1 Physiology and Pharmacology, Institute of Medical Biology, University of Southern Denmark, Winsloewparken 21,DK-5000 Odense C, Denmark, and 2 1st Department Obstetrics and Gynaecology, University of Bari, I-70124 Bari, Italy
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Abstract |
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Key words: blood supply/local transfer/temperature/uterus/vagina
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Introduction |
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Among the different mechanisms that could explain the preferential distribution to the uterus after vaginal administration, the counter-current transfer from the vaginal veins to the uterine artery probably plays a pivotal role (Einer-Jensen et al, 1993; Cicinelli and DeZiegler, 1999; Cicinelli et al., 2000
). It has previously been reported that in postmenopausal women, the corpus of the human uterus is supplied from the uterine artery while the tubal part is supplied from the ovarian artery (Einer-Jensen et al., 2001
). This conclusion was based on a decrease in temperature of the uterine corpus but not of the tubal corner of the uterus after cooling of the vagina. The corpus area must be supplied from the uterine artery, since the arterial blood is cooled in the vaginauterine veins and uterine artery transfer complex. The tubal corner must receive its blood supply from a different source, probably the ovarian artery, since the arterial blood was not cooled. The first investigation was made with a stainless steel uterine sound with two built-in thermoprobes (in the tip and 3 cm from the tip respectively); the uterine catheter was inserted blind through the cervical canal until the tip was in contact with the tubal corner. The two-point catheter was able to distinguish between the corpus and tubal corner, but was unable to indicate the position of the border between the uterine and ovarian arterial supply.
The present investigation was made with a 4-point thin, flexible thermocatheter positioned under hysteroscopic control near the tubal ostium; each measurement point was separated by 5 mm. Thus more detailed studies of temperature changes during vaginal cooling were possible and consequently of the border between the arterial supplies.
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Materials and methods |
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The women were conscious during the investigation, and no sedatives or painkillers were administered. The trial followed safe gynaecological procedures. Careful disinfection of external and internal genitalia preceded the insertion of the probe. Hysteroscopy was performed with vaginoscopic approach without speculum and tenaculum on the cervix by means of a 2.9 mm lens-based hysteroscope (Karl Stroz, Tuttlingen, Germany) with single-flow operative sheet carrying a 5 Fr. operative channel. Distension was obtained by means of 37°C pre-heated saline contained in a bag suspended 1 m above the patient. A special autoclavable thermoprobe fitting the 5 Fr. operative channel of the endoscope was developed. The probe (ELLAB, Roedovre, Denmark; www.ELLAB.com) was 0.8 mm in diameter, flexible, and 70 cm long. It was equipped with four Cu/CuNi elements, one in the very tip, the others positioned 5, 10, and 15 mm from the tip.
The probe was positioned in two different ways. In the first three cases, the probe was inserted into the operative channel of the hysteroscope with the tip just visible. When the hysteroscope entered the uterine cavity, the probe was pushed and directed under visual control towards the tubal ostium. The temperature probe was left with the tip just at the entrance to the tube, while the scope was withdrawn to the cervix. In the last seven cases, the hysteroscope was stopped just below the internal cervical ostium, the saline flow switched off, and the probe advanced into the uterine cavity toward the tubal ostium (Figure 1). The method was changed because with the first method, the temperature took a long time to return to basal values, probably because of the cooling effect induced by the contact of the endometrial mucosa with the hysteroscope. After a period with temperature baseline measurements, the vagina was flushed for 15 min with sterile saline (10001500 ml per 15 min, 22°C) infused by means of a soft and blunt catheter inserted into the vagina.
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The position of the probe was hysteroscopically controlled at the end of the vaginal cooling period by re-establishing the flow of the hysteroscope distension medium. All temperature tracings were printed and the curves inspected visually. In addition, the temperature readings before, as well as 2, 10 and 15 min after start of the vaginal flushing were measured using the ELLAB Windows based software. Two-minute readings were selected to catch `rapid' changes and 15 min chosen as a `steady state' value.
Absolute temperature values and differences at different times in each measurement point were evaluated. Data were reported as mean ± SD. Statistical analysis was performed by ANOVA and post-hoc Student-Neuman-Keuls test; P < 0.05 was considered significant.
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Results |
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In the first three cases, basal uterine temperatures were very low, probably due to contact with the hysteroscope, after which they continued to increase for more than 15 min. A steady state was not reached, and therefore no further cases of insertion of the temperature probe with the hysteroscope inside the uterus were investigated.
In one of the seven cases in the second group, the thermoprobe was found curled in the uterine lumen at the final endoscopic control; the case was excluded from the experimental group. The same decrease in temperature was found at all four positions. The case may be considered a control for the method, as it showed that no `extra' cooling from the vagina was passing through the probe itself.
The results from the remaining six women (in whom the correct position of the thermoprobe was verified) were used for the statistical analysis (Figure 2). A decrease in temperature was observed at all four points. The mean decrease was small after 2 min and increased over time (ANOVA, P < 0.0001). However, the decrease in temperature at 10 and 15 min reached statistical significance only at point 4; moreover, at 15 min, mean temperature reduction at point 4 was significantly greater than at all other measurement points (Figure 3
). Ten and 15 min after the start of cooling, the decrease at point 4 was 1.6 and 1.5 times greater than at point 3.
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Discussion |
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The results support a previous investigation in postmenopausal women (Einer-Jensen et al., 2001) with the additional information that the border between the supply from the uterine and ovarian arteries is 510 mm from the tubal ostium. This finding has clinical implications. It may be deduced that substances or hormones administered vaginally to postmenopausal women will semi-selectively and rapidly distribute to most of the endometrium. This is of critical importance for progesterone administration during postmenopausal hormone replacement therapy.
The study does not contradict previous findings of a possible extension to the ovary of the first uterine pass effect. Mizutani and co-workers reported that danazol concentrations in the ovary and uterus, after daily vaginal administration of a suppository containing 100 mg danazol, were comparable with those after daily oral administration of 400 mg danazol, but the serum danazol concentration was much lower (Mizutani et al., 1995). However, the danazol determinations were performed after repeated administrations, while the variations evaluated in this study occurred after a few minutes. Therefore the slower mechanisms of transfer from the lymph to the ovarian arterial blood may explain the increased concentration of danazol in the ovary. Alternatively, subsequent countercurrent transfer between uteroovarian venous blood and ovarian artery may also explain the increased concentration in the ovary after vaginal administration. The anatomical structure facilitating the transfer was described more than 300 years ago (De Graaf, 1668). Local transfer of 85krypton and 13C-progesterone has been found in women from the uteroovarian vein blood to the ovarian arterial blood (Bendz et al., 1979
; Halket et al., 1985
; see Einer-Jensen and Hunter, 2000
).
The women participating in the current trial were all in the menopause. A similar investigation in ovulating women would be interesting. However, due to the potential influence of steroids, the study would be difficult. The ovarian steroids may, due to the local transfer to the ovarian arterial blood (Einer-Jensen, 1988), have a local effect on the flow in the ovarian artery (Tan et al., 1996
; Kunz et al., 1997). Since estradiol is high close to ovulation, and since estradiol induces vasodilatation, the border may actually move in the same individual during the ovulatory cycle.
The greater cooling at point 4 compared with the other measurement points of the thermoprobe during vaginal cooling indicates that the lowest point of the thermo-probe is more exposed to vaginal `influences' compared with the other points; thus the border was 510 mm from the tubal ostium. It is not known whether the border is abrupt or consists of a gradual transfer of blood supply originating from the uterine and ovarian arteries.
The demonstration by the `cold transfer method' that vagina-to-uterus vascular mediated distribution influences most of the uterus is in agreement with a study in which pertechnetate was administered vaginally in postmenopausal women (with or without a sealed cervix). Visual examination of scintigraphs of the uterus showed a greater concentration of radiotracer in the corpus of the uterus compared with horn areas and ovaries (Cicinelli et al., 2001). The result is in agreement with recent experience in postmenopausal women treated for 1 year with twice a week transdermal estradiol and vaginal progesterone as continuous combined hormone replacement therapy. The high percentage of amenorrhoea (100% of compliant women) and endometrial atrophy (92.3%) after 1 year of treatment speaks in favour of a distribution of vaginal progesterone to most of the uterus (Cicinelli et al., 2002
).
Temperatures in healthy abdominal organs can only change within minutes, if the arterial blood supply changes temperature. The decrease in temperature in the uterus is probably the result of cooling of the uterine arterial blood by cold vaginaluterine venous blood (cooled by the vaginal saline). The small temperature decrease in the Fallopian tube clearly indicates that the blood supply does not originate from the uterine artery. A small decrease in the ovarian arterial blood temperature may be expected, since the vaginal venous blood is mixed with uterine, and part of the uterine venous blood enters the uteroovarian vein, which is part of the transfer system in the ovarian adnexa.
It could be argued that the wall of the uterus is thinner in the tubal corners and that heat from the intestines could interfere with the results. It is, however, less likely, since heat differences do not diffuse far due to the active blood supply. Moreover, it could be also argued that leaving the hysteroscope in the cervical canal could induce cooling in the uterine cavity directly by simple cold conductance along the metal sheath. Simple cold conductance cannot explain the significantly greater temperature decrease at point 4 compared with points 2 and 3, which showed the same cooling.
The major difference between the present and previous investigations on cold transfer is that the present use of a thin, flexible four-point thermocatheter versus the previous two-point stainless steel catheter, and the use of an endoscope for the insertion (Einer-Jensen et al., 2001). The four points allowed more detailed plotting and the endoscope provided visual and video control of the position of the thermocatheter. The accuracy of the two probes (the stainless steel two-points and the present four-points) is the same (±0.05°C) but the thin catheter registered the changes with a shorter time constant due to the small mass involved. Despite this, the temperature changes were slower and smaller in the present experiment compared with the previous. The reason is not obvious, but the stainless steel probe may have a better contact with the endometrial surface. Probably, the small amounts of fluid in the uterine lumen make the thin probe somewhat insensitive to changes in the tissue due to a `temperature buffer' effect of the layer of unstirred fluid.
In conclusion, the present investigation does support the suggestion that in postmenopausal women the uterine artery supplies most of the uterus and that only areas close to the tubal ostium are supplied from the ovarian artery. The border between uterine and ovarian influences seems to be 510 mm from the entrance to the tube; individual variations have been found. The result represents a rationale base for vaginal administration of drugs when rapid and specific effect on the uterus (e.g. progestational or relaxation) is requested.
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Acknowledgements |
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Notes |
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References |
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Submitted on December 21, 2001; resubmitted on April 18, 2002; accepted on July 26, 2002.