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The Insulin-Related Ovarian Regulatory System in Health and Disease

Division of Endocrinology, Department of Medicine (L.P.) and Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology (Z.R.), New York Presbyterian Hospital and Weill Medical College of Cornell University, New York, New York 10021; and Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Stanford University Medical Center (N.A.C., L.C.G.), Stanford, California 94305

I. Introduction

II. Insulin and Insulin Receptor

A. Structures of insulin and insulin receptor

B. Presence of insulin and insulin receptor in the ovary

C. Insulin action and the ovary

D. Summary

III. IGFs and Their Receptors

A. IGF peptides and receptors

B. Expression of IGFs and IGF receptors in the ovary

C. Role of IGFs in ovulatory function and steroidogenesis

D. Summary

IV. IGF-Binding Proteins (IGFBPs) and Proteases

A. Structural relationships among IGFBPs

B. IGFBP expression in the ovary

C. IGFBP proteases in the ovary

D. IGFBP actions in the ovary

E. Role of IGFBPs in follicular development and atresia

F. Summary

V. Polycystic Ovary Syndrome (PCOS)

A. Clinical features

B. Theories of pathogenesis

C. Insulin resistance in PCOS

D. Alterations of IGFs and IGFBPs in PCOS

E. Summary

VI. The Insulin-Related Ovarian Regulatory System: Implications for Therapy

A. Treatment of PCOS

B. Therapeutic use of IGF-I and IGF-II

C. Use of GH in ovulation induction

VII. Summary and Conclusions

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				D. Zaczek, J. Hammond, L. Suen, S. Wandji, D. Service, A. Bartke, V. Chandrashekar, K. Coschigano, and J. Kopchick Impact of Growth Hormone Resistance on Female Reproductive Function: New Insights from Growth Hormone Receptor Knockout Mice Biol Reprod, October 1, 2002; 67(4): 1115 - 1124. [Abstract] [Full Text] [PDF]

				L. Ibanez, C. Valls, A. Ferrer, K. Ong, D. B. Dunger, and F. de Zegher Additive Effects of Insulin-Sensitizing and Anti-Androgen Treatment in Young, Nonobese Women with Hyperinsulinism, Hyperandrogenism, Dyslipidemia, and Anovulation J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2870 - 2874. [Abstract] [Full Text] [PDF]

				A. Hourvitz, A. Kuwahara, J. D. Hennebold, A. B. Tavares, H. Negishi, T. H. Lee, G. F. Erickson, and E. Y. Adashi The Regulated Expression of the Pregnancy-Associated Plasma Protein-A in the Rodent Ovary: A Proposed Role in the Development of Dominant Follicles and of Corpora Lutea Endocrinology, May 1, 2002; 143(5): 1833 - 1844. [Abstract] [Full Text] [PDF]

				R. Homburg Should patients with polycystic ovarian syndrome be treated with metformin?: A note of cautious optimism Hum. Reprod., April 1, 2002; 17(4): 853 - 856. [Abstract] [Full Text] [PDF]

				I. Ek, P. Arner, M. Ryden, C. Holm, A. Thorne, J. Hoffstedt, and H. Wahrenberg A Unique Defect in the Regulation of Visceral Fat Cell Lipolysis in the Polycystic Ovary Syndrome as an Early Link to Insulin Resistance Diabetes, February 1, 2002; 51(2): 484 - 492. [Abstract] [Full Text] [PDF]

				M. E. Silfen, A. M. Manibo, M. Ferin, D. J. McMahon, L. S. Levine, and S. E. Oberfield Elevated Free IGF-I Levels in Prepubertal Hispanic Girls with Premature Adrenarche: Relationship with Hyperandrogenism and Insulin Sensitivity J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 398 - 403. [Abstract] [Full Text] [PDF]

				S. A. El Mkadem, C. Lautier, F. Macari, N. Molinari, P. Lefebvre, E. Renard, J. C. Gris, G. Cros, J. P. Daures, J. Bringer, et al. Role of Allelic Variants Gly972Arg of IRS-1 and Gly1057Asp of IRS-2 in Moderate-to-Severe Insulin Resistance of Women With Polycystic Ovary Syndrome Diabetes, September 1, 2001; 50(9): 2164 - 2168. [Abstract] [Full Text] [PDF]

				J.E. Fortune, G.M. Rivera, A.C.O. Evans, and A.M. Turzillo Differentiation of Dominant Versus Subordinate Follicles in Cattle Biol Reprod, September 1, 2001; 65(3): 648 - 654. [Abstract] [Full Text] [PDF]

				L. Ibanez, C. Valls, A. Ferrer, M. V. Marcos, F. Rodriguez-Hierro, and F. de Zegher Sensitization to Insulin Induces Ovulation in Nonobese Adolescents with Anovulatory Hyperandrogenism J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3595 - 3598. [Abstract] [Full Text] [PDF]

				L. Poretsky, D. Seto-Young, A. Shrestha, S. Dhillon, M. Mirjany, H.-C. Liu, M. C Yih, and Z. Rosenwaks Phosphatidyl-Inositol-3 Kinase-Independent Insulin Action Pathway(s) in the Human Ovary J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3115 - 3119. [Abstract] [Full Text] [PDF]

				N. Sekar and J. D. Veldhuis Concerted Transcriptional Activation of the Low Density Lipoprotein Receptor Gene by Insulin and Luteinizing Hormone in Cultured Porcine Granulosa-Luteal Cells: Possible Convergence of Protein Kinase A, Phosphatidylinositol 3-Kinase, and Mitogen-Activated Protein Kinase Signaling Pathways Endocrinology, July 1, 2001; 142(7): 2921 - 2928. [Abstract] [Full Text] [PDF]

				G.M. Rivera, Y.A. Chandrasekher, A.C.O. Evans, L.C. Giudice, and J.E. Fortune A Potential Role for Insulin-Like Growth Factor Binding Protein-4 Proteolysis in the Establishment of Ovarian Follicular Dominance in Cattle Biol Reprod, July 1, 2001; 65(1): 102 - 111. [Abstract] [Full Text] [PDF]

				G.M. Rivera and J.E. Fortune Development of Codominant Follicles in Cattle Is Associated with a Follicle-Stimulating Hormone-Dependent Insulin-Like Growth Factor Binding Protein-4 Protease Biol Reprod, July 1, 2001; 65(1): 112 - 118. [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]

				C. T.F. Huang, S. R. Weitsman, B. N. Dykes, and D. A. Magoffin Stem Cell Factor and Insulin-Like Growth Factor-I Stimulate Luteinizing Hormone-Independent Differentiation of Rat Ovarian Theca Cells Biol Reprod, February 1, 2001; 64(2): 451 - 456. [Abstract] [Full Text]

				N. Sekar, H. A. LaVoie, and J. D. Veldhuis Concerted Regulation of Steroidogenic Acute Regulatory Gene Expression by Luteinizing Hormone and Insulin (or Insulin-Like Growth Factor I) in Primary Cultures of Porcine Granulosa-Luteal Cells Endocrinology, November 1, 2000; 141(11): 3983 - 3992. [Abstract] [Full Text] [PDF]

				S. M. Quirk, R. M. Harman, and R. G. Cowan Regulation of Fas Antigen (Fas, CD95)-Mediated Apoptosis of Bovine Granulosa Cells by Serum and Growth Factors Biol Reprod, November 1, 2000; 63(5): 1278 - 1284. [Abstract] [Full Text]

				S. E. Oberfield Metabolic Lessons from the Study of Young Adolescents with Polycystic Ovary Syndrome--Is Insulin, Indeed, the Culprit? J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3520 - 3525. [Full Text]

				G. M. Weber and C. V. Sullivan Effects of Insulin-Like Growth Factor-I on In Vitro Final Oocyte Maturation and Ovarian Steroidogenesis in Striped Bass, Morone saxatilis Biol Reprod, October 1, 2000; 63(4): 1049 - 1057. [Abstract] [Full Text]

				J. Liu, A. T. Koenigsfeld, T. C. Cantley, C. K. Boyd, Y. Kobayashi, and M. C. Lucy Growth and the Initiation of Steroidogenesis in Porcine Follicles Are Associated with Unique Patterns of Gene Expression for Individual Componentsof the Ovarian Insulin-Like Growth Factor System Biol Reprod, September 1, 2000; 63(3): 942 - 952. [Abstract] [Full Text]

				I. J. Gonzalez-Robayna, A. E. Falender, S. Ochsner, G. L. Firestone, and J. S. Richards Follicle-Stimulating Hormone (FSH) Stimulates Phosphorylation and Activation of Protein Kinase B (PKB/Akt) and Serum and Glucocorticoid-Induced Kinase (Sgk): Evidence for A Kinase-Independent Signaling by FSH in Granulosa Cells Mol. Endocrinol., August 1, 2000; 14(8): 1283 - 1300. [Abstract] [Full Text]

				B. D. Murphy Models of Luteinization Biol Reprod, July 1, 2000; 63(1): 2 - 11. [Abstract] [Full Text]

				E. W. C. M. Van Dam, F. Roelfsema, J. D. Veldhuis, F. M. Helmerhorst, M. Frolich, A. E. Meinders, H. M. J. Krans, and H. Pijl Increase in daily LH secretion in response to short-term calorie restriction in obese women with PCOS Am J Physiol Endocrinol Metab, April 1, 2002; 282(4): E865 - E872. [Abstract] [Full Text] [PDF]