Follicular fluid vascular endothelial growth factor concentrations are elevated in women of advanced reproductive age undergoing ovulation induction

Objective(s): To determine whether follicular fluid (FF) from women of advanced reproductive age had a relative deficiency of the angiogenic cytokine vascular endothelial growth factor/vascular permeability factor. Furthermore, we sought to determine whether luteinized granulosa cells secrete vascular endothelial growth factor/vascular permeability factor in response to hypoxia. Design: Retrospective cohort study. Setting: University teaching hospital. Patients: Women undergoing follicular aspiration after superovulation in preparation for IVF-ET. Women of advanced reproductive age consisted of 21 women ≤38 years old (range, 38 to 46 years); 15 subjects ≤30 years served as the control population. Intervention(s): Granulosa cells and FF were collected by transvaginal aspiration 35 hours after hCG. Granulosa cells from two women were cultured for 24 and 48 hours in M199 + 10% fetal bovine serum in 1% O₂-5% CO₂-94% N₂ (hypoxic) or 95% air-5% CO₂ (normoxic) without or with 0.1 mol/L cobalt chloride. Main Outcome Measure(s): Pooled FF vascular endothelial growth factor/vascular permeability factor concentrations and media vascular endothelial growth factor/vascular permeability factor accumulation at 24 and 48 hours were determined. Result(s): Follicular fluid vascular endothelial growth factor/vascular permeability factor concentrations were higher in advanced reproductive age women compared with younger women (3,735 ± 2,155 versus 2,205 ± 952 pg/mL, mean ± SD). Accumulation of vascular endothelial growth factor/vascular permeability factor at 24 and 48 hours was 391 ± 54 and 744 ± 2 pg/mL in media maintained in 5% CO₂ and air. Cobalt chloride induced a marked increase in vascular endothelial growth factor/vascular permeability factor (2,008 ± 52 pg/mL at 24 hours and 3,630 ± 519 pg/mL at 48 hours). An intermediate but significant increase in vascular endothelial growth factor/vascular permeability factor (733 ± 35 pg/mL at 24 hours and 2,675 ± 864 pg/mL at 48 hours) was observed with 1% O₂ compared with normoxic controls. Conclusion(s): After hMG and hCG administration the FF from women of advanced reproductive age showed increased vascular endothelial growth factor/vascular permeability factor concentrations compared with younger women. Increased vascular endothelial growth factor/vascular permeability factor concentrations could be consistent with a hypoxic environment within follicles of older women.