1 Department of Obstetrics and Gynecology, University of Bari, Italy and 2 Physiology and Pharmacology, University of Southern Denmark, DK-5000 Odense M, Denmark
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Abstract |
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Key words: counter-current transfer/preferential distribution/urethra/urinary atrophy treatment/vagina
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Introduction |
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Vaginal oestrogens that are able to resolve urethral atrophy without inducing endometrial proliferation may be another example of targeted therapy based on a counter-current transfer of oestrogens from vagina to the arterial blood supplying the urethra. However, since it is impossible to obtain blood samples from the urethral arteries or collect biopsies from the urethra, and since the nature of counter-current exchange of substances is similar to the transfer of heat (Glad Sorensen et al., 1991), we decided to use a heat-exchange in-vivo model. It is our experience that heat will be transferred if steroids are transferred and vice versa. This has been found in four different situations: between testicular vein blood and arterial blood; between ovarian vein blood and arterial blood; between vaginaluterine vein blood and uterine arterial blood and between venous blood in the cavernous sinus and internal carotid blood (Einer-Jensen, 1988
; Einer-Jensen and Khorooshi, 2000
;Einer-Jensen et al., 2001
). In no case was transfer of one and not the other found; the reason is probably that the transfer is based on passive diffusion, no pumping mechanism has been found. In this study, we investigated cold transfer from vagina to the vesical trigone and urethra, both in close anatomical relationship with the anterior vaginal wall. Plastic tubes filled with cold saline at different temperatures were inserted into the vagina of volunteers, while the temperature was recorded at vesical trigone and at three different sites of the urethra. Any cooling of the bladder and urethra that could not be explained by a simple diffusion of cold from the vagina may therefore suggest the occurrence of preferential distribution.
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Materials and methods |
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The participants were asked to empty the urinary bladder before the trial. The women were conscious and reported only minor discomfort during the insertion of the urethral probe. No painkillers or anaesthetics were administered during the trial. Standard gynaecological procedures were used throughout; the probes were autoclaved before insertion. During the investigation, bladder and urethral temperatures were collected every 2 s with a four-canal ELLAB TM9604 electronic thermometer (WWW.ELLAB.COM). The output from the thermometer was transferred to an IBM ThinkPad, Type 2625 with ELLAB TSII software installed. The urethral probes were produced by ELLAB according to our specification and they were based on Cu/CuNi thermo-elements. The probes were 25 cm long, 0.8 mm in diameter, and had four points of measurements: 1 mm from the tip (bladder); 38 mm from the tip (urethra 1); 45 mm from the tip (urethra 2); and 52 mm from the tip (urethra 3). The four points were painted blue and therefore visible during the insertion. The probe was inserted into the urethra until the tip was free in the bladder and the last urethral point disappeared above the urethral external ostium; correct positioning was verified by ultrasound. The probe was taped to a leg; the clinician controlled the position throughout the trial. The probe had a 3 m long connector to the thermometer. One minute after insertion of the probe, the vagina was cooled by means of a disposable plastic tube of 3 cm diameter and 10 cm length (50 ml disposable centrifuge tubes, Corning Incorporated, NY, USA) inserted for 5 min into the vagina (Figure 1). The tubes were used in three different ways: filled with saline at room temperature (2225°C) (14 women), at 5°C temperature (12 women) and with air at room temperature as controls (four women). Comparisons were performed 2 and 4.5 min after starting of cooling, and 4.5 min after removal of the plastic tube. All registrations were printed and the temperatures calculated manually, after which the results were transferred to a spreadsheet (MS Excel).
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Results |
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Discussion |
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Local or preferential transfer of substances is a common phenomenon in the reproductive system (Schramm et al., 1986; Einer-Jensen, 1988
). Among the different mechanisms advocated to explain the uterine first pass effect after vaginal administration, a counter-current exchange between adjacent veins and arteries may play a critical role (Einer-Jensen, 1988
). The anatomy of the blood vessels seems to favour such a possibility, since the vagina is surrounded by rich arterial and venous meshes and the blood supply of the urethra and the anterior vaginal wall are closely related. In addition to the vaginal blood supply received from branches of the internal pudendal artery, diffuse anastomoses between them and branches of the uterine, inferior vesical, and vaginal arteries are found. The confluence of these anastomotic branches forms longitudinal azygos vaginal arteries in the midline of the anterior or posterior vaginal walls, or both (Nichols and Milley, 1995
). The vaginal arteries send branches to the urethra and the bladder; the small arteries run lateral and parallel to the urethra and vagina, entering the urethrovaginal septum where extensive perforating vessels supply the urethra; accordingly, in the urethrovaginal septum, extensive capillary plexuses have been demonstrated (Krantz, 1951
). The upper thirds of the urethra receive branches from the inferior vesical artery, while the blood supply of the middle and lower third of the urethra derives from vaginal arteries (Krantz, 1951
). The veins draining the vagina communicate with the contralateral veins around the vagina and in the paracolpium form a rich venous mesh that cranially continues in the uterovaginal plexus. Part of the vaginal outflow reaches other larger veins via communicants with the vesical and the haemorrhoideal venous plexi (Williams et al., 1989
). It thus seems evident that most of the vaginal blood outlet is in close contact with arteries supplying the urethra and part of the bladder (Williams et al., 1989
).
The anatomy provides a possible interpretation of results. The vaginal wall, and therefore the venous blood, is cooled by the saline. The close contact between the veins and arteries means that the colder vein blood cools the vaginal arterial blood. The non-vaginal tissues, including the urethra, supplied with the cooler arterial blood will, therefore, decrease their temperature. The mechanism is similar to the heat transfer that takes place between the pampiniform venous plexus and the testicular artery in the ram (Waites and Moule, 1961). Temperature gradients between Graafian follicles and ovarian stroma also indicate heat transfer in the ovarian adnexa or between the intra-ovarian blood vessels (Hunter et al., 2000
). The vascular distribution may thus explain why larger and more rapid changes in temperature were found in the middle and in the lower third of the urethra than in the upper site. We postulate that such changes happen because the lower part of the urethra is supplied by arteries that run close to the vagina; the upper half of the urethra, on the other hand, is mainly supplied with arterial blood from the bladder. It is possible to conceive that vaginal arterial blood flowing from the upper part to the lower part of the vagina is exposed for longer to cold venous blood, so that blood to the lower part of the urethra could be colder than that to the upper part of the urethra and bladder. An additional hypothesis is that part of cold blood from venous vaginal plexus drains in the clitoral and bulbo-cavernosus venous plexus cooling vessels of the ischiocavernosus, bulbo-cavernosus and clitoral arteries that supply the lowest part of the urethra. The small changes in bladder temperature we have observed are in agreement with the hypothesis indicating that vesical vessels are not included in the transfer system; a simple `temperature buffer' effect of urine is excluded as patients voided their bladder before the trial.
The present data support the hypothesis of a preferential distribution to the urethra of vaginally administered oestrogens. However, according to that previously demonstrated for progesterone (Miles et al., 1994; Cicinelli et al., 2000
), a greater endometrial effect of oestradiol administered vaginally compared with that administered by systemic routes has been recently reported (Tourgeman et al., 2001
). This suggests that also in case of vaginal administration of oestradiol, direct vagina to uterus transport takes place and therefore, while some vaginal weak/low dose oestrogens are proven safe (in the absence of progestin), the risk of administration of any oestrogen preparation should be always considered.
In conclusion, our results indicate that the distribution of cold from vagina to the urethra is not the result of simple diffusion and that mechanisms of preferential distribution may exist from vagina to the urethra. The preferential distribution may contribute to explaining the efficacy of low-dose oestrogen therapy by the vaginal route for treating low urinary atrophy without inducing endometrial proliferation. On the basis of arterial distribution to the pelvic organs, a therapeutic scenario could be conceivable that introduces a new concept of targeted therapy via vaginal administration. In fact, by applying oestrogen in the lower part of the vagina, preferential distribution mainly from the vagina to the urethra could take place; on the other hand, by applying oestrogens or progesterone in the upper part of the vagina, preferential distribution to the uterus via the uterine artery could occur (Cicinelli and De Ziegler, 1999;Tourgeman et al., 2001
).
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Notes |
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References |
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Submitted on April 2, 2001; accepted on August 28, 2001.