Human Reproduction, Vol. 15, No. 12, 2451-2454,
December 2000
© 2000 European Society of Human Reproduction and Embryology
Understanding the apical surface markers of uterine receptivity
Pinopods—or uterodomes?
Department of Anatomy and Histology, F13, The University of Sydney, NSW 2006, Australia. E-mail: histology{at}anatomy.usyd.edu.au
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The plasma membrane of uterine epithelial cells is very sensitive to ovarian hormones and protrusions of the apical portion of this membrane have been used as indicators of endocrine status and preparation for implantation in the human uterus in particular. Protrusions of the apical plasma membrane were first identified in rats and mice where their established pinocytotic function gave rise to the name `pinopod'. In humans and many other animals however, little evidence of the functional nature of such protrusions is available but what is available suggests that human `pinopods' (useful though they are as indicators of endocrine status) might be more similar morphologically to other, larger, membrane protrusions, or apical domes, which have been shown not to be pinocytotic. Hence, I propose that these latter protrusions, including those in the human uterus, should be referred to by a term which does not imply a particular function and have settled on the name `uterodome'.
Key words: apical plasma membrane/pinopods/uterine receptivity
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In recent years, much interest has been aroused in projections of the apical surface of uterine epithelial cells called pinopods (or pinopodes) which have been associated with changes in the uterine surface in preparation for implantation of the blastocyst. In humans in particular, there have been many papers using these structures as markers of uterine receptivity. The function of these structures in most animals, including humans is unknown, and this article argues that (useful though they may be as a measure of normal uterine function) the term `pinopod' has been applied to structures which display considerable morphological variation and which in some cases bear only a passing resemblance to the structures of known pinocytotic function—the true `pinopods' of rats and mice.
Probably the first observations on projections from the apical surface of uterine epithelial cells were those in mice (Nilsson, 1958
) and rats (Warren and Enders, 1964), although it was Nilsson who provided the first extensive discussion and illustration of apical projections which he referred to simply as cytoplasmic protrusions and blebs (Nilsson, 1966). Such structures on the apical surface of uterine epithelial cells in rats and mice have been known by different names: using the scanning electron microscope `sea-anemone like' structures were identified (Psychoyos and Mandon, 1971), as were `fungus-like' projections (Ljungkvist, 1971) and `morel-like' protrusions were also described in later work (Nilsson, 1972). In most micrographs, these structures were seen to measure several µm across and to project into the uterine lumen above the level of the microvilli. They had a comparative lack of cellular organelles and an undulating irregular surface, the membrane of which was devoid of typical microvilli.
Early speculation on the function of these variously named projections focused mostly on apocrine secretion but the possibility of absorption of luminal contents was also entertained (Nilsson, 1972; Enders and Nelson, 1973). Speculation on function in rats at least was promptly ended however, when in an elegant experiment, an electron-dense tracer (ferritin) was introduced into the uterine lumen and it was found that the tracer was taken up by the projections and entered the uterine epithelial cells in large vacuoles (Enders and Nelson, 1973). This demonstrated unequivocally a pinocytotic function for the projections and the term `pinopod' (drinking foot) was coined as a result (Enders and Nelson, 1973). Similar experiments in both mice and rats (Parr and Parr, 1974, 1977) extended and confirmed the pinocytotic nature of these apical protrusions and contributed to the popularity of the term `pinopod' which came to be used more generally across species, even though there was little evidence that somewhat comparable structures in other species had pinocytotic activity.
These true pinocytotic structures (pinopods) in rats and mice have several important morphological features. They arise from the cell surface on stalks or pedicels which rise above the level of microvilli (Enders and Nelson, 1973; Parr and Parr, 1974; Murphy, 1993). While the surface of the pinopod is smooth and devoid of typical microvilli, microvilli underneath the pinopods, as well as on cell surface not `overhung' by pinopod, are short and stubby but still fairly regular. This is to be expected, since pinopods are progesterone-dependent structures and progesterone results in short microvilli (Ljungkvist 1971; Murphy and Rogers 1981) which have, after the first 3 days of pregnancy, replaced the long regular microvilli of oestrus/day 1 of pregnancy (Murphy, 1993). These pinocytotic structures are also frequently seen to contain large vacuoles which transport the endocytosed material into the cell (Enders and Nelson, 1973; Parr and Parr, 1974). Moreover, the `stalk' of true pinopods in rats and mice usually arises from the apical plasma membrane near the lateral border of the cell (Enders and Nelson, 1973; Luxford and Murphy, 1992). Importantly, these structures of known pinocytotic function in rats and mice do not occupy the entire cell surface nor are they `bulges' of the entire cell surface, although they may appear to overhang much of the cell surface especially when viewed from above—as in scanning electron microscopy.
Work on pinopods in rats using specialized ultrastructural techniques has shown that, while they lack typical membrane-bound organelles (Nilsson, 1966, 1972), they are far from devoid of regular cellular components and are richly invested with actin filaments. Across the `neck' of the pinopod, these actin filaments form a band which descends onto the lateral plasma membrane and connects with the junctional complex region (Luxford and Murphy, 1992; Murphy, 1995, 2000). These structural observations are consistent with the pinocytotic function of rat pinopods since such bands of actin filaments are known to be involved in endocytosis in other systems (Young et al., 1992).
In passing, it is worth commenting on just what uterine state pinopods might really indicate. It is sometimes thought that pinopods indicate a uterus which is actually receptive for implantation but in rats and mice where most studies have been performed, it is known that whereas receptivity requires both progesterone and oestrogen, development of pinopods depends on progesterone alone and is actually inhibited by oestrogen (Ljungkvist, 1971; Psychoyos, 1973; Parr and Parr 1977; Martel et al., 1991; Singh et al., 1996). In clinical situations, which have driven much of the recent interest in human `pinopods' or `pinopodes', this distinction may not be so important because reliable markers of normal uterine maturation are the main objective. Even so, since the highest frequency of pinopods is found in response to progesterone alone, it may be that pinopods indicate a uterus which is coming into receptivity rather than actually in it (Martel et al., 1991; Murphy, 1995).
Structures with varying degrees of similarity to the pinopods of rats and mice have been described in the uterine epithelia of an impressive array of animals (Murphy, 1995). To date, such species include gerbils (Kress and Mardi 1990), cows (Guillomot and Guay, 1982), rabbits (Segalen et al., 1982), sheep (Guillomot et al., 1981), hamsters (Blankenship et al., 1990), deer (Aitken, 1975), pigs (Keys and King, 1990), monkeys (Bhartiya and Bajpai, 1995), camels (Abd-Elnaeim et al., 1999) and even viviparous lizards (Murphy et al., 2000). Humans are, of course, among these other species and have attracted by far the greatest interest because of the reported utility in clinical medicine of the pinopod-like structures in the human uterine epithelium (Johannisson and Nilsson, 1972; Psychoyos and Martel, 1985; Murphy et al., 1987; Martel et al., 1991; Psychoyos and Nikas, 1994; Paulson et al., 1997; Nikas and Psychoyos, 1997; Nikas et al., 1995, 1999; Nikas, 1999a,b).
Notwithstanding the considerable clinical interest in these human `pinopods' or `pinopodes' there are some important morphological differences between the structures seen arising from the apical plasma membrane in these other animals (including humans) and those structures of known pinocytotic function (the pinopods) in rats and mice. Of major importance is the observation that in animals other than rats and mice, the structures generally arise from the entire apical cell surface and essentially involve all of the apical plasma membrane. This seems particularly so in humans where Psychoyos and Nikas (1994) refer to `the entire surface of each epithelial cell' being covered by a folded structure and Develioglu et al. (1999) refer to the human `pinopodes' as smooth membrane projections that arise from the entire cell surface. Nikas (1999a) also shows developing human `pinopodes' as occupying the entire cell apex. In rabbits, it has been noted (Parr and Parr, 1982) that apical protrusions or `domes' in this species do not contain the typical vacuoles seen in the true rat pinopods and that they too were bulges of the entire apical plasma membrane. Enders and Nelson (1973) also commented on the lack of the typical pinopod vacuole in projections of the human uterine surface and Guillomot et al. (1986) made the same observation about the `dome-shaped cytoplasmic protrusions' of cow uterine epithelial cells. In camels, it has been shown that structures identified as `ectoplasmic pads' in this species are also a bulge of all of the cell surface (Abd-Elnaeim et al., 1999).
There are other morphological distinctions between the known pinocytotic structures and the apical bulges or domes of the uterine surface in other animals. The latter for instance sometimes appear to contain numerous membranous cellular organelles. Guillomot and Guay (1982) found mitochondria in the bulging apical surface of cow epithelial cells they studied with transmission electron microscopy. Parr and Parr (1982) found mitochondria and even the occasional nucleus in the rabbit apical domes they examined. Similarly, Dockery et al. (1997) showed transmission electron micrographs of membranous whorls and mitochondria in apical bulges of the human epithelial surface and the organelle content of these human structures has also been noted by other investigators (Bentin-Ley et al., 1999). There may also be a difference in the frequency of the known pinopods and the structures in other animals. In rats and mice, pinopods were only observed on ~20% of cells, depending on the exact time of pregnancy (Enders and Nelson, 1973; Parr and Parr, 1974) and most other studies on rodent pinopods show them on cells at about this frequency (Parr and Parr, 1982; Murphy, 1993). However, in other animals, the apical bulges appear on at least one in two or more cells (Bhartiya and Bajpai, 1995; Abd-Elnaeim et al., 1999) and also seem to be visible on a majority of the non-ciliated cells in human studies (Psychoyos and Nikas, 1994; Bentin-Ley et al., 1999; Nikas, 1999a).
Studies in which tracer is introduced into the uterine lumen to determine whether it is taken up by the apical protrusions would, of course, be the most convincing evidence of function and are, indeed, the origin of the term `pinopod' (Enders and Nelson, 1973). In animals other than rats and mice, such studies are rare but the conclusion from them seems unequivocal. In an experiment similar to the ones earlier performed on rats and mice, ferritin was injected into the uterine lumen of rabbits and it was found that the ferritin was not taken up by the apical domes seen in this species (Parr and Parr, 1982). It was concluded that the structures were not pinocytotic (Parr and Parr, 1982). Similarly, horseradish peroxidase was introduced into the uterine lumen of cows (Guillomot et al., 1986) and it was found little of it entered the epithelial cells at all, and that which did enter the cells did not do so by means of the apical protrusions seen arising from all of the cell surface in this species. Hence, Guillomot et al. (1986) also stated that they could find no evidence that the structures they described as large cytoplasmic protrusions were pinocytotic.
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Thus in animals other than rats and mice, bulges or domes of the apical surface of uterine epithelial cells are only somewhat morphologically similar to the pinopods of rats and mice. Moreover, functional studies, where they exist, actually indicate that pinocytosis is not a function of these structures.
None of this of course should be interpreted to suggest that the structures in the human uterus which have been called `pinopods' or' pinopodes' are not important indicators of uterine endocrine progression under a range of normal and experimental conditions. Excellent recent work (Nikas et al., 1995, 1999; Nikas 1999a,b) establishes their utility as indicators of uterine development. However, the morphology of these human structures is not consistent with that of the known pinocytotic structures (the pinopods of rats and mice) and is rather more similar to other structures (the apical domes) in rabbits and cows, which have been shown experimentally not to be pinocytotic. This article thus suggests that in future, we should avoid a term that implies a particular function. Alternative names that do not imply function but are nonetheless descriptive of one or more aspects of these enigmatic and important human structures include `epidome', `epiuterodome', `uterodome' and `endometriodome', but for the present, for simplicity and to signify their organ of origin as the uterus, this article settles on `uterodome'.
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Acknowledgments |
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I am grateful to Susan Adams and Martin Johnson for discussions on this paper. The Australian Research Council has supported aspects of the author's work in recent years, as has Serono Australia Ltd.
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This debate was previously published on Webtrack, August 21, 2000
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