A Novel Approach to Improving the Reliability of Manual Semen Analysis: A Paradigm Shift in the Workup of Infertile Men

Preamble:This article explores standard male fertility evaluation, focusing on challenges in conventional semen analysis (SA). SA is globally accepted as the primary test in assessing male fertility. SA has been a contentious issue among fertility researchers for a considerable period. Its subjective nature has led to criticism regarding the interpretation by clinicians and the assessment variability among lab technicians. The absence of standardized protocols and inherent individual variations have made the test highly error prone. Consequently, doubts have emerged about its accuracy and efficiency, prompting the need for consistent implementation of quality control programs. These programs aim to mitigate the considerable variability in assessing most variables of conventional SA.

Capsule: Contributors: Hussein Kandil, MD (UAE), Dongsuk Kim, MD, PhD (South Korea)
The intricacies and challenges faced while assessing semen parameters using SA has a more profound implication when it comes to clinical practice, as seen for instance during the process of deciding between IUI, versus IVF/ICSI which is a decision that is based upon the total motile sperm count.
Because of the aforementioned factors, over the last decade, there has been constant trial of coming about with new techniques and technologies that would more accurately assess male fertility. There has been a shift towards a computerized technology, as with the computer assisted semen analysis (CASA), which was aspired to offer higher accuracy in assessing male fertility, overcoming the shortcomings of conventional SA, but unfortunately, this has come about with the cost of increased price and concerns regarding the technological calibration.

Further innovations involved the emergence of home-based kits to assess male fertility, which probably have alleviated the issues of privacy and have found some degree of appreciation by the end users, like patients who had concerns with undergoing lab based testing. The current devices only measure sperm concentration or motility, leading to inaccurate and unreliable results. Evaluating sperm DNA fragmentation, crucial for sperm function and male fertility, lacks standardized testing methods. Moreover, the different available assays and techniques for SDF testing vary, raising concerns about their cost. Due to these issues, DNA fragmentation testing hasn't emerged as a reliable alternative to semen analysis (SA) for assessing male fertility. Although physiological levels of oxidative stress (OS) are required for sperm function, OS derived from excess of oxidants or a deficiency in antioxidants can disrupt the homeostasis of the redox system and can be associated with sperm DNA damage compromising male fertility. Chemiluminescence is widely used in the measurement of seminal ROS, but it has several limitations including inability to measure ROS in frozen samples, requiring a large semen volume and low reliability in the presence of ROS producing leukocytes in semen. The total antioxidant capacity (TAC) assay, which measures the antioxidant concentration only in the seminal fluid cannot evaluate the enzymatic antioxidants or individual antioxidants in the entire ejaculate and is not cost effective. Measuring the oxidation-reduction potential (ORP) is an innovative tool used in identifying a single direct marker of male factor infertility. ORP measured via Male Infertility Oxidative System (MiOXSYS) predicts abnormal semen parameters with high sensitivity and specificity, in short time (<5 minutes) and is simple to perform, cost effective, highly reliable, requiring little training and only 30 uL of sample. The MiOXSYS overcomes many of the challenges however, it cannot be used in cases of severe oligozoospermia (≤1×106 sperm/mL) or azoospermia. When it comes to the test’s accuracy, ROC curve analysis resulted in a cut off value of 1.36 mV/106 sperm/mL, which could differentiate between normal and abnormal semen samples with a high sensitivity, specificity, and positive and negative predictive value. Further multi-center study with 2,092 men of diverse ethnicity from nine institutions located in seven countries showed that an ORP cutoff value of 1.34 mV/106 sperm/mL could reliably distinguish between normal and abnormal semen quality with 98.1% sensitivity, 40.6% specificity, 94.7% positive predictive value, and 66.6% negative predictive value (area under the curve [AUC] = 0.765)

Take Home Message:
Various methods have emerged for male fertility assessment, but challenges remain. Manual semen analysis methods measuring sperm concentration, motility or morphology are unreliable. Innovations like computerized analysis are hampered by cost and calibration issues. Home-based kits address privacy concerns but lack comprehensive testing. Sperm DNA fragmentation testing lacks standardized methods, hindering its reliability. MiOXSYS shows promise in detecting abnormalities in redox status but has limitations in severe cases. Establishing an ORP cutoff value offers potential, but more diverse studies are needed for accurate semen quality distinction. Despite advancements, a unified, comprehensive approach remains elusive in assessing male fertility. (Contributor: Ashok Agarwal, USA)

Meet the Contributors:
Hussein Kandil, MBBCh, FACS, MBA: Short Biography