Asthenospermia accounts for about 30% of the causes of male infertility. Currently, most drugs for asthenospermia lack specificity and desirable therapeutic efficiency. An insight into the pathogenesis of asthenospermia is important for the development of specific therapies for this disease. The protein Na+/K(+)- ATPase α4 isoform (NKA4) presents in both mature testis tissue and the sperm tail, the absence or reduced activity of which may significantly decrease sperm motility. Ouabain is a natural inhibitor of NKA4, suppressing its activity by specifically binding the ouabain site in it. The hypothalamus and adrenal cortex excrete an ouabain-like steroid hormone called endogenous ouabain (EO), which may be associated with the pathogenesis of asthenospermia by inhibiting the activity of NKA4, affecting Na+/H+ exchange, Na+/Ca2+ exchange and sperm cell membrane potential, and eventually reducing sperm motility.