Regulation of vascular endothelial growth factor-A and its soluble receptor sFlt-1 by luteinizing hormone in vivo: implication for ovarian follicle angiogenesis.
OBJECTIVE
To determine in vivo whether LH supplementation during the late follicular phase induces ovarian follicle angiogenesis in humans, as reflected by vascular endothelial growth factor (VEGF)-A, its soluble receptor sFlt-1, and placental growth factor (PlGF) expression.


METHODS
Randomized, double-blind, placebo-controlled study.


METHODS
Academic tertiary care medical center.


METHODS
Twenty infertile, healthy women (aged 18-39 years) undergoing IVF.


METHODS
Administration of recombinant FSH after down-regulation and equal randomization of subjects to receive recombinant LH 75 IU/day or placebo when two or more follicles reached a mean diameter of 14 mm.


METHODS
Serum and follicular fluid (FF) VEGF-A, sFlt-1, and PlGF protein levels were measured.


RESULTS
Recombinant LH increased both the FF VEGF-A/sFlt-1 ratio statistically significantly and PlGF/sFlt-1 insignificantly. Recombinant LH did not affect the serum VEGF/sFlt-1 ratio. Plasma levels of PlGF were undetectable.


CONCLUSIONS
This in vivo study demonstrates for the first time in humans that LH induces ovarian follicular angiogenesis via modulation of VEGF-A and its soluble receptor sFlt-1 expression. A constant VEGF-A/sFlt-serum ratio may prevent adverse effects of VEGF-A. Because angiogenesis is essential during the periovulatory period, recombinant LH supplementation during the late follicular phase may improve ovulation induction outcome.
Gutman
Guy
G
Sara Racine IVF Unit, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Barak
Vivian
V
Maslovitz
Sharon
S
Amit
Ami
A
Lessing
Joseph B
JB
Geva
Eli
E
D000328:Adult; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004624:Embryo Transfer; D005260:Female; D005300:Fertility Agents, Female / Q000008:administration & dosage*; D005307:Fertilization in Vitro; D005640:Follicle Stimulating Hormone / Q000008:administration & dosage; D015571:Follicular Fluid / Q000378:metabolism*; D005498:Follicular Phase / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007247:Infertility, Female / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D007986:Luteinizing Hormone / Q000008:administration & dosage*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D054315:Oocyte Retrieval; D006080:Ovarian Follicle / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D010062:Ovulation Induction / Q000379:methods*; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000378:metabolism; D011446:Prospective Studies; D011994:Recombinant Proteins / Q000008:administration & dosage; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood / Q000378:metabolism*
D005300:Fertility Agents, Female; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1