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Angiogenic Effects of Norplant Contraception on Endometrial Histology and Uterine Bleeding

Center for Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, California 94143

Address all correspondence and requests for reprints to: Robert N. Taylor, M.D., Ph.D., Center for Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, 513 Parnassus, Health Sciences West 1656, University of California, San Francisco, San Francisco, California 94143-0556. E-mail: taylorr{at}obgyn.ucsf.edu.

Norplant, a sc contraceptive device, releases levonorgestrel in a sustained fashion. Its effectiveness is offset by irregular bleeding patterns. Because vascular endothelial growth factor (VEGF) is stimulated by synthetic progestogens in vitro and in vivo, we postulated that correlations between this angiogenic factor and uterine bleeding patterns might exist. Twenty-eight women who were exposed to Norplant and 13 control women were prospectively followed for 6–8 months. Bleeding diaries were collected, hysteroscopies were performed, endometrial biopsies were obtained for standardized histological evaluation, and VEGF histochemical immunostaining (H)-scores were assigned. Cluster determination-34 (CD34) staining was also performed to quantify the number of endometrial blood vessels per high-power field. Irregular uterine bleeding was common among women using Norplant devices. Endometrial VEGF H-scores were greater in women using Norplant than in control women. New findings of this study show that vessel density did not correlate with epithelial VEGF H-scores but was highly associated with the intensity of stromal and perivascular VEGF. VEGF expression in the latter regions correlated significantly with hysteroscopic abnormalities and irregular bleeding. The expression of this angiogenic protein, particularly in the stromal and perivascular compartments, correlated with microvascular density, hysteroscopically documented hypervascularity, and uterine bleeding profiles. Irregular bleeding with Norplant use appears to reflect paracrine-mediated effects on vascular function by angiogenic factors, such as VEGF.

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