Single Injections of Vascular Endothelial Growth Factor Trap Block Ovulation in the Macaque and Produce a Prolonged, Dose-Related Suppression of Ovarian Function (2005)

The development of ovarian follicles is accompanied by marked angiogenesis and increased permeability of blood vessels. These changes are regulated by locally produced angiogenic factors, including vascular endothelial growth factor (VEGF). Experiments to date have inhibited the VEGF pathway using antibodies directed against VEGF itself. The investigators have used a very potent receptor-based VEGF antagonist, VEGF TrapA40, for the same purpose. This study examined the effects of transiently inhibiting VEGF on pituitary–ovarian function in macaques. Test animals received a single intravenous injection of VEGF Trap in doses of 0.25 to 4 mg/kg in the midfollicular phase or 1 mg/kg in the late follicular phase. Control animals received either vehicle or a control protein, recombinant human Fc. A total of 13 adult female macaques were used in the study. Treatment with VEGF TrapA40 in the midfollicular phase inhibited the expected late follicular increase in plasma estradiol and also led to a rapid fall in estradiol concentrations to levels expected in the early follicular phase. Plasma gonadotropin levels increased progressively within 2 to 3 days after injection, and the ratio of follicle-stimulating hormone (FSH) to luteinizing hormone (LH) increased in all animals (Fig. 1). After treatment, estradiol levels were significantly lower in VEGE Trap-treated cycles than in control cycles (Fig. 2). Levels of inhibin G also decreased after injection of VEGF Trap. Ovulation and formation of a functional corpus luteum failed to occur when expected, as indicated by increased serum progesterone levels. Ovarian activity returned to normal when plasma levels of unbound VEGF Trap had decreased to approximately 1 mg/L. Both suppression of ovarian function and the delay in ovulation induced by VEGF Trap were dose-dependent. Posttreatment hormonal profiles were normal after ovarian function recovered.Fig. 1: Serum concentrations of estradiol (open circles), progesterone (P4, closed circles) (left panel), FSH (closed squares), and LH (open squares) (right panel) in individual macaques injected in the midfollicular phase with either Fc (1 mg/kg, IV) (control) or 0.25, 1, or 4 mg/kg VEGF TrapR1R2 IV (arrow). Note the suppression of estradiol, failure of ovulatory progesterone rises, and increases in LH and FSH after treatment, followed by dose-related recovery of normal pituitary-ovarian function. J Clin Endocrinol Metab 2005;90:1114–1122. Copyright ©2005 The Endocrine Society. All rights reserved.Fig. 2: Serum concentrations of estradiol, progesterone, LH, and FSH after treatment with vehicle/Fc or 0.25, 1, or 4 mg/kg VEGF TrapR1R2 in the midfollicular phase. Vales are means ± SEM plotted with reference to the day of injection (d 0). Note the timely rise in estradiol, followed by the preovulatory LH/FSH surge and sustained rise in luteal progesterone levels in controls. VEGF TrapR1R2 treatment results in the failure of the characteristic increases in estradiol and progesterone and the induction of a persistent increase in LH and FSH. Note the dose-related duration of response followed by recovery initiated by the rise in estradiol. J Clin Endocrinol Metab 2005;90:1114–1122. Copyright ©2005 The Endocrine Society. All rights reserved.These findings indicate that VEGF Trap can aid the development of new treatments for some forms of ovarian dysfunction and infertility. This is particularly the case for conditions associated with pathologic angiogenesis and excessive vascular permeability such as polycystic ovary syndrome, ovarian hyperstimulation syndrome, and endometriosis.