Metformin: Direct Inhibition of Rat Ovarian Theca-Interstitial Cell Proliferation

Metformin activates adenosine monophosphate–activated protein kinase (AMPK) in rat ovarian thecainterstitial cells and subsequently inhibits cell proliferation and insulin-induced mitogenic signaling pathways.

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Authors

Matthew A. Will, M.D., Murugesan Palaniappan, Ph.D., Helle Peegel, M.S., Pradeep Kayampilly, Ph.D., K.M.J. Menon, Ph.D.

Vol 98, Issue 1, Pages 207-214

Abstract

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).

Read the full text at: http://www.fertstert.org/article/S0015-0282(12)00442-6/fulltext


Fertility and Sterility

Editorial Office, American Society for Reproductive Medicine

Fertility and Sterility® is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders. The journal publishes juried original scientific articles in clinical and laboratory research relevant to reproductive endocrinology, urology, andrology, physiology, immunology, genetics, contraception, and menopause. Fertility and Sterility® encourages and supports meaningful basic and clinical research, and facilitates and promotes excellence in professional education, in the field of reproductive medicine.

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