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Submitted on May 31, 2005
Accepted on July 14, 2005
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
* To whom correspondence should be addressed. 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. To determine effects of inhibiting VEGF by a VEGF Trap, a receptor-based inhibitor, administered at the early or mid-luteal phase on pituitary-ovarian function.
Design. Effects of a single injection of VEGF Trap at three doses at the early luteal phase or a single dose in the mid-luteal phase were investigated and compared with control cycles.
Setting. Primate Unit.
Participants. Eleven stump-tailed macaques with regular ovulatory cycles. 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 mid-luteal phase. Controls received vehicle or Fc.
Main outcome measures. Changes in serum concentrations of progesterone, estradiol. LH, FSH, inhibin A, VEGF Trap and menstrual bleeding.
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. Mid-luteal 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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