Etiology of Male Infertility: an Update

Spermatogenesis is a complex process of germ cell division and differentiation that involves extensive cross-talk between the developing germ cells and the somatic testicular cells. Defective endocrine signaling and/or intrinsic defects within the testes can adversely affect spermatogenic progression, leading to subfertility/infertility. In recent years, male infertility has been recognized as a global public health concern, and research over the last few decades has elucidated the complex etiology of male infertility. Congenital reproductive abnormalities, genetic mutations, and endocrine/metabolic dysfunction have been demonstrated to be involved in infertility/subfertility in males. Furthermore, acquired factors like exposure to environmental toxicants and lifestyle-related disorders such as illicit use of psychoactive drugs have been shown to adversely affect spermatogenesis. Despite the large body of available scientific literature on the etiology of male infertility, a substantial proportion of infertility cases are idiopathic in nature, with no known cause. The inability to treat such idiopathic cases stems from poor knowledge about the complex regulation of spermatogenesis. Emerging scientific evidence indicates that defective functioning of testicular Sertoli cells (Sc) may be an underlying cause of infertility/subfertility in males. Sc plays an indispensable role in regulating spermatogenesis, and impaired functional maturation of Sc has been shown to affect fertility in animal models as well as humans, suggesting abnormal Sc as a potential underlying cause of reproductive insufficiency/failure in such cases of unexplained infertility. This review summarizes the major causes of infertility/subfertility in males, with an emphasis on infertility due to dysregulated Sc function.