Chrono-targeting the prostate: a hypothesis on circadian regulation of androgen receptor activity in benign prostatic hyperplasia

Abstract

Despite decades of research, 30–40% of patients with benign prostatic hyperplasia (BPH) remain dissatisfied with conventional therapies, highlighting an unmet need for precision approaches. Emerging evidence from prostate cancer and endocrine systems reveals that androgen receptor (AR) activity follows circadian rhythms—yet this critical dimension is overlooked in BPH management. Here, we propose the chrono-targeting hypothesis: circadian-driven fluctuations in AR signaling modulate lower urinary tract symptoms (LUTS) and influence the efficacy of 5-alpha-reductase inhibitors (5-ARIs). Supporting this, a clinical pilot study (n = 22) identified peak LUTS severity in the afternoon/evening, coinciding with predicted AR activity surges. We further outline three mechanistic pillars: (1) circadian regulation of 5-alpha-reductase activity, (2) rhythmic AR nuclear translocation, and (3) chronotype-dependent treatment responses. By integrating chronobiology into BPH care—such as timed 5-ARI dosing—clinicians could exploit these rhythms to enhance symptom control without additional costs or side effects. This paradigm shift toward circadian-aware urology may bridge the gap between variable drug responses and patient-centered outcomes.

Keywords: Benign prostatic hyperplasia, chronotherapy, circadian rhythms, androgen receptor, lower urinary tract symptoms, 5-alpha-reductase inhibitors, chronobiology, personalized medicine, urology