Vascular endothelial growth factor trap suppresses ovarian function at all stages of the luteal phase in the macaque

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.