Resistance Mechanisms to Hormonal Therapy in Endometrial Cancer: AComprehensive Review

Abstract

Background: Endometrial cancer (EC) is the most common gynaecological malignancy in developed countries, with its incidence rising globally in parallel with obesity and metabolic syndrome. Hormonal therapy, principally progestins and selective oestrogen receptor modulators, represents an essential, fertility-sparing treatment strategy in early-stage, low-grade disease and an alternative systemic option in advanced or recurrent settings. However, a substantial proportion of patients exhibit primary or acquired resistance to hormonal agents, resulting in treatment failure and disease progression.

Objectives: This review systematically evaluates the molecular and cellular mechanisms underpinning resistance to hormonal therapy in endometrial cancer, with particular emphasis on receptor-level alterations, intracellular signalling dysregulation, epigenetic modifications, the tumour microenvironment, and emerging biomarkers of resistance.

Methods: A comprehensive search of PubMed, Scopus, and Web of Science databases was conducted for original research articles, systematic reviews, and clinical trials published from 2015 to 2025. Search terms included 'endometrial cancer', 'hormonal therapy resistance', 'progestin resistance', 'progesterone receptor', 'PI3K/AKT/mTOR', 'PTEN', 'microsatellite instability', and related terms.

Results: Resistance to hormonal therapy in endometrial cancer is multifactorial. Key mechanisms include loss or downregulation of progesterone receptor (PR) and oestrogen receptor (ER) expression, PTEN loss and PI3K/AKT/mTOR pathway hyperactivation, KRAS and CTNNB1 mutations, epigenetic silencing of hormone receptors, altered tumour microenvironment, and upregulation of drug efflux transporters. Emerging evidence implicates mismatch repair deficiency, POLE mutations, and HER2 amplification as modulators of both hormonal responsiveness and therapeutic targetability.

Conclusion: A mechanistic understanding of hormonal therapy resistance is critical for optimising patient selection, developing combination strategies, and integrating novel targeted agents and immunotherapy into management algorithms for endometrial cancer. Prospective biomarker-driven clinical trials are urgently needed.