title: Follicular fluid vascular endothelial growth factor concentrations are elevated in women of advanced reproductive age undergoing ovulation induction.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Retrospective cohort study.
  
  
  METHODS
  University teaching hospital.
  
  
  METHODS
  Women undergoing follicular aspiration after superovulation in preparation for IVF-ET. Women of advanced reproductive age consisted of 21 women > or = 38 years old (range, 38 to 46 years); 15 subjects < or = 30 years served as the control population.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Reproductive Endocrinology and Infertility, Ohio State University, Columbus, USA.
authors.forename: C I
authors.initials: CI
authors.lastname: Friedman
authors.forename: D R
authors.initials: DR
authors.lastname: Danforth
authors.forename: C
authors.initials: C
authors.lastname: Herbosa-Encarnacion
authors.forename: L
authors.initials: L
authors.lastname: Arbogast
authors.forename: B M
authors.initials: BM
authors.lastname: Alak
authors.forename: D B
authors.initials: DB
authors.lastname: Seifer
mesh_terms: D000328:Adult; D000375:Aging / Q000378:metabolism; D003035:Cobalt / Q000494:pharmacology; D015331:Cohort Studies; D003338:Corpus Luteum / Q000502:physiology; D016228:Endothelial Growth Factors / Q000378:metabolism*; D005260:Female; D015571:Follicular Fluid / Q000378:metabolism*; D006107:Granulosa Cells / Q000187:drug effects; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology; D008222:Lymphokines / Q000378:metabolism*; D008423:Maternal Age; D008875:Middle Aged; D009994:Osmolar Concentration; D010062:Ovulation Induction; D011247:Pregnancy; D018566:Pregnancy, High-Risk; D012189:Retrospective Studies; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D003035:Cobalt; C018021:cobaltous chloride