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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 Syndrome¹

Hospital Clinicas Caracas (D.J.J.) and Central University of Venezuela (D.J.J., S.J., O.R.A., A.R.S.), 1050 Caracas, Venezuela; Department of Obstetrics and Gynecology, University of Helsinki (M.S., H.K., R.K.), SF-00290 Helsinki, Finland; and Departments of Medicine and Obstetrics and Gynecology, Medical College of Virginia, Virginia Commonwealth University (J.E.N.), Richmond, Virginia 23298

Address all correspondence and requests for reprints to: John E. Nestler, M.D., Medical College of Virginia, P.O. Box 980111, Richmond, Virginia 23298-0111. E-mail: nestler{at}hsc.vcu.edu

We hypothesized that hyperinsulinemia contributes to early pregnancy loss in the polycystic ovary syndrome by adversely affecting endometrial function and environment. Serum glycodelin, a putative biomarker of endometrial function, is decreased in women with early pregnancy loss. Insulin-like growth factor-binding protein-1 may also play an important role in pregnancy by facilitating adhesion processes at the feto-maternal interface.

We studied 48 women with polycystic ovary syndrome before and after 4 weeks of administration of 500 mg metformin (n = 26) or placebo (n = 22) 3 times daily. Oral glucose tolerance tests were performed, and serum glycodelin and insulin-like growth factor-binding protein-1 were measured during the follicular and clomiphene-induced luteal phases of menses.

In the metformin group, the mean (±SE) area under the serum insulin curve after glucose administration decreased from 62 ± 6 to 19 ± 2 nmol/L·min (P < 0.001). Follicular phase serum glycodelin concentrations increased 20-fold from 150 ± 46 to 2813 ± 1192 pmol/L (P < 0.001), and serum insulin-like-growth factor-binding protein-1 concentrations increased from 936 ± 152 to 2396 ± 300 pmol/L (P < 0.001). Similarly, luteal phase serum glycodelin concentrations increased 3-fold from 3434 ± 1299 to 10624 ± 1803 pmol/L (P < 0.001), and serum insulin-like growth factor-binding protein-1 concentrations increased from 1220 ± 136 to 4916 ± 596 pmol/L (P < 0.001). Uterine vascular penetration also increased in the metformin group, as did blood flow of spiral arteries, as demonstrated by a 20% decrease in the resistance index from 0.71 ± 0.02 to 0.57 ± 0.03 (P < 0.001). These variables did not change in the placebo group.

We conclude that insulin reduction with metformin increases follicular and luteal phase serum glycodelin and insulin-like growth factor-binding protein-1 concentrations and enhances luteal phase uterine vascularity and blood flow in the polycystic ovary syndrome. These changes may reflect an improved endometrial milieu for the establishment and maintenance of pregnancy.

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