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

Abstract

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.

Multifactorial etiology of male and female infertility/ assisted reproductive technique

“…Male infertility is major and important medical issue, although; the exact etiological cause is poorly understood, but male infertility account for more than half of the infertile couple among the world [7]. Male infertility largely dependent on spermatogenesis and linear development of spermatozoa from spermatogonia that characterized by mitotic and meiotic division followed by chemical and functional differentiation until it reach full mature sperm [8].…”

“…Male infertility some time underestimated because of socioeconomic dilemmas, in addition to inaccurate sampling and analysis, it can potentiate the male anxiety about hegemonic masculinity, and can be associated with psychological rather than marital tension, risk of cancer development, decrease in quality of health and life [9]. The most acceptable diagnostic method for male infertility is quality of sperm, concentration and motility, though; there are some limitations, like ambiguous threshold value affecting the accuracy of sperm analysis [7]. The abnormal spermatozoal differentiation that contributed to male infertility includes total sperm absence or Azoospermia, low sperm count or oligospermia, abnormal sperm shape or teratozoospermia, abnormal sperm motility or asthenozoospermia [10].…”

“…Several factors (anatomical and pathophysiological) affected male infertility like sperm duct occlusion (either in vas deference or occlusion in epididymis), ejaculation abnormality, disease of the testis, genetic disorders, hormonal imbalance in addition to iatrogenic factors [7]. Oligospermia and Azoospermia are indication of duct occlusion that occurs in about 5% of infertile men [11].…”

“…Many factors of given male infertility etiology can be interact, combination of several parameters are required to explains the molecular and pathophysiological reasons of male infertility like seminal fluid analysis, sperm morphology, mutation and so on, using these parameters can leads to more accurate diagnosis and effective therapies [7].…”

“…The seminal fluid analysis and sperm morphology regarded primary morphological and physiochemical diagnostic test of male infertility, the WHO developed in 1980s a standardized laboratory technique to avoid the bias between laboratories and more recent update published in 2021s [29]. The parameters of semen analysis according to update to diagnose the male infertility are (i) liquefaction time should be 15-20 minutes at room temperature (ii) Viscosity (increased viscosity indicate prostatic malfunction) (iii) Volume (after 3-5 abstinence the volume should be 1.5-6 ml, no more no less or it indicate hyper or hypospermia respectively) (iv) Color, the normal color of seminal fluid should be pearl white or yellowish (v) pH should be >7.1 while decreased values indicate efferent vessels digenesis that lead to decreased sperm concentration (vi) concentration, should be >15 million spermatozoa for each 1 milliliter of ejaculation (vii) Motility should be >32% (viii) Vitality should be >58% of live spermatozoa (ix) leukocyte should be < 1million per 1 milliliter (x) morphology should be >4% have normal morphology (xi) anti-sperm antibody (attachment of >50% of the sperm to other cells or particles indicated of immune disorders [7,29].…”