Metformin inhibits human androgen production by regulating steroidogenic enzymes HSD3B2 and CYP17A1 and complex I activity of the respiratory chain.
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.
Department of Pediatrics, Division of Pediatric Endocrinology, Diabetology and Metabolism, University Hospital Inselspital, University of Bern, 3010 Bern, Switzerland.
Andrea
A
Hirsch
Dagmar
D
Hahn
Petra
P
Kempná
Gaby
G
Hofer
Jean-Marc
JM
Nuoffer
Primus E
PE
Mullis
Christa E
CE
Flück
D000728:Androgens / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D011375:Progesterone Reductase / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism*
D000728:Androgens; D027701:Organic Cation Transport Proteins; D008687:Metformin; C533068:3 beta-hydroxysteroid dehydrogenase type II; D011375:Progesterone Reductase; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; D042967:Electron Transport Complex I