Re: Cure for PFS

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 reaction. He pushed back on the idea that PFS involves androgen-receptor downregulation, arguing instead that metabolites build up massively intracellularly while receptors are actually upregulated, and illustrated signaling with a contrast metaphor: like lidocaine, which first depolarizes pain neurons (causing burning) then leaves them stuck and unable to fire, signaling requires contrast and obliteration of contrast produces numbness. He hypothesized PSSD works similarly — the drug alters some internal mechanism so a concentration gradient of some molecule is obliterated — and listed candidates: sex hormones (since many of these drugs interact with the same enzymes disrupted in PFS), a specific neurotransmitter, or a second messenger like cyclic AMP, while running genomes and labs and "poking the black box" to infer mechanism from outputs. On post-accutane syndrome with genital/sexual symptoms, he proposed the opposite of PFS: baseline defects in sex-hormone transporters and cellular exporters that already trapped androgen metabolites in skin, with accutane further downregulating an already-broken export system (possibly globally, affecting genitals and CNS too), and guessed the PAS solution would be heavily epigenetic.