What advances may the future bring to the diagnosis, treatment, and care of male sexual and reproductive health?

Abstract

Over the past 40 years, since the publication of the original WHO Laboratory Manual for the Examination and Processing of Human Semen, the laboratory methods used to evaluate semen markedly changed and benefited from improved precision and accuracy, as well as the development of new tests and improved, standardized methodologies. Herein, we present the impact of the changes put forth in the sixth edition together with our views of evolving technologies that may change the methods used for the routine semen analysis, up-and-coming areas for the development of new procedures, and diagnostic approaches that will help to extend the often-descriptive interpretations of several commonly performed semen tests that promise to provide etiologies for the abnormal semen parameters observed. As we look toward the publication of the seventh edition of the manual in approximately 10 years, we describe potential advances that could markedly impact the field of andrology in the future.

Keywords: Semen analysis; genes; motility; sperm morphology.

Figure 1

Macrozoospermia results from damaging mutations in aurora kinase C (AURKC). When AURKC is mutated, there is premature chromosome segregation, and cytokinesis is blocked during meiosis, resulting in large, headed multitailed, polyploid sperm formation. The c.144delC mutation is common in men of European and North African origin with macrozoospermia. For these men, intracytoplasmic sperm injection-in vitro fertilization is not recommended because the chances of a normal pregnancy are slim. AURKB/C = aurora kinase B/C.

Figure 2

Multiple morphological anomalies of the sperm flagella (MMAF) refer to sperm morphology anomalies usually associated with asthenoteratozoospermia. In men with asthenoteratozoospermia, there is a relatively high frequency of mutations in dynein axonemal heavy chain 1 (DNAH1), cilia and flagella associated protein 44 (CFAP44), and cilia and flagella associated protein (CFAP43) (these 3 protein defects account for approximately one-third 3 of MMAF cases) with mutations involving adenylate kinase 7 (AK7), cilia and flagella associated protein 69 (CFAP69), centrosomal protein 135 (CEP135), A-kinase anchoring protein 3 (AKAP3), or A-kinase anchoring protein 4 (AKAP4). As a result, structural defects of the centriole assembly, peri-axenome structure, and the axenome can be present, affecting the proximal centriole, 9 + 2 central pairs of microtubules, fibrous sheath and outer dense fibers, mitochondrial sheath, outer and inner dynein arms, radial spokes, and nexin-dynein regulation complex.

Figure 3

Genes encoding the critical proteins required for the acrosome biosynthesis. Globozoospermia is a sperm morphology anomaly that is readily identified in a routine semen analysis when the sperm appear round-headed with an absent, atrophied, or misplaced acrosome. There are 2 main defective genes commonly present in globozoospermic men. Spermatogenesis associated protein 16 (SPATA16) is highly expressed in human testis, and damaging mutations are identified in a significant percentage of globozoospermic men. A second gene, DPY19L2, exhibits either copy number variations (gene dosage changes) or damaging mutations that are more common in men in some different geographic and ethnic regions who show mainly type I globozoospermia with a high percentage of abnormal sperm. For men with complete globozoospermia, intracytoplasmic sperm injection with oocyte activation can be attempted, but the likelihood of achieving successful fertilization and live birth is significantly reduced compared with men with sperm with a normal acrosome.