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What is in the future of sperm analysis?

Ashok Agarwal, PhD, HCLD (ABB) Director, Center for Reproductive Medicine Professor, Lerner College of Medicine and Case Western Reserve University Cleveland Clinic Cleveland, OH 44195 E-mail: agarwaa@ccf.org

Throughout the approximately 50 years that it has been in existence, the standard semen analysis has largely remained unchanged. Even though the value of a semen analysis has significantly eroded over this period of time ( due primarily to the subjective nature of its results and lack of standardized training for laboratory personnel as well as the presence of significant inter and intra observer variability in results) the basic test remains the mainstay of an infertility workup because it is perceived as simple, inexpensive and noninvasive. As advances are made however, other tests are being introduced, not to supplant or replace the standard semen analysis test, but rather to delve further into the specific causes of male infertility. This editorial reviews some of these new fertility tests that are emerging and which promise to provide great insight and understanding into the rapidly developing field of male infertility.

What is in the future of sperm analysis? MicroarrayThis powerful method analyzes the transcriptome of cells and tissues. Comparison of transcriptomes between different stages of spermatogenesis may provide important clues into molecular mechanisms related to genetic infertility (ie, Yq microdeletions) and highlight potential biochemical markers for infertility. The primary application of this technology in the field of andrology is directed towards uncovering still unknown genes, molecular pathways, and mechanisms of sperm production. The creation of mRNA profiles may be able to distinguish between spermatogenic based infertility and other more environmental causes. The use of ICSI is generally thought to bypass the natural selection of the most healthy normal sperm and therefore allow the transmission of potentially defective genes. Clues may be provided from those men requiring ICSI treatment and who suffer from genetic based infertility to make use of treatment modalities based on the expression of genes revealed in these RNA profiles.Proteomics Body fluids composed of complex proteins are ideal candidates for proteomic studies as they have the potential to contain many unique biomarkers. The advent of electrospray ionization (ESI) and matrix-associated laser desorption/ ionization (MALDI) has pushed this field into the sequencing of peptides and proteins of reproductive tissues including those responsible for the production of seminal fluid. Seminal fluid has been found to contain 923 proteins, and at least 20 of these proteins have altered expressions in infertile men. This noninvasive technique of semen analysis not only provides the potential to detect causes of infertility, but may also play a role in the development of male contraceptives. It has also been shown that there are possible biomarkers available for the identification of normal cellular functions during in-vivo embryonic development.

Metabolic Profiling (metabolomics)Metabolites are brake down components formed by intracellular metabolic processes which are often released into the immediate in-vivo environment or surrounding in-vitro culture medium. These biochemical intracellular substances can provide both qualitative and quantitative information leading to a better understanding of the mechanisms and conditions responsible for producing these metabolites as well as giving us a glimpse into how conditions might be altered to enhance cellular function. In the investigation of male infertility, the production of oxidative stress byproducts, together with naturally occurring antioxidants, can serve as biomarkers which potentially could be used to differentiate fertile from subfertile men having idiopathic infertility. The same principle can be applied to assisted reproductive techniques as oxidative stress can markedly affect embryo development and pregnancy outcomes. The noninvasiveness of this type of diagnostic test is the primary advantage for its use in the clinical setting.

Atomic force microscopyIn 1986, a very high-resolution type of microscope having resolution in the fractions of a nanometer was invented. Its main advantage over EM has been the three-dimensional images it can provide, and the simplicity of the sample preparation (air drying). It also allows observation in an air or liquid milieu and thus the potential of observing biomolecules in vivo. The disadvantage of this process is that the image quality is limited by the radius of curvature of the probe tip, and use of an incorrect tip can result in image artifacts. Spermatozoa have been reported as good subjects for this high resolution microscopy because of their small size and rigidity. Although this method presently requires expensive equipment, its use in andrology research will no doubt provide important information on the intricate interrelationship between spermatozoon form and function and uncover some of the unknown causes of male infertility.
 
In summary, the advent of these and other high technology tests should be focused toward a better understanding of the intricacies of haploid cell interactions. However, one must continue to carefully assess the male factor component within this process and continue to strive and cure both male and female infertility by using assisted reproductive technologies judiciously. Although a carefully performed semen analysis remains the initial choice in the evaluation of the male partner by clinical andrologists, exciting new developments in semen testing technology promise continued advancement toward the diagnosis, management and even cure of male infertility.