Gene families

These enzymes build and interconvert androgens, estrogens, progestogens, glucocorticoids, and neurosteroids from cholesterol. 5-alpha-reductase inhibitors act directly inside this network (SRD5A1/2/3), and SSRIs can alter neurosteroid tone downstream — so inherited variation here is a prime candidate for susceptibility to persistent post-drug phenotypes.

Phase II enzymes — UGT glucuronidation, SULT sulfation, and the sulfatases that reverse it — are the exit routes for androgens and their metabolites. Powers' current PFS model centers on broken clearance: defective UGT2B17/SULT2A1 trapping androgens intracellularly, with SLCO1B1 implicated in recycling of the conjugates. Gut bacterial beta-glucuronidase can undo glucuronidation, linking this family to the microbiome findings.

Nuclear receptors convert steroid signals into lasting gene-expression programs. Androgen-receptor upregulation has been reported in PFS tissue (Khera, cited by Powers), and persistent receptor-level remodeling — or epigenetic silencing of receptor expression, as Powers theorizes — is a leading hypothesis for symptoms that outlast drug exposure.

HSP90-based chaperone and co-chaperone complexes fold steroid receptors and tune their ligand sensitivity, localization, and nuclear trafficking. This machinery — including FKBP5, a stress-axis regulator of the glucocorticoid receptor — sits one layer above the receptors and modulates androgen/glucocorticoid signaling tone.

Chromatin writers, erasers, readers, and remodelers control which genes stay on or off without changing DNA sequence. Epigenetic persistence is the leading hypothesis for post-drug syndromes: Powers theorizes failed removal of epigenetic marks after drug withdrawal (AR/SRD5A1 silencing, HDAC-reversible changes) and reports overrepresentation of epigenetic-gene variants in PFS genomes — all unpublished theorizing.

ABC, SLC, and SLCO membrane transporters govern absorption, distribution, and excretion of drugs and conjugated metabolites. They set systemic exposure to finasteride and SSRIs and clear steroid conjugates — Powers names ABCC transporters and implicates SLCO1B1 in his PFS mechanism (unpublished).

Cytochrome P450 and related enzymes determine how quickly the body clears implicated drugs. CYP2D6 and CYP3A4/5 directly metabolize many SSRIs (and CYP3A4 acts on finasteride); variation here shapes drug exposure and the likelihood of adverse persistence.

Serotonin, dopamine, GABA, glutamate, acetylcholine, and monoamine systems are the direct targets of SSRIs/SNRIs (PSSD) and the downstream effectors of neurosteroids — in Powers' PFS models, GABA-A modulation by allopregnanolone/THDOC links steroid disruption to anhedonia and sexual symptoms.

Mitochondria power the first steps of steroidogenesis (cholesterol delivery) and whole-cell energy production; antioxidant defenses live here too. Mitochondrial dysfunction and oxidative stress are reported in PFS/PSSD patient work and plausibly underlie fatigue, cognitive, and sexual symptoms.

Hypothalamic-pituitary-gonadal signaling and steroid carrier proteins govern testosterone production, bioavailability, and feedback. Disruption of this axis is central to the endocrine phenotype of post-drug syndromes.

Peptide hormones, nitric oxide, and related GPCR signaling modulate sexual function, stress responses, and social behavior — symptom domains prominent in PSSD/PFS. PDE5A and NOS1/3 sit directly in erectile physiology; oxytocin/vasopressin systems shape sexual and social behavior.

Cholesterol is the obligate precursor of every steroid hormone. Lipid-handling genes set the substrate supply for steroidogenesis and neurosteroid synthesis, and several double as drug/xenobiotic transporters.

One-carbon metabolism generates S-adenosylmethionine, the methyl donor for DNA and histone methylation — the epigenetic layer implicated in persistent post-drug changes. Powers reports high MTHFR variant rates in his patient population (unpublished, adjacent work).

Signal transducers and transcription factors orchestrating broad gene-expression programs. Most members have no direct post-drug-syndrome link established; included for completeness of the panel.

RNA polymerase II subunits and general transcription factors — core cellular machinery with no direct post-drug-syndrome link established.

MicroRNA biogenesis and RNA handling — an epigenetic-adjacent regulatory layer with no direct post-drug-syndrome link established.

Cohesin complex and regulators of 3D genome architecture — general cellular function with no direct post-drug-syndrome link established.

Importin/exportin machinery moving proteins and RNAs across the nuclear pore — general cellular function with no direct post-drug-syndrome link established.

Gap-junction, mechanosensitive, and voltage-gated channel genes, several linked to auditory function. No established post-drug-syndrome link; included for completeness of the panel.

Genes with established roles outside the core post-drug-syndrome pathways (blood-pressure regulation, apoptosis, protein turnover). No direct PFS/PSSD link established; included for completeness.

These proteins take vitamin A from blood to gene regulation: RBP4 carries retinol, STRA6 takes it into cells, LRAT stores it, RDH10 and the ALDH1A enzymes turn it into retinoic acid (DHRS3 reverses the first step), CRABP2 carries retinoic acid to the nucleus, the RAR and RXR receptors act on it, and CYP26A1 and CYP26B1 break it down. Isotretinoin, the drug behind post-retinoid sexual dysfunction, is a retinoid; and several retinol dehydrogenases (RDH16, HSD17B6, RDH5) also oxidize androgen metabolites such as 3α-androstanediol, a point of contact with the steroid pathways implicated in PFS.