Cited by 109Ovarian function and disordersMetabolism, Diabetes, and CancerAdrenal Hormones and Disorders

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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·Endocrinology

DOI 10.1210/en.2012-1145

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Abstract

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.

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Authors: Hirsch, A., Hahn, D., Kempná, P., Hofer, G., Nuoffer, J.-M., Mullis, P. E., & Flück, C. E.
Affiliations: University Children’s Hospital Bern (CH)
University of Bern (CH)
Corresponding author: Flück, Christa E.
ORCID: Hofer, Gaby
Nuoffer, Jean-Marc
Flück, Christa E.
Venue: Endocrinology
Publisher: The Endocrine Society
Published: 2012-09-01
Volume: 153
Issue: 9
Pages: 4354-4366
ISSN: 0013-7227 (ISSN-L)
1945-7170
DOI: 10.1210/en.2012-1145
OpenAlex: W2134583596
Cited by: 109
References: 68
Citations by year: 2026: 4 · 2025: 12 · 2024: 13 · 2023: 12 · 2022: 17 · 2021: 7 · 2020: 14 · 2019: 3 · 2018: 2 · 2017: 8 · 2016: 3 · 2015: 2 · 2014: 7 · 2013: 4 · 2012: 1
FWCI: 5.22
Type: journal article
Language: en
Open access: closed
Locations: Endocrinology (publishedVersion)
PubMed (publishedVersion)
BORIS (University Library Bern) (submittedVersion)
Topics: Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Keywords: metformin, androgen production, polycystic ovary syndrome, HSD3B2, CYP17A1, steroidogenic enzymes, mitochondrial complex I, electron transport chain, organic cation transporters, AMPK, H295R cells, rotenone, insulin-sensitizing drugs
MeSH terms: Androgens, Cell Line, Humans, Metformin, Progesterone Reductase, Steroid 17-alpha-Hydroxylase, Reverse Transcriptase Polymerase Chain Reaction, Organic Cation Transport Proteins, Electron Transport Complex I, Cell Proliferation, Real-Time Polymerase Chain Reaction

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Metformin Inhibits Human Androgen Production by Regulating Steroidogenic Enzymes HSD3B2 and CYP17A1 and Complex I Activity of the Respiratory Chain

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