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Single Injections of Vascular Endothelial Growth Factor Trap Block Ovulation in the Macaque and Produce a Prolonged, Dose-Related Suppression of Ovarian Function

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

Address all correspondence and requests for reprints to: Hamish M. Fraser, Ph.D., D.Sc., MRC Human Reproductive Sciences Unit, The University of Edinburgh Chancellor’s Building, 49 Little France Crescent, Edinburgh EH16 4SB, United Kingdom. E-mail: h.fraser{at}hrsu.mrc.ac.uk.

Follicular development is associated with intense angiogenesis and increased permeability of blood vessels under the control of locally produced angiogenic factors such as vascular endothelial growth factor (VEGF). The aim of the present study was to evaluate the effects of transient inhibition of VEGF on pituitary-ovarian function in the macaque. Animals were given a single, iv injection of a potent, receptor-based VEGF antagonist, the VEGF Trap. VEGF Trap was given at a dose of 4, 1, or 0.25 mg/kg in the midfollicular phase or at 1.0 mg/kg in the late follicular phase. Controls were treated with vehicle or a control protein, recombinant human Fc (1 mg/kg). Blood samples were collected once daily for 12 d after injection, and three times per week thereafter until normal ovulatory cycles had resumed. The VEGF Trap produced a rapid suppression of estradiol and inhibin B concentrations at all doses tested, followed by a marked and sustained increase in LH and FSH. Ovulation and formation of a functional corpus luteum, as evidenced by increased serum progesterone levels, failed to occur at the anticipated time. Normal ovarian activity resumed when plasma concentrations of unbound VEGF Trap fell below about 1 mg/liter. When treatment was initiated in the midfollicular phase, control macaques ovulated 7.2 ± 0.4 d later, but ovulation was delayed in a dose-dependent manner by VEGF Trap, occurring 23 ± 0.7, 30 ± 1.4, and 43 ± 0.8 d after injection of 0.25, 1, or 4 mg/kg, respectively. Thus, the VEGF Trap exerts a potent, dose-dependent, but reversible inhibitory effect on ovarian function.

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