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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 10 3828-3839
Copyright © 2000 by The Endocrine Society

Original Studies

Hormonal Regulation of Estrogen Receptor {alpha} and ß Gene Expression in Human Granulosa-Luteal Cells in Vitro1

Chi-Hsin Chiang2, Kwai Wa Cheng2, Shigeo Igarashi, Parimal S. Nathwani and Peter C. K. Leung3

Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia, Canada V6H 3V5

Estrogen is one of the major sex steroid hormones that is produced from the human ovary, and its actions are established to be a receptor-mediated process. Despite the demonstration of estrogen receptor (ER) expression, little is known regarding the regulation of ER in the human ovary. In the present study we investigated the expression and hormonal regulation of ER{alpha} and ERß in human granulosa-luteal cells (hGLCs). Using RT-PCR amplification, both ER{alpha} and ERß messenger ribonucleic acid (mRNA) were detected from hGLCs. Northern blot analysis revealed that ER{alpha} is expressed at a relatively lower level than ERß. Basal expression studies indicated that ER{alpha} mRNA levels remain unchanged, whereas ERß mRNA levels increased with time in culture in vitro, suggesting that ERß is likely to play a dynamic role in mediating estrogen action in hGLCs.

The regulation of ER{alpha} and ERß expression by hCG was examined. hCG treatment (10 IU/mL) significantly attenuated the ER{alpha} (45%; P < 0.01) and ERß (40%; P < 0.01) mRNA levels. The hCG-induced decrease in ER{alpha} and ERß expression was mimicked by 8-bromo-cAMP (1 mmol/L) and forskolin (10 µmol/L) treatment. Additional studies using a specific protein kinase A (PKA) inhibitor (adenosine 3',5'-cyclic monophosphorothioate, Rp-isomer, triethylammonium salt) and an adenylate cyclase inhibitor (SQ 22536) further implicated the involvement of the cAMP/PKA signaling pathway in hCG action in these cells. The hCG-induced decrease in ER{alpha} and ERß mRNA levels was prevented in the presence of these inhibitors. Next, the effect of GnRH on ER expression was studied. Sixty-eight percent (P < 0.001) and 60% (P < 0.001) decreases in ER{alpha} and ERß mRNA levels, respectively, were observed after treatment with 0.1 µmol/L GnRH agonist (GnRHa). Pretreatment of the cells with a protein kinase C (PKC) inhibitor (GF109203X) completely reversed the GnRHainduced down-regulation of ER{alpha} and ERß expression, suggesting the involvement of PKC in GnRH signal transduction in hGLCs. In agreement with the semiquantitative RT-PCR results, Western blot analysis detected a decrease in ER{alpha} and ERß proteins levels in hGLCs after treatment with hCG (10 IU/mL), GnRH (0.1 µmol/L), 8-bromo-cAMP (1 mmol/L), forskolin (10 µmol/L), or phorbol 12-myristate 13 acetate (10 µmol/L). Functionally, we demonstrated an inhibition of progesterone production in hGLCs in vitro by 17ß-estradiol, and this inhibitory effect was eliminated by pretreatment of 10 IU/mL hCG or 0.1 µmol/L GnRHa for 24 h before 17ß-estradiol administration.

In summary, we observed a differential expression of ER{alpha} and ERß mRNA in hGLCs in vitro. The demonstration of hCG- and GnRHa-induced down-regulation of ER{alpha} and ERß gene expression suggests that hCG and GnRH may contribute to the control of granulosa-luteal cell function. Furthermore, our data suggest that the effects of hCG and GnRH on ER{alpha} and ERß expression in hGLCs are mediated in part by activation of PKA and PKC signaling pathways, respectively.




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