Skip to main content
SpringerLink
Log in

Induction of G protein-coupled estrogen receptor (GPER) and nuclear steroid hormone receptors by gonadotropins in human granulosa cells

  • Original Paper
  • Published:
Histochemistry and Cell Biology Aims and scope Submit manuscript

Abstract

Estradiol and progesterone mediate their actions by binding to classical nuclear receptors, estrogen receptor α (ERα) and estrogen receptor β (ERβ) and progesterone receptor A and B (PR-A and PR-B) and the non-classical G protein-coupled estrogen receptor (GPER). Several animal knock-out models have shown the importance of the receptors for growth of the oocyte and ovulation. The aim of our study was to identify GPER in human granulosa cells (GC) for the first time. Moreover, the effect of different doses of gonadotropins on estrogen and progesterone receptors in the human ovary should be investigated as follicle stimulating hormone (FSH) and luteinizing hormone (LH) are also responsible for numerous mechanisms in the ovary like induction of the steroid biosynthesis. Human GC were cultured in vitro and stimulated with different doses of recombinant human FSH or LH. Receptor expression was analyzed by immunocytochemistry and quantitative real-time RT-PCR. GPER could be identified for the first time in human GC. It could be shown that high concentrations of LH increase GPER protein expression. Furthermore FSH and LH increased ERβ, PR-A and PR-B significantly on protein level. These findings were verified for high doses of FSH and LH on mRNA level. ERα was not affected with FSH or LH. We assume that gonadotropins induce GPER, ERβ and PR in luteinized granulosa cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Acharya U, Small J, Randall J, Hamilton M, Templeton A (1992) Prospective study of short and long regimens of gonadotropin-releasing hormone agonist in in vitro fertilization program. Fertil Steril 57:815–818

    PubMed  CAS  Google Scholar 

  • Andreani CL, Pierro E, Lanzone A, Lazzarin N, Capitanio G, Giannini P, Mancuso S (1994) Effect of gonadotropins, insulin and IGF I on granulosa luteal cells from polycystic ovaries. Mol Cell Endocrinol 106:91–97

    Article  PubMed  CAS  Google Scholar 

  • Britt KL, Saunders PK, McPherson SJ, Misso ML, Simpson ER, Findlay JK (2004) Estrogen actions on follicle formation and early follicle development. Biol Reprod 71:1712–1723

    Article  PubMed  CAS  Google Scholar 

  • Brosens JJ, Tullet J, Varshochi R, Lam EW (2004) Steroid receptor action. Best Pract Res Clin Obstet Gynaecol 18:265–283

    Article  PubMed  Google Scholar 

  • Byers M, Kuiper GG, Gustafsson JA, Park-Sarge OK (1997) Estrogen receptor-beta mRNA expression in rat ovary: down-regulation by gonadotropins. Mol Endocrinol 11:172–182

    Article  PubMed  CAS  Google Scholar 

  • Carmeci C, Thompson DA, Ring HZ, Francke U, Weigel RJ (1997) Identification of a gene (GPR30) with homology to the G-protein-coupled receptor superfamily associated with estrogen receptor expression in breast cancer. Genomics 45:607–617

    Article  PubMed  CAS  Google Scholar 

  • Chiang CH, Cheng KW, Igarashi S, Nathwani PS, Leung PC (2000) Hormonal regulation of estrogen receptor alpha and beta gene expression in human granulosa-luteal cells in vitro. J Clin Endocrinol Metab 85:3828–3839

    Article  PubMed  CAS  Google Scholar 

  • Couse JF, Yates MM, Deroo BJ, Korach KS (2005) Estrogen receptor-beta is critical to granulosa cell differentiation and the ovulatory response to gonadotropins. Endocrinology 146:3247–3262

    Article  PubMed  CAS  Google Scholar 

  • de los Santos MJ, Tarin JJ, Gomez E, Remohi J, Pellicer A (1993) Daily measurements and in vitro effects of human chorionic gonadotrophin in the early luteal phase. Hum Reprod 8:2047–2051

    Google Scholar 

  • Drummond AE, Findlay JK (1999) The role of estrogen in folliculogenesis. Mol Cell Endocrinol 151:57–64

    Article  PubMed  CAS  Google Scholar 

  • Duffy DM, Wells TR, Haluska GJ, Stouffer RL (1997) The ratio of progesterone receptor isoforms changes in the monkey corpus luteum during the luteal phase of the menstrual cycle. Biol Reprod 57:693–699

    Article  PubMed  CAS  Google Scholar 

  • Feng Y, Gregor P (1997) Cloning of a novel member of the G protein-coupled receptor family related to peptide receptors. Biochem Biophys Res Commun 231:651–654

    Article  PubMed  CAS  Google Scholar 

  • Filardo EJ, Graeber CT, Quinn JA, Resnick MB, Giri D, DeLellis RA, Steinhoff MM, Sabo E (2006) Distribution of GPR30, a seven membrane-spanning estrogen receptor, in primary breast cancer and its association with clinicopathologic determinants of tumor progression. Clin Cancer Res 12:6359–6366

    Article  PubMed  CAS  Google Scholar 

  • Hecht S, Pavlik R, Lohse P, Noss U, Friese K, Thaler CJ (2009) Common 677C→T mutation of the 5, 10-methylenetetrahydrofolate reductase gene affects follicular estradiol synthesis. Fertil Steril 91:56–61

    Article  PubMed  CAS  Google Scholar 

  • Iwai T, Nanbu Y, Iwai M, Taii S, Fujii S, Mori T (1990) Immunohistochemical localization of estrogen-receptors and progesterone receptors in the human ovary throughout the menstrual-cycle. Virchows Arch A 417:369–375

    Article  CAS  Google Scholar 

  • Krege JH, Hodgin JB, Couse JF, Enmark E, Warner M, Mahler JF, Sar M, Korach KS, Gustafsson JA, Smithies O (1998) Generation and reproductive phenotypes of mice lacking estrogen receptor beta. Proc Natl Acad Sci USA 95:15677–15682

    Article  PubMed  CAS  Google Scholar 

  • Kvingedal AM, Smeland EB (1997) A novel putative G-protein-coupled receptor expressed in lung, heart and lymphoid tissue. FEBS Lett 407:59–62

    Article  PubMed  CAS  Google Scholar 

  • Leonhardt SA, Edwards DP (2002) Mechanism of action of progesterone antagonists. Exp Biol Med (Maywood) 227:969–980

    CAS  Google Scholar 

  • Lydon JP, DeMayo FJ, Funk CR, Mani SK, Hughes AR, Montgomery CA Jr, Shyamala G, Conneely OM, O’Malley BW (1995) Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev 9:2266–2278

    Article  PubMed  CAS  Google Scholar 

  • Lydon JP, DeMayo FJ, Conneely OM, O’Malley BW (1996) Reproductive phenotypes of the progesterone receptor null mutant mouse. J Steroid Biochem Mol Biol 56:67–77

    Article  PubMed  CAS  Google Scholar 

  • Maggiolini M, Vivacqua A, Fasanella G, Recchia AG, Sisci D, Pezzi V, Montanaro D, Musti AM, Picard D, Ando S (2004) The G protein-coupled receptor GPR30 mediates c-fos up-regulation by 17beta-estradiol and phytoestrogens in breast cancer cells. J Biol Chem 279:27008–27016

    Article  PubMed  CAS  Google Scholar 

  • Misao R, Nakanishi Y, Iwagaki S, Fujimoto J, Tamaya T (1998) Expression of progesterone receptor isoforms in corpora lutea of human subjects: correlation with serum oestrogen and progesterone concentrations. Mol Hum Reprod 4:1045–1052

    Article  PubMed  CAS  Google Scholar 

  • Natraj U, Richards JS (1993) Hormonal regulation, localization, and functional activity of the progesterone receptor in granulosa cells of rat preovulatory follicles. Endocrinology 133:761–769

    Article  PubMed  CAS  Google Scholar 

  • O’Dowd BF, Nguyen T, Marchese A, Cheng R, Lynch KR, Heng HH, Kolakowski LF Jr, George SR (1998) Discovery of three novel G-protein-coupled receptor genes. Genomics 47:310–313

    Article  PubMed  Google Scholar 

  • Oh SY, Kim CJ, Park I, Romero R, Sohn YK, Moon KC, Yoon BH (2005) Progesterone receptor isoform (A/B) ratio of human fetal membranes increases during term parturition. Am J Obstet Gynecol 193:1156–1160

    Article  PubMed  CAS  Google Scholar 

  • Owman C, Blay P, Nilsson C, Lolait SJ (1996) Cloning of human cDNA encoding a novel heptahelix receptor expressed in Burkitt’s lymphoma and widely distributed in brain and peripheral tissues. Biochem Biophys Res Commun 228:285–292

    Article  PubMed  CAS  Google Scholar 

  • Palter SF, Tavares AB, Hourvitz A, Veldhuis JD, Adashi EY (2001) Are estrogens of import to primate/human ovarian folliculogenesis? Endocr Rev 22:389–424

    Article  PubMed  CAS  Google Scholar 

  • Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER (2005) A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science 307:1625–1630

    Article  PubMed  CAS  Google Scholar 

  • Richards JS (1980) Maturation of ovarian follicles: actions and interactions of pituitary and ovarian hormones on follicular cell differentiation. Physiol Rev 60:51–89

    PubMed  CAS  Google Scholar 

  • Robker RL, Russell DL, Espey LL, Lydon JP, O’Malley BW, Richards JS (2000) Progesterone-regulated genes in the ovulation process: ADAMTS-1 and cathepsin L proteases. Proc Natl Acad Sci USA 97:4689–4694

    Article  PubMed  CAS  Google Scholar 

  • Robker RL, Akison LK, Russell DL (2009) Control of oocyte release by progesterone receptor-regulated gene expression. Nucl Recept Signal 7:e012

    PubMed  Google Scholar 

  • Saunders PT, Millar MR, Williams K, Macpherson S, Harkiss D, Anderson RA, Orr B, Groome NP, Scobie G, Fraser HM (2000) Differential expression of estrogen receptor-alpha and -beta and androgen receptor in the ovaries of marmosets and humans. Biol Reprod 63:1098–1105

    Article  PubMed  CAS  Google Scholar 

  • Schipper I, Fauser BC, van Gaver EB, Zarutskie PW, Dahl KD (1993) Development of a human granulosa cell culture model with follicle stimulating hormone responsiveness. Hum Reprod 8:1380–1386

    PubMed  CAS  Google Scholar 

  • Shao R, Markstrom E, Friberg PA, Johansson M, Billig H (2003) Expression of progesterone receptor (PR) A and B isoforms in mouse granulosa cells: stage-dependent PR-mediated regulation of apoptosis and cell proliferation. Biol Reprod 68:914–921

    Article  PubMed  CAS  Google Scholar 

  • Smith HO, Leslie KK, Singh M, Qualls CR, Revankar CM, Joste NE, Prossnitz ER (2007) GPR30: a novel indicator of poor survival for endometrial carcinoma. Am J Obstet Gynecol 196:386 e381–e389 (discussion 386 e389–311)

    Google Scholar 

  • Smith HO, Arias-Pulido H, Kuo DY, Howard T, Qualls CR, Lee SJ, Verschraegen CF, Hathaway HJ, Joste NE, Prossnitz ER (2009) GPR30 predicts poor survival for ovarian cancer. Gynecol Oncol 114:465–471

    Article  PubMed  CAS  Google Scholar 

  • Suzuki T, Sasano H, Kimura N, Tamura M, Fukaya T, Yajima A, Nagura H (1994) Immunohistochemical distribution of progesterone, androgen and estrogen-receptors in the human ovary during the menstrual-cycle—relationship to expression of steroidogenic enzymes. Hum Reprod 9:1589–1595

    PubMed  CAS  Google Scholar 

  • Takada Y, Kato C, Kondo S, Korenaga R, Ando J (1997) Cloning of cDNAs encoding G protein-coupled receptor expressed in human endothelial cells exposed to fluid shear stress. Biochem Biophys Res Commun 240:737–741

    Article  PubMed  CAS  Google Scholar 

  • Taylor AH, Al-Azzawi F (2000) Immunolocalisation of oestrogen receptor beta in human tissues. J Mol Endocrinol 24:145–155

    Article  PubMed  CAS  Google Scholar 

  • Teilmann SC, Clement CA, Thorup J, Byskov AG, Christensen ST (2006) Expression and localization of the progesterone receptor in mouse and human reproductive organs. J Endocrinol 191:525–535

    Article  PubMed  CAS  Google Scholar 

  • Thomas P, Pang Y, Filardo EJ, Dong J (2005) Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells. Endocrinology 146:624–632

    Article  PubMed  CAS  Google Scholar 

  • van den Driesche S, Smith VM, Myers M, Duncan WC (2008) Expression and regulation of oestrogen receptors in the human corpus luteum. Reproduction 135:509–517

    Article  PubMed  Google Scholar 

  • Voutilainen R, Tapanainen J, Chung BC, Matteson KJ, Miller WL (1986) Hormonal regulation of P450scc (20, 22-desmolase) and P450c17 (17 alpha-hydroxylase/17, 20-lyase) in cultured human granulosa cells. J Clin Endocrinol Metab 63:202–207

    Article  PubMed  CAS  Google Scholar 

  • Wang C, Prossnitz ER, Roy SK (2007) Expression of G protein-coupled receptor 30 in the hamster ovary: differential regulation by gonadotropins and steroid hormones. Endocrinology 148:4853–4864

    Article  PubMed  CAS  Google Scholar 

  • Wang C, Prossnitz ER, Roy SK (2008) G protein-coupled receptor 30 expression is required for estrogen stimulation of primordial follicle formation in the hamster ovary. Endocrinology 149:4452–4461

    Article  PubMed  CAS  Google Scholar 

  • Yang P, Wang J, Shen Y, Roy SK (2004) Developmental expression of estrogen receptor (ER) alpha and ERbeta in the hamster ovary: regulation by follicle-stimulating hormone. Endocrinology 145:5757–5766

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We gratefully acknowledge the following colleagues: (1) from the Department of Obstetrics and Gynecology Maistrasse, Ludwig-Maximilians-University: Christina Kuhn, Simone Hofmann and Verena Ackermann for technical assistance, Laurent Soussana for English language examination (2) from the Walter Brendel Centre of Experimental Medicine, Campus Downtown, Ludwig–Maximilians–University: Ludwig Weckbach for helpful discussion concerning primary cell culture.

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynaecology, Ludwig-Maximilians-University, Innenstadt, Maistrasse 11, 80337, Munich, Germany

    Roman Pavlik, Gabriela Wypior, Panos Papadopoulos, Markus Kupka, Irmi Wiest, Aurelia Pestka, Klaus Friese & Udo Jeschke

  2. Division of Endocrinology and Reproductive Medicine, Department of Obstetrics and Gynaecology, Großhadern, Ludwig-Maximilians-University, Munich, Germany

    Stefanie Hecht, Christian Thaler & Klaus Friese

Authors
  1. Roman Pavlik
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gabriela Wypior
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stefanie Hecht
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Panos Papadopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Markus Kupka
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Christian Thaler
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Irmi Wiest
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Aurelia Pestka
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Klaus Friese
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Udo Jeschke
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Udo Jeschke.

Additional information

R. Pavlik and G. Wypior contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pavlik, R., Wypior, G., Hecht, S. et al. Induction of G protein-coupled estrogen receptor (GPER) and nuclear steroid hormone receptors by gonadotropins in human granulosa cells. Histochem Cell Biol 136, 289–299 (2011). https://doi.org/10.1007/s00418-011-0846-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00418-011-0846-7

Keywords

Search

Navigation