Idiopathic male infertility - what are we missing?

Couple's infertility is a rising issue worldwide affecting approximately 15% of couples. In 50% of the couples, a male factor infertility can be identified. Moreover, 30% of the men exhibit reduced sperm quality without any identifiable reason, thereby delineating the condition of idiopathic male infertility (IMI). Despite numerous improvements in the diagnosis and treatment of male infertility over the last decades, idiopathic forms are still the most challenging clinical dilemmas. The aim of this article is to describe the comprehensive diagnostic work-up that each idiopathic infertile man should follow. Moreover, potential new pathophysiological mechanisms and suggested treatment options are discussed. A detailed medical history and an extensive physical examination are mandatory to investigate potential treatable causes of MFI. Similarly, standard semen analysis has been proven to be limited in capturing the fecundability of the spermatozoa itself, therefore more advanced examinations, such as sperm DNA fragmentation (SDF) and oxidative stress measurement, are becoming important in clinical practice for IMI. In terms of diagnostic tools, imaging and genetic investigations are useful to classify idiopathic infertile men, however, epigenetic changes have demonstrated to have a role in sperm production and a prognostic value in fertility outcomes. Antioxidant treatment for IMI has been found to be a valid option to counteract ROS action, while gonadotropins are used to improve sperm quality and SDF. Artificial intelligence is promising to better manage idiopathic infertile men in terms of diagnosis and treatment options.