Sperm motility: things are moving in the lab!

Sperm motility is one of the three fundamental tenets of semen analysis providing diagnostic and prognostic information for both natural and assisted reproduction technology (ART) conception. The landmark papers of John MacLeod and Ruth Gold demonstrated clear differences between subfertile and fertile men in sperm motility (MacLeod and Gold, 1951) which have been confirmed by a plethora of subsequent studies (Barratt et al., 2011). The WHO new reference values for motility, as well as sperm concentration (Cooper et al., 2010), are remarkably similar to those proposed by MacLeod and Gold in 1951 (32% motile cells as a 5% centile of a fertile population), suggesting that these observations are robust. The primary conclusion from all these studies is that although there is no magic number or threshold for in vivo fertility, at the lower ends of the motility spectrum, there are significantly higher chances of subfertility (Fig. 1). This overwhelming body of clinical information ignited a series of studies developing new methods to obtain sperm kinematic data. Initial information was very encouraging, e.g. using the biological endpoints of penetration of cervical mucus (Mortimer et al., 1986). With the advent of computer-assisted semen analysis (CASA) machines, making kinematics more widely available, there was an explosion in studies reporting the relationship of quantitative motility and kinematic parameters with conception in vivo (Barratt et al., 1992), in donor insemination (Irvine and Aitken, 1986), in IUI (Bollendorf et al., 1996), IVF (Liu et al., 1991) and even ICSI (Van den Bergh et al., 1998). However, in the last 15 years, there have been a paucity of further studies perhaps due to the limitations in CASA technology but more likely due to the perceived lack of clinical need following the development of ICSI. Another clinically relevant aspect of sperm motility research that has apparently been shelved in the archives is the potential for in vitro enhancement of motility using a wide variety of drugs that target phosphodiesterases (PDEs) and increase [cAMP]. Simplistically, increasing the number of functional cells at the site of fertilization would appear to be a rational objective (Fig. 1). Historically, the most widely used drug was pentoxifylline where results were encouraging in both IVF and IUI (Yovich et al., 1990; Stone et al., 1999). However, the lack of recent research is particularly noticeable in the context of the overwhelming progress on specific (third generation) PDE inhibitors. While targeting of PDE5 is not likely to be very useful (Lefièvre et al., 2000), there are a number of new-generation PDE inhibitors available that may positively influence sperm function. It is of course not just PDEs that require investigation and the modification of other enzymes, e.g. kinases and phosphatases, will provide a wealth of interesting data. In contrast to the above, which could be described as sleeping giants of ‘clinical andrology’, there has been breathtaking progress in the understanding of sperm motility in the research laboratory, largely brought on by developments in technology: patch clamping, imaging and the rudimentary synergy of mathematics/physics with sperm biology (systems biology of sperm). A primary example is the role of Ca2+ in regulating the activity of the flagellum. Central to this has been the discovery of CatSper channels and elucidation of their role(s) in sperm function. In mice, the main source of Ca2+ entry for hyperactivation appears to be via pH-dependent CatSper channels in the plasma membrane of the flagellar principal piece. These channels are essential for male fertility as sperm from CatSper null mice are motile but unable to hyperactivate, rendering them unable to migrate to or within the oviduct and unable to fertilize oocytes even by IVF (Ren et al., 2001; Carlson et al., 2003; Quill et al., 2003). CatSper channels are also present in the flagellum of human