SRD5A1
steroid 5 alpha-reductase 1
Named by Dr Will Powers
Gene summary
A protein-coding gene on chromosome 5 (steroid hormone synthesis). Steroid 5-alpha-reductase (EC 1.3.99.5) catalyzes the conversion of testosterone into the more potent androgen, dihydrotestosterone (DHT). Also see SRD5A2 (MIM 607306).
Source: NCBI Gene, accessed 2026-10-07.
Protein reference (UniProt)
- Protein
3-oxo-5-alpha-steroid 4-dehydrogenase 1
- Function
Catalyzes the irreversible stereospecific reduction of the delta 4,5 bond (double bond between carbons 4 and 5) of various 3-oxo steroids (3-keto steroids) producing their 5alpha dihydro-3-oxo forms. Converts testosterone into 5-alpha-dihydrotestosterone (DHT), a more potent androgen as it is the preferred ligand for androgen receptor (AR) transactivation, making this reaction a key step in male sexual differentiation during development. Besides testosterone, it can also act on other steroids, including progesterone, androstenedione, and corticoids, producing metabolites with diverse roles. Hence, it plays a central role in sexual differentiation and androgen physiology.
- Subcellular location
Microsome membrane; Endoplasmic reticulum membrane.
- Tissue specificity
Liver and prostate (at a low level).
Source: UniProtKB/Swiss-Prot P18405, release 2026_03, licensed CC BY 4.0. This is the protein’s normal biology, not evidence about post-drug syndromes; associated conditions are inherited disorders of the gene, not PFS, PSSD or PRSD.
Why its pathway is in the library
Steroid-synthesis enzymes sit directly on the pathways perturbed by 5-alpha-reductase inhibitors and SSRIs; inherited variation here is a candidate susceptibility factor for persistent post-drug phenotypes.
Written for the whole steroid synthesis family, not for SRD5A1 specifically.
Powers’ note (his unpublished theorizing)
Named by Powers (DWP-003, unpublished): described as epigenetically silenceable, with silencing reportedly reversible by valproic acid (an HDAC inhibitor) in his patients over months. Unpublished clinical theorizing — not medical advice.
Narrative library record
Function
3-oxo-5-alpha-steroid 4-dehydrogenase 1; converts testosterone to the more potent DHT and reduces progesterone, corticosterone, and other steroids via 5-alpha-reduction (hydride transfer from NADPH to carbon 5). Also active in bile-acid biosynthesis; broadly expressed including skin and liver.
Corpus relevance
One of three 5-alpha-reductase isoenzymes reviewed in PFS-011 (Rodriguez-Cerdeira systematic review of 83 articles on SRD5A neurosteroid biology). Finasteride inhibits type 2 (and type 1 at higher doses); dutasteride blocks types 1 and 2 - so SRD5A1 is the isoenzyme left partially active under finasteride, relevant to differential drug effects. The 5AR enzymes are the direct drug targets whose blockade initiates every downstream PFS mechanism in the corpus. Attribution: peer-reviewed (drug-target biology).
Powers’ claims naming SRD5A1
- Powers gene claim
AKR1C1; AKR1C2; AKR1C3; AKR1C4 — defects (unspecified)
Confidence: direct
Defects in AKR1C enzymes can contribute, but their products are mostly cleared via glucuronidation — so a bad glucuronidation enzyme (UGT2B1X) is the more fundamental defect. AKR1C enzymes and SRD5A1 are also epigenetically silenceable, and valproic acid may…
AKR1C1AKR1C2AKR1C3AKR1C4SRD5A1PGL-AKR1C1-AKR1C2-AKR1C3-AKR1C4circa May 2026PFS - Powers gene claim
SRD5A1 — epigenetic silencing (acquired, not germline)
Confidence: direct
SRD5A1 (like AKR1C enzymes) can be epigenetically silenced, and valproic acid (an HDAC inhibitor) appears able to reverse this in his patients, with slow normalization over months.
SRD5A1PGL-SRD5A1circa May 2026PFS
Mentioned in 14 corpus records
- Powers · Reddit post
I think I have figured out at least one specific phenotype of PFS, and it is different from the "allopregnanolone" theory
u/drwillpowers · r/DrWillPowers
Powers' key genetics-first post: he proposed a specific PFS phenotype whose "base, core defect" is defective UGT2B17, disabling testosterone's main glucuronidation exit pathway. Carriers show shockingly low 3α-androstanediol glucuronide and near-zero urinary…
AKR1C1AKR1C2AKR1C3AKR1C4HSD17B2+3DWP-0032026PFSCore corpus - Peer-reviewed paper
5α-Reductase Isoenzymes: From Neurosteroid Biosynthesis to Neuropsychiatric Outcomes
Rodríguez-Cerdeira, Carmen; Freus, Marika; Misiakiewicz-Has, Kamila; Pilutin, Anna; Kolasa, Agnieszka; Maksym, Radoslaw; Kajdy, Anna · NeuroSci (systematic review; PRISMA 2020)
PRISMA systematic review (PubMed/Scopus/Web of Science to Feb 2025; 83 included articles) on SRD5A1/2/3 tissue distribution: SRD5A1 drives CNS allopregnanolone synthesis; impaired neurosteroidogenesis from 5α-reductase inhibition is linked to anxiety…
SRD5A1SRD5A2SRD5A3PFS-0112025Core corpus - Peer-reviewed paper
Prefrontal 5α-reductase 2 mediates male-specific acute stress response
Roberto Cadeddu; Giulia Braccagni; Gabriele Floris; Caterina Branca; Eleonora Corridori; Sara Salviati; Pilar Sánchez; Luca Spiro… · Science Advances
Acute stress selectively raises 5α-reductase type 2 — not type 1 — in the medial prefrontal cortex of male rats, and 5αR2 knockdown or knockout blunts the hormonal and behavioral stress response in males only. The authors demonstrate a division of labor: 5αR1…
SRD5A1SRD5A2MECH-0082025Systems review · Oct 2026 - Peer-reviewed paper
Epigenetic regulation of 5α reductase-1 underlies adaptive plasticity of reproductive function and pubertal timing
Ben Bar-Sadeh; Or E. Amichai; Lilach Pnueli; Khurshida Begum; Gregory Leeman; Richard D. Emes; Reinhard Stöger; Gillian R. Bentley · BMC Biology
Women who experienced high energetic demands in childhood show altered adult ovarian function and shorter reproductive lifespan, suggesting early-life programming of reproduction. Combining a mouse model with methylation analysis of proxy-tissue DNA from a…
ARSRD5A1LIT-0582022Literature sweep · Oct 2026 - Peer-reviewed paper
Methylated CpG dinucleotides in the 5-alpha reductase 2 gene may explain finasteride resistance in benign prostatic enlargement patients
Zhemin Lin, Dongdong Fan, Song Jin, Zhanliang Liu, Yi-Nong Niu · Asian Journal of Andrology
Finds methylated CpG dinucleotides in the SRD5A2 gene and proposes that methylation status of the 5-alpha-reductase-2 gene explains variable finasteride response in benign prostatic enlargement patients. DNA methylation at the very locus encoding…
SRD5A1SRD5A2EPI-0022021PFSEpigenetics supplement · Oct 2026 - Peer-reviewed paperPSSD Discord pickSIDEfxHUB pick
Altered methylation pattern of the SRD5A2 gene in the cerebrospinal fluid of post-finasteride patients: a pilot study
Roberto Cosimo Melcangi, Livio Casarini, Marco Marino, Daniele Santi, Samantha Sperduti, Silvia Giatti, Silvia Diviccaro, Maria Grimoldi… · Endocrine Connections
In this pilot case-control study, 16 PFS patients were compared with 36 controls who had never used finasteride: 18 surgical patients giving cerebrospinal fluid (2 of whom also gave blood) and 18 blood-only donors; controls' mean age was 40.8 years vs 34.5 in…
SRD5A1SRD5A2DISC-0252019PFSPSSDPSSD Discord picks - Peer-reviewed paper
Steroid 5α-reductase isozymes in the adult female rat brain: central role of dihydrotestosterone
J. M. Torres; E. Ortega · Journal of Molecular Endocrinology
5-alpha-reductase exists as two isoforms, type 1 associated with catabolic functions and type 2 with sexually dimorphic functions, and the authors had previously shown both are present and oppositely regulated by androgens in the adult male rat brain. This…
ARSRD5A1SRD5A2LIT-0572006PFSLiterature sweep · Oct 2026 - Peer-reviewed paper
Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis
Roberto C. Agís-Balboa; Graziano Pinna; Adrian Zhubi; Ekrem Maloku; Marin Veldic; Erminio Costa; Alessandro Guidotti · Proceedings of the National Academy of Sciences
Using in situ hybridization combined with neuronal and glial markers, the authors mapped 5α-reductase type I and 3α-hydroxysteroid dehydrogenase — the two enzymes that convert progesterone and deoxycorticosterone into allopregnanolone and THDOC — across mouse…
SRD5A1MECH-0072006Systems review · Oct 2026 - Glossary term
SRD5A1
enzyme
Gene encoding 5-alpha-reductase type 1, the isoenzyme expressed broadly including brain and liver. Covered in the systematic review of 5-alpha-reductase isoenzyme biology (PFS-011).
SRD5A1GL-srd5a1PFSCore corpus - Gene recordPowers’ theory
AKR1C1 — aldo-keto reductase family 1 member C1
10p15-p14 (AKR1C gene cluster, chromosome 10)
Cytosolic NAD(P)H-dependent oxidoreductase with mainly 20-alpha-hydroxysteroid dehydrogenase activity; converts progesterone to the inactive 20-alpha-hydroxyprogesterone and also reduces a range of aldehydes, ketones, and xenobiotics. One of four closely…
AKR1C1AKR1C2AKR1C3AKR1C4SRD5A1+1GENE-AKR1C1PFSCore corpus - Gene record
3-oxo-5-alpha-steroid 4-dehydrogenase 2; the dominant isoenzyme in prostate and genital skin, converting testosterone to DHT. Loss-of-function variants cause 5-alpha-reductase-2 deficiency, a 46,XY difference of sex development - direct human proof of what…
AKR1C2ARSRD5A1SRD5A2SRD5A3GENE-SRD5A2PFSCore corpus - Gene record
Third 5-alpha-reductase isoenzyme (318 amino acids; about 20 percent homology with types 1 and 2); less characterized than types 1 and 2, with roles in protein N-glycosylation as well as steroid reduction.
SRD5A1SRD5A2SRD5A3GENE-SRD5A3PFSCore corpus - Gene record
Bifunctional enzyme oxidizing delta-5-3-beta-hydroxysteroids and isomerizing them to delta-4-ketosteroids - an essential step in making all classes of active steroid hormones. HSD3B1 is expressed in placenta and peripheral tissues (critical for placental…
AKR1C1CYP17A1HSD3B1HSD3B2SRD5A1GENE-HSD3B1PFSPSSDCore corpus - Gene record
Dual-function P450 enzyme with 17-alpha-hydroxylase and 17,20-lyase activities - the key branch point of steroidogenesis that diverts pregnenolone/progesterone toward glucocorticoids versus DHEA and androstenedione (androgen precursors). Expressed in…
ARCYP17A1CYP19A1HSD3B2SRD5A1GENE-CYP17A1PFSPSSDCore corpus
Also in steroid hormone synthesis
All 38 genes- SRD5A2
steroid 5 alpha-reductase 2
chr 2· Steroid synthesis· 19 records - AKR1C2Powers
aldo-keto reductase family 1 member C2
chr 10· Steroid synthesis· 12 records - AKR1C3Powers
aldo-keto reductase family 1 member C3
chr 10· Steroid synthesis· 9 records - CYP17A1
cytochrome P450 family 17 subfamily A member 1
chr 10· Steroid synthesis· 9 records - AKR1C4Powers
aldo-keto reductase family 1 member C4
chr 10· Steroid synthesis· 8 records - AKR1C1Powers
aldo-keto reductase family 1 member C1
chr 10· Steroid synthesis· 7 records - HSD3B2
hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2
chr 1· Steroid synthesis· 7 records - SRD5A3
steroid 5 alpha-reductase 3
chr 4· Steroid synthesis· 6 records
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