Faculty of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK
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Abstract |
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Key words: assisted reproductive technologies/ectopic pregnancy/endometrial transplants/endometriosis/Fallopian tube
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Introduction |
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Anomalous tubal transport |
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Viewed conventionally, loss of tubal patency would be a sequel to one or more episodes of infection arising, for example, from Chlamydia trachomatis (Henry-Suchet and Loffredo, 1980; Sweet, 1982
; Brunham et al., 1985
; Tuffrey et al., 1986
). Gonococcal and tuberculous infection may also be involved in such pelvic inflammatory disease, and complications can arise at a tubal level following septic abortions. Scarring and subsequent occlusion of the Fallopian tube tend to be frequent sequelae to inflammation arising from bacterial infection. Even if patency had not been seriously compromised by infection, the endosalpinx would have been damaged and its surface modified during one or more episodes of salpingitis. The condition of the ciliated epithelium should certainly be questioned. At a biochemical level the epithelium may no longer present molecular markers representative of a Fallopian tube.
As to the site of tubal ectopic pregnancies, implantation usually favours the mid-portion of the Fallopian tube, but has also been noted in both the proximal (cranial) ampulla and interstitial region. In a series reported from Jamaica, the distribution was 7% on the fimbriated infundibulum, 42% in the ampulla, 28% in the isthmus and 13% interstitial, with the remainder being imprecisely determined (Douglas, 1963). Diverse Fallopian tube sites have also been noted in monkeys (Benirschke, 1969
).
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Role of luminal fluids |
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What bearing do these various points have on the physiology of early embryonic development in primates? The very occurrence of tubal ectopic pregnancies would suggest some flexibility in the provision ofor requirement forsubstrate in the tubal luminal fluid. It could perhaps be argued that the substrate requirements of primate embryos are less stringent than those of laboratory rodents or, more plausibly, that there is a considerable overlap in the composition of luminal fluid in primates between the Fallopian tubes and uterus. Bearing in mind the nature of the tubo-uterine interface within the intramural portion of the tube and the lack of swollen polypoid processes at the actual junction (Lee, 1928; Patek, 1974
), the latter seems a strong possibility. Tubal fluids would enter the uterus and vice-versa, mixing would occur, and their compositions would no longer be unique, even if they were so at the time of their formation. Not only does the existence of tubal ectopic pregnancy support these views, but the fact that gametes can be introduced directly into the uterus and generate a pregnancy emphasizes the ability of the zygote and developing embryo to tolerate such fluids (Hunter, 1977
, 1998
). The result of Estes' operation, transplantation of an ovary into the uterus in patients with blocked Fallopian tubes (Estes, 1924
; Estes and Heitmeyer, 1934
), when followed by pregnancy, would lead to a similar conclusion. In reality, both flexibility in the embryo's substrate requirements and overlap in the composition of tubal and uterine fluids could underlie the occurrence of ectopic pregnancy. Indeed, development of an ectopic pregnancy at diverse sites within the abdomen clearly demonstrates tolerance in the initial fluid environment of the human embryo.
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Ectopic pregnancy adequately explained? |
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Involvement of endometriosis |
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Whereas sperm might be able to progress within a Fallopian tube containing one or more endometrial fragments, the possibility of an oocyte or embryo descending such a tube would be much reduceda point already made in terms of relative dimensions of spermatozoon and oocyte. Not only might an embryo be arrested or trapped in such a manner, but the fluid microenvironment of the pseudo-endometrial surface together with its specific molecular architecture might act to promote and sustain development and implantation of an embryo. In a phrase, an embryo might perceive components characteristic of a uterine milieu, albeit within the constraints of a tubal site, these facilitating and indeed encouraging the processes of attachment and implantation.
Although one could speculate on the nature of the endometrial molecules that might be involved in such a scenario, and which would modulate interactions with the highly invasive trophoblast (Edwards, 1980), it would be more instructive to examine clinical specimens at known stages of development. An approach to tubal pregnancy currently in favour involves laparoscopic-guided injection of methotrexate, PGF2
or hypertonic glucose into the gravid Fallopian site to compromise the embryo and conserve the tube (Maymon and Shulman, 1996
). However, there will also be clinical circumstances in which portions of tubal tissue and contents are removed from the patient during salpingostomy or salpingectomy. If such tissues could be subjected to rigorous modern analysis to establish the presence of endometrial marker molecules (proteins or mRNAs) interacting with chorionic tissue, then the present hypothesis would be strengthened (Campbell and Thomas, 2001
). Overall, what has been argued in this section is that human uterine fluid and endometrial tissue can reflux into the Fallopian tube lumen or even abdomen, enabling a trapped or expelled embryo to continue development and implant in an ectopic site, even though the site may not be distinguished as such; in other words, it may present a uterine-like environment (Hunter, 1998
).
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Development of an animal model |
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The value of developing such an animal model of tubal ectopic pregnancy would lie in its affording a means of systematic analysis of the molecular messages underlying and perhaps even prompting initiation of embryoepithelial interactions in an extrauterine site (Campbell and Thomas, 2001). If the model could generate a tubal pregnancy with a predictable level of success, then molecular studies would be placed on a precise chronological footing. Such findings might in turn lead to simpler non-invasive treatments for relieving this life-threatening condition upon early detection and act to combat the reduction in fertility potential after current treatments. The primary objectives would be to develop an approach that (i) imposed minimum physical damage upon the Fallopian tube and (ii) reduced or negated the attractiveness of any remaining endometrial fragments to any future embryos in their vicinity. Ultimately, a means might be revealed of preventing attachment and establishment of refluxed endometrial fragments within the Fallopian tubes. Overall, a principal category of patients that comes to mind in the above context would be those undergoing treatment for infertility by means of assisted reproduction technology.
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Acknowledgements |
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Notes |
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References |
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