title: Metformin directly inhibits androgen production in human thecal cells.
abstract: OBJECTIVE
  To examine the direct effect of metformin on thecal cell androgen production.
  
  
  METHODS
  Basic science research laboratory, University of Texas Southwestern, Dallas, Texas.
  
  
  METHODS
  Human ovarian theca-like tumor cells were treated with various concentrations of metformin in the presence and absence of forskolin for 48 hours.
  
  
  METHODS
  Media were collected, and radioimmunoassay (RIA) for progesterone, 17 alpha-hydroxyprogesterone (17OHP), androstenedione, and testosterone was performed. The effect of metformin on the expression of various enzymes involved in theca cell steroidogenesis was examined.
  
  
  RESULTS
  Metformin (50 microM and 200 microM) significantly inhibited androstenedione production from both forskolin-stimulated and unstimulated theca cells. Testosterone production was also significantly inhibited in forskolin-treated cells in the presence of 200 microM of metformin-treated compared with forskolin-only-treated cells. Western blot analysis revealed that metformin significantly inhibited the expression of steroidogenic acute regulatory (StAR) protein and 17 alpha-hydroxylase (CYP17) expression in cells stimulated with forskolin compared with forskolin treatment alone. There was no significant change in either 3beta-hydroxysteroid dehydrogenase (3 beta HSD) or cholesterol side-chain cleavage (CYP11A1) protein expression. Northern analysis revealed a significant decrease in the expression of CYP17 mRNA in forskolin-stimulated cells treated with metformin (200 microM) compared with forskolin-only-treated cells, however, there was no significant change in steroidogenic acute regulatory protein mRNA expression.
  
  
  CONCLUSIONS
  Our results suggest that metformin may have a direct effect on thecal cells' androgen production.
authors.affiliation: Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235-9032, USA.
authors.forename: G R
authors.initials: GR
authors.lastname: Attia
authors.forename: W E
authors.initials: WE
authors.lastname: Rainey
authors.forename: B R
authors.initials: BR
authors.lastname: Carr
mesh_terms: D019326:17-alpha-Hydroxyprogesterone / Q000378:metabolism; D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics; D000728:Androgens / Q000096:biosynthesis*; D000735:Androstenedione / Q000378:metabolism; D002478:Cells, Cultured; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics; D005576:Colforsin / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D010750:Phosphoproteins / Q000235:genetics; D011374:Progesterone / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics; D013739:Testosterone / Q000378:metabolism; D013799:Theca Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D000728:Androgens; D010750:Phosphoproteins; D012333:RNA, Messenger; D000098682:Steroidogenic Acute Regulatory Protein; D005576:Colforsin; D013739:Testosterone; D000735:Androstenedione; D011374:Progesterone; D019326:17-alpha-Hydroxyprogesterone; D008687:Metformin; D015096:3-Hydroxysteroid Dehydrogenases; D013254:Steroid 17-alpha-Hydroxylase; D002786:Cholesterol Side-Chain Cleavage Enzyme