Male factor infertility contributes to roughly 50% of the causes of infertility among couples. Advancements in the diagnostic field of reproduction allowed for the recognition of various etiologies for male factor infertility. Various pretesticular, testicular, and posttesticular etiologies have been identified and are believed to arise from genetic causes in 15–30% of cases. While a number of laboratory tests are available, the indication of genetic testing relies primarily on the findings in the history, physical examination, and semen analysis. Men with suspicion of nonobstructive azoospermia and those with idiopathic severe oligozoospermia are investigated with karyotype and Y-chromosome microdeletion assays. Analysis of the cystic fibrosis transmembrane conductance regulator (CFTR) gene is reserved for patients with obstructive azoospermia secondary to a unilateral or bilateral complete absence of the vas deference. In addition to the more commonly adopted tests, the genetic evaluation may have a role in patients with congenital hypogonadotropic hypogonadism and androgen insensitivity syndrome. Genetic testing of male infertility is a rapidly evolving field in andrology. Epigenetics, next-generation DNA sequencing, and microarray-based technologies represent some of the promising development in the area and may further expand the clinical utilization of genetic evaluation.

The prevalence of azoospermia in the general population is 1% and azoospermic men constitute approximately 10–15% of all infertile men. While the advent of microTESE substantially improved sperm recovery compared to standard biopsy or other techniques, the procedure remains inefficient, costly, and very time consuming, both in retrieval and separation/sorting. Three conventional sperm sorting techniques are commonly used in andrology clinics: density gradient centrifugation, sperm washing, and swim-up, all of which have provided reliable solutions to isolate normal sperm from highly concentrated semen samples. The field of microfluidics is the most rapidly developing field for sperm selection related to the field of ART. It is particularly powerful when considering applications in single-cell or low-cell number analyses. Magnetically activated cell sorting and fluorescence-activated cell sorting are alternative and promising technologies. Further research is needed to optimally identify and isolate sperm to help couples achieve the goal of biologic children.

The office evaluation of the infertile male involves a comprehensive history and physical structured to uncover all potential causes including congenital, medical, surgical, environmental, genetic, and psychosocial etiologies. The physical exam begins with the patient’s general appearance, body habitus, and progresses to the genital exam in which the testicles are examined for size, consistency, and location. Prior surgical scars, absence of the vas deferens, or the presence of varicoceles may be identifiable causes of infertility. The semen analysis is the cornerstone laboratory evaluation of the male undergoing an infertility workup. The semen is evaluated for several key parameters including volume as well as sperm concentration, number, motility, and form. An endocrine evaluation is indicated in men with oligospermia, azoospermia, or a history of physical examination findings suggestive of hormonal abnormalities including sexual dysfunction, decreased libido, or physical evidence of impair androgenization. Pending the initial workup genetic testing may be indicated.

Testicular histopathology has been found to be the most reliable predictive factor of successful sperm retrieval in nonobstructive azoospermia patients. Some studies have proposed performing a diagnostic biopsy before assisted reproductive technology. However, its application in clinical practice has been debated due to some criticisms, including its cost-ineffective nature. Another important advantage of histopathology is the revealing of germ cell neoplasia in situ, which occurs in 1–3 percent of infertile patients. Testicular histopathology also offers important information in cases of failed sperm retrieval. When areas of active spermatogenesis are found, the histological pattern could guide the clinician in choosing the more suitable therapeutic option.

All sperm accrue varying amounts of DNA damage during maturation and storage, a process that appears to be mediated through oxidative stress. The clinical significance of genetic damage in the male germ line depends upon severity and how that damage is distributed among the sperm population. In human reproduction, the embryo is capable of significant DNA repair, which occurs prior to the first cleavage event. However, when the magnitude of genomic damage reaches pathologic levels, reproductive outcomes begin to be affected. Evidence now exists linking excessive sperm DNA fragmentation with time to pregnancy for natural conception, pregnancy outcomes of intrauterine insemination and in vitro fertilization, and miscarriage rates when intracytoplasmic sperm injection is employed. This review will discuss the pathophysiology of sperm DNA damage, the studies linking it to impaired reproductive outcomes, and how clinicians may render treatment to optimize the chance of paternity for their patients.