GnRH actions on rat preovulatory follicles are mediated by paracrine EGF-like factors.
Gonadotropin releasing hormone (GnRH) has been shown to mimic the actions of LH/hCG on oocyte maturation and ovulation. Recent studies demonstrated that induction of ovulation by LH/hCG is mediated, at least in part, by transactivation of epidermal growth factor receptors (EGFR) by autocrine/paracrine EGF-like factors activated by metalloproteases. Here we have examined whether the action of GnRH on the preovulatory follicles is exerted through similar mechanisms involving activation of EGFR. The EGFR kinase inhibitor, AG1478, inhibited GnRH-induced oocyte maturation in explanted follicles in vitro. Its inactive analog, AG43, did not affect GnRH-stimulated resumption of meiosis. GnRH, like LH, stimulated transient follicular expression of EGF-like agents, as well as rat cycloxygenase-2 (rCOX-2), rat hyaluronan synthase-2 (rHAS-2), and rat tumor necrosis factor-alpha-stimulated gene 6 (rTSG-6) mRNAs, known ovulatory enzymes. Likewise, GnRH stimulated follicular progesterone synthesis. Conversely AG1478 inhibited all these actions of GnRH. Furthermore, Galardin, a broad-spectrum metalloprotease inhibitor, blocked GnRH-induced oocyte maturation and follicular progesterone synthesis. In conclusion, we have demonstrated that follicular EGF-like factors mediate also the GnRH-stimulation of ovulatory changes, like these of LH/hCG.
Motola
Shmulik
S
The Bernhard Zondek Hormone Research Laboratory, Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.
Cao
Xiumei
X
Ashkenazi
Helena
H
Popliker
Malka
M
Tsafriri
Alex
A
D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology*; D000076002:Hyaluronan Synthases; D008540:Meiosis; D006080:Ovarian Follicle / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D010060:Ovulation; D010766:Phosphorylation; D011374:Progesterone / Q000096:biosynthesis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D020032:Tyrphostins / Q000494:pharmacology
D015815:Cell Adhesion Molecules; D004151:Dipeptides; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D012333:RNA, Messenger; C513056:Tnfaip6 protein, rat; D020032:Tyrphostins; C101044:RTKI cpd; D007987:Gonadotropin-Releasing Hormone; D011374:Progesterone; D004815:Epidermal Growth Factor; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D014453:Glucuronosyltransferase; C491097:Has2 protein, rat; D000076002:Hyaluronan Synthases; D066246:ErbB Receptors