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Vascular Endothelial Growth Factor Trap Suppresses Ovarian Function at All Stages of the Luteal Phase in the Macaque

Medical Research Council Human Reproductive Sciences Unit (H.M.F., H.W., K.D.M., I.S.), Centre for Reproductive Biology, Edinburgh EH16 4TJ, United Kingdom; and Regeneron Pharmaceuticals (S.J.W.), Tarrytown, New York 10591

Address all correspondence and requests for reprints to: Hamish M. Fraser, D.Sc., Medical Research Council Human Reproductive Sciences Unit, The Queen’s Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom. E-mail: h.fraser{at}hrsu.mrc.ac.uk.

Context: Fertility is dependent on a functioning corpus luteum, the formation of which is associated with intense angiogenesis. The role of angiogenic factors, such as vascular endothelial growth factor (VEGF), in luteal function has yet to be defined in primates.

Objective: The objective of this study was to determine effects of inhibiting VEGF by a VEGF Trap, a receptor-based inhibitor, administered at the early or midluteal phase, on pituitary-ovarian function.

Design: Effects of a single injection of VEGF Trap at three doses in the early luteal phase or a single dose in the midluteal phase were investigated and compared with control cycles.

Setting: This work was conducted in the Primate Unit.

Participants: Eleven stump-tailed macaques with regular ovulatory cycles participated in this study. VEGF Trap was well tolerated, and all completed the study.

Interventions: A single injection of VEGF Trap at a dose of 4, 1, or 0.25 mg/kg was administered in the early luteal phase or 1 mg/kg in the midluteal phase. Controls received vehicle or the constant region of human IgG.

Main Outcome Measures: Changes in serum concentrations of progesterone, estradiol, LH, FSH, inhibin A, VEGF Trap, and menstrual bleeding were the main outcome measures.

Results: Early luteal treatment caused a significant attenuation of the normal serum progesterone and estradiol concentrations, followed by a marked increase in LH and FSH. Inhibin A was not significantly reduced. After 1- and 4-mg/kg doses, progesterone remained suppressed throughout the luteal phase, and premature menstruation occurred; whereas the response to the 0.25-mg/kg dose was transitory, and menstruation was at the normal time. Midluteal treatment also resulted in a significant suppression of progesterone secretion.

Conclusions: VEGF is essential for both the development and maintenance of luteal function.

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