Treffer: Female Mice with HSD17B1 Inactivation Show Mild Hyperandrogenism without Notable Impact on Reproductive Function or Bone.
Title:
Female Mice with HSD17B1 Inactivation Show Mild Hyperandrogenism without Notable Impact on Reproductive Function or Bone.
Authors:
Junnila A; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku FI-20520, Finland., Petruk N; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku FI-20520, Finland., Heikelä H; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku FI-20520, Finland., Postila P; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku FI-20520, Finland., Hakkarainen J; Organon R&D Finland, Turku FI-20520, Finland., Martinez-Nieto G; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku FI-20520, Finland.; Turku Center for Disease Modeling, University of Turku, Turku FI-20520, Finland., Uceda-Rodriguez E; Department of Cell Biology, Physiology and Immunology, University of Cordoba, and Instituto Maimónides de Investigación Biomédica de Córdoba, 14071 Córdoba, Spain., Ruiz-Pino F; Department of Cell Biology, Physiology and Immunology, University of Cordoba, and Instituto Maimónides de Investigación Biomédica de Córdoba, 14071 Córdoba, Spain., Tena-Sempere M; Department of Cell Biology, Physiology and Immunology, University of Cordoba, and Instituto Maimónides de Investigación Biomédica de Córdoba, 14071 Córdoba, Spain., Ohlsson C; The Sahlgrenska Osteoporosis Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 41345 Gothenburg, Sweden., Sipilä P; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku FI-20520, Finland.; Turku Center for Disease Modeling, University of Turku, Turku FI-20520, Finland., Heino TJ; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku FI-20520, Finland., Määttä J; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku FI-20520, Finland.; Turku Center for Disease Modeling, University of Turku, Turku FI-20520, Finland., Poutanen M; Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku FI-20520, Finland.; The Sahlgrenska Osteoporosis Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 41345 Gothenburg, Sweden.
Source:
Endocrinology [Endocrinology] 2025 Dec 05; Vol. 167 (1).
Publication Type:
Journal Article
Language:
English
Journal Info:
Publisher: Oxford University Press Country of Publication: United States NLM ID: 0375040 Publication Model: Print Cited Medium: Internet ISSN: 1945-7170 (Electronic) Linking ISSN: 00137227 NLM ISO Abbreviation: Endocrinology Subsets: MEDLINE
Imprint Name(s):
Publication: 2017- : New York : Oxford University Press
Original Publication: Los Angeles, Calif. : Association for the Study of Internal Secretions,
Original Publication: Los Angeles, Calif. : Association for the Study of Internal Secretions,
MeSH Terms:
Reproduction*/genetics , Reproduction*/physiology , Hyperandrogenism*/genetics , Hyperandrogenism*/metabolism , Estradiol Dehydrogenases*/genetics , Bone and Bones*/metabolism, Animals ; Female ; Mice ; Ovary/metabolism ; Estradiol/metabolism ; Humans ; Estrone/metabolism ; 17-Hydroxysteroid Dehydrogenases/genetics
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J Steroid Biochem Mol Biol. 2022 Sep;222:106136. (PMID: 35691460)
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Eur J Biochem. 1996 Mar 1;236(2):482-90. (PMID: 8612620)
Bioinformatics. 2013 Jan 1;29(1):15-21. (PMID: 23104886)
J Mol Endocrinol. 2005 Apr;34(2):489-503. (PMID: 15821112)
J Endocrinol. 1994 Oct;143(1):139-50. (PMID: 7525828)
Reprod Biol Endocrinol. 2008 Mar 18;6:10. (PMID: 18348723)
Endocrinology. 1999 Aug;140(8):3507-17. (PMID: 10433206)
Trends Endocrinol Metab. 2006 Mar;17(2):65-71. (PMID: 16460956)
Am J Physiol Endocrinol Metab. 2023 Oct 1;325(4):E346-E362. (PMID: 37584608)
Endocrinology. 2015 Jul;156(7):2492-502. (PMID: 25856427)
FASEB J. 2018 Jun;32(6):3229-3241. (PMID: 29401623)
J Adv Res. 2024 Apr;58:163-173. (PMID: 37315842)
Reprod Toxicol. 2019 Aug;87:32-41. (PMID: 31059772)
Biol Reprod. 2015 Oct;93(4):83. (PMID: 26269506)
Hum Reprod Update. 2018 Nov 1;24(6):639-651. (PMID: 30204868)
Endocrinology. 2007 Aug;148(8):3827-36. (PMID: 17510238)
FASEB J. 2020 May;34(5):6111-6128. (PMID: 32190925)
FASEB J. 2015 Sep;29(9):3806-16. (PMID: 26018678)
J Ovarian Res. 2015 Apr 13;8:24. (PMID: 25887459)
J Endocrinol. 2012 Jan;212(1):27-40. (PMID: 22045753)
Hum Reprod. 2014 Aug;29(8):1637-50. (PMID: 24908673)
Mol Endocrinol. 1997 Jan;11(1):77-86. (PMID: 8994190)
Am J Pathol. 2010 Mar;176(3):1443-51. (PMID: 20093485)
Int J Cancer. 1992 Feb 1;50(3):386-90. (PMID: 1735607)
J Biol Chem. 2025 Jan;301(1):108042. (PMID: 39615688)
Biochem Biophys Res Commun. 2003 May 23;305(1):37-45. (PMID: 12732193)
Reprod Biol. 2025 Dec;25(4):101085. (PMID: 41027258)
J Endocrinol. 1994 Mar;140(3):409-17. (PMID: 8182368)
Gynecol Obstet Invest. 1999;47(4):247-50. (PMID: 10352386)
FASEB J. 2003 Feb;17(2):274-6. (PMID: 12490543)
Biol Reprod. 2001 Sep;65(3):704-9. (PMID: 11514331)
Endocrinology. 1997 Aug;138(8):3532-9. (PMID: 9231808)
Mol Cell Endocrinol. 2009 Mar 25;301(1-2):216-24. (PMID: 19014997)
Mol Endocrinol. 2006 Feb;20(2):437-43. (PMID: 16166196)
PLoS One. 2014 Feb 05;9(2):e87327. (PMID: 24505284)
Front Pharmacol. 2023 Apr 28;14:1155558. (PMID: 37188267)
Hum Reprod. 2020 May 1;35(5):1145-1158. (PMID: 32372097)
BMC Bioinformatics. 2014 Jun 12;15:182. (PMID: 24925680)
J Biol Chem. 2004 Apr 16;279(16):16778-85. (PMID: 14966133)
Nucleic Acids Res. 2000 Jan 1;28(1):235-42. (PMID: 10592235)
J Comput Aided Mol Des. 2004 Jun;18(6):401-19. (PMID: 15663001)
Endocr Rev. 2011 Feb;32(1):81-151. (PMID: 21051590)
FEBS J. 2019 Jun;286(11):2155-2166. (PMID: 30768851)
J Clin Invest. 1999 Jan;103(2):197-206. (PMID: 9916131)
Proc Natl Acad Sci U S A. 1999 Feb 2;96(3):840-5. (PMID: 9927655)
FASEB J. 2020 Aug;34(8):10373-10386. (PMID: 32557858)
Mol Cell Endocrinol. 2017 Feb 5;441:116-123. (PMID: 27471004)
J Endocrinol. 2024 May 06;261(3):. (PMID: 38593833)
Endocrinology. 2009 Sep;150(9):4154-62. (PMID: 19556422)
J Ovarian Res. 2024 Feb 12;17(1):38. (PMID: 38347589)
Nat Methods. 2012 Jun 28;9(7):676-82. (PMID: 22743772)
PLoS One. 2007 Dec 19;2(12):e1334. (PMID: 18092000)
Endocrinology. 2006 Nov;147(11):5333-9. (PMID: 16916945)
Sci Rep. 2017 Nov 27;7(1):16406. (PMID: 29180785)
Nature. 2021 Aug;596(7873):583-589. (PMID: 34265844)
Chem Biol Interact. 2003 Feb 1;143-144:247-53. (PMID: 12604210)
Nucleic Acids Res. 2023 Jan 6;51(D1):D638-D646. (PMID: 36370105)
Endocrinology. 2019 Jun 1;160(6):1377-1393. (PMID: 30951142)
Mol Cell Endocrinol. 2019 Apr 15;486:47-54. (PMID: 30802529)
Endocrinology. 2017 Apr 1;158(4):993-1004. (PMID: 28324045)
Mol Endocrinol. 2010 Apr;24(4):832-45. (PMID: 20172961)
Lab Invest. 1991 Nov;65(5):582-7. (PMID: 1721669)
Endocrinology. 2024 Apr 29;165(6):. (PMID: 38785348)
Endocrinology. 2006 Sep;147(9):4222-33. (PMID: 16763059)
Reprod Sci. 2020 Jul;27(7):1436-1442. (PMID: 32016798)
Endocrinology. 2022 Sep 1;163(9):. (PMID: 35869782)
Mol Cell Endocrinol. 2012 Mar 5;350(1):1-9. (PMID: 22155568)
Clin Genet. 2025 Jul;108(1):80-85. (PMID: 39840549)
J Steroid Biochem Mol Biol. 2022 Sep;222:106136. (PMID: 35691460)
Endocrinology. 2025 Dec 5;167(1):. (PMID: 41219171)
Eur J Biochem. 1996 Mar 1;236(2):482-90. (PMID: 8612620)
Bioinformatics. 2013 Jan 1;29(1):15-21. (PMID: 23104886)
J Mol Endocrinol. 2005 Apr;34(2):489-503. (PMID: 15821112)
J Endocrinol. 1994 Oct;143(1):139-50. (PMID: 7525828)
Reprod Biol Endocrinol. 2008 Mar 18;6:10. (PMID: 18348723)
Endocrinology. 1999 Aug;140(8):3507-17. (PMID: 10433206)
Trends Endocrinol Metab. 2006 Mar;17(2):65-71. (PMID: 16460956)
Am J Physiol Endocrinol Metab. 2023 Oct 1;325(4):E346-E362. (PMID: 37584608)
Endocrinology. 2015 Jul;156(7):2492-502. (PMID: 25856427)
FASEB J. 2018 Jun;32(6):3229-3241. (PMID: 29401623)
J Adv Res. 2024 Apr;58:163-173. (PMID: 37315842)
Reprod Toxicol. 2019 Aug;87:32-41. (PMID: 31059772)
Biol Reprod. 2015 Oct;93(4):83. (PMID: 26269506)
Grant Information:
University of Turku; Research Council of Finland's Flagship InFLAMES; Sigrid Juselius Foundation; Organon R&D Finland Ltd
Contributed Indexing:
Keywords: HSD17B1; bone health; estrogens; female reproduction; hyperandrogenism; steroidogenesis
Substance Nomenclature:
EC 1.1.1.62 (Estradiol Dehydrogenases)
4TI98Z838E (Estradiol)
EC 1.1.- (hydroxysteroid (17-beta) dehydrogenase 1, mouse)
2DI9HA706A (Estrone)
EC 1.1.- (17-Hydroxysteroid Dehydrogenases)
4TI98Z838E (Estradiol)
EC 1.1.- (hydroxysteroid (17-beta) dehydrogenase 1, mouse)
2DI9HA706A (Estrone)
EC 1.1.- (17-Hydroxysteroid Dehydrogenases)
Entry Date(s):
Date Created: 20251111 Date Completed: 20251206 Latest Revision: 20251208
Update Code:
20251208
PubMed Central ID:
PMC12680499
DOI:
10.1210/endocr/bqaf167
PMID:
41219171
Database:
MEDLINE
Weitere Informationen
17β-hydroxysteroid dehydrogenase 1 (HSD17B1) is the primary enzyme responsible for the activation of estrone (E1) to estradiol (E2) in ovaries and extra-gonadal tissues of both humans and rodents. In the present study, molecular modeling identified the substitution of His222 in the human HSD17B1 enzyme with glycine in the mouse as the key determinant for the different steroid specificity between the species. Furthermore, Ser143Ala mutation at the active site of mouse HSD17B1 resulted in a total loss of E1 to E2 conversion by HSD17B1. This resulted in elevated intraovarian and circulating E1 concentrations in adult HSD17B1 Ser143Ala knock-in (HSD17B1-KI) females, but no changes in E2 concentrations were observed compared to the wild-type mice. Androstenedione and dihydrotestosterone were also elevated in the HSD17B1-KI ovaries, associated with elevated circulating LH. However, the effect of HSD17B1 inactivation on female reproductive development and function was mild, primarily resulting in a slight decrease in ovarian weight in older HSD17B1-KI mice, without notable effects on fertility. Expression of genes related to steroid biosynthesis, mitochondrial metabolism, and known markers of polycystic ovary syndrome was found to be upregulated in adult HSD17B1-KI ovaries. However, no alterations in the structure or function of extra-gonadal tissues were observed, and the uterus and bone phenotypes in the HSD17B1-KI females were unaffected. Our results demonstrate that the blockade of HSD17B1-dependent E2 synthesis is successfully compensated for in mouse in vivo, resulting in only a mild ovarian estrogen and androgen imbalance but no significant adverse effects on reproductive or bone health.
(© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society.)