This Article Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by ERICKSON, G. F. Articles by CHANG, R. J. Search for Related Content PubMed PubMed Citation Articles by ERICKSON, G. F. Articles by CHANG, R. J.

The Effects of Insulin and Insulin-Like Growth Factors-I and -II on Estradiol Production by Granulosa Cells of Polycystic Ovaries^*

Department of Reproductive Medicine, M-025, University of California-San Diego (G.F.E., D.A.M.) La Jolla, California 92093
the Department of Obstetrics and Gynecology University of California-Davis (J.R.C., R.J.C.) Sacramento, California 95816

Address requests for reprints to: Dr. Gregory F. Erickson, Department of Reproductive Medicine M-025, University of California-San Diego, La Jolla, California 92093.

The objective of this work was to examine the effects of insulin-like growth factors (IGFs) on estradiol (E₂)production by granulosa cells obtained from ovaries of patients with polycystic ovary disease (PCO). Granulosa cells, isolated from ovaries of three PCO patients, were cultured in serum-free medium containing either androstenedione alone (10^–7 M) or androstenedione plus graded doses of FSH, IGF-I, IGF-II, and/or insulin. At the end of the culture period (2, 4, or 6 days) E₂ levels in the medium were measured by RIA. The results from each patient were similar, and therefore, the data were pooled. In the 6-day time-course experiments, the control (untreated) cells produced relatively high levels of E₂ at 2 days; however, none was detected thereafter. Treatment with FSH (30 ng/mL) stimulated E₂ production 4-fold at 2 days, but the stimulatory effects of FSH were not sustained during culture. IGF-I at 30 ng/mL mimicked the effects of FSH. Concomitant treatment with FSH and IGF-I caused synergistic increases in E₂ production (3-, 13-, and 33-fold at 2, 4, and 6 days, respectively). Doseresponse studies revealed that FSH and IGF-I stimulated E₂ production in a dose-dependent fashion (ED₅₀ of FSH and IGF-I, were 1.1 ± 0.3 and 7.6 ± 7.2 ng/mL, respectively). In the presence of a maximally effective dose of FSH (30 ng/mL), the cells appeared to become more responsive to IGF-I (ED₅₀ of IGF-I plus FSH, 1.09 ± 0.29 ng/mL); however, this effect was not significant (P = 0.086). In the presence of a maximally effective dose of IGF-I (30 ng/mL), the stimulatory effect of FSH on E₂ production was dramatically amplified, but the IGF-I did not significantly (P = 0.85) change the potency of FSH (ED₅₀ of FSH plus IGF-I, 1.07 ± 2.3 ng/mL). Treatment with IGF-II over the concentration range of 0.1–100 ng/mL had no effect on either control or FSH-stimulated E₂ production. Treatment with insulin, either alone or together with FSH, increased the levels of E₂, but the insulin effects were seen only at the highest doses tested (0.3–10 Mg/mL).

The results in these in vitro experiments with PCO granulosa cells indicate that 1) physiological concentrations of IGF-I are as effective as FSH in stimulating E₂ production; 2) IGF-I and FSH act synergistically to control the level of E₂ production; and 3) this synergy was not observed with insulin or IGF-II.

^* This work was supported by Academic Senate Grant RH-52-M (to G.F.E.).

Received July 13, 1989.

This article has been cited by other articles:

				S. Rice, L. Pellatt, K. Ramanathan, S. A. Whitehead, and H. D. Mason Metformin Inhibits Aromatase via an Extracellular Signal-Regulated Kinase-Mediated Pathway Endocrinology, October 1, 2009; 150(10): 4794 - 4801. [Abstract] [Full Text] [PDF]

				M. THILL, S. BECKER, D. FISCHER, T. CORDES, A. HORNEMANN, K. DIEDRICH, D. SALEHIN, and M. FRIEDRICH Expression of Prostaglandin Metabolising Enzymes COX-2 and 15-PGDH and VDR in Human Granulosa Cells Anticancer Res, September 1, 2009; 29(9): 3611 - 3618. [Abstract] [Full Text] [PDF]

				S. Palomba, A. Falbo, F. Zullo, and F. Orio Jr. Evidence-Based and Potential Benefits of Metformin in the Polycystic Ovary Syndrome: A Comprehensive Review Endocr. Rev., February 1, 2009; 30(1): 1 - 50. [Abstract] [Full Text] [PDF]

				D. S. Wachs, M. S. Coffler, P. J. Malcom, S. Shimasaki, and R. J. Chang Increased Androgen Response to Follicle-Stimulating Hormone Administration in Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., May 1, 2008; 93(5): 1827 - 1833. [Abstract] [Full Text] [PDF]

				L.J. Spicer and P.Y. Aad Insulin-Like Growth Factor (IGF) 2 Stimulates Steroidogenesis and Mitosis of Bovine Granulosa Cells Through the IGF1 Receptor: Role of Follicle-Stimulating Hormone and IGF2 Receptor Biol Reprod, July 1, 2007; 77(1): 18 - 27. [Abstract] [Full Text] [PDF]

				J. Zhao, D.-H. Xiong, Y. Guo, T.-L. Yang, R. R. Recker, and H.-W. Deng Polymorphism in the insulin-like growth factor 1 gene is associated with age at menarche in caucasian females Hum. Reprod., June 1, 2007; 22(6): 1789 - 1794. [Abstract] [Full Text] [PDF]

				E. J P van Santbrink, F. P Hohmann, M. J C Eijkemans, J. S E Laven, and B. C J M Fauser Does metformin modify ovarian responsiveness during exogenous FSH ovulation induction in normogonadotrophic anovulation? A placebo-controlled double-blind assessment Eur. J. Endocrinol., April 1, 2005; 152(4): 611 - 617. [Abstract] [Full Text] [PDF]

				G. A. R. Maciel, E. C. Baracat, J. A. Benda, S. M. Markham, K. Hensinger, R. J. Chang, and G. F. Erickson Stockpiling of Transitional and Classic Primary Follicles in Ovaries of Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5321 - 5327. [Abstract] [Full Text] [PDF]

				J. L. Phy, C. A. Conover, D. H. Abbott, M. A. Zschunke, D. L. Walker, D. R. Session, I. S. Tummon, A. R. Thornhill, T. G. Lesnick, and D. A. Dumesic Insulin and Messenger Ribonucleic Acid Expression of Insulin Receptor Isoforms in Ovarian Follicles from Nonhirsute Ovulatory Women and Polycystic Ovary Syndrome Patients J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3561 - 3566. [Abstract] [Full Text] [PDF]

				M. S. Coffler, K. Patel, M. H. Dahan, R. Y. Yoo, P. J. Malcom, and R. J. Chang Enhanced Granulosa Cell Responsiveness to Follicle-Stimulating Hormone during Insulin Infusion in Women with Polycystic Ovary Syndrome Treated with Pioglitazone J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5624 - 5631. [Abstract] [Full Text] [PDF]

				V. De Leo, A. la Marca, and F. Petraglia Insulin-Lowering Agents in the Management of Polycystic Ovary Syndrome Endocr. Rev., October 1, 2003; 24(5): 633 - 667. [Abstract] [Full Text] [PDF]

				M. S. Coffler, K. Patel, M. H. Dahan, P. J. Malcom, T. Kawashima, R. Deutsch, and R. J. Chang Evidence for Abnormal Granulosa Cell Responsiveness to Follicle-Stimulating Hormone in Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1742 - 1747. [Abstract] [Full Text] [PDF]

				A. Shobokshi and M. Shaarawy Correction of Insulin Resistance and Hyperandrogenism in Polycystic Ovary Syndrome By Combined Rosiglitazone and Clomiphene Citrate Therapy Reproductive Sciences, February 1, 2003; 10(2): 99 - 104. [Abstract] [PDF]

				T. R. Davidson, C. S. Chamberlain, T. S. Bridges, and L. J. Spicer Effect of Follicle Size on In Vitro Production of Steroids and Insulin-Like Growth Factor (IGF)-I, IGF-II, and the IGF-Binding Proteins by Equine Ovarian Granulosa Cells Biol Reprod, June 1, 2002; 66(6): 1640 - 1648. [Abstract] [Full Text] [PDF]

				P. Fedorcsak, P. O. Dale, R. Storeng, T. Tanbo, and T. Abyholm The impact of obesity and insulin resistance on the outcome of IVF or ICSI in women with polycystic ovarian syndrome Hum. Reprod., June 1, 2001; 16(6): 1086 - 1091. [Abstract] [Full Text] [PDF]

				D. J. Jakubowicz, M. Seppälä, S. Jakubowicz, O. Rodriguez-Armas, A. Rivas-Santiago, H. Koistinen, R. Koistinen, and J. E. Nestler Insulin Reduction with Metformin Increases Luteal Phase Serum Glycodelin and Insulin-Like Growth Factor-Binding Protein 1 Concentrations and Enhances Uterine Vascularity and Blood Flow in the Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1126 - 1133. [Abstract] [Full Text]

				V. De Leo, A. la Marca, G. Morgante, L. Ciotta, L. Mencaglia, A. Cianci, and F. Petraglia Clomiphene citrate increases insulin-like growth factor binding protein-1 and reduces insulin-like growth factor-I without correcting insulin resistance associated with polycystic ovarian syndrome Hum. Reprod., November 1, 2000; 15(11): 2302 - 2305. [Abstract] [Full Text] [PDF]

				V. De Leo, A. la Marca, R. Orvieto, and G. Morgante Effect of Metformin on Insulin-Like Growth Factor (IGF) I and IGF-Binding Protein I in Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., April 1, 2000; 85(4): 1598 - 1600. [Abstract] [Full Text]

				L. Poretsky, N. A. Cataldo, Z. Rosenwaks, and L. C. Giudice The Insulin-Related Ovarian Regulatory System in Health and Disease Endocr. Rev., August 1, 1999; 20(4): 535 - 582. [Abstract] [Full Text] [PDF]

				V. L. Nelson, R. S. Legro, J. F. Strauss III, and J. M. McAllister Augmented Androgen Production Is a Stable Steroidogenic Phenotype of Propagated Theca Cells from Polycystic Ovaries Mol. Endocrinol., June 1, 1999; 13(6): 946 - 957. [Abstract] [Full Text]

				C.S. Wright, O. Hovatta, R. Margara, G. Trew, R.M.L. Winston, S. Franks, and K. Hardy Effects of follicle-stimulating hormone and serum substitution on the in-vitro growth of human ovarian follicles Hum. Reprod., June 1, 1999; 14(6): 1555 - 1562. [Abstract] [Full Text] [PDF]

				T. M. Fiad, T. P. Smith, S. K. Cunningham, and T. J. McKenna Decline in Insulin-Like Growth Factor I Levels after Clomiphene Citrate Does Not Correct Hyperandrogenemia in Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., July 1, 1998; 83(7): 2394 - 2398. [Abstract] [Full Text]

				J. E. Nestler and D. J. Jakubowicz Lean Women with Polycystic Ovary Syndrome Respond to Insulin Reduction with Decreases in Ovarian P450c17{alpha} Activity and Serum Androgens J. Clin. Endocrinol. Metab., December 1, 1997; 82(12): 4075 - 4079. [Abstract] [Full Text] [PDF]

				A. M. Fulghesu, P. Villa, V. Pavone, M. Guido, R. Apa, A. Caruso, A. Lanzone, A. Rossodivita, and S. Mancuso The Impact of Insulin Secretion on the Ovarian Response to Exogenous Gonadotropins in Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., February 1, 1997; 82(2): 644 - 648. [Abstract] [Full Text] [PDF]