Progestogen-resistant forms of endometrial hyperplasia without atypia. Molecular diagnostic criteria and pathogenetic therapy strategy

Authors

DOI:

https://doi.org/10.18370/2309-4117.2025.77.40-46

Keywords:

progestogen-resistant forms of endometrial hyperplasia without atypia, diagnostics, estrogen receptors, progesterone receptors, markers of cell proliferation and differentiation Cdk-D1, Ki-67, glycoprotein E-cadherin, pathogenetic therapy, gonadotropin-releasing hormone analogues

Abstract

Background. Justification. The article discusses the issues of diagnosis and treatment of progestogen-resistant forms of endometrial hyperplasia without atypia, which are relevant today due to numerous negative consequences for women, namely abnormal uterine bleeding, infertility, and the risk of malignancy.

Objective of the study: Аssessment of the degree of pathological molecular changes in endometrial cells, which may act as predictors for determining an individual treatment strategy for endometrial hyperplasia without atypia in women

Materials and methods. 311 women with a histological diagnosis of endometrial hyperplasia without atypia were treated with various forms of progestogens for 6 months in a continuous mode.

Results. The absence of regression of endometrial hyperplasia without atypia or its recurrence over the next 3 years was diagnosed in 23 (23.9%) of 96 women after therapy with micronized progesterone at a dose of 200 mg/day, in 30 (18.6%) of 161 women who received 20 mg of dydrogesterone daily and in 9 (16.7%) of 54 women who received an intrauterine system with levonorgestrel as therapy. To clarify the reason for this circumstance, the expression of estrogen receptors and progesterone receptors (PGR), kinase-dependent cyclin Cdk-D1, Ki-67 protein, and glycoprotein E-cadherin was studied by immunohistochemical methods in primary and control morphological samples of the endometrium after treatment. 63 endometrial samples with negative and 48 samples with positive results of progestogen therapy were studied. It was found that in 73.02% of women with negative results of progestogen therapy, the expression of PGR was absent in the studied endometrial samples (H-index PGR < 50), in the remaining 26.98% of samples their low expression was found, both in the glands and in the stroma (H-index 53.6 ± 0.8 and 42.5 ± 0.6, respectively). On the contrary, in endometrial samples of women with regression of endometrial hyperplasia without atypia against the background of treatment with progestogens, the expression of PGR was positive in 97.92% of cases, and the average values of the PGR H-index, which were 194.1 ± 4.1 and 168.2 ± 2.1 in glandular and stroma cells, respectively, were significantly higher than in the previous sample (p < 0.05).

Therefore, adequate receptivity is a necessary condition for the implementation of the genomic-mediated mechanism of the influence of progestogens on the activity of genes that control proliferation and contribute to its inhibition. The authors believe that the lack of regression of endometrial hyperplasia under the influence of progestogens is probably associated with the features of the expression of PGR in progestogen-resistant patients. After the appointment of the gonadotropin-releasing hormone analogue goserelin acetate (Zoladex®, AstraZeneca) to such women for the next six months, regression of endometrial hyperplasia occurred in 93.8% of cases. At the molecular level, a 7.3-fold decrease in the number of glandular cells expressing cyclin Cdk-D1 and a 64.2% decrease in the expression of the Ki-67 protein was noted.

Conclusions. The study showed that there are objective grounds for the use of gonadotropin-releasing hormone analogues in women with endometrial hyperplasia without atypia, in whom progestogen therapy was insufficiently effective, as well as as a first-line therapy in women with low expression of PGR in glandular cells at the stage of primary histological screening.

Author Biographies

V.A. Potapov, Dnipro State Medical University, Dnipro

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

D.A. Khaskhachykh, Dnipro State Medical University, Dnipro

MD, associate professor, Department of Obstetrics and Gynecology

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

MD, associate professor of the Department of Obstetrics and Gynecology and Neonatal Postgraduate Education

O.V. Poslavska, Dnipro State Medical University, Dnipro

MD, professor, head of the Department of Pathological Anatomy, Forensic Medicine and Pathological Physiology

G.O. Kukina, Dnipro State Medical University, Dnipro

postgraduate student, Department of Obstetrics and Gynecology

I.S. Garagulya, Dnipro State Medical University, Dnipro

PhD, associate professor, Department of Obstetrics and Gynecology

References

  1. Endometrial hyperplasia. Evidence-based clinical guideline. [Internet]. State Expert Center of the Ministry of Health of Ukraine, 2021. Available from: https://www.dec. gov.ua/wp-content/uploads/2021/05/2021_869_ kn_gipendom_dor.pdf
  2. Auclair MH, Yong PJ, Salvador S, et al. Guideline No. 392. Classification and Management of Endometrial Hyperplasia. J Obstet Gynaecol Can. 2019;41(12):1789–800. DOI: 10.1016/j.jogc.2019.03.025
  3. Russo M, Newell JM, Budurlean L, et al. Mutational profile of endometrial hyperplasia and risk of progression to endometrioid adenocarcinoma. Cancer. 2020 Jun 15;126(12):2775–83. DOI: 10.1002/cncr.32822.
  4. Tian Y, Liu Y, Wang G, et al. Endometrial hyperplasia in infertile women undergoing IVF/ICSI: A retrospective cross-sectional study. J Gynecol Obstet Hum Reprod. 2020 Apr 29:101780. DOI: 10.1016/j.jogoh.2020.101780.
  5. Kuzyk YuI, Chornenka GM. Hyperplastic processes of the endometrium in women with infertility: comparison of the results of ultrasonographic and pathomorphological studies of the endometrium. Zdorove zhenschy 2018;7 (133):129–33.
  6. Travaglino A, Raffone A, Saccone G, et al. Significant risk of occult cancer in complex non-atypical endoemtrial hyperplasia. Arch Gynecol Obstet. 2019; 300:1147–54.
  7. Sattanakho P, Kleebkaow P, Sangkomkumhang U, et al. Rate of significant endometrial pathology in women at low risk for endometrial hyperplasia or cancer presenting with abnormal uterine bleeding. Pragmat. Obs. Res. 2020; 11:13–8. DOI: 110.2147/POR.S240930.
  8. Giannella L, Cerami LB, Setti T, et al. Prediction of endometrial hyperplasia and cancer among premenopausal women with abnormal uterine bleeding. Biomed. Res. Int. 2019; 2019: 8598152. DOI: 10.1155/2019/8598152.
  9. Zaporozhan VM, Fetescu SA. Immuno-morphological features of the development of endometrial hyperplastic processes. Reproductive Endocrinology. 2015; 1:15–8. DOI: 10.18370/2309-4117.2015.21.15-18
  10. Tatarchuk TF, Kalugina LV, Tutchenko TN. Hyperplastic processes of the endometrium: what is new? Reproductive endocrinology. 2015;5 (25):7–13. DOI: 10.18370/2309-4117.2015.25.7-13
  11. Vesich TL, Tucheina IO, Guz IA, Blagoveshchensky RE. Biomolecular markers in the pathogenesis of endometrial hyperplastic processes. International Medical Journal. 2019; (1):52–7.
  12. Yang X, Wang J. The Role of Metabolic Syndrome in Endometrial Cancer: A Review. Frontiers in oncology 2019;9:744. DOI: 10.3389/ fonc.2019.00744.
  13. Hutt S, Tailor A, Ellis P, et al. The role ofbiomarkers in endometrial cancer and hyperplasia: a literature review. Acta Oncol. 2019 Mar;58(3):342–52. DOI: 10.1080/0284186X.2018.1540886.
  14. Shapoval Yu.S. State of cellular and humoral systemic immunity in women of reproductive age under the development of proliferative processesin the endometry of the uterus and breast glands. Scientific Journal «ScienceRise: Medical Science». 2022;3(48):21–6. DOI: 10.15587/2519-4798.2022.257621
  15. Stoenescu VE, Niculescu M, Novac L, et al. Immunohistochemical reaction of the glandular epithelium in endometrial hyperplasia compared to endometrial carcinoma. Rom J Morphol Embryol. 2017;58(3):791-800.
  16. Travaglino A, Raffone A, Saccone G, et al. Immunohistochemical predictive markers of response to conservative treatment of endometrial hyperplasia and early endometrial cancer: a systematic review. Acta Obstet. Gynecol. Scand. 2019 Sep;98(9):1086–99. DOI: 10.1111/aogs.13587
  17. Uysal G, Acmaz G, Madendag Y, et al. The efficacy of dienogest in the treatment of simple endometrial hyperplasia without atypia. Gynecol. Obstet. Invest. 2018; 83(2):151–5. DOI: 10.1159/000477618
  18. Nosenko O M, Yurchenko S V. Retrospective analysis of the effectiveness of treatment of atypical endometrial hyperplasia in infertile women. Bulletin of Marine Medicine. 2019;2(83):36–42. DOI: 10.5281/zenodo.3267326
  19. Patel MV, Rodriguez-Garcia M, Shen Z, Wira CR. Medroxyprogesterone acetate inhibits wound closure of human endometrial epithelial cells and stromal fibroblasts in vitro. Sci Rep. 2021;11(1):23246. DOI: 10.1038/s41598-021-02681-6.
  20. Nooh AM, Abdeldayem HM, Girbash EF, et al. Depo-Provera versus norethisterone acetate in management of endometrial hyperplasia without atypia. Reprod. Sci. 2016 Apr;23(4):448–54.
  21. Mittermeier T, Farrant C, Wise MR. Levonorgestrel-releasing intrauterine system for endometrial hyperplasia. Cochrane Database Syst Rev. 2020 Sep 6;9:CD012658. DOI: 10.1002/14651858.CD012658.
  22. Abu Hashim H, Ghayaty E, El Rakhawy M. Levonorgestrel-releasing intrauterine system vs oral progestins for non-atypical endometrial hyperplasia: a systematic review and meta-analysis of randomized trials. Am J Obstet Gynecol 2015; 213:469–78. DOI: 10.1016/j.ajog.2015.03.037
  23. El Behery MM, Saleh HS, Ibrahiem MA, et al. Levonorgestrel-releasing intrauterine device versus dydrogesterone for management of endometrial hyperplasia without atypia. Reprod Sci. 2015 Mar; 22(3):329–34. DOI: 10.1177/1933719114542014.
  24. Kornienko S.M. Risk factors for recurrence of endometrial hyperplastic processes in women of late reproductive and premenopausal age. Reproductive Endocrinology. 2017;2 (34):28-31. DOI: 10.18370/2309-4117.2017.34.28-31.]
  25. Kornienko SM. Hyperplastic processes of the endometrium in women in the late reproductive and premenopausal period: what affects relapses. Bulletin of social hygiene and health care organizations of Ukraine. 2017; 2(72):39–47. DOI: 10.11603/1681-2786.2017.2.8106
  26. Li X, Feng Y, Lin JF, et al. Endometrial progesterone resistance and PCOS. J Biomed Sci. 2014;21(1):2. DOI:10.1186/1423-0127-21-2
  27. Iversen ML, Dueholm M. Complex non atypical hyperplasia and the subsequent risk of carcinoma, atypia and hysterectomy during the following 9–14 years. Eur J Obstet Gynecol Reprod Biol. 2018; 222:171–175. DOI: 10.1016/j.ejogrb.2018.01.026
  28. Sletten ET, Arnes M, Lysa LM, et al. Significance ofprogesterone receptors (PR-A and PR-B) expression as predictors for relapse after successful therapy of endometrial hyperplasia: a retrospective cohort study. BJOG. 2019 Jun;126(7):936-943. DOI: 10.1111/1471-0528.15579
  29. Sletten ET, Smaglyukova N, Ørbo A, Sager G. Expression of nuclear progesterone receptors (nPRs), membrane progesterone receptors (mPRs) and progesterone receptor membrane components (PGRMCs) in the human endometrium after 6 months levonorgestrel low dose intrauterine therapy. J. Steroid Biochem. Mol. Biol. 2020; 202: 105701. DOI: 10.1016/j.jsbmb.2020.105701.
  30. Grimm SL, Hartig SM, Edwards DP. Progesterone receptor signaling mechanisms. J Mol Biol. 2016 Sep 25;428(19):3831–49. DOI: 10.1016/j.jmb.2016.06.020.
  31. Unified clinical protocol for primary, secondary (specialized), tertiary (highly specialized) medical care “Endometrial hyperplasia”. Order of the Ministry of Health of Ukraine No. 869 dated 05.05.2021. [Internet]. State Expert Center of Ukraine. 2021. Available from: https://www.dec.gov.ua/wp-content/uploads/2021/05/2021_869_ykpmd_ gipendom_dor.pdf
  32. Bahriy MM, Dibrova VA, Popadynets OG, Hryshchuk MI. Methods of morphological research. Vinnytsia: Novaya Knyga, 2016. 328 p.
  33. Antomonov MY. Mathematical processing and analysis of medical and biological data. Kyiv: Medical Center «Medinform», 2018. 579 p.
  34. Sletten ET, Arnes M, Lyså LM, Larsen M, Ørbo A. Significance of progesterone receptors (PR-A and PR-B) expression as predictors for relapse after successful therapy of endometrial hyperplasia: a retrospective cohort study. BJOG. 2019;126(7):936–43. DOI:10.1111/1471-0528.15579
  35. Tumansky VA, Chepets AV. Immunohistochemical characteristics of the expression of cell adhesion molecules E-cadherin and ОІ-catenin in invasive endometrioid adenocarcinoma of the uterus. Pathology 2015. 2 (34):75–80.
  36. Shevra CR, Ghosh A, Kumar M. Cyclin D1 and Ki-67 expression in normal, hyperplastic and neoplastic endometrium. J Postgrad Med 2015;61(1):15–20.
  37. Masjeed NMA, Khandeparkar SGS, Joshi AR, et al. Immunohistochemical Study of ER, PR, Ki67 and p53 in endometrial hyperplasias and endometrial carcinomas. Journal of Clinical and Diagnostic Research. 2017;11(8):31–4. DOI: 10.7860/JCDR/2017/28750.10475
  38. Arjunan A, Nilavu J, Thiriveni-Balajji GS, Praba V. Expression of Bcl-2 and Ki-67 in cyclical endometrium and in endometrial hyperplasia – an analysis. Journal of Dental and Medical Sciences. 2016;15(4):43-49. DOI: 10.1007/s12663-015-0766-5.
  39. Sangwan К, Garg М, Pathak N, Bhart L. Expression of Cyclin D1 in Hyperplasia and Carcinoma of Endometrium and Its Correlation with Histologic Grade, Tumor Type, and Clinicopathological Feat. Journal of Laboratory Physicians. 2020;12(3):165–70. DOI: 10.1055/s-0040-1721150
  40. Shawana S, Kehar SI, Masood S, Aamir I. Immunoexpression of cyclin D1 and PTEN in various endometrial pathologies. J Coll Physicians Surg Pak 2016;26(4):277–82
  41. Zhou H, Cao D, Yang J, et al. Gonadotropin-releasing hormone agonist combined with a levonorgestrel-releasing intrauterine system or letrozole for fertility-preserving treatment of endometrial carcinoma and complex atypical hyperplasia in young women. Int J Gynecol Cancer. 2017 Jul;27(6):1178-1182. DOI: 10.1097/IGC
  42. Chandra V, Kim J, Benbrook D, et al. Therapeutic options for management of endometrial hyperplasia. J Gynecol Oncol. 2016 Jan;27(1):e8 DOI: 10.3802/jgo.2016.27.e8

Downloads

Published

2025-05-30

How to Cite

Potapov, V., Khaskhachykh, D., Gromova, A., Poslavska, O., Kukina, G., & Garagulya, I. (2025). Progestogen-resistant forms of endometrial hyperplasia without atypia. Molecular diagnostic criteria and pathogenetic therapy strategy. REPRODUCTIVE ENDOCRINOLOGY, (77), 40–46. https://doi.org/10.18370/2309-4117.2025.77.40-46

Issue

No. 77 (2025)

Section

Gynecology

License

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Authors who publish with this journal agree to the following terms:

    1. Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.

    1. Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.