Metformin inhibits human androgen production by regulating steroidogenic enzymes HSD3B2 and CYP17A1 and complex I activity of the respiratory chain

Hirsch, Andrea; Hahn, Dagmar; Kempná, Petra; Hofer, Gaby; Nuoffer, Jean-Marc; Mullis, Primus E; Flück, Christa E (2012). Metformin inhibits human androgen production by regulating steroidogenic enzymes HSD3B2 and CYP17A1 and complex I activity of the respiratory chain. Endocrinology, 153(9), pp. 4354-66. Chevy Chase, Md.: Endocrine Society 10.1210/en.2012-1145

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Metformin is treatment of choice for the metabolic consequences seen in polycystic ovary syndrome for its insulin-sensitizing and androgen-lowering properties. Yet, the mechanism of action remains unclear. Two potential targets for metformin regulating steroid and glucose metabolism are AMP-activated protein kinase (AMPK) signaling and the complex I of the mitochondrial respiratory chain. Androgen biosynthesis requires steroid enzymes 17α-Hydroxylase/17,20 lyase (CYP17A1) and 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2), which are overexpressed in ovarian cells of polycystic ovary syndrome women. Therefore, we aimed to understand how metformin modulates androgen production using NCI-H295R cells as an established model of steroidogenesis. Similar to in vivo situation, metformin inhibited androgen production in NCI cells by decreasing HSD3B2 expression and CYP17A1 and HSD3B2 activities. The effect of metformin on androgen production was dose dependent and subject to the presence of organic cation transporters, establishing an important role of organic cation transporters for metformin's action. Metformin did not affect AMPK, ERK1/2, or atypical protein kinase C signaling. By contrast, metformin inhibited complex I of the respiratory chain in mitochondria. Similar to metformin, direct inhibition of complex I by rotenone also inhibited HSD3B2 activity. In conclusion, metformin inhibits androgen production by mechanisms targeting HSD3B2 and CYP17-lyase. This regulation involves inhibition of mitochondrial complex I but appears to be independent of AMPK signaling.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Institute of Clinical Chemistry

UniBE Contributor:

Hirsch, Andrea, Hahn, Dagmar Karen, Kempna, Petra, Hofer, Gaby, Nuoffer, Jean-Marc, Mullis, Primus-Eugen, Flück Pandey, Christa Emma

ISSN:

0013-7227

Publisher:

Endocrine Society

Language:

English

Submitter:

Anette van Dorland

Date Deposited:

04 Oct 2013 14:36

Last Modified:

02 Mar 2023 23:21

Publisher DOI:

10.1210/en.2012-1145

PubMed ID:

22778212

Web of Science ID:

000308194900025

Additional Information:

Hirsch, Andrea;Hahn, Dagmar;Kempna, Petra;Hofer, Gaby;Nuoffer, Jean-Marc;Mullis, Primus E;Fluck, Christa E;Endocrinology. 2012 Sep;153(9):4354-66. doi: 10.1210/en.2012-1145. Epub 2012 Jul 9.

BORIS DOI:

URI:

https://boris.unibe.ch/id/eprint/14662 (FactScience: 221744)

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