Sonomorphologic Changes in Colorectal Deep Endometriosis: The Long-Term Impact of Age and Hormonal Treatment

Keywords

deep infiltrating endometriosis - transvaginal sonography - hormonal therapy - bowel endometriosis - long-term observation

Introduction

The natural history of deep endometriosis in reproductive-aged women is unclear [1] since the pathophysiology of onset and growth are unclear [2] [3]. Deep endometriosis lesions are less frequent and smaller in adolescence. Therefore, the lesions must have grown after initiation, at least for a certain period of time. However, growth itself has not been documented, and growth might be self-limiting, as suggested by the volumes of deep endometriosis lesions at different ages [4].

Although imaging of DE by magnetic resonance imaging (MRI) or transvaginal ultrasound (TVS) has been established as a reliable and accurate diagnostic method to measure deep endometriosis [5] [6], sequential measurements over longer periods of time in women not undergoing surgery have not been performed, except to evaluate the effect of medical therapy.

Deep endometriosis is treated by medical therapy or surgical excision [7]. Medical therapy is often the first line of therapy to avoid often difficult and complication-prone surgery. If pain symptoms are sufficiently reduced, this therapy can be continued for longer. It was estimated that some two-thirds of patients can be managed by medical therapy [8]. It is equally well documented that during medical therapy, lesions regress. Fedele et al. observed no relevant progression of colorectal DE lesions in most asymptomatic and untreated women over six years using transrectal sonography [9]. Barra and colleagues observed a significant reduction in the volume of the nodule during the administration of dienogest [10]. Netter et al. demonstrated that the length of amenorrhea, induced through hormonal intake or pregnancy, correlated with regression of the size of rectal DE [1].

However, endometriosis lesions are biochemically heterogeneous with a variable degree of aromatase activity and progesterone resistance. This might explain why some 10% of women do not respond and 20% respond poorly to medical therapy [11]. It is unclear whether a decrease in the nodule volume and symptom relief correlate. Abrao et al. found that pain symptoms correlate with the sonographic dimensions of DE [6]. Since some occasional nodules were observed to progress during medical therapy, explained by the variable response and the biochemical heterogeneity, follow-up with US was recommended [6].

There are no data on the growth or microscopic changes of DE managed without treatment [10] [12].

Since data of longitudinal follow-up range from 6 months to 10 years, we decided to review our patients managed conservatively without surgery with a follow-up of up to 18 years.

Patients and methods

Study design

The study was conducted as a monocentric case series of all women with deep endometriosis of the rectum not undergoing surgery and managed conservatively. Informed consent about the anonymous use and publication of the data was obtained.

The ethical committee approved the study (approval number S2022–16) on the August 10, 2022.

Study population and data collection:

The inclusion criteria were women with deep infiltrating endometriosis of the rectum followed up clinically and by US by JK at the tertiary center between July 2002 and May 2021. Patients were seen at irregular intervals. Their symptoms, the type and duration of hormone intake, possible pregnancies and interventions, and DE dimensions were documented. For data analysis, every visit was screened, but only those in which there were changes compared to the previous visit were included in the study.

Transvaginal examination followed a standardized protocol. The typical transvaginal sonographic pattern of rectal endometriosis is a hypoechogenic widening of the muscle layer, visualized in the sagittal plane ([Fig. 1]) and documented photographically. The rectosigmoid was also inspected caudally and cranially to the lesion to identify or exclude additional separate lesions. The measurement included the length of the nodule, measured between the cranial and caudal poles of the nodule, where the musculature pattern looks normal. The thickness measurement was perpendicular to the length measurement and was taken at the widest part of the lesion [13] [14] [15]. The individual measurements of nodule length and thickness for each patient over time are depicted in [Fig. 2]. TVS was performed using the ultrasound device Sonoace SA-X8LV-GER (Samsung Medison Co. Ltd.; Seoul, South Korea) with a 5.0–9.0 MHz transvaginal probe and the ultrasound device Samsung WS80A (Samsung Medison Co. Ltd.; Seoul, South Korea) with a 5.0–9.0 MHz transvaginal probe.

Fig. 1 The sonographic image shows sample images of rectal endometriosis in three different patients. Measurement of length (D1) and thickness (D2).

Fig. 2 These charts show each patient’s development of nodule length and thickness with increasing age. Periods without hormone treatment are depicted with dashed lines.

The results were also classified using the Enzian and #Enzian classification, whereby only the C-compartment was calculated for the study [16].

Statistical analysis

Data collection and management for this paper were performed using the OpenClinica open-source software (Version 3.1, Copyright OpenClinica LLC and collaborators, Waltham, MA, USA, www.OpenClinica.com). The data set for this analysis can be found in the online supplement.

To model the temporal development of the length and thickness of the lesions, we fitted mixed-effects models using the cumulative duration of hormone treatment (CDHT) up to the considered visit and associated age as explanatory variables. To be more precise, lesion size is assumed to be the sum of a random effect for each individual, a quadratic function of CDHT, a cubic function of age, and a residual error for each observation. The random effect allows us to adjust for the serial correlation of the measurements within each patient and each patient’s starting size of the lesion. The choice of a quadratic function in CDHT reflects the expectation that the longer the treatment, the stronger its impact on lesion size, possibly non-linearly. The cubic function can model the hypothesis that lesion size may initially increase with age and then stagnate or even decrease. To interpret the fitted model, it is preferable to represent the quadratic (cubic) function as a weighted sum of two positive quadratic (three positive cubic) hat-shaped basis functions of CDHT (age), see panel A1 (A2) in supplementary fig. 1. Technically speaking, the quadratic (cubic) functions in our models are represented as B-splines of order 2 (3); see panel B1 (B2) in the supplementary fig. 1 and for more details, see [17]. We have also made the data set available in supplementary table 1.

Data processing and statistical analysis were performed using the statistical programming environment R, version 4.1.2 [18] and R-libraries lme4 and lmerTest to fit and evaluate random effects models.

Results

Our study included 38 premenopausal women with a mean age at first examination of 34.28 years. The average observation time was 7.24 years. Data points of an average of 3.10 examinations per patient were considered during the observation period. Twenty women had at least one previous gynecological operation before the first presentation (rectal endometriosis operation excluded). Only four women had been successfully pregnant before the primary presentation, and 18 were under hormonal treatment at the first visit. During the observational period, 14 women underwent surgery (rectal endometriosis operation excluded), 11 had been pregnant, and 15 were under hormonal treatment at their last visit ([Table 1]).

Table 1 Characteristics of the study population. For numerical variables, the mean and standard deviations are given. For classification, frequencies and, in brackets, relative frequencies are shown.

Characteristics of the study population
Number of patients	38
Mean age at first visit in years	33.60 ± 6.21
Mean age at last visit in years	40.85 ± 5.96
Mean time of observation in years	7.24 ± 4.21
Mean number of included visits	3.10 ± 2.16
Women with a previous gynecological operation	20 (52.6%)
Women with operations during the observational period	14 (36.8%)
Women with previous pregnancies	4 (10.5%)
Women who got pregnant during the observational period	11 (28.9%)
Hormone intake at first visit	18 (47.3%)
Hormone intake at last visit	15 (39.4%)

All women only had one rectal nodule detected sonographically. The average nodule length at the first visit was 23.26 mm, and the average length at the last visit regressed to 22.53 mm. The average nodule thickness at the first visit was 10.55 mm. Also, the thickness regressed slightly at the last visit to an average of 8.81mm. Accordingly, there were hardly any changes in the C-compartment of the #Enzian classification ([Table 2]).

Table 2 The characteristics of rectal endometriosis are shown. The values of nodule length and thickness show the mean and the standard deviation. The #Enzian classification classifies the rectal endometriosis into three grades depending on the length of the nodules (C1: <1cm; C2: 1–3cm; C3: >3cm).

Characteristics of rectal endometriosis
Nodule length at first visit	23.26 ± 8.44 mm
Nodule length at last visit	22.53 ± 8.42 mm
Nodule thickness at first visit	10.55 ± 4.17 mm
Nodule thickness at last visit	8.81 ± 4.11 mm
#Enzian C compartment at first visit
C1	0
C2	29
C3	9
#Enzian C compartment at last visit
C1	1
C2	28
C3	9

To study the influence of age and duration of hormone treatment (CDHT) on lesion size, we fitted mixed-effects models to our data. Since our data contain long-term observations, it is to be expected that age and duration of hormone treatment will have a non-linear effect on the temporal development of the lesion size.

As some women were successfully pregnant between two visits and subsequently started hormone therapy again (and there was no visit during the pregnancy), we decided not to include the pregnancy factor in our calculations to avoid possible misinterpretation. Our model based on rectal nodule length has a significant negative correlation with CDHT. Furthermore, there is a significant positive correlation with age, where an increase in the length of the lesion until the 4th decade of life can be seen with a stabilization effect of length afterwards ([Table 3]). Regarding the thickness of rectal endometriosis, only CDHT shows a significant negative correlation. Age does not seem to influence nodule thickness ([Table 3]) significantly.

Table 3 The table shows the mixed effects models of the length and thickness of the rectal nodule. For each patient, her random effect is considered as the realization of independent normally distributed random variables with zero mean and unknown standard deviation whose estimate is given in sub-tables a). These random effects may be considered as the patient’s individual deviation from a common intercept. Similarly, the residual errors are assumed to be normally distributed with zero mean and common standard deviation. CDHT and age enter the model as the sum of two weighted sums of two and three B-spline basis functions, respectively. The basis functions and the weighted sums are depicted in the upper and lower row of Figure 1 in the Supplement, respectively. The weights are given in the “Estimate” column in sub-tables b). For more details, see the section Statistical Analysis. An analysis of the variance table in sub-tables c) examines the contribution of each B-spline to the fit of the model. Significant results are marked with asterisks (p < 0.05: *); SE: standard error, DF: degrees of freedom.

Nodule length
a) Random effects
Groups	Purpose		Variance	Estimate of standard deviation
Patients (n=38)	One random effect for each patient		71.441	8.452
Residual error (n=154)	One random error for each observation		9.957	3.156
b) Fixed effects
	Basis function	Estimate	SE	DF	T-value	P-value
Intercept		15.9672	3.449	131.649	4.630	<0.0001*
B-spline (CTHT, degree = 2)	1st	0.3499	2.296	147.000	0.152	0.8791
	2nd	–7.3109	3.129	137.063	–2.336	0.0209*
B-spline (age, degree = 3)	1st	10.9956	6.437	136.187	1.708	0.0899
	2nd	9.5019	4.083	147.636	2.327	0.0213
	3rd	8.1569	5.480	134.320	1.486	0.1397
c) Type III analysis of variance table with Satterthwaite’s method
	Sum of squares	Mean squares	DF numerator	DF denominator	F-value	P-value
B-spline (CTHT, degree = 2)	67.805	33.902	2	118.27	3.405	0.0365 *
B-spline (age, degree = 3)	80.846	26.949	3	117.33	2.706	0.0485 *
Nodule thickness
a) Random effects
Groups	Purpose		Variance	Estimate of standard deviation
Patients (n=38)	One random effect for each patient		11.657	3.414
Residual error (n=154)	One random error for each observation		3.445	1.856
b) Fixed effects
	Basis function	Estimate	SE	DF	T-value	P-value
Intercept		9.539	1.761	128.262	5.415	<0.0001*
B-spline (CTHT, degree = 2)	1st	–2.987	1.232	147.503	–2.426	0.0165*
	2nd	–3.876	1.597	124.012	–2.426	0.0167*
B-spline (age, degree = 3)	1st	–0.464	3.587	145.233	–0.129	0.8972
	2nd	3.469	2.166	144.323	1.602	0.1114
	3rd	0.590	2.780	117.067	0.212	0.8323
c) Type III analysis of variance table with Satterthwaite’s method
	Sum of squares	Mean squares	DF numerator	DF denominator	F-value	P-value
B-spline (CTHT, degree = 2)	32.343	16.172	2	109.27	4.695	0.0111*
B-spline (age, degree = 3)	9.058	3.010	3	107.42	0.877	0.4557

Discussion

Rectal endometriosis is a deeply infiltrating form of the disease. The origin and the reason for the specific location of this form, and especially the time at which the rectal lesion started, have not been clarified yet [4]. The extensive fibroblastic reaction with entrapped endometrial foci leads to marked thickening of the rectal wall of varying length, thickness, and width. Some cases show clinically relevant lumen narrowing and stiffening of the entire intestinal tube [19]. The extent of findings plays an important role in evaluating symptoms and planning and managing noninvasive and invasive treatments [20] [21]. Transvaginal sonography and MRI of the pelvis have become the methods of choice for imaging and measuring deep infiltrating endometriosis with high sensitivity and specificity.

Since there is still little information about the onset of the disease and possible factors influencing its growth or regression, both imaging techniques might help to understand the growth dynamics of rectal endometriosis over time and the influence of age and hormonal treatment. Fedele et al. could not detect any further growth trend during the observation period using transrectal ultrasound [9].

In contrast, Netter et al., who monitored the TIE of the rectum via MRI, found partially progressive nodules [1]. They could demonstrate that hormonal treatments, which induce amenorrhea, may prevent the growth of nodules and may even result in the regression of lesions. However, the regression or stability of nodule size did not correlate with pain relief in many patients.

Barra et al. observed the regression of rectosigmoid endometriosis under Dienogest therapy using a standardized ultrasound examination in a 3D model [10]. However, the observation period was maximum overall 36 months, and no findings were recorded after cessation of therapy. A mean volume reduction of the nodules was observed by at least 10%, but 5–10% of patients experienced an increase in volume without worsening clinical symptoms. Knez et al. conducted a retrospective investigation on a cohort of women with deep endometriosis who were not undergoing hormonal therapy from various locations. The findings demonstrated that the number of endometriotic nodules is a negative predictor for disease progression [22].

The effect of hormonal therapy on rectal endometriosis has been demonstrated by various studies analyzing only the symptoms [12] [23]. The use of the oral contraceptive pill, norethisterone acetate (NETA) [24], desogestrel, and triptorelin [25] decreases symptoms and improves quality of life. However, the relationship between the size of the finding and the symptomatology is controversial. The available data show partially divergent results regarding the growth behavior of the nodule in terms of progression and regression, depending on the different affecting factors.

Our study aims to investigate the influence of hormone therapy and the age of the patient on the growth and regression of the deep lesion in the rectal wall in a multifactorial analysis. We observed the lesions intraindividually over a period of time, with the longest period being more than 16 years.

To describe the growth pattern of the length and the thickness of the rectal foci, we fitted multiple mixed-effects models, including the factors of age and hormone intake (represented by the CDHT).

Our study shows that continuous administration of a progestogen or an estrogen/progestogen medication in the long cycle reduces nodule size and thickness. As our models show, there is no linear correlation between the regression of nodule length and thickness and the duration of therapy. The histopathological composition of the nodule can explain this. Most of the findings consist of fibrosis in which stroma and epithelial cells are embedded. Fibroblasts are much less responsive to hormone modulation than stromal and epithelial cells, which may explain the small reduction in size [26]. The fact that the relative length changes more than the thickness ([Fig. 3]) of the foci could be explained by mobility (fixation with surrounding structures) and partly by the different dimensions. Proliferation may occur more in a longitudinal direction than in a radial direction.

Fig. 3 Images A and D show the relative change in nodule length and thickness depending on age, as predicted by our model as described in [Table 3] while assuming that there is no hormone intake. Images B and E show the predicted relative change in nodule length and thickness depending on the cumulative time of hormone treatment (CDHT) so far, assuming the patient is 35 years old. The gray bands indicate point-wise 95% confidence intervals. Images C and F show the growth behavior of the length and thickness of rectal endometriosis depending on the duration of hormone intake. The age is shown in years. While the sample patient on the black curve has never taken hormones (same curve as in images A and D), the sample patient on the green curve has taken hormones continuously over a period of 15 years. The patients shown in the red and blue curves started hormone therapy at the age of 25 and paused therapy after 5 and 10 years, respectively.

The growth tendency of the rectal lesions, depending on the patient’s age, was significantly increased between 20 and 40 years of age. Similar trends were found by Koninckx in his retrospective study comparing the different focal sizes with age [27]. His data refer only to surgical and histological findings. The accuracy of the measurements can be compared with the sonography findings to a limited extent.

The #Enzian classification within the C-compartment (<1 cm = C1, 1–3 cm = C2, >3 cm = C3) can identify the changes in rectal foci size. However, the threshold values for the individual C-compartments are probably too large to be able to calculate a significance of the change in the sizes.

Our study has several limitations. Firstly, we have a study population in which a primarily conservative approach was chosen, and no operative treatment of rectal endometriosis was necessary until the end of the observation period. For instance, Roman et al. described symptomatic and size-progressive rectal nodules that required rapid surgical treatment [28]. The exclusion of patients with nodules exhibiting a more aggressive growth behavior hinders the generalizability of the study results to all patients with deep infiltrating rectal endometriosis. However, this limitation is a common issue, as the few other studies investigating growth patterns over time have also focused on women without prior rectal surgery [1] [6]. Another limitation of our study is the rather small study population.

With correspondingly fewer data points from patients in their early 20s or late 40s, this naturally leads to a larger confidence interval. Therefore, the curves should not be overinterpreted in these specific ranges. However, it must also be acknowledged that a single experienced gynecologist examined all patients. Thus, high accuracy and precision of the measurements can be assumed. Additionally, our study was designed retrospectively, and data was collected from patient records. Finally, there is a known inter- and intra-observer variability of measurements using TVS, as observed by Egekvist et al., which may influence the presented results [29]. Therefore, further studies covering the entire reproductive period are warranted to gain a more comprehensive understanding of the growth behavior of rectal endometriosis.

Conclusion

Transvaginal sonography is an ideal method to study and monitor morphologic changes of rectal endometriosis over time for clinical management considerations.

The growth pattern of deep endometriosis (DE) is influenced by patient age and the duration of conservative therapy. In patients without any treatment, rectal endometriosis shows a moderate increase in size until the end of the fourth decade of life, after which it tends to stabilize. While hormonal therapy can reduce the size or prevent the further progression of deep endometriosis, its growth does not follow a linear function.

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