Reciprocal cross talk between gonadotropin-releasing hormone (GnRH) and prostaglandin receptors regulates GnRH receptor expression and differential gonadotropin secretion.
The asynchronous secretion of gonadotrope LH and FSH under the control of GnRH is crucial for ovarian cyclicity but the underlying mechanism is not fully resolved. Because prostaglandins (PG) are autocrine regulators in many tissues, we determined whether they have this role in gonadotropes. We first demonstrated that GnRH stimulates PG synthesis by induction of cyclooxygenase-2, via the protein kinase C/c-Src/phosphatidylinositol 3'-kinase/MAPK pathway in the LbetaT2 gonadotrope cell line. We then demonstrated that PGF(2alpha) and PGI2, but not PGE2 inhibited GnRH receptor expression by inhibition of phosphoinositide turnover. PGF(2alpha), but not PGI2 or PGE2, reduced GnRH-induction of LHbeta gene expression, but not the alpha-gonadotropin subunit or the FSHbeta subunit genes. The prostanoid receptors EP1, EP2, FP, and IP were expressed in rat gonadotropes. Incubations of rat pituitaries with PGF(2alpha), but not PGI2 or PGE2, inhibited GnRH-induced LH secretion, whereas the cyclooxygenase inhibitor, indomethacin, stimulated GnRH-induced LH secretion. None of these treatments had any effect on GnRH-induced FSH secretion. The findings have thus elaborated a novel GnRH signaling pathway mediated by PGF(2alpha)-FP and PGI2-IP, which acts through an autocrine/paracrine modality to limit autoregulation of the GnRH receptor and differentially inhibit LH and FSH release. These findings provide a mechanism for asynchronous LH and FSH secretions and suggest the use of combination therapies of GnRH and prostanoid analogs to treat infertility, diseases with unbalanced LH and FSH secretion and in hormone-dependent diseases such as prostatic cancer.
Naor
Zvi
Z
Medical Research Council (MRC), Huamn Reproduction Sciences, Centre for Reproductive Biology, The Queen's Medical Research Institute, Edinburgh, United Kingdom. zvin@tauex.tau.ac.il
Jabbour
Henry N
HN
Naidich
Michal
M
Pawson
Adam J
AJ
Morgan
Kevin
K
Battersby
Sharon
S
Millar
Michael R
MR
Brown
Pamela
P
Millar
Robert P
RP
D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004790:Enzyme Induction; D005640:Follicle Stimulating Hormone / Q000378:metabolism*; D037201:Follicle Stimulating Hormone, beta Subunit / Q000378:metabolism; D005786:Gene Expression Regulation; D007987:Gonadotropin-Releasing Hormone / Q000502:physiology*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007986:Luteinizing Hormone / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D010902:Pituitary Gland / Q000378:metabolism; D011453:Prostaglandins / Q000096:biosynthesis; D011493:Protein Kinase C / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D011966:Receptors, LHRH / Q000096:biosynthesis*; D011982:Receptors, Prostaglandin / Q000502:physiology*; D015398:Signal Transduction; D019061:src-Family Kinases
D000081247:CSK Tyrosine-Protein Kinase; D051546:Cyclooxygenase 2; D016861:Cyclooxygenase Inhibitors; D005640:Follicle Stimulating Hormone; D037201:Follicle Stimulating Hormone, beta Subunit; D007987:Gonadotropin-Releasing Hormone; D007213:Indomethacin; D007986:Luteinizing Hormone; D019869:Phosphatidylinositol 3-Kinases; D010716:Phosphatidylinositols; D011453:Prostaglandins; D011493:Protein Kinase C; D011505:Protein-Tyrosine Kinases; D011966:Receptors, LHRH; D011982:Receptors, Prostaglandin; D019061:src-Family Kinases