title: GnRH Agonist Triggering Modulates PEDF to VEGF Ratio Inversely to hCG in Granulosa Cells.
abstract: BACKGROUND
  GnRH agonist (GnRH-a) triggering is associated with a reduced risk of ovarian hyperstimulation syndrome (OHSS) compared with human chorionic gonadotropin (hCG) in assisted reproduction technology cycles. We have shown that ovarian pigment epithelium derived factor (PEDF), a potent antiangiogenic factor, counteracts vascular endothelial growth factor (VEGF) expression and that OHSS is correlated with hCG-induced impaired PEDF to VEGF ratio.
  
  
  OBJECTIVE
  The objective of the study was to explore whether GnRH-a triggering could directly modulate PEDF/VEGF balance in granulosa cells.
  
  
  METHODS
  The design of the study was a mouse model and cultured granulosa cells.
  
  
  RESULTS
  Changes in PEDF and VEGF were measured by quantitative PCR and Western blot analysis. OHSS symptoms were recorded by changes in body weight and in peritoneal vascular leakage, quantified by the modified Miles vascular permeability assay.
  
  
  RESULTS
  GnRH-a stimulation significantly increased PEDF and decreased VEGF mRNA and protein levels both in rat granulosa cell line and human primary granulosa cells in vitro. GnRH-a and hCG triggering inversely modulated PEDF mRNA and protein level in human granulosa cells in vivo. In the GnRH-a triggering mouse model, we showed similar increase in PEDF to VEGF ratio as in the in vitro results. OHSS-predisposed mice did not develop OHSS parameters after GnRH-a triggering, opposed to hCG-triggered mice. Finally, GnRH-a triggering of OHSS-predisposed mice significantly increased ovarian PEDF to VEGF ratio compared with hCG-triggered mice and control mice.
  
  
  CONCLUSIONS
  GnRH-a triggering induces a direct effect on PEDF/VEGF balance in granulosa cells inversely to hCG. Our results suggest a novel elucidation to the GnRH-a triggering-mediated risk reduction of OHSS and may clarify the pros and cons of this triggering method.
authors: Department of Cell and Developmental Biology (I.M., D.C., R.S.), Sackler Faculty of Medicine, and IVF and Infertility Unit (R.R.-E., I.B.-A.), Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin 70300, Israel.
authors: Irit
authors: I
authors: Miller
authors: Department of Cell and Developmental Biology (I.M., D.C., R.S.), Sackler Faculty of Medicine, and IVF and Infertility Unit (R.R.-E., I.B.-A.), Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin 70300, Israel.
authors: Dana
authors: D
authors: Chuderland
authors: Department of Cell and Developmental Biology (I.M., D.C., R.S.), Sackler Faculty of Medicine, and IVF and Infertility Unit (R.R.-E., I.B.-A.), Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin 70300, Israel.
authors: Raphael
authors: R
authors: Ron-El
authors: Department of Cell and Developmental Biology (I.M., D.C., R.S.), Sackler Faculty of Medicine, and IVF and Infertility Unit (R.R.-E., I.B.-A.), Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin 70300, Israel.
authors: Ruth
authors: R
authors: Shalgi
authors: Department of Cell and Developmental Biology (I.M., D.C., R.S.), Sackler Faculty of Medicine, and IVF and Infertility Unit (R.R.-E., I.B.-A.), Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin 70300, Israel.
authors: Ido
authors: I
authors: Ben-Ami
mesh_terms: D000328:Adult; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000009:adverse effects / Q000494:pharmacology; D005136:Eye Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D005260:Female; D005300:Fertility Agents, Female / Q000009:adverse effects* / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D007987:Gonadotropin-Releasing Hormone / Q000009:adverse effects / Q000819:agonists* / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D006107:Granulosa Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D016729:Leuprolide / Q000009:adverse effects / Q000494:pharmacology; D008813:Mice, Inbred ICR; D009414:Nerve Growth Factors / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D016471:Ovarian Hyperstimulation Syndrome / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D010062:Ovulation Induction / Q000009:adverse effects; D051381:Rats; D011966:Receptors, LHRH / Q000819:agonists* / Q000378:metabolism; D015843:Serpins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D055815:Young Adult; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D006063:Chorionic Gonadotropin; D005136:Eye Proteins; D005300:Fertility Agents, Female; D007987:Gonadotropin-Releasing Hormone; D016729:Leuprolide; D009414:Nerve Growth Factors; D011966:Receptors, LHRH; D015843:Serpins; D042461:Vascular Endothelial Growth Factor A; D000099174:Pigment Epithelium-Derived Factor; C484844:GNRHR protein, human; C467484:VEGFA protein, human; C062876:cetrorelix