Abstract
Objective
To study the expression of nuclear receptors and cofactors in human endometrium and myometrium in proliferative and secretory phases of the menstrual cycle.
Methods
Multiprobe ribonuclease protection assay and real-time reverse transcriptase polymerase chain reaction were used to quantitate mRNA levels of steroid receptors, vitamin D receptor (VDR), retinoic acid receptors (RAR), and cofactors AIB1 (amplified in breast cancer-1), CBP (cyclic adenosine monophosphate response element binding protein), pCAF (p300/CBP-associated factor), TIF2 (transcription intermediary factor-2), N-CoR (nuclear receptor corepressor), and SMRT (silencing mediator of repressed transcription). Cyclin A expression was analyzed to determine the proliferation status of the tissues. p ]Results: The expression of androgen receptor, estrogen receptors α and β, progesterone receptor, and RARα followed cyclin A expression. There was more abundant expression in the proliferative phase endometrium than in the secretory phase endometrium. Glucocorticoid receptor, VDR, RARβ, and RARγ were stably expressed during the menstrual cycle in both endometrium and myometrium. Cofactors N-CoR, SMRT, pCAF, CBP, TIF2, AIB1, and p300 mRNAs were expressed in all samples in both endometrium and myometrium. N-CoR, pCAF, AIB1, and p300 appeared not to be regulated when comparing proliferative and secretory phases of the cycle. Individual differences were found in the expression levels of both nuclear receptors and cofactors.
Conclusion
The menstrual cycle-dependent regulation of nuclear receptor expression was more apparent in the endometrium than in the myometrium, whereas cofactor expression was not cycle dependent. There were individual differences in the expression levels of different receptors and cofactors. In hormonal therapy these differences might result in different responses, depending on the patient as well as the ligand used.
Similar content being viewed by others
References
Press MF, Udove JA, Greene GL. Progesterone receptor distribution in the human endometrium. Analysis using monoclonal antibodies to the human progesterone receptor. Am J Pathol 1988;131:112–24.
Snijders MP, de Goeij AF, Debets-Te Baerts MJ, Rousch MJ, Koudstaal J, Bosman FT. Immunocytochemical analysis of oestrogen receptors and progesterone receptors in the human uterus throughout the menstrual cycle and after the menopause. J Reprod Fertil 1992;94:363–71.
Coppens MT, Dhont MA, De Boever JG, Serreyn RF, Vandekerckhove DA, Roels HJ. The distribution of oestrogen and progesterone receptors in the human endometrial basal and functional layer during the normal menstrual cycle. An immunocytochemical study. Histochemistry 1993;99:121–6.
Critchley HO, Bailey DA, Au CL, Affandi B, Rogers PA. Immunohistochemical sex steroid receptor distribution in endometrium from long-term subdermal levonorgestrel users and during the normal menstrual cycle. Hum Reprod 1993;8:1632–9.
Mote PA, Balleine RL, McGowan EM, Clarke CL. Colocalization of progesterone receptors A and B by dual immunofluorescent histochemistry in human endometrium during the menstrual cycle. J Clin Endocrinol Metab 1999;84:2963–71.
Critchley HO, Brenner RM, Henderson TA, et al. Estrogen receptor beta, but not estrogen receptor alpha, is present in the vascular endothelium of the human and nonhuman primate endometrium. J Clin Endocrinol Metab 2001;86:1370–8.
Lecce G, Meduri G, Ancelin M, Bergeron C, Perrot-Applanat M. Presence of estrogen receptor beta in the human endometrium through the cycle: Expression in glandular, stromal, and vascular cells. J Clin Endocrinol Metab 2001;86:1379–86.
Chen JD, Evans RM. A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature 1995;377:454–7.
Horlein AJ, Naar AM, Heinzel T, et al. Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature 1995;377:397–404.
Onate SA, Tsai SY, Tsai MJ, O’Malley BW. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 1995;270:1354–7.
Voegel JJ, Heine MJ, Zechel C, Chambon P, Gronemeyer H. TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors. EMBO J 1996;15:3667–75.
Anzick SL, Kononen J, Walker RL, et al. AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science 1997;277:965–8.
Chen H, Lin RJ, Schütz RL, et al. Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell 1997;90:569–80.
Li H, Gomes PJ, Chen JD. RAC3, a steroid/nuclear receptor-associated coactivator that is related to SRC-1 and TIF2. Proc Natl Acad Sci U S A 1997;94:8479–84.
Takeshita A, Cardona GR, Koibuchi N, Suen CS, Chin WW. TRAM-1, a novel 160-kDa thyroid hormone receptor activator molecule, exhibits distinct properties from steroid receptor coactivator-1. J Biol Chem 1997;272:27629–34.
Brzozowski AM, Pike AC, Dauter Z, et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 1997;389:753–8.
Shiau AK, Barstad D, Loria PM, et al. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 1998;95:927–37.
Jackson TA, Richer JK, Bain DL, Takimoto GS, Tung L, Horwitz KB. The partial agonist activity of antagonist-occupied steroid receptors is controlled by a novel hinge domain-binding coactivator L7/SPA and the compressors N-CoR or SMRT. Mol Endocrinol 1997;11:693–705.
Smith CL, Nawaz Z, O’Malley BW. Coactivator and corepressor regulation of the agonist/antagonist activity of the mixed antiestrogen, 4-hydroxytamoxifen. Mol Endocrinol 1997;11:657–66.
Lavinsky RM, Jepsen K, Heinzel T, et al. Diverse signaling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes. Proc Natl Acad Sci U S A 1998;95:2920–5.
Shang Y, Hu X, DiRenzo J, Lazar MA, Brown M. Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription. Cell 2000;103:843–52.
Shang Y, Myers M, Brown M. Formation of the androgen receptor transcription complex. Mol Cell 2002;9:601–10.
Gregory CW, Wilson EM, Apparao KB, et al. Steroid receptor coactivator expression throughout the menstrual cycle in normal and abnormal endometrium. J Clin Endocrinol Metab 2002;87:2960–6.
Rose PG. Endometrial carcinoma. N Engl J Med 1996;335:640–9.
Fukuda K, Mori M, Uchiyama M, Iwai K, Iwasaka T, Sugimori H. Prognostic significance of progesterone receptor immunohistochemistry in endometrial carcinoma. Gynecol Oncol 1998;69:220–5.
Arnett-Mansfield RL, de Fazio A, Wain GV, et al. Relative expression of progesterone receptors A and B in endometrioid cancers of the endometrium. Cancer Res 2001;61:4576–82.
Rein MS, Barbieri RL, Friedman AJ. Progesterone: A critical role in the pathogenesis of uterine myomas. Am J Obstet Gynecol 1995;172:14–8.
Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987;162:156–9.
Vienonen A, Miettinen S, Manninen T, Altucci L, Wilhelm E, Ylikomi T. Regulation of nuclear receptor and cofactor expression in breast cancer cell lines. Eur J Endocrinol 2003;148:469–79.
Laird SM, Tuckerman EM, Dalton CF, Dunphy BC, Li TC, Zhang X. The production of leukaemia inhibitory factor by human endometrium: Presence in uterine flushings and production by cells in culture. Hum Reprod 1997;12:569–74.
Shiozawa T, Li SF, Nakayama K, Nikaido T, Fujii S. Relationship between the expression of cyclins/cyclin-dependent kinases and sex-steroid receptors/Ki67 in normal human endometrial glands and stroma during the menstrual cycle. Mol Hum Reprod 1996;2:745–52.
Lau TM, Witjaksono J, Affandi B, Rogers PA. Expression of progesterone receptor mRNA in the endometrium during the normal menstrual cycle and in Norplant users. Hum Reprod 1996;11:2629–34.
Matsuzaki S, Fukaya T, Suzuki T, Murakami T, Sasano H, Yajima A. Oestrogen receptor alpha and beta mRNA expression in human endometrium throughout the menstrual cycle. Mol Hum Reprod 1999;5:559–64.
Matsuzaki S, Uehara S, Murakami T, Fujiwara J, Funato T, Okamura K. Quantitative analysis of estrogen receptor alpha and beta messenger ribonucleic acid levels in normal endometrium and ovarian endometriotic cysts using a real-time reverse transcription-polymerase chain reaction assay. Fertil Steril 2000;74:753–9.
Slayden OD, Nayak NR, Burton KA, et al. Progesterone antagonists increase androgen receptor expression in the rhesus macaque and human endometrium. J Clin Endocrinol Metab 2001;86:2668–79.
Noe M, Kunz G, Herbertz M, Mail G, Leyendecker G. The cyclic pattern of the immunocytochemical expression of oestrogen and progesterone receptors in human myometrial and endometrial layers: Characterization of the endometrial-subendometrial unit. Hum Reprod 1999;14:190–7.
Bamberger AM, Milde-Langosch K, Loning T, Bamberger CM. The glucocorticoid receptor is specifically expressed in the stromal compartment of the human endometrium. J Clin Endocrinol Metab 2001;86:5071–4.
Henderson TA, Saunders PT, Moffett-King A, Groome NP, Critchley HO. Steroid receptor expression in uterine natural killer cells. J Clin Endocrinol Metab 2003;88:440–9.
Yabushita H, Hirata M, Noguchi M, Nakanishi M. Vitamin D receptor in endometrial carcinoma and the differentiation-inducing effect of 1,25-dihydroxyvitamin D3 on endometrial carcinoma cell lines. J Obstet Gynaecol Res 1996;22:529–39.
Kumarendran MK, Loughney AD, Prentice A, Thomas EJ, Redfern CP. Nuclear retinoid receptor expression in normal human endometrium throughout the menstrual cycle. Mol Hum Reprod 1996;2:123–9.
Fukunaka K, Saito T, Wataba K, Ashihara K, Ito E, Kudo R. Changes in expression and subcellular localization of nuclear retinoic acid receptors in human endometrial epithelium during the menstrual cycle. Mol Hum Reprod 2001;7:437–46.
Ito K, Suzuki T, Moriya T, et al. Retinoid receptors in the human endometrium and its disorders: A possible modulator of 17 beta-hydroxysteroid dehydrogenase. J Clin Endocrinol Metab 2001;86:2721–7.
Wieser F, Schneeberger C, Hudelist G, et al. Endometrial nuclear receptor co-factors SRC-1 and N-CoR are increased in human endometrium during menstruation. Mol Hum Reprod 2002;8:644–50.
Shiozawa T, Shih HC, Miyamoto T, et al. Cyclic changes in the expression of steroid receptor coactivators and corepressors in the normal human endometrium. J Clin Endocrinol Metab 2003;88:871–8.
Shang Y, Brown M. Molecular determinants for the tissue specificity of SERMs. Science 2002;295:2465–8.
Author information
Authors and Affiliations
Corresponding author
Additional information
This study was supported by grants from Medical Research Fund of Tampere University Hospital, the European Community PL 963433, TEKES Drug 2000, and the Pirkanmaa Cancer Society.
The authors thank Tarja Arvela. Taina Eskola, and Hilkka Mäkinen for excellent technical assistance and Heini Huhtala for statistical advice; Dr. H. Gronemeyer and coworkers for providing the VDR/RAR and cofactor RPA probe sets. The cofactor RPA kit is a proprietary development of the laboratory of Dr. H. Gronemeyer (lGHMe. Department ofCelJ Biology and Signal Transduction, Illkirch. France), who also provided plasmids encoding human RARα, RARβ, RARγ, TIF2, and ERα; and Dr. E. Enmark (Department of Biosciences at Novum, Karolinska Institute. Huddinge, Sweden) for the plasmid encoding human ERβ
Rights and permissions
About this article
Cite this article
Vienonen, A., Miettinen, S., Bläuer, M. et al. Expression of Nuclear Receptors and Cofactors in Human Endometrium and Myometrium. Reprod. Sci. 11, 104–112 (2004). https://doi.org/10.1016/j.jsgi.2003.09.003
Published:
Issue Date:
DOI: https://doi.org/10.1016/j.jsgi.2003.09.003