17β-Hydroxysteroid dehydrogenase#Clinical significance

File:Steroidogenesis.svg. 17β-HSD visible in bottom-left region.]]

17β-HSDs have been known to catalyze the following redox reactions of sex steroids:

• 20α-Hydroxyprogesterone ↔ Progesterone
• {{abbrlink|DHEA|Dehydroepiandrosterone}} ↔ Androstenediol
• Androstenedione ↔ Testosterone
• Dihydrotestosterone ↔ 5α-Androstanedione / 3α-Androstanediol / 3β-Androstanediol
• Estrone ↔ Estradiol
• 16α-Hydroxyestrone ↔ Estriol

File:Estrogenic 17β-HSD activity.png {{Clear}}

Genes coding for 17β-HSD include:

• HSD17B1: Referred to as "estrogenic". Major subtype for activation of estrogens from weaker forms (estrone to estradiol and 16α-hydroxyestrone to estriol). Catalyzes the final step in the biosynthesis of estrogens. Highly selective for estrogens; 100-fold higher affinity for estranes over androstanes. However, also catalyzes the conversion of DHEA into androstenediol. Recently, has been found to inactivate DHT into 3α- and 3β-androstanediol.{{cite journal | vauthors = Aka JA, Mazumdar M, Chen CQ, Poirier D, Lin SX | title = 17beta-hydroxysteroid dehydrogenase type 1 stimulates breast cancer by dihydrotestosterone inactivation in addition to estradiol production | journal = Molecular Endocrinology | volume = 24 | issue = 4 | pages = 832–45 | date = April 2010 | pmid = 20172961 | pmc = 5417535 | doi = 10.1210/me.2009-0468 }} Expressed primarily in the ovaries and placenta but also at lower levels in the breast epithelium.{{cite journal | vauthors = Hilborn E, Stål O, Jansson A | title = Estrogen and androgen-converting enzymes 17β-hydroxysteroid dehydrogenase and their involvement in cancer: with a special focus on 17β-hydroxysteroid dehydrogenase type 1, 2, and breast cancer | journal = Oncotarget | volume = 8 | issue = 18 | pages = 30552–30562 | date = May 2017 | pmid = 28430630 | pmc = 5444764 | doi = 10.18632/oncotarget.15547 }} Major isoform of 17β-HSD in the granulosa cells of the ovaries.{{cite journal | vauthors = Andersson S, Moghrabi N | title = Physiology and molecular genetics of 17 beta-hydroxysteroid dehydrogenases | journal = Steroids | volume = 62 | issue = 1 | pages = 143–7 | date = January 1997 | pmid = 9029729 | doi = 10.1016/s0039-128x(96)00173-0| s2cid = 54341481 }} Mutations and associated deficiency have not been reported in humans.{{cite book | first1 = J. Larry | last1 = Jameson | title = Principles of Molecular Medicine|url=https://books.google.com/books?id=UhjyBwAAQBAJ&pg=PA549|date=13 July 1998|publisher=Springer Science & Business Media|isbn=978-1-59259-726-0|page=549}} Knockout mice show altered ovarian sex steroid production, normal puberty, and severe subfertility due to defective luteinization and ovarian progesterone production.{{cite journal | vauthors = Hakkarainen J, Jokela H, Pakarinen P, Heikelä H, Kätkänaho L, Vandenput L, Ohlsson C, Zhang FP, Poutanen M | title = Hydroxysteroid (17β)-dehydrogenase 1-deficient female mice present with normal puberty onset but are severely subfertile due to a defect in luteinization and progesterone production | journal = FASEB Journal | volume = 29 | issue = 9 | pages = 3806–16 | date = September 2015 | pmid = 26018678 | doi = 10.1096/fj.14-269035 | doi-access = free}}
• HSD17B2: Describable as "antiestrogenic" and "antiandrogenic".{{cite journal | vauthors = Wang CT, Li CF, Wu WJ, Huang CN, Li CC, Li WM, Chan TC, Liang PI, Hsing CH, Liao KM | title = High Expression of 17β-hydroxysteroid Dehydrogenase Type 2 is Associated with a Better Prognosis in Urothelial Carcinoma of the Urinary Tract | journal = Journal of Cancer | volume = 7 | issue = 15 | pages = 2221–2230 | year = 2016 | pmid = 27994658 | pmc = 5166531 | doi = 10.7150/jca.16777 | quote = HSD17B2 has both anti-estrogenic and anti-androgenic functions. }} Major subtype for inactivation of estrogens and androgens into weaker forms (estradiol to estrone, testosterone to androstenedione, and androstenediol to DHEA). Also converts inactive 20α-hydroxyprogesterone into active progesterone. Preferential activity on androgens. Expressed widely in the body including in the liver, intestines, lungs, pancreas, kidneys, endometrium, prostate, breast epithelium, placenta, and bone.{{cite book|first1=Shlomo|last1=Melmed|title=Williams Textbook of Endocrinology|url=https://books.google.com/books?id=YZ8_CwAAQBAJ&pg=PA904|year=2016|publisher=Elsevier Health Sciences|isbn=978-0-323-29738-7|page=904|access-date=16 July 2017|archive-date=4 May 2024|archive-url=https://web.archive.org/web/20240504042311/https://books.google.com/books?id=YZ8_CwAAQBAJ&pg=PA904#v=onepage&q&f=false|url-status=live}}{{cite book|first1=Jerome Frank|last1=Strauss|first2=Robert L.|last2=Barbieri|title=Yen and Jaffe's Reproductive Endocrinology|url=https://books.google.com/books?id=KZ95AAAAQBAJ&pg=PA82|date=13 September 2013|publisher=Elsevier Health Sciences|isbn=978-1-4557-2758-2|page=82|access-date=16 July 2017|archive-date=4 May 2024|archive-url=https://web.archive.org/web/20240504042340/https://books.google.com/books?id=KZ95AAAAQBAJ&pg=PA82#v=onepage&q&f=false|url-status=live}} Said to be responsible for 17β-HSD activity in the endometrium and placenta.{{cite book|first1=J. Larry|last1=Jameson|first2=Leslie J.|last2=De Groot|title=Endocrinology: Adult and Pediatric E-Book|url=https://books.google.com/books?id=xmLeBgAAQBAJ&pg=PA2078|date=25 February 2015|publisher=Elsevier Health Sciences|isbn=978-0-323-32195-2|page=2078|access-date=17 July 2017|archive-date=4 May 2024|archive-url=https://web.archive.org/web/20240504042321/https://books.google.com/books?id=xmLeBgAAQBAJ&pg=PA2078#v=onepage&q&f=false|url-status=live}} Mutations and associated congenital deficiency have not been reported in humans. However, local deficiency in expression of HSD17B2 has been associated with endometriosis.{{cite journal | vauthors = Bulun SE, Cheng YH, Pavone ME, Yin P, Imir G, Utsunomiya H, Thung S, Xue Q, Marsh EE, Tokunaga H, Ishikawa H, Kurita T, Su EJ | title = 17Beta-hydroxysteroid dehydrogenase-2 deficiency and progesterone resistance in endometriosis | journal = Seminars in Reproductive Medicine | volume = 28 | issue = 1 | pages = 44–50 | date = January 2010 | pmid = 20108182 | pmc = 4511594 | doi = 10.1055/s-0029-1242992 }}
• HSD17B3: Referred to as "androgenic". Major subtype in males for activation of androgens from weaker forms (androstenedione to testosterone and DHEA to androstenediol). Also activates estrogens from weaker forms to a lesser extent (estrone to estradiol). This is essential for testicular but not ovarian production of testosterone. Not expressed in the ovaries, where another 17β-HSD subtype, likely HSD17B5, is expressed instead. Mutations are associated with 17β-Hydroxysteroid dehydrogenase III deficiency. Males with this condition have pseudohermaphroditism, while females are normal with normal androgen and estrogen levels.
• HSD17B4: Also known as D-bifunctional protein (DBP). Involved in fatty acid β-oxidation and steroid metabolism (specifically estrone to estradiol, for instance in the uterus).{{cite journal | vauthors = Pierce SB, Walsh T, Chisholm KM, Lee MK, Thornton AM, Fiumara A, Opitz JM, Levy-Lahad E, Klevit RE, King MC | title = Mutations in the DBP-deficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault Syndrome | journal = American Journal of Human Genetics | volume = 87 | issue = 2 | pages = 282–8 | date = August 2010 | pmid = 20673864 | pmc = 2917704 | doi = 10.1016/j.ajhg.2010.07.007 }} Mutations are associated with DBP deficiency and Perrault syndrome (ovarian dysgenesis and deafness).
• HSD17B5: Also known as aldo-keto reductase 1C3 (AKR1C3), encoded by the AKR1C3 gene in humans. Has {{abbrlink|3α-HSD|3α-hydroxysteroid dehydrogenase}} and {{abbrlink|20α-HSD|20α-hydroxysteroid dehydrogenase}} activity in addition to 17β-HSD activity. Expressed in the adrenal cortex and may act as the "androgenic" 17β-HSD in ovarian thecal cells. Also expressed in the prostate gland, mammary gland, and Leydig cells.
• HSD17B6: Has {{abbrlink|3α-HSD|3α-hydroxysteroid dehydrogenase}} activity and catalyzes conversion of the weak androgen androstanediol into the powerful androgen dihydrotestosterone in the prostate gland. Also involved into a backdoor pathway from 17α-hydroxyprogesterone to dihydrotestosterone by 3α-reduction of a metabolic intermediary, 17α-hydroxydihydroprogesterone, into another intermediary, 17α-hydroxyallopregnanolone.{{cite journal|doi=10.15347/WJM/2023.003 |doi-access=free|title=Alternative androgen pathways |year=2023 |last1=Masiutin |first1=Maxim |last2=Yadav |first2=Maneesh |journal=WikiJournal of Medicine |volume=10 |pages=X |s2cid=257943362}} May be involved in the pathophysiology of {{abbrlink|PCOS|polycystic ovary syndrome}}.
• HSD17B7: Is involved in cholesterol metabolism but is also thought to activate estrogens (estrone to estradiol) and inactivate androgens (dihydrotestosterone to androstanediol). Expressed in the ovaries, breasts, placenta, testes, prostate gland, and liver.
• HSD17B8: Inactivates estradiol, testosterone, and dihydrotestosterone, though can also convert estrone into estradiol. Expressed in the ovaries, testes, liver, pancreas, kidneys, and other tissues.{{cite journal | vauthors = Fomitcheva J, Baker ME, Anderson E, Lee GY, Aziz N | title = Characterization of Ke 6, a new 17beta-hydroxysteroid dehydrogenase, and its expression in gonadal tissues | journal = The Journal of Biological Chemistry | volume = 273 | issue = 35 | pages = 22664–71 | date = August 1998 | pmid = 9712896 | doi = 10.1074/jbc.273.35.22664| doi-access = free }}{{cite journal | vauthors = Kikuti YY, Tamiya G, Ando A, Chen L, Kimura M, Ferreira E, Tsuji K, Trowsdale J, Inoko H | title = Physical mapping 220 kb centromeric of the human MHC and DNA sequence analysis of the 43-kb segment including the RING1, HKE6, and HKE4 genes | journal = Genomics | volume = 42 | issue = 3 | pages = 422–35 | date = June 1997 | pmid = 9205114 | doi = 10.1006/geno.1997.4745 }}
• HSD17B9: Also known as retinol dehydrogenase 5 (RDH5). Involved in retinoid metabolism.{{cite journal | vauthors = Lidén M, Tryggvason K, Eriksson U | title = Structure and function of retinol dehydrogenases of the short chain dehydrogenase/reductase family | journal = Molecular Aspects of Medicine | volume = 24 | issue = 6 | pages = 403–9 | date = December 2003 | pmid = 14585311 | doi = 10.1016/s0098-2997(03)00036-0}} Mutations are associated with fundus albipunctatus.{{cite journal | vauthors = Skorczyk-Werner A, Pawłowski P, Michalczuk M, Warowicka A, Wawrocka A, Wicher K, Bakunowicz-Łazarczyk A, Krawczyński MR | title = Fundus albipunctatus: review of the literature and report of a novel RDH5 gene mutation affecting the invariant tyrosine (p.Tyr175Phe) | journal = Journal of Applied Genetics | volume = 56 | issue = 3 | pages = 317–27 | date = August 2015 | pmid = 25820994 | pmc = 4543405 | doi = 10.1007/s13353-015-0281-x }}
• HSD17B10: Also known as 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD). Substrates include steroids, neurosteroids, fatty acids, bile acids, isoleucine, and xenobiotics.{{cite journal | vauthors = Yang SY, He XY, Miller D | title = Hydroxysteroid (17β) dehydrogenase X in human health and disease | journal = Mol. Cell. Endocrinol. | volume = 343 | issue = 1–2 | pages = 1–6 | year = 2011 | pmid = 21708223 | doi = 10.1016/j.mce.2011.06.011 | s2cid = 8608312 }}{{cite journal | vauthors = Yang SY, He XY, Isaacs C, Dobkin C, Miller D, Philipp M | title = Roles of 17β-hydroxysteroid dehydrogenase type 10 in neurodegenerative disorders | journal = J. Steroid Biochem. Mol. Biol. | volume = 143 | pages = 460–72 | year = 2014 | pmid = 25007702 | doi = 10.1016/j.jsbmb.2014.07.001 | doi-access = free }} Mutations are associated with 17β-Hydroxysteroid dehydrogenase X deficiency (also known as HSD10 disease or MHBD deficiency) and mental retardation, X-linked, syndromic 10 (MRXS10), which are characterized by neurodegeneration and mental retardation, respectively.
• HSD17B11: very little is known on the role/function of this iszyme.{{cite journal|doi=10.1016/j.mce.2018.10.014 |title=Role of HSD17B13 in the liver physiology and pathophysiology |date=2019 |journal=Molecular and Cellular Endocrinology |volume=489 |pages=119–125 |pmid=30365983 | vauthors = Su W, Mao Z, Liu Y, Zhang X, Zhang W, Gustafsson J, Guan Y }}{{cite journal|doi=10.1186/s12944-021-01476-y|doi-access=free |title=Identification of prognostic lipid droplet-associated genes in pancreatic cancer patients via bioinformatics analysis |date=2021 |journal=Lipids in Health and Disease |volume=20 |issue=1 |page=58 |pmid=34078402 |pmc=8171034 | vauthors = Bai R, Rebelo A, Kleeff J, Sunami Y }}
• HSD17B12
• HSD17B13
• HSD17B14

At least 7 of the 14 isoforms of 17β-HSD are involved in interconversion of 17-ketosteroids and 17β-hydroxysteroids.

Mutations in HSD17B3 are responsible for 17β-hydroxysteroid dehydrogenase III deficiency.

Inhibitors of 17β-HSD type II are of interest for the potential treatment of osteoporosis.{{cite journal | vauthors = Perspicace E, Cozzoli L, Gargano EM, Hanke N, Carotti A, Hartmann RW, Marchais-Oberwinkler S | title = Novel, potent and selective 17β-hydroxysteroid dehydrogenase type 2 inhibitors as potential therapeutics for osteoporosis with dual human and mouse activities | journal = European Journal of Medicinal Chemistry | volume = 83 | pages = 317–37 | date = August 2014 | pmid = 24974351 | doi = 10.1016/j.ejmech.2014.06.036 }}

Some inhibitors of 17β-HSD type I have been identified, for example esters of cinnamic acid and various flavones (e.g. fisetin).{{cite journal |vauthors=Brozic P, Kocbek P, Sova M, Kristl J, Martens S, Adamski J, Gobec S, Lanisnik Rizner T |date=March 2009 |title=Flavonoids and cinnamic acid derivatives as inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 |url=https://hal.archives-ouvertes.fr/hal-00532074/document |journal=Molecular and Cellular Endocrinology |volume=301 |issue=1–2 |pages=229–34 |doi=10.1016/j.mce.2008.09.004 |pmid=18835421 |s2cid=26950431 |access-date=4 March 2022 |archive-date=4 March 2022 |archive-url=https://web.archive.org/web/20220304221754/https://hal.archives-ouvertes.fr/hal-00532074/document |url-status=live }}

• Steroidogenic enzyme
• 3α-Hydroxysteroid dehydrogenase

{{Reflist|33em}}

• {{MeshName|3(or+17)beta-hydroxysteroid+dehydrogenase}}

{{Steroid metabolism enymes}}

{{Alcohol oxidoreductases}}

{{Enzymes}}

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{{DEFAULTSORT:Hydroxysteroid dehydrogenase, 17β-}}

Category:EC 1.1.1

Category:NADPH-dependent enzymes

Category:NADH-dependent enzymes

Category:Enzymes of known structure

Category:Steroid hormone biosynthesis