The biologic pathway and physiologic function of sperm will be explored in subsequent chapters, but a brief mention regarding the basics of sperm function is worth noting. The first major step in sperm development is when Type B spermatogonia undergo mitosis to give rise to diploid primary spermatocytes. The primary spermatocyte crosses over the blood–testis barrier of the Sertoli cell tight junctions to begin the differentiation process of spermatogenesis within the immune-privileged adluminal compartment. Meiosis then occurs to give rise to haploid secondary spermatocytes, which undergo a second meiotic division with the entire process resulting in four haploid spermatids [15].

There are three basic genetic causes of UMI, and will be discussed separately as: alterations in chromosomal complement, gene mutations and polymorphisms, and DNA integrity defects.

Genetic recombination is a necessary step in spermatogenesis as it provides genetic variation and prepares for chromosomal separation later on in meiosis. An error in this process has been reported in 10 % of patients with nonobstructive azoospermia , and in one-half of men with specific diagnosis of maturation arrest [16]. Errors of recombination are commonly known as nondisjunction events, which result in either a missing or an extra chromosome. An abnormal number of chromosomes is simply referred to as aneuploidy. Increased paternal age, ingestion of alcohol, and previous treatment with chemotherapy have been implicated in cases of aneuploidy; although, the exact cause has yet not been discovered [17]. Further, testing for this condition is expensive and therapeutic options are limited .

The role of specific gene mutations on UMI has been extrapolated from multiple animal studies on mice. These studies have identified 300 null mutations and 50 additional deletions that produce murine infertility [17]. In human studies, DNA microarray analysis has demonstrated underexpression of specific genes in normospermic infertile males compared to fertile controls [18]. Further studies are needed in this area before any definitive conclusion can be made.

Damage to the integrity of DNA may also affect sperm function. It has been observed that increased DNA damage leads to inferior outcomes with IVF and ICSI [19], and it is estimated that 8 % of infertile men have DNA damage despite a normal semen analysis [20]. Potential contributors to DNA damage can be classified as either extrinsic or intrinsic factors. Examples of extrinsic causes, include heat, tobacco exposure, alcohol exposure, radiation, and other gonadotoxins. Intrinsic factors identified, include protamine deficiency, specific genetic mutations, reactive oxygen species, and aging [17]. One can examine for DNA damage by testing for chromatin compaction (assesses DNA susceptibility to gonadotoxins) or by testing for DNA fragmentation [21]. However, routine use of these assays is controversial and not yet endorsed by society guidelines.

Oxidative stress is known as the effect induced on cells by reactive oxygen species (ROS) , and is a known contributor to male infertility in up to 80 % cases [22, 23]. There are many documented causes of oxidative stress, most of which contribute to damaging the DNA integrity as discussed previously. Smoking tobacco has been shown to significantly increase ROS, both, by increasing leukocyte concentration and ROS generation in semen and also by decreasing the level of seminal superoxide dismutase, an antioxidant enzyme that combats ROS [24]. Varicoceles have also been shown to cause increased ROS levels, and surgical repair by varicocelectomy leads to a decline in ROS in the testes as well as in the seminal fluid in addition to an improvement in overall sperm quality [25].

ROS have the potential to cause infertility without affecting commonly measured semen parameters. Thus, many men with infertility secondary to ROS fall into the category of UMI as they have normal semen analyses. Finally, the presence of increased ROS is an independent marker of male factor infertility [26].

If oxidative stress is suspected as a cause of UMI, one can test for it either by directly detecting ROS via chemiluminescence or flow cytometry, or indirectly via colorimetry [17]. A later chapter is dedicated to the topic of ROS and will discuss these methods in further detail .