| Summary: | Considering the extrapituitary roles for gonadotropin-releasing hormone (GnRH) in
reproductive tissues, the present study investigated role of GnRH in the ovarian cells. The GnRH
and GnRH receptor (GnRHR) mRNA were expressed and autoregulated in a biphasic mariner by
a GnRH agonist (GnRH-a) in human ovarian surface epithelium (hOSE) cells and an ovarian
cancer cell line, OVCAR-3. The GnRH-a had a receptor-mediated growth inhibitory effect in
both cell types. The growth inhibitory effect was associated with apoptosis in OVCAR-3 cells. In
addition, 17β-estradiol induced a significant down-regulation of GnRH mRNA in OVCAR-3,
but not in hOSE cells and of GnRHR mRNA in both hOSE and OVCAR-3 cells. Pre- or cotreatment
with 17β-estradiol significantly attenuated the growth inhibitory effect of the GnRH-a
in OVCAR-3 cells, but not in hOSE cells. These results strongly support the presence of
functional autocrine GnRH/GnRHR loop and potential interaction with estrogen/estrogen
receptor.
The GnRH-a stimulated MAPK activation in human granulosa-luteal cells (hGLCs) via a
PKC-dependent pathway, which mediated the inhibitory effect of GnRH-a in progesterone
secretion. The GnRH-a also stimulated MAPK activation in OVCAR-3 cells, normal placenta-derived
cells (IEVT) and placental carcinoma (JEG-3) cells. The GnRH-induced MAPK
activation mediated the growth inhibitory effect of GnRH-a in OVCAR-3 cells, but not the
stimulatory effect of GnRH-a on the hCG mRNA level in JEG-3 cells. These results
demonstrated that GnRH stimulated MAPK activation that mediated the cellular functions of
GnRH in normal and neoplastic cells of human ovary.
The present study demonstrates that one mechanism by which cell-specific expression of the
human GnRHR is achieved is through the binding of distinct cell-specific regulatory factors to
various promoter elements in the 5'-flanking region of the gene.
In this study, the second form of GnRH (GnRH-II) and GnRH-I differentially regulated
GnRHR and its ligands. Gonadotropins also differentially regulated GnRH-II and GnRH-I
mRNA levels. GnRH-II inhibited basal and hCG-stimulated progesterone secretion. The
antigonadotropic effect of GnRH-II was mediated through down-regulating gonadotropin
receptors without affecting cAMP levels.
In summary, on the basis of the expression, differential regulation and/or functional roles of
GnRH, our studies strongly support the notion that an intrinsic GnRH axis plays an important
role in regulating normal and malignant ovarian cell functions.
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