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

Ultraschall in Med 2024; 45: 285 –292 DOI 10.1055/a-2209-5653 ISSN 0172-4614 © 2023. Thieme. All rights reserved. Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany Correspondence Dr. Simon Keckstein Department of Obstetrics and Gynecology, LMU University Hospital, Marchioninistraße 15, 81377 Munich, Germany [email protected] Additional material is available at https://doi.org/ 10.1055/a-2209-5653.

Purpose The progression of deep endometriosis (DE) in wom- en of reproductive age is highly variable. This study aimed to analyze the sonomorphological changes of rectal endome- triosis over long periods of time and the influence of hormo- nal treatment.

This retrospective study included premenopausal women with rectal DE treated conservatively between 2002 and 2021. The lesion length and thickness of the nodule were evaluated at regular intervals over time. We created sta- tistical models with mixed effects to identify potential factors influencing lesion progression and regression.

38 patients were monitored over a mean period of 7.2 (± 4.2) years with a mean of 3.1 (± 2.1) check-ups within the observation period. We detected a significant increase in le- sion length until the end of the fourth decade of life. In addi- tion, we found a substantial decrease in the length and thick- ness of the nodule depending on the length of hormonal treatment.

In conservatively managed patients with rectal endometriosis, without hormonal therapy, lesion size can ex- hibit a moderate increase up to the end of the fourth decade of life, after which it appears to stabilize. This increase does not follow a linear pattern. Hormonal therapy is crucial in im- peding further progression, resulting in either a cessation or a regression of lesion growth. ZUSAMMENFASSUNG Ziel Das Wachstumsverhalten tie f-infiltrierender Endome- triose bei Frauen im reproduktionsfähigen Alter variiert stark. Ziel dieser Studie war es, die sonomorphologischen Verände- rungen einer rektalen Endometriose im zeitlichen Verlauf zu analysieren und den Einfluss einer Hormontherapie zu unter- suchen.

und Methoden In dieser retrospektiven Studie wur- den prämenopausale Frauen mit rektosigmoidaler Endome- triose eingeschlossen, die zwischen 2002 und 2021 primär konservativ behandelt wurden. Hierzu wurden Länge und Dicke der Herde in regelmäßig en Abständen sonographisch gemessen. Um Faktoren zu identifizieren, welche das Wach- Original Article 285Keckstein S et al. Sonomorphologic Changes in … Ultraschall in Med 2024; 45: 285 –292 | © 2023. Thieme. All rights reserved. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Article published online: 2023-12-15 stumsverhalten beeinflussen könnten, wurden „Mixed-ef- fect“-Modelle zur statistischen Analyse angewandt. Ergebnisse Achtunddreißig Patientinnen wurden über einen Zeitraum von 7,2 (± 4,2) Jahren mit einer durchschnittlichen Anzahl von 3,1 (± 2,1) Untersuchungen überwacht. Wir konn- ten eine signifikante Zunahme der Herdlängen bis zum Ende des vierten Lebensjahrzehnts feststellen. Abhängig von der Dauer der Hormonbehandlung zeigte sich eine signifikante Abnahme der Länge und Dicke der Herde. Schlussfolgerung Bei konservativ behandelten Patientinnen mit rektosigmoidaler Endometriose, ohne hormonelle Thera- pie, kann die Größe der Läsionen bis zum Ende des vierten Le- bensjahrzehnts moderat zunehmen. Danach scheint diese sich zu stabilisieren. Die hormonelle Therapie kann eine wei- tere Progression des Wachstums verhindern und führt bei län- gerer Einnahme sogar zu einer Regression der Herde.

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 fre- quent 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 endo- metriosis 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. ob- served no relevant progression of colorectal DE lesions in most asymptomatic and untreated women over six years using trans- rectal 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, cor- related with regression of the size of rectal DE [1]. However, endometriosis lesions are biochemically heteroge- neous with a variable degree of aromatase activity and progester- one 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 o ccasional nodules were observed to progress during medical therapy, ex- plained by the variable response and the biochemical heterogene- ity, 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 wom- en with deep endometriosis of the rectum not undergoing sur- gery 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 endome- triosis 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 com- pared to the previous visit were included in the study. Transvaginal examination followed a standardized protocol. The typical transvaginal sonogr aphic pattern of rectal endome- triosis 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 meas- urement 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 perpendi- cular 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. The results were also classified using the Enzian and #Enzian classification, whereby only the C-compartment was calculated for the study [16]. 286 Keckstein S et al. Sonomorphologic Changes in … Ultraschall in Med 2024; 45: 285 –292 | © 2023. Thieme. All rights reserved. Original Article This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Statistical analysis Data collection and management for this paper were performed using the OpenClinica open-source software (Version 3.1, Copy- right OpenClinica LLC and coll aborators, 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 thick- ness of the lesions, we fitted mixed-effects models using the cu- mulative duration of hormone treatment (CDHT) up to the con- sidered 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 ran- dom effect allows us to adjust for the serial correlation of the measurements within each patient and each patient ’ss t a r t i n g size of the lesion. The choice of a quadratic function in CDHT re- ▶ 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. ▶ Fig. 1 The sonographic image shows sample images of rectal endometriosis in three different patients. Measurement of length (D1) and thick- ness (D2). 287Keckstein S et al. Sonomorphologic Changes in … Ultraschall in Med 2024; 45: 285 –292 | © 2023. Thieme. All rights reserved. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. flects 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 fit- ted model, it is preferable to represent the quadratic (cubic) func- tion as a weighted sum of two positive quadratic (three positive cubic) hat-shaped basis funct ions 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 or- der 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 ef- fects models.

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. Twen- ty women had at least one previous gynecological operation be- fore the first presentation (rectal endometriosis operation exclud- ed). 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 under- went surgery (rectal endometriosis operation excluded), 11 had been pregnant, and 15 were under hormonal treatment at their last visit ( ▶ Table 1). All women only had one rectal nodule detected sonographical- ly. The average nodule length at the first visit was 23.26 mm, and the average length at the last v isit 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 8.81 mm. Accordingly, there wer e hardly any changes in the C- compartment of the #Enzian classification ( ▶ Table 2). To study the influence of age and duration of hormone treat- ment (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 le- sion size. As some women were successfully pregnant between two vis- its 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 misin- terpretation. Our model based on rectal nodule length has a sig- nificant 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 signifi- cant negative correlation. Age does not seem to influence nodule thickness ( ▶ Table 3) significantly.

Rectal endometriosis is a deeply infiltrating form of the disease. T h eo r i g i na n dt h er e a s o nf o rt h es p e c i f i cl o c a t i o no ft h i sf o r m , and especially the time at which the rectal lesion started, have not been clarified yet [4]. The extensive fibroblastic reaction with ▶ Table 1 Characteristics of the study population. For numerical variables, the mean and standard deviations are given. For classifi- cation, 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 observa- tional period 14 (36.8 %) Women with previous pregnancies 4 (10.5 %) Women who got pregnant during the ob- servational period 11 (28.9 %) Hormone intake at first visit 18 (47.3 %) Hormone intake at last visit 15 (39.4 %) ▶ 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: 3 cm). 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 9 288 Keckstein S et al. Sonomorphologic Changes in … Ultraschall in Med 2024; 45: 285 –292 | © 2023. Thieme. All rights reserved. Original Article This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. entrapped endometrial foci leads to marked thickening of the rec- tal 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 noninva- sive and invasive treatments [20, 21]. Transvaginal sonography and MRI of the pelvis have become the methods of choice for ima- ▶ 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 con- sidered 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 resi- dual 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 3 rd 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 denomi- nator 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 3 rd 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 denomi- nator 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 289Keckstein S et al. Sonomorphologic Changes in … Ultraschall in Med 2024; 45: 285 –292 | © 2023. Thieme. All rights reserved. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. ging and measuring deep infiltrating endometriosis with high sen- sitivity and specificity. Since there is still little information about the onset of the dis- ease 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 trans- rectal ultrasound [9]. In contrast, Netter et al., who monitored the TIE of the rectum via MRI, found partially progressive nodules [1]. They could de- monstrate that hormonal treatments, which induce amenorrhea, may prevent the growth of nodules and may even result in the re- gression 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 endome- triosis under Dienogest therapy using a standardized ultrasound examination in a 3 D 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 no- dules was observed by at least 10 %, but 5 –10 % of patients experi- enced an increase in volume without worsening clinical symp- toms. Knez et al. conducted a retrospective investigation on a cohort of women with deep endometriosis who were not under- going hormonal therapy from various locations. The findings demonstrated that the number of endometriotic nodules is a neg- ative predictor for disease progression [22]. The effect of hormonal therapy on rectal endometriosis has been demonstrated by various studies analyzing only the symp- toms [12, 23]. The use of the oral contraceptive pill, norethister- one acetate (NETA) [24], desogestrel, and triptorelin [25] decrea- ses symptoms and improves quality of life. However, the relationship between the size of the finding and the symptomatol- ogy is controversial. The available data show partially divergent re- sults regarding the growth behavior of the nodule in terms of pro- gression and regression, depending on the different affecting factors. Our study aims to investigate the influence of hormone ther- apy and the age of the patient on the growth and regression of t h ed e e pl e s i o ni nt h er e c t a lw a l lin 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, includ- ing the factors of age and hormone intake (represented by the CDHT). Our study shows that continuous administration of a progesto- gen or an estrogen/progestogen medication in the long cycle re- duces 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 com- position of the nodule can explain this. Most of the findings con- sist 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 direc- tion than in a radial direction. 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 find- ings to a limited extent. The #Enzian classification within the C-compartment (3c m=C 3 ) c a n i d e n t i f y t h e c h a n g e s 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 pop- ulation 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. d e s c r i b e ds y m p t o m a t i ca n ds i z e -progressive rectal nodules that required rapid surgical treatment [28]. The exclusion of patients with nodules exhibiting a more aggressive growth behavior hin- ders 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 rec- tal surgery [1, 6]. Another limitation of our study is the rather small study population. With correspondingly fewer data points from patients in their early 20 s or late 40 s, this naturally leads to a larger confidence in- terval. Therefore, the curves should not be overinterpreted in these specific ranges. Howeve r, it must also be acknowledged that a single experienced gynecologist examined all patients. Thus, high accuracy and precision of the measurements can be as- sumed. 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

[29]. Therefore, further studies covering the entire repro- ductive period are warranted to gain a more comprehensive un- derstanding of the growth behavior of rectal endometriosis.

Transvaginal sonography is an ideal method to study and monitor morphologic changes of rectal endometriosis over time for clini- cal management considerations. The growth pattern of deep endometriosis (DE) is influenced by patient age and the duration of conservative therapy. In pa- tients without any treatment, rectal endometriosis shows a mod- erate increase in size until the end of the fourth decade of life, after which it tends to stabilize. While hormonal therapy can re- duce the size or prevent the further progression of deep endome- triosis, its growth does not follow a linear function. 290 Keckstein S et al. Sonomorphologic Changes in … Ultraschall in Med 2024; 45: 285 –292 | © 2023. Thieme. All rights reserved. Original Article This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. ▶ 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 de- pending 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. 291Keckstein S et al. Sonomorphologic Changes in … Ultraschall in Med 2024; 45: 285 –292 | © 2023. Thieme. All rights reserved. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Conflict of Interest George Condous: Luminary for GE Healthcare and Samsung

[1] Netter A et al. Progression of deep infiltrating rectosigmoid endome- triotic nodules. Human Reproduction 2019; 34 (11): 2144 –2152 [2] Vercellini P et al. Endometriosis: pathogenesis and treatment. Nature Reviews Endocrinology 2014; 10 (5): 261 –275 [3] Gordts S, Koninckx P, Brosens I. Pathogenesis of deep endometriosis. Fertility and sterility 2017; 108 (6): 872 –885 [4] Koninckx PR et al. The epidemiology of endometriosis is poorly known as the pathophysiology and diagnosis are unclear. Best Pract Res Clin Ob- stet Gynaecol 2021; 71: 14 –26 [5] Abrao MS et al. Comparison between clinical examination, transvaginal sonography and magnetic resonance imaging for the diagnosis of deep endometriosis. Human Reproduction 2007; 22 (12): 3092 –3097 [6] Abrao MS et al. Clinical and Sonographic Progression of Bowel Endome- triosis: 3-Year Follow-up. Reproductive Sciences 2021; 28 (3): 675 –682 [7] Nezhat C et al. Bowel endometriosis: diagnosis and management. American journal of Obstetrics and Gynecology 2018; 218 (6): 549 –562 [8] Egekvist AG et al. Conservative treatment of rectosigmoid endometrio- sis: A prospective study. Acta Obstet Gynecol Scand 2019; 98 (9): 1139 – 1147 [9] Fedele L et al. Is rectovaginal endometriosis a progressive disease? American journal of obstetrics and gynecology 2004; 191 (5): 1539 – 1542 [10] Barra F et al. Long-term administration of dienogest for the treatment of pain and intestinal symptoms in patients with rectosigmoid endome- triosis. Journal of clinical medicine 2020; 9 (1): 154 [11] Becker CM et al. Reevaluating response and failure of medical treatment of endometriosis: a systematic review. Fertil Steril 2017; 108 (1): 125 – 136 [12] Vercellini P et al. Medical treatment of endometriosis-related pain. Best Pract Res Clin Obstet Gynaecol 2018; 51: 68 –91 [13] Hudelist G et al. Can transvaginal sonography predict infiltration depth in patients with deep infiltrating endometriosis of the rectum? Hum Re- prod 2009; 24 (5): 1012 –1017 [14] Guerriero S et al. Systematic approach to sonographic evaluation of the pelvis in women with suspected endometriosis, including terms, defini- tions and measurements: a consensus opinion from the International Deep Endometriosis Analysis (IDEA) group. Ultrasound Obstet Gynecol 2016; 48 (3): 318 –332 [15] Leonardi M, Condous G. How to perform an ultrasound to diagnose en- dometriosis. Australasian journal of ultrasound in medicine 2018; 21 (2): 61–69 [16] Keckstein J et al. The #Enzian classification: A comprehensive non-inva- sive and surgical description system for endometriosis. Acta Obstet Gy- necol Scand 2021; 100 (7): 1165 –1175 [17] Perperoglou A et al. A review of spline function procedures in R. BMC medical research methodology 2019; 19 (1): 1 –16 [18] R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 2020. https:// www.R-project.org/ [19] Liu X, Zhang Q, Guo SW. Histological and immunohistochemical char- acterization of the similarity and difference between ovarian endome- triomas and deep infiltrating endometriosis. Reproductive Sciences 2018; 25 (3): 329 –340 [20] Chapron C et al. Surgery for bladder endometriosis: long-term results and concomitant management of associated posterior deep lesions. Human Reproducti on 2010; 25 (4): 884 –889 [21] Donnez O, Roman H. Choosing the right surgical technique for deep endometriosis: shaving, disc excision, or bowel resection? Fertil Steril 2017; 108 (6): 931 –942 [22] Knez J et al. Natural progression of deep pelvic endometriosis in women who opt for expectant management. Acta Obstet Gynecol Scand 2023. doi:10.1111/aogs.14491 [23] Vercellini P et al. Advances in the medical management of bowel endo- metriosis. Best Practice & Research Clinical Obstetrics & Gynaecology 2021; 71: 78 –99 [24] Ferrero S et al. Norethisterone acetate in the treatment of colorectal endometriosis: a pilot study. Human reproduction 2010; 25 (1): 94 –100 [25] Ferrero S et al. Triptorelin improves intestinal symptoms among patients with colorectal endometriosis. International journal of gynaecology and obstetrics 2010; 108 (3): 250 –251 [26] Vigano P et al. Time to redefine endometriosis including its pro-fibrotic nature. Human Reproduction 2018; 33 (3): 347 –352 [27] Koninckx PR et al. The severity and frequency distribution of endome- triosis subtypes at different ages: a model to understand the natural history of endometriosis based on single centre/single surgeon data. Facts, Views & Vision in ObGyn 2021; 13 (3): 209 [28] Roman H et al. Colorectal Endometriosis Responsible for Bowel Occlu- sion or Subocclusion in Women With Pregnancy Intention: Is the Policy of Primary in Vitro Fertilization Always Safe? J Minim Invasive Gynecol 2015; 22 (6): 1059 –1067 [29] Egekvist AG et al. Intra- and interobserver variability in nodule size of rectosigmoid endometriosis measured by two- and three-dimensional transvaginal sonography. Acta Obstetricia et Gynecologica Scandinavica 2018; 97 (6): 734 –743 292 Keckstein S et al. Sonomorphologic Changes in … Ultraschall in Med 2024; 45: 285 –292 | © 2023. Thieme. All rights reserved. Original Article This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.