RESEARKA

Critical endpoints remain unmeasured within this corpus. No source reports prospective data on HRT-related cancer incidence (breast, endometrial, or ovarian) as a primary outcome, despite this being one of the most debated risks in the clinical literature. Quality-of-life outcomes are mentioned anecdotally (Karakida 2025; Villa 2024) but are not systematically captured with validated instruments across multiple studies, nor is patient-reported vasomotor symptom burden quantitatively pooled. Long-term fracture incidence under HRT is referenced only through a single BMD meta-analysis (Xue 2013) using the surrogate endpoint of bone density rather than actual fracture events (Ioannidis 2005). Finally, the mechanism-to-clinic gap is substantial: several reviews (Srensen 2001, Blackburn 2026) articulate plausible biological pathways linking sex hormones to cardiometabolic and body-composition improvements, but the absence of parallel hard-outcome RCT evidence means mechanistic plausibility cannot be translated into a clinical recommendation within the boundaries of this evidence set.

Citation Support

• source_1 Saleh 2023
• source_2 Gu 2024
• source_3 Abdalla 2026
• source_4 Villa 2024
• source_5 Segerer 2020