The Male Is Significantly Implicated as the Cause of Unexplained Infertility

Abstract

Male infertility is recognized as a relatively common, complex condition, generated by a broad array of environmental and genetic factors. Historical reliance on the conventional semen profile has tended to underestimate the true contribution of “the male factor” to human infertility. This review highlights the importance of genetic and epigenetic factors in the etiology of male infertility, identifying a range of mutations responsible for primary testicular failure and impaired fertilizing potential. More than three quarters of all de novo mutations arise in the male germline via mechanisms that involve the inefficient or defective repair of DNA damage. Understanding the range of factors capable of creating genetic turmoil in the paternal germline is essential, if we are to gain a deep understanding of the causes of male infertility, rather than just the symptoms that characterize its presence. High levels of DNA fragmentation induced by oxidative stress are part of this equation. Oxidative stress is, in turn, driven by biological (age, ejaculation frequency, varicocele, infection), lifestyle (smoking, obesity), and environmental factors (heat, other forms of electromagnetic radiation, and toxins) that can impair the fertilizing potential of the spermatozoa and influence the incidence of spontaneous mutations that may cause infertility in the offspring.

The changing tide of human fertility

“…Nowhere is this more evident than in the male. Human semen quality is notoriously poor and male infertility is known to be a highly prevalent condition ( Agarwal et al , 2015 ; Aitken, 2020a ). Moreover, sperm counts have halved in the past 50 years in both the industrialized West and the East, including China ( Levine et al , 2017 ; Lv et al , 2021 ; Swan and Colino, 2021 ).…”

“…Other aspects of modern society that are thought to impair male and female fertility include a variety of environmental and lifestyle factors (diet, smoking, excess alcohol consumption, exposure to industrial pollutants, electromagnetic radiation, stress, sedentary behaviour etc. ), many of which are associated with the induction of oxidative stress within the reproductive tract ( Aitken and Baker, 2013 , 2020 ; Aitken, 2020a , b ). Understanding the various factors that cause oxidative stress in our species and controlling levels of exposure through the imposition of appropriate regulatory frameworks and adoption of relevant protective behaviours, will also be important in keeping this particular cause of human infertility under control ( Alonso et al , 2009 ; De Iuliis et al , 2009 ; Hajizadeh Maleki et al , 2013 ; Dai et al , 2015 ; Durairajanayagam et al , 2015 ; Rengaraj et al , 2015 ; Samarasinghe et al , 2018 ; Bellastella et al , 2019 ; He et al , 2020 ; Nguyen-Powanda and Robaire, 2020 ; Skoracka et al , 2020 ).…”

Male Sexual Dysfunction and Infertility in Spinal Cord Injury Patients: State-of-the-Art and Future Perspectives

“…It is believed that many unexplained cases of infertility are associated with sperm DNA damage and defective repair. Indeed, oxidative stress is the result of complex mechanisms due to biological factors (age, ejaculation frequency, varicocele, infection), lifestyle factors (smoking, obesity), and environmental factors (heat, other forms of electromagnetic radiation, toxins) that can impair spermatogenesis, triggering spontaneous mutations in the progenitors of spermatozoa [ 32 ]. Specifically, advanced paternal age represents a risk factor associated with the progressive increase in the prevalence of infertility factors in males [ 33 ].…”

Sperm Oxidative Stress during In Vitro Manipulation and Its Effects on Sperm Function and Embryo Development

“…Moreover, 30-50% of male infertility cases are idiopathic as routine semen analysis has no identifiable etiology, and a female factor seems to be absent [5][6][7]. Indeed, the incidence of male infertility oscillates in a wide range (5-35%) due to multifactorial differences among the patient's populations [8,9].…”