Abstract
Background
Inhibins (INH) are dimeric glycoproteins, composed of an alpha subunit (INH-α) and one of two possible beta subunits (INH-βA or INH-βB). They have substantial roles in human reproduction and in endocrine-responsive tumours. Therefore, the aims of this study were to determine the frequency and tissue distribution of INH-α, INH-βA and INH-βB in normal human endometrium and glandular-cystic endometrial polyps, and polyps caused by tamoxifen use.
Materials and methods
Tissue samples were obtained from women in the proliferative, early secretory and late secretory phase as well as glandular-cystic polyps and endometrial polyps associated with tamoxifen use (n=5 each). Immunohistochemistry with specific monoclonal antibodies, a semi-quantitative analysis and statistical evaluation was performed.
Results
INH-α, INH-βA and INH-βB were primarily observed in glandular and luminal epithelial cells, with a variant staining intensity in stromal cells. INH-α in glands was significantly higher during the early secretory phase (p<0.05) and the late secretory phase (p<0.01) than in the proliferative phase with a significant difference between the early secretory and the late secretory phases (p<0.01). INH-βA expression was significantly higher during the late secretory than the proliferative phase (p<0.05) and the late secretory than the early secretory phase (p<0.05), with no significant differences for INH-βB. Glandular-cystic polyps showed significantly lower expression of INH-α and INH-βA than the late secretory endometria (p<0.05 and p<0.01 respectively). Additionally, tamoxifen-associated polyps also demonstrated a significantly lower expression of INH-α and INH-βA than late secretory endometria (p<0.01 and p<0.01 respectively). No statistical differences were observed between tamoxifen-associated and glandular-cystic polyps.
Discussion
INH-α, INH-βA and INH-βB were expressed in normal endometrium and endometrial polyps. A cyclical expression of INH-α and INH-βA in normal glands may reflect a functional and hormone-dependent role in human endometrium. Significant differences in staining reaction between the late secretory endometria and polyps suggest that this tissue remains in the proliferating state rather than the secretory state. Therefore, endometrial polyps may be tumours of dysregulation with mainly proliferating characteristics, being unable to synchronise with normal endometrium.
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References
Kurman RJ, Kaminski PF, Norris HJ (1985) The behavior of endometrial hyperplasia. A long-term study of “untreated” hyperplasia in 170 patients. Cancer 56:403–412
Mittal K, Schwartz L, Goswami S, Demopoulos R (1996) Estrogen and progesterone receptor expression in endometrial polyps. Int J Gynecol Pathol 15:345–348
Savelli L, De Iaco P, Santini D, Rosati F, Ghi T, Pignotti E, Bovicelli L (2003) Histopathologic features and risk factors for benignity, hyperplasia, and cancer in endometrial polyps. Am J Obstet Gynecol 188:927–931
Dal Cin P, Vanni R, Marras S, Moerman P, Kools P, Andria M, Valdes E, Deprest J, Van de Ven W, Van den Berghe H (1995) Four cytogenetic subgroups can be identified in endometrial polyps. Cancer Res 55:1565–1568
Ismail SM (1998) Endometrial changes during tamoxifen treatment. Lancet 351:838
Ismail SM (1994) Pathology of endometrium treated with tamoxifen. J Clin Pathol 47:827–833
Vosse M, Renard F, Coibion M, Neven P, Nogaret JM, Hertens D (2002) Endometrial disorders in 406 breast cancer patients on tamoxifen: the case for less intensive monitoring. Eur J Obstet Gynecol Reprod Biol 101:58–63
Silva EG, Tornos CS, Follen-Mitchell M (1994) Malignant neoplasms of the uterine corpus in patients treated for breast carcinoma: the effects of tamoxifen. Int J Gynecol Pathol 13:248–258
Vale W, Rivier C, Hsueh A, Campen C, Meunier H, Bicsak T, Vaughan J, Corrigan A, Bardin W, Sawchenko P et al (1988) Chemical and biological characterization of the inhibin family of protein hormones. Recent Prog Horm Res 44:1–34
Ying SY (1988) Inhibins, activins, and follistatins: gonadal proteins modulating the secretion of follicle-stimulating hormone. Endocr Rev 9:267–293
De Kretser DM, Hedger MP, Loveland KL, Phillips DJ (2002) Inhibins, activins and follistatin in reproduction. Hum Reprod Update 8:529–541
Welt CK (2002) The physiology and pathophysiology of inhibin, activin and follistatin in female reproduction. Curr Opin Obstet Gynecol 14:317–323
Matzuk MM, Finegold MJ, Su JG, Hsueh AJ, Bradley A (1992) Alpha-inhibin is a tumour-suppressor gene with gonadal specificity in mice. Nature 360:313–319
Leung PH, Salamonsen LA, Findlay JK (1998) Immunolocalization of inhibin and activin subunits in human endometrium across the menstrual cycle. Hum Reprod 13:3469–3477
Jones RL, Salamonsen LA, Critchley HO, Rogers PA, Affandi B, Findlay JK (2000) Inhibin and activin subunits are differentially expressed in endometrial cells and leukocytes during the menstrual cycle, in early pregnancy and in women using progestin-only contraception. Mol Hum Reprod 6:1107–1117
Mylonas I, Jeschke U, Wiest I, Hoeing A, Shabani N, Kuhn C, Schulze S, Kupka MS, Friese K (2004) Inhibin/activin subunits alpha (-α), beta-A (-βA) and beta-B (-βB) are differentially expressed in normal human endometrium throughout the menstrual cycle. Histochem Cell Biol (in press)
Jones RL, Salamonsen LA, Findlay JK (2002) Potential roles for endometrial inhibins, activins and follistatin during human embryo implantation and early pregnancy. Trends Endocrinol Metab 13:144–150
Dallenbach-Hellweg G, Poulsen H (1985) Atlas der Histopathologie des Endometriums. Springer, Berlin Heidelberg New York
Mylonas I, Makovitzky J, Richter DU, Jeschke U, Briese V, Friese K (2003) Immunohistochemical expression of the tumour marker CA-125 in normal, hyperplastic and malignant endometrial tissue. Anticancer Res 23:1075–1080
Mylonas I, Makovitzky J, Richter DU, Jeschke U, Briese V, Friese K (2003) Cathepsin D expression in normal, hyperplastic and malignant endometrial tissue: an immunohistochemical analysis. Acta Histochem 105:245–252
Remmele W, Stegner HE (1987) Vorschlag zur einheitlichen Definierung eines immunreaktiven Score (IRS) für den immunhistochemischen Östrogenrezeptornachweis (ER-ICA) im Mammakarzinomgewebe. Pathologe 8:138–140
Mylonas I, Jeschke U, Winkler L, Makovitzky J, Richter DU, Briese V, Friese K (2003) Immunohistochemical expression of inhibin-alpha in human endometrium and the in vitro secretion of inhibin, estradiol and cortisol in cultured human endometrial glandular cells. Arch Gynecol Obstet 268:142–150
Mylonas I, Makovitzky J, Richter DU, Jeschke U, Briese V, Friese K (2004) Expression of the inhibin-alpha subunit in normal, hyperplastic and malignant endometrial tissue: an immunohistochemical analysis. Gynecol Oncol 93:92–97
Nuovo MA, Nuovo GJ, McCaffrey RM, Levine RU, Barron B, Winkler B (1989) Endometrial polyps in postmenopausal patients receiving tamoxifen. Int J Gynecol Pathol 8:125–131
Maia H, Maltez A, Calmon LC, Oliveira M, Marques D, Coutinho EM (1998) Histopathology and steroid receptors in endometrial polyps of postmenopausal patients under hormone replacement therapy. Gynecol Endosc 7:267–272
Taylor LJ, Jackson TL, Reid JG, Duffy SR (2003) The differential expression of oestrogen receptors, progesterone receptors, Bcl-2 and Ki67 in endometrial polyps. Br J Obstet Gynaecol 110:794–798
Petraglia F, Florio P, Luisi S, Gallo R, Gadducci A, Vigano P, Di Blasio AM, Genazzani AR, Vale W (1998) Expression and secretion of inhibin and activin in normal and neoplastic uterine tissues. High levels of serum activin A in women with endometrial and cervical carcinoma. J Clin Endocrinol Metab 83:1194–1200
Mylonas I, Winkler L, Jeschke U, Briese V, Friese K (2003) Investigations on isolation, purification and cultivation of human endometrial cells and on the in vitro inhibin expression in glandular epithelial cells. Zentralbl Gynakol 125:415–423
Hubner G, Alzheimer C, Werner S (1999) Activin: a novel player in tissue repair processes. Histol Histopathol 14:295–304
Ni X, Luo S, Minegishi T, Peng C (2000) Activin A in JEG-3 cells: potential role as an autocrine regulator of steroidogenesis in humans. Biol Reprod 62:1224–1230
Keelan JA, Zhou RL, Mitchell MD (2000) Activin A exerts both pro- and anti-inflammatory effects on human term gestational tissues. Placenta 21:38–43
Liu QY, Niranjan B, Gomes P, Gomm JJ, Davies D, Coombes RC, Buluwela L (1996) Inhibitory effects of activin on the growth and morphogenesis of primary and transformed mammary epithelial cells. Cancer Res 56:1155–1163
Ying SY, Zhang Z (1996) Expression and localization of inhibin/activin subunits and activin receptors in MCF-7 cells, a human breast cancer cell line. Breast Cancer Res Treat 37:151–160
McCarthy SA, Bicknell R (1993) Inhibition of vascular endothelial cell growth by activin-A. J Biol Chem 268:23066–23071
Robinson GW, Hennighausen L (1997) Inhibins and activins regulate mammary epithelial cell differentiation through mesenchymal-epithelial interactions. Development 124:2701–2708
Li Q, Karam SM, Coerver KA, Matzuk MM, Gordon JI (1998) Stimulation of activin receptor II signaling pathways inhibits differentiation of multiple gastric epithelial lineages. Mol Endocrinol 12:181–192
Di Simone N, Schneyer AL, Caliandro D, Castellani R, Caruso A (2002) Regulation of endometrial adenocarcinoma cell proliferation by activin-A and its modulation by 17beta-estradiol. Mol Cell Endocrinol 192:187–195
Luisi S, Florio P, Reis FM, Petraglia F (2001) Expression and secretion of activin A: possible physiological and clinical implications. Eur J Endocrinol 145:225–236
Dallenbach-Hellweg G, Schmidt D, Hellberg P, Bourne T, Kreuzwieser E, Doren M, Rydh W, Rudenstam G, Granberg S (2000) The endometrium in breast cancer patients on tamoxifen. Arch Gynecol Obstet 263:170–177
Cohen I, Beyth Y, Altaras MM, Shapira J, Tepper R, Cardoba M, Yigael D, Figer A, Fishman A, Berenhein J (1997) Estrogen and progesterone receptor expression in postmenopausal tamoxifen-exposed endometrial pathologies. Gynecol Oncol 67:8–15
Acknowledgements
We would like to thank Mrs S. Höffer, Mrs F. Winzer (Rostock) and Mrs I. Wiest, Mrs C. Kuhn (Munich) for their excellent work with the endometrial samples. This study was supported in part by FORUN—University Rostock, Rostock, Germany and FöFoLe—Ludwig-Maximilians-University Munich, Munich, Germany for I. Mylonas.
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Mylonas, I., Makovitzky, J., Fernow, A. et al. Expression of the inhibin/activin subunits alpha (α), beta-A (βA) and beta-B (βB) in benign human endometrial polyps and tamoxifen-associated polyps. Arch Gynecol Obstet 272, 59–66 (2005). https://doi.org/10.1007/s00404-004-0666-2
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DOI: https://doi.org/10.1007/s00404-004-0666-2