Background Spermatozoa acquire their fertilizing ability and forward motility properties during epididymal transit. Our knowledge of gamete physiology is based on studies conducted in laboratory and domestic species; our knowledge of these processes in humans is limited. Medical indications for assisted reproductive technologies (ART) have progressed to include male infertility. Surgical procedures allow collection of spermatozoa from all along the human excurrent ducts, and the former have been used with some success in reproductive medicine. This has raised questions over the role of the epididymis in human sperm physiology. Objective and rationale To reanalyze what we now know about epididymal physiology in humans and to assess the relevance of laboratory animal models for understanding human physiology and the pathophysiology of the epididymis. Search methods A systematic bibliographic search of PubMed for articles published in English before May 2015 was carried out using the search terms 'epididymis' and 'sperm maturation'. Literature on the consequences of vasectomy on the epididymis was also searched. Outcomes Whereas the proximal epididymis is almost exclusively occupied by efferent ducts, the sperm reservoir capacity is poorly developed in humans. At the molecular level, the human transcriptome and proteome show some segment specificity; conflicting results persist with regard to secretome variation along the tubule. The number of genes regulated along the excurrent ducts in men is lower when compared to rodent species, but remains significant. It is challenging to reconcile biochemical and physiological studies with clinical data obtained from men undergoing reanastomosis of the vas deferens at different points along the excurrent duct. We propose that vasectomy/vasovasostomy is a model to understand the consequences of obstruction on epididymis function in humans. Wider implications Despite the scarcity of biological material available, the interspecies variability of the male reproductive tract urges us to use modern molecular and cellular biology tools to better understand human epididymis physiology in order to apply ART in a more responsible manner.

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The human epididymis: its function in sperm maturation

The function of the epididymis is considered in the context that it is necessary to transport spermatozoa for internal fertilization, but is also an adaptation involved in the competition between males to achieve paternity. Post-testicular sperm maturation and storage occur in lower vertebrates, such as the chondrichthyes, in which sperm storage is essential due to the slow rate of spermatogenesis. These roles persist in higher vertebrates, including mammals. However, they are less important in certain birds, in which the rate of sperm production by the testes is sufficient to supply enough spermatozoa to cope with the demands of a competitive mating system.



There is no evidence for mammals, other than humans, that spermatozoa can achieve the capacity to fertilize an ovum without passing through some of the proximal epididymis. Storage of spermatozoa in the epididymis is probably not essential for a male to achieve conception in a protected mating system, but is very important in a competitive mating system. There is some variation between species in the magnitude of the epididymal storage region. This is related to the descent of the epididymides (and testes) into a scrotal sac in some species and/or the demands of the mating system in other species. The claims that humans are not dependent on post-testicular sperm maturation and storage need to be qualified, as they are based on studies of abnormal tracts and tests of fertility which are not rigorous. Nevertheless, the claims are of considerable clinical significance and may indicate that humans are less dependent on post-testicular sperm maturation and storage than other mammals. This may be an adaptation of the testes and epididymides to the scrotal conditions of modern man or a response to changing environmental factors.

To store or mature spermatozoa? The primary role of the epididymis.

The Common marmoset monkey, Callithrix jacchus jacchus, breeds more rapidly in captivity than any other primate Because of its small size (adult body weight 400 g) it is easy to maintain in family groups in captivity, so eliminating the boredom and neuroses sometimes seen in the larger macaques and baboons that are often caged singly Marmosets adapt well to captive conditions, to handling, sampling and experimental procedures, particularly if a system of rewards is used They are economical to keep, normally produce twins, and because of their short generation interval, with sexual maturity at about 18 months of age, they can be established in captive, self-sustaining breeding colonies at a fraction of the time and cost taken for the larger, more conventional, laboratory primates

The Common Marmoset (Callithrix jacchus)

Human epididymal secretome and proteome.

The structure of the human caput epididymidis was examined by gross morphological and light and electron microscopic techniques. There were at least seven types of tubules, each characterized by a different epithelium. These tubules were connected with one another by at least eight types of junctions to form a network. Most of the caput epididymidis was composed of efferent ducts. Within these, five types of tubules, each with a different ciliated epithelium, were found in different regions; and four types of junctions between the efferent ducts and the epididymal tubule were observed. The efferent ducts left the testis, initially as parallel straight tubules containing both ciliated and non-ciliated cells in an epithelium of irregular height. Each efferent duct then coiled tortuously into lobules that folded over one another. These efferent ducts then branched out as thin tubules to join a network of dark tubules which were lined by a regular epithelium containing prominently vacuolated, non-ciliated cells. These tubules anastomosed via common cavities characterized by a ciliated cuboidal epithelium and sometimes joined tubules exhibiting a non-vacuolated ciliated epithelium. The latter, as well as typical efferent ducts, made connection with the epididymis proper in both end-to-end and end-to-side junctions. In the more distal junctions with the epididymis, the efferent ducts joined to a transitional epididymal ductule before joining to the side of the epididymis proper. Post-junctional epithelia in the beginning of the epididymis occasionally contained patches of cells characteristic of efferent ducts. Tall cells with long stereocilia constituted a discontinuous "initial segment"-like region of the epididymis. This is the most detailed study so far of the epithelia and the tubule organization in the caput epididymidis of any species, and most of the results are reported for the first time for the human. Although the pattern of the tubule network resembles that of some domestic species, the rich variety of epithelia has not been appreciated before.

Organization of tubules in the human caput epididymidis and the ultrastructure of their epithelia.

To assess both the need and potential of different primates for studying human epididymal function, the ultrastructure of the epididymis in several New and Old World monkeys has been compared with that of man. Sexually mature monkeys of six species were used; three talapoin monkeys, two pig-tail macaques, one patas monkey, one capuchin, one spider monkey, and four common marmosets. Samples of human epididymis were obtained from men undergoing vasectomy. Tissue was examined by light and electron microscopy and observations were quantified using image analysis. The primate epididymis displayed several ultrastructural features not observed in other mammals. These included the presence of small membrane-bound granules in the infranuclear cytoplasm of principal cells, and a close association of blood capillaries with the basal lamina and mitochondria-rich cells. Differences were apparent in the number and volume of organelles in principal cells from different regions of the epididymis and between species. Epididymal tissue in man showed a much greater ultrastructural diversity than that of monkeys. The significance of these results is discussed in relation to the need for an animal model for studying the primate epididymis.

The comparative ultrastructure of the epididymis in monkeys and man: A search for a suitable animal model for studying epididymal physiology in primates.

H. D. M. Moore

Papers

The comparative ultrastructure of the epididymis in monkeys and man: A search for a suitable animal model for studying epididymal physiology in primates.