Clinical, metabolic and pro­inflammatory mechanisms of progesterone resistance formation in recurrent endometrial hyperplasia in women of late reproductive age

Abstract

DOI: 10.52705/2788-6190-2026-02-2
УДК 618.14-007.61-06:616.379-008.64:616-092-08

Recurrent hyperplastic changes of the endometrium in women of late reproductive age are increasingly associated with metabolic and inflammatory disturbances that may influence the response to hormonal therapy. In clinical practice, a considerable proportion of patients demonstrate incomplete regression of endometrial proliferation or repeated recurrence after conservative progestin treatment. Recent evidence suggests that obesity, insulin resistance, chronic low-grade inflammation, and altered progesterone receptor sensitivity may contribute to persistence of proliferative endometrial changes. Long-term metabolic imbalance accompanied by elevated inflammatory cytokines creates conditions that may reduce the effectiveness of progestin therapy and
support recurrent disease progression [8–12].
The objective: to evaluate the role of insulin resistance and systemic inflammation in the development of resistance to progestin therapy in women with recurrent endometrial hyperplasia and to identify clinical and metabolic predictors of treatment failure.
Materials and methods. A prospective cohort clinical and laboratory study was conducted involving 120 women aged 36–45 years. The main group consisted of 60 patients with recurrent non-atypical endometrial hyperplasia. Depending on treatment outcomes, patients were divided into responders (n = 34) and non-responders (n = 26). The comparison group included 30 women with primary endometrial hyperplasia, while the control group consisted of 30 apparently healthy women. The examination included clinical, ultrasound, histological, and laboratory assessment. Body mass index, waist circumference, carbohydrate and lipid metabolism parameters, HOMA-IR, insulin, IL-6, TNF-α, CRP, estradiol, and progesterone levels were determined.
Results. Patients with progesterone resistance demonstrated significantly higher levels of HOMA-IR, insulin, IL-6, TNF-α, and CRP compared with responders and the control group. The most pronounced changes were observed in women with obesity and abdominal fat distribution. A direct correlation was identified between HOMA-IR and endometrial thickness (r = 0.48; p < 0.001), as well as between IL-6 levels and recurrence frequency (r = 0.44; p < 0.01). Independent predictors of ineffective therapy included HOMA-IR > 3.5, IL-6 > 7 pg/mL, obesity, and decreased progesterone levels.
Conclusions. Insulin resistance and chronic systemic inflammation are important components of the pathogenesis of progesterone resistance in recurrent endometrial hyperplasia. Integration of metabolic and pro-inflammatory markers into clinical algorithms makes it possible to personalize treatment and predict the risk of recurrence.