AKR1C2
aldo-keto reductase family 1 member C2
Theoretical — per Powers
Gene summary
A protein-coding gene on chromosome 10 (steroid hormone synthesis, steroid conjugation and clearance). Encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. These enzymes catalyze the conversion of aldehydes and ketones to their corresponding alcohols using NADH and/or NADPH as cofactors.
Source: NCBI Gene, accessed 2026-10-07.
Protein reference (UniProt)
- Protein
Aldo-keto reductase family 1 member C2
- Function (excerpt)
Cytosolic aldo-keto reductase that catalyzes NADPH-dependent reduction of ketosteroids to hydroxysteroids. Displays broad substrate specificity with distinct positional and stereochemistry, primarily generating 3alpha-hydroxysteroids, but also 3beta-, 17beta- and 20alpha-hydroxysteroids. Required for male sex determination as a component of the 'backdoor' androgen biosynthesis pathway that generates 5alpha-dihydrotestosterone (5alpha-DHT) via pregnanes. Acts together with AKR1C4 to convert 5alpha-dihydroprogesterone (5alpha-DHP) to 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP/allopregnanolone), leading to 5alpha-DHT secretion necessary for embryonic gonad differentiation into testis. In androgen catabolism, may predominantly act as a phase I enzyme by introducing a hydroxyl group prior to conjugation. It can nevertheless participate in the alternative phase II pathway by directly reducing sulfate- or glucuronide-conjugated androgens.
- Pathway
Steroid metabolism.
- Subcellular location
Cytoplasm, cytosol.
- Tissue specificity
Expressed in fetal testes. Expressed in fetal and adult adrenal glands.
- Associated conditions
46,XY sex reversal 8 (SRXY8).
Source: UniProtKB/Swiss-Prot P52895, 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. Steroid clearance is the exit route for androgens and their metabolites — the pathway at the center of Powers' PFS model (defective glucuronidation/sulfation trapping androgens intracellularly). Gut bacterial enzymes can undo this clearance, linking it to the microbiome thread.
Written for the whole steroid synthesis / conjugation & clearance family, not for AKR1C2 specifically.
Powers’ note (his unpublished theorizing)
Named by Powers (DWP-001 2020 model; DWP-002 2026 model; DWP-003, unpublished): his 2020 model proposed deficient AKR1C-mediated neurosteroid synthesis; his 2026 model instead invokes upregulated 3α-HSD (AKR1C2/AKR1C4) overproducing cerebral THDOC, a GABA-A modulator. Described as epigenetically silenceable.
Narrative library record
Function
3-alpha-hydroxysteroid dehydrogenase type 3; interconverts DHT and the much weaker 5-alpha-androstane-3-alpha,17-beta-diol (3-alpha-diol), effectively switching DHT's androgenic signal off, and participates in synthesis of neurosteroids such as allopregnanolone and tetrahydrodeoxycorticosterone. Human AKR1C2 variants are linked to differences of sex development, underscoring its role in androgen handling.
Corpus relevance
The most mechanistically pivotal AKR1C member for the corpus: its DHT-to-3-alpha-diol reaction is the enzymatic 'off switch' Powers invokes in both his 2020 deficiency model (DWP-001, where impaired AKR1C function starves neurosteroid synthesis) and his 2026 revision (DWP-002, where upregulated 3-alpha-HSD activity drives neurosteroid excess). Powers' reported patient mutations (DWP-003) are framed against this pathway. Attribution: theoretical-per-Powers; the gene's androgen-metabolism role is established biology, its PFS link is not.
- DWP-001Has anyone here taken finasteride or dutasteride and gotten post finasteride syndrome (PFS) from them? I have a theory as to why this seems to happen in transgender women more than cis men
- DWP-002Untitled long-form research update — new model of PFS/PSSD/post-drug syndromes (Sept 2026)
- DWP-003I think I have figured out at least one specific phenotype of PFS, and it is different from the "allopregnanolone" theory
Powers’ claims naming AKR1C2
- 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
3α-HSD (3α-hydroxysteroid oxidoreductase/dehydrogenase; encoded by AKR1C2/AKR1C4) — upregulated (acquired)
Confidence: direct
Upregulated 3α-HSD acts as the enzymatic bridge overproducing downstream metabolites (3α-androstanediol, 3α-ADG) and, critically, cerebral THDOC — a GABA-A positive allosteric modulator. Chronic excess remodels downstream neural networks (benzodiazepine…
AKR1C2AKR1C4
Mentioned in 9 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 - 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 recordPowers’ theory
AKR1C3 — aldo-keto reductase family 1 member C3
10p15-p14 (AKR1C gene cluster, chromosome 10)
3-alpha-hydroxysteroid dehydrogenase type 2 (also 17-beta-hydroxysteroid dehydrogenase type 5); metabolizes prostaglandins, estrogens, and progesterone in addition to androgens, and is overexpressed in prostate cancer. Broadest substrate range of the four…
AKR1C1AKR1C2AKR1C3AKR1C4CYP19A1GENE-AKR1C3Core corpus - Gene recordPowers’ theory
AKR1C4 — aldo-keto reductase family 1 member C4
10p15-p14 (AKR1C gene cluster, chromosome 10)
3-alpha-hydroxysteroid dehydrogenase type 1; liver-restricted isoform that reduces 3-keto-5-dihydrosteroids to tetrahydro products and participates in neurosteroid synthesis. Loss of AKR1C4 alone does not cause developmental phenotypes but can worsen the…
AKR1C1AKR1C2AKR1C3AKR1C4UGT1A1+1GENE-AKR1C4Core corpus - Gene record
Steroid-hormone-activated transcription factor (nuclear receptor subfamily 3, group C, member 4). On binding testosterone or DHT it sheds accessory proteins, moves to the nucleus, dimerizes, and switches on androgen-responsive genes. Its N-terminal domain…
AKR1C2ARCYP17A1HSD3B2SRD5A2GENE-ARPFSCore corpus - Gene record
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…
AKR1C2HSD3B1SRD5A1SRD5A2SRD5A3GENE-SRD5A1PFSCore 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 recordPowers’ theory
UGT2B15 — UDP glucuronosyltransferase family 2 member B15
chromosome 4 (UGT2B gene cluster, 4q13 region)
Androgen-conjugating UGT expressed in liver, prostate, adipose, skin, and other tissues; glucuronidates DHT, androsterone, and androstane-3-alpha,17-beta-diol, directly terminating their activity and marking them for urinary excretion.
AKR1C2ARUGT1A1UGT2B15UGT2B17+1GENE-UGT2B15Core corpus - Gene recordPowers’ theory
Short-chain dehydrogenase/reductase (17-beta-HSD type 2) that inactivates sex steroids, oxidizing testosterone to androstenedione, estradiol to estrone, and androstenediol to DHEA; described as the key 17-beta-HSD isozyme in androgen and estrogen…
AKR1C2CYP17A1CYP19A1HSD17B2SRD5A2+1GENE-HSD17B2PFSCore corpus
Also in steroid hormone synthesis
All 38 genes- SRD5A2
steroid 5 alpha-reductase 2
chr 2· Steroid synthesis· 19 records - SRD5A1Powers
steroid 5 alpha-reductase 1
chr 5· Steroid synthesis· 17 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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