Expression of human gonadotropin-releasing hormone receptor gene in the placenta and its functional relationship to human chorionic gonadotropin secretion.
Placental GnRH is one of the potential paracrine regulators of hCG secretion from the trophoblasts during pregnancy. Maternal serum hCG levels exhibit an exponential rise during the first 6 weeks of pregnancy, peak at 9-10 weeks, decline to a nadir at 20 weeks, and remain at low levels during the rest of pregnancy. However, the placental content of GnRH does not parallel the time course of hCG secretion, and GnRH messenger ribonucleic acid (mRNA) levels in the placenta remain unchanged during pregnancy. These data do not conform with a simple paracrine mechanism of GnRH as a regulator of hCG secretion. We, therefore, examined the potential variation in GnRH receptor gene expression in the placenta, which may account for the GnRH-mediated dynamic pattern of hCG secretion during gestation. First, we established a functional relationship of GnRH and hCG secretion. Using a placental explant culture system, a dose-response effect of hCG secretion was observed in the placental explant at 9 weeks when treated with GnRH ranging from 10(-9)-10(-7) mol/L. The effect of GnRH was completely blocked by a GnRH antagonist (Nal-Glu). The relative responsiveness of hCG secretion to GnRH stimulation at 10(-7) mol/L was further evaluated in placental explants at 6, 9, and 40 weeks gestation. Whereas the 9-week placenta showed a maximal response (> 300%) relative to the 6-week placenta, there was no response in term placenta. Again, the effects of GnRH on hCG secretion were blocked by Nal-Glu, supporting a receptor-mediated event. Localization of mRNA encoding human GnRH receptor in human placenta at 6, 9, 12, 20, and 40 weeks gestation was established by in situ hybridization. The mRNA signals were present in both cytotrophoblast and syncytiotrophoblast cell layers. Signal intensities varied with gestational ages and were abundant at 6 weeks, peaked at 9 weeks, declined at 12 and 20 weeks, and were undetectable at term. The present study demonstrates, for the first time, that GnRH receptor mRNA is expressed in both cytotrophoblasts and syncytiotrophoblasts and exhibits changes paralleling the time course of hCG secretion during pregnancy. These data provide a mechanistic understanding that the paracrine/autocrine regulation of hCG secretion by placental GnRH is mediated through an increase followed by a decline in GnRH receptor gene expression from the first trimester to term placenta.
Department of Reproductive Medicine, University of California-San Diego, La Jolla 92093-0802.
L S
LS
Lin
V J
VJ
Roberts
S S
SS
Yen
D006063:Chorionic Gonadotropin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression; D005865:Gestational Age; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives / Q000494:pharmacology*; D006801:Humans; D010920:Placenta / Q000502:physiology*; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D011966:Receptors, LHRH / Q000235:genetics*
D006063:Chorionic Gonadotropin; C057805:LHRH, N-Ac-2-Nal(1)-4-Cl-Phe(2)-3-Pal(3)-Arg(5)-Glu(6)-AlaNH2(10)-; D012333:RNA, Messenger; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone