A unique human chorionic gonadotropin antagonist suppresses ovarian hyperstimulation syndrome in rats.
Ovarian hyperstimulation syndrome (OHSS) is a complication of in vitro fertilization associated with physiological changes after hCG administration to induce final oocyte maturation. It presents as widespread increases in vascular permeability and, in rare cases, results in cycle cancellation, multi-organ dysfunction, and pregnancy termination. These physiological changes are due primarily to activation of the vascular endothelial growth factor (VEGF) system in response to exogenous human chorionic gonadotropin (hCG). An hCG antagonist (hCG-Ant) could attenuate these effects by competitively binding to the LH/CG receptor, thereby blocking LH activity in vivo. We expressed a form of hCG that lacks three of its four N-linked glycosylation sites and tested its efficacy as an antagonist. The hCG-Ant binds the LH receptor with an affinity similar to native hCG and inhibits cAMP response in vitro. In a rat model for ovarian stimulation, hCG-Ant dramatically reduces ovulation and steroid hormone production. In a well-established rat OHSS model, vascular permeability and vascular endothelial growth factor (VEGF) expression are dramatically reduced after hCG-Ant treatment. Finally, hCG-Ant does not appear to alter blastocyst development when given after hCG in mice. These studies demonstrate that removing specific glycosylation sites on native hCG can produce an hCG-Ant that is capable of binding without activating the LH receptor and blocking the actions of hCG. Thus hCG-Ant will be investigated as a potential therapy for OHSS.
Vardhana
Pratibhasri A
PA
Columbia University Medical Center, Department of Obstetrics and Gynecology, New York, New York 10032, USA.
Julius
Martin A
MA
Pollak
Susan V
SV
Lustbader
Evan G
EG
Trousdale
Rhonda K
RK
Lustbader
Joyce W
JW
D000818:Animals; D001755:Blastocyst / Q000187:drug effects; D015153:Blotting, Western; D006063:Chorionic Gonadotropin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005260:Female; D006727:Hormone Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D016471:Ovarian Hyperstimulation Syndrome / Q000188:drug therapy*; D010060:Ovulation / Q000187:drug effects; D011485:Protein Binding; D051381:Rats; D011974:Receptors, LH / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
D006063:Chorionic Gonadotropin; D006727:Hormone Antagonists; D011974:Receptors, LH; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2