Classical pathway of steroidogenesis with Glucocorticoid and Mineralocorticoid Metabolism (Homo sapiens)

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12, 17, 2112, 2112, 213722101351815311Lipoid adrenal hyperplasia14DihydrotestosteroneSTARCytochrome b5CholesterolCorticosterone Methyl OxidaseP450c21H6PD18-hydroxycorticosterone17-beta-HSD3PORAndrostenedioneCorticosteroneCortisolPregnenolonePOR17-hydroxypregnenolone5-alpha-Reductase2OestradiolCortisonePORP450scc11beta-HSD2P450c17Aldosterone17-hydroxyprogesterone11beta-HSD13-beta-HSDDHEA(11)-DeoxycorticosteroneProgesteroneTestosteroneP450Aro11-Deoxycortisol12, 21712, 213-beta-HSDP450c11P450c17P450c173-beta-HSDCholesterol side-chain cleavage deficiency2617-Alpha-hydroxylase / 17-lyase deficiency63-beta-HSD type II deficiency21-Hydroxylase deficiency201911-beta-hydroxylase type I deficiencyCorticosterone methyl oxidase deficiency19Cortisone reductase deficiencyApparent mineralocorticoid excess2717-beta-HSD deficiency255-alpha-reductase type II deficiency1623Aromatase deficiency24P450 oxidoreductase deficiency223-beta-HSD type II deficiency20PORProgesterone resistanceOestrogen resistance84NADP+NADPHCholesterol BiosynthesisCYP11A112, 21HSD3B13B-OH-delta-Steroid DhHSD3B1HSD3B2Androgen Synthesis and MetabolismCYP11B212, 21Corticosterone 18-Monooxy11b, 21-Dihydroxy-3,20-5b-Pregnan-18-al12, 213a,11b,21-Trihydroxy-20-Oxo-5b-Pregnan-18-al3-Oxo-5b-Steroid Dh3a-Hydroxy-steroid Dh3a-OH-5b-Pregnane-20-one5b-Pregnane-3,20-dioneProgesterone Degradation20b-Hydroxy-steroid DhPregnanediolGlucuronides17a,21-Dihydroxy-5b-17a,21-Dihydroxy-5b-Pregnane-3,11,20-trioneUrocortisoneCortoloneCortisone beta-reductase3a-Hydroxy-steroid Dh(R)20-hydroxy-steroid DhUrocortisol11b,17a 21-Trihydroxy-5bPregnane 3,20-dioneCortisolGlucocorticoidsSteroid Hormone Signaling


The biosynthesis of steroid hormones is a difficult process in which Cholesterol is transformed into mineralocorticoids, glucocorticoids and sex hormones via a series of hydroxylation, oxidation and reduction steps. To better understand the molecular level of sexual organ maturation in humans, the classical pathway and the alternative pathway of this process are produced. The pathways produce the main steroid hormones in humans, namely Progestogen, Corticosteroids, Androgens and Estrogens.

The classical pathway is meant to produce an important steroid called Androgen, which is a synthetic steroid hormone that regulates sexual development and the maintenance of the male sex organs via binding to androgen receptors. Next to the classical pathway of androgen synthesis, alternative pathways are known, such as [1].

For more information and details about Androgens and the diseases linked with this molecular pathway, please visit Chapter 37 of the book of Blau (ISBN 3642403360 (978-3642403361)) .

We have recently expanded this pathway with information from the Glucocorticoid and Mineralocorticoid Metabolism (previously captured in WP273; overlapping content is indicated with double borders for individual datanodes; information previously missing is added with dashed borders).

Mineralocorticoid (M) and glucocorticoid (G) receptors regulate transcription; either through 11-beta-hydroxysteroid dehydrogenase influencing aldosterone specificity on epithelial M-receptors or by modulcation of AP-1- and NF-kappa-B-induced transcription through G-receptors. Specifically for the first case, aldosterone resistance in an autosomal form (aka pseudohypoaldosteronism) is linked to loss-of-function in epithelical Na-channel subunits [2].

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  1. Kuribayashi I, Nomoto S, Massa G, Oostdijk W, Wit JM, Wolffenbuttel BH, Shizuta Y, Honke K; ''Steroid 11-beta-hydroxylase deficiency caused by compound heterozygosity for a novel mutation, p.G314R, in one CYP11B1 allele, and a chimeric CYP11B2/CYP11B1 in the other allele.''; Horm Res, 2005 PubMed Europe PMC Scholia
  2. HAYANO M, DORFMAN RI; ''On the mechanism of the C11 beta-hydroxylation of steroids.''; J Biol Chem, 1954 PubMed Europe PMC Scholia
  3. Pascoe L, Curnow KM, Slutsker L, Rösler A, White PC; ''Mutations in the human CYP11B2 (aldosterone synthase) gene causing corticosterone methyloxidase II deficiency.''; Proc Natl Acad Sci U S A, 1992 PubMed Europe PMC Scholia
  4. Palmisano BT, Zhu L, Stafford JM; ''Role of Estrogens in the Regulation of Liver Lipid Metabolism.''; Adv Exp Med Biol, 2017 PubMed Europe PMC Scholia
  5. Mindnich R, Haller F, Halbach F, Moeller G, Hrabé de Angelis M, Adamski J; ''Androgen metabolism via 17beta-hydroxysteroid dehydrogenase type 3 in mammalian and non-mammalian vertebrates: comparison of the human and the zebrafish enzyme.''; J Mol Endocrinol, 2005 PubMed Europe PMC Scholia
  6. Kim SM, Rhee JH; ''A case of 17 alpha-hydroxylase deficiency.''; Clin Exp Reprod Med, 2015 PubMed Europe PMC Scholia
  7. Kotelevtsev Y, Holmes MC, Burchell A, Houston PM, Schmoll D, Jamieson P, Best R, Brown R, Edwards CR, Seckl JR, Mullins JJ; ''11beta-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress.''; Proc Natl Acad Sci U S A, 1997 PubMed Europe PMC Scholia
  8. Patel BG, Rudnicki M, Yu J, Shu Y, Taylor RN; ''Progesterone resistance in endometriosis: origins, consequences and interventions.''; Acta Obstet Gynecol Scand, 2017 PubMed Europe PMC Scholia
  9. Yong AB, Montalto J, Pitt J, Oakes S, Preston T, Buchanan C; ''Corticosterone methyl oxidase type II (CMO II) deficiency: biochemical approach to diagnosis.''; Clin Biochem, 1994 PubMed Europe PMC Scholia
  10. Baquedano MS, Ciaccio M, Marino R, Perez Garrido N, Ramirez P, Maceiras M, Turjanski A, Defelipe LA, Rivarola MA, Belgorosky A; ''A novel missense mutation in the HSD3B2 gene, underlying nonsalt-wasting congenital adrenal hyperplasia. new insight into the structure-function relationships of 3β-hydroxysteroid dehidrogenase type II.''; J Clin Endocrinol Metab, 2015 PubMed Europe PMC Scholia
  11. Ghosh D, Griswold J, Erman M, Pangborn W; ''Structural basis for androgen specificity and oestrogen synthesis in human aromatase.''; Nature, 2009 PubMed Europe PMC Scholia
  12. Fardella CE, Miller WL; ''Molecular biology of mineralocorticoid metabolism.''; Annu Rev Nutr, 1996 PubMed Europe PMC Scholia
  13. Makridakis NM, di Salle E, Reichardt JK; ''Biochemical and pharmacogenetic dissection of human steroid 5 alpha-reductase type II.''; Pharmacogenetics, 2000 PubMed Europe PMC Scholia
  14. Kaur J, Casas L, Bose HS; ''Lipoid congenital adrenal hyperplasia due to STAR mutations in a Caucasian patient.''; Endocrinol Diabetes Metab Case Rep, 2016 PubMed Europe PMC Scholia
  15. Carvajal CA, Gonzalez AA, Romero DG, González A, Mosso LM, Lagos ET, Hevia Mdel P, Rosati MP, Perez-Acle TO, Gomez-Sanchez CE, Montero JA, Fardella CE; ''Two homozygous mutations in the 11 beta-hydroxysteroid dehydrogenase type 2 gene in a case of apparent mineralocorticoid excess.''; J Clin Endocrinol Metab, 2003 PubMed Europe PMC Scholia
  16. Mendonca BB, Gomes NL, Costa EM, Inacio M, Martin RM, Nishi MY, Carvalho FM, Tibor FD, Domenice S; ''46,XY disorder of sex development (DSD) due to 17β-hydroxysteroid dehydrogenase type 3 deficiency.''; J Steroid Biochem Mol Biol, 2017 PubMed Europe PMC Scholia
  17. Blau, Nenad, Duran, Marinus, Gibson, K, Michael, Dionisi-Vici, Carlo; ''Physician's Guidee to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Disease'''; ISBN 978-3-64240337-8, 2014
  18. Strushkevich N, MacKenzie F, Cherkesova T, Grabovec I, Usanov S, Park HW; ''Structural basis for pregnenolone biosynthesis by the mitochondrial monooxygenase system.''; Proc Natl Acad Sci U S A, 2011 PubMed Europe PMC Scholia
  19. Parsa AA, New MI; ''Steroid 21-hydroxylase deficiency in congenital adrenal hyperplasia.''; J Steroid Biochem Mol Biol, 2017 PubMed Europe PMC Scholia
  20. Pang S, Wang W, Rich B, David R, Chang YT, Carbunaru G, Myers SE, Howie AF, Smillie KJ, Mason JI; ''A novel nonstop mutation in the stop codon and a novel missense mutation in the type II 3beta-hydroxysteroid dehydrogenase (3beta-HSD) gene causing, respectively, nonclassic and classic 3beta-HSD deficiency congenital adrenal hyperplasia.''; J Clin Endocrinol Metab, 2002 PubMed Europe PMC Scholia
  21. Funder JW; ''Glucocorticoid and mineralocorticoid receptors: biology and clinical relevance.''; Annu Rev Med, 1997 PubMed Europe PMC Scholia
  22. Burkhard FZ, Parween S, Udhane SS, Flück CE, Pandey AV; ''P450 Oxidoreductase deficiency: Analysis of mutations and polymorphisms.''; J Steroid Biochem Mol Biol, 2017 PubMed Europe PMC Scholia
  23. Kostyrko A, Antkowiak J, Warenik-Szymankiewicz A, Trzeciak WH; ''[The importance of DNA analysis in the diagnosis of steroid 5-alpha-reductase deficiency].''; Ginekol Pol, 1994 PubMed Europe PMC Scholia
  24. Unal E, TaÅŸ FF, Demir V, Onay H, Haspolat YK; ''Aromatase Deficiency due to a Novel Mutation inCYP19A1Gene''; J Clin Res Pediatr Endocrinol, 2018 PubMed Europe PMC Scholia
  25. Funder JW; ''Apparent mineralocorticoid excess.''; J Steroid Biochem Mol Biol, 2017 PubMed Europe PMC Scholia
  26. Katsumata N; ''Cholesterol Side-Chain Cleavage Enzyme (SCC) Deficiency.''; Clin Pediatr Endocrinol, 2007 PubMed Europe PMC Scholia
  27. Lawson AJ, Walker EA, Lavery GG, Bujalska IJ, Hughes B, Arlt W, Stewart PM, Ride JP; ''Cortisone-reductase deficiency associated with heterozygous mutations in 11beta-hydroxysteroid dehydrogenase type 1.''; Proc Natl Acad Sci U S A, 2011 PubMed Europe PMC Scholia


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113593view09:42, 4 November 2020DeSlUpdated second cortisol ID to avoid duplicate mappings
113574view16:12, 2 November 2020DeSlAdded missing protein IDs (Ec numbers only).
113573view16:10, 2 November 2020DeSlAdded more IDs for metabolites
113572view16:03, 2 November 2020DeSlStarted annotating metabolites missing an ID.
113048view15:20, 31 October 2020EgonwModified title
113034view09:45, 30 October 2020DeSlAnother small layout change, converted complex with 3B-OH-delta steroid DH to proteins iso GeneProducts
113033view09:38, 30 October 2020DeSlSmall layout change in bottom left corner
113032view09:36, 30 October 2020DeSlAdded 3 EC ID from comments as DataNode IDs
113031view08:56, 30 October 2020DeSlOntology Term : 'C21-steroid hormone biosynthetic pathway' added !
113030view08:55, 30 October 2020DeSlOntology Term : 'glucocorticoid biosynthetic pathway' added !
113029view08:54, 30 October 2020DeSlAdded progesterone link to steroid hormone signalling.
113025view08:49, 30 October 2020DeSlAdded missing refrence on cortisone -> cortisol conversion through 11beta-HSD1
113024view08:37, 30 October 2020DeSlAdded details on merging PWs.
113023view08:35, 30 October 2020DeSlUpdated description to include new PW info
113022view08:25, 30 October 2020DeSlUpdated title
113010view16:12, 29 October 2020DeSlSmall layout change
113009view16:08, 29 October 2020DeSlAdded "Glucocorticoids" path from WP237
113007view15:59, 29 October 2020DeSlUpdated until cortolone metabolite
113004view15:51, 29 October 2020DeSlAdded progesteron degradation track
113003view15:39, 29 October 2020DeSlAdded up to androgen synthesis and metabolism PW-node from WP237
113002view15:32, 29 October 2020DeSlStarted integrating WP237 info (in dark grey)
112970view09:13, 24 October 2020DeSlUpdating ID for cortisol to avoid duplicate mappings
108086view11:53, 28 November 2019FehrhartOntology Term : 'disease pathway' added !
104251view12:05, 12 May 2019EgonwRemoved the RHEA: prefix from the identifier.
104033view17:45, 25 April 2019IreneHemelModified description
103565view09:57, 15 March 2019ElineSandersChanged geneproducts into proteins
103497view14:17, 6 March 2019DeSlModified description
103496view14:14, 6 March 2019DeSlRemoved weird signs in lit. ref (second try).
103402view09:45, 27 February 2019DeSlRemoved weird signs in lit. ref; changed long OMIM links to short ones.
103345view12:55, 22 February 2019DeSlConnected unconnected line to P450c17
103344view12:54, 22 February 2019DeSlUpdated OMIM for Aromatase deficiency (was linked to gene iso disease before).
103343view12:51, 22 February 2019DeSlOntology Term : 'pseudohermaphroditism' added !
103342view12:47, 22 February 2019DeSlOntology Term : 'congenital adrenal hyperplasia' added !
103341view12:45, 22 February 2019DeSlOntology Term : 'congenital adrenal hyperplasia pathway' added !
103340view12:44, 22 February 2019DeSlOntology Term : 'apparent mineralocorticoid excess syndrome pathway' added !
103339view12:43, 22 February 2019DeSlOntology Term : 'lipoid congenital adrenal hyperplasia pathway' added !
103338view12:43, 22 February 2019DeSlOntology Term : 'congenital adrenal insufficiency' added !
103337view12:42, 22 February 2019DeSlChanged Omim for Cholesterol side-chain cleavage deficiency to correct one (previous OMIM was for gene, not for disease).
103336view12:36, 22 February 2019DeSlOntology Term : 'apparent mineralocorticoid excess syndrome' added !
103335view12:36, 22 February 2019DeSlOntology Term : 'apparent mineralocorticoid excess' added !
103334view12:36, 22 February 2019DeSlOntology Term : 'cortisone reductase deficiency' added !
103320view10:38, 22 February 2019ElineSanderschanged label
103318view10:04, 22 February 2019ElineSandersAdded Rhea identifiers to reactions and changed the H6PD conversion. Also changed some CheBI identifiers which were in the secondary form according to Jenskin
103290view15:38, 21 February 2019ElineSanders
103268view10:56, 20 February 2019ElineSandersnew annotation for some metabolites
103267view10:19, 20 February 2019ElineSanderschanged CMO lines and added Rhea
103248view10:31, 18 February 2019ElineSandersOntology Term : 'C19-steroid hormone biosynthetic pathway' added !
103247view10:30, 18 February 2019ElineSandersOntology Term : 'steroid biosynthetic pathway' added !
103244view10:13, 18 February 2019ElineSandersannotation to H6PD
103242view09:51, 18 February 2019ElineSandersModified description

External references


View all...
NameTypeDatabase referenceComment
(11)-DeoxycorticosteroneMetaboliteCHEBI:16973 (ChEBI)
(R)20-hydroxy- steroid DhProtein1.1.1.53 (Enzyme Nomenclature), similiar SP:2BHD STREX
11-DeoxycortisolMetaboliteCHEBI:28324 (ChEBI)
11b, 21-Dihydroxy-3,20- 5b-Pregnan-18-alMetabolite44263338 (PubChem-compound)
11b,17a 21-Trihydroxy-5b Pregnane 3,20-dioneMetabolite1482-50-4 (CAS) AKA 11-BETA,17-ALPHA,21-TRIHYDROXY-5-BETA-PREGNANE-3,20-DIONE
11beta-HSD1ProteinENSG00000117594 (Ensembl) Reference study in mice [PMID:9405715]
11beta-HSD2ProteinENSG00000176387 (Ensembl)
17-beta-HSD3ProteinENSG00000130948 (Ensembl)
17-hydroxypregnenoloneMetaboliteCHEBI:28750 (ChEBI)
17-hydroxyprogesteroneMetaboliteCHEBI:17252 (ChEBI)
17a,21-Dihydroxy-5b-17a,21-Dihydroxy -5b-Pregnane-3,11,20-trioneMetabolite65554 (PubChem-compound) aka 4,5beta-Dihydrocortisone
18-hydroxycorticosteroneMetaboliteCHEBI:16485 (ChEBI)
20b-Hydroxy- steroid DhProtein1.1.1.53 (Enzyme Nomenclature), similiar SP:2BHD STREX
3-Oxo-5b- Steroid DhProtein3O5B (Uniprot-TrEMBL)
3-beta- HSDProteinENSG00000203859 (Ensembl)
3-beta-HSDProteinENSG00000203859 (Ensembl)
3B-OH-delta- Steroid DhProtein1.1.1.145 (Enzyme Nomenclature)
3a,11b,21-Trihydroxy-20- Oxo-5b-Pregnan-18-alMetabolite44263346 (PubChem-compound)
3a-Hydroxy- steroid DhProtein1.1.1.50 (Enzyme Nomenclature) SPs:DIDH RAT
3a-OH-5b-Pregnane-20-oneMetabolite24779614 (PubChem-compound)
5-alpha-Reductase2ProteinENSG00000277893 (Ensembl)
5b-Pregnane-3,20-dioneMetabolite92745 (PubChem-compound)
AldosteroneMetaboliteCHEBI:27584 (ChEBI)
Androgen Synthesis and MetabolismPathwayWP496 (WikiPathways)
AndrostenedioneMetaboliteCHEBI:16422 (ChEBI)
CYP11A1GeneProduct1583 (Entrez Gene)
CYP11B2GeneProduct1585 (Entrez Gene)
Cholesterol BiosynthesisPathwayWP197 (WikiPathways)
CholesterolMetaboliteCHEBI:16113 (ChEBI)
Corticosterone 18-MonooxyProtein1.14.15.5 (Enzyme Nomenclature) EC number:
Corticosterone Methyl OxidaseProteinENSG00000179142 (Ensembl)
CorticosteroneMetaboliteCHEBI:16827 (ChEBI)
CortisolMetaboliteQ190875 (Wikidata)
Cortisone beta-reductaseProtein1.3.1.3 (Enzyme Nomenclature)
CortisoneMetaboliteCHEBI:16962 (ChEBI)
CortoloneMetabolite516-42-7 (CAS)
Cytochrome b5ProteinJ3KNC7 (Uniprot-TrEMBL)
DHEAMetaboliteCHEBI:28689 (ChEBI)
DihydrotestosteroneMetaboliteCHEBI:16330 (ChEBI)
GlucuronidesMetaboliteCHEBI:26763 (ChEBI)
H6PDProteinENSG00000049239 (Ensembl)
  • This enzyme produces NADPH which is neccessary for 11beta-HSD1 to convert cortisone into cortisol.
  • Type your comment here
HSD3B1GeneProduct3283 (Entrez Gene)
HSD3B2GeneProduct3284 (Entrez Gene)
NADP+MetaboliteCHEBI:58349 (ChEBI)
NADPHMetaboliteCHEBI:57783 (ChEBI)
OestradiolMetaboliteCHEBI:16469 (ChEBI)
P450AroProteinENSG00000137869 (Ensembl)
P450c11ProteinENSG00000160882 (Ensembl)
P450c17ProteinENSG00000148795 (Ensembl)
P450c21ProteinENSG00000231852 (Ensembl)
P450sccProteinENSG00000140459 (Ensembl)
  • also known as CYP11A1
  • Type your comment here
PORProteinP16435 (Uniprot-TrEMBL)
PregnanediolMetabolite80-92-2 (CAS)
PregnenoloneMetaboliteCHEBI:16581 (ChEBI)
ProgesteroneMetaboliteCHEBI:17026 (ChEBI)
STARProteinENSG00000147465 (Ensembl)
Steroid Hormone SignalingPathwayWP170 (WikiPathways)
TestosteroneMetaboliteCHEBI:17347 (ChEBI)
UrocortisolMetabolite5864 (PubChem-compound) AKA Tetrahydrocortisol
UrocortisoneMetabolite618110 (PubChem-compound)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
(11)-DeoxycorticosteroneCorticosteronemim-conversion15630 (Rhea)
11-DeoxycortisolCortisolmim-conversion15630 (Rhea)
17-hydroxypregnenolone17-hydroxyprogesteronemim-conversion24077 (Rhea)
17-hydroxypregnenoloneDHEAmim-conversion50245 (Rhea)
17-hydroxyprogesteroneAndrostenedionemim-conversion14754 (Rhea)
18-hydroxycorticosteroneAldosteronemim-conversion50794 (Rhea)
AndrostenedioneTestosteronemim-conversion14983 (Rhea)
CholesterolPregnenolonemim-conversion35740 (Rhea)
Corticosterone18-hydroxycorticosteronemim-conversion11873 (Rhea)
CortisolCortisonemim-conversion53117 (Rhea)
CortisoneCortisolmim-conversion11390 (Rhea) Reference study in mice [PMID:9405715]
Pregnenolone17-hydroxypregnenolonemim-conversion50237 (Rhea)
PregnenoloneProgesteronemim-conversion24077 (Rhea)
Progesterone17-hydroxyprogesteronemim-conversion46309 (Rhea)
TestosteroneDihydrotestosteronemim-conversion54385 (Rhea)
TestosteroneOestradiolmim-conversion38192 (Rhea)
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