Phosphodiesterase-5 Inhibitors in Erectile Dysfunction: Human Penile Sexual Physiology and AI/ML Insights into CBAD and Sex-Chromosome Genetic Syndromes

Abstract

Erectile dysfunction (ED) is a multifactorial disorder with a vascular, endothelial, neurological, endocrine and psychological etiology. This review summarizes human physiology during penile sexual stimulation and of erection, focusing on the nitric oxide–cyclic guanosine monophosphate (NO–cGMP) pathway and the therapeutic potential of phosphodiesterase-5 inhibitors (PDE5Is). The efficacy and clinical significance of sildenafil, tadalafil, vardenafil and avanafil is discussed in detail, along with their safety information. The review also explores congenital bilateral absence of the vas (CBAVD), Jacobs syndrome (47, XYY), De la Chapelle syndrome (46, XX testicular DSD) and Klinefelter syndrome (47, XXY) as it relates to male sexual and reproductive health. Human evidence shows that the outcome of infertility and erectile function may be different. Emerging uses of AI/ML applications are also considered, with the most human evidence so far reported for Klinefelter syndrome, and with limited evidence for CBAVD and rarer sex-chromosome syndromes. The review underscores the need for a deeper exploration of the potential synergy between sexual medicine, reproductive genetics, and AI/ML to provide a more personalized assessment and management of the disease.