Sex steroid receptors in colorectal cancer: implications for tumor progression, therapeutic opportunities, and sex-specific outcomes

Colorectal cancer (CRC) is a common malignancy with high incidence and mortality. Hormone signaling pathways, including estrogen, progesterone (P4), and androgen receptors (ARs), influence tumor development and progression and offer potential therapeutic opportunities. This study investigates the role of sex steroid receptors in CRC, explores therapeutic strategies, and considers sex-specific implications. Multiple cohort studies were analyzed based on gender, age, clinical stage, and tumor location. A structured literature search was conducted across PubMed, Web of Science, and Google Scholar, selecting studies with relevant sex-specific data and study designs. ERβ exhibits antitumor effects, with lower levels linked to tumors in females, while ERα and AR promote growth, particularly in postmenopausal women. Progesterone receptors (PGRs) are associated with poorer prognosis, though P4 treatment inhibits CRC cell proliferation. Malignant tissues show increased ERα and AR but decreased ERβ and PGR. ER isoforms' mRNA is lower in malignant females, and AR expression is higher in males. Women more often develop proximal colon tumors (reduced ERβ) and men develop distal tumors, reflecting nuanced gene transcription modulation by ERα, ERβ, and G-protein coupled estrogen receptor (GPER). The mechanism of P4's protective effect remains unclear. Variability in cell lines, hormone concentrations, receptor expression, and hormone replacement therapy outcomes complicates interpretation, as do interactions between cytokines and estrogen signaling in the tumor microenvironment. Future strategies include combined ERβ and PGR activation, sequential estrogen-P4 therapy for early stage CRC, and simultaneous therapy for advanced cases. Research should clarify sex hormone roles, advance prognostic markers, explore selective estrogen receptor modulators, target ERβ pharmacologically, and investigate gut microbiome influences for tailored interventions.