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Editorial
Man-made versus female-made environment—will the real capacitation please stand up?
Reproductive Biology & Genetics Group, Division of Reproductive and Child Health, The University of Birmingham and The Assisted Conception Unit, Birmingham Women’s Hospital, Birmingham, UK
1 To whom correspondence should be addressed E-mail: c.l.barratt{at}bham.ac.uk
Abstract
Two recent reviews discuss the importance of the female tract in regulating the function of the spermatozoon during its eventful journey to the site of fertilization in this journal. However, our understanding of the nature of this journey, specifically in the human, is remarkably poor. What is also clear is the discourse between what is likely happening in vivo and the design of our experiments in vitro. Our conclusion is that, to date, we have been studying the spermatozoa in the wrong environment, in the wrong way and at the wrong time.
What is the nature of the interaction between the female reproductive tract and the human spermatozoon? How dynamic is this? How do spermatozoa remain in a fertile state for up to 6 days before ovulation? These are not new questions but two recent reviews examining the biological basis of human sperm capacitation (De Jonge, 2005
), and the dynamics of sperm transport within the reproductive tract (Suarez and Pacey, 2005) have readdressed these and other related questions and focused our attention on this neglected research area. These reviews provide sufficient evidence to suggest that the journey of the sperm cell from the site of deposition to the site of fertilization is both dynamic (on the part of the sperm and the female tract) and highly complex. Additionally, they reveal an unacceptable gap in our knowledge of sperm capacitation in particular how the cells are modulated (controlled) by the female tract. The purpose of this editorial is to highlight some of the salient issues raised in these reviews and try to put them into perspective on why the dynamic interaction between the female tract and the human spermatozoon deserves considerably more investigation if we are to make real progress in understanding how a sperm cell functions.
There are a number of elegant in vivo investigations studying the transport of sperm in several species (e.g. pigs, hamsters, cows) which show that the female tract sequesters spermatozoa in a functional reservoir (primarily in the oviduct). Although there is considerable speculation about the nature of the interaction between the oviductal epithelium and the spermatozoon, several plausible mechanisms have been proposed. However, the situation in the human maybe somewhat different. There are ethical, technical and logistical difficulties in performing experiments in humans, but data from in vivo experiments fail to reveal such an oviductal reservoir (e.g. Williams et al., 1993). Additionally, in vitro experiments using a series of oviductal tissues preparations (including explants) have shown that human sperm will bind to these tissues but with noticeably less tenacity than in animals. In fact, what is remarkable is that the human spermatozoon will bind, release, then bind again, potentially repeating this cycle several times (Pacey et al., 1995). As human sperm move in and out of a hyperactivated state (Mortimer and Swann, 1995), it would appear that hyperactivated cells have the ability to bind to the oviductal epithelium. Why is it important to understand this? In animals, binding to the oviduct acts to prolong the survival of the sperm cell—perhaps keeping it in a state of suspended animation. From the available data, it appears that the human is likely to be different. However, this model (oviductal attachment/release) provides an excellent tool to study the switching behaviour of the cell and the interaction between the environment and the intrinsic physiology of the cell. We know very little about what controls sperm activation, e.g. hyperactivation and this would be an ideal starting point to provide potentially physiological answers to fundamental questions.
In the human, it is not just the oviduct that may influence the physiological state of the sperm cell. Several experiments in the 1970s and 1980s have shown that cervical mucus acts to rapidly activate the sperm yet maintain it in a state ready for fertilization for several days (De Jonge, 2005). Such experiments reveal the strong influence of the female reproductive tract but at the same time make us aware of gaping holes in our understanding of the true biological basis of sperm capacitation, e.g. how is the process arrested/suspended? In fact, extrapolating from De Jonge’s thesis, there is almost a complete divorce in thinking between researchers studying capacitation (in vitro) and what is likely to be happening in vivo. For our understanding to progress, there needs to be a remarrying of the two schools. For example, it does not take 6–24 hours to fully capacitate a human sperm cell. A sperm may, however, begin the process of capacitation very rapidly, e.g. when in cervical mucus but then be prevented from further activation. What is evident are the potential differences when studying human IVF compared to in vivo. IVF is an excellent tool to study sperm function/dysfunction, but the dynamics of this are very different to what happens in vivo. The IVF system, specifically the culture medium, is designed to, almost immediately, maximize the fertilizing potential of the sperm, switching on a series of capacitation-related events very rapidly with no intention to put a brake in the system (Moseley et al., 2005). Thus, potential defects in the synchrony of the sperm capacitation sequence may be overcome and/or further exposed in the IVF situation. Defects in putative capacitation pathways, e.g. tyrosine phosphorylation are associated with low fertilization rates (Sakkas et al., 2003) thus, IVF presents as a functional outcome tool. However, the differences in the systems (in vivo, in vitro in a research laboratory and IVF) need to be realized and used to complement our understanding. The message is simple, studies on sperm capacitation should not be performed in intellectual isolation.
These timely reviews (De Jonge, 2005; Suarez and Pacey, 2005) act to emphasize the importance of the female tract in interacting with and regulating the sperm on its remarkable journey. There must be a reinvigorated application of research to studying sperm interaction with the female reproductive tract. Additionally, this knowledge needs to be integrated with the progress being made in elucidating the pathways of sperm capacitation in order that we may understand the subtlety of sperm physiology as it relates to its natural environment. Whilst there is a pure academic interest to study these processes, the practical driving force is the almost universal failure of the field, to date, to develop non-assisted reproduction treatments (ART) for sperm dysfunction. Put simply, it is likely that we have been studying the spermatozoa in the wrong environment, in the wrong way and at the wrong time.
References
De Jonge CJ (2005) Biological basis for human capacitation. Hum Reprod Update 11,205–214.
Moseley F, Jha KN, Bjorndahl L, Brewis IA, Publicover SJ, Barratt CL and Lefièvre L (2005) Induction of human sperm capacitation varies between incubation media; an effect that is not associated with protein kinase A activation. Mol Hum Reprod 11,523–529.
Mortimer ST and Swann M (1995) Variable kinematics of capacitating human spermatozoa. Hum Reprod 10,3178–3182.
Pacey AA, Davies N, Warren MA, Barratt CLR and Cooke ID (1995) Hyperactivation may assist human spermatozoa to detach from intimate association with the endosalpinx. Hum Reprod 10,2603–2609.
Sakkas D, Leppens-Luisier G, Lucas H, Chardonnens D, Campana A, Franken DR and Urner F (2003) Localization of tyrosine phosphorylated proteins in human sperm and relation to capacitation and zona pellucida binding. Biol Reprod 68,1463–1469.
Suarez S and Pacey AA (2005) Sperm transport in the female tract. Hum Reprod Update 12,23–27.
Williams M, Hill CJ, Scudamore I, Dunphy B, Cooke ID and Barratt CLR (1993) Sperm numbers and distribution within the human fallopian tube around ovulation. Hum Reprod 8,2014–2026.
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