The role of vascular endothelial growth factor (VEGF) in physiology and pathology of reproductive function
Vascular endothelial growth factor (VEGF) is a multifunctional cytokine. It has potent angiogenic properties and makes endothelial cells hyperpermeable to plasma proteins. In the clinical studies that constitute this thesis, serum concentrations of VEGF were measured by enzyme immunoassay. Initial studies documented fluctuations of serum VEGF in women during the normal menstrual cycle and their relationship to pelvic blood flow, as assessed by colour Doppler ultrasonography. The hypothesis that VEGF plays a role in the pathogenesis of ovarian hyperstimulation syndrome (OHSS) was explored. Women who recruit an excessive number of follicles overexpress VEGF, which may result in a fluid shift into the extravascular space, which characterises the syndrome of OHSS. Women with polycystic ovaries (PCO), who are at high risk of OHSS, and women who developed OHSS had higher serum concentrations of VEGF and pelvic blood flow velocities than women with normal ovaries and than those who did not develop OHSS. Pregnancy was also associated with higher circulating VEGF concentrations than non-pregnant states. A further study explored the contribution of the reproductive tract to circulating VEGF concentrations. Women who had their uterus and ovaries in situ had higher VEGF concentrations than women who had previously undergone hysterectomy and oophorectomy. Treatment of postmenopausal women with hormone replacement therapy (HRT) was associated with higher serum VEGF than no treatment with HRT. The hypothesis that raised serum VEGF concentrations in women with PCO results from excess release by granulosa cells was tested in in-vitro studies. VEGF released by cultured human luteinised granulosa cells was measured by a sensitive "sandwich" enzyme immunoassay. Release of VEGF into the culture medium was augmented by incubation of cells with hCG, FSH and LH. Co-incubation with insulin augmented hCG - stimulated release of VEGF. More VEGF was released from granulosa cells obtained from women with PCO than from granulosa cells obtained from women with normal ovaries. These results were consistent with the hypothesis that raised serum VEGF concentrations in women with PCO results from excessive VEGF release by granulosa cells. The reproductive tract contributes significantly to circulating VEGF concentrations. The presence of PCO, OHSS, pregnancy and treatment with HRT were all associated with elevated serum VEGF concentrations.