The DOI matches its Crossref record; 66 of the 68 references it cites were found in a registry or an index.
Metformin Inhibits Human Androgen Production by Regulating Steroidogenic Enzymes HSD3B2 and CYP17A1 and Complex I Activity of the Respiratory Chain
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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“Given that chronic hyperinsulinemia can stimulate an excessive production of androgens in PCOS women, the antiandrogenic effects of resveratrol are probably indirect and driven by the reduction of IR in these patients [141,142,143,144], in contrast to pharmacologic intervention with metformin [145,146].”
From Mediterranean diet nutrients to turn the tide against insulin resistance and related diseases (2020) · cites this paper as [146]
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1 retracted
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RetractedRole of AMP-Activated Protein Kinase in Mechanism of Metformin Action
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The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders
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The Kinase LKB1 Mediates Glucose Homeostasis in Liver and Therapeutic Effects of Metformin
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Insulin Resistance and the Polycystic Ovary Syndrome: Mechanism and Implications for Pathogenesis
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Munkboel, C. H., Hansen, H. S., Jessen, J. B., Johannsen, M. L., & Styrishave, B. (2020) · Toxicology in Vitro · doi:10.1016/j.tiv.2020.105007
Tonelli, F., Cotti, S., Leoni, L., Besio, R., Gioia, R., Marchese, L., Giorgetti, S., Villani, S., Gistelinck, C., Wagener, R., et al. (2021) · Yearbook of pediatric endocrinology · doi:10.1530/ey.18.5.11
Metformin Inhibit Cell Proliferation and Secretion Function in NCI-H295R CellsPreprint
Li, C., Wang, F., Tong, A., Yan, Z., & Li, Y. (2020) · doi:10.21203/rs.3.rs-26937/v1
Honour, J. W. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-818124-9.00016-4
Joshi, S., Sharma, V., Bhandari, S., Joshi, P., & Mondal, S. (2024) · Research Square · doi:10.21203/rs.3.rs-4384391/v1
Metformin dosage and galectin-3 levels: insights from PCOS patients preparing for IVF
Nikolic, V. N., Stefanović, M., Mitić, D., Sunaric, S. M., Stojiljković, V., Trajković, H., Ignjatović, A., & Stokanović, D. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1505022 · Cited by 1
AMPK–PP1/PP2 axis regulates GSDMD-mediated pyroptosis via phosphorylation
Zhang, T., Gao, C., Xu, J., Zhang, W., Xing, Y., Li, G., Li, M., 郭彦伟, Zhang, Z., Zheng, P., et al. (2026) · Frontiers in Oncology · doi:10.3389/fonc.2026.1737869
Brogaard, E., & Thomsen, S. F. (2026) · Targets · doi:10.3390/targets4040033
庞, 坤. (2026) · Advances in Clinical Medicine · doi:10.12677/acm.2026.16103392
Metadata
- 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.
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2012-09-01
- Volume
- 153
- Issue
- 9
- Pages
- 4354-4366
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- 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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