Epigenetic profile of endometrial proliferation in the different morphotypes of endometrial hyperplasia





epigenetic profiles, endometrial hyperplasia without atypia, endometrial hyperplasia with atypia, estradiol receptor expression, progesterone receptor expression, cyclin D1, nuclear antigen Кі-67, E-cadherin, β-catenin


Research aim: to investigate the proliferative status of endometrium in the different morphotypes of endometrial hyperplasia based upon the identification of key molecular markers of the cell cycle.
Materials and methods. Endometrial samples taken from 137 women were investigated: 40 – normal endometrium (NE), 61 – non-atypical endometrial hyperplasia (ЕH), 36 – atypical hyperplasia (AHE). Expression of gene cyclin D1, nuclear antigen Кі-67, glycoproteins Е-cadherin and β-catenin, estradiol receptors (ER) and progesterone receptors (PGR) were investigated.
Results. ER expression of NE was high in the proliferative phase and decreased significantly in the secretory phase. PGR expression was high in both phases. ER expression of EH in glandular (180 ± 8.3) and in stromal cells (170.5 ± 4.1) exceed the indicators of the secretory phase. PGR expression in the stromal cells of EH (197.5 ± 9.3) exceed significantly indicators of NE. ER and PGR expression significantly and reliably decreased if there was AHE. ER expression of glandular cells was 2.6 times lower (74.6 ± 3.9) compere to proliferative NE (p <0.05) and 2.4 times lower to EH (р <0.05). ER of stromal AHE cells dropped to 30.3 ± 2.8, which was 5.5–5.6 times lower than in the proliferative NE and EH (p <0.002). PGR expression was 2.5–2.7 times lower (71.1 ± 2.3) in AHE glands than in NE and 2.8 times lower than in EH (p <0.05). Gene cyclin D1 expression was reliably increased in AHE cells compere to NE and EH. Protein Кі-67 expression in the glandular cells of EH was 2.6 times lower (p <0.05) and in AHE 2.9 times lower (p <0.05) than NE proliferative phase. We discovered strong direction to decreasing Е-cadherin expression in EH and it was lowest for AHE. Opposite direction was expression of β-catenin. The highest numbers of positive samples were observed in AHE and it was 100%. The highest numbers of negative β-catenin samples were in the NE cells (32,5–35%).
Conclusion. The epigenetic profile investigation of endometrial hyperplasia will be useful for future development of carcinogenesis risk stratification, identifying patients with high risk of endometrial cancer and also for choosing the optimal way to influence the pathological process in the endometrium.

Author Biographies

O.L. Gromova, O.O. Bogomolets National Medical University

PhD, assistant, Obstetrics and Gynecology Department of Postgraduate Education

V.O. Potapov, SI “Dnipropetrovsk Medical Academy of the MoH of Ukraine”

MD, professor, head of the Department of Obstetrics and Gynecology

D.A. Khaskhachykh, SI “Dnipropetrovsk Medical Academy of the MoH of Ukraine”

PhD, associate professor, Department of Obstetrics and Gynecology

O.P. Finkova, Dnipro City Clinical Hospital № 9

General director

O.V. Gaponova, SI “Dnipropetrovsk Medical Academy of the MoH of Ukraine”

Assistant, Department of Obstetrics and Gynecology

G.O. Kukina, SI “Dnipropetrovsk Medical Academy of the MoH of Ukraine”

Graduate student, Department of Obstetrics and Gynecology

K.V. Penner, Kharkiv City Clinical Maternity Hospital No. 7



Abu Hashim, H., Ghayaty, E., El Rakhawy, M. “Levonorgestrel-releasing intrauterine system vs oral progestins for non-atypical endometrial hyperplasia: a systematic review and metaanalysis of randomized trials.” American journal of obstetrics and gynecology 213.4 (2015): 469–78. DOI: 10.1016/j.ajog.2015.03.037

Ahmed, A.R.H., Muhammad, E.M.S. “E-cadherin and CD10 expression in atypical hyperplastic and malignant endometrial lesions.” J Egypt Natl Canc Inst 26 (2014): 211–7.

American College of Obstetricians and Gynecologists, Society of Gynecologic Oncology. “Practice Bulletin No. 149: Endometrial cancer.” Obstet Gynecol 125.4 (2015): 1006–26.

Antomonov, M.Y. Mathematic processing and analysis of medico-biological data. Kyiv. MIC “Medinform” (2018): 579 р.

Antypkin, Y.G., Vdovichenko, Y.P., Graziottin, A., Kaminskyi, V.V. “Uterine bleeding and women’s life quality.” Reproductive endocrinology 3.47 (2019): 8–12.

Augustin, G.T., et al. “Histopathological, Immunohistochemical and Therapeutical Assessment of Premalignant Endometrial Lesions in a Hospital Based Series of Cases.” Maedica 11.2 (2016): 115.

Carico, E., Atlante, M., Giarnieri, E., et al. “E-cadherin and alpha-catenin expression in normal, hyperplastic and neoplastic endometrium.“ Anticancer Res 30 (2010): 4993–8.

Chernukha, G.E., Dumanovskaya, M.R. “Modern concepts of endometrial hyperpalasia.” Obstet Gynecol 37 (2013): 26–32.

Crosbie, E., Morrison, J. “The emerging epidemic of endometrial cancer: Time to take action.” Cochrane Database Syst Rev 12 (2014): ED000095.

Doherty, M.T., Sanni, O.B., Coleman, H.G., et al. “Concurrent and future risk of endometrial cancer in women with endometrial hyperplasia: A systematic review and meta-analysis.” PloS One 15.4 (2020): e0232231. DOI: 10.1371/journal.pone.0232231

Gallos, I.D., Ganesan, R., Gupta, J.K. “Prediction of regression and relapse of endometrial hyperplasia with conservative therapy.” Obstet Gynecol 121.6 (2013): 1165–71. DOI: 10.1097/AOG.0b013e31828cb563

Gallos, I.D., Alazzam, M., Clark, T., et al. “RCOG/BSGE Green-top Guideline No. 67: Management of Endometrial Hyperplasia.” (2016). Available from: [https://www.rcog.org.uk/en/guidelines-research-services/guidelines/gtg67], last accessed Mar 2, 2021.

Gibson, D.A., Saunders, P.T.K. “Estrogen dependent signaling in reproductive tissues – a role for estrogen receptors and estrogen related receptors.” Mol Cell Endocrinol 348 (2012): 361–72.

Iversen, M.L, Dueholm, M. “Complex non atypical hyperplasia and the subsequent risk of carcinoma, atypia and hysterectomy during the following 9-14 years.” European journal of obstetrics, gynecology, and reproductive biology 222 (2018): 171–5. DOI: 10.1016/j.ejogrb.2018.01.026

Kurman, R., Carcangiu, M., Herrington, C. Jr. World Health Organisation Classification of Tumors of Female Reproductive Organs, 4th edn. Lyon Fr Int Agency Res Cancer Press (2014).

Levin, B., Cassimeris, L., Lingappa, V., Plotter, G., eds. Cells. Jones and Bartlett Publishers (2010): 950 p.

Liang, S., Mu, K., Wang, Y., et al. “CyclinD1, a prominent prognostic marker for endometrial diseases.” Diagn Pathol 8 (2013): 138.

Lortet-Tieulent, J., Ferlay, J., Bray, F., Jemal, A. “International Patterns and Trends in Endometrial Cancer Incidence, 1978–2013.” Journal of the National Cancer Institute 110.4 (2018): 354–61. DOI: 10.1093/jnci/djx214

van der Zee, M., Jia, Y., Wang, Y., et al. “Аterations in Wnt-β-catenin and Pten signalling play distinct roles in endometrial cancer initiation and progression.” The Journal of Pathology 230.1 (2013): 48–58.

Paltcev, М.А., Аylamazyan, E.К., Kvetnoy, I.M., et al. Molecular mechanismes of reproductive system diseases. Sankt-Petersburg. Eco-Vector (2017): 256 p.

Petrov, S.V., Raykhlin, N.T. Guideline of immunohistochemistry diagnostic of human tumors. Kazan (2012): 624 p.

Pieczyńska, B., Wojtylak, S., Żawrocki, A., Biernat, W. “Analysis of PTEN, estrogen receptor and progesterone receptor expression in endometrial hyperplasia using tissue microarray.” Polish Journal of Pathology 62.3 (2011): 133–8.

Rusakevich, P.S. Endometrial hyperplastic processes in gynecology. Minsk. Adukatsiya i vykhavannye (2012): 448 p.

Sanderson, P.A. “New concepts for an old problem: the diagnosis of endometrial hyperplasia.” Human reproduction update 23.2 (2017): 232–54.

Shawana, S., et al. “Immunoexpression of Cyclin D1 and PTEN in Various Endometrial Pathologies.” Journal of the College of Physicians and Surgeons-Pakistan: JCPSP 26.4 (2016): 277–82.

Shevra, C.R., Ghosh, A., Kumar, M. “Cyclin D1 and Ki-67 expression in normal, hyperplastic and neoplastic endometrium.” J Postgrad Med 61.1 (2015): 15–20.

Strizhakov, A.N., Davydov, A.I., Pashkov, V.M. Benign uterine diseases. Moscow. GEOTAR-Media (2011): 288 p.

Tangen, I.L., Werner, H.M.J., Berg, A., et al. “Loss of progesterone receptor links to high proliferation and increases from primary to metastatic endometrial cancer lesions.” Eur J Cancer 50 (2014): 3003–10.

Tatarchuk, T., Kovalenko, E., Filonenko, T. “Expression of steroid hormones receptors and estrogen and progesterone levels in the uterine fluids in women with endometrial hyperplasia.” Women’s Health 6.62 (2011): 105–9.

Tatarchuk, T., Yefimenko, O., Zanko, O., Schavinskaya, M. “Comparison of ultrasound investigation methods in postmenopause.” Georgian medical news 283.1 (2018): 19–26.

van der Putten, L.J.M., et al. “Molecular profiles of benign and (pre) malignant endometrial lesions.” Carcinogenesis 38.3 (2017): 329–35.

Zaporozhan, V.N., Tatarchuk, T.F., Dubinina, V.G., Kosei, N.V. “Modern diagnosis and treatment of hyperplastic process of endometrium.” Gynecological Endocrinology 1.3 (2012): 5–12.





Tumors and pretumoral pathology