Mechanistic and Clinical Insights into Menopausal Hormone TherapyAssociated Breast Carcinogenesis

Abstract

Objective: To synthesize clinical, epidemiological, and molecular evidence on the association between menopausal hormone therapy (MHT) and breast cancer risk, with emphasis on formulation-specific effects and mechanistic pathways. Data Sources: A narrative literature review was conducted using PubMed, Scopus, and Web of Science databases. Search terms included menopausal hormone therapy, estrogen-only therapy, estrogen–progestin therapy, breast cancer risk, mammographic density, and progesterone receptor signaling. Studies published in English from 1995 to 2024 were prioritized. Data Summary: Evidence from randomized controlled trials, including the Women's Health Initiative, and large cohort studies demonstrates divergent breast cancer risk profiles for estrogenonly therapy (ET) and estrogen–progestin therapy (EPT). ET using conjugated equine estrogen is associated with neutral or reduced breast cancer incidence, whereas EPT significantly increases risk, particularly for estrogen receptor–positive tumors. Mechanistically, estrogen and progestogens influence carcinogenesis through receptor-mediated transcription, non-genomic kinase signaling, altered 
steroid metabolism, epigenetic remodeling, expansion of mammary progenitor cells, and tumor microenvironment changes. Synthetic progestins promote tumor progression via RANKL, STAT, PI3K/Akt, and MAPK pathways. MHT also increases mammographic density, contributing to increased carcinogenic susceptibility and reduced screening sensitivity. Conclusions: Breast cancer risk associated with MHT is heterogeneous and strongly dependent on hormone composition, duration of exposure, and individual patient 
factors. Estrogen-only regimens appear biologically and clinically safer than combined estrogen–progestin therapy. Improved mechanistic understanding and molecular risk stratification are essential for individualized menopausal symptom management with reduced oncologic risk.