Hormone resistance in non-atypical endometrial hyperplasia: role of PgR-A and PgR-B expression in predicting treatment response

Background. Endometrial hyperplasia (EH) without atypia remains a significant clinical challenge due to a high recurrence rate following hormone therapy, reaching up to 64.7%. One of the key causes of treatment failure is hormone resistance, which is associated with an altered receptor profile–particularly the expression of progesterone receptor isoforms PgR-A and PgR-B. Investigating the role of these receptors as biomarkers may significantly improve therapy outcome prediction and enable individualized treatment approaches. Purpose – to determine the prognostic significance of PgR-A and PgR-B expression in women with non-atypical EH in assessing the risk of recurrence after progestin therapy. Materials and Methods. The prospective study included 55 women of reproductive age (35–46 years) with histologically confirmed endometrial hyperplasia without atypia without atypia (40 – the first group (study), 15 – the second group (comparison group)). The observation period was 2 years. All patients were prescribed therapy with micronized progesterone 400 mg/day for 6 months. Immunohistochemical analysis was performed to determine the expression of PgR-A and PgR-B before and after treatment using the H-score scale in the glands and stroma. Statistical analysis included t-test, χ², significance criterion p < 0.05. Results. Before treatment, most patients with non-atypical endometrial hyperplasia demonstrated low PgR-A expression (in glands: 4.0 ± 0.41 to 5.1 ± 0.31; in stroma: 3.3 ± 0.61 to 3.6 ± 0.71) and high PgR-B expression, indicating a hormone-resistant phenotype. After six months of progestin therapy, patients who responded positively showed a statistically significant increase in PgR-A levels (in glands: up to 6.1–7.7; in stroma: 5.1–8.2) and normalization of the PgR-A:PgR-B ratio >1, which correlated with histological normalization of the endometrium. Among women with a PgR-A:PgR-B ratio ≤1 before treatment, the recurrence rate was 71 %, whereas in those with a PgR-A:PgR-B ratio >1, it was only 19% (p < 0,001). Absence or very low expression of PgR-A before treatment was considered a marker of progestin resistance, whereas increased PgR-A expression after therapy was regarded as a predictor of treatment efficacy. Conclusions. Low PgR-A expression and an imbalance in the PgR-A:PgR-B ratio before the start of progestin therapy are prognostic markers of hormonal resistance and an increased risk of recurrence of endometrial hyperplasia. Determination of PgR-A and PgR-B levels in endometrial biopsies before the start of treatment allows predicting the response to therapy, as well as optimizing the patientʼs management by individually selecting the type, duration, and dose of hormonal treatment. This approach helps to reduce the frequency of recurrences and increase the effectiveness of therapy in women with endometrial hyperplasia without atypia. Practical Significance. Immunohistochemical evaluation of PgR-A and PgR-B prior to initiating therapy may serve as a tool of personalized medicine to improve the effectiveness of treatment for non-atypical EH in reproductive-aged women.