Infertility in Men: Advances towards a Comprehensive and Integrative Strategy for Precision Theranostics

Male infertility is an increasing and serious medical concern, though the mechanism remains poorly understood. Impaired male reproductive function affects approximately half of infertile couples worldwide. Multiple factors related to the environment, genetics, age, and comorbidities have been associated with impaired sperm function. Present-day clinicians rely primarily on standard semen analysis to diagnose male reproductive potential and develop treatment strategies. To address sperm quality assessment bias and enhance analysis accuracy, the World Health Organization (WHO) has recommended standardized sperm testing; however, conventional diagnostic and therapeutic options for male infertility, including physical examination and semen standard analysis, remain ineffective in relieving the associated social burden. Instead, assisted reproductive techniques are becoming the primary therapeutic approach. In the post-genomic era, multiomics technologies that deeply interrogate the genome, transcriptome, proteome, and/or the epigenome, even at single-cell level, besides the breakthroughs in robotic surgery, stem cell therapy, and big data, offer promises towards solving semen quality deterioration and male factor infertility. This review highlights the complex etiology of male infertility, especially the roles of lifestyle and environmental factors, and discusses advanced technologies/methodologies used in characterizing its pathophysiology. A comprehensive combination of these innovative approaches in a global and multi-centric setting and fulfilling the suitable ethical consent could ensure optimal reproductive and developmental outcomes. These combinatorial approaches should allow for the development of diagnostic markers, molecular stratification classes, and personalized treatment strategies. Since lifestyle choices and environmental factors influence male fertility, their integration in any comprehensive approach is required for safe, proactive, cost-effective, and noninvasive precision male infertility theranostics that are affordable, accessible, and facilitate couples realizing their procreation dream.