Circulating levels of free and total vascular endothelial growth factor (VEGF)-A, soluble VEGF receptors-1 and -2, and angiogenin during ovarian stimulation in non-human primates and women

Background: In a prospective study we measured circulating levels of vasoactive factors and their soluble receptors in women undergoing controlled ovarian stimulation (COS) for IVF who were at risk for ovarian hyperstimulation syndrome (OHSS), and compared them to those in a primate model, the rhesus monkey. Methods: A total of 23 women were enrolled in the study and serum vascular endothelial growth factor (VEGF)-A (free and total), soluble (s)VEGF-R1 and -R2, and angiogenin levels were compared in pregnant and non-pregnant women, and in monkeys, during follicular stimulation, the luteal phase and early pregnancy. Results: VEGF levels were similar during the period of follicular stimulation in pregnant and non-pregnant women, but a significant rise in both free and total VEGF occurred in pregnant women during the luteal phase (P < 0.05). The level of sVEGF-R1 (but not -R2) increased (P < 0.05) following implantation, and the rise in sVEGF-R1 corresponded to an abrupt fall in free (but not total) VEGF. In contrast, total VEGF levels remained similar to those observed on the day of hCG injection. Angiogenin levels tended to decline during follicular stimulation, then increased marginally during the luteal phase and were unchanged in early pregnancy. In contrast to women, free VEGF levels were non-detectable and total levels remained constant through the natural menstrual cycle and COS protocols in monkeys. Conclusions: The levels of circulating angiogenic factors and soluble receptors demonstrate significant changes during COS cycles and early pregnancy in women. Thus, the systemic effect of these agents is influenced by ligand-receptor protein-binding interactions, and these relationships may exhibit dynamic changes during COS cycles and early pregnancy, and could contribute to the development of OHSS.