Knowledge gaps in male infertility: a reproductive endocrinology and infertility perspective.

Reproductive research has moved forward at a remarkable pace. Some of these advances are the result of a separation between male and female specialties, allowing focused study in specific areas of the field. However, the different training programs between male and female fertility specialists has created an environment in which some discoveries are not put in the greater context of clinical care. At times, interventions have been measured against surrogate markers of outcome that may not impact the most meaningful outcome for patients-the delivery of a healthy neonate. For example, medical and surgical interventions that use changes in semen parameters may have a limited impact on the likelihood of achieving a live birth due to the limitations inherent in the semen analysis for predicting outcomes. Other commonly used tests, such as sperm DNA fragmentation assays provide promising biological plausibility to account for subfertility of some male partners. However, until well defined thresholds for predicting outcomes in different treatment scenarios are available, changes in sperm DNA fragmentation testing is not an adequate outcome for measuring the utility of interventions. The biggest limitation for these tests remains their analysis of bulk semen. Tests allowing interrogation of the reproductive competence of a given sperm, while allowing that sperm to be used in assisted reproductive technology procedures remain elusive. Progress toward reaching this end (whether by hyaluronic acid binding, IMSI, or Ramen spectroscopy) is underway, but much remains to be learned. Achieving testing and capture of individual sperm would better facilitate studies that measure the most meaningful outcome for patients and providers-the delivery of a healthy baby.