Молекулярні критерії діагностики гормонорезистентних форм гіперплазії ендометрія без атипії у жінок репродуктивного віку

Анотація

Introduction. Endometrial hyperplasia is a fairly widespread disease of the female reproductive sphere and occupies one of the leading places among the proliferative processes of the endometrium. In most cases, this pathology occurs in women of reproductive age and has a benign course. One of the main factors that unite all these factors is the excessive influence of estrogens, with the lost protection of progesterone on the endometrium. Aim. To investigate the molecular factors that can influence on the decrease in the sensitivity of endometrial tissue to the action of progesterone for the differential diagnosis of hormone-resistant forms of endometrial hyperplasia. Methods. The study was conducted in the department of obstetrics and gynecology on the basis of the perinatal center of the Dnipro Clinical Hospital in 2017-2019 in 25 women of reproductive age (25-46 years) with abnormal uterine bleeding in scrapings, in which endometrial hyperplasia without atypia was confirmed by morphological method. Samples of endometrial hyperplasia without atypia, fixed in formalin and embedded in paraffin, were taken from the archives of the " Dnipro Clinical Hospital 9". Microscopy was carried out using a ZEISS "Primo Star" light microscope with a Zeiss Primo Star - Axiocam ERC 5s camera and the use of licensed ZEN 2 blue edition software. Primary monoclonal antibodies against ER (sp1, RTU), PgR (YR85, 1:200), E-cadherin (EP700Y, RTU), b-catenin (E247, RTU) and the UltraVision Quanto imaging system (LabVision) were used for immunohistochemical examination. Results. A change in the PR-A:PR-B ratio that affects the sensitivity of endometrial hyperplasia to conventional hormone therapy in women of reproductive age was investigated. Micronized progesterone was used for treatment at a dose of 200 mg per day for 3 months. A control study of an endometrial biopsy after 3 months of therapy showed that 74% had a histological normalization of the ratio of the stromal and epithelial components, and 18.7% were diagnosed with simple atypical hyperplasia of the endometrium. 7.3% of women were diagnosed with complex atypical hyperplasia of the endometrium. Before treatment, there was low expression of PR-A in endometrial glands (P = 0.013) and stroma (P < 0.001) and high expression of PR-B in endometrial glands (P = 0.001) in endometrial biopsy. Thus, the study showed that in women with resistance to progesterone therapy in 86.4% of cases, E-cadherin expression was absent, and in 13.6% it was reduced. In progestin-positive women, E-cadherin expression was weak in 49.2% of cases, moderate in 34.4%, and negative in 16.4%, indicating a relationship between PgR and E-cadherin expression . Also, in women with endometrial hyperplasia without atypia with no effect from the use of progestins, the membrane-cytoplasmic expression of b-catenin reached 80% of cases, which can be interpreted as a fairly sensitive marker of the progression of non-atypical endometrial hyperplasia into an atypical form. Conclusion. The study showed that the use of progestins for the treatment of endometrial hyperplasia without atypia in women may be ineffective in cases where there is a low expression of progesterone receptors in the glandular epithelium, therefore their use is not appropriate and other therapy should be chosen depending on age and reproductive function. Given the small percentage of transformation of endometrial hyperplasia without atypia in women of reproductive age into atypical forms and endometrial cancer (~1%), it is best to focus the efforts of scientists and doctors on preventing relapses of the disease, which lead to the development of abnormal uterine bleeding, reduced fertility, and worsen the prognosis of disease progression.