Analysis of the causes of unsuccessful hormonal treatment of non-atypical endometrial hyperplasia in premenopousal women

  • O. Gromova
  • V. Potapov
  • D. Hasachih
  • O. Haponova
  • G. Kukina
Keywords: non-atypical endometrial hyperplasia, progestins, unsuccessful treatment, progesterone receptors, Е-cadherin.


Annotation. Non-atypical endometrial hyperplasia (NEH), despite of benign morphology, may be insensitive to the hormonal treatment and has a tendency to recurrence and progression to atypia in some cases. The study purpose was the investigation of different type of progestins treatment results and comparison of progesterone receptors (PGR) and Е-cadherin expression in the sensitive NEH(+) and resistant NEH(–) to progestin treatment type of NEH. Prospective study of three groups of women with histologically confirmed NEH, who took different progestins during 6 months was done: І group – 96 women, who took micronized progesterone orally 200 mg per day continually, ІІ group – 161 women, who took dydrogesterone 20 mg per day continually, ІІІ group – 54 women, who were inserted LNG-IUD 52 mg. Control histopathological investigations of the endometrial samplings at 3 and 6 months were done. Expression of PGR and Е-cadherin by immunohistochemistry were investigated in the start samples of endometrium for all 63 NEH(–) women, 48 NEH(+) women and 20 control samples of normal proliferative and secretory endometrium. In the result of the study only nonsignificant and unreliable differences between different progestins efficacy were found. It was 75% normal endometrium samples till 6 months for micronized progesterone, 81.4% for dydrogesterone and 83.3% for LNG-IUD. Data analysis of PGR expression in the NEH(–) endometrium has shown significantly less week expression as for glandular cells (50.82±0.73), as for stromal cells (47.34±0.82) in comparison to the NEH(+) endometrial samples (glandular – 183.7±3.1; stroma 166.4±2.3; р<0.05) and normal proliferative (193.2±8.5 і 178.7±6.3 respectively; р<0.05) and secretory (140.2±4,4 і 116.6±3,1 respectively; р<0.05) endometrium. Е-cadherin expression in the glandular endometrial cells NEH(–) mostly was negative (86.4%) and 13.6% cells only demonstrated its week expression. NEH(+) women cells predominantly showed a positive reaction. It was often enough week (49.2%) and moderate (34.4%), but only in the 16.4% samples were negative. Thus, the use of progestogens for the treatment of NEH in women with low expression of PGR and negative expression of E-cadherin in the endometrium is inappropriate. Investigations of PGR та Е-cadherin expression in the endometrium of women with NEH before starting treatment may provide an opportunity to predict negative result in advance and chose alternative therapeutical approach.


1. Antamonov, M. Y. (2018). Matematicheskaya obrabotka i analiz mediko-biologicheskikh dannykh [Mathematic processing and analysis of medico-biological data]. Kiev: Medinform.

2. Tatarchuk, T., Kovalenko, E., & Filonenko, T. (2011). Ekspressiya retseptorov k steroidnym gormonam i uroven' estrogena i progesterona v matochnykh smyvakh zhenshchin s giperplaziyami endometriya [Expression of steroid hormones receptors and estrogen and progesterone levels in the uterine fluids in women with endometrial hyperplasia]. Zdorovye Zenshiny – Woman health, 62 (6), 105–109. ISSN: 1992-5921 (Print).

3. Palcev, М. А., Malcev, М. А., Аylamazyan, E. К., Kvetnoy, I. M. & Polyakova, V. O. (2017). Molekulyarnyye mekhanizmy zabolevaniy reproduktivnoy sistemy [Molecular mechanismes of reproductive system diseases]. SPb.: Eco-Vector.

4. Petrov, S. V., & Rayhlin, N. T. (2012). Rukovodstvo po immunogistokhimicheskoĭ diagnostike opukholey cheloveka [Guideline of immunohistochemistry diagnostic of humans tumors]. Kazan: Titul. ISBN: 978-5-85247-559-6

5. Abu Hashim, H., Ghayaty, E., & El Rakhawy, M. (2015). 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), 469–478.

6. Abu Hashim, H., Zayed, A., Ghayaty, E., & El Rakhawy, M. (2013). LNG-IUS treatment of non-atypical endometrial hyperplasia in perimenopausal women: a randomized controlled trial. Journal of Gynecologic Oncology, 24 (2), 128–134.

7. American College of Obstetricians and Gynecologists, Society of Gynecologic Oncology. (2015). Practice Bulletin No. 149: Endometrial cancer. Obstetrics & Gynecology, 125 (4), 1006–1026.

8. Avci, M. E., Sadik, S., & Uçar, M. G. (2012). A prospective study of rollerball endometrial ablation in the management of refractory recurrent symptomatic endometrial hyperplasia without atypia. Gynecologic and Obstetric Investigation, 74(4), 282–287.

9. Baker, J., Obermair, A., Gebski, V., & Janda, M. (2012). Efficacy of oral or intrauterine device-delivered progestin in patients with complex endometrial hyperplasia with atypia or early endometrial adenocarcinoma: a meta-analysis and systematic review of the literature. Gynecologic oncology, 125 (1), 263–270.

10. Behnamfar, F., Ghahiri, A., & Tavakoli, M. (2014). Levonorgestrel-releasing intrauterine system (Mirena) in compare to medroxyprogesterone acetate as a therapy for endometrial hyperplasia. Journal of Research in Medical sciences: the Official Journal of Isfahan University of Medical Sciences, 19 (8), 686–690.

11. Bian, J., Shao, H., Liu, H., Li, H., Fang, L., Xing, C., … & Tao, M. (2015). Efficacy of the Levonorgestrel-Releasing Intrauterine System on IVF-ET Outcomes in PCOS With Simple Endometrial Hyperplasia. Reproductive Sciences (Thousand Oaks, Calif.), 22 (6), 758–766. doi: 10.1177/1933719114561553

12. Cells. (2006). Ed.: Levin, B., Cassimeris, L., Lingappa, V., & Plotter, G. Jones and Bartlett Publishers. ISBN-10: 0763739057

13. Doherty, M. T., Sanni, O. B., Coleman, H. G., Cardwell, C. R., McCluggage, W. G., Quinn, D., ... & McMenamin, Ú. C. (2020). Concurrent and future risk of endometrial cancer in women with endometrial hyperplasia: A systematic review and meta-analysis. PloS One, 15 (4), e0232231.

14. Dolanbay, M., Kutuk, M. S., Uludag, S., Bulut, A. N., Ozgun, M. T., Ozcelik, B., & Serin, I. S. (2015). Concurrent endometrial carcinoma in hysterectomy specimens in patients with histopathological diagnosis of endometrial hyperplasia in curettage specimens. Ginekologia Polska, 86 (10), 753–758.

15. Dolapcioglu, K., Boz, A., & Baloglu, A. (2013). The efficacy of intrauterine versus oral progestin for the treatment of endometrial hyperplasia. A prospective randomized comparative study. Clinical and Experimental Obstetrics & Gynecology, 40 (1), 122–126. PMID: 23724525

16. Gallos, I. D., Ganesan, R., & Gupta, J. K. (2013). Prediction of regression and relapse of endometrial hyperplasia with conservative therapy. Obstetrics and Gynecology, 121 (6), 1165–1171.

17. Gallos, I. D., Krishan, P., Shehmar, M., Ganesan, R., & Gupta, J. K. (2013). LNG-IUS versus oral progestogen treatment for endometrial hyperplasia: a long-term comparative cohort study. Human reproduction (Oxford, England), 28 (11), 2966–2971.

18. Gallos, I. D., Alazzam, M., Clark, T., Faraj, R., Rosenthal, A., & Smith, P. G. J. (2016). RCOG/BSGE Green-top Guideline No. 67: Management of Endometrial Hyperplasia. Royal College of Obstetricians & Gynaecologists. Retrieved from

19. Ismail, M. T., Fahmy, D. M., & Elshmaa, N. S. (2013). Efficacy of levonorgestrel-releasing intrauterine system versus oral progestins in treatment of simple endometrial hyperplasia without atypia. Reproductive Sciences (Thousand Oaks, Calif.), 20 (1), 45–50.

20. Iversen, M. L., & Dueholm, M. (2018). 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, 171–175.

21. Koskas, M., Uzan, J., Luton, D., Rouzier, R., & Daraï, E. (2014). Prognostic factors of oncologic and reproductive outcomes in fertility-sparing management of endometrial atypical hyperplasia and adenocarcinoma: systematic review and meta-analysis. Fertility and Sterility, 101(3), 785–794.

22. Lacey, J. V., Jr, Sherman, M. E., Rush, B. B., Ronnett, B. M., Ioffe, O. B., Duggan, M. A. … & Langholz, B. (2010). Absolute risk of endometrial carcinoma during 20-year follow-up among women with endometrial hyperplasia. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 28 (5), 788–792.

23. Lai, H. C., Wang, Y. C., Yu, M. H., Huang, R. L., Yuan, C. C., Chen, K. J. … & Chao, T. K. (2014). DNA methylation as a biomarker for the detection of hidden carcinoma in endometrial atypical hyperplasia. Gynecologic Oncology, 135 (3), 552–559.

24. Lortet-Tieulent, J., Ferlay, J., Bray, F., & Jemal, A. (2018). International Patterns and Trends in Endometrial Cancer Incidence, 1978-2013. Journal of the National Cancer Institute, 110 (4), 354–361.

25. Mentrikoski, M. J., Shah, A. A., Hanley, K. Z., & Atkins, K. A. (2012). Assessing endometrial hyperplasia and carcinoma treated with progestin therapy. American Journal of Clinical Pathology, 138 (4), 524–534.

26. Ørbo, A., Vereide, A. B., Arnes, M., Pettersen, I., & Straume, B. (2014). Levonorgestrel-impregnated intrauterine device as treatment for endometrial hyperplasia: a national multicentre randomised trial. British Journal of Obstetrics and Gynecology, 121, 477–486. doi: 10.1111/1471-0528.12499

27. Ordi, J., Bergeron, C., Hardisson, D., & McCluggage, W. G. (2014). Reproducibility of current classifications of endometrial endometrioid glandular proliferations: further evidence supporting a simplified classification. Histopathology, 64 (2), 284–292.

28. Ozdegirmenci, O., Kayikcioglu, F., Bozkurt, U., Akgul, M. A., & Haberal, A. (2011). Comparison of the efficacy of three progestins in the treatment of simple endometrial hyperplasia without atypia. Gynecologic and Obstetric Investigation, 72 (1), 10–14.

29. Penner, K. R., Dorigo, O., Aoyama, C., Ostrzega, N., Balzer, B. L., Rao, J., Walsh, C. S., Cass, I., & Holschneider, C. H. (2012). Predictors of resolution of complex atypical hyperplasia or grade 1 endometrial adenocarcinoma in premenopausal women treated with progestin therapy. Gynecologic Oncology, 124 (3), 542–548.

30. Pieczyńska, B., Wojtylak, S., Żawrocki, A., & Biernat, W. (2011). Analysis of PTEN, estrogen receptor and progesterone receptor expression in endometrial hyperplasia using tissue microarray. Polish Journal of Pathology, 62 (3), 133–138. PMID: 22102068

31. Sanderson, P. A., Critchley, H. O., Williams, A. R., Arends, M. J., & Saunders, P. T. (2017). New concepts for an old problem: the diagnosis of endometrial hyperplasia. Human Reproduction Update, 23 (2), 232–254.

32. Travaglino, A., Raffone, A., Saccone, G., D’Alessandro, P., Arduino, B., de Placido, G., … & Zullo, F. (2019). Significant risk of occult cancer in complex non-atypical endometrial hyperplasia. Archives of Gynecology and Obstetrics, 300 (5), 1147–1154.

33. Trimble, C. L., Method, M., Leitao, M., Lu, K., Ioffe, O., Hampton, M., … & Mutter, G. L. (2012). Management of endometrial precancers. Obstetrics and Gynecology, 120 (5), 1160–1175.

34. WHO Classification of Tumours of Female Reproductive Organs. 4th ed.: Kurman, R. J., Carcangiu, M. L., Herrington, C. S., & Young, R. H. (2014). Lyon: Fr. Int. Agency Res. Cancer Press.
How to Cite
Gromova, O., Potapov, V., Hasachih, D., Haponova, O., & Kukina, G. (2020). Analysis of the causes of unsuccessful hormonal treatment of non-atypical endometrial hyperplasia in premenopousal women. Reports of Vinnytsia National Medical University, 24(4), 604-610.