Human Reproduction, Vol. 15, (Suppl. 1), pp. 81-89, 2000
Uterine contractility during the menstrual cycle
Carlo Bulletti1'4, Dominique de Ziegler2'3, Valeria Polli1,
Lidia Diotallevi1, Elena Del Ferro1 and Carlo Flamigni1
1 st
l Institute of Obstetrics and Gynecology, University of Bologna,
Department of Obstetrics and Gynecology and Physiopathology of
Reproduction, Rimini's General Hospital Infermi, Rimini, Italy, 2Columbia
Laboratories, Paris, France and 3Nyon Medical Center, Nyon, Switzerland
4
To whom correspondence should be addressed at: Ostretricia, Ginecologia e
Fisiopatologia della Riproduzione, Via Settembrini, 2, 47841 Rimini, Italy
The non-pregnant uterus shows different patterns of contractility during the
menstrual cycle. A renewed interest in uterine contractility has resulted
fFom reports of non-invasive ultrasound (US) based studies. To clarify the
changes in uterine contractility occurring throughout the menstrual cycle,
we prospectively studied uterine contractions (UC) at six representative
stages with US and intrauterine pressure (IUP) based approaches in 30
cycling volunteers. Results showed UC frequency could be measured by
either US or IUP. UC amplitude and resting pressure tone could only be
assessed by IUP. Conversely, direction of UC displacement could only be
assessed by US. UC frequency increased at mid-cycle and decreased throughout the luteal phase suggesting oestradiol and progesterone exert positive
and negative actions on uterine contractility, respectively. UC amplitude
increased throughout the menstrual cycle to maximum values in the late
luteal phase. Retrograde UC were most frequent at mid-cycle and convergent
('opposing') UC predominated during the luteal phase. While the former
pattern ensures sperm transport, the latter may facilitate embryo implantation. In conclusion, UC changes throughout the menstrual cycle assessed by
US and IUP emphasize the hormonal dependence of uterine contractility.
Although UC patterns favouring sperm transport appear regulated by
oestradiol, uterine quiescence and the dominance of convergent UC prevailing
at the time of implantation are linked to progesterone. These data will serve
to identify and treat possible dyskinetic changes in uterine contractility,
particularly in women suffering from infertility, endometriosis, and dysmenorrhea.
Key words: dysmenorrhea/endometriosis/implantation/menstrual cycle/uterine
contraction
Introduction
The uterus is mostly composed of smooth muscle that exhibits spontaneous and
rhythmic contractions and relaxations (Heinricius, 1889; Kelly, 1962). This
Human Reproduction Volume 15 Supplement 1 2000
© European Society of Human Reproduction and Embryology
8 1
C.Bulletti et al.
activity of myogenic origin persists in denervated preparations (Bulletti et al,
1993). Outside of pregnancy, uterine contractions (UC) are involved in the
expulsion of menstrual debris at the time of menses (early follicular phase), in
the migration of spermatozoa from the cervix to the distal end of tubes (Heinricius,
1889; Birnholz, 1984; Toner and Adler, 1985; De Vries et al, 1990; Kunz et al,
1997, 1998; Wildt et al, 1998), and the return of oocytes/embryos to the uterine
cavity. Finally, UC may favour the proper placement of concepti in the uterine
cavity and thereby favour their implantation.
Typically, two methods have been used to assess UC: the classical approach
consists in recording changes in intrauterine pressure (IUP) using probes that
detect intraluminal variation of pressure produced by UC (Martinez-Gaudio et al,
1973). Recently, an alternative approach has been proposed based on direct
visualization of UC with transvaginal ultrasound (US) using various forms of
analysis, some from digitized scans (Birnholz 1984; Fleischer et al, 1986; de
Vries et al, 1990). The latter method, although indirect, benefits from being noninvasive. US-based assessments of UC potentially provide information on
direction of UC propagation not easily available with IUP recordings. Conversely,
IUP measurements allow a quantification of UC amplitude reflected by the
magnitude of pressure changes. The present study was undertaken to compare
both methods of UC measurement during the various phases of the menstrual cycle.
Materials and methods
Patients and study protocol
Thirty healthy, nulliparous, normally ovulating and menstruating female volunteers (age ± SD 26.3 ± 5.5 years) were studied during their menstrual cycles.
The mean cycle length of these subjects was 28.6 ± 1.6 days (mean ± SD).
Each woman was studied for at least one complete cycle. The day of ovulation,
arbitrarily identified as day 0, was established ultrasonographically by witnessing
follicular rupture (Grinsted et al, 1989). Furthermore, ovulation was confirmed
by measurement of serum progesterone on cycle day 21. UC assessments were
performed during six representative stages of the menstrual cycle. These were
defined as early (-11, -7) and late (-6, -2) follicular, peri-ovulatory (-1, +1),
early ( + 2, +6) and late (+7, +14) luteal phase, and during menses (-14, -12).
UC assessments were made using both US and IUP approaches. All examinations
were performed between 07:30 and 10:30.
UC measurements
IUP recording
Each woman had one IUP recording at one of the six arbitrarily predetermined
menstrual cycle stages, and one IUP recording session during menses. At least
five IUP recordings were obtained at each menstrual cycle stage. IUP was
82
Uterine contractility
recorded as follows: two 1.2 mm ureteral probes with side opening (Neoplex
AC 5907 ureteral catheter, Sarlat, France) were simultaneously inserted in the
uterine cavity and continuously perfused with distilled water at the rate of 0.45
ml/min using a constant-perfusion syringe pump (Hospal K10 infusion pump,
Terumo, Italy). There was no need for cervical dilatation or use of a tenaculum,
although a uterine sound was sometimes used. The probe tips were placed in the
fundal (fundus: 2 cm) and internal os areas, respectively, using the 'put
through' technique; for this, constant pressure recording probes were introduced
sequentially. Passage through the inner cervix was identified by a drop in pressure.
The first probe was pushed until the fundus was reached and pulled back 2 cm.
The second probe was placed just where the drop in pressure was recorded (inner
os of the cervix).
The probes were connected to a transducer (Beckman 4-237; Fullerton, CA,
USA) calibrated to convert mechanical to electrical signals that were transferred
to an analog-digital convertor and stored in a PC equipped with a custom designed
software allowing real time visualization of mechanical events. Recordings lasted
21 min. During the first 3 min, changes in intraluminal pressure were evaluated
from fundal to cervical areas with one 30 s recording every 1 cm. Subsequently,
the record of contractility was conducted with two probes positioned as described
above for at least 15 min. Finally, an additional 3 min of recording was obtained
while the two probes were slowly and simultaneously removed from the organ.
The 'pull through' recordings (before the procedure with one probe and after the
procedure with two probes) served to verify the proper changes in pressure
values between each side of the internal os of the cervix.
Frequency of UC was established by counting the number of oscillations in
IUP detected from the two pressure transducers positioned into the lumen
cavity of the uterus for 15 min and were expressed as number of UC per minute
(UC/min). The amplitude of contractions was expressed in mmHg (change from
baseline). Basal pressure tone (BPT) was expressed in mmHg and reflects the
'isotonic' myometrial activity.
Ultrasound
All women had a US-based measurement of UC at each stage of the menstrual
cycle studied resulting in 180 US determinations. For this, at least 2 min of
sagittal scans were digitized at the rate of 2 frames/s using a high resolution
transvaginal 7.5 mHz transducer (Siemens, Erlangen, Germany) connected to a
Macintosh computer (Apple Computer, Cuppertino, CA, USA) equipped with a
software system specially designed for acquisition, storage, analysis and threedimensional (3D) reconstruction of US images (I6DP, Paris, France). Images
were later analysed using the 3D software which permitted 'TM' reconstructions
when applied to a series of images acquired without displacement of the US
probe as previously reported (Fanchin et al., 1998). Hence, in this model, the Zaxis of the 3D reconstruction system became time. On computer-generated 'TM'
reconstructions, UC appeared as vertical displacement of the myometrial83
CBulletti et al.
Table I. Uterine contractility (UC) frequency
Menstrual cycle stages
Mens
Cycle days
-14,-12
(day 0 = ovulation)
Frequency:
US (UC/min)
1.2 ± 0.5
(n = 30)
IUP (UC/min)
1.1 ± 0.3
(n = 5)
P
NS
EF
LF
PO
EL
LL
-11,-7
-6,-2
- 1 , +1
+2, +6
+7, +14
1 ± 0.3
2.7 ± 0.6
3.5 ± 0.6
1.9 ± 0.6
0.8 ± 0.3
1.0 ± 0.3
2.9 ± 1.0
3.9 ± 0.5
2.2 ± 0.3
0.9 ± 0.3
NS
NS
NS
NS
NS
UC frequency at the six menstrual cycle stages measured by US and intrauterine pressure (IUP).
Data obtained with the two methodologies are analysed and P values are here reported. Stages
studied were during menses (Mens), early follicular (EF), late follicular (LF), peri-ovulatory
(PO), early luteal (EL), and late luteal (LL). Values shown are means ± SD. NS = not
significant.
endometrial interphase which could easily be counted, thus providing precise
accounts of UC frequency.
The direction of propagation of UC was also studied and determined on
accelerated plays of the image sequences. The patterns of directions of wave
propagation identified were: (i) retrograde (cervix to fundus), (ii) antegrade
(fundus to cervix), (iii) convergent (opposing) starting simultaneously from cervix
and fundus, and (iv) focal local contractions (which are not involving the whole
uterine walls).
Analysis
Statistical analysis was performed using unpaired Student Mest. Fast Fourier
analysis was used to detect the frequency of waves with both IUP and US. The
coefficient of agreement (K) was also used.
Results
UC frequency
UC frequencies detected by IUP and US during the six stages of the menstrual
cycle are reported in Table I. There were no significant differences between the
value obtained with US and IUP in each stage of the menstrual cycle studied.
The coefficient of agreement K was always >80. UC frequency increased from
early follicular to peri-ovulatory phase of the menstrual cycle and then decreased
progressively during the luteal phase. Mean UC frequency (calculated by IUP
and US) during the early and late follicular phase (1.8 ± 1.9 contractions/min)
were significantly higher than mean values during the early and late luteal phase
84
Uterine contractility
Frequency of Uterine Contractions
s
3
E
2 _
V':
:.•'.'?•:•
••&•
0
Hffii"
Intervals of Menstrual Cycle
Figure 1. Frequency of uterine contractions (UC). Uterine contraction frequency (mean of intrauterine
pressure and ultrasound data) showed an increase during the follicular phase followed by a period of uterine
quiescence during the luteal phase.
Table II. Uterine contractility (UC) amplitude
Menstrual cycle stages
IUP (mmHg)
PO
EL
LL
Mens
EF
LF
18 ± 7.4
16.6 ± 8
25.2 ± 7.1 25.6 ± 11.5 36.2 ± 5.5 43.2 ± 6.1
mean ± SD)
UC amplitude is reported as mean changes in intrauterine pressure (IUP) values ± SD in
mmHg. Menstrual cycle stages are as described in Table I.
when progesterone exerts its utero-quiescent effects: 1.4 ± 1.5 contractions/min
(P < 0.05). Paralleling oestradiol concentrations, UC frequencies were the
highest during the peri-ovulatory time. During menses, UC frequency increased
by comparison to late luteal phase measurements (P < 0.05).
UC amplitude
IUP recording but not US allowed the evaluation of UC amplitude. UC amplitude
was significantly higher in the luteal than in the follicular phase of the menstrual
cycle (P < 0.001) with an evidence of progressive increase from early follicular
to the late luteal phase of the menstrual cycle, when the highest UC amplitude
was observed (Table II). UC amplitude decreased during menses.
Basal pressure tone
Basal pressure tone represents the isotonic contraction of the muscle. It progressively increased from the early to late follicular phase and then decreased during
the late luteal phase of the menstrual cycle with an isolated re-increase during
menses (Table III).
85
C.Bulletti et ah
Table III. Basal pressure tone of uterine contractility (UC)
Menstrual cycle stages
IUP (mmHg)
(n = 5,
mean ± SD)
Mens
EF
LF
PO
EL
LL
36.6 ± 10.2
23.8 ± 8.2 56.2 ± 8.4 44.4 ± 11.7 36.2 ± 5.5 23.4 ± 11.4
Basal pressure tone of UC is reported as mean intrauterine pressure (IUP) values ± SD in
mmHg. Menstrual cycle stages are as described in Table I.
Table IV. Uterine contractility (UC) direction of displacement
UC patterns:
(% of total
UC ± SD)
Menstrual cycle stages
Mens
EF
Retrograde
Antegrade
Convergent
Focal
18.4 ± 17.9
2.1 ± 4.8
0
3.3 ± 1.1
23.3 ± 7.7 26.5 ± 5.8 37.5 ± 5.4
12.2 ± 7.5 16.9 ± 7.1 29.7 ± 37.1
0
0
3 ± 2
0
0
10.9 ± 9.7
LF
PO
EL
LL
33.7
6.5
12.1
7.8
±8
8 ± 3.1
± 5.3 4.1 ± 3.1
± 4.2 10.3 ± 2.2
±5
9.7 ± 4.7
Four patterns of propagation of UC displacement were identified: retrograde (cervix to fundus);
antegrade (fundus to cervix); convergent UC starting simultaneously from cervix and fundus;
focal or local contractions (not involving the entire uterus). Menstrual cycle stages are as
described in Table I.
Direction of UC propagation
Only data obtained with US permitted an assessment of the direction of UC
displacement. UC with retrograde (cervix to fundus) displacement represented
the dominant UC pattern throughout the menstrual cycle as previously described
(Lyons et al, 1991; Ijland et al, 1996). It is increased from 18.4 ± 17.9% of
all UC during menses to peak at 37.5 ± 5.4% at the time of ovulation. The
proportion of retrograde contractions subsequently decreased during the luteal
phase only representing 8% of all UC in the late luteal phase. Convergent UC
peaked during the luteal phase where it represented 10.3 ± 2.2% of all UC. Data
are reported in Table IV.
Discussion
Uterine contractility may influence sperm transport, oocyte migration through
tubes, embryonic transport from tubes to the uterine cavity, and possibly
embryo implantation itself (Bulletti et al., 1997). Abnormal uterine contractility
(dyskinesia) may cause pelvic pain (dysmenorrhea), abortion and preterm labour
(Kelly, 1962; Bulletti et al., 1993, 1997). Uterine contractility has been previously
investigated in several clinical conditions in which abnormal UC have been
86
Uterine contractility
reported, e.g. endometriosis, spontaneous and recurrent abortion, implantation
failures (Bulletti et al., 1994, 1997) mostly with IUP-based approaches. The
present study showed that UC frequency can be detected by both IUP and US.
From our results, we see an increase in UC frequency during the follicular phase
followed by a decrease during the luteal phase of the menstrual cycle, which
confirms previous data (Lyons et al., 1991; Bulletti et al., 1993; Ijland et al.,
1996). Globally, these results suggest a role of oestrogens as stimulator and
progesterone as inhibitor of UC (Graham and Clarke, 1997; Kunz et al., 1998;
NoeetaL, 1999).
Of the two methodological approaches used, only US can assess the direction
of UC displacement. Our results showed a marked increase in the percentage of
UC with retrograde displacement during the follicular phase with a peak in the
peri-ovulatory period. On the contrary, we witnessed a dramatic and progressive
decrease of retrograde UC throughout the luteal phase when convergent UC
predominated. This supports the concept that, in the late follicular phase, UC
facilitate sperm transport toward the distal end of the tubes. In the luteal phase,
the decrease in UC frequency and the predominance of the convergent pattern
may favour embryo positioning and implantation. UC amplitude, however, can
only be appreciated from IUP data. Our results indicate that UC amplitude
increased during the luteal phase, peaked during the late luteal phase, and
subsequently decreased at the time of menses. Basal pressure tone, also not
accessible to US-based investigations, peaked during the late follicular phase,
decreased during the luteal phase and re-increased during menses. The endometrium is covered with a film of fluid containing several endometrial proteins and
other nutritional/growth factors (Bulletti and Flamigni, 1994) important for the
developing embryo before it receives its needs from the maternal blood supply.
From our results, it appears that the displacement of fluid containing spermatozoa/
oocyte/embryo is primarily linked to the sequencing of the various phases of the
menstrual cycle.
IUP recordings (Martinez-Gaudio et al., 1973) suffer from being invasive and
possibly altering results by direct effects of the methodology on uterine contractility (Lyons et al., 1991). Yet, this methodology remains the only one capable of
providing data on UC amplitude and basal pressure tone. Increased UC amplitude
and basal pressure tone has been blamed in dysmenorrhea (Akerlund et al.,
1979). Hence, IUP readings provide data pertinent to clinical evaluation of
various physiopathological conditions.
US offers the advantage of its non-invasiveness which permits evaluations in
actual conception cycles. Our results indicate that US is as effective as IUP
recordings for measurements of UC frequency. Furthermore, it potentially offers
valuable information on direction of UC displacement not available to IUP
recordings. Yet to this stage, assessment of direction of UC displacement as
visualized on US cannot be taken as proof of actual displacement of uterine
content. The latter parameter, which is most relevant clinically, must still be
assessed by techniques using various contrast media to follow the true displacement of uterine content through the utero-tubal unit. Indeed, current readings of
87
CBulletti et al.
US scans cannot distinguish true intrauterine displacement from dyskinetic
processes where UC displacement shown by US is not followed by actual
displacement of uterine content. Using "Tc-labelled macro-albumin aggregates,
it has been shown (Leyendecker et al., 1996) that some individuals, particularly
women suffering from endometriosis, failed to have proper retrograde displacement of uterine content in the pre-ovulatory phase. More recently, we showed
that this form of dyskinetic process may be even more easily identifiable by
mock intrauterine inseminations (IUI) done with X-ray contrast medium (de
Ziegler et al., 2000). Taken together, these data indicate that late follicular phase
dyskinetic processes exist and may alter female fecundity and outcome of
infertility treatments involving IUI or intercourse.
Studying the direction of UC displacement is also important at the time
of menses when UC should participate in the forward emptying of uterine
content (menstrual blood and debris). Conversely, inappropriate UC affected
by various forms of dyskinetic process may be the underlying mechanism
responsible for retrograde bleeding and development of pelvic endometriosis
(Samson, 1927). Dyskinesia at the time of menses may not be detectable by
US-based studies, while UC amplitude and basal pressure tone may be the
most relevant parameters impacting on proper forward uterine emptying. To
date, both of these parameters have been accessible only to IUP-based
evaluations. Further trials should be conducted on the direction of actual
displacement of uterine content in an attempt to single out the nature of the
dyskinetic process partaking in the development of dysmenorrhea. New
developments may offer improved approaches to clinical conditions associatedwith uterine dyskinesia (Eta et al., 1994; Andersen and Barclay, 1995;
Dawood 1995).
In conclusion, our study looking at changes in UC patterns throughout the
menstrual cycle using IUP- and US-based approaches emphasized the roles
of oestradiol and progesterone on uterine contractility. Retrograde transport
characterizing the end follicular phase, crucial to sperm transport and
fertilization, appears to depend on oestradiol. Uterine quiescence and the
predominance of convergent patterns of UC probably critical to embryo
implantation are under the influence of progesterone. Finally, the menstrual
pattern of UC with the highest basal pressure tone, important for the proper
forward emptying of the uterus, appears to be induced by progesterone
withdrawal. Improving our understanding of the hormonal control of uterine
contractility as provided by this study may be crucial to potentially helpful
uses of exogenous hormone supplement for treating dyskinetic processes in
conditions such as infertility, endometriosis, and dysmenorrhea. Our study
also showed the relative interest of both IUP- and US-based studies. We
conclude that US offers a simple and valid form of UC frequency assessment,
a relevant parameter at the time of implantation. Conversely, IUP measurements
remain the primary mode for studying UC parameters at the time of menses.
Uterine contractility
Acknowledgements
Expert secretarial help for this manuscript was provided by Stephanie Roy.
References
Akerlund, M., Stomberg, P. and Forsling, M.L. (1979) Primary dysmenorrhoea and vasopressin.
Br. J. Obstet. GynecoL, 86, 484^87.
Andersen, H.F. and Barclay, M.L. (1995) A computer model of uterine contraction based on
discrete contractile elements. Obstet. GynecoL, 86, 108-111.
Birnholz, J.C. (1984) Ultrasonic visualization of endometrial movement. Fertil. Steril., 41, 157-158.
Bulletti, C , Prefetto, R.A., Bazzocchi, G. et al. (1993) Electromechanical activities of human uteri
during extra-corporeal perfusion with ovarian steroids. Hum. Reprod., 8, 1558-1563.
Bulletti, C. and Flamigni, C. (1994) Reproductive failure due to spontaneous abortion and recurrent
miscarriage. Hum. Reprod., 7, 533-536.
Bulletti, C , Polli, V., Licastro, F. et al. (1994) Endometrial and embryonic factors involved in
successfull implantation. Ann. NY Acad. Sci., 734, 221-231.
Bulletti, C , DeZiegler, D., Rossi, S. et al. (1997) Abnormal uterine contractility in non-pregnant
women. Ann. NY Acad. Sci., 828, 223-229.
Dawood, Y. (1995) Pharmacological stimulation of uterine contractions. Semin. Perinatol., 19,
73-83.
De Ziegler, D., Fanchin, R., Bulletti, C. et al. (2000) Active hysterosalpingoscintigraphy (A-HSG):
New look at the functionality of retrograde utero-tubal contractility at mid-cycle. 47th Annual
Meeting of the Society for Gynecologic Investigation, Chicago, Illinois, March 23-25, J. GynecoL
Invest., Abstract, in press.
De Vries, K., Lyons, E.A., Ballard, G. et al. (1990) Contractions of the inner third of the
myometrium. Am. J. Obstet. GynecoL, 162, 679-682.
Eta, E., Ambrus, G. and Rao, Ch.V. (1994) Direct regulation of human myometrial contraction by
human chorionic gonadotropin. J. Clin. Endocrinol. Metab., 79, 1582-1586.
Fanchin, R., Righini, C , Olivennes, F. et al. (1998) Uterine contractions at the time of embryo
transfer alter pregnancy rates after in-vitro fertilization. Hum. Reprod., 13, 1968-1974.
Fleischer, A.C., Kalemeris, G.C. and Entman, S.S. (1986) Sonographic depiction of the endometrium
during normal cycles. Ultrasound Med. BioL, 12, 271-277.
Grinsted, J., Jacobsen, J.D., Grinsted, L. et al. (1989) Prediction of ovulation. Fertil. Steril., 52,
388-394.
Heinricius, G. (1889) En metod att grafiskt atergiva kontraktioner hos en icke gravid livmoder.
Finsk Lakaresallsk HandL, 31, 349-355.
Ijland, M.M., Evers, J.L.H., Dunselman, G.A.J. et al. (1996) Endometrial wavelike movements
during the menstrual cycle. Fertil. Steril., 65, 746-749.
Kelly, J.V. (1962) Myometrial participation in human sperm transport: A dilemma. Fertil. Steril.,
13, 84-92.
Leyendecker, G., Kunz, G., Wildt, L. et al. (1996) Uterine hyperperistalsis and dysperistalsis as
dysfunctions of the mechanism of rapid sperm transport in patients with endometriosis and
infertility. Hum. Reprod., 11, 1542-1551.
Lyons, E.A., Taylor, P.J., Zheng, X.H. et al. (1991) Characterization of subendometrial myometrial
contractions throughout the menstrual cycle in normal fertile women. Fertil. Steril., 55, 771-774.
Martinez Gaudo, M., Yoshiba, T. and Bentason, L.P. (1973) Propagated and non propagated
myometrial contraction in normal menstrual cycle. Am. J. Obstet. GynecoL, 115, 107-111.
Samson, J.A. (1927) Peritoneal endometriosis due to menstrual dissemination of endometrial tissue
into venous circulation. Am. J. Pathol., 3, 93-98.
89