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Insulin and Messenger Ribonucleic Acid Expression of Insulin Receptor Isoforms in Ovarian Follicles from Nonhirsute Ovulatory Women and Polycystic Ovary Syndrome Patients

Departments of Obstetrics and Gynecology (J.L.P., D.L.W., D.R.S., I.S.T., A.R.T., D.A.D.), Internal Medicine (C.A.C., D.R.S., D.A.D.), Experimental Pathology (M.A.Z.), and Biostatistics (T.G.L.), Mayo Clinic, Rochester, Minnesota 55905; and Wisconsin Primate Research Center (D.H.A., D.A.D.) and Department of Obstetrics and Gynecology (D.H.A.), University of Wisconsin, Madison, Wisconsin 53792

Address all correspondence and requests for reprints to: Jennifer L. Phy, D.O., Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. E-mail: phy.jenniferlynn{at}mayo.edu.

Insulin action is mediated by two insulin receptor (IR) isoforms, differing in mitogenic and metabolic function. IR isoform expression might occur in human granulosa cells and could be altered in polycystic ovary syndrome (PCOS) from hyperinsulinemia. To determine the relationship between granulosa cell IR isoform expression and follicular fluid insulin concentration in individual follicles, 18 normal women and seven PCOS patients receiving gonadotropins for in vitro fertilization were studied. Glucose tolerance testing was performed before pituitary desensitization, and fasting serum insulin was measured at oocyte retrieval. Granulosa cells and fluid aspirated from the first follicle were used to determine IR isoform mRNA expression and insulin concentration, respectively. IR isoform A mRNA expression was greater than that of IR isoform B expression in normal mural granulosa and cumulus cells, without a cell type effect. Intrafollicular insulin levels increased with adiposity and serum insulin levels at oocyte-retrieval but did not predict IR mRNA expression. Total IR mRNA expression, but not intrafollicular insulin levels, was elevated in PCOS patients, whereas intrafollicular insulin levels were increased in women with impaired glucose tolerance. Granulosa cell IR heterogeneity, together with adiposity-dependent intrafollicular insulin availability, introduces a novel mechanism by which insulin may affect granulosa cell function within the follicle.

This work was supported by National Institutes of Health Grant U01 HD044650-01, Grant 5P51 RR 000167 to the National Primate Research Center, University of Wisconsin-Madison, Mayo Clinical Research Grant 2123-01, Mayo Grant M01-RR-00585 and Serono Pharmaceuticals.

Abbreviations: AUC, Area under the curve; BMI, body mass index; CV, coefficient of variation; DHEAS, dehydroepiandrosterone sulfate; HSA, human serum albumin; IR, insulin receptor; IR-A, IR isoform A mediating primarily mitogenic signaling; IR-B, IR isoform B predominating in metabolic tissues; IVF, in vitro fertilization; OGTT, oral glucose tolerance test; PCOS, polycystic ovary syndrome; TVUS, transvaginal ultrasound.

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