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Insulin Attenuates the Insulin-Like Growth Factor-I (IGF-I)-Akt Pathway, not IGF-I-Extracellularly Regulated Kinase Pathway, in Luteinized Granulosa Cells with an Increase in PTEN

Departments of Obstetrics and Gynecology (A.I., M.G., T.H., S.T., T.N., K.S., S.M., F.K.) and Maternal and Perinatal Medicine (A.I., T.H.), Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan

Address all correspondence and requests for reprints to: Dr. Akira Iwase, Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. E-mail: akiwase{at}med.nagoya-u.ac.jp.

Context: Insulin resistance is considered as part of the pathogenesis of polycystic ovary syndrome (PCOS), and PCOS patients often show hyperinsulinemia. The influence of insulin on folliculogenesis in women with PCOS has not been fully investigated.

Objective: Our objective was to assess the induction of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression with insulin treatment and effects of PTEN on IGF-I-induced granulosa cell proliferation as well as the correlation of PTEN levels with the concentration of insulin in follicular fluid in PCOS and non-PCOS patients.

Design, Setting, Patients, and Main Outcome Measures: A cell proliferation assay, real-time RT-PCR, and Western blotting for PTEN, Akt, and ERK1/2 were conducted in primary cultured granulosa cells under IGF-I stimulation with or without insulin pretreatment. Phosphorylation of Akt and ERK1/2 was also determined by Western blotting. We also measured the insulin concentration in follicular fluid and the levels of PTEN expression in granulosa cells collected at the time of oocyte retrieval of in vitro fertilization in PCOS (n = 13) and non-PCOS patients (n = 37).

Results: PTEN expression was induced by insulin. Pretreatment with insulin attenuated the IGF-I-induced Akt phosphorylation and cell proliferation but not ERK1/2 phosphorylation. A phosphatidylinositol 3-kinase inhibitor, LY294002, inhibited the IGF-I-induced cell proliferation. Suppression of insulin-induced PTEN expression using small interfering RNA recovered IGF-I-induced Akt phosphorylation. PTEN levels in granulosa cells, which tended to be higher in PCOS patients, were correlated with the insulin concentration in follicular fluid.

Conclusions: PTEN may influence the proliferation of human granulosa cells as well as disturbance of follicular growth in PCOS patients.