At coitus, human sperm are deposited into the anterior vagina, where, to avoid vaginal acid and immune responses, they quickly contact cervical mucus and enter the cervix. Cervical mucus filters out sperm with poor morphology and motility and as such only a minority of ejaculated sperm actually enter the cervix. In the uterus, muscular contractions may enhance passage of sperm through the uterine cavity. A few thousand sperm swim through the uterotubal junctions to reach the Fallopian tubes (uterine tubes, oviducts) where sperm are stored in a reservoir, or at least maintained in a fertile state, by interacting with endosalpingeal (oviductal) epithelium. As the time of ovulation approaches, sperm become capacitated and hyperactivated, which enables them to proceed towards the tubal ampulla. Sperm may be guided to the oocyte by a combination of thermotaxis and chemotaxis. Motility hyperactivation assists sperm in penetrating mucus in the tubes and the cumulus oophorus and zona pellucida of the oocyte, so that they may finally fuse with the oocyte plasma membrane. Knowledge of the biology of sperm transport can inspire improvements in artificial insemination, IVF, the diagnosis of infertility and the development of contraceptives.

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Sperm transport in the female reproductive tract

Background The epididymis performs an important role in the maturation of spermatozoa including their acquisition of progressive motility and fertilizing ability. However, the molecular mechanisms that govern these maturational events are still poorly defined. This review focuses on recent progress in our understanding of epididymal function including its development, role of the luminal microenvironment in sperm maturation, regulation and novel mechanisms the epididymis utilizes to carry out some of its functions. Methods A systematic search of Pubmed was carried out using the search term 'epididymis'. Articles that were published in the English language until the end of August 2008 and that focused on the specific topics described above were included. Additional papers cited in the primary reference were also included. Results While the majority of these findings were the result of studies in animal models, recent studies in the human epididymis are also presented including gene profiling studies to examine regionalized expression in normal epididymides as well as in those from vasectomized patients. Conclusions Significant progress has been made in our understanding of epididymal function providing new insights that ultimately could improve human health. The data also indicate that the human epididymis plays an important role in sperm maturation but has unique properties compared with animal models.

New insights into epididymal biology and function

Bicarbonate/CO2 is believed to be the key in vitro effector of sperm capacitation, a process which induces major changes in the sperm plasma membrane in preparation for fertilization. In a flow cytometric study, we examined the effect of bicarbonate on boar spermatozoa using merocyanine, an impermeant lipophilic probe which binds to plasma membranes with increasing affinity as their lipid components become more disordered. We found that bicarbonate causes a rapid increase in the ability of live boar spermatozoa to bind merocyanine. First detected about 100 sec after exposure to bicarbonate and largely complete by 300 sec, this increase appears to result from individual cells within the sperm population switching from a low merocyanine-binding state to a high binding state. The majority of live spermatozoa are capable of responding in this way, and do so in proportion to bicarbonate concentration, half-maximal response being induced by about 3 mM bicarbonate; however, overall population response varies greatly between ejaculates. Increased merocyanine stainability is observed over the whole surface area of the cell, and is reversible both with respect to temperature (it is only manifested above 30 degrees C) and with respect to presence of bicarbonate. A similar effect can be induced by phosphodiesterase inhibitors such as isobutylmethylxanthine, and enhanced by a permeant cyclic nucleotide analogue. We conclude that bicarbonate causes a major alteration in sperm plasma membrane lipid architecture, apparently by perturbing enzymic control processes. This novel action of bicarbonate may represent an initial permissive event in the capacitation sequence.

Bicarbonate/CO2, an effector of capacitation, induces a rapid and reversible change in the lipid architecture of boar sperm plasma membranes

The Epididymis: From Molecules to Clinical Practice

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2605.1995.tb00408.x

Testicular heating and its possible contributions to male infertility: a review.

As far as can be determined now, the general organization of the human epididymis, the regional character of its epithelium and luminal environment, and the maturation changes that spermatozoa undergo there are quite similar in many respects in both animals and man. None the less, the outcomes of some clinical procedures aimed at overcoming duct obstruction (high epididymovasostomy or microaspiration of some fertile spermatozoa from the caput or vasa efferentia) suggest a flexibility in the sperm/epididymal relationship that may cast an element of doubt as to the essential place of the epididymis in the chain of human conception. While such clinical results make it difficult yet to be quite sure that the epididymis has the same essential sperm maturation role in man that it does in the few animals tested, they raise intriguing questions as to the potential ability of the human vas deferens, and even the vasa efferentia, to contribute in that respect. The human epididymis possesses other traits which collectively seem to resemble the suppressive effects of subjecting animal epididymides to body temperature. In that regard, it is a real possibility that the elevation of scrotal temperature imposed by clothing may be affecting in an adverse manner several aspects of epididymal function, especially those concerned with the storage and viability of spermatozoa, and thereby the quality of the ejaculate.

The status and the state of the human epididymis

Failures of fertilization in in-vitro fertilization have been often linked to visually recognizable defects in spermatozoa, and occasionally to anti-sperm antibodies. However, some total failures and the frequent lack of fertilization in some eggs of normal appearance (partial failure) often remain unexplained. Simple evaluation of the configuration of sperm binding to the zona pellucida and of the oocyte features revealed by acetic alcohol fixation and lacmoid staining, may provide diagnostic clues in this respect. Among 25 cases of unanticipated total failure, this approach identified some men with normal semen analyses whose spermatozoa displayed either a total inability to bind to the zona or, after binding, an inability to intrude into the zona matrix. However, in 10 of these cases significant numbers of spermatozoa were bound to and intruded deep into the zona, a pattern consistent with the possibility of an egg defect, specifically a resistance to the passage of spermatozoa past the inner portion of the zona pellucida. Such a block also appeared to be the main cause of fertilization failure among 442 unfertilized eggs from 154 partial failure patients. As in the total failures, the inability of apparently competent spermatozoa to penetrate the zona was often associated with ooplasmic anomalies (refractile bodies, extra groups of chromosomes, chromatin rings or masses, one or more pronuclei with one or no polar bodies, and other occasional anomalies). These anomalies occurred in 79.4% of this unfertilized oocyte subset, in contrast to a 27.4% incidence in 238 oocytes not fertilized because of sperm defects. Simple retrospective assessment of sperm binding patterns and oocyte cytology can be a valuable complement to semen analysis in diagnosis of fertilization failure in vitro.

Sperm/egg binding patterns and oocyte cytology in retrospective analysis of fertilization failure in vitro

A specialist in reproduction and infertility reviews the physiology of fertilization and the contraceptive potential of fertilization. Suppression of the process by which spermatozoa can fertilize an ovum (capacitation) would be an attractive mode of contraception but we do not know what factor(s) promote sperm capacitation in vivo. Other potential interventions are along the approach of spermatozoa to the ovum: sperm transport and the cumulus oophorus which houses the ovum. Sperm interaction with the egg is another potential intervention mechanism. This comprises several stages: sperm binding to the zona pellucida induction of the acrosome reaction sperm penetration of the zona pellucida and zona penetrability and the block to polyspermy. A detailed discussion revolves around gamete fusion (i.e. sperm fusion with the zona pellucida). There is limited information about the accessibility of the fertilization site to drugs or other molecules and the principles that regulate their transfer. Fertilization research has focused almost entirely on mammals and not other vertebrates which provides little biological perspective to the relative complexity of humans. The immunogenetics of each major sperm antigen needs to be established to avoid unacceptable variability.

The contraceptive potential of fertilization: a physiological perspective

The epididymis was reflected unilaterally or bilaterally to the abdomen in adult hamsters, leaving normally functioning testes in the scrotum. In unilateral cases, spermatozoa taken from the abdominal cauda, 1 month or more post-operatively, underwent a reversal of head agglutination and dispersed earlier, and underwent hyperactivation and fertilized cumulus-free eggs about 30-45 min sooner than did spermatozoa from the contralateral scrotal cauda. In addition, spermatozoa from the abdominal cauda began to undergo a spontaneous acrosome reaction 30-45 min earlier and to a greater extent than in control spermatozoa. Finally, in females mated at or soon after ovulation, spermatozoa ejaculated by bilaterally cryptepididymal males fertilized eggs 30-45 min before those from normal males. Other females mated to bilaterally cryptepididymal males gave birth to normal litters. The results are considered in terms of the possibility that temperature-sensitive sperm-binding macromolecules, which may be involved in sperm storage in the cauda epididymis, could be one determinant of the need for capacitation.

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Epididymal storage at abdominal temperature reduces the time required for capacitation of hamster spermatozoa.

Unlike those of many mammals, rat and hamster spermatozoa do not appear to be fully activated at ejaculation. Most rat spermatozoa transported en masse to the uterus approximately 2 minutes after coitus were vigorously motile on recovery soon thereafter in uterine fluid, whereas a majority, and sometimes all, were immotile in samples collected less than 2 minutes after coitus from the anterior vagina of normal females and up to 15 minutes after coitus from the anterior vagina in females with obstructed cervices. Many of these immotile rat vaginal spermatozoa began instant vigorous movement upon exposure to Tyrode's solution or uterine fluid. Hamster spermatozoa recovered from the vagina about 2 minutes after coitus were also immotile or displayed only slow, languid serpentine movements, but that motility profile remained very similar in spermatozoa taken 0.5 hours to 6 hours after coitus from the uterus, which is essentially fluid-free in the hamster. In the hamster, actively motile spermatozoa were evident only in the isthmus of the (transilluminated) oviduct. As in the rat, immotile vaginal and uterine hamster spermatozoa instantly began vigorous progressive motility in vitro on contact with Tyrode's solution or rat uterine fluid. Immotile spermatozoa from the rat and hamster cauda epididymidis immediately became highly motile in Tyrode's solution, and they developed a somewhat less rapid flagellar beat in 150 mmol/L NaCI or KCI, with or without 2mmol/L CaCI2. In contrast, dilution with an isotonic sucrose solution containing no ions, or only 2mmol/L CaCI2, evoked very slow and transient movement of rat and hamster epididymal sperm tails. We conclude that uterine fluid is a primary activating agent of sperm motility in the rat, whereas in the hamster active motility first develops only in the oviduct. The motility initiation factors in the female reproductive tract of the rat and hamster appear to be nonspecific. In vitro observations confirm that, although dilution of epididymal immobilin in which spermatozoa are enmeshed may play some minor part in initiating motility, other elements, including monovalent cations, are the major stimulus for the initiation of epididymal sperm motility in these species.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/j.1939-4640.1992.tb03341.x

J.M. Bedford

Papers

The status and the state of the human epididymis

Sperm/egg binding patterns and oocyte cytology in retrospective analysis of fertilization failure in vitro

The contraceptive potential of fertilization: a physiological perspective

Epididymal storage at abdominal temperature reduces the time required for capacitation of hamster spermatozoa.

Initiation of Sperm Motility after Mating in the Rat and Hamster