O-120 The role of CatSper in male infertility - from bench to bedsite and back

Abstract

Abstract Infertility is on the rise, but the underlying causes still remain mostly unknown. In fact, for about one third of infertile men, semen parameters are within reference limits. This so called ‘unexplained male infertility’ seems to rest on elusive functional defects of the sperm undetectable by semen analysis, precluding early diagnosis of the infertility and evidence-based treatment by medically assisted reproduction (MAR). As a result, affected couples often experience failed MAR attempts, subjecting the ‘healthy’ female to recurring medical risks. We set out to gain insight into the pathomechanisms underlying unexplained male infertility. To this end, we systematically assessed the function of the sperm-specific multisubunit CatSper-channel complex in sperm of 2,300 men undergoing a fertility workup at our center, using a simple motility-based ‘CatSper-Test’ combined with [Ca2+]i fluorimetric and electrophysiological recordings. Thereby, we identified a group of men with normal semen parameters, but defective CatSper function. These men or couples failed to conceive naturally and upon MAR via intrauterine insemination and in vitro fertilization. Intracytoplasmic sperm injection (ICSI) was, ultimately, required to conceive a child. We revealed that the defective CatSper function was caused by variations in CATSPER genes. Moreover, we unveiled that CatSper-deficient human sperm were unable to undergo hyperactive motility and, therefore, failed to penetrate the egg coat. Thus, we provide the experimental evidence that sperm hyperactivation is required for human fertilization, explaining the infertility of CatSper-deficient men and need of ICSI for medically assisted reproduction. Finally, our study also revealed that defective CatSper function and ensuing failure to hyperactivate represents the most common cause of unexplained male infertility known thus far and that this sperm channelopathy can readily be diagnosed, enabling future evidence-based treatment of affected couples.