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Hum. Reprod. Advance Access originally published online on March 3, 2006
Human Reproduction 2006 21(7):1863-1868; doi:10.1093/humrep/del056
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© The Author 2006. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Role of estrogen and progesterone in the regulation of uterine peristalsis: results from perfused non-pregnant swine uteri

A. Mueller 1 , J. Siemer, S. Schreiner, H. Koesztner, I. Hoffmann, H. Binder, M.W. Beckmann and R. Dittrich

Department of Obstetrics and Gynecology, University Hospital Erlangen, Erlangen, Germany

1 To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, Erlangen University Hospital, Universitätsstrasse 21–23, 91054 Erlangen, Germany. E-mail: andreas.mueller{at}gyn.imed.uni-erlangen.de


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
References
 
BACKGROUND: Adequate uterine contractility and peristalsis are involved in the transport of semen and gametes and in successful embryo implantation. Estrogen and progesterone fluctuate characteristically during the menstrual cycle. It has been suggested that both hormones influence uterine peristalsis in characteristic ways. METHODS: An extracorporeal perfusion model of the swine uterus was used that keeps the uterus in a functional condition and is suitable for the study of physiological questions. The effects of estrogen and progesterone on oxytocin-induced uterine peristalsis were assessed using an intrauterine double-chip microcatheter. RESULTS: Estrogen perfusion was associated with an increase in intrauterine pressure (IUP) in a dose-dependent manner. There was a significant difference between the IUP increase measured in the isthmus uteri and that in the corpus uteri, resulting in a cervico-fundal pressure gradient. Estrogen perfusion resulted in a significantly higher rate of peristaltic waves starting in the isthmus uteri and directed towards the corpus uteri. Progesterone was able to antagonize the estrogen effect in general. CONCLUSIONS: This study demonstrates that estrogen and progesterone have differential effects in the regulation of uterine peristalsis. The present observation shows that estrogen stimulates uterine peristalsis and is able to generate a cervico-fundal direction of peristalsis, whereas progesterone inhibits directed uterine peristalsis.

Key words: fertility/oxytocin/peristalsis/sperm transport/uterine contractility


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Acknowledgements
References
 
Adequate uterine contractility is involved in the transport of the semen and gametes and in successful embryo implantation, whereas inadequate uterine contractility may lead to ectopic pregnancies, miscarriages, retrograde bleeding and endometriosis (Leyendecker et al., 2004Go; Bulletti and de Ziegler, 2005Go; Kissler et al., 2005Go). In fertile women, directed unilateral transport of immotile sperm-like material through the genital tract to the side bearing the dominant follicle can be assessed using hysterosalpingoscintigraphy (HSSG) (Kissler et al., 1995Go, 2004aGo,b; Kunz et al., 1996Go). Normally, uterine contraction waves show the highest frequency and amplitudes during the periovulatory phase, whereas in the other phase, contraction waves with lower frequency and amplitudes are observed. Particularly during menstruation, peristalsis appears to be directed towards the cervix (Lyons et al., 1991Go; Fukuda and Fukuda, 1994Go). In women with intact periovulatory uterotubal transport function as assessed by HSSG, the pregnancy rate achieved spontaneously or by intrauterine insemination was significantly higher in comparison with women with a negative transport assessment (Kissler et al., 2004bGo).

The original extracorporeal perfusion model of an isolated uterus was first described by Bulletti et al. (1986)Go. Previous investigations validated the feasibility of this perfusion model of isolated uteri for various purposes (Bulletti et al., 1987Go, 1988aGo,bGo; Richter et al., 2000Go, 2003Go, 2004Go, 2005Go). First results on electromechanical activities and endoluminal pressure during extracorporeal perfusion with ovarian steroids in a group of ten isolated human uteri were also described by Bulletti et al. (1993)Go. 17beta-Estradiol increased the frequency and duration of uterine contractility, whereas progesterone decreased both. According to the previously reported in vitro experiments, there is a possible clinical relationship between uterine contractility and steroid hormones (Bulletti et al., 2001Go, 2002Go). Furthermore, this perfusion model is suitable for the study of other physiological questions (Dittrich et al., 2003Go; Maltaris et al., 2005aGo,bGo). Continuous monitoring of intrauterine pressure (IUP) using multiple probes at different locations inside the uterus may be a suitable method of evaluating directed uterine peristaltic waves.

The goal of this study was to assess dynamic changes in oxytocin-induced uterine peristalsis and pressure gradients and to show directed uterine peristaltic waves in response to estrogen and progesterone alone and in combination with a large group of isolated extracorporeally perfused non-pregnant swine uteri, using the perfusion system described. The first intention was to show that estrogens induce cervico-fundal peristalsis in the ex vivo animal model used and to confirm and strengthen the results presented by Bulletti et al. (1993)Go. The second intention was to validate the swine uterus perfusion model used for the purpose of uterine contractility with regard to different physiological hormones and mediators, so that it can later serve for further experiments—e.g. for the study of the effects of different prostaglandins on uterine contractility.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Acknowledgements
References
 
Swine uterus
Swine (Sus scrofa domestica) are widely used in research. The swine uterus is a long bicornuate uterus with a single corpus and a single cervix (Bartol, 1999Go). The uterine wall has an architecture similar to that of humans and other domestic animals, with the three classical histological elements of the uterine wall, including endometrium; myometrium that consists of clearly oriented smooth muscle cells and perimetrium. The endometrium contains many hundreds of glands in a cross-section of the uterine wall, and the myometrium is clearly differentiated into inner circular and outer longitudinal layers (Bartol, 1999Go; Spencer et al., 2005Go). The Fallopian tubes in the adult female have the same diameter as those in humans. However, they are much longer, and the uterine corpus is also longer in comparison with human uteri. The sow has an estrous cycle of 20–21 days. A total of 180 swine uteri were obtained from the local slaughter house. The uteri were selected on the basis of their size and overall condition, as well as the condition of the uterine arterial stumps. The mean weight of the swine uteri was 124 g (range 85.5–165.8 g). They all came from healthy animals aged 5–18 months. Swine uteri are very easily separated from the rest of the body within approximately 2 min after the animal is killed by electric shock (1.5 A, 400 V, 4 s). The isolated swine uteri were provided by the local slaughter house, avoiding the costs and responsibilities of an animal breeding unit or doing surgery on the animals. Furthermore, using the swine uteri model makes it possible to avoid in vivo testing.

Perfusion system
After catheter placement in the uterine vessels with 16–24 G needles (Abbocath-T; Abbott Ireland, Sligo, Ireland), depending on the uterus size, the organ was placed in a controlled-temperature perfusion chamber (Karl Lettenbauer, Erlangen, Germany) filled with the perfusion medium (Figure 1). The uterus was then connected bilaterally with two reservoirs containing the perfusion buffer (Krebs–Ringer bicarbonate glucose buffer, Sigma, Deisenhofen, Germany). The perfusion medium was oxygenated with carbogen gas (a mixture of 95% oxygen and 5% carbon dioxide) and then forced into the uterine arterial catheters with two roller pumps. The flow rate of the perfusion medium was constantly monitored and kept at 15 ml/min and 100 mmHg. 17 beta-Estradiol (Sigma) was added to the perfusion buffer at concentrations of 1, 10, 25 and 50 pg/ml, and 15 swine uteri were perfused with each concentration. Progesterone (Sigma) was added to the perfusion buffer at concentrations of 1, 10, 25 and 50 pg/ml, and 15 swine uteri were perfused with each concentration. A schematic view of the perfusion system is shown in Figure 2.


Figure 1
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  		Figure 1. Swine uterus placed in the perfusion chamber with an intrauterine microchip catheter inside and connected to the Datalogger.

 

Figure 2
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  		Figure 2. Schematic view of the perfusion system.

 
Vitality parameters
Perfusate samples were taken at 1-h intervals for measurement of pH, PO2, PCO2, HCO3, lactate and oxygen saturation. The perfusate samples were analysed with an i-STAT portable clinical analyser (Abbott Diagnostics, Abbott Park, IL, USA).

IUP measurement
IUP was recorded using an intrauterine double-chip microcatheter (Urobar 8 DS-F; Raumedic, Muenchberg, Germany) with a distance of 8 cm between the two pressure sensors. One sensor was placed in the isthmus uteri (lower corpus), and the other sensor was placed in the upper corpus uteri in the swine uterus. The double-chip microcatheter was connected to a Datalogger (MPR1, Raumedic) for continuous monitoring of IUP, with the data being transferred to a personal computer. When the increase in IUP started first in the lower part of the uterus—detectable by the first intrauterine sensor which was placed in the isthmus uteri and then later becoming detectable in the upper part of the uterus, where the second sensor was placed—this contraction was counted as a cervico-fundal peristalsis. When the opposite movement was observed in the IUP, this contraction was counted as fundo-cervical peristalsis.

Induction of uterine contractions
Oxytocin (Syntocinon; Novartis Germany Ltd., Nuremberg, Germany) was used to induce contractions of the uterus at increasing dosages of 0.1, 0.3 and 1 IU every 15 min until regular uterine contractions were observed. Oxytocin was administered as a bolus through the uterine arterial catheters. Oxytocin administration was started after 2 h of initial perfusions containing the above-mentioned concentrations of the steroids. Uterine contractions occurred normally immediately after oxytocin administration. The time lag limits after administration of oxytocin did not differ between all experiments. When regular uterine contraction and peristalsis had not occurred after the described oxytocin administration procedure, this procedure was repeated immediately, whereas an augmentation of the used oxytocin dosages was not performed (Kunz et al., 1998aGo). Uterine contractions and peristalsis were recorded during the complete perfusion time (approximately 7–8 h).

Statistical analysis
A paired Student’s t-test was used for statistical evaluation of significant differences between IUP increases in the isthmus uteri and corpus uteri. Pressure differences between the different concentrations of each tested steroid were evaluated using analysis of variance (ANOVA). In addition, it was assessed whether uterine contractions started in the isthmus uteri or the corpus uteri, tested using the chi-squared test of independence. All the calculations were performed using the Statistical Program for the Social Sciences (SPSS, version 10.1 for Windows; SPSS, Chicago, IL, USA). P values of <0.05 were considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Acknowledgements
References
 
The experiments were only carried out when it was possible to maintain constant flow rates of the perfusion medium of 15 ml/min through each artery, with an ideal pressure of 100 mmHg, throughout the duration of the experiments. The vitality parameters remained physiological during the first 8 h of perfusion (data not shown; for details, see Dittrich et al., 2003Go). A typical pressure profile of a swine uterus perfused with 17beta-estradiol is shown in Figure 3. The results of the perfusion experiments are summarized in Table I and Figures 4–567.


Figure 3
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  		Figure 3. Typical pressure profile of a perfused swine uterus (the perfusion buffer contains 10 pg/ml 17beta-estradiol). After administration of oxytocin, clearly visible regular peristaltic waves directed from the cervix uteri towards the corpus uteri occurred, demonstrated by an intrauterine pressure (IUP) increase first in the isthmus uteri (upper curve), followed by IUP increase in the corpus uteri (lower curve) (change in IUP in mm/Hg).

 

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  		Table I. The increase in intrauterine pressure (IUP) in the isthmus uteri and corpus uteri during perfusion with 17beta-estradiol, progesterone and 17beta-estradiol plus progesterone

 

Figure 4
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  		Figure 4. The increase in intrauterine pressure (IUP) during perfusion with different concentrations of 17beta-estradiol (grey bars, IUP measured in the corpus uteri; black bars, IUP measured in the isthmus uteri; n = 15 uteri each concentration tested).

 

Figure 5
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  		Figure 5. The increase in intrauterine pressure (IUP) during perfusion with different concentrations of progesterone (grey bars, IUP measured in the corpus uteri; black bars, IUP measured in the isthmus uteri; n = 15 uteri each concentration tested).

 

Figure 6
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  		Figure 6. The increase in intrauterine pressure (IUP) during perfusion with different concentrations of 17beta-estradiol plus progesterone (grey bars, IUP measured in the corpus uteri; black bars, IUP measured in the isthmus uteri; n = 15 uteri each concentration tested).

 

Figure 7
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  		Figure 7. The numbers of peristaltic (n = number x 10) waves starting in the corpus uteri (grey bars) and isthmus uteri (black bars). Each group contains 60 perfused uteri. Uterine contractions starting in the isthmus uteri or the corpus uteri were tested using the chi-squared test of independence.

 
Estrogen
Estrogen perfusion resulted in a dose-dependent increase in IUP in the isthmus (P < 0.001) and corpus uteri (P < 0.001; Figure 4). The pressure increase was significantly higher in the isthmus uteri than in the corpus uteri at all concentrations tested. In addition, estrogen perfusion resulted in a significant increase in peristalsis starting in the isthmus uteri and moving in the direction of the corpus uteri (P < 0.001).

Progesterone
Progesterone perfusion was generally associated with a lower increase in IUP (Figure 5). No differences were observed between the IUP increase in the isthmus uteri and that in the corpus uteri at the concentrations tested. No concentration-dependent change in IUP was observed. In addition, progesterone perfusion resulted in a significant increase in peristalsis starting in the corpus uteri and moving in the direction of the isthmus uteri (P < 0.005).

Estrogen plus progesterone
During estrogen and progesterone perfusion, similar results were observed to those seen during progesterone perfusion alone (Figure 6). Estrogen and progesterone perfusion resulted in a dose-dependent decrease in IUP in the isthmus (P < 0.001) and corpus uteri (P < 0.001). The pressure increase was significantly higher in the isthmus uteri than in the corpus uteri at 50 pg/ml of the steroids tested. No differences were observed in the IUP increase in the isthmus uteri in comparison with the corpus uteri at the other concentrations tested. No peristalsis directed towards the isthmus or corpus uteri was detectable (P = 0.27).


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Acknowledgements
References
 
Oxytocin is one of the most potent uterotonic agents and exerts a wide spectrum of central and peripheral physiological effects (McNeilly et al., 1983Go; Russell and Leng, 1998Go; Thornton et al., 2001Go; Caba et al., 2003Go; Woodcock et al., 2004Go). Several studies have shown that levels of oxytocin increase during sexual stimulation and arousal, with a peak during orgasm in women and in men (Carmichael et al., 1987Go; Murphy et al., 1990Go; Carter, 1992Go; Gimpl and Fahrenholz, 2001Go; Argiolas and Melis, 2003Go; Salonia et al., 2005Go). In rodents, endometrial oxytocin and oxytocin receptor mRNA expression is highest at oestrus and is up-regulated by estradiol (Zingg et al., 1995Go). Richter et al. (2003)Go reported that oxytocin receptor expression is up-regulated by estrogens not only in pregnant human uteri but also in non-pregnant human uteri (Richter et al., 2003Go, 2004Go). Stimulation with high-dose 17beta-estradiol has been found to increase myometrial oxytocin receptor density, with maximum levels found in the uterine fundus (Richter et al., 2003Go). Otherwise, long-term stimulation with oxytocin alone leads to mRNA down-regulation in human non-pregnant myometrial cells (Richter et al., 2004Go) and subsequently to an increase in myometrial activity only for the first time, followed by relative uterine quiescence during the further perfusion time (Richter et al., 2005Go). It has therefore logically been suggested that estrogens may support uterine contractility and that they act synergistically with oxytocin in the regulation of uterine peristalsis and in the mechanism of transport towards the corpus uteri and the Fallopian tubes. Fanchin et al. (2000)Go reported a significantly decreased frequency of uterine contractions in a group of women with high progesterone levels (>100 ng/ml) on the day of embryo transfer in comparison with the day of HCG. Progesterone is therefore believed to suppress uterine contractility. Subsequently, visualization of uterine peristalsis using ultrasound and ultrafast magnetic resonance imaging showed different peristaltic patterns in the different cycle phases (Birnholz, 1984Go; Abramowicz and Archer, 1990Go; Kunz et al., 1996Go; Wildt et al., 1998Go; Kido et al., 2005Go). The results of previously published studies (Richter et al., 2003Go, 2004Go) suggest that the effect of estrogens appears to be genomic via oxytocin receptor up-regulation, whereas the effect of progesterone seems to be non-genomic, because of the inhibition of oxytocin action on its receptor (Burger et al., 1999Go; Dunlap and Stormshak, 2004Go).

In this study, 17beta-estradiol perfusion was able to generate a cervico-fundal pressure gradient and an increasing number of peristaltic waves starting in the isthmus uteri, whereas progesterone had no effect. When the uteri were perfused with both steroids, progesterone was able to antagonize the estradiol effect. This study demonstrates that estrogen and progesterone have differential effects in the regulation of uterine peristalsis, and our results are in accordance with those first described by Bulletti et al. (1993)Go in a group of 10 extracorporeally perfused human uteri and by Richter et al. (2005)Go in extracorporeally perused human uteri, as well as those described by Fanchin et al. (2000)Go during ovarian stimulation for in vitro fertilization in 59 women. Furthermore, we were able to demonstrate the presence of uterine peristaltic waves with a cervico-fundal direction during 17beta-estradiol perfusion (Figure 7).

Continuous monitoring of IUP, using multiple probes at different locations in the uterine cavity, may be useful for evaluating directed uterine peristalsis and pressure gradients that can cause directed transport mechanisms. A double-chip microcatheter with two pressure sensors, of the type normally used for urodynamic examination of the bladder and urethra, may therefore be appropriate for investigating uterine peristalsis; this type of instrument was used in the experiments presented here. From our earlier experiments in the swine uterus model, we know that the frequency and basal pressure tone is especially influenced and manipulable by the method of oxytocin administration. In contrast, the rise in IUP is not further strengthened by multiple administrations of oxytocin alone or higher dosages of oxytocin and reaches a plateau with the administration of 2 IU of oxytocin (Kunz et al., 1998aGo,bGo; Dittrich et al., 2003Go). Therefore, we conclude that the IUP increase is a more independent parameter in comparison with the frequency or basal pressure tone in the in vitro model used. The swine uterus may be more practicable than the human uterus for the in vitro study of uterine transport mechanisms caused by peristaltic contractions and waves, and their regulation, as the swine uterus is more analogous to a muscular tube. The swine uterine cavity is also more elongated than the human uterus. Peristaltic waves are easy to visualize, and IUP changes at different locations can easily be recorded at the same time using an intrauterine multichip microcatheter. Delayed pressure changes may be better detectable in the swine uterus. Despite the general limitation of the results from animal models, which are not easily transferable to humans, this perfusion model may represent a useful and practicable method of studying the effects of different substances and hormones on uterine contractility and uterine transport mechanisms.

In summary, this study demonstrates that estrogen stimulates uterine peristalsis and is able to generate a cervico-fundal direction of peristalsis, whereas progesterone generally inhibits directed uterine peristalsis. The extracorporeal perfusion model of an isolated non-pregnant swine uterus used can serve as an adequate model for studying uterine peristaltic activity in vitro, permitting more invasive approaches not generally authorized in humans. The data obtained in the human can also be obtained in the perfusion model of non-pregnant swine uteri described. The advantage of the animal model used is that a large number of uteri from young and healthy animals in their reproductive lifespan can be tested. Using uteri from young mammals makes it possible to detect definite differences in contraction peaks between the distal and proximal uterus compartments (Figure 3).


   Acknowledgements
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
References
 
This work was supported by the ELAN Fund at the University of Erlangen-Nuremberg.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
References
 
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Submitted on January 3, 2006; resubmitted on January 26, 2006; accepted on January 30, 2006.


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