GnRH Agonist Triggering Modulates PEDF to VEGF Ratio Inversely to hCG in Granulosa Cells

J Clin Endocrinol Metab. 2015 Nov;100(11):E1428-36. doi: 10.1210/jc.2015-2312. Epub 2015 Aug 26.

Abstract

Context: 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.

Design: The design of the study was a mouse model and cultured granulosa cells.

Main outcome: 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Cell Line
  • Cells, Cultured
  • Chorionic Gonadotropin / adverse effects
  • Chorionic Gonadotropin / pharmacology
  • Eye Proteins / agonists*
  • Eye Proteins / genetics
  • Eye Proteins / metabolism
  • Female
  • Fertility Agents, Female / adverse effects*
  • Fertility Agents, Female / pharmacology
  • Gene Expression Regulation, Developmental / drug effects
  • Gonadotropin-Releasing Hormone / adverse effects
  • Gonadotropin-Releasing Hormone / agonists*
  • Gonadotropin-Releasing Hormone / analogs & derivatives
  • Gonadotropin-Releasing Hormone / metabolism
  • Gonadotropin-Releasing Hormone / pharmacology
  • Granulosa Cells / cytology
  • Granulosa Cells / drug effects*
  • Granulosa Cells / metabolism
  • Humans
  • Leuprolide / adverse effects
  • Leuprolide / pharmacology
  • Mice, Inbred ICR
  • Nerve Growth Factors / agonists*
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / metabolism
  • Ovarian Hyperstimulation Syndrome / etiology
  • Ovarian Hyperstimulation Syndrome / metabolism*
  • Ovarian Hyperstimulation Syndrome / prevention & control
  • Ovulation Induction / adverse effects
  • Rats
  • Receptors, LHRH / agonists*
  • Receptors, LHRH / metabolism
  • Serpins / agonists*
  • Serpins / genetics
  • Serpins / metabolism
  • Signal Transduction / drug effects
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism
  • Young Adult

Substances

  • Chorionic Gonadotropin
  • Eye Proteins
  • Fertility Agents, Female
  • GNRHR protein, human
  • Nerve Growth Factors
  • Receptors, LHRH
  • Serpins
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • pigment epithelium-derived factor
  • Gonadotropin-Releasing Hormone
  • Leuprolide
  • cetrorelix