Contractile reactivity of human myometrium in isolated non-pregnant uteri

© The Author 2005. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. 1

Human Reproduction Page 1 of 10 doi:10.1093/humrep/dei295

Contractile reactivity of human myometrium in isolated non-pregnant uteri

O.N.Richter1,2,3, C.Bartz1, J.Dowaji1, M.Kupka2, J.Reinsberg2, U.Ulrich2 and W.Rath1

1Department of Obstetrics and Gynaecology, University of Aachen School of Medicine, Aachen and 2Department of Obstetrics and Gynaecology, University of Bonn School of Medicine, Bonn, Germany3To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, University of Aachen School of Medicine, Pauwelsstraße 30, D-52057 Aachen, Germany. E-mail: [email protected]

BACKGROUND: Perfusion of the isolated uterus has been shown to be a feasible experimental system for studies ofthe human endometrium and myometrium. Utilizing our established experimental perfusion model we perfused 20uteri for 27 h and investigated the contractile reactivity of the myometrium in response to 17�-estradiol (E2) and oxy-tocin (OT). METHODS: Uteri of group A (n = 4) were stimulated with OT; group B (n = 4) was treated continuouslywith E2; group C (n = 4) received both E2 and OT for 27 h; group D (n = 4) was perfused for 27 h with E2 with theaddition of OT for the last 3 h of the experiment; group E (n = 4) as control group remained without any treatment.The pressure and duration of uterine contractions were recorded during the entire perfusion period using intramuraland endoluminal pressure catheters. RESULTS: Compared to the other treatment groups and controls, the mosteffective myometrial activity was achieved in group D during the OT stimulation period. No relevant myometrialactivity was detected in the control group. CONCLUSIONS: Continuous E2 treatment, with the addition of OT forthe last 3 h of the 27 h perfusion period, led to the most pronounced uterotonic effects in the presented experimentalcondition.

Key words: human non-pregnant uterus/myometrial contractility/oxytocin/perfusion of the isolated uterus

Introduction

Myometrial contractions of the human non-pregnant uterus areassumed to be receptor-mediated via the oxytocin receptor (OTR)which can be modulated by steroid hormones and oxytocin (OT)respectively (Bulletti et al., 1986, 1993; Maggi et al., 1992;Kimura, 1998; Tahara et al., 2000; Richter et al., 2003, 2004).Based on these observations, some authors postulate that idio-pathic pelvic complaints—one of the most frequent clinicalsymptoms of the non-pregnant, menstruating woman—arecausally related to hypercontractility of the non-pregnant myo-metrium (Ekström et al., 1992; Åkerlund et al., 1995; Noeet al., 1999; Åkerlund, 2002). Furthermore, uterine hyperactiv-ity may contribute to the control of other important clinicalpathologies such as embryo implantation failure, abortion andpreterm labour (Fuchs et al., 1998; Goldenberg, 2002; Gimpland Fahrenholz, 2001; Goldenberg et al., 2000). For furtherunderstanding of these clinical disorders, several investigatorshave pointed out the importance of in vivo studies to examinethe related physiological and pathophysiological conditions inthe non-pregnant and pregnant human uterus.

Perfusion of the isolated non-pregnant human uterus simulat-ing physiological conditions, first described by Bulletti et al.(1986), has been shown to be a promising experimental system toinvestigate myometrial activities stimulated by ovarian hormones(Bulletti et al., 1993; Richter et al., 2000). In particular, previous

results showed that the OTR expression of myometrial cells canbe affected by stimulation with 17β-estradiol (E2) and OT notonly in the pregnant uterus, but also in the non-pregnant uterus(Richter et al., 2003, 2004). In the present study we addressed thequestion as to what degree uterine contractions can be induced bytreatment with different combinations of E2 and OT.

Materials and methods

Surgical specimens and perfusion procedure

Twenty uteri in the proliferative phase of the menstrual cycle wereobtained by standard abdominal or vaginal hysterectomy for benignconditions. Oral contraceptives or hormone therapy were discontinued6–8 weeks prior to the operation, and hormone serum levels for eachpatient were evaluated on the day of operation for the assessment ofE2, progesterone, LH and FSH. Ethical committee approval for thestudy protocol and written informed consent of the patients wasobtained prior to the investigation.

The pre-operative selection of the patients, cannulation of bothuterine arteries, bilateral flush perfusion followed by the original per-fusion procedure were performed identically as previously describedin detail (Bulletti et al., 1986, 1993; Richter et al., 2000, 2003, 2004).

Appropriate oxygenation of the perfusion medium (modifiedheparinized Krebs–Henseleit bicarbonate buffer) was monitored bytaking arterial and venous samples of perfusate every 60 min withsyringes for measurements of pH, partial pressure of oxygen (pO2),

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partial pressure of carbon dioxide (pCO2), lactate, lactate dehydroge-nase (LDH) and creatine kinase (CK). These samples were analysedas previously described (Richter et al., 2000, 2003). Organ weightswere always measured immediately before and after perfusion.

To investigate the myometrial reactivity, i.e. amplitudes and durationof uterine contractions, to OT (group A) or E2 (group B) alone and to acombined treatment with E2 and OT (group C, group D), we carried outthe following study. While the entire experiment was running, all speci-mens were perfused for 27 h with the modified heparinized Krebs–Henseleit bicarbonate buffer (Richter et al., 2000); uteri of group Areceived only OT stimulation during the whole experimental period(n = 4) (Figure 1a); uteri of group B were treated only with E2 (1.0 ng/min)throughout the perfusion period (n = 4) (Figure 1b); uteri of group Cwere perfused with E2 (1.0 ng/min) and with OT throughout the per-fusion period (n = 4) (Figure 1c); uteri of group D were stimulated by E2

perfusion (1.0 ng/min) throughout the experimental period and with OTperfusion for the last 3 h of the experiment (n = 4) (Figure 1d); the con-trol group (group E) remained without any treatment (n = 4) (Figure 1e).

Based on data of oxytocin doses for induction and augmentationof labour (Muller et al., 1992) and the previous observations of thedynamics of the oxytocin receptor (OTR) under E2 and OT stimula-tion (Richter et al., 2003, 2004) OT was added beginning with8 mIU/min and increased by doubling the previous concentrationevery hour. OT stimulation was stopped when relevant uterine con-tractions occurred or the recommended maximum dose of 30 mIU/minwas reached. All perfusion and monitoring proceedings were per-formed as previously described (Richter et al., 1998, 2000, 2003,2004).

Signal acquisition of uterine activity

For the examination of the uterine pressure profile, two catheter sys-tems and a digital data acquisition system were used. First, usual 20Gcanulas (Braun, Melsungen, Germany), prepared with three side-opening perforations of 1.5 mm in diameter and then covered with a0.5 mm silicon rubber slice and filled up bubble-free with distilledwater, were inserted in the median line of the uterus 1.5 cm into thefundus, corpus and the isthmus uteri of the uterine wall. The secondcatheter system consisted of a microtip catheter with two measuringsensors as usually used for urodynamic examinations (Raumediccatheter, Rehau, Germany), which was also filled up bubble-free withdistilled water and then inserted into the uterine cavity.

All catheters were connected via silicone rubber lines (diameter:1.5 mm) to the digital data acquisition system DASYLab 5.0 (Data-log, Mönchengladbach, Germany) which consisted of an analogue–digital transducer, a high speed 16-Bit analogue–digital multifunctionPCI-card (PCI-9118HR) and the data acquisition software.

The intramural and the intraluminal pressure as well as the per-fusion flow and pressure rates monitored by the roller perfusionpumps (Storz, Tuttlingen, Germany) were all measured in mmHg andcontinuously recorded during the entire experimental period.

Statistical analysis

All biomathematical calculations were performed using the StatView 5.0 statistical software (SAS Institute Inc., SAS CampusDrive, Cary, NC, USA) and the Sigma Plot 2000 graphic software(SPSS, Chicago, IL, USA). The recorded data were statistically ana-lysed considering each 5, 15 and 30 min time-interval separately anddemonstrated as mean values ± SEM. Biochemical perfusion param-eters were statistically evaluated using the Kruskal–Wallis one-wayanalysis of variance for non-parametric data as previously described(Richter et al., 2000).

The degree and duration of intramural and intraluminal pressurewere analysed by analysis of variance (ANOVA) followed by Fisher’sprotected least significance difference (PLSD) test and paired t-tests.P < 0.05 was considered significant.

Results

Myometrial activity

The myometrial activity was measured continuously using thedescribed intramural and endoluminal catheters. For all groups,analysis of the intramural and endoluminal pressure showedsimilar values for the amplitude and duration of the uterinecontractions. The values of the duration of contractions showedsignificant differences between fundus, corpus and isthmusuteri. Data for this parameter are demonstrated as pooled datawith mean values ± SEM

Group A

In group A, uteri (n = 4) were treated with OT during the entireexperimental period (Figure 1a). The increase of the OT dosecaused a significant increase of the amplitude of contractionsfor all localizations compared to the control uteri (n = 4) in thefirst 5 h of perfusion (P < 0.0001) (Figure 2a). Considering alldata of group A, the maximum pressure values were detectedin this period with significant differences between fundus,corpus and isthmus uteri (P < 0.0001) (Figure 2a). After a sig-nificant decrease of contractions in the period from 5 to 9 h ofperfusion (P < 0.0001 for fundus, corpus and isthmus uteri) no

Figure 1. (a–e) Treatment courses of the respective groups. Group Areceived OT only for 27 h. Group B was stimulated with E2 only for27 h. Group C was treated with E2 and OT for 27 h. In group D, E2 wasgiven for 27 h with additional OT stimulation in the last 3 h of the per-fusion. Group E (control group) was free from any hormonal treatment.

t = 27 ht = 0 h Group A

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relevant changes could be measured in the further course of theexperiment (Figure 2a). Comparing contractions of fundus,corpus and isthmus uteri with each other, the difference in thefirst 9 h of perfusion was significant (P < 0.0001). Furtherobservation during the continuing experiment showed signifi-cance of fundus versus corpus (P < 0.01), fundus versus

isthmus uteri (P < 0.0001), fundus versus controls(P < 0.0001), corpus versus isthmus uteri (P < 0.01), corpusversus controls (P < 0.0001) and isthmus uteri versus controls(P < 0.0001) (Figure 2a).

Regarding the data for the duration of uterine contractions,significant differences were reached for fundus versus isthmus

Figure 2. (a) The stimulation with OT only led to significant changes in the first hours of the experiment followed by a relative uterine quies-cence in the further course of perfusion. (b) The significant increase of uterine contractions caused by E2 treatment occurred in the first 3 h and isfollowed by a pronounced undulation of fundal and corporal activity throughout the continuing experiment. (c) The exposure to E2 and OTachieved maximum myometrial contractility in the first 5 h of perfusion with undulant uterine activity throughout the further course of perfusion.(d) The most pronounced and significant changes in group D were detected during the OT stimulation in the last 3 h of perfusion. (e) Uterine con-tractions measured after the onset of oxytocin administration at 24 h of perfusion time. Both endoluminal and intramural sensors detect a signific-ant increase of myometrial activity already in the first 30 min of oxytocin stimulation. (f) Uterine contractions measured in the last hour of theexperiment. Compared to the onset of oxytocin stimulation the unaltered dose of 8 mIU/min has led to a further distinct increase in uterine activ-ity detected by both endoluminal and intramural catheters. (g) Fundal activities of the respective groups compared to each other.

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uteri (P < 0.05), fundus versus controls (P < 0.01) and corpusversus controls (P < 0.05) (Figure 3).

Group B

Comparing all localizations to each other, including the controlgroup, the stimulation of uteri of group B (n = 4) with E2 (1.0ng/min) throughout the perfusion period (Figure 1b) causedsignificant changes of the myometrial activity (P < 0.0001)(Figure 2b). The most relevant increase was detected in thefirst 3 h of perfusion followed by a pronounced undulation ofthe contraction activity during the further treatment with E2

(Figure 2b). For the duration of contractions, significant dif-ferences were measured as follows: fundus versus corpus(P < 0.05), fundus versus isthmus uteri (P < 0.01), fundus versuscontrols (P < 0.001), corpus versus isthmus uteri (P < 0.05),corpus versus controls (P < 0.01) and isthmus uteri versus con-trols (P < 0.05) (Figure 3).

Group C

Uteri of group C (n = 4) received OT and E2 (1.0 ng/min) for27 h (Figure 1c). For OT, it was necessary to applicate themaximum dose after 4 h of perfusion. Under these conditions

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maximum increase of contractions was detected for all locali-zations in the first 5 h of stimulation (P < 0.0001) (Figure 2c).In the following 3 h of perfusion fundal activity decreased sig-nificantly (P < 0.0001) and remained stable throughout thecontinuing experiment. The contractile activity of the corpuswas characterized by a distinct undulation of the measuredcontractions (P < 0.0001) (Figure 2c). The activity of the isth-mus uteri after 5 h of perfusion showed significant changes(P < 0.01). The measurement of the duration of contractionsshowed the following results: fundus versus corpus (P < 0.01),fundus versus isthmus uteri (P < 0.001), fundus versus controls(P < 0.0001), corpus versus isthmus uteri (P < 0.01), corpusversus controls (P < 0.0001), isthmus uteri versus controls(P < 0.001) (Figure 3).

Group D

The uterine activity of group D (n = 4) was modulated by stim-ulation with E2 (1.0 ng/min) for 27 h and OT in the last 3 h ofthe experiment (Figure 1d). In this case the initial dose of8 mIU/min was sufficient to achieve a steadily increasing uterinecontraction within all localizations throughout the OT treat-ment period (P < 0.0001) (Figure 2d–f). In the first 24 h of per-fusion the sole E2 stimulation caused changes in themyometrial activity similar to the analogous treatment of groupB (P < 0.0001) concerning fundus, corpus and isthmus utericompared to each other (Figure 2d). Concerning the durationof contractions the following were significant: fundus versuscorpus (P < 0.001), fundus versus isthmus uteri (P < 0.0001),fundus versus controls (P < 0.0001), corpus versus isthmus

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uteri (P < 0.001), corpus versus controls (P < 0.0001), isthmusuteri versus controls (P < 0.001).

Comparing all groups the maximum degree of contractionscan be achieved in the fundus uteri independent of the courseof stimulation (Figure 2a–e). Yet, the most pronouncedchanges occur in those groups with a combined stimulation ofE2 and OT (Figure 2e).

Perfusions and biochemical evaluations

All uteri were removed from pre-menopausal women in theproliferative phase of the cycle. The median age of the patientswas 38 years (range: 34–43 years). In seven cases a contracep-tive or hormone treatment with various estrogen–gestagen

combinations was discontinued 6–8 weeks prior to the operation.No other patients had any hormonal therapy. Hormone serumlevels were given as median (range) levels as follows: estrogen:112.8 (85.4–151.2) pg/ml; progesterone: 1.04 (0.73–1.38) ng/ml;LH: 7.2 (5.4–8.1) IU/l; FSH: 4.9 (3.7–5.8) IU/l. Similar to ourprevious results (Richter et al., 1998, 2000, 2003, 2004) allhypoxia and cytolysis parameters (pH, pO2, pCO2, lactate, LDH,CK) remained stable throughout the entire perfusion period as asign of physiological oxygen consumption of the perfusedorgan. All perfusions were maintained in physiological rangeswith constant flow rates of 15–35 ml/min through each arteryand pressure rates from 60 to 140 mmHg (data not shown).Organ weights did not show significant differences within therespective group at t = 0 h versus t = 27 h (cumulative mean

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organ weights measured in grams ± SD); group A: 92.3 ± 9.3versus 96.3 ± 7.4; group B: 90.5 ± 15.9 versus 94.0 ± 12.1; groupC: 103.3 ± 21.7 versus 106.5 ± 26.6; group D: 84.8 ± 8.7 versus88.5 ± 10.9; group E (control): 84.3 ± 7.8 versus 86.0 ± 5.9.

Discussion

This study presents our results for the uterine reactivity to uter-otonic drugs obtained by utilizing our established experimental

system of the perfusion of the isolated human uterus (Richteret al., 1998, 2000).

There are numerous experimental perfusion models report-ing on uterine contractions under various conditions for vari-ous purposes. On one hand there are in vitro models such asanimal models of different species (Engstrom et al., 1999;Ahn et al., 2004; Ocal et al., 2004; Raynal and Houdeau,2004; Tsatsaris et al., 2004; Mota-Rojas et al., 2005). On theother hand there are models utilizing perfusion systems of

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FUNDUS

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Figure 3. Cumulative data of the duration of contractions recorded throughout the entire perfusion period. Data are shown as means + SEMrelated to the respective localizations and groups.

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separated myometrial stripes obtained from the uterine inci-sion during Caesarean section at different stages of preg-nancy (Kawarabayashi et al., 1990; Pierzynski et al., 2004;Young and Zhang, 2004; Hurd et al., 2005). There exist sev-eral in vivo studies in humans for questions on the field ofuterine hyperperistalsis in connection with dysmenorrhoeaand endometriosis (Åkerlund et al., 1995; Åkerlund, 2002;Bossmar et al., 1995; Ijland et al., 1998; Kunz et al., 1998;Leyendecker et al., 1996, 2004; Kunz and Leyendecker,2002; de Gestel et al., 2003). However, experimental modelssimulating physiological conditions for understanding thephysiology and pathophysiology of uterine contractions andcontractile disorders are important.

Previous investigations emphasized the feasibility of theperfusion of the isolated human uterus for various purposesavoiding the risks of in vivo testing for the patient (Bullettiet al., 1986, 1987, 1988a,b, 1993; Richter et al., 2000, 2003,2004). The original model of the perfusion of the isolateduterus was first described by Bulletti et al. (1986). Our furtherdeveloped perfusion system—as performed in the presentstudy—has been validated biologically by extensive biochemi-cal, light- and electron-microscopic examinations (Richteret al., 2000). Both uterine perfusion models have been con-firmed to be a new scientific approach, especially for mid-termand long-term perfusion experiments (Bulletti et al., 1987,1988a,b; Richter et al., 1998, 2000, 2003, 2004). However, thescientific information resulting from a perfused uterus repre-sents the electrical and mechanical activities of all tissues andcells of the organ as they occur in vivo, indicating proper nutri-tion and oxygenation of the perfused uterus (Bulletti et al.,1993; Richter et al., 2000, 2003, 2004).

The analysis of uterine contractility and its regulation maycontribute to the investigation of important clinical patholo-gies such as dysmenorrhoea, failure of sperm and/or oocytetransportation, embryo implantation failure, spontaneousabortion and preterm labour (Ekström et al., 1992; Starbucket al., 1998; Goldenberg et al., 2000; Åkerlund, 2002). Pre-vious investigations have suspected that such hypercontrac-tility of the non-pregnant uterine myometrium is mediatedthrough myometrial receptors (Ekström et al., 1992; Åkerlund,1994, 2002; Åkerlund et al., 1995). In particular, theseresults in both pregnant and non-pregnant myometrium haveshown that there are good correlations between myometrialOTR density and contractile effects. It was assumed that inthe non-pregnant myometrium, oxytocin acts specifically onits own receptor (Ekström et al., 1992; Åkerlund et al., 1995;Bossmar et al., 1995). These authors found that oxytocinseemed to be less important for the aetiology of uterinehyperactivity of dysmenorrhoea than vasopressin. In thiscontext various data concerning receptor-specific antago-nists for hypercontractility of the non-pregnant and pregnantuterus have been available hitherto (Åkerlund, 2004). Con-tractions of both the non-pregnant and pregnant uterus canundoubtedly also be a result of stimulation by endogenousprostaglandins.

Its inhibitors play a central role in the therapeutic principlesof dysmenorrhoea, and, occasionally also, because of its side-effects for the unborn child, in preterm labour. Previous results

showed that oxytocin treatment of estrogen-primed non-pregnantrats down-regulated uterine contractile responsiveness to pros-taglandin F2α, leaving mRNA values of the prostaglandin F2αreceptor unchanged (Engstrom et al., 2000). Furthermore, thecontractile in vitro response remained unaltered by receptor-specific antagonism with atosiban (Engstrom et al., 2000).Investigations on cyclic and early pregnant swines showed thatthe prostaglandin F2α release by oxytocin stimulation occursmainly in the late luteal phase whereas responsiveness tooxytocin was suppressed to maintain corpus luteum functionduring early pregnancy (Carnahan et al., 1996). We did notaddress this particular question in the present study but the roleof endogenous prostaglandins in our experimental conditioncan be further investigated.

Our team have demonstrated previously that the dynamics ofthe oxytocin receptor (OTR) expression can be modulated bystimulation with E2 and OT, not only in the pregnant but also inthe non-pregnant human uterus (Richter et al., 2003, 2004).Based on these observations the data of the present study con-firm that the receptor-mediated reactivity of the non-pregnantmyometrium can be modulated by E2 or OT treatment or bydifferent combinations of both.

Regarding the results of group A (only OT treatment), theincrease in myometrial activity during the first hours couldonly be achieved by increasing the OT dose given. Our resultsfor the density of myometrial OTR of the non-pregnant myo-metrium (Richter et al., 2003, 2004) may explain on the onehand this initial uterine reactivity to OT and on the other handthe significantly lower extent and duration of the contractionscompared to group C (E2 + OT for 27 h) and group D (E2 for27 h + OT in the last 3 h of perfusion). Once the maximum OTdose was reached, no further increase but rather a decrease ofcontractile activity occurred. These changes might beexplained by previous observations which have shown thatlong-term OT stimulation of human non-pregnant myometrialcells for up to 48 h led to OTR mRNA down-regulation includ-ing transcriptional suppression and destabilization of mRNAby RNA-binding proteins while the total amount of receptorprotein seemed to be unaffected (Phaneuf et al., 1997, 2000).

Results of group B (E2 for 27 h) confirm previous data thatstimulation with high-dose E2 increases myometrial activity(Bulletti et al., 1993). Similiar to group A (OT for 27 h),contractions rose significantly in the first hours of perfusion(Figure 2b). But in contrast to group A, no relevant decrease,rather a slight increase without significance, was measured inthe further course of perfusion (Figure 2b and e). Furthermore,myometrial activity caused by E2 seems to be more effective,as degree and duration of contractions reach significant differ-ences compared to group A (Figures 2e and 3).

The effect of stimulation with E2 and OT for 27 h (group C)is demonstrated in Figure 2c and e. Similar to group A (OT)the significant increase of contractions in all three localizationsin the first 5 h of the treatment is followed by a relevantdecrease in the following 3 h of perfusion concerning fundusand corpus (Figure 2c). While further stimulation did not affectthe activity of fundus and isthmus uteri, significant differencesof the amplitude of the contractions occurred in the corpus(Figure 2c). The course of these changes of group C (E2 and



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OT for 27 h), which on a significantly higher level are very similarto both the changes in group A (OT for 27 h) and group B(E2 for 27 h) (Figure 2c and e), may be explained by our previ-ous observations that the myometrial OTR expression as wellas the OTR sensitivity to OT are significantly influenced by E2and OT stimulation respectively (Richter et al., 2003, 2004).

Regarding the results of group D (E2 for 27 h and OT for thelast 3 h of perfusion, Figure 1d), the uterine activity to a largedegree reflects our data for the expression of the myometrialOTR under analogous experimental conditions (Figure 2d)(Richter et al., 2003, 2004). In the first 24 h of perfusion the E2stimulation caused changes in contractions analogous to groupB (E2 for 27 h) (Figure 2b and d). Additional treatment withOT starting from 24 h of the experiment led to a pronouncedincrease of both the amplitude and duration of uterine contrac-tions throughout the further course of perfusion with signific-ant differences from the other groups (Figure 2d and 3).Furthermore, considering all data and comparing all groupswith each other, the most effective contractions resulted fromthe fundal activity (Figure 2a–e). On closer observation thetreatment with E2 and OT (group C and D) caused the most dis-tinct uterine contractions compared to stimulation with E2 oronly OT (group A and B) (Figure 2e). These results could beexplained by our previous observations which demonstrate asignificant rise in the myometrial OTR by E2 and OT stimula-tion and showed a significantly increasing density of myome-trial OTR from the isthmus uteri to the fundus uteri (Richteret al., 2003, 2004).

In conclusion, the present data reveal that the uterine activityof an isolated, perfused, non-pregnant human uterus can beaffected by stimulation with E2 and/or OT. Treatment coursesusing different combinations of E2 and OT in most of casescaused significant myometrial contractions, signifying thevitality of the myometrial tissue throughout the experimentalperiod.

With respect to our data on the influence of E2 and OT stim-ulation on the myometrial OTR expression utilizing the equi-valent experimental system (Richter et al., 2003, 2004) and theresults of the present study, the perfusion of the isolated non-pregnant human uterus has been confirmed to be a suitableexperimental system for investigations of the physiology ofmyometrial contractions and might be an ideal model to studythe mechanism of action of uterotonic and tocolytic drugs.

AcknowledgementThis research was supported by the Deutsche Forschungsgemeinschaft(DFG), Gz RI 958/1-1 and the BONFOR-Forschungskommission,Gz 103/17.

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Submitted on March 24, 2005; resubmitted on August 8, 2005; accepted onAugust 11, 2005



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Contractile reactivity of human myometrium in isolated non-pregnant uteri