Effects of selective estrogen receptor agonists on estrogen receptor expression in the uterus of ovariectomized rats


The aim of the present study was to investigate effects of short time treatment with estrogen receptor (ER) selective agonists on ERα, ERβ and G-protein coupled estrogen receptor-1 (GPER) expression in the uterus of ovariectomized rats. The rats were treated with either estradiol (E2), the specific ERα agonist PPT or the specific ERβ agonist DPN for 18 hrs. Uterine weights were higher after E2 or PPT treatment than after DPN or no treatment. ERα mRNA levels decreased significantly in PPT and DPN treated animals as compared to controls. Stromal ERα immunostaining was higher after E2 treatment than in controls. The ERβ mRNA level was lower in the E2 and PPT groups compared with controls. ERβ immunoreactivity was higher in the myometrium after DPN treatment than in controls. The GPER mRNA level was lower in the E2 and DPN groups as compared to the controls, whereas total protein levels did not display any change. The proliferation marker Ki-67 increased after PPT treatment in stroma and myometrium, as compared to controls. Thus, uterine growth and proliferation are predominately regulated via ERα. Also ERβ expression showed regulation via ERα, while GPER expression indicated control via ERβ. This short term treatment did not result in any regulation of the total protein level as determined by Western blot. However, treatment by E2 increased ERα immunostaining in the stroma and DPN augmented ERβ immunostaining in the myometrium. Thus, the estrogen receptors in the rat uterus are differently regulated depending on the ligand and tissue type.

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S. Blesson, C. , Masironi, B. and Sahlin, L. (2012) Effects of selective estrogen receptor agonists on estrogen receptor expression in the uterus of ovariectomized rats. Open Journal of Molecular and Integrative Physiology, 2, 35-43. doi: 10.4236/ojmip.2012.22006.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Kuiper, G.G., Enmark, E., Pelto-Huikko, M., Nilsson, S. and Gustafsson, J.A. (1996) Cloning of a novel receptor expressed in rat prostate and ovary. Proceedings of the National Academy of Sciences of USA, 93, 5925-5930. doi:10.1073/pnas.93.12.5925
[2] Green, S., Walter, P., Kumar, V., Krust, A., Bornert, J.M., Argos P. and Chambon, P. (1986) Human oestrogen receptor cDNA: Sequence, expression and homology to verb-A. Nature, 320, 134-139. doi:10.1038/320134a0
[3] Mosselman, S., Polman, J. and Dijkema, R. (1996) ER beta: Identification and characterization of a novel human estrogen receptor. FEBS Letters, 392, 49-53. doi:10.1016/0014-5793(96)00782-X
[4] Tremblay, G.B., Tremblay, A., Copeland, N.G., Gilbert, D.J., Jenkins, N.A., Labrie, F. and Giguere, V. (1997) Cloning, chromosomal localization, and functional analysis of the murine estrogen receptor beta. Molecular Endocrinology, 11, 353-365. doi:10.1210/me.11.3.353
[5] Pettersson, K., Grandien, K., Kuiper, G.G. and Gustafsson, J.A. (1997) Mouse estrogen receptor beta forms estrogen response element-binding heterodimers with estrogen receptor alpha. Molecular Endocrinology, 11, 1486-1496. doi:10.1210/me.11.10.1486
[6] Kuiper, G.G., Carlsson, B., Grandien, K., Enmark, E., Haggblad, J., Nilsson, S. and Gustafsson, J.A. (1997) Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology, 138, 863-870. doi:10.1210/en.138.3.863
[7] Clark, B.F. (1971) The effects of oestrogen and progesterone on uterine cell division and epithelial morphology in spayed, adrenalectomized rats. Journal of Endocrinology, 50, 527-528. doi:10.1677/joe.0.0500527
[8] Tachi, C., Tachi, S. and Lindner, H.R. (1972) Modification by progesterone of oestradiol-induced cell proliferation, RNA synthesis and oestradiol distribution in the rat uterus. Journal of Reproduction and Fertility, 31, 59-76. doi:10.1530/jrf.0.0310059
[9] Cooke, P.S., Buchanan, D.L., Lubahn, D.B. and Cunha, G.R. (1998) Mechanism of estrogen action: Lessons from the estrogen receptor-alpha knockout mouse. Biology of Reproduction, 59, 470-475. doi:10.1095/biolreprod59.3.470
[10] Filardo, E.J., Quinn, J.A., Frackelton, A.R., Jr. and Bland, K.I. (2002) Estrogen action via the G protein-coupled receptor, GPR30: Stimulation of adenylyl cyclase and cAMPmediated attenuation of the epidermal growth factor receptor-to-MAPK signaling axis. Molecular endocrinology, 16, 70-84. doi:10.1210/me.16.1.70
[11] Revankar, C.M., Cimino, D.F., Sklar, L.A., Arterburn, J.B. and Prossnitz, E.R. (2005) A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science, 307, 1625-1630. doi:10.1126/science.1106943
[12] Olde, B. and Leeb-Lundberg, L.M. (2009) GPR30/GPER1: Searching for a role in estrogen physiology. Trends in Endocrinology & Metabolism, 20, 409-416. doi:10.1016/j.tem.2009.04.006
[13] Martensson, U.E., Salehi, S.A., Windahl, S., Gomez, M.F., Sward, K., Daszkiewicz-Nilsson, J., Wendt, A., Andersson, N., Hellstrand, P., Grande, P.O., Owman, C., Rosen, C.J., Adamo, M.L., Lundquist, I., Rorsman, P., Nilsson, B.O., Ohlsson, C., Olde, B. and Leeb-Lundberg, L.M. (2009) Deletion of the G protein-coupled receptor 30 impairs glucose tolerance, reduces bone growth, increases blood pressure, and eliminates estradiol-stimulated insulin release in female mice. Endocrinology, 150, 687-698. doi:10.1210
[14] Thomas, P., Pang, Y., Filardo, E.J. and Dong, J. (2005) Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells. Endocrinology, 146, 624-632. doi:10.1210/en.2004-1064
[15] Prossnitz, E.R. and Barton, M., (2011) The G-proteincoupled estrogen receptor GPER in health and disease. Nature Reviews Endocrinology, 7, 715-726. doi:10.1038/nrendo.2011.122
[16] Windahl, S.H., Andersson, N., Chagin, A.S., Martensson, U.E., Carlsten, H., Olde, B., Swanson, C., Moverare-Skrtic, S., Savendahl, L., Lagerquist, M.K., Leeb-Lundberg, L.M. and Ohlsson, C. (2009) The role of the G protein-coupled receptor GPR30 in the effects of estrogen in ovariectomized mice. American Journal of Physiology—Endocrinology and Metabolism, 296, E490-E496. doi:10.1152/ajpendo.90691.2008
[17] Otto, C., I. Fuchs, G. Kauselmann, H. Kern, B. Zevnik, P. Andreasen, G. Schwarz, H. Altmann, M. Klewer, M. Schoor, R. Vonk, and K.H. Fritzemeier. (2009) GPR30 does not mediate estrogenic responses in reproductive organs in mice. Biology of Reproduction, 80, 34-41. doi:10.1095/biolreprod.108.071175
[18] Smith, H.O., Leslie, K.K., Singh, M., Qualls, C.R., Revankar, C.M., Joste, N.E. and Prossnitz, E.R. (2007) GPR30: A novel indicator of poor survival for endometrial carcinoma. American Journal of Obstetrics and Gynecology, 196, e1-e9, e9-e11. doi:10.1016/j.ajog.2007.01.004
[19] Gao, F., Ma, X., Ostmann, A.B. and Das, S.K. (2011) GPR30 activation opposes estrogen-dependent uterine growth via inhibition of stromal ERK1/2 and estrogen receptor alpha (ERalpha) phosphorylation signals. Endocrinology, 152, 1434-1447. doi:10.1210/en.2010-1368
[20] Kraichely, D.M., Sun, J., Katzenellenbogen, J.A. and Katzenellenbogen, B.S. (2000) Conformational changes and coactivator recruitment by novel ligands for estrogen receptor-alpha and estrogen receptor-beta: Correlations with biological character and distinct differences among SRC coactivator family members. Endocrinology, 141, 3534-3545. doi:10.1210/en.141.10.3534
[21] Stauffer, S.R., Coletta, C.J., Tedesco, R., Nishiguchi, G., Carlson, K., Sun, J., Katzenellenbogen, B.S. and Katzenellenbogen, J.A. (2000) Pyrazole ligands: Structure-affinity/activity relationships and estrogen receptor-alpha-selective agonists. Journal of Medicinal Chemistry, 43, 4934-4947. doi:10.1021/jm000170m
[22] Meyers, M.J., Sun, J., Carlson, K.E., Marriner, G.A., Katzenellenbogen, B.S. and Katzenellenbogen, J.A. (2001) Estrogen receptor-beta potency-selective ligands: Structure-activity relationship studies of diarylpropionitriles and their acetylene and polar analogues. Journal of Medicinal Chemistry, 44, 4230-4251. doi:10.1021/jm010254a
[23] Lowry, O.H., Rosebrough, N.J., Farr, A.L. and Randall, R.J. (1951) Protein measurement with the Folin phenol reagent. Journal of Biological Chemistry, 193, 265-275.
[24] Frasor, J., Barnett, D.H., Danes, J.M., Hess, R., Parlow, A.F. and Katzenellenbogen, B.S. (2003) Response-specific and ligand dose-dependent modulation of estrogen receptor (ER) alpha activity by ERbeta in the uterus. Endocrinology, 144, 3159-3166. doi:10.1210/en.2002-0143
[25] Santollo, J. and Eckel, L.A. (2009) Effect of a putative ERalpha antagonist, MPP, on food intake in cycling and ovariectomized rats. Physiology & Behavior, 97, 193-198. doi:10.1016/j.physbeh.2009.02.021
[26] Lindberg, M.K., Weihua, Z., Andersson, N., Moverare, S., Gao, H., Vidal, O., Erlandsson, M., Windahl, S., Andersson, G., Lubahn, D.B., Carlsten, H., Dahlman-Wright, K., Gustafsson, J.A. and Ohlsson., C. (2002) Estrogen receptor specificity for the effects of estrogen in ovariectomized mice. Journal of Endocrinology, 174, 167-178. doi:10.1677/joe.0.1740167
[27] Ing, N.H. (1995) The steroid hormone receptor superfamily: molecular mechanisms of action. In: Weintraub, B.D., Ed., Molecular Endocrinology: Basic Concepts and Clinical Correlations, Raven Press, New York, 195-216.
[28] Wang, H., Masironi, B., Eriksson, H. and Sahlin, L. (1999) A comparative study of estrogen receptors alpha and beta in the rat uterus. Biology of Reproduction, 61, 955-964. doi:10.1095/biolreprod61.4.955
[29] Sahlin, L., Norstedt, G. and Eriksson, H. (1994) Estrogen regulation of the estrogen receptor and insulinlike growth factor-I in the rat uterus: A potential coupling between effects of estrogen and IGF-I. Steroids, 59, 421-430. doi:10.1016/0039-128X(94)90011-6
[30] Parker, M.G. (1995) Structure and function of estrogen receptors. Vitamins & Hormones, 51, 267-287. doi:10.1016/S0083-6729(08)61041-9
[31] Bjornstrom, L. and Sjoberg, M. (2005) Mechanisms of estrogen receptor signaling: Convergence of genomic and nongenomic actions on target genes. Molecular Endocrinology, 19, 833-842. doi:10.1210/me.2004-0486
[32] Ariazi, E.A., Brailoiu, E., Yerrum, S., Shupp, H.A., Slifker, M.J., Cunliffe, H.E., Black, M.A., Donato, A.L., Arterburn, J.B., Oprea, T.I., Prossnitz, E.R., Dun, N.J. and Jordan, V.C. (2010) The G protein-coupled receptor GPR30 inhibits proliferation of estrogen receptor-positive breast cancer cells. Cancer research, 70, 1184-1194. doi:10.1158/0008-5472.CAN-09-3068
[33] Gotte, M. (2010) MicroRNAs in breast cancer pathogenesis. Minerva Ginecologica, 62, 559-571.
[34] Sahlin, L., Masironi, B., Akerberg, S. and Eriksson, H. (2006) Tissueand hormone-dependent progesterone receptor distribution in the rat uterus. Reproductive Biology and Endocrinology, 4, 47. doi:10.1186/1477-7827-4-47

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