The pathogenesis of endometrial polyps: a systematic semi-quantitative review

The pathogenesis and natural history of endometrial polyps are not very clear. The objective of this study was to assess the opinions of international medical literature regarding the factors involved in the pathogenesis of endometrial polyps and to organize the results consistently with what is known about endometrial physiology. Materials and Methods: A systematic review was carried out with the following search engines: PubMed, OVID, Scopus, SCIELO, and AJOL. Two hundreds forty-six abstracts were selected from the literature; of these abstracts, 58 factors were extracted and set as causative, non-causative, unclear or protective link with endometrial polyps. This relation is described through a correspondence analysis and tested with a main effect hierarchical log-linear model. Results: The log-linear model resulted significant for the correspondence found with the following factors: (i) causative link (ageing, bcl-2 protein, excess weight/obesity, tamoxifen regardless of timing, relationship between estrogen receptors and progestinics, unbalanced estrogen therapy, estrogen-like effect, and unbalance between estrogens and progestinics), (ii) protective link (progestinics, antiestrogenic action), (iii) unclear link (menopause, ki-67 protein, angiogenesis, tamoxifen for a short time, tamoxifen for a long time, hormone replacement therapy (HRT), endometritis/inflammation), and (iv) non-causative link (none of the factors specifically). Discussion: Subsequently to a review of the physiology of the endometrium, the onsetting of endometrial polyps was suggested through estrogen-related and non-estrogen related ways; the two ways can overlap. The most implied factors in the development of endometrial polyps are linked with one of these or both ways.

Endometrial polyps; Pathogenesis; Estrogens; Progesterone; Apoptosis.

[1] Silberstein T., Saphier O., vanVoorhis B.J., Plosker S.M.: “Endometrial polyps in reproductive-age fertile and infertile women”. Isr. Med. Ass. J., 2006, 8, 192.

[2] Sharma M., Taylor A., Magos A.: “Management of endometrial polyps: a clinical review”. Rev. Gynaecol. Pract., 2004, 4, 1.

[3] Di Spiezio Sardo A., Bettocchi S., Spinelli M., Guida M., Nappi L., Angioni S. et al.: “Review of new office-based hysteroscopic procedures 2003-2009”. J. Minim. Invasive Gynecol., 2010, 17, 436.

[4] Gregoriou O., Konidaris S., Vrachnis N., Bakalianou K., Salakos N., Papadias K. et al.: “Clinical parameters linked with malignancy in endometrial polyps”. Climateric., 2009, 12, 454.

[5] Antunes A. Jr., Costa-Paiva L., Arthuso M., Costa J.V., Pinto-Neto A.M.: “Endometrial polyps in pre- and postmenopausal women: factors associated with malignancy”. Maturitas., 2007, 57, 415.

[6] Ben-Arie A., Goldchmit C., Laviv Y., Levy R., Caspi B., Huszar M. et al.: “The malignant potential of endometrial polyps”. Eur. J. Obstet. Gynecol. Reprod. Biol., 2004, 115, 206.

[7] deWaay D.J., Syrop C.H., Nygaard I.E., Davis W.A., Van Voorhis B.J.: “Natural history of uterine polyps and leiomyomata”. Obstet. Gynecol., 2002, 100, 3.

[8] Thompson P., Nawaz R., McNaught J., Ananiadou S.: “Enriching a biomedical event corpus with meta-knowledge annotation”. BMC Bioinformatics., 2011, 12, 393.

[9] Carreira R., Carneiro S., Pereira R., Rocha M., Rocha I., Ferreira E.C. et al.: “Semantic annotation of biological concepts interplaying microbial cellular responses”. BMC Bioinformatics., 2011, 12, 460.

[10] Antal P., Fannes G., Timmerman D., Moreau Y., De Moor B.: “Using literature and data to learn Bayesian networks as clinical models of ovarian tumors”. Artif. Intell. Med., 2004, 30, 257.

[11] No Authors listed. Multidimensional scaling and correspondence analysis. In: Multivariate data analysis, sixth edition, Hair Jr J.F., Black W.C., Babin B.J., Anderson R.E., Tatham R.L. (eds.), Upper Saddle River, Pearson International Editions, 2006, 629.

[12] Miranda S.M., Gomes M.T., Silva I.D., Girão M.J.: “Endometrial polyps: clinical and epidemiological aspects and analysis of polymorphisms”. Rev. Bras. Ginecol. Obstet., 2010, 32, 327.

[13] Reslova T., Tošner J., Rešl M., Kugler R., Vávrová I.: “Endometrial polyps. A clinical study of 245 cases”. Arch. Gynecol. Obstet., 1999, 262, 133.

[14] Sit A.S., Modugno F., Hill L.M., Martin J., Weissfeld J.L.: “Transvaginal ultrasound measurement of endometrial thickness as a biomarker for estrogen exposure”. Cancer Epidemiol. Biomarkers Prev., 2004, 13, 1459.

[15] McGurgan P., Taylor L.J., Duffy S.R., O’Donovan P.J.: “Are endometrial polyps from pre-menopausal women similar to postmenopausal women? An immunohistochemical comparison of endometrial polyps from pre- and post-menopausal women”. Maturitas., 2006, 54, 277.

[16] Kao L.C., Tulac S., Lobo S., Imani B., Yang J.P., Germeyer A. et al.: “Global gene profiling in human endometrium during the window of implantation”. Endocrinology, 2002, 143, 2119.

[17] Kao L.C., Germeyer A., Tulac S., Lobo S., Yang J.P., Taylor R.N. et al.: “Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility”. Endocrinology, 2003, 144, 2870.

[18] Critchley H.O., Kelly R.W., Brenner R.M., Baird D.T.: “The endocrinology of menstruation-a role for the immune system”. Clin. Endocrinol. (Oxf.), 2001, 55, 701.

[19] Slayden O.D., Brenner R.M.: “Hormonal regulation and localization of estrogen, progestin and androgen receptors in the endometrium of nonhuman primates: effects of progesterone receptor antagonists”. Arch. Histol. Cytol., 2004, 67, 393.

[20] Hewitt S.C., Harrell J.C., Korach K.S.: “Lessons in estrogen biology from knockout and transgenic animals”. Ann. Rev. Physiol., 2005, 67, 285.

[21] Chauchereau A., Savouret J.F., Milgrom E.: “Control of biosynthesis and post-transcriptional modification of the progesterone receptor”. Biol. Reprod., 1992, 46, 174.

[22] Xue Q., Lin Z., Cheng Y.H., Huang C.C., Marsh E., Yin P. et al.: “Promoter methylation regulates estrogen receptor 2 in human endometrium and endometriosis”. Biol. Reprod., 2007, 77, 681.

[23] Hertrampf T., Seibel J., Laudenbach U., Fritzemeier K.H., Diel P.: “Analysis of the effects of the of oestrogen receptor alpha (ERalpha)- and Erbeta-selective ligands given in combination to ovariectomized rats”. Br. J. Pharmacol., 2008, 153, 1432.

[24] Bulun S.E., Cheng Y.H., Pavone M.E., Xue Q., Attar E., Trukhacheva E. et al.: “Estrogen receptor-beta, estrogen receptoralpha, and progesterone resistance in endometriosis”. Semin. Reprod. Med., 2010, 28, 36.

[25] Snijders M.P., de Goeij A.F., Koudstaal J., Thunnissen E.B., de Haan J., Bosman F.T.: “Oestrogen and progesterone receptor immunocytochemistry in human hyperplastic and neoplastic endometrium”. J. Pathol., 1992, 166, 171.

[26] McCluggage W.G.: “Miscellaneous disorders involving the endometrium”. Semin. Diagn. Pathol., 2010, 27, 287.

[27] Ludwig H., Spornitz U.M.: “Microarchitecture of the human endometrium by scanning electron microscopy: menstrual desquamation and remodelling”. Ann. N.Y. Acad. Sci., 1991, 622, 28.

[28] Peng X., Li T., Xia E., Xia C., Liu Y., Yu D.: “A comparison of oestrogen receptor and progesterone receptor expression in endometrial polyps and endometrium of premenopausal women”. J. Obstet. Gynaecol., 2009, 29, 340.

[29] Gul A., Ugur M., Iskender C., Zulfikaroglu E., Ozaksit G.: “Immunohistochemical expression of estrogen and progesterone receptors in endometrial polyps and its relationship to clinical parameters”. Arch. Gynecol. Obstet., 2010, 281, 479.

[30] Lopes R.G., Baracat E.C., de Albuquerque Neto L.C., Ramos J.F., Yatabe S., Depser D.B. et al.: “Analysis of estrogen- and progesterone-receptor expression in endometrial polyps”. J. Minim. Invasive Gynecol., 2007, 14, 300.

[31] Mittal K., Schwartz L., Goswami S., Demopoulos R.: “Estrogen and progesterone receptor expression in endometrial polyps”. Int. J. Gynecol. Pathol., 1996, 15, 345.

[32] Pickartz H., Beckmann R., Fleige B., Düe W., Gerdes J., Stein H.: “Steroid receptors and proliferative activity in non-neoplastic and neoplastic endometria”. Virchows Arch A Pathol. Anat. Histopathol., 1990, 417, 163.

[33] Liu Z., Kuokkanen S., Pal L.: “Steroid hormone receptor profile of premenopausal endometrial polyps”. Reprod. Sci., 2010, 17, 377.

[34] Chritchley H.O., Brenner R.M., Henderson T.A., Williams K., Nayak N.R., Slayden O.D. 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.

[35] Lecce G., Meduri G., Ancelin M., Bergeron C., Perrot-Applanant 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.

[36] Ye H., Xu X.R., Liu Y.K., Liu Z.H., Zhao A.Z.: “Study on the relationship between estrogen receptor beta and etiology of human endometrial polyps”. Zhonghua Fu Chan Ke Za Zhi., 2006, 41, 814.

[37] Taylor L.J., Jackson T.L., Reid J.G., Duffy S.R.: “The difference expression of oestrogen receptors, progesterone receptors, Bcl-2 and Ki67 in endometrial polyps”. BJOG, 2003, 110, 794.

[38] Vinatier D., Dufour P., Subtil D.: “Apoptosis: a programmed cell death involved in ovarian and uterine physiology”. Eur. J. Obstet. Gynecol. Reprod. Biol., 1996, 67, 85.

[39] Adams J.M., Cory S.: “The Bcl-2 protein family: arbiters of cell survival”. Science, 1998, 281, 1322.

[40] McGurgan P., Taylor L.J., Duffy S.R., O’Donovan P.J.: “Does tamoxifen therapy affect the hormone receptor expression and cell proliferation indices of endometrial polyps? An immunohistochemical comparison of endometrial polyps from postmenopausal women exposed and not exposed to tamoxifen”. Maturitas., 2006, 54, 252.

[41] McGurgan P., Taylor L.J., Duffy S.R., O’Donovan P.J.: “An immunohistochemical comparison of endometrial polyps from postmenopausal women exposed and not exposed to HRT”. Maturitas., 2006, 53, 454.

[42] Inceboz U.S., Nese N., Uyar Y., Ozcakir H.T., Kurtul O., Baytur Y.B. et al.: “Hormone receptor expressions and proliferation markers in postmenopausal endometrial polyps”. Gynecol. Obstet. Invest., 2006, 61, 24.

[43] Duffy S.R., Taylor L.: “Molecular markers in the endometrium at baseline of postmenopausal patients with early breast cancer in the ATAC (Arimidex, tamoxifen, alone, or in combination) trial”. Am. J. Obstet. Gynecol., 2004, 191, 1921.

[44] Habiba M., Ramsay J., Akkad A., Hart D.M., al-Azzawi F.: “Immunohistochemical and hysteroscopic assessment of postmenopausal women with uterine bleeding whilst taking Tibolone”. Eur. J. Obstet. Gynecol. Reprod. Biol., 1996, 66, 45.

[45] Risberg B., Karlsson K., Abeler V., Lagrelius A., Davidson B., Karlsson M.G.: “Dissociated expression of Bcl-2 and Ki-67 in endometrial lesions: diagnostic and histogenetic implications”. Int. J. Gynecol. Pathol., 2002, 21, 155.

[46] Maia H. Jr., Maltez A., Studart E., Athayde C., Coutinho E.M.: “Ki-67, Bcl-2 and p53 expression in endometrial polyps and in the normal endometrium during the menstrual cycle”. BJOG, 2004, 111, 1242.

[47] Harada T., Kaponis A., Iwabe T., Taniguchi F., Makrydimas G., Sofikitis N. et al.: “Apoptosis in human endometrium and endometriosis”. Hum. Reprod. Update, 2004, 10, 29.

[48] Agic A., Djalali S., Diedrich K., Hornung D.: “Apoptosis in endometriosis”. Gynecol. Obstet. Invest., 2009, 68, 217.

[49] Taniguchi F., Kaponis A., Izawa M., Kiyama T., Deura I., Ito M. et al.: “Apoptosis and endometriosis”. Front. Biosci (Elite Ed), 2011, 3, 648.

[50] Bulun S.E.: “Endometriosis”. NEJM, 2009, 360, 268.

[51] Meresman G.F., Vighi S., Buquet R.A., Contreras-Ortiz O., Tesone M., Rumi L.S.: “Apoptosis and expression of Bcl-2 and Bax in eutopic endometrium from women with endometriosis”. Fertil. Steril., 2000, 74, 760.

[52] Critchley H.O., Kelly R.W., Lea R.G., Drudy T.A., Jones R.L., Baird D.T.: “Sex steroid regulation of leukocyte traffic in human decidua”. Hum. Reprod., 1996, 11, 2257.

[53] Critchley H.O., Jones R.L., Lea R.G., Drudy T.A., Kelly R.W., Williams A.R. et al.: “Role of inflammatory mediators in human endometrium during progesterone withdrawal and early pregnancy”. J. Clin. Endocrinol. Metab., 1999, 84, 240.

[54] Milne S.A., Critchley H.O., Drudy T.A., Kelly R.W., Baird D.T.: “Perivascular interleukin-8 messenger ribonucleic acid expression in human endometrium varies across the menstrual cycle and in early pregnancy decidua”. J. Clin. Endocrinol. Metab., 1999, 84, 2563.

[55] Critchley H.O., Kelly R.W., Kooy J.: “Perivascular location of a chemokine interleukin-8 in human endometrium: a preliminary report”. Hum. Reprod., 1994 9, 1406.

[56] Jones R.L., Kelly R.W., Critchley H.O.: “Chemokine and cyclooxygenase-2 expression in human endometrium coincides with leukocyte accumulation”. Hum. Reprod., 1997, 12, 1300.

[57] Ludwig-Galezowska A.H., Flanagan L., Rehm M.J.: “Apoptosis repressor with caspase recruitment domain, a multifunctional modulator of cell death”. Cell. Mol. Med., 2011, 15, 1044.

[58] Morris H.: “Surgical pathology of the lower uterine segment caesarean section scar: is the scar a source of clinical symptoms?”. Int. J. Gynecol. Pathol., 1995, 14, 16.

[59] Ozalp S., Kabukcuoglu S., Tanir H.M.: “Should endometrial hyperplasia be regarded as a reason for abnormal uterine bleeding in users of the intrauterine contraceptive device?”. Eur. J. Contracept. Reprod Health Care, 2003, 8, 17.

[60] Kishore N., Khambatta R., Mullick S.: “Menstrual disorders after sterilization with special reference to ovarian activity”. J. Obstet. Gynaecol. India, 1972, 22, 180.

[61] Gupta A.S., Saha M., Premanik A.: “Post-tubal ligation hysterectomy”. J. Indian. Med. Assoc., 1981, 76, 208.

[62] Cicinelli E., Resta L., Nicoletti R., Zappimbulso V., Tartagni M., Saliani N.: “Endometrial micropolyps at fluid hysteroscopy suggest the existence of chronic endometritis”. Hum. Reprod., 2005, 20, 1386.

[63] Indraccolo U., Barbieri F.: “Relationship between adenomyosis and uterine polyps”. Eur. J. Obstet. Gynecol. Reprod. Biol., 2011, 157, 185.

[64] Bennett M.W., Dick E.J. Jr., Schlabritz-Loutsevitch N.E., LopezAlvarenga J.C., Williams P.C., Mark Sharp R. et al.: “Endometrial and cervical polyps in 22 baboons (Papio sp.), 5 cynomolgus macaques (Macaca fascicularis) and one marmoset (Callithrix jacchus)”. J. Med. Primatol., 2009, 38, 257.

[65] Erdemoglu E., Güney M., Karahan N., Mungan T.: “Expression of cyclooxygenase-2, matrix metalloproteinase-9 in premenopausal and postmenopausal endometrial polyps”. Maturitas., 2008, 59, 268.

[66] Maia H. Jr., Maltez A., Studard E., Zausner B., Athayde C., Coutinho E.: “Effect of the menstrual cycle on cyclooxygenase2 expression in the endometrium”. Gynecol. Endocrinol., 2005, 21, 57.

[67] Maia H. Jr., Casoy J., Pimentel K., Correia T., Athayde C., Cruz T. et al.: “Effect of oral contraceptives on vascular endothelial growth factor, Cox-2 and aromatase expression in the endometrium of uteri affected by myomas and associated pathologies”. Contraception, 2008, 78, 479.

[68] King A.E., Critchley H.O.: “Oestrogen and progesterone regulation of inflammatory processes in the human endometrium”. J. Steroid. Biochem. Mol. Biol., 2010, 120, 116.

[69] Chan R.W., Schwab K.E., Gargett C.E.: “Clonogenicity of human endometrial epithelial and stromal cells”. Biol Reprod., 2004, 70, 1738.

[70] Jabbour H.N., Kelly R.W., Fraser H.M., Critchley H.O.: “Endocrine regulation of menstruation”. Endocr. Rev., 2006, 27, 17.

[71] Bruner K.L., Eisenberg E., Gorstein F., Osteen K.G.: “Progesterone and transforming growth factor-beta coordinately regulate suppression of endometrial matrix metalloproteinases in a model of experimental endometriosis”. Steroids., 1999, 64, 648.

[72] Maia Jr H.A., Maltez A., Fahel P.E., Coutinho E.M.: “Histochemical detection of c-erb-2 overexpression in endometrial polyps removed by hysteroscopy”. Gynecol. Endoscopy, 2000, 9, 253.

[73] Gray K., Bullock B., Dickson R., Raszmann K., McLachlan J., Merlino G.: “Mechanisms of DES carcinogenicity: effects of the TGFalpha transgene”. Prog. Clin. Biol. Res., 1997, 396, 217.

[74] Gray K., Bullock B., Dickson R., Raszmann K., Walmer D., McLachlan J. et al.: “Potentiation of diethylstilbestrol-induced alterations in the female mouse reproductive tract by transforming growth factor-alpha transgene expression”. Mol. Carcinog., 1996, 17, 163.

[75] Zhang L., Scott P.A., Turley H., Leek R., Lewis C.E., Gatter K.C. et al.: “Validation of anti-vascular endothelial growth factor (antiVEGF) antibodies for immunohistochemical localization of VEGF in tissue sections: expression of VEGF in the human endometrium”. J. Pathol., 1998, 185, 402.

[76] Gargett C.E., Lederman F.L., Lau T.M., Taylor N.H., Rogers P.A.: “Lack of correlation between vascular endothelial growth factor production and endothelial cell proliferation in the human endometrium”. Hum. Reprod., 1999, 14, 2080.

[77] Niklaus A.L., Babischkin J.S., Aberdeen G.W., Pepe G.J., Albrecht E.D.: “Expression of vascular endothelial growth/permeability factor by endometrial glandular epithelial and stromal cells in baboons during the menstrual cycle and after ovariectomy”. Endocrinology, 2002, 143, 4007.

[78] Hornung D., Lebovic D.I., Shifren J.L., Vigne J.L., Taylor R.N.: “Vectorial secretion of vascular endothelial growth factor by polarized human endometrial epithelial cells”. Fertil. Steril., 1998, 69, 909.

[79] Gargett C.E., Lederman F., Heryanto B., Gambino L.S., Rogers P.A.: “Focal vascular endothelial growth factor correlates with angiogenesis in human endometrium. Role of intravascular neutrophilis”. Hum. Reprod., 2001, 16, 1065.

[80] Nayak N.R., Brenner R.M.: “Vascular proliferation and vascular endothelial growth factor expression in the rhesus macaque endometrium”. J. Clin. Endocrinol. Metab., 2002, 87, 1845.

[81] Lash G.E., Innes B.A., Drury J.A., Robson S.C., Quenby S., Bulmer J.N.: “Localization of angiogenic growth factors and their receptors in the human endometrium throughout the menstrual cycle and in recurrent miscarriage”. Hum. Reprod., 2012, 27, 183.

[82] Xuebing P., Tinchiu L., Enlan X., Jing L., Xiaowu H.: “Is endometrial polyp formation associated with increased expression of vascular endothelial growth factor and transforming growth factorbeta1?”. Eur. J. Obstet. Gynecol. Reprod. Biol., 2011, 159, 198.

[83] Hague S., Manek S., Oehler M.K., MacKenzie I.Z., Bicknell R., Rees M.C.: “Tamoxifen induction of angiogenic factor expression in endometrium”. Br. J. Cancer, 2002, 86, 761.

[84] Cheng W., Wang Y.J., Zhang X., Gao X.M.: “The effect on angiogenesis of endometrium after transcervical resection of polyp”. Sichuan Da Xue Xue Bao Yi Xue Ban., 2010, 41, 854.

[85] Ferrari G., Cook B.D., Terushkin V., Pintucci G., Mignatti P.: “Transforming growth factor-beta 1 (TGF-beta1) induces angiogenesis through vascular endothelial growth factor (VEGF)-mediated apoptosis”. J. Cell. Physiol., 2009, 219, 449.

[86] Giudice L.C., Dsupin B.A., Jin I.H., Vu T.H., Hoffman A.R.: “Differential expression of messenger ribonucleic acid encoding insulinlike growth factors and their receptors in human uterine endometrium and decidua”. J. Clin. Endocrinol. Metab., 1993, 76, 1115.

[87] Rutanen E.M., Pekonen F., Nyman T., Wahlström T.: “Insulin-like growth factors and their binding proteins in benign and malignant uterine diseases”. Growth Regul., 1993, 3, 74.

[88] Rutanen E.M.: “Insulin-like growth factors in endometrial function”. Gynecol. Endocrinol., 1998, 12, 399.

[89] Rutanen E.M., Stenman S., Blum W., Kärkkäinen T., Lehtovirta P., Stenman U.H.: “Relationship between carbohydrate metabolism and serum insulin-like growth factor system in postmenopausal women: comparison of endometrial cancer patients with healthy controls”. J. Clin. Endocrinol. Metab., 1993, 77, 199.

[90] Ben-Nagi J., Miell J., Yazbek J., Holland T., Jurkovic D.: “The effect of hysteroscopic polypectomy on the concentrations of endometrial implantation factors in uterine flushings”. Reprod. Biomed. Online, 2009, 19, 737

[91] Kooijman R.: “Regulation of apoptosis by insulin-like growth factor (IGF)-I”. Cytokine Growth Factor Rev., 2006, 17, 305.

[92] Onalan R., Onalan G., Tonguc E., Ozdener T., Dogan M., Mollamahmutoglu L.: “Body mass index is an independent risk factor for the development of endometrial polyps in patients undergoing in vitro fertilization”. Fertil. Steril., 2009, 91, 1056.

[93] Belisario M.S., Vassallo J., Andrade L.A., Alvarenga M., Pinto G.A., Monteiro I.M.: “The expression of the hormone receptors in the endometrium and endometrial polyps in postmenopausal women and its relationship to body mass index”. Maturitas, 2006, 53, 114.

[94] Vilodre L.C., Bertat R., Petters R., Reis F.M.: “Cervical polyp as a risk factor for hysteroscopically diagnosed endometrial polyps”. Gynecol. Obstet. Invest., 1997, 44, 191.

[95] Nappi L., Indraccolo U., Di Spiezio Sardo A., Gentile G., Palombino K., Castaldi M.A. et al.: “Are diabetes, hypertension, and obesity independent risk factors for endometrial polyps?”. J. Minim. Invasive Gynecol., 2009, 16, 157.

[96] Sant’Ana de Almeida E.C., Nogueira A.A., Candido dos Reis F.J., Zambelli Ramalho L.N., Zucoloto S.: “Immunohistochemical expression of estrogen and progesterone receptors in endometrial polyps and adjacent endometrium in postmenopausal women”. Maturitas, 2004, 49, 229.

[97] de Carvalho S., Campaner A.B., Lima S.M., Silva M.A., Ribeiro P.A.: “Differential expression of estrogen and progesterone receptors in endometrial polyps and adjacent endometrium in postmenopausal women”. Anal. Quant. Cytol. Histol., 2011, 33, 61.

[98] Han Z., Kokkonen G.C., Roth G.S.: “Effect of aging on populations of estrogen receptor-containing cells in the rat uterus”. Exp. Cell. Res., 1989, 180, 234.

[99] McCormack S.A., Glasser S.R.: “Differential response of individual uterine cell types from immature rats treated with estradiol”. Endocrinology, 1980, 106, 1634.

[100] Punnonen R., Kouvonen I., Lövgren T., Rauramo L.: “Uterine and ovarian estrogen receptor levels in climacteric women”. Acta Obstet. Gynecol. Scand., 1979, 58, 389.

[101] Nephew K.P., Long X., Osborne E., Burke K.A., Ahluwalia A., Bigsby R.M.: “Effect of estradiol on estrogen receptor expression in rat uterine cell types”. Biol. Reprod., 2000, 62, 168.

[102] Kenemans P., Genazzani A.R., Palacios S., Schneider H.P.: “Pulsed estrogen exposure selectively modulates tissue response: a hypothesis”. Gynecol. Endocrinol., 2004, 18, 159.

[103] Loverro G., Perlino E., Maiorano E., Cormio G., Ricco R., Marra E. et al.: “TGF-beta 1 and IGF-1 expression in atrophic postmenopausal endometrium”. Maturitas, 1999, 31, 179.

[104] Giordano G., Gnetti L., Merisio C., Melpignano M.: “Postmenopausal status, hypertension and obesity as risk factors for malignant transformation in endometrial polyps”. Maturitas, 2007, 56, 190.

[105] Pinkerton J.V., Archer D.F., Utian W.H., Menegoci J.C., Levine A.B., Chines A.A., Constantine G.D. “Bazedoxifene effects on the reproductive tract in postmenopausal women at risk for osteoporosis”. Menopause, 2009, 16, 1102.

[106] Goldstein S.R.: “Update on raloxifene to prevent endometrialbreast cancer”. Eur. J. Cancer, 2000, 36 (suppl. 4), S54.

[107] Premkumar A., Venzon D.J., Avila N., Johnson D.V., Remaley A.T., Forman M.R. et al.: “Gynecologic and hormonal effects of raloxifene in premenopausal women”. Fertil. Steril., 2007, 88, 1637.

[108] Zhou W.B., Ding Q., Chen L., Liu X.A., Wang S.: “Toremifene is an effective and safe alternative to tamoxifen in adjuvant endocrine therapy for breast cancer: results of four randomized trials”. Breast Cancer Res. Treat., 2011, 128, 625.

[109] Senkus-Konefka E., Konefka T., Jassem J.: “The effects of tamoxifen on the female genital tract”. Cancer Treat. Rev., 2004, 30, 291.

[110] Pickar J.H., MacNeil T., Ohleth K.: “SERMs: progress and future perspectives”. Maturitas., 2010, 67, 129.

[111] Cano A., Hermenegildo C.: “The endometrial effects of SERMs”. Hum. Reprod. Update, 2000, 6, 244.

[112] Mourits M.J., Ten Hoor K.A., van der Zee A.G., Willemse P.H., de Vries E.G., Hollema H.: “The effects of tamoxifen on proliferation and steroid receptor expression in postmenopausal endometrium”. J. Clin. Pathol., 2002, 55, 514.

[113] Elkas J., Armstrong A., Pohl J., Cuttitta F., Martínez A., Gray K.: “Modulation of endometrial steroid receptors and growth regulatory genes by tamoxifen”. Obstet. Gynecol., 2000, 95, 697.

[114] Hachisuga T., Hideshima T., Kawarabayashi T., Eguchi F., Emoto M., Shirakusa T.: “Expression of steroid receptors, Ki-67, and epidermal growth factor receptor in tamoxifen-treated endometrium”. Int. J. Gynecol. Pathol., 1999, 18, 297.

[115] Wang H., Isaksson E., Von Schoultz B., Cline J.M., Sahlin L.: “The effect of long-term treatment with steroid hormones or tamoxifen on oestrogen receptors (alpha and beta) in the endometrium of ovariectomized cynomolgus macaques”. J. Endocrinol., 2002, 175, 673.

[116] Tregón M.L., Blümel J.E., Tarín J.J., Cano A.: “The early response of the postmenopausal endometrium to tamoxifen: expression of estrogen receptors, progesterone receptors, and Ki67 antigen”. Menopause, 2003, 10, 154.

[117] Karack U., Kommoss F.: “Does tamoxifen change oestrogen and progesterone receptor expression in the endometrium and breast?”. Eur. J. Cancer, 2000, 36 (suppl. 4), S45.

[118] Leslie K.K., Walter S.A., Torkko K., Stephens J.K., Thompson C., Singh M.: “Effect of tamoxifen on endometrial histology, hormone receptors, and cervical cytology: a prospective study with followup”. Appl. Immunohistochem. Mol. Morphol., 2007, 15, 284.

[119] Schwartz L.B., Krey L., Demopoulos R., Goldstein S.R., Nachtigall L.E., Mittal K.: “Alteration in steroid hormon receptors in the tamoxifen-treated endometrium”. Am. J. Obstet. Gynecol., 1997, 176, 129.

[120] Dibi R.P., Zettler C.G., Pessini S.A., de Almeida S.B., de Silveira G.P.: “Tamoxifen use and endometrial lesions: hysteroscopic, histological, and immunohistochemical finding in postmenopausal women with breast cancer”. Menopause, 2009, 16, 293.

[121] Negoi M., Mihailovici M.S.: “Expression of hormonal receptors (alpha-estrogen, beta-estrogen, progesteron), Ki-67 and P53 in endometrium of tamoxifen treated breast cancer patients”. Rev. Med. Chir. Soc. Med. Nat. Iasi., 2011, 115, 834.

[122] Zhao Y., Hague S., Manek S., Zhang L., Bicknell R., Rees M.C.: “PCR display identifies tamoxifen induction of the novel angiogenic factor adrenomedullin by a non estrogenic mechanism in the human endometrium”. Oncogene, 1998, 16, 409.

[123] Elkas J., Gray K., Howard L., Petit N., Pohl J., Armstrong A.: “The effects of tamoxifen on endometrial insulin-like growth factor-1 expression”. Obstet. Gynecol., 1998, 91, 45.

[124] Vesna A., Neli B.: “Benefit and safety of 28-day transdermal estrogen regimen during vaginal hysterectomy (a controlled trial)”. Maturitas, 2006, 53, 282.

[125] Iatrakis G., Zervoudis S., Antoniou E., Tsionis C., Pavlou A., Kourounis G., Siskos K.: “Is dosage of hormone replacement therapy related with endometrial polyp formation?”. Eur. J. Gynaecol. Oncol., 2006, 27, 393.

[126] Oguz S., Sargin A., Kelekci S., Aytan H., Tapisiz O.L., Mollamahmutoglu L.: “The role of hormone replacement therapy in endometrial polyp formation”. Maturitas, 2005, 50, 231.

[127] Piegsa K., Calder A., Davis J.A., McKay-Hart D., Wells M., Bryden F.: “Endometrial status in post-menopausal women on long-term continuous combined hormone replacement therapy (Kliofem). A comparative study of endometrial biopsy, outpatient hysteroscopy and transvaginal ultrasound”. Eur. J. Obstet. Gynecol. Reprod. Biol., 1997, 72, 175.

[128] Hanifi-Moghaddam P., Boers-Sijmons B., Klaassens A., van Wijk F.H., den Bakker M.A., Ott M.C. et al.: “Molecular analysis of human endometrium: short-term tibolone signaling differs significantly from estrogen and estrogen + progestagen signaling”. J. Mol. Med. (Berl.), 2007, 85, 471.

[129] Hanifi-Moghaddam P., Boers-Sijmons B., Klaassens A.H., Van Ijcken W.F., Van der Spek P., Verheul H.A. et al.: “Difference in signalling between various hormone therapies in endometrium, myometrium and upper part of the vagina”. Hum. Reprod., 2008, 23, 298.

[130] Maia Jr H., Maltez A., Studard E., Athayde C., Coutinho E.M.: “Effect of previous hormone replacement therapy on endometrial polyps during menopause”. Gynecol. Endocrinol., 2004, 18, 299.

[131] Maia Jr H., Maltez A., Calmon L.C., Oliveira M., Marques D., Coutinho D.: “Histopathology and steroid receptors in endometrial polyps of postmenopausal patients under hormone replacement therapy”. Gynecol. Endoscopy, 1998, 7, 267.

[132] Scholzen T., Gerdes J.: “The Ki-67 protein: from the known and the unknown”. J. Cell. Physiol., 2000, 182, 311.

[133] Lipponen P.: “Apoptosis in breast cancer: relationship with other pathological parameters”. Endocr. Relat. Cancer, 1999, 6, 13.

[134] Glinsky G.V.: “Genomic models of metastatic cancer: functional analysis of death-from-cancer signature genes reveals aneuploid, anoikis-resistant, metastasis-enabling phenotype with altered cell cycle control and activated Polycomb Group (PcG) protein chromatin silencing pathway”. Cell. Cycle, 2006, 5, 1208.

[135] Nabilsi N.H., Broaddus R.R., McCampbell A.S., Lu K.H., Lynch H.T., Chen L.M. et al.: “Sex hormone regulation of survivin gene expression”. J. Endocrinol., 2010, 207, 237.

[136] Miranda S.P., Traiman P., Cândido E., Lages E.L., Freitas G., Loamaita R.M. et al.: “Expression of p53, Ki-67, and CD31 proteins in endometrial polyps of postmenopausal women treated with tamoxifen”. Int. J. Gynaecol. Cancer, 2010, 20, 1525.

[137] Fletcher J.A., Pinkus J.L., Lage J.M., Morton C.C., Pinkus G.S.: “Clonal 6p21 rearrangement is restricted to the mesenchymal component of an endometrial polyp”. Genes Chromosomes Cancer, 1992, 5, 260.

[138] Vanni R., Marras S., Andria M., Faa G.: “Endometrial polyps with predominant stromal component are characterized by a t(6, 14)(p21, q24) translocation”. Cancer Res., 1995, 55, 31.