Functional determinants of uterine contractility in endometriosis and adenomyosis: A systematic review and meta-analysis

Abstract

Importance:

Evidence suggests that aberrant uterine contractility in nonpregnant women with endometriosis and adenomyosis contributes to symptoms and potentially heralds their pathogenesis. However, uterine peristalsis remains understudied, inconsistently measured, and poorly understood.

Objective:

To summarize evidence on uterine contractility across the menstrual cycle phases in women with endometriosis and adenomyosis.

Data sources:

PubMed/MEDLINE, Embase and Scopus databases searched up to May 2nd, 2024.

Study selection and synthesis:

Observational studies compared quantitative measures of uterine contractility using MRI, ultrasound, electrophysiology or direct intrauterine pressure recording across different menstrual cycle phases between women with endometriosis/adenomyosis and controls based on pre-defined PICOS criteria. Study quality was assessed using the Newcastle-Ottawa Scale. Pooled estimates for primary (risk ratios (RR) with 95% confidence intervals (CIs)) and secondary outcomes (mean difference (MD) with 95% CIs) were calculated using random-effects models.

Main outcomes:

Pooled risk of retrograde menstruation uterine contraction pattern in cases versus controls; pooled MD in continuous measures of uterine contractility (frequency, amplitude, and velocity of contractions) across all the menstrual cycle phases in cases versus controls.

Results:

Nine studies met the inclusion criteria; most were studies that evaluated women with endometriosis. An increased risk of retrograde uterine contractions during menstruation was observed in women with endometriosis compared to controls (RR, 8.63; 95% CI, 3.24–22.95; I²=0%). The pooled MD in contraction frequency between cases and controls was 0.82 (95% CI, 0.13–1.52; I²=18.61%) in the menstrual phase and 0.52 (95% CI, 0.22–0.83; I²=27.18%) in the luteal phase. Results for the follicular and peri-ovulatory phases were more heterogeneous. Higher contraction amplitudes in women with endometriosis or adenomyosis were reported across all menstrual cycle phases. Due to the paucity of data, especially for adenomyosis, evidence certainty was graded as low for most comparisons.

Conclusion and relevance:

The approximately 9-fold increased risk of retrograde pattern during menstruation in endometriosis supports the potential role of retrograde menstruation in its etiopathogenesis. Abnormal uterine contractility, likely not limited to the menstrual phase, may be a mechanical factor contributing to development of endometriosis and related symptoms, including menstrual pain and infertility, with limited, mostly concordant evidence for adenomyosis.

Study registration:

PROSPERO ID CRD42024512273 – accepted on February 23rd, 2024.

Capsule

Retrograde uterine peristalsis during menstruation is associated with a 9-fold increased risk among women with endometriosis. Higher frequency, amplitude, and likely changes in velocity and coordination of contractions may also contribute to symptoms and pathogenesis.

Introduction

Peristalsis is a fundamental function of smooth muscle within the nonpregnant uterus (1). Across the menstrual cycle, wavelike activity aids the expulsion of menses, the migration of spermatozoa from the cervix to the distal end of the tubes, the transport of oocytes/embryos to the uterine cavity after ovulation/fertilization, and the embryo placement in the uterine cavity during implantation (2). Cervix-to-fundus contractions prevail during the follicular and luteal phases, whereas fundus-to-cervix waves become predominant during menses (3). Uterine peristaltic activity and pattern is likely influenced by cyclical hormonal fluctuations across the menstrual cycle. During the follicular phase, it may be affected by estradiol released from the dominant follicle (4), whereas during the luteal phase it is impacted by hormonal secretion from the newly-formed corpus luteum (5).

While the patterns of uterine contractility are essential to the normal nonpregnant uterine physiology, altered peristalsis could play a role in the development and symptoms related to the reproductive diseases, endometriosis and adenomyosis. Quantifying abnormal patterns and measures of uterine contractility, including frequency, amplitude, velocity, and coordination of contractions, offers a potential new tool for explaining menstrual pain and infertility associated with endometriosis and adenomyosis (6,7). Altered uterine contractility likely serves as a mechanical factor in the endometriosis development, facilitating transtubal egress of endometrial tissue during menstruation (8). Retrograde menstruation, combined with the proliferative potential of endometrial cells and the peritoneal response, results in the establishment of ectopic implants (9,10). Hyperperistalsis or other abnormal contractions may disrupt the endo-myometrial interface and induce proliferation of basal endometrium into the myometrial wall defects, resulting in adenomyosis (11,12).

This meta-analysis aimed to summarize evidence on measures of uterine contractility across menstrual cycle phases in women with endometriosis and adenomyosis, to explore the potential contribution of uterine contractility to these conditions.

Materials and Methods

The study protocol was registered on PROSPERO (CRD42024512273–accepted on February 23rd, 2024). The findings were reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines (13,14).

Search strategy

Two reviewers (N.S.,G.D.) searched the PubMed/MEDLINE, Embase and Scopus databases from study inception up to May 2nd, 2024. The search strategy included a combination of Medical Subject Headings (MeSH) terms and equivalent keywords (Appendix I).

Eligibility criteria

Inclusion criteria were defined using the PICOS framework (15): 1) Population: Premenopausal women with endometriosis and/or adenomyosis. Accepted diagnoses for inclusion were: a) surgical visualization and histological confirmation of the disease; b) transvaginal ultrasound (TVUS) and/or magnetic resonance imaging (MRI) diagnosis of ovarian endometriosis (endometriomas), deep endometriosis lesions, or adenomyosis. Diagnosis based on medical records or patient self-reporting were not included; 2) Investigated condition (measure): Quantitative assessment of uterine contractility across the menstrual cycle phases; 3) Comparator: Premenopausal women without endometriosis and/or adenomyosis; 4) Outcomes: Primary: Pooled risk of retrograde menstruation pattern of contractions in cases versus controls (primary); Secondary: Pooled mean difference (MD) in continuous measures of uterine contractility (frequency, amplitude, and velocity of contractions) in cases vs. controls across multiple menstrual cycle phases; 5) Study type: Observational studies meeting criteria, excluding non-original articles. In vitro and non-human studies were excluded. All included studies were published in peer-reviewed journals with full texts available in English.

Study selection and data extraction

Records were independently screened by two reviewers (N.S.,G.D.), first by title and abstract, followed by a full-text review based on eligibility criteria. Any discrepancies were resolved by consulting a third reviewer (P.Ve.). A full list of data abstracted and tabulated is provided in Appendix II.

Risk of bias assessment

Risk of bias assessment was conducted independently by two reviewers (N.S.,G.D.) using the Newcastle-Ottawa Scale quality appraisal checklist (16). The assessment scored study subject selection (4 points), group comparability (2 points), and outcome assessment (3 points).

Certainty of the evidence assessment

The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach (17).

Data analysis

The risk estimate of the primary outcome was calculated in each study from raw data using 2×2 tables. Pooled risk ratios (RR) with 95% confidence intervals (CIs) were calculated. For secondary outcomes, means and standard deviations (SDs) were obtained from individual studies. For studies that reported standard errors of the mean rather than SDs, SDs were derived. The number of contractions were standardized to n/minute for the mean and SD using available study data. Pooled mean differences (MD) between cases and controls with 95% CIs were calculated from individual study findings and expressed as contractions per minute.

Pooled estimates were calculated using random-effects models, following the DerSimonian-Laird method (18). Statistical heterogeneity was assessed using I² statistics, as follows (19): 0%-40% (not important), 30%-60% (moderate), 50%-90% (substantial), and 75%-100% (considerable). Fixed-effects models were implemented alongside random-effects models in cases of low statistical heterogeneity to address the impact of pooling models on summary effect estimates. Sensitivity analysis was performed to assess the effect of individual studies on the pooled estimate. Subgroup analyses were conducted in cases of high heterogeneity to assess the impact of confounders. Mediators were chosen based on clinical relevance and availability, requiring at least two studies per subgroup. Publication bias was investigated using the Egger’s test for small-study effect (20). Analyses were performed using STATA version 18 (Stata Corp LLC, 2024, College Station, TX, USA).

Results

Of 1,040 records identified, 350 were duplicates and 491 were removed during title and abstract screening. Of 199 assessed full-text articles, 9 studies (n=800 women) met inclusion criteria (21–29). Of these, three studies were excluded from the quantitative synthesis: one without other studies for comparison, reported uterine contractility patterns in adenomyosis only during the peri-ovulatory phase (21), another did not report raw data (25), and the third lacked comparable measures (29). The PRISMA flow diagram is shown in Figure 1.

Figure 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 flow diagram of the studies selection process.

Studies overview

Included studies were prospective observational (21–29), with one being a multicentric study (27). Sample sizes varied significantly, ranging from 240 (23) to 22 women (29). In three studies, cases had adenomyosis (21,23,26), of which two (21,26) adopted the Morphological Uterus Sonographic Assessment (MUSA) criteria (30). Five studies included cases with surgically confirmed endometriosis (22,23,25,27,29), one included endometriomas at TVUS and/or MRI (24). One study defined cases as having deep endometriosis on MRI (28), reporting concomitant adenomyosis in one-third of the cases. Definition of controls varied across studies. Some studies excluded endometriosis/adenomyosis in controls through imaging (21,28), surgery (22), or clinical history lacking endometriosis-associated symptoms (25,29). Three studies defined controls as those without any gynecological abnormalities (24,26,27), and one study conducted in an infertility setting defined controls as having a tubal factor but no other diseases (23)(Table 1).

Table 1.

Baseline characteristics of the included studies (n = 9).

Author, year	Study design	Study country	Study years	Study population: a) sample size b) age range c) fertility/HT status	Groups of comparison
Arena et al., 2024 (21)1	prospective observational	Italy	March 2019 to March 2021	a) n = 36 b) 18–45 years old c) all nulliparous	- cases: adenomyosis defined by the MUSA criteria (n = 18) - controls: non-adenomyosis at TVUS (n = 18)
Bulletti et al., 2002 (22)	prospective observational	Italy	NR	a) n = 44 b) NR c) all nulliparous with unexplained infertility	- cases: surgically confirmed endometriosis stage 2 or 3 according to r-AFS (n = 22) - controls: non-endometriosis at surgery (n = 22)
He et al., 2016 (23)2	prospective observational	China	December 2014 to July 2015	a) n = 240 b) 20–45 years old c) all with infertility undergoing frozen–thawed ET	- cases: surgically confirmed endometriosis (n = 120) - controls: tubal factor infertility (n = 120)
Kido et al., 2007 (24)	prospective observational	China	September 2002 to April 2004	a) n = 32 b) endometriosis: 24–51 years old; controls: 23–32 years old c) NA	- cases: endometriomas visualized by TVUS and/or MRI (n = 26) - controls: no identifiable gynecological abnormality (n = 12)
Leyendecker et al., 1996 (25)1	prospective observational	Germany	NR	a) n = 205 b) 21–46 years old c) all of those with endometriosis had a history of infertility of 1–7 years	- cases: surgically diagnosed endometriosis stage 1 to 4 according to r-AFS (n = 111) - controls: fertile, with regular cycles (n = 94) (endometriosis ruled out by laparoscopy in those undergoing HSSG, n = 28/94)
Rees et al., 2024 (26)	multicenter prospective observational	Netherlands, Italy, Greece	September 2014 to January 20233	a) n = 171 (n = 145 after quality check) b) >18 years old, all premenopausal c) all with natural cycles (no HT)	- cases: adenomyosis defined by the MUSA criteria (n = 46; n = 39 after quality check) - controls: no uterine pathologies at TVUS and no symptoms (n = 125; n = 106 after quality check)
Salamanca et al., 1995 (27)	prospective observational	Spain	NR	a) n = 37 (n = 33 after quality check) b) NR c) NA	- cases: surgically confirmed endometriosis (n = 16; n = 14 after quality check) - controls: negative medical and gynecological histories and normal TVUS and clinical evaluation (n = 21; n = 19 after quality check)
Soares et al., 2023 (28)	prospective observational	Brazil	May 2018 to March 2019	a) n = 64 (n = 43 included in analysis) b) 18–45 years old c) all with natural menstrual cycles (no HT); 11/43 (25.5%) with adenomyosis at MRI	- cases: deep endometriosis at MRI (n = 18); 33.3% with adenomyosis at MRI - controls: negative MRI (n = 25)
Wang et al al., 2023 (29)1	prospective observational with longitudinal sampling	USA	NR	a) n = 22 b) 18–37 years old c) cases with natural menstrual cycle (no HT)	- cases: surgically confirmed endometriosis (n= 5; total of n = 679 uterine peristalsis over 12.5 hours) - controls: regular menstrual cycles and no infertility (n = 17; total of n = 4968 uterine peristalsis over 34 hours)

Abbreviations: NR, not reported; NA, not applicable; HT, hormonal treatment; MUSA, Morphological Uterus Sonographic Assessment; TVUS, transvaginal ultrasound; r-AFS, revised American Fertility Society; MSMCs, myometrial smooth muscle cells; ET, embryo transfer; MRI, magnetic resonance imaging; HSSG, Hysterosalpingoscintigraphy.

Notes:

¹Studies excluded from quantitative synthesis because reporting pattern of uterine contractility only in peri-ovulatory phase, not reporting crude data for cases and controls and/or comparable measures of the estimate.

²This study reported also results of a randomized controlled trial (atosiban vs. placebo) on the endometriosis cohort only; data not reported because not relevant for the purpose of this review.

³The authors declared a pause in patient recruitment because of the Covid-19 pandemic between 2018 and 2021.

Uterine contractility characteristics from five TVUS studies (21,23,25–27) were recorded for 3–5 minutes in the sagittal or mid-sagittal plane, and then analyzed at 4–5x regular speed. Two studies used cine-MRI (24,28), one measured intrauterine pressure with catheters and laparoscopy during menstruation to detect retrograde bleeding (22), and one study employed a novel noninvasive electrophysiological tool with sophisticated computational analysis (29). Only one study detailed the definition of menstrual phases using laboratory data for estrogen and progesterone levels (29)(Table 2). The risk of bias assessment is reported in Supplemental Table 1.

Table 2.

Quantitative assessment of uterine contractility and main findings (n = 9).

Author, year	Modality for measurement of uterine contractility	Menstrual cycle phase(s)	Uterine contractility measure(s)	Main findings
Arena et al., 2024 (21)1	Steps: 1) 3-minutes TVUS in the sagittal plane of the uterus using a 4–9 MHz volumetric probe (Voluson TM E8, GE Healthcare) by 2 blinded examiners; 2) records analyzed by the same 2 examiners at 4x regular speed	peri-ovulatory (CDs 11–14)	1) contraction pattern (anterograde, retrograde, opposing or random)	1) Higher prevalence of opposing pattern in adenomyosis vs. controls
Bulletti et al., 2002 (22)	Steps: 1) intrauterine pressure measured from 2 intrauterine/intracervical catheters (at 1 cm from the fundus and the tip of the second inside the internal os of the cervix); measurement for 15 minutes with “pullthrough” steps (before the first catheter and after catheter procedure) to rule out cervical sphincter-like mechanisms; 2) laparoscopy to detect macroscopic presence of blood in the pelvic cavity	CDs 2–4	1) baseline pressure tone (mmHg) 2) frequency (oscillations/10 minutes) 3) amplitude (mmHg) 4) retrograde bleeding (at laparoscopy)	1–3) Higher baseline uterine pressure, frequency and amplitude of contractions in endometriosis vs. controls 4) Higher prevalence of retrograde bleeding in endometriosis vs. controls
He et al., 2016 (23)	Steps: 1) 4-minutes TVUS recording in the sagittal plane of the uterus using a 7.5-MHz probe (Toshiba Nemio SSA-550A, Toshiba) by a single examiner; 2) records analyzed by 2 examiners at 4x regular speed	approximately 1 hour before ET (both natural and artificial frozen-thawed ET cycles)	1) frequency (waves/minute), calculated as the average of the observations by 2 observers	1) Higher frequency of contractions in endometriosis vs. controls
Kido et al., 2007 (24)	Steps: 1) cine-mode MRI with 60 serial images of midsagittal plane of the uterus by HASTE technique using 1.5-T magnet unit with a phased-array coil; 2) records analyzed by 2 examiners at 12x regular speed	phases of the menstrual cycle (no CDs ranges): peri-ovulatory, luteal, menstrual	1) contraction pattern (cervix-fundus, fundus-cervix, and both cervix-fundus and fundus-cervix) 2) frequency (contractions/2 minutes)	1) Higher prevalence of cervix-fundal pattern in endometriosis vs. controls in the peri-ovulatory phase 2) Lower frequency of contractions in endometriosis vs. controls in the peri-ovulatory phase
Leyendeck er et al., 1996 (25)1	■ TVUS: Steps: 1) 5-minutes TVUS recording in the sagittal plane of the uterus using a 7.5-MHz probe (Sonoline SM 5, Siemens); 2) records analyzed at 5x regular speed ■ HSSG: Steps: 1) 0.5 ml saline suspension containing albumin macrospheres labelled with technetium-99m placed into the posterior vaginal fornix with the patient in the supine position; 2) serial anterior-posterior scintigrams performed with a gamma camera (Orbiter, Siemens) over 32 min	phases of the menstrual cycle (no CDs ranges): menstruation, early, mid- and late follicular, mid-luteal	1) at TVUS: frequency of subendometrial peristaltic waves (contractions/min), with distribution pattern of peristalsis frequency (normalized to the mean frequency in controls as 100%) 2) at HSSG: ascension of the labelled macrospheres from the upper vagina (compartment 1, place of application) to the uterine cavity (compartment 2), the isthmic part of the tubes (compartment 3), the ampullary part of the tubes and the peritoneal cavity (compartment 4)	1) Higher peristaltic activity in endometriosis vs. controls during the early follicular, mid-follicular and mid-luteal phases, independently of the disease severity 2) Increased transport of radioactive particles from the vaginal depot, through the uterus into the tubes and the peritoneal cavity in the early and mid-follicular phases and reduction of uterine transport capacity in the late follicular phase
Rees et al., 2024 (26)	Steps: 1) 4-minutes TVUS recording in the mid-sagittal plane of the uterus using a V5–9 transvaginal probe (bandwidth 5–9 MHz; Accuvix WA80S with Elite, Samsung) or a RIC5–9W-RS probe (bandwidth 3.8–9.3 MHz; GE Voluson, GE Healthcare); 2) records analyzed by 2 examiners at 4x regular speed	phases of the menstrual cycle: menstrual (CDs 1–5), mid-follicular (CDs 6–10), late follicular (CDs 11–14), early luteal (CDs 15–20)2, late luteal (CDs 21–28)	1) frequency (waves/minute) 2) amplitude 3) contraction pattern (cervico-fundal, fundo-cervical, and opposing) 3) velocity, defined as the mean over a window of 20 seconds sliding over the full recording time (mm/second) 4) coordination, depending on the similarity in the dominant contraction direction between the anterior and posterior uterine walls (mean squared error)	1) Lower frequency of uterine contractions in adenomyosis vs. controls in the mid and late follicular phases3 2) Higher amplitude in adenomyosis vs. controls in the late follicular and late luteal phases3 3) Lower velocity in adenomyosis vs. controls in the late follicular and late luteal phases3 4) Reduced contraction coordination in adenomyosis vs. controls in the late follicular and late luteal phases3
Salamanca et al., 1995 (27)	Steps: 1) 5-minutes TVUS recording in the mid-sagittal plane of the uterus with high-resolution real-time sector scanner using a 5-MHz transvaginal probe (Toshiba SAL-77 B, Toshiba); 2) records analyzed by 2 blinded examiners on the fast-forward mode	CDs 1–2 (first 48 hours of the menstrual cycle)	1) contraction pattern, defined as subendometrial conctractile waves (anterograde, retrograde or not recognizable/absent)	1) Higher prevalence of retrograde pattern in endometriosis vs. controls
Soares et al., 2023 (28)	Steps: 1) cine-mode MRI with 60 serial images of mid-sagittal plane of the uterus by HASTE technique using a 3-T scanner (Prisma, Siemens); 2) records analyzed at 12x regular speed by 2 independent examiners blinded to the day of the cycle	phases of the menstrual cycle3: initial follicular (CDs 1–10), peri-ovulatory (CDs 10–18), luteal (CDs 18–28)	1) frequency (waves/2 minutes)	1) Trends of higher frequency of uterine peristalsis in deep endometriosis vs. controls in the peri-ovulatory and luteal phases
Wang et al al., 2023 (29)1	Uterine Peristalsis Imaging, a novel noninvasive electrophysiological tool; multi-steps: 1) anatomical T2W MRI using 3-T magnet to acquire the patient-specific uterus-body surface geometry; application of customized BioSemi pin-type electrode patch; 2) body surface electrical signals recorded for 20 minutes and waves generated at each point on the 3D uterine surface; 3) inverse computation to derive activation sequences, uterine potential maps, and uterine isochrone maps	phases of the menstrual cycle4: menses, early proliferative (E2 <200 pg/ml and PG <3 ng/ml), late proliferative/peri-ovulatory (positive result on an ovulation predictor kit, E2 >200 pg/ml, PG <3 ng/ml, and/or a dominant follicle at TVUS ≥16mm), secretory (PG >3 ng/ml)	1) contraction propagation, determined from the uterine peristalsis activation maps (fundus-cervix, cervix-fundus, others) 2) initiation and termination sites, defined as the region experiencing the earliest and latest activation of uterine peristalsis (cervical, fundal, others) 3) duration, defined as the duration of a complete peristalsis wave (sec) 4) magnitude, defined as the average peak amplitude of electrical potential over the uterine region experiencing activation (mV) 5) uterine peristalsis power, defined as the product of magnitude and duration for each uterine peristalsis (mV*sec)	1–2) Higher frequency of Cervix-Fundus waves and lower frequency of Fundus–Cervix waves in endometriosis vs. controls in the menstrual phase; Lower frequency of Cervix-Fundus waves and higher frequency of Fundus–Cervix waves in endometriosis vs. controls in the periovulatory phase 3–5) Cervix-Fundus waves with longer duration, higher magnitude and power in endometriosis vs. controls in the menstrual phase; Fundus-Cervix waves with longer duration, higher magnitude and power in endometriosis vs. controls in the peri-ovulatory phase

Abbreviations: TVUS, transvaginal ultrasound; CDs, cycle days; MSMCs, myometrial smooth muscle cells; NR, not reported; ET, embryo transfer; MRI, magnetic resonance imaging; HASTE, half-Fourier acquisition single-shot turbo spin echo; HSSG, Hysterosalpingoscintigraphy; E2, serum estradiol; PG, serum progesterone.

Notes:

¹Studies excluded from quantitative synthesis because reporting pattern of uterine contractility only in peri-ovulatory phase, not reporting crude data for cases and controls and/or comparable measures of the estimate.

²Authors reported that the analysis in the early luteal (CDs 15–20) phase was not performed because of only one patient with adenomyosis being included in this menstrual cycle phase.

³Similar trends observed in all the other phases of the menstrual cycle, although small sample sized (<30 patients) and non-significant between-groups differences.

⁴Each patient assessed in multiple phases. Between-groups comparisons reported for the menstrual and peri-ovulatory phases.

Risk of retrograde contraction pattern

Three studies assessed the risk of retrograde pattern during menstruation in women with endometriosis (22,24,27), while no studies evaluated this in adenomyosis.

Menstrual phase

Retrograde contraction pattern was visualized as retrograde bleeding at laparoscopy (22) or by the occurrence of retrograde contractions on TVUS (27) or MRI (24) at the time of menses. A significantly increased risk was observed in cases compared to controls (RR, 8.63; 95% CI, 3.24–22.95; 3 studies; n=109) with no heterogeneity (I2=0%) and non-significant publication bias (Egger’s test: p=0.38;z=−0.87; Figure 2). Similar results were obtained using the fixed effects model (Supplemental Figure 1). Sensitivity analyses confirmed the robustness of the estimate (Supplemental Figure 2). The quality of the evidence was judged as moderate (Supplemental Table 2).

Figure 2.

Risk of retrograde contraction pattern in endometriosis versus controls (random-effects). Abbreviations: CI = confidence interval.

Differences in frequency of uterine contractions

Four studies reported data on the frequency of uterine contractions: three in women with endometriosis (22,24,28) and one in those with adenomyosis (26).

Menstrual phase

Two studies evaluated women with endometriosis (22,24), and another included those with adenomyosis (26). The pooled MD in frequency of contractions between cases and controls was 0.45 (95% CI, −0.24–1.15; 3 studies; n=84), with high heterogeneity (I2=71.20%) and non-significant publication bias (Egger’s test: p=0.12;z=1.57; Supplemental Figure 3). Subgroup analysis disaggregating data on women with endometriosis revealed a higher frequency of contractions compared to controls, with a MD of 0.82 (95% CI, 0.13–1.52) and lower heterogeneity (I2=18.61%; Figure 3). The quality of the evidence was judged as low (Supplemental Table 2).

Figure 3.

Pooled mean difference in frequency of uterine contractions in endometriosis versus controls, in the menstrual phase. Abbreviations: CI = confidence interval; SD = standard deviation.

Follicular phase

One study included cases with deep endometriosis (28), and another included those with adenomyosis (26). Pooled analysis revealed a slightly lower frequency of contractions in cases (pooled MD: −0.15; 95% CI, −0.29–0.00; 2 studies; n=61), with no heterogeneity (I2=0%) and non-significant publication bias (Egger’s test: p=0.55;z=−0.58; Supplemental Figure 4). The quality of the evidence was judged as low to very low (Supplemental Table 2).

Peri-ovulatory phase

One study included cases with deep endometriosis (28), one included those with adenomyosis (26), and another was on women with endometriomas (24). Pooled analysis revealed non-significant differences in the frequency of contractions (pooled MD: −0.15; 95% CI, −0.84–0.54; 3 studies; n=116), despite high heterogeneity (I2=73.18%) and non-significant publication bias (Egger’s test: p=0.93;z=0.08; Supplemental Figure 5). Subgroup analysis did not reduce the estimated heterogeneity (Supplemental Figure 6). The quality of the evidence was judged as very low (Supplemental Table 2).

Luteal phase

Three studies evaluated women with endometriosis (24,28,23), and one those with adenomyosis (26). The pooled MD in frequency of contractions between cases and controls was 0.27 (95% CI, −0.23–0.77; 4 studies; n=323), with high heterogeneity (I2=89%) and non-significant publication bias (Egger’s test: p=0.92;z=0.11; Supplemental Figure 7). Subgroup analysis disaggregating data on women with endometriosis revealed a higher frequency of contractions compared to controls, with a MD of 0.52 (95% CI, 0.22–0.83) and lower heterogeneity (I2=27.18%; Supplemental Figure 8). The quality of the evidence was judged as low to very low (Supplemental Table 2).

Differences in amplitude and velocity of uterine contractions

Three studies reported on the amplitude and velocity of contractions in women with endometriosis/adenomyosis versus controls (22,26,29). Due to the use of different measurement techniques, data could not be pooled in a meta-analysis.

Two studies reported higher amplitude of contractions in women with endometriosis versus controls during the menstrual phase (22,29). Of them, one study using electrophysiological recordings (29), found a higher amplitude of cervix-to-fundus waves during menstruation, and a higher amplitude of fundus-to-cervix waves in the peri-ovulatory phase. One study reported overall trends of increased amplitude and decreased velocity across all menstrual cycle phases in women with adenomyosis (26). A descriptive summary with individual study findings is reported in Supplemental Table 3.

Discussion

Main findings

This meta-analysis shows approximately a 9-fold increased risk of retrograde pattern of uterine contractions during menstruation in women with endometriosis compared to controls. Results on continuous measures of uterine contractility across multiple phases of the menstrual cycle were more heterogeneous, with high variability in assessment methods and variable quantification. Consistent data found a significantly higher frequency of uterine contractions in women with endometriosis during menstruation, with about one extra contraction per minute compared to controls. Overall, trends of higher contraction amplitudes in women with endometriosis or adenomyosis across all phases of the menstrual cycle were reported.

Interpretation

With a nearly 9-fold higher risk of endometriosis in women with retrograde uterine contractions during menstruation, this meta-analysis supports retrograde menstruation as a mechanical factor potentially contributing to the pathogenesis of endometriosis. An inverse causal relationship, where endometriosis leads to altered uterine contractility, cannot be ruled out.

The lack of standardized measures to assess peristaltic patterns and insufficient knowledge of basic uterine and menstrual physiology have significantly hindered understanding the role of uterine contraction dynamics across the menstrual cycle. This gap in knowledge has limited progress in studying how contractions impact symptoms or development of menstruation-related disorders, particularly endometriosis and adenomyosis (31).

In this meta-analysis, we found that during menstruation, women with endometriosis exhibited not only a retrograde pattern but also a higher frequency of contractions compared to controls. Additionally, higher amplitudes of contractions were consistently described, although differing measurement techniques prevented meta-analysis of this outcome (22,29). The most recent study (29), utilizing electrophysiological recordings and advanced computational techniques to derive activation sequences, uterine potential and isochrone maps, specifically described longer duration, higher amplitude, and greater power of peristaltic waves with a retrograde direction during menstruation in women with endometriosis. Higher amplitudes of uterine contractions were reported in a study that evaluated women with adenomyosis (26), which found a strong association between increased contraction amplitudes and higher dysmenorrhea pain scores. Indeed, cramping pain in dysmenorrhea is believed to result from a combination of myometrial hyperactivity, which increases uterine pressure, hemodynamic dysfunction and release of inflammatory cytokines, as evidenced by the directionality of myometrial signal changes and their temporal relationship to pain onset in MRI studies (32). Regarding other menstrual cycle phases, results of pattern characteristics like direction, frequency, and amplitude of uterine contractions are still very limited.

In the peri-ovulatory phase, a study that evaluated women with adenomyosis (21) reported a higher prevalence of opposing waves, defined as conflicting waves originating simultaneously from the fundus and the cervix and converging in the middle, according to van Gestel et al. (4). Another study (26) showed significantly higher amplitudes, lower velocities and reduced contraction coordination in women with adenomyosis compared to controls. An in-vitro study not included in this meta-analysis also found higher uterine contraction amplitudes in adenomyosis using smooth muscle cells from hysterectomy samples (33). Although the characteristics and specific role of altered uterine contractility in the peri-ovulatory phase are not well understood, it may contribute to myometrial structural and functional changes associated with disease symptoms and morphological alterations in the myometrium leading to adenomyosis. In the peri-ovulatory phase in women with endometriosis, one study (24) found a lower frequency of contractions compared to controls, whereas two other studies reported higher frequencies (28) and enhanced peristaltic activity (25). Despite these conflicting findings, this evidence suggests that abnormal uterine contractility in the peri-ovulatory phase could play a role in endometriosis-related infertility. Interestingly, Leyendecker et al. (25) found that in the late follicular phase, in women without endometriosis, labeled macrospheres preferentially entered the tube ipsilateral to the dominant follicle, whereas in women with endometriosis, the macrospheres preferentially entered the tube contralateral to the dominant follicle. Similar findings were observed in another recent study (29), where peristaltic waves during the peri-ovulatory phase more often moved toward the side without the dominant follicle than toward the side with the dominant follicle. As suggested by Leyendecker et al. (25), in women with “chaotic” uterine peristaltic activity, as is likely in endometriosis, the mechanism of directed rapid sperm transport is likely overridden. Therefore, aberrant uterine contractility may significantly impact sperm transport and fertilization, contributing to infertility in women with endometriosis, but current in-vivo study limitations prevent definitive conclusions.

In the luteal phase, we consistently found a higher frequency of contractions in women with endometriosis (23,25,28) and higher amplitudes of contractions in women with endometriosis or adenomyosis (23,25,26,28), suggesting that uterine contractions or perhaps dysperistalsis could interfere with embryo implantation and contribute to infertility. Evidence from assisted reproductive technology (ART) models supports this hypothesis. Indeed, He et al. (23) demonstrated that treatment with atosiban, a combined oxytocin/vasopressin antagonist with potent tocolytic effects, before embryo transfer (ET) in women with endometriosis increased implantation rates per transfer and clinical pregnancy rates per cycle compared to those not treated. Although a Cochrane review suggests that uncertainties persist regarding whether intravenous atosiban improves pregnancy outcomes, in general, for women undergoing ART (34), independent studies specifically focusing on endometriosis have shown that other smooth muscle spasmolytic agents administered before ET improved implantation rates (35). This “priming of the uterus” effect of tocolytic agents in endometriosis suggests that altered uterine contractility during the luteal phase may be a critical determinant of impaired implantation in women with the disease. Even when pregnancy is established, structural and functional alterations in the junctional zone, along with disrupted uterine peristalsis, may lead to aberrant placentation and obstetrical complications (36). Uterine “irritability” has been identified as a crucial mechanical factor in adverse pregnancy outcomes, particularly placenta previa and preterm birth (37), which are significantly more prevalent in women with endometriosis and adenomyosis compared to controls (38).

Strengths and limitations

The main strength of this review is that it is the first summary of available knowledge on the role of uterine dynamics in endometriosis and adenomyosis. We examined estimates for different phases of the menstrual cycle, acknowledging that uterine peristaltic activity likely varies across phases (1). Another important strength of this review is adherence to strict methodology regarding both qualitative and quantitative synthesis. The use of the DerSimonian-Laird method in random-effects models incorporated between-study variance into the estimate of the pooled effect measure (18).

The most important limitation of this review is that different studies adopted various methods for assessing uterine peristalsis, leading to potential measurement bias for continuous parameters and misclassification bias for binary variables. Specifically, the direction of contractions may have been misclassified, given the challenges of assessment and the fact that only few studies followed specific defined criteria (3). This meta-analysis summarized a limited number of studies and individuals. This limited sample size, combined with the design of the original studies, led to a low certainty of evidence according to the GRADE system for most comparisons. The results in endometriosis were more consistent, particularly in the menstrual phase, likely because more studies were available. Most data for adenomyosis came from a single study (26) with small sample sizes for each menstrual cycle phase. Importantly, it has only been recently recognized that endometriosis and adenomyosis frequently cooccur. Thus, studies were not designed to consider their cooccurrence with diagnosis by ultrasound or MRI. Further, available evidence for adenomyosis was restricted because standardized criteria for non-invasive diagnosis of adenomyosis have only been defined recently (30). An additional limitation is that the measurement of hormonal levels in women regularly cycling, as well as the type and use of hormonal treatments, was not consistently reported. Hormonal modulation is a crucial variable of uterine dynamics, as cellular changes in hormone receptor expression and production of inflammatory molecules likely contribute to abnormal uterine contractility (6). The occurrence of progesterone resistance in endometriosis adds further complexity. In addition, the growing follicle or the corpus luteum release other molecules (39) that could influence uterine peristalsis. Metabolic perturbations in plasma/serum, peritoneal or follicular fluid, as well as in ectopic and eutopic endometrium associated with endometriosis (40,41), may also play a role. Further, previous pregnancies impact uterine dynamics, considering the changes in myometrial function and architecture that occur during pregnancy, which may affect uterine peristalsis in the postpartum nonpregnant uterus (42,43).

Conclusions

This meta-analysis on functional determinants of uterine contractility, combined with previous findings on anatomical determinants (44), robustly supports the role of retrograde menstruation in the etiopathogenesis of endometriosis. Other disease-promoting factors, including germline and somatic genetic and epigenetic changes, further contribute to the final multisystemic phenotype (45). Abnormal uterine contractility in women with endometriosis likely acts as a catalyst for its related symptoms and likely the development of the disease. Increased frequency of contractions with a retrograde pattern during the menstrual phase likely drives the tubal transport of endometrial cells into the peritoneal cavity. Furthermore, higher amplitudes of contractions are linked with more severe dysmenorrhea. Although quantification of the direction, amplitude, velocity, and coordination of uterine waves remains challenging and not yet standardized, evidence suggests that altered uterine contractility in women with endometriosis and adenomyosis persists across the entire menstrual cycle. This abnormal pattern may contribute to infertility either by altering sperm transport in the peri-ovulatory phase or by impairing embryo implantation in the luteal phase. To date, we cannot exclude the possibility that abnormal uterine contractility may be a consequence of having endometriosis rather than a feature contributing to its symptoms or pathogenesis. It is scientifically plausible that the two phenomena mutually reinforce each other, with endometriosis arising from dysperistalsis and subsequently exacerbating it through local inflammation, creating a vicious cycle, as is seen with the inflammasome in autoimmune diseases.

Given the extremely limited evidence, especially for adenomyosis, we advocate for a system engineering approach to research on uterine dynamics in these diseases, as was recently recommended in the report to the Advisory Committee to the National Institutes of Health Director “Catalyzing the Development and Use of Novel Alternative Methods” (46). In vitro studies could comprehensively assess the physiological components of uterine contractility, including the contractile apparatus, the regulation of its Ca2+ sensitivity and the electrophysiology of myocytes (excitation-contraction coupling)(47). As an overarching principle, uterine dynamics should be examined across menstrual cycle phases in relation to physiological hormonal fluctuations, hormonal treatments, and pregnancy and fertility history. Integrating comprehensive assessment of uterine dynamics with the role of the endometrium and the progesterone withdrawal-related shedding of endometrial cells during menstruation can significantly enhance comprehension of the pathogenesis and associated symptoms of endometriosis and adenomyosis.

Appendix I. Search Strategy.

1). PubMed/MEDLINE

“uterus”[MeSH Terms] OR “myometrium”[MeSH Terms] OR uter*[tiab] OR myometr*[tiab]

“uterine, contraction”[MeSH Terms] OR “pressure”[MeSH Terms] OR contract*[tiab] OR peristal*[tiab] OR wave*[tiab] OR pressure[tiab]

“endometriosis”[MeSH Terms] OR “adenomyosis”[MeSH Terms] OR “adenomyoma”[MeSH Terms] OR endometriosis[tiab] OR adenomyo*[tiab] measur* OR quant* OR ultrasound OR US OR TVUS OR sonogr* OR MRI OR resonance OR electroph* OR elastog*

Search on May 2^nd, 2024; 151 results

Search	Query	Items found
#7	#6 AND #4	151
#6	#5 AND #3	324
#5	#1 AND #2	22,059
#4	measur* OR quant* OR ultrasound OR US OR TVUS OR sonogr* OR MRI OR resonance OR electroph* OR elastog*	9,338,954
#3	“endometriosis”[MeSH Terms] OR “adenomyosis”[MeSH Terms] OR “adenomyoma”[MeSH Terms] OR endometriosis[tiab] OR adenomyo*[tiab]	37,898
#2	“uterine, contraction”[MeSH Terms] OR “pressure”[MeSH Terms] OR contract*[tiab] OR peristal*[tiab] OR wave*[tiab] OR pressure[tiab]	1,776,015
#1	“uterus”[MeSH Terms] OR “myometrium”[MeSH Terms] OR uter*[tiab] OR myometr*[tiab]	290,142

2). Embase

‘uterus’/exp OR ‘myometrium’/exp OR ‘uter*’:ti,ab,kw OR ‘myometr*’:ti,ab,kw

‘uterus contraction’/exp OR ‘pressure’/exp OR ‘contract*’:ti,ab,kw OR ‘peristal*’:ti,ab,kw OR ‘wave*’:ti,ab,kw OR ‘pressure’:ti,ab,kw

‘endometriosis’/exp OR ‘adenomyosis’/exp OR ‘adenomyoma’/exp OR ‘endometriosis’:ti,ab,kw OR ‘adenomyo*’:ti,ab,kw

‘measur*’ OR ‘quant*’ OR ‘ultrasound’ OR ‘us’ OR ‘tvus’ OR ‘sonogr*’ OR ‘mri’ OR ‘resonance’ OR ‘electroph*’ OR ‘elastog*’

Search on May 2^nd, 2024; 353 results

Search	Query	Items found
#7	#6 AND #4	353
#6	#5 AND #3	638
#5	#1 AND #2	30,311
#4	‘measur*’ OR ‘quant*’ OR ‘ultrasound’ OR ‘us’ OR ‘tvus’ OR ‘sonogr*’ OR ‘mri’ OR ‘resonance’ OR ‘electroph*’ OR ‘elastog*’	10,949,847
#3	‘endometriosis’/exp OR ‘adenomyosis’/exp OR ‘adenomyoma’/exp OR ‘endometriosis’:ti,ab,kw OR ‘adenomyo*’:ti,ab,kw	62,349
#2	‘uterus contraction’/exp OR ‘pressure’/exp OR ‘contract*’:ti,ab,kw OR ‘peristal*’:ti,ab,kw OR ‘wave*’:ti,ab,kw OR ‘pressure’:ti,ab,kw	2,205,958
#1	‘uterus’/exp OR ‘myometrium’/exp OR ‘uter*’:ti,ab,kw OR ‘myometr*’:ti,ab,kw	374,943

3). Scopus

TITLE-ABS-KEY (uterus OR myometrium OR uter* OR myometr*)

TITLE-ABS-KEY (“uter* contraction” OR pressure OR contract* OR peristal* OR wave*)

TITLE-ABS-KEY (endometriosis OR adenomyosis OR adenomyoma)

ALL (measur* OR quant* OR ultrasound OR us OR tvus OR sonogr* OR mri OR resonance OR electroph* OR elastog*)

Search on May 2^nd, 2024; 536 results

Search	Query	Items found
#7	#6 AND #4	536
#6	#5 AND #3	728
#5	#1 AND #2	42,105
#4	ALL (measur* OR quant* OR ultrasound OR us OR tvus OR sonogr* OR mri OR resonance OR electroph* OR elastog*)	39,385,744
#3	TITLE-ABS-KEY (endometriosis OR adenomyosis OR adenomyoma)	52,987
#2	TITLE-ABS-KEY (“uter* contraction” OR pressure OR contract* OR peristal* OR wave*)	7,895,148
#1	TITLE-ABS-KEY (uterus OR myometrium OR uter* OR myometr*)	520,265

Appendix II. List of data abstracted from original studies (n=9) and tabulated.

i) first author and year of publication;

ii) study design;

iii) study country;

iv) study years, when reported;

v) descriptive parameters on the study population, including total sample size, age range, and any reported information on fertility history and hormonal treatment status;

v) definition of cases, including diagnostic modality and criteria used to identify endometriosis and/or adenomyosis;

vi) definition of controls, including the method used to rule out endometriosis and/or adenomyosis, regularity of menstrual cycles and associated symptoms, and any reported details on medical and gynecological history;

vii) number of cases and controls, including total number, and number addressed at different phases of the menstrual cycle;

viii) method used for the measurement and analysis of uterine contractility, including details on the recording and analysis phases, and any additional computational steps performed to obtain the final reported estimate;

ix) phases of the menstrual cycle in which the measurements were collected, with cycle day (CD) ranges when reported;

x) uterine contractility measures assessed, including criteria used to define the outcomes and units of measure adopted;

xi) number of cases and controls with RM pattern, for pooled analysis on the primary outcome;

xii) measures of central tendency and dispersion (variability) for each phase of the menstrual cycle, for pooled analysis on the continuous outcomes.

Data sharing Statement:

The data included in this article were extracted as published in the available original articles. No new data were generated to support this paper.