Cells 2022, 11, 1711. https://doi.org/10.3390/cells11101711 www.mdpi.com/journal/cells Review Infertility in Men: Advances towards a Comprehensive and Integrative Strategy for Precision Theranostics Mourad Assidi 1,2 1 Center of Excellence in Genomic Medicine Research, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia; mourad.assidi@gmail.com; Tel.: +966-(012)-6402000 (ext. 69267) 2 Medical Laboratory Department, Faculty of Applied Medical Sciences, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia Abstract: Male infertility is an increasing and serious medical concern, though the mechanism re- mains poorly understood. Impaired male reproductive function affects approximately half of infer- tile couples worldwide. Multiple factors related to the environment, genetics, age, and comorbidi- ties 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 Organ- ization (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 envi- ronmental 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 compre- hensive approach is required for safe, proactive, cost-effective, and noninvasive precision male in- fertility theranostics that are affordable, accessible, and facilitate couples realizing their procreation dream. Keywords: male infertility; sperm; etiology; aging; biomarkers; lifestyle; multiomics; precision theranostics 1. Introduction Infertility has been defined as a reproductive disease that prevents a healthy woman from conceiving after at least 12 months of regular unprotected sexual intercourse [1]. Male infertility encompasses any health issue that impedes the likelihood of conception and can be caused by abnormal sperm function or obstructions that prevent ejaculation. Multiple factors, including illness, injury, chronic morbidity, and lifestyle choices, con- tribute to its onset and progression [2]. Male fertility is largely determined in spermato- genesis, the development of spermatozoa from spermatogonia in the testes. This meticu- lous developmental process is marked by both mitotic and meiotic divisions, followed by extensive morphological and biochemical differentiation, leading to a mature spermato- zoan. Male infertility is attributed to abnormal spermatozoa parameters (spermatogenic Citation: Assidi, M. Infertility in Men: Advances towards a Comprehensive and Integrative Strategy for Precision Theranostics. Cells 2022, 11, 1711. https://doi.org/ 10.3390/cells11101711 Academic Editor: Alice Luddi Received: 21 April 2022 Accepted: 20 May 2022 Published: 22 May 2022 Publisher’s Note: MDPI stays neu- tral with regard to jurisdictional claims in published maps and institu- tional affiliations. Copyright: © 2022 by the author. Li- censee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and con- ditions of the Creative Commons At- tribution (CC BY) license (https://cre- ativecommons.org/licenses/by/4.0/).