremors, paranoia, signs of the GABA system being disrupted in the negative direction…

Powers reported that for the neurosteroid phenotype of PFS, neurosteroid precursors — pregnenolone/progesterone — are the intervention that has worked most often in his experience, which he put at roughly 50 cases, aside from one patient with a paradoxical…

Powers laid out three PFS phenotypes and their prognoses: the neurosteroid phenotype, which he considers recoverable in almost all cases since he has never seen anyone permanently stuck in it; the "melty" phenotype of skin/connective-tissue damage, where he…

Powers argued that finasteride is an irreversible "suicide inhibitor" that permanently disables any 5AR enzyme it touches, requiring 2–3 weeks for the enzyme to be degraded and remade — so even a single pill can suffice if the patient's system is already at…

Powers offered a thought experiment: if a PFS-susceptible man were chemically castrated, given dutasteride for two months, withdrawn, then "uncastrated," he would never develop PFS if the theory is correct — because it is about metabolite load, not just the…

Powers explained that under his model, the risk on quitting finasteride mirrors the risk on starting: the problem is an inability to adjust to the change. Since the drug remains active in the system for about 21 days, he advised anyone fearful of a cessation…

Powers reported having seen recoveries following alteration of gut flora, and cited a PMC article (PMC6962501) for the mechanism: changing the gut microbiome changes beta-glucuronidase production, which changes how much glucuronidated hormone is de-conjugated…

Asked for his opinion on fecal microbiota transplant (FMT), Powers said it simply alters the microbiota, which alters beta-glucuronidase production, which in turn determines how much glucuronidated hormone is de-conjugated in the gut and reabsorbed to add to…

Powers said 17α-hydroxylase deficiency is one of the mutations he has seen several times in PFS genomes, with no 3β-HSD signal observed (though 3α is a different story). He reasoned such a defect would produce higher baseline progesterone in affected males…

The export-captured text of this post presents Powers' observations on hormones and sexuality drawn from 15 years and nearly 5,000 patients: he estimates human sexuality is about 75% hard-coded and 25% hormone-state influenced, citing transgender patients…

Post body unavailable. From the title, Powers announced he was beginning to see recurring trends in the genomes of his PSSD patients, singling out DBH — dopamine beta-hydroxylase, the enzyme converting dopamine to norepinephrine — as one such trend. This is…

Post body unavailable. From the title, Powers publicly floated the hypothesis that PSSD and PFS may actually be the same condition, and solicited patient data to test it. This post predates and anticipates the data-driven unification seen a month later in…

Post body unavailable. From the title (truncated in the export), Powers published a document summarizing the laboratory findings he personally suspects are associated with PFS — evidently a promised deliverable consolidating his biomarker observations (the…

Post body unavailable. From the title (truncated in the export at "elevated sul…"), Powers shared a new thought extending his glucuronidation theory and asked PFS patients whether they have elevated sulf- markers — in context, most plausibly…

Post body unavailable. From the title (truncated in the export), Powers posed a survey-style question to the community: how many PSSD patients were on hormone replacement therapy at the time they developed the condition. This reads as a data-gathering probe…

Post body unavailable. From the title, Powers issued a direct request to PFS and PSSD patients who were taking calcium D-glucarate for symptom relief, asking them to do something for him — evidently a data-collection or experimental ask tied to his CDG work…

Post body unavailable. From the title, Powers surveyed the community for PFS/PSSD/post-drug patients who developed osteoporosis or hypermobility after their onset event. This directly probes the connective-tissue dimension of his model — the "melty" phenotype…

In a reply on his own treatments-list post, Powers states that the mechanism of PFS is, in his view, settled: every PFS patient in his practice shows the same underlying lab pattern with minor variations, which he describes as a near-complete resolution of…

Replying to a PSSD sufferer who theorized that TRT injections had depleted his androgens and caused penile shrinkage, Powers lays out the excess model in plain terms: the problem is too many androgens, not too few — but trapped intracellularly as accumulated…

Powers argues that PFS patients do not lack 5α-reductase — at baseline the enzyme is upregulated, with DUTCH tests often showing a shunt toward 5α metabolites — calling the popular understanding of the disease the inverse of the actual mechanism. He explains…

Powers reports that every PFS genome he has examined matches his theory — including one case he initially thought was an exception, until re-review found the missed defect. He also describes reviewing five anonymized SIDEfxHUB patient lab collections, finding…

Replying to a commenter who posted blood and DUTCH results — midrange blood testosterone with near-zero urinary androgens, no finasteride history but past ashwagandha, saw palmetto, Zoloft and Cymbalta exposure — Powers sketches informal PFS subtypes, the…

Answering a commenter who asked whether the model works in reverse — they were not notably masculine before finasteride/dutasteride — Powers describes a threshold dynamic: patients with only the DHT-metabolism pathway available can present highly…

Replying to [username removed]'s question about why East Asian populations — with roughly 60–70% homozygous UGT2B17 deletion prevalence — don't show higher PFS rates, Powers states that glucuronidation failure alone is insufficient: it was merely the first…

Answering questions about variable onset and post-cessation crashes, Powers gives three linked explanations. First, milder or slower onsets reflect fewer defects — it takes longer to reach threshold. Second, people who crash on quitting had upregulated…

Replying to a cis male who experienced severe 5ARI side effects without developing PFS, Powers tells him his epigenetic system is "rewritable" (DVD-RW) rather than stuck (DVD-R), and suggests most people with PFS share the same side-effect genes — the…

On r/tressless, answering whether flushing metabolites would let the body normalize or whether damage is irreversible, Powers reports early results from the "unplug and reboot" protocol: his first patient reached female-range testosterone/DHT in about two…

Replying to a post-letrozole case with PFS-identical symptoms (a Klinefelter patient), Powers frames PFS and PSSD as the same mechanism in different flavors — inborn metabolic error plus drug, with recovery blocked by an epigenetic glitch — and notes…

Replying to a commenter theorizing about common denominators among disparate reported PSSD recoveries (a GSK3β-inhibition hypothesis), Powers states there is no single PFS mutation — he has identified on the order of 30, and it is their combination that…

Answering specificity concerns — UGT2B17 deletion is common, so would testing just produce nocebo? — Powers states that a heterozygous UGT2B17 deletion alone is insufficient for PFS, citing his own long-term finasteride/dutasteride use without issue and his…

Reading a commenter's labs in the PFS/PSSD-sameness data thread, Powers identifies a likely heterozygous UGT2B17 defect: DHT high but the 3α metabolite at the very bottom — the conversion step incompletely performed, less than half of what the androgen load…

Replying to a commenter flagging CYP2D6 slow-metabolizer variants surfacing in community-read PSSD genomes, Powers describes a genetic variant that amplifies SSRI exposure — a standard dose can feel like three to four times the dose — and notes the same gene…

Asked whether DHEA is still used alongside progesterone/pregnenolone for neurosteroid-type patients, Powers splits PSSD into androgenic-metabolite vs strictly-neurosteroid cases. Pregnenolone: yes for strictly-neurosteroid PSSD — it backfills the DHEA…

Replying to an r/autism OP reporting striking mental clarity in the first weeks of MTF HRT, Powers sketches a mechanism centered on COMT (catechol-O-methyltransferase): the enzyme both clears catechol estrogens and breaks down dopamine. In slow-COMT (val/met)…

In the PAS markers thread, answering what tests a PAS sufferer should pursue, Powers reports a new lead he stumbled on: the constitutive androstane receptor (CAR) dimerizes with the retinoid X receptor (RXR) — a molecular intersection of neurosteroids…

In the r/PSSD data-request thread, Powers states that most people recover from SSRI sexual dysfunction on stopping; those who don't likely carry an inborn metabolic error or genetic anomaly — e.g., HDAC dysfunction or methylation/demethylation problems…

Powers says he has few PSSD genomes so far; his working model mirrors PFS — inborn anomalies create a fragile system that cannot adapt to the drug — with a second group that adapts while on the drug but fails epigenetic reprogramming after stopping. His PSSD…

Replying to reports of corticosteroid and potassium-iodide windows, Powers theorizes that potassium iodide affects transporters relevant to his model; that thyroid upregulates UGT activity; and that iodine feeds sulfation — one of the last clearance routes…

Powers gives his canonical definitions: windows happen when something clears enough metabolite load that androgens can reach the receptor again; crashes happen when something slows that clearance. Patients are stuck in a configuration they would normally…

Replying to a community member's 3α-HSD oxidation-inhibition proposal — fluoxetine inhibiting allopregnanolone oxidation via RoDH-4 as the direct drug→metabolite-accumulation link — Powers contrasts the two syndromes: PFS, he says, rests on an overwhelming…

In his PSSD lab-signal request thread, Powers reports that PSSD patients trying zuranolone had horrific effects. His point, he stresses, is not that all PSSD is high-neurosteroid — but that some cases could be, and ignoring the possibility is unwise…

In the r/PSSD thread where he introduced himself as a doctor treating both conditions, Powers gives his current ranking of SSRI effects on allopregnanolone: SSRIs whose names begin with F raise it; paroxetine raises it slightly; the rest are slightly to…

In the 3a-diol plasma/CSF findings thread, Powers theorizes that the sexual-sensation problem is not loss of feeling but loss of erogenous integration — sensation is felt but not registered as sexually pleasurable. He proposes an unusual test: finding a…

Replying to a commenter proposing HPTA shutdown followed by bypass hormones (Primobolan/E2/progesterone) to route around the UGT2B17 clearance defect, Powers describes his current protocol direction: shut the HPA axis fully off (LH/FSH to zero), then track…

Powers gives case notes: one patient with an unmeasurably high 3α value, another with astronomical urinary testosterone — suggesting that normalization of these markers may track recovery, though patient-dependently. He mentions valproic acid (VPA) as "DNA…

Answering the objection that some people were cured by TRT/anabolic-steroid courses — which his theory supposedly disallows — Powers theorizes that exposing the system to a potent synthetic androgen could epigenetically upregulate alternative…

Replying to a question — relayed via a friend — about how androgen-clearance problems could produce anhedonia, Powers points readers to his cyclic-AMP/concentration-gradient theory for numbness and anhedonia, and states he does not consider the conditions…

In the r/AccutaneRecovery cross-post thread, Powers states he sees two distinct post-accutane syndromes: one essentially identical to PSSD (mostly sexual symptoms), another of physical degeneration — collagen, skin, and joint damage. Since isotretinoin is…

In the "why do anti-androgens help" thread, Powers reasons through a case: a gay man with severe lifelong cystic acne but low muscle mass and low testosterone may have an ABCC transporter defect trapping androgens in skin while starving the rest of the body…

Replying in Spanish to a Spanish-speaking commenter, Powers states his primary PAS theory: in some people accutane epigenetically and permanently tones down androgen-export transporters — curing acne in those with overactive transport, but in people with an…

In his PSSD hormone-exposure survey thread, Powers states that stinging nettle is a weak 5ARI which could push someone near the threshold over it, citing saw-palmetto cases. The problem, he argues, is not unique to finasteride but to the individual's…

In the post-anastrozole castration-trial thread, Powers lays out his developing excess-side theory: after the drug, susceptible people go through a crash phase of severe anxiety, paranoia and panic, which over months remodels into a different deep depression…

Replying to concerns about trying the castration protocol with severe osteoporosis and soft-tissue problems, Powers states the conundrum plainly: if a month of chemical castration restores normal androgen signaling in someone effectively castrated for a…

In the "melty skin" explainer thread, Powers states the PFS mechanism is figured out; the remaining questions are (1) the best treatment — he reports one working for androgenic-signaling loss and some melty-skin cases, with neurosteroid issues mostly…

In the "PFS-mark" dispute thread, Powers describes a patient who had a lasting negative reaction to a single course of progesterone at roughly triple normal daily production — something he says never happened in five years of using pregnenolone/progesterone…

Answering a hypothetical about working up genital numbness with completely normal baseline labs, Powers gives a clinical pearl: rule out peripheral-nerve causes of numbness/ED — and reports finding Tarlov cysts impinging the S2–S4 nerve roots more often than…

Reacting to a community member's discovery of a twelve-year-old propeciahelp comment that independently derived the neurosteroid-excess model, Powers says the remaining barrier to treatment is characterizing each patient's specific neurosteroid profile and…

Powers marvels that a non-physician reached the same conclusion he did about the mechanism a decade ago using only forum access, calling it astounding and expressing a wish to know who the author was.

Answering a patient who blamed a two-day, 250 mg course of calcium-D-glucarate taken 25 days earlier for tanked testosterone/estrogen and full-body anhedonia, Powers gives a pharmacokinetic rebuttal: CDG acts for roughly 8 hours by directly inhibiting…

Powers quantifies the dose argument against the CDG crash claim: broccoli contains roughly 3.5 g of glucaric acid per kilogram — the precursor to the commercial calcium-D-glucarate salt and the natural beta-glucuronidase inhibitor — so one dinner's broccoli…

In the same CDG thread, Powers condenses the dose argument: he does not say CDG cannot do anything — he says it cannot do anything at 250 mg taken 25 days ago, because a single apple delivers more D-glucaric acid than that dose.

Replying to an AFAB trans/NB person with 3-beta-hydroxylase CAH on cortisol replacement who has been on testosterone for 15+ years without ever achieving menstrual cessation (despite multiple birth-control pills, a Mirena IUD, and depot injections), Powers…

Replying to a user's report of sexual-function collapse after six days of 500 mg/day calcium-D-glucarate (morning erections ceased, libido 2/10 → 0/10, emotional flattening), Powers gives a mechanistic account: CDG inhibits the reabsorption of glucuronide…

Replying to [username removed]'s question ("Have you ever tried this on a trans woman who goes through weird monthly cycles? 🤔" — Oct 9 20:03 UTC), Powers responds: "Define weird monthly cycles." Two words; a clarification request, not a theory statement.