Document Detail

Metformin: direct inhibition of rat ovarian theca-interstitial cell proliferation.
MedLine Citation:
PMID:  22608319     Owner:  NLM     Status:  MEDLINE    
OBJECTIVE: To determine whether metformin has direct effects on ovarian theca-interstitial (T-I) cell proliferation through activation of adenosine monophosphate-activated protein kinase (AMPK).
DESIGN: In vitro experimental study.
SETTING: Academic medical center laboratory.
ANIMAL(S): Immature Sprague-Dawley female rats.
INTERVENTION(S): Ovarian T-I cells were isolated, purified, and cultured in the absence (control) or presence of insulin (1 μg/mL) with or without metformin or other activators/inhibitors of AMPK (AICAR, compound C).
MAIN OUTCOME MEASURE(S): Proliferation assessed by determination of expression levels of proteins involved in cell cycle progression, cyclin D3, and cyclin-dependent kinase 4 (CDK4) with Western blot analysis, and determination of DNA synthesis with bromodeoxyuridine (BrdU) incorporation assay; activation of AMPK, Erk1/2, and S6K1 determined by Western blot analysis with the use of antibodies specific for the phosphorylated (activated) forms.
RESULT(S): Metformin inhibited insulin-induced ovarian T-I cell proliferation and the up-regulation of the cell cycle regulatory proteins, cyclin D3 and CDK4. Metformin independently activated AMPK in a dose-dependent manner. Treatment with metformin inhibited insulin-induced activation of Erk1/2 and S6K1. This effect was reversed with the addition of compound C, a known AMPK inhibitor.
CONCLUSION(S): Metformin directly inhibits proliferation of ovarian T-I cells via an AMPK-dependent mechanism. These findings further validate the potential benefits of metformin in the treatment of conditions associated with hyperinsulinemia and excessive growth of ovarian T-I cells (such as polycystic ovary syndrome).
Matthew A Will; Murugesan Palaniappan; Helle Peegel; Pradeep Kayampilly; K M J Menon
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-05-17
Journal Detail:
Title:  Fertility and sterility     Volume:  98     ISSN:  1556-5653     ISO Abbreviation:  Fertil. Steril.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-07-03     Completed Date:  2012-09-05     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  0372772     Medline TA:  Fertil Steril     Country:  United States    
Other Details:
Languages:  eng     Pagination:  207-14     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
Department of Obstetrics and Gynecology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
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MeSH Terms
AMP-Activated Protein Kinases / metabolism
Cell Cycle Checkpoints / drug effects,  physiology
Cell Proliferation / drug effects*
Cells, Cultured
Drug Evaluation, Preclinical
Enzyme Activation / drug effects
Hypoglycemic Agents / pharmacology
MAP Kinase Signaling System / drug effects
Metformin / pharmacology*
Ovary / cytology,  drug effects*
Rats, Sprague-Dawley
Ribosomal Protein S6 Kinases / metabolism
Theca Cells / cytology,  drug effects*,  physiology
Grant Support
Reg. No./Substance:
0/Hypoglycemic Agents; 657-24-9/Metformin; EC Protein Kinases; EC Protein S6 Kinases; EC protein, rat

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