how to manage bowel endometriosis: the etic approach
TRANSCRIPT
Accepted Manuscript
How to manage bowel endometriosis: the Etic approach
Giulia Alabiso, Luigi Alio, Saverio Arena, Allegra Barbasetti di Prun, ValentinoBergamini, Nicola Berlanda, Mauro Busacca, Massimo Candiani, Gabriele Centini,Annalisa Di Cello, Caterina Exacoustos, Luigi Fedele, Laura Gabbi, Elisa Geraci,Elena Lavarini, Domenico Incandela, Lucia Lazzeri, Stefano Luisi, Antonio Maiorana,Francesco Maneschi, Alberto Mattei, Ludovico Muzii, Luca Pagliardini, AlessioPerandini, Federica Perelli, Serena Pinzauti, Valentino Remorgida, Ana MariaSanchez, Renato Seracchioli, Edgardo Somigliana, Claudia Tosti, Roberta Venturella,Paolo Vercellini, Paola Viganò, Michele Vignali, Fulvio Zullo, Errico Zupi
PII: S1553-4650(15)00085-0
DOI: 10.1016/j.jmig.2015.01.021
Reference: JMIG 2481
To appear in: The Journal of Minimally Invasive Gynecology
Received Date: 11 December 2014
Revised Date: 7 January 2015
Accepted Date: 8 January 2015
Please cite this article as: Alabiso G, Alio L, Arena S, di Prun AB, Bergamini V, Berlanda N, BusaccaM, Candiani M, Centini G, Di Cello A, Exacoustos C, Fedele L, Gabbi L, Geraci E, Lavarini E, IncandelaD, Lazzeri L, Luisi S, Maiorana A, Maneschi F, Mattei A, Muzii L, Pagliardini L, Perandini A, Perelli F,Pinzauti S, Remorgida V, Sanchez AM, Seracchioli R, Somigliana E, Tosti C, Venturella R, VercelliniP, Viganò P, Vignali M, Zullo F, Zupi E, How to manage bowel endometriosis: the Etic approach, TheJournal of Minimally Invasive Gynecology (2015), doi: 10.1016/j.jmig.2015.01.021.
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Full title: 1
How to manage bowel endometriosis: the Etic approach 2
Authors: 3
Endometriosis Treatment Italian Club 4
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Giulia Alabiso, Luigi Alio, Saverio Arena, Allegra Barbasetti di Prun, Valentino Bergamini, Nicola 6
Berlanda,, Mauro Busacca, Massimo Candiani, Gabriele Centini, Annalisa Di Cello, Caterina Exacoustos, 7
Luigi Fedele, Laura Gabbi, Elisa Geraci, Elena Lavarini, Domenico Incandela, Lucia Lazzeri, Stefano Luisi, 8
Antonio Maiorana, Francesco Maneschi, Alberto Mattei, Ludovico Muzii, Luca Pagliardini, Alessio 9
Perandini, Federica Perelli, Serena Pinzauti, Valentino Remorgida, Ana Maria Sanchez, Renato Seracchioli, 10
Edgardo Somigliana, Claudia Tosti, Roberta Venturella, Paolo Vercellini, Paola Viganò, Michele Vignali, 11
Fulvio Zullo, Errico Zupi 12
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From the Departments of Obstetrics and Gynecology, Macedonio Melloni Hospital, University of Milan, 14
Milan (Drs Alabiso, Barbasetti di Prun, Busacca and Vignali), Civico Hospital, Palermo (Drs. Alio, 15
Incandela, Maiorana), Santa Maria della Misericordia Hospital, Perugia (Dr. Arena), University of Verona, 16
Verona (Dr. Bergamini, Lavarini, Perandini), Isituto Luigi Mangiagalli, University of Milan, Milan (Drs. 17
Berlanda, Fedele and Vercellini), University of Siena, Siena (Dr, Centini, Lazzeri, Luisi, Pinzauti, Tosti and 18
Zupi), San Raffaele Hospital, University of Milan (Drs. Candiani, Sanchez, Pagliardini, Viganò), Infertility 19
Unit, Fondazione Ca' Granda, Ospedale Maggiore Policlinico, Milan (Dr. Somigliana), University of Magna 20
Graecia, Catanzaro (Drs. Di Cello, Venturella and Zullo), University of Tor Vergata, Rome (Dr. 21
Exacoustos), Santa Maria Goretti Hospital, Latina (Dr. Maneschi), University of Florence, Florence (Dr. 22
Mattei, Dr Perelli), “Sapienza” University of Rome, Rome (Dr. Muzii), University of Genova, Genova (Dr. 23
Remorgida, Gabbi), University of Bologna, Bologna (Dr. Seracchioli, Geraci), Italy. 24
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Corresponding author: 27
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Prof Errico Zupi 28
Department of Molecular and Developmental Medicine 29
University of Siena 30
Viale Bracci, 53100, Siena – Italy 31
Tel: +39 0577586607; Fax: +39 0577233454 32
E-mail: [email protected] 33
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Abstract: 36
A panel of experts in the field of endometriosis expressed their opinions on management 37
options in a 35-year-old patient, desiring pregnancy, with a previous surgery for endometrioma and 38
with bowel obstructive symptoms. Many questions that this paradigmatic patient may pose to the 39
clinician are addressed, and all clinical scenarios are discussed. A decision algorithm derived from 40
this discussion is also proposed. 41
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Key words: Bowel endometriosis, previous surgery, diagnosis, treatment 43
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Introduction 55
The Endometriosis Treatment Italian Club (ETIC) includes a panel of Italian experts on 56
endometriosis and pelvic pain disorders. The primary goal of ETIC, starting always from the 57
patient’s desire, is to clarify insofar as possible the controversies in the management of 58
endometriosis herein focusing the attention on deep infiltrating endometriosis (DIE). Distribution of 59
deep endometriotic lesions is variable (1), but the disease has a typical multi-focal presentation. The 60
most common site of extragenital endometriosis is the intestinal tract, which accounts for 61
approximately 80% of this kind of endometriosis (2,3). Although bowel endometriosis may cause 62
severe gastrointestinal symptoms, these disturbances are frequently not adequately investigated 63
resulting as unexpected finding at surgery, and the lesions may not be treated due to the lack of 64
preoperative informed consent or surgical competence (4). In fact, surgical treatment must be 65
carried out by surgical teams expert on the disease. The patient should be informed preoperatively 66
on surgical risks such as bowel or bladder dysfunction. The aim of the present study is to answer to 67
all potential questions posed by a paradigmatic case of bowel endometriosis in order to clarify the 68
main problems potentially encountered during the management of the disease. 69
Clinical case: 70
A 35-years old patient, currently desiring pregnancy, presenting with severe dysmenorrhea (graded 71
9/10 on a Visual Analogue Scale VAS), moderate dyspareunia and moderate dyschezia (graded 72
5/10 and 4/10 VAS, respectively) and intermittent lumbar bilateral pain worsened with menses. 73
She had a background of 6 months of obstructive symptoms with constipation and diarrhea. In 74
2001, she underwent a previous surgery for right endometrioma, followed by 7 years of medical 75
treatment (continuous oral contraceptives) and 3 failed IVF attempts. On physical examination, she 76
had normal blood pressure and no systemic disease. Results of her abdominal examination were 77
significant for mild left upper quadrant tenderness, but the abdomen was otherwise non distended 78
with well-healed laparoscopy incisions. Vaginal examination was undertaken before transvaginal 79
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ultrasound. On pelvic examination a normal sized, anteverted and extremely sore on side-to-side 80
mobility uterus was appreciated. There was a palpable, markedly tender deep nodule in the posterior 81
vaginal fornix infiltrating the left parametrium and no palpable adnexal masses giving a positive 82
finding. In general, bimanual examination is considered positive and therefore suggestive of 83
endometriotic infiltration if a palpable nodule, a thickened area or a palpable cystic expansion with 84
topographic-anatomical correlation to the left and/or right uterosacral ligaments, vagina, uterus, 85
rectovaginal space, pouch of Douglas, the rectosigmoid and the urinary bladder are found. Vaginal 86
and cervical exposure to detect the potential presence of visible blue lesions using a disposable 87
speculum completes the examination. 88
The role of pelvic ultrasound imaging in detecting bowel disease 89
- Standard ultrasound examination 90
Bimanual pelvic-gynecologic examination may suggest the presence of DIE by the presence of 91
tender nodules and fibrosis in the vagina and in cul de sac but it has poor accuracy in determining 92
the extent of disease (5-7). Knowing the anatomical localization, the size and number of DIE 93
nodules, the depth of infiltration of the nodules and the degree of stenosis of the bowel lumen 94
allows to plan an appropriate surgical and /or medical management of the patients, to better counsel 95
the patients and to choose the adequate surgical team. In case of posterior DIE when the recto-96
sigma is infiltrated by endometriotic tissue, the bowel is so retracted that the upper segments 97
can adhere to the posterior wall of the uterus, with a complete disruption of the normal anatomy 98
and it is difficult to distinguish between the rectum and sigma. From a surgical point of view it is 99
important that the diagnostic imaging determinates the lowest limit of the nodule on the bowel wall, 100
the lower rectal lesions are more difficult to remove by shaving or segmental resection and have 101
higher complication rate. In regard of the infiltration of the mucosal layer, it seems not to be the 102
determining factor to decide whether to perform segmentary resection or not, but more likely this 103
decision depends on the diameters of infiltrating tissue and the lumen stenosis (6). Knowledge and 104
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related informations as detailed as possible about the disease spread and its localization are 105
extremely useful to the surgeon and to whom take care of the patients from a medical point of view. 106
AFSr classification (8) was considered to assess stage of the disease, presence and extension of 107
adhesions, endometrioma size and pouch of Douglas obliteration. Deep endometriotic lesions are 108
not described in this classification. 109
All potential locations of DIE in the anterior (bladder) or posterior-lateral compartment 110
(rectovaginal septum, uterosacral ligaments, torus uterinum, i.e. tissue behind the cervix in the mid-111
sagittal plane between the uterosacral ligaments, posterior vaginal fornix, rectum and rectosigmoid 112
junction, parametria and ureteral involvement) can be evaluated by transvaginal sonography. 2D 113
(two dimensional)sonographic findings of adenomyosis (9,10) are useful for a correct management 114
and counseling of the patient. Recently it has been observed that on the coronal section of the 115
uterus, obtained with three dimensional (3D) transvaginal sonography, it is possible to visualize the 116
junctional zone more clearly (11-13). Alterations of the junctional zone are defined as distortion and 117
infiltration of the hypoechoic inner myometrium by hyperechoic endometrial tissue. 118
Endometriotic nodules of the bladder and the rectum can be evaluated with transvaginal probe and 119
if necessary a transrectal examination with the same convex probe can be performed. During the 120
transrectal examination a fluid contrast medium can be inserted in the vagina to visualize better the 121
recto-vaginal septum (sonovaginography). 122
Transabdominal ultrasound shows not an accurate detection of DIE mainly because of bowel gas 123
that reduce the ability to evaluate abdominal retroperitoneal or small bowel lesions which are 124
difficult to detect with transabdominal ultrasound probes. Only endometriotic nodules of the 125
abdominal wall can be easily evaluated by high frequency transabdominal probe. 126
Deep nodes appears as hypoechoic lesions, linear or nodular retroperitoneal thickening with 127
irregular borders, and few vessels at power Doppler evaluation (14-17). Patients with suspected 128
pelvic endometriosis, should underwent at first a detailed examination of the pelvis to evaluate the 129
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anatomy of the uterus and the adnexa, both in the sagittal and horizontal plane, with gentle probe 130
movements to assess the presence of adhesion between them too. Transvaginal sonographic 131
examination is based on a detailed evaluation of organ and tissues dividing the pelvis in anterior and 132
posterior compartment according to DIE classification of Chapron (18). Utilizing transvaginal and 133
transrectal sonography (if needed) an accurate assessment of the vagina, particularly the areas of the 134
posterior and lateral vaginal fornixes, the retro cervical area with torus uterinum and uterine sacral 135
ligaments, the parametria laterally and the recto-vaginal septum should be performed. In case of 136
endometriotic lesion of uterosacral ligaments and homolateral parametria special attention is paid to 137
ureteral evaluation in the paracervical tract. In order to assess rectal wall infiltration, if suspected, 138
transrectal evaluation with the transvaginal probe could be performed. Special attention has to be 139
paid to the pain felt by the patient in order to perform a careful evaluation of all the painful sites 140
evocated by a gentle pressure of the probe (‘tenderness-guided’ ultrasonography) (19). The 141
following structures must be evaluated by TVS in the pelvis and are strictly anatomically defined by 142
sonographic landmarks : vagina, recto-vaginal septum (RSV), torus, uterosacral ligaments (USLs), 143
parametria and lateral pelvis, ureter, pouch of Douglas, rectum and recto-sigmoid junction 144
Regarding in particular rectal sigmoid nodules they are visualized as an irregular hypoechoic mass 145
penetrating into the intestinal wall distorting its normal structure. At transvaginal sonography the 146
normal rectal wall layers are seen: the rectal serosa and smooth muscle layer appear as a thin, 147
hypoechogenic line covered by the rectal submucosa and mucosa which is visualized as a 148
hyperechogenic rim covering the rectal smooth muscle layer (20). With respect to the posterior 149
uterine wall, intestinal nodules located below the level of the insertion of the USLs on the cervix are 150
considered low rectal lesions, while the ones above this level are considered upper rectal or the 151
recto-sigmoid junction lesions. This virtual line should delimitated the plane under the peritoneum 152
of the pouch of Douglas and corresponds laterally to the parametria and medially to the recto-153
vaginal septum. Also the distance from the anus can be taken by transrectal sonography. 154
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Transvaginal sonography has low accuracy in diagnosing the infiltration of the mucosal layer (6). 155
Also transrectal ultrasound, which is a valuable tool for detecting rectal endometriosis as 156
endometriotic infiltration of the muscularis layer, is less accurate in assessing submucosal/mucosal 157
layer involvement (16, 21). Therefore transvaginal and transrectal sonography does not help 158
surgeons in deciding whether or not perform segmental or discoid resection of the lesion. More 159
likely this decision is dependent on patients symptoms and it is also related to the diameters of 160
infiltrating tissue, and lumen stenosis. Recent studies have shown that transvaginal sonography, 161
when carried out by experienced sonographers, may indeed be a highly valuable test for the 162
detection of DIE (14, 15,16,17,22,23). The reported accuracy of the ultrasonographic diagnosis of 163
DIE varies between different studies, which may reflect the variations in the examination technique, 164
quality of ultrasound equipment and experience of the operators. Although the sensitivity and 165
specificity of transvaginal sonography in the prediction of DIE in published (14,15,19,20,22,23) 166
studied is high, to evaluate DIE by transvaginal sonography is difficult and needs a great expertise. 167
Therefore some easily detectable utrasonographic sign has been recently proposed to predict the 168
risk of the presence of DIE. Real-time dynamic transvaginal sonography evaluation of the posterior 169
compartment using the “sliding sign” seems to establish whether the pouch of Douglas is obliterated 170
and may also be useful in the identification of women who may be at a higher risk for bowel 171
endometriosis and needs further imaging performed by experts sonographer or radiologists (24, 25). 172
It has been reported that adding water-contrast in the rectum during transvaginal ultrasonography 173
(RWC-TVS) might improve the diagnosis of rectal infiltration in women with rectovaginal 174
endometriosis as RWC-TVS detected infiltration of the rectal muscularis propria more accurately 175
than transvaginal sonography (26). RWC-TVS might be used when transvaginal sonography cannot 176
exclude the presence of rectal infiltration. The surgical management of low intestinal endometriosis 177
mainly depends on the depth of infiltration of the lesion and the degree of bowel stenosis (27). 178
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Regarding the specific case of this paper the results of this detailed transvaginal and transrectal 179
examination revealed a deep endometriotic plaque of the posterior compartment which infiltrated 180
not only the rectal and sigmoid wall (both caudal and cranial tract) but extend laterally to the left 181
USL, left parametrium, centrally and caudally to the torus uterinum, RVS and posterior vaginal 182
fornix (Figure 1a,b). No pelvic ureter dilatation was seen however due to the localisation of the DIE 183
an extrinsic of the ureter is highly suspected. Also a mild hydronephrosis detected by TAS may be 184
an indirect signs that such nodule involved the left ureter along its pelvic course. The right ovary is 185
adherent to the posterior uterine wall, is showed slightly reduced volume and a normal ovarian 186
tissue. The left ovary is completely attached to the uterus and to the deep endometriotic fibrotic 187
plaque. No endometrioma are seen. The pouch of Douglas is completely obliterated. 188
Our patients showed also clear 2D sonographic findings of adenomyosis of the posterior uterine 189
wall for the presence of an asymmetric diffuse thickness of the myometrium and hyperechoic areas 190
with scattered vessel distribution. Also the uterine junctional zone appears at 3D TVS infiltrated 191
especially posteriorly and laterally on the left. The posterior uterine adenomyotic wall is attached to 192
the posterior deep endometriotic tissue and seems like an extension or an invasion of it. 193
This careful evaluation of TVS diagnostic imaging findings gives to the clinicians the opportunity 194
to decide : 195
• the need of further imaging to clarify the involvement of specific site (ureter, bowel stenosis, 196
upper intestinal localization) 197
• to establish a correct tailored management of the disease, 198
• to properly inform patients of the extent of their disease and therapeutic options 199
• the best surgical approach and the potential need to involve other surgical specialists than a 200
gynaecologic surgeon (e.g. colorectal surgeon or urologist). 201
- Saline Contrast Sonovaginography, Rectum water contrast sonography 202
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In order to increase accuracy in the evaluation of the recto-sigmoid involvement new ultrasound 203
techniques have been developed or other ones already in use were adapted to the study of the 204
endometriotic lesions. These techniques are better performed with some bowel preparation before 205
the procedures, such as a rectal enema one hour prior to the exams (15). 206
Saline Contrast Sonovaginography (SCSV) was first described by Dessole et al. in 2003 (28) (6). It 207
combines a TVS with the introduction of saline solution in the vagina to have a better imaging of 208
the vaginal walls, the fornix, the pouch of Douglas, the USLs and the rectovaginal septum. A 209
specifically developed rubber ring (Colpo-Pneumo Occluder ®, Cooper Surgical, Berlin, Germany) 210
is inflated with saline at the base of the vaginal ultrasound probe to occlude the meatus, then the 211
vagina is dilated with a variable quantity of saline solution (about 60-120 ml) inserted through to a 212
Foley catheter. The acoustic window so created allows a high detailed scan of all the anterior as 213
well as the posterior compartment. Published data showed a positive predictive value (PPV) and a 214
negative predictive value (NPV) better or at least similar than usual TVS and the Magnetic 215
Resonance Imaging in the study of vaginal fornix, USLs, rectovaginal septum involvement and also 216
in the evaluation of bowel infiltration by deep endometriotic nodule (metterei la referenza e 217
toglierei table 1). Despite the exam might last longer than conventional TVS, the level of 218
discomfort reported by the 54 women of the study did not differ between the two techniques (VAS 219
2.1 ± 1.8 vs. 2.6 ± 1.7 respectively, P= 0.14) (29) . 220
Transvaginal sonography with Water-Contrast in the Rectum (RWC-TVS) is performed using a 221
flexible 25 Ch diameter catheter (i.e. Pharmaplast® Redditch, Worcs, UK) inserted into the rectal 222
lumen up to 20 cm from the anus. Saline solution is then instilled in the rubber balloon of the 223
catheter under ultrasound control. The amounts of water to get a suitable image range from 100 to 224
300 ml usually, depending by the wall distensibility. By means of this adjustable water-contrast, 225
high definition images of rectal wall and its layers can be obtained, together with a dynamic 226
evaluation of endometriotic lesion and rectal stenosis. Bergamini and al. (30) showed that this 227
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method had the same accuracy as transrectal sonography and Barium enema in the preoperative 228
assessment of low intestinal endometriosis in a series of 61 patients undergoing surgical 229
management for bowel lesions. In particular, the PPV in the diagnosis of endometriosis of the 230
rectosigmoid tract was reported to be 98%, and the NPV was 81.8%. Concerning the degree of 231
bowel stenosis, PPV was 82.3% while NPV was 94.1%. Another study (31) compared the accuracy 232
of multidetector computerized tomography enteroclysis (MDCT-e) and rectal water contrast 233
transvaginal ultrasonography (RWC-TVS) in determining the presence and extent of bowel 234
endometriosis. RWC-TVS and MDCT-e showed similar accuracy in the detecting rectosigmoid 235
endometriosis, but RWC-TVS was tolerated better than MDCT-e. Thus, RWC-TVS could be used 236
whenever TVS cannot exclude the presence of rectal infiltration (26) or an evaluation of degree of 237
penetration is needed. It represents a single low cost and minimally invasive procedure for the 238
preoperative assessment of rectosigmoid endometriosis and can be used to predict the need for 239
segmental bowel resection. 240
- Rectal endoscopic sonography 241
Rectal endoscopic sonography (RES) is another valuable tool to investigate the depth of nodule 242
infiltration in the sigma and rectum. It consists of a colonscope coupled with a high frequency 243
sonography (7.5 and/or 12 MHz ). The transducer is positioned in the sigmoid and then slowly 244
withdrawn through the sigmoid and rectum. Evaluation of the bowel wall and adjacent areas is 245
carried out by moving the probe up and down several times before and after instilling water into the 246
intestinal lumen. Involvement of USLs, vagina, and colon/rectum is analyzed. Normal intestinal 247
wall usually appears as a five-layer structure. The surrounding areas are also scanned, with 248
particular attention paid to the ovaries, cervix and body of the uterus, pouch of Douglas, USL areas 249
and torus uterinum. Deep pelvic endometriosis is defined by the presence of a hypoechoic nodule or 250
mass, with or without regular contours. In the rectum and/or sigmoid colon, as the hypoechoic 251
muscolaris layer is clearly different from the hyperechoic submucosa, it is possible to define the 252
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depth of invasion and to measure of the nodule correctly. The largest diameter of the lesions, their 253
location from the anus margins, and infiltration of adjacent pelvic organs can be recorded (32). 254
However, the need of a high frequency probe, its invasiveness and sometimes the need for 255
anesthesia makes this approach not routinely recommended (33 ). In a retrospective longitudinal 256
study, Bazot et al. compared physical examination, TVS and RES for the assessment of different 257
locations of DIE. The sensitivity of physical examination, TVS, RES and MRI were, respectively, 258
73.5%, 78.3%, 48.2%, 84.4%, for uterosacral ligament endometriosis; 50%, 46.7%, 6.7%, and 80%, 259
for vaginal endometriosis; and 46%, 93.6%, 88.9%, and 87.3% for intestinal endometriosis (33). 260
RES results were compared with surgical findings (21). The analysis of the results showed that RES 261
can help to identify the presence and the degree of wall infiltration in bowel sites. For the detection 262
of muscularis layer infiltration by endometriosis, the PPV of RES was 100%, whereas for the 263
detection of submucosal/mucosal layer involvement, the sensitivity was 89%, specificity was 26%, 264
PPV was 55%, NPV was 71%, test accuracy was 58% and positive and negative LRs were 1.21 and 265
0.40, respectively. The final consideration on this technique, based on several studies, is that this is 266
a valuable tool for detecting bowel endometriosis in the muscularis layer but not in the 267
submucosal/mucosal one. Finally, as RES has demonstrated low accuracy in detecting uterosacral 268
and rectovaginal septum endometriosis involvement, it can be viewed as a second level 269
examination in diagnosing posterior compartment disease (21,34) . 270
- Magnetic resonance, Computerized Tomography and Virtual Colonoscopy 271
Nowadays magnetic resonance (RM) is widely used for the imaging of endometriotic lesions due 272
to its extremely good results. This is an highly efficient method considering a sensibility of 88%, a 273
specificity of 98% , a PPV of 95% and a NPV of 96% coupled with a diagnostic accuracy of 96% 274
make one (35). The presence of blood (iron) inside the nodule undoubtedly helps in identifying the 275
pathological localizations. Unfortunately not all nodules are the same and in same cases the fibrotic 276
component is predominant over the glandular one and this explains why this “atypical” lesions 277
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might be missed at the examination (36). Adding a paramagnetic contrast medium does not increase 278
the diagnostic accuracy as the “atypical“ nodules tend to be fibrotic and to have a reduced 279
vascularization and thus the contrast medium scarcely delineates them. Distending the bowel walls 280
with a solution is indeed an helpful support for the diagnosis of bowel endometriosis as it helps the 281
detection of wall defects against other anatomical structures such as small bowel loops, flexures of 282
the colon, vessels and lymph nodes. Unfortunately, large reports are not yet available in the 283
literature on the usefulness of RM coupled with bowel distension for the detection of bowel 284
endometriosis. A larger experience is conversely available for the multislice CT enteroclysis. Since 285
2007 (37) this approach has been proposed as the primary method to detect both colonic and ileal 286
pathology. The enteroclysis coupled to a mechanical bowel preparation yields to a very high 287
sensibility in detecting even minute bowel nodule with a 7-8 mm minimal spatial resolution. It is 288
then clear that even if direct visualization at surgery remains yet unsurpassed among imaging 289
techniques, this approach is extremely successful. CT enteroclysis not only permits to detect the 290
nodule and allows its measurement but clearly defines the degree of infiltration among the different 291
bowel wall layers. In the last three years, the amount of radiation needed to perform this exam has 292
been reduced by 60-70% and this is a very important aspect in fertile women. Unfortunately, the 293
contrast media is still an organ iodized one which is not the best for young women. It is in the effort 294
of abolishing the use of this contrast media that virtual colonoscopy has been proposed for this 295
pathology. As matter of fact, virtual colonoscopy is a CT scan with low radiation dose and no 296
contrast media. Preliminary clinical data are not suggestive of a wide application of this approach 297
for this pathology as its main application field is for endoluminal (mucosal) disease while bowel 298
endometriosis is almost exclusively an extraluminal (muscular) pathology only rarely reaching the 299
wall lumen. While bowel preparation and distension certainly helps in finding bowel abnormalities 300
the absence of contrast does not clearly differentiate between normal and abnormal bowel wall thus 301
making the evaluation of the degree of infiltration very difficult. Similarly, a distinction between 302
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colic and “pericolic “ findings (small bowel loops, flexures of the colon, vessels and lymphnodes) is 303
harder to reach in the absence of contrast media. 304
Pre and post treatment counseling 305
The management of patient with DIE is very difficult, not only for clinical reason but also for 306
psychological aspects This is reason for which a careful and accurate counseling represents a key 307
moment in pre-and post-operative communicative steps with patient. Above all, it is necessary to 308
inform the patient about the actual indications for proposed treatment, debating the efficacy and the 309
risk of surgical complications. DIE is related to a wide range of symptoms closely depending on the 310
type, location and extent of the lesion. The presence of large nodules protruding in the bowel lumen, 311
results in almost 100% of patients in catamenial pain and major intestinal symptoms (diarrhea, 312
constipation, dischezia) (38,39). Women should be informed preoperatively that in her case, as in 313
60-80% of patients (40,41), the severity of bowel symptoms are the main indication for surgical 314
treatment (42). Furthermore, patient should be properly informed that the surgery for DIE is 315
challenging: while a resolution of dysmenorrhea and dyspareunia is expected in 70% and 65 % of 316
operated women (43) this is not devoid of possible (serious) complications or sequelae. Further this 317
immediate resolution of the intestinal symptoms (in 60-70% of cases) along with of dysmenorrhea, 318
(44,45) might not be everlasting (especially when surgery is not supported by a post-operative 319
medical treatment) with absence of improvement in 30-40% and even recurrence in 50-70% of 320
cases (42,44,45). Patient should be aware of the complexity of surgery and on the relationship 321
between surgical strategy and the risk of complications as for instance we might expect a higher 322
rate of post-surgical complications with increased surgical aggressiveness (bowel resection: an 323
overall complications rate of 22% with 11% of major complications rate; shaving or discoid 324
resection: an overall complications rate of 3-5% with 1-2% of post-operative complications) (46). In 325
addition, the surgeon should advise patient pre-operatively on the need of a protective colostomy 326
keeping in mind that bowel resection is performed in 30-35% of women with DIE undergoing 327
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surgery with a colostomy needed in 10-14% of cases (47); unfortunately , in more than 80% of 328
cases, the decision to perform resection is taken during surgery (46). Surgeon should also accurately 329
inform patient on her post-operative chances to conceive (if interested). Even if post-surgical 330
pregnancy rate of 40-45%, with 75% of spontaneous pregnancies (48,49,50) have been reported on 331
the general population, when considering only women who were infertile before surgery and who 332
achieved conception after surgery, results are much less optimistic (51,52,53). Thus, while pain is 333
always the indication for surgery the use of IVF/ICSI techniques should be always kept in mind 334
(53). In order to offer an adequately counseling about the best pre and postoperative support to 335
achieve pregnancy (52,53,54) a careful and reliable information about the ovarian reserve of that 336
specific patient is needed (as that could be already reduced due to previous surgery). Finally 337
infertility counseling should be made on a personalized evaluation of the reproductive chance and 338
not on indicators referring to the general female population (55). 339
Surgical treatment 340
Many variables might be taken into account when planning surgery such as the anatomical sites 341
involved, depth, infiltration and size of the lesion as well as the possibility of a multifocal or 342
multicentric involvement. Other factors that influence the surgeon’s decision are quality of life, 343
presenting symptoms, associated infertility and failure of medical therapy. Two surgical approaches 344
are usually employed: colorectal resection or nodule excision. The latter that can be performed 345
without opening the bowel wall (shaving) or by removing the nodule along with surrounding rectal 346
wall (discoid resection) (41). Unfortunately, there are no universal guidelines on when and what 347
technique should be chose. In fact while the ultimate aim is removing all visible endometriotic 348
lesions, avoiding surgical complications and preserving or restoring reproductive function if needed 349
(56), on the other hand it is known that removing all endometriotic cells from all sites might 350
represent an over treatment if not infeasible. This explains the emerging surgical trend for a less 351
aggressive approach (6). Therefore, considering endometriosis as a benign disease, the surgical 352
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approach of rectal endometriosis should primarily focus on the relief of digestive symptoms and 353
pelvic pain rather than on mandatory “oncologic ” resection of lesions (41). Most commonly 354
accepted indications for a bowel resection approach are: bowel stenosis, multifocal lesions, 355
sigmoid involvement, lesions larger than 3 cm, or involving more than 50% of the circumference of 356
the bowel wall (57). Bowel resection is associated with improved patient symptoms (both 357
gynecologic and digestive symptoms) and quality of life and it is also associated with good results 358
in terms of recurrence rate and long-term pain relief (3,56,58). The main complications described in 359
literature are laparoconversion, rectovaginal fistulae, pelvic abscesses, dehiscence of the bowel 360
anastomosis and urinary disfunction with variable percentages depending on the different series 361
(3,51,46). Similarly to what happens for oncology, an improvement in clinical outcomes and a 362
reduction in complications rate can be achieved if surgery is performed by experienced surgeons in 363
a referral center (56). When the resection is ultra-low (less than 6 cm from the anal verge) or when a 364
defective anastomosis is suspected, a protective ileostomy might be considered (57) to reduce the 365
risk of fistulae and dehiscence of the anastomosis. An original technique in approaching rectal 366
endometriosis has been described by Roman in 2013. His procedure is based on the use of 367
PlasmaJet because of the reduction of thermal spread in shaving endometriotic implants even in the 368
lowest part of the rectal wall. This new technique appears very promising even large series are not 369
yet available (59). The less invasive shaving technique may be performed for lesions of 3 cm 370
diameter or less, with bowel wall infiltration lower than 50% and in cases of less than three lesions 371
infiltrating the muscular layer (38). This technique could have the advantage of preserving 372
vascularization and innervation of the bowel, and preventing an opening of the bowel wall (57,60). 373
In a study series of 500 patients operated with shaving technique, the authors reported that in young 374
women, conservative surgery is associated with higher pregnancy rate and lower complication and 375
recurrence rates than resection (0 % vs 12.5%) (61). The risk for persistent lesions has been 376
estimated to reach almost 50% of women who undergo this procedure (38). In a recent review by 377
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Vercellini et al., the recurrence rate of lesions at 1 years follow up has been expected at 20%. 378
Furthermore, about 50% of the patients needed analgesics or hormonal treatments because of 379
recurrence pain and the reoperation rate has been shown to be of 25% (62). 380
As previously stated, there are no clear evidence regarding the effects of deep endometriosis surgery 381
on fertility rate. As other relevant locations (ureter, bladder, ovary , diaphragm etc) besides the 382
bowel are often involved, these factors must be taken into account (63). Whichever the technique 383
used, there is a general consensus that patients with deep endometriosis should be operated the least 384
minimal number of times (ideally only once) and only by multidisciplinary surgical teams 385
experienced with removal of the disease 386
Does the patient need drug therapy after surgery? 387
Treatment of DIE requires long-term planning including both surgery and medical therapy. As for 388
other chronic diseases, i.e. Crohn disease, a combined approach based on a long-life medical 389
therapy and an occasional surgical treatment is, at present, the best treatment strategy. Besides, 390
endometriosis - especially the deep-infiltrating type - often affects the nervous fibers, resulting in 391
central sensitization. This condition is responsible for a chronic pain syndrome (64) which can be 392
reduced not only by surgery, but also with a long-life medical therapy. It is however difficult to 393
identify a single post-operative approach to manage DIE. Published studies are often not 394
comparable and results are strongly influenced by centers preference. The rationale behind 395
administering medical treatment after surgery is, as reported in ESHRE guidelines, to reduce or 396
prevent "pain symptoms (dysmenorrhea, dyspareunia, non-menstrual pelvic pain) and the 397
recurrence of disease in the long-term (more than 6 months after surgery)" (43). 398
We should divide endometriosis patients into two main groups: 399
1) patients who wish to become pregnant immediately after surgery 400
2) patients who do not wish to become pregnant “ immediately” after surgery. 401
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The pregnancy-seeking group should receive appropriate counseling in order to conceive as soon as 402
possible. The second group needs a secondary prevention therapy . The patient is protected against 403
disease relapses as long as she is receiving postoperative hormone therapy (65). Published data 404
strongly support the idea of prescribing postoperative medical therapy (66). ESHRE guidelines 405
reported the results of drug therapy after surgery for ovarian endometrioma, but we think that this 406
statement can be easily applied to DIE too. If the patient is not trying to become pregnant, medical 407
therapy should be prolonged for about 18 to 24 months (65) as we all know that endometriosis can 408
recur (even if, according to Busacca et al. we should define this as persistence rather than as 409
recurrence of the disease). Recurrence rates increase constantly in time, but higher risk factors 410
include: 1) younger age, 2) lack of a radical surgery, 3) stage III to IV, 4) not achieving pregnancy 411
in the pregnancy-seeking group (67). 412
What is the best medical therapy? 413
As published studies failed to identify the perfect molecule and all the considered studies report a 414
good result (68,69) with different molecules, it is reasonable that the patient should stick to the 415
treatment administered in the pre-surgical period. In the view of a long term therapy, patient ‘s 416
compliance is more important than the molecule administered. Regardless of type and route of 417
administration, there is a real benefit in post-operative hormone therapy compared to expectant 418
management (65). Long-term hormone therapy should be always considered in the treatment of 419
endometriosis, and strategies should be developed for increasing the low compliance seen in the 420
long term and for those women presenting with absolute contraindications to steroid treatment. 421
The rationale for medical treatment is the reduction of intra- and perilesional inflammation with 422
diminished production of prostaglandins and cytokines and thus less stimulation of pain fibers i.e 423
drugs controlling pain symptoms. A reduction in nodules’ size has also been repeatedly reported in 424
the majority of women with DIE of the rectovaginal septum or Douglas’ pouch undergoing medical 425
treatment (70-74). Accordingly, the rationale for medical treatment prior to surgery in these women 426
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may be to reduce the extent of the disease in order to facilitating surgical radicality or allowing 427
surgical procedures that are more conservative, such as shaving or discoid resection of intestinal 428
nodules rather than segmental bowel resection. On the other hand, this approach may be 429
questionable, since it has also been reported that medical therapy shrinks the endometriotic lesions, 430
but does not treat the fibrosis that usually surrounds deep endometriosis and is responsible for 431
bowel obstruction (4). Unfortunately, however, no previous studies have compared the outcome of 432
surgical treatment for DIE with and without preoperative medical therapy. 433
The available medical treatments that may be effective in pain control for this woman include: 434
estrogen-progestin oral contraceptives (OC), progestin alone, gonadotropin releasing hormone 435
agonists (GnRH-a), danazol and aromatase inhibitors. When a long term medical therapy is 436
planned, a low-dose progestin only (i.e. oral norethindrone acetate 2.5 mg/day) might be considered 437
as first line treatment (70,75), based on a good balance between efficacy, side effects and costs. 438
Alternatively, OC may be proposed as a therapy for this woman, with a continuous rather than 439
cyclic administration since dysmenorrhea is her main complaint (76). Finally, if surgery is 440
inevitable, a 3 to 6 months preoperative treatment with a GnRH-a or an association of progestin 441
with an aromatase inhibitor (77) may be considered, especially if the patient has a history of poor 442
response to OC or progestin alone. 443
- OC and progestins: the only randomized controlled trail available, evaluating the medical 444
treatment of rectovaginal endometriosis, has compared a combined estrogen-progestin regimen with 445
low–dose progestin alone (70). Both regimen were effective in reducing pain from dysmenorrhea, 446
dyspareunia and dyschezia. Overall, 62% of the women in the ethinyl E2 plus cyproterone acetate 447
group were satisfied or very satisfied after 12 months of treatment compared with 73% in the 448
norethindrone acetate group (p=ns). Following treatment, 6 to 11 percent of women continued to 449
have moderate to severe symptoms. The therapies were well tolerated: few women withdrew from 450
the study because of side effects (two in the estrogen-progestin group; three in the progestin-only 451
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group). Another study has evaluated the effect of low-dose norethindrone (2.5 mg per day) in 452
relieving gastrointestinal symptoms among 40 women with rectosigmoid endometriosis who were 453
still symptomatic following non-radical surgery (75). At 12-month follow-up, treatment was 454
associated with significant improvements in diarrhea, intestinal cramping, passage of mucus with 455
stool, and cyclic rectal bleeding. Constipation was improved only in women who had cyclic 456
symptoms. No significant improvement was found in abdominal bloating or feeling of incomplete 457
evacuation. With the aim of detecting possible differences across different preparations, a 458
prospective study including 59 women with rectovaginal endometriosis who were still symptomatic 459
after conservative surgery compared a contraceptive vaginal ring (15 µg ethinyl estradiol and 120 460
µg etonogestrel per day) with a patch (20 µg ethinyl estradiol and 150 µg norelgestromin per day). 461
The ring was associated with a significantly greater improvement in dysmenorrhea, while 462
improvement in dyspareunia and chronic pelvic pain was similar for the two preparations (78). A 463
recent paper has demonstrated that both a desogestrel-only pill and the vaginal ring are efficacious 464
in treating symptoms caused by rectovaginal endometriosis infiltrating the rectum. Patient 465
satisfaction was higher for the former rather than the latter treatment (79). 466
- GnRH-a: gonadotropin releasing hormone agonists have been found to improve either pain 467
symptoms and intestinal symptoms in women with rectovaginal endometriosis (73). However, long-468
term use of these agents is generally avoided because it may result in menopausal symptoms and a 469
decreased bone density. 470
- Danazol: since oral Danazol is often not well tolerated because of androgenic side effects, a study 471
has evaluated the postoperative administration of Danazol vaginally (one 200 mg vaginal 472
capsule/daily) to 21 women with rectovaginal endometriosis. After 12 months of treatment, a 473
significant reduction in pain symptoms was observed, without major side effects and without 474
significant modifications of metabolic and coagulative parameters (72). 475
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- Levonorgestrel-releasing intrauterine device (LNG-IUD): a small study has shown that insertion 476
of the LNG-IUD was associated with improvement in dysmenorrhea, pelvic pain, and dyschezia in 477
11 women with rectovaginal endometriosis (71). 478
- Aromatase inhibitors: the aromatase inhibitor Letrozole, in a combination therapy with 479
norethindrone acetate, has been found effective in improving symptoms in women with 480
rectovaginal endometriosis (77,80). 481
Treatment of coexisting infertility. 482
The impact of DIE on fertility status. 483
Mechanisms that account for a negative impact of DIE on fertility may include mechanical 484
distorsion of pelvic anatomy and interferences in the reproductive process due to presence of 485
adhesions. Moreover, peritoneal factors are dramatically altered even in presence of DIE and 486
inflammatory effects associated with activated macrophages or alterations of cytokine signalling 487
affecting fallopian tubes, gamete and endometrium function have also been reported (81-84). As a 488
matter of fact, DIE has a detrimental effect on ART outcomes. However, the pregnancy rate differs 489
considerably mainly depending on the presence of adenomyosis, AMH serum level and patient’s 490
age. Two prospective studies from the same group have provide information of the effect of DIE on 491
ART outcomes and on determinant factors of fertility outcome (85,86). In a prospective longitudinal 492
study on 142 consecutive endometriosis patients who had undergone ICSI–IVF treatment, Ballester 493
et al have shown that clinical pregnancy rate per patient in women with and without DIE was 58 494
and 83%, respectively (P=0.03) (85). About 60% of the patients had previously undergone an 495
intervention for endometriosis. Increased patient’s age, AMH serum level ≤1 ng/ml and increased 496
number of ICSI–IVF cycles were associated with a decreased clinical pregnancy rate but the 497
presence of DIE was the strongest determinant factor of the clinical pregnancy rate (85). In a 498
multicentre study, the same group has evaluated n=75 patients with colorectal endometriosis and 499
proved infertility after ICSI–IVF cycles. Three-quarters of the patients had undergone prior surgery 500
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for endometriosis. In the whole population the cumulative pregnancy rate per patient after one, two 501
and three ICSI–IVF cycles were 29.3, 52.9 and 68.6%, respectively. Presence of adenomyosis, a 502
patient age over 35 years and an anti-Mullerian hormone serum level under 2 ng/ml were associated 503
with a decreased cumulative pregnancy per patient (86). 504
These data were confirmed in studies that compared ART outcomes in patients with endometriomas 505
with and without DIE. 506
The role of surgery for DIE in relation to infertility 507
Data on the impact of surgery for DIE on fertility are controversial . In a patient preference trial 508
comparing women with rectovaginal endometriosis opting for surgery (n=44) with those choosing 509
expectant management (n=61), the 24-month cumulative pregnancy rate was, respectively, 44.9% 510
and 46.8% (87). In another study the outcomes of ART treatments in infertile women undergone 511
extensive laparoscopic excision of endometriosis before ICSI-IVF were compared to those who 512
underwent ICSI-IVF only in a patient-based choice study. Significantly higher implantation (32.1% 513
vs 19%, p5.03) and pregnancy rates (41% vs 24%, p5.004) were identified in the surgical group. 514
The odds ratio for women in the combined surgery/ART group to achieve pregnancy was 2.45 (95% 515
CI 51.34–4.51) (49). Therefore, the overall infertility picture of the couple should be considered and 516
not just the endometriosis (88). Assessment of the current infertility status including evaluation of 517
the ovarian reserve and of male factor should be suggested before proceeding with the surgical 518
intervention. In this scenario, the gynecologist should be able to formulate a reproductive prognosis. 519
The aim of surgery is to normalize the anatomy and improved the chance of spontaneous pregnancy. 520
Following surgery, a strict time line needs to be implemented that the couple can follow. If no 521
pregnancy has occurred after 6 months then IVF should be offered. 522
Pregnancy outcome 523
It is important that all endometriotic patients should be aware both that pregnancy, thanks to the 524
rise in progesterone levels, will probably have a great beneficial effect on their disease and on their 525
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symptoms, and that her disease could be an independent risk factor for adverse pregnancy 526
outcomes, both for spontaneous and ART pregnancies. Surgical treatment does not completely 527
prevent the development of complications associated with these pregnancies. Fortunately, even if 528
potentially dangerous for the mother and the child, all these events are extremely rare. A serious 529
complication described in literature is represented by spontaneous hemoperitoneum in pregnancy 530
(SHiP): it can occur in the second half of pregnancy, in labour, and infrequently in the early 531
postpartum period and it is caused by ectopic decidualization of deep endometriotic implants with 532
vascular invasion. Maternal and fetal fatality of 22% and 56% respectively has been reported. A 533
total number of 25 SHiP cases were published during the last 20 years. Among them, endometriosis 534
was reported in 13, thus resulting as the major risk factor for ShiP (89,90). Pregnancy may also 535
increase the risk of severe bowel complications, arising during the third trimester, both in treated 536
and untreated patient. Fifteen case reports of bowel perforation have been reported (91). While a 537
pregnancy-related constipation (due to hormone-mediated reduction of colon mobility) causing a 538
colonic hyperpressure ending in the rupture of the operated weakened tract might be the most 539
likely pathogenetic mechanism for the operated patients, the pathogenetic mechanism in the 540
untreated ones is still largely unclear. An extensive decidualization weakening the bowel wall 541
coupled to traction on the associated adhesions has been speculated. The same authors also 542
reported 6 cases of bowel occlusion in pregnant patients with deep endometriotic lesions. The same 543
decidualization of ectopic implants in pregnant women might occasionally results in episodes of 544
massive gastrointestinal bleeding (92). The patient should be informed that endometriosis can also 545
increase the risk of many pregnancy-associated disorders such as placenta praevia (odds ratio 1,7), 546
preterm birth (OR 1,33) and postpartum haemorrage (OR 1.3). There is no association between 547
endometriosis and fetal growth restriction (93,94) while controversial findings have been reported 548
for pre eclampsia risk as it was found to be decreased, increased or unchanged. Thus, more studies 549
are required to define a potential relationship between these two diseases (95). A series of old 550
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uncontrolled and retrospective studies seemed to suggest an increased rate of miscarriage in patients 551
with endometriosis (96) with a reduction in the rate after surgical treatment but more recent 552
prospective studies have not detected such improvement after surgery; thus, clinical evidence of an 553
association between endometriosis and miscarriage is still lacking (97). A decision algorithm 554
derived from this discussion is proposed in Figure 2. Some of these decisions are not based on 555
evidence from RCTs but on the opinion of a panel of 29 experts in the field of endometriosis. 556
In conclusion, management of bowel endometriosis is still one of the most challenging aspect of 557
benign gynecology. In our opinion it is mandatory to emphasize the role of a correct counseling for 558
the patient in order to clarify in advance all the surgical related risks, the chance of further 559
pregnancies or the need of a continuous medical treatment. 560
561
562
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References 577
578
1. Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364(9447): 1789–1799. 579
2. Lewis LA, Nezhat C. Laparoscopic treatment of bowel endometriosis. Surg Technol Int. 580
2007;16:137–141. 581
3. Darai E, Ackerman G, Bazot M et al. Laparoscopic segmental colorectal resection for 582
endometriosis: limits and complications. Surg Endosc 2007; 21: 1572–1577. 583
4. Remorgida V, Ferrero S, Fulcheri E, Ragni N, Martin DC. Bowel endometriosis: 584
presentation, diagnosis, and treatment. Obstet Gynecol Surv. 2007;62:461– 470. 585
5. Koninckx, P.R., C. Meuleman, S. Demeyere, et al.. Suggestive evidence that pelvic 586
endometriosis is a progressive disease, whereas deeply infiltrating endometriosis is associated with 587
pelvic pain. Fertil. Steril. 1991;55: 759–765. 588
6. Koninckx PR, Ussia A, Adamyan L, Wattiez A, Donnez J. Deep endometriosis: definition, 589
diagnosis, and treatment. Fertil Steril 2012;98:564-71. 590
7. Hudelist G, Oberwinkler KH, Singer CF, Tuttlies F, Rauter G, Ritter O, Keckstein J. 591
Combination of transvaginal sonography and clinical examination for preoperative diagnosis of 592
pelvic endometriosis. Hum Reprod. 2009; 24: 1018-24. 593
8. Society AF: Revised American fertility society classification of endometriosis. Fertil Steril 594
1985;43:351–352. 595
9. Dueholm M. Transvaginal ultrasound for diagnosis of adenomyosis: a review. Best Pract 596
Res Clin Obstet Gynaecol. 2006; 20:569–582. 597
10. Lazzeri L, Di Giovanni A, Exacoustos C, Tosti C, Pinzauti S, Malzoni M, Petraglia F, Zupi 598
E. Preoperative and Postoperative Clinical and Transvaginal Ultrasound Findings of Adenomyosis 599
in Patients With Deep Infiltrating Endometriosis. Reprod Sci. 2014;14;21:1027-1033. 600
MANUSCRIP
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11. Naftalin J, Jurkovic D. The endometrial-myometrial junction: a fresh look at a busy 601
crossing. Ultrasound Obstet Gynecol 2009;34:1-11. 602
12. Exacoustos C, Luciano D, Corbett B, De Felice G, Di Feliciantonio M, Luciano A, Zupi E. 603
The uterine junctional zone: a 3-dimensional ultrasound study of patients with endometriosis. Am J 604
Obstet Gynecol. 2013; 209: 248-55. 605
13. Exacoustos C, Manganaro L, Zupi E. Imaging for the evaluation of endometriosis and 606
adenomyosis. Best Pract Res Clin Obstet Gynaecol. 2014;28:655-81. 607
14. Bazot M, Thomassin I, Hourani R, Cortez A, Darai E. Diagnostic accuracy of transvaginal 608
sonography for deep pelvic endometriosis. Ultrasound Obstet Gynecol 2004;24:180–18. 609
15. Abrao MS, Goncalves MO, Dias JA Jr, Podgaec S, Chamie LP, Blasbalg R. Comparison 610
between clinical examination, transvaginal sonography and magnetic resonance imaging for the 611
diagnosis of deep endometriosis. Hum Reprod 2007;22:3092–3097. 612
16. Piketty M, Chopin N, Dousset B, Millischer-Bellaische AE, Roseau G, Leconte M, et al. 613
Preoperative work-up for patients with deeply infiltrating endometriosis: transvaginal 614
ultrasonography must definitely be the first-line imaging examination. Hum Reprod 2009;24:602-7. 615
17. Hudelist G, Ballard K, English J, Wright J, Banerjee S, Mastoroudes H, et al. Transvaginal 616
sonography vs. clinical examination in the preoperative diagnosis of deep infiltrating 617
endometriosis. Ultrasound Obstet Gynecol 2011;37:480-7. 618
18. Chapron C, Fauconnier A, Vieira M, et al. Anatomical distribution of deeply infiltrating 619
endometriosis: surgical implications and proposition for a classification. Hum Reprod 2003;18:157-620
61. 621
19. Guerriero S, Ajossa S, Gerada M, Virgilio B, Angioni S, Melis GB. Diagnostic value of 622
transvaginal 'tenderness-guided' ultrasonography for the prediction of location of deep 623
endometriosis. Hum Reprod 2008;23:2452-7. 624
MANUSCRIP
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20. Hudelist G, Tuttlies F, Rauter G, Pucher S, Kekstein J . Can transvaginal sonography predict 625
infiltration depth in patients with deep infiltrating endometriosis of the rectum? Hum Reprod 626
2009;24:1012-7. 627
21. Rossi L, Palazzo L, Yazbeck C, Walker F, Chis C, Luton D, Koskas M. Can rectal 628
endoscopic sonography be used to predict infiltration depth in patients with deep infiltrating 629
endometriosis of the rectum? Ultrasound Obstet Gynecol. 2014;43:322-7. 630
22. Holland TK, Cutner A, Saridogan E, Mavrelos D, Pateman K, Jurkovic D. Ultrasound 631
mapping of pelvic endometriosis: does the location and number of lesions affect the diagnostic 632
accuracy? a multicentre diagnostic accuracy study. BMC Womens Health. 2013;13:43-51. 633
23. Exacoustos C, Malzoni M, Di Giovanni A, Lazzeri L, Tosti C, Petraglia F, Zupi E. 634
Ultrasound mapping system for the surgical management of deep infiltrating endometriosis. Fertil 635
Steril. 2014;102:143-150. 636
24. Hudelist G, Fritzer N, Staettner S, Tammaa A, Tinelli A, Sparic R, Keckstein J. Uterine 637
sliding sign: a simple sonographic predictor for presence of deep infiltrating endometriosis of the 638
rectum. Ultrasound Obstet Gynecol. 2013;41:692-5. 639
25. Reid S, Lu C, Casikar I, Reid G, Abbott J, Cario G, Chou D, Kowalski D, Cooper M, 640
Condous G. Prediction of pouch of Douglas obliteration in women with suspected endometriosis 641
using a new real-time dynamic transvaginal ultrasound technique: the sliding sign. Ultrasound 642
Obstet Gynecol. 2013;41:685-91 643
26. Valenzano Menada M, Remorgida V, Abbamonte LH, Nicoletti A, Ragni N, Ferrero S. Does 644
transvaginal ultrasonography combined with water-contrast in the rectum aid in the diagnosis of 645
rectovaginal endometriosis infiltrating the bowel? Hum Reprod. 2008;23:1069–1075. 646
27. Massein A., et al. Imaging of intestinal involvement in endometriosis. Diagnostic and 647
Interventional Imaging. 2013;94:281-291. 648
MANUSCRIP
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28. Dessole S, Farina M, et al. Sonovaginography is a new technique for assessing rectovaginal 649
endometriosis. Fertility and Sterility. 2003;89:1023-27. 650
29. Saccardi C, Cosmi E, Borghero A, Tregnaghi A, Dessole S, Litta P. Comparison between 651
transvaginal sonography, saline contrast sonovaginography and magnetic resonance imaging in the 652
diagnosis of posterior deep infiltrating endometriosis. Ultrasound in Obsterics and Gynecology. 653
2012;40:464-469. 654
30. Bergamini V, Ghezzi F, Scarperi S, Raffaelli R, Cromi A, Franchi M. Preoperative 655
assessment of intestinal endometriosis: a comparison of transvaginal sonography with water-656
contrast in the rectum, transrectal sonography, and barium enema. Abdominal Imaging. 2010;35: 657
732-736. 658
31. Ferrero S, Biscaldi E, Morotti M, Venturini PL, Remorgida V, Rollandi GA, et al. 659
Multidetector computerized tomography enteroclysis vs. rectal water contrast transvaginal 660
ultrasonography in determining the presence and extent of bowel endometriosis. Ultrasound Obstet 661
Gynecol. 2011;37:603-13. 662
32. A. Maiorana, D. Incandela, L. Giambanco, W. Alio, L. Alio.: Ultrasound diagnosis of pelvic 663
endometriosis. Journal of Endometriosis 2011;3:105-119. 664
33. Bazot M, Lafont C, Rouzier R, Roseau G, Thomassin-Naggara I, Daraï E. Diagnostic 665
accuracy of physical examination, transvaginal sonography,rectal endoscopic sonography, and 666
magnetic resonance imaging to diagnose deep infiltrating endometriosis. Fertility and Sterility. 667
2009;92:1825-33. 668
34. Bazot M, Malzy P, Cortez A, Roseau G, Amouyal P, Daraï E. Accuracy of transvaginal 669
sonography and rectal endoscopic sonography in the diagnosis of deep infiltrating 670
endometriosis.Ultrasound Obstet Gynecol. 2007; 30: 994-1001. 671
MANUSCRIP
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35. Bazot M, Darai E, Hourani R, Thomassin I, Cortez A, Uzan S, Buy JN. Deep pelvic 672
endometriosis: MR imaging for diagnosis and prediction of extension of disease. Radiology. 673
2004;232:379–389. 674
36. Biscaldi E, Ferrero S, Remorgida V, Fulcheri E, Rollandi GA. Rectosigmoid endometriosis 675
with unusual presentation at magnetic resonance imaging. Fertil Steril. 2009;91:278–280. 676
37. Biscaldi E, Ferrero S, Fulcheri E, Ragni N, Remorgida V, Rollandi GA. Multislice CT 677
enteroclysis in the diagnosis of bowel endometriosis. Eur Radiol. 2007;17:211–219. 678
38. Remorgida V, Ragni N, Ferrero S, Anserini P, Torelli P, Fulcheri E. How complete is full 679
thickness disc resection of bowel endometriotic lesions? A prospective surgical and histological 680
study. Hum Reprod. 2005;20:2317-20. 681
39. Ferrero S, Abbamonte LH, Anserini P, Remorgida V, Ragni N. Future perspectives in the 682
medical treatment of endometriosis. Obstet Gynecol Surv. 2005;60:817-26. 683
40. Dousset B1, Leconte M, Borghese B, Millischer AE, Roseau G, Arkwright S, Chapron C. 684
Complete surgery for low rectal endometriosis. Long-term results of a 100-case prospective study. 685
Ann Surg 2010;251:887-95. 686
41. Roman H, Vassilieff M, Gourcerol G, Savoye G, Leroi AM, Marpeau L, Michot F, Tuech 687
JJ. Surgical management of deep infiltrating endometriosis of the rectum: pleading for a symptom-688
guided approach. Hum Reprod. 2011;26:274-81. 689
42. Dunselman GA, Vermeulen N, Becker C, Calhaz-Jorge C, D'Hooghe T, De Bie B, 690
Heikinheimo O, Horne AW, Kiesel L, Nap A, Prentice A, Saridogan E, Soriano D, Nelen W. 691
ESHRE guideline: management of women with endometriosis. Hum Reprod. 2014;29:400-12. 692
43. Dubernard G, Piketty M, Rouzier R, Houry S, Bazot M, Darai E. Quality of life after 693
laparoscopic colorectal resection for endometriosis. Hum Reprod 2006;21:1243-7. 694
MANUSCRIP
T
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29
44. Roman H, Bridoux V, Tuech JJ, Marpeau L, da Costa C, Savoye G, Puscasiu L.Dubernard 695
Hum Reprod 2006; Bowel dysfunction before and after surgery for endometriosis. Am J Obstet 696
Gynecol. 2013;209:524-30. 697
45. De Cicco C, Corona R, Schonman R, Mailova K, Ussia A, Koninckx P. Bowel resection for 698
deep endometriosis: a systematic review. BJOG. 2011;118:285-91. 699
46. Fanfani F, Fagotti A, Gagliardi ML, Ruffo G, Ceccaroni M, Scambia G, Minelli L. Discoid 700
or segmental rectosigmoid resection for deep infiltrating endometriosis: a case-control study. Fertil 701
Steril. 2010;94:444-9. 702
47. Kondo W, Branco AW, Trippia CH, Ribeiro R, Zomer MT. Retrocervical deep infiltrating 703
endometriotic lesions larger than thirty millimeters are associated with an increased rate of ureteral 704
involvement. J Minim Invasive Gynecol. 2013;20:100-3. 705
48. Bianchi, P.H., Pereira, R.M., Zanatta, A., Alegretti, J.R., Motta, E.L., Serafini, P.C.,. 706
Extensive excision of deep infiltrative endometriosis before in vitro fertilization significantly 707
improves pregnancy rates. J. Minim. Invasive Gynecol. 2009;16:174-80. 708
49. Darai, E., Lesieur, B., Dubernard, G., Rouzier, R., Bazot, M., Ballester, M., 2011. Fertility 709
after colorectal resection for endometriosis: results of a prospective study comparing laparoscopy 710
with open surgery. Fertil. Steril. 2011;95:1903–1908. 711
50. Meuleman C, Tomassetti C, D'Hoore A, Van Cleynenbreugel B, Penninckx F, Vergote I, 712
D'Hooghe T. Surgical treatment of deeply infiltrating endometriosis with colorectal involvement. 713
Hum Reprod Update. 2011;17:311-26. 714
51. Vercellini P, Barbara G, Buggio L, Frattaruolo MP, Somigliana E, Fedele L. Effect of 715
patient selection on estimate of reproductive success after surgery for rectovaginal endometriosis: 716
literature review. Reprod Biomed Online. 2012;24:389-95. 717
MANUSCRIP
T
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ACCEPTED MANUSCRIPT
30
52. Vercellini P, Consonni D, Barbara G, Buggio L, Frattaruolo MP, Somigliana E. 718
Adenomyosis and reproductive performance after surgery for rectovaginal and colorectal 719
endometriosis: a systematic review and meta-analysis. Reprod Biomed Online. 2014 ;28:704-13. 720
53. Sun W, Stegmann BJ, Henne M, Catherino WH, Segars JH. A new approach to ovarian 721
reserve testing. Fertil Steril. 2008;90:2196-202. 722
54. Stepniewska A, Pomini P, Bruni F, Mereu L, Ruffo G, Ceccaroni M, et al. Laparoscopic 723
treatment of bowel endometriosis in infertile women. Hum Reprod. 2009;24:1619-25. 724
55. Ballester, M., d’Argent, E.M., Morcel, K., Belaisch-Allart, J., Nisolle, M., Daraı¨, E., 2012. 725
Cumulative pregnancy rate after ICSI-IVF in patients with colorectal endometriosis: results of a 726
multicentre study. Hum. Reprod. 2012;27:1043-9. 727
56. Wattiez A, Puga M, Albornoz J, Faller E. Surgical strategy in endometriosis. Best Pract Res 728
Clin Obstet Gynaecol. 2013;27:381-92. 729
57. Bassi MA, Podgaec S, Dias JA, Jr, D’Amico Filho N, Petta CA, Abrao MS. Quality of Life 730
after Segmental Resection of the Rectosigmoid by Laparoscopy in Patients with Deep Infiltrating 731
Endometriosis with Bowel Involvement. J of Minim Inv Gyn 2011;18:730–733. 732
58. Ballester M, Chereau E, Dubernard G, Coutant C, Bazot M, Darai E. Urinary dysfunction 733
after colorectal resection for endometriosis: results of a prospective randomized trial comparing 734
laparoscopy to open surgery. Am J Obstet Gynecol 2011;204:303.e1-6. 735
59. Roman H Rectal shaving using PlasmaJet in deep endometriosis of the rectum. Fertil Steril. 736
2013;100:e33. doi: 10.1016/j.fertnstert.2013.07.1973. Epub 2013 Aug 7 737
60. Mohr C, Nezhat FR, Nezhat CH, Seidman DS, Nezhat CR. Fertility Considerations in 738
Laparoscopic Treatment of Infiltrative Bowel Endometriosis. JSLS. 2005;9:16–24. 739
61. Donnez J, Squifflet J. Complications, pregnancy and recurrence in a prospective series of 740
500 patients operated on by the shaving technique for deep rectovaginal endometriotic nodules. 741
Hum Reprod 2010;25:1949–1958. 742
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
31
62. Vercellini P, Crosignani PG, Abbiati A, Somigliana E, Viganò P, Fedele L. The effect of 743
surgery for symptomatic endometriosis: the other side of the story. Hum Reprod Update 744
2009;15:177–188. 745
63. Berlanda N, Vercellini P, Somigliana E, Frattaruolo MP, Buggio L, Gattei U. Role of 746
surgery in endometriosis-associated subfertility. Semin Reprod Med. 2013;31:133-43. 747
64. Stratton P, Berkley KJ. Chronic pelvic pain and endometriosis: translational evidence of the 748
relationship and implications. Hum Reprod Update. 2011;17:327–46. 749
65. Busacca M, Chiaffarino F, Candiani M, Vignali M, Bertulessi C, Oggioni G, Parazzini F. 750
Determinants of long-term clinically detected recurrence rates of deep, ovarian, and pelvic 751
endometriosis. Am J Obstet Gynecol. 2006;195:426-32. 752
66. Somigliana E, Vercellini P, Vigano P, Benaglia L, Busnelli A, Fedele L. Postoperative 753
Medical Therapy After Surgical Treatment of Endometriosis: From Adjuvant Therapy to Tertiary 754
Prevention. JMIG. 2014;21:328-34. 755
67. Seracchioli R, Mabrouk M, Manuzzi L, et al. Post-operative use of oral contraceptive pills 756
for prevention of anatomical relapse or symptom- recurrence after conservative surgery for 757
endometriosis. Hum Reprod. 2009;24:2729–35. 758
68. Wu L, Wu Q, Liu L. Oral contraceptive pills for endometriosis after conservative surgery: a 759
systematic review and meta-analysis. Gynecol Endocrinol. 2013;29:883–90. 760
69. Vercellini P, Viganò P, Somigliana E, Fedele L. Endometriosis: pathogenesis and treatment. 761
Nat Rev Endocrinol. 2014;10:261-75. 762
70. Vercellini P, Pietropaolo G, De Giorgi O, et al. Treatment of symptomatic rectovaginal 763
endometriosis with an estrogen-progestogen combination versus low-dose norethindrone acetate. 764
Fertil Steril. 2005;84:1375. 765
71. Fedele L, Bianchi S, Zanconato G, et al. Use of a levonorgestrel-releasing intrauterine 766
device in the treatment of rectovaginal endometriosis. Fertil Steril. 2001;75:485. 767
MANUSCRIP
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32
72. Razzi S, Luisi S, Calonaci F, et al. Efficacy of vaginal danazol treatment in women with 768
recurrent deeply infiltrating endometriosis. Fertil Steril. 2007;88:789. 769
73. Fedele L, Bianchi S, Zanconato G, et al. Gonadotropin-releasing hormone agonist treatment 770
for endometriosis of the rectovaginal septum. Am J Obstet Gynecol. 2000;183:1462. 771
74. Ferrero S, Leone Roberti Maggiore U, Scala C, Di Luca M, Venturini P, Remorgida V. 772
Changes in the size of rectovaginal endometriotic nodules infiltrating the rectum during hormonal 773
therapies. Arch Gynecol Obstet. 2013,287:447–53. 774
75. Ferrero S, Camerini G, Ragni N, et al. Norethisterone acetate in the treatment of colorectal 775
endometriosis: a pilot study. Hum Reprod. 2010;25:94. 776
76. Vercellini P, Frontino G, De Giorgi O, Pietropaolo G, Pasin R, Crosignani PG. Continuous 777
use of an oral contraceptive for endometriosis-associated recurrent dysmenorrhea that does not 778
respond to a cyclic pill regimen. Fertil Steril. 2003;80:560-3. 779
77. Ferrero S, Camerini G, Seracchioli R, et al. Letrozole combined with norethisterone acetate 780
compared with norethisterone acetate alone in the treatment of pain symptoms caused by 781
endometriosis. Hum Reprod. 2009;24:3033. 782
78. Vercellini P, Barbara G, Somigliana E, et al. Comparison of contraceptive ring and patch for 783
the treatment of symptomatic endometriosis. Fertil Steril 2010; 93:2150. 784
79. Leone Roberti Maggiore U, Remorgida V, Scala C, Tafi E, Venturini PL, Ferrero S. 785
Desogestrel-only contraceptive pill versus sequential contraceptive vaginal ring in the treatment of 786
rectovaginal endometriosis infiltrating the rectum: a prospective open-label comparative study. Acta 787
Obstet Gynecol Scand. 2014;93:239-47. 788
80. Ferrero S, Camerini G, Ragni N, Menada MV, Venturini PL, Remorgida V. Triptorelin 789
improves intestinal symptoms among patients with colorectal endometriosis. Int J Gynaecol Obstet. 790
2010;108:250-1. 791
MANUSCRIP
T
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33
81. Gentilini D, Perino A, Viganò P, Chiodo I, Cucinella G, Vignali M, Di Blasio AM, Busacca 792
M. Gene expression profiling of peripheral blood mononuclear cells in endometriosis identifies 793
genes altered in non-gynaecologic chronic inflammatory diseases. Hum Reprod. 2011;26:3109-17. 794
82. Somigliana E, Vigano P, Benaglia L, Busnelli A, Vercellini P, Fedele L. Adhesion 795
prevention in endometriosis: a neglected critical challenge. J Minim Invasive Gynecol. 796
2012;19:415-21. 797
83. Viganò P, Somigliana E, Panina P, Rabellotti E, Vercellini P, Candiani M. Principles of 798
phenomics in endometriosis. Hum Reprod Update. 2012;18:248-59. 799
84. Lessey BA1, Lebovic DI, Taylor RN. Eutopic endometrium in women with endometriosis: 800
ground zero for the study of implantation defects. Semin Reprod Med. 2013;31:109-24. 801
85. Ballester M, Oppenheimer A, Mathieu d'Argent E, Touboul C, Antoine JM, Nisolle M, 802
Daraï E. Deep infiltrating endometriosis is a determinant factor of cumulative pregnancy rate after 803
intracytoplasmic sperm injection/in vitro fertilization cycles in patients with endometriosis. Fertil 804
Steril. 2012;97:367-72. 805
86. Ballester M, d'Argent EM, Morcel K, Belaisch-Allart J, Nisolle M, Daraï E. Cumulative 806
pregnancy rate after ICSI-IVF in patients with colorectal endometriosis: results of a multicentre 807
study. Hum Reprod. 2012;27:1043-9. 808
87. Vercellini P, Pietropaolo G, De Giorgi O, Daguati R, Pasin R, Crosignani PG. Reproductive 809
performance in infertile women with rectovaginal endometriosis: Is surgery worthwhile? Am J 810
Obstet Gynecol. 2006;195,1303-10. 811
88. Tsaltas J. Surgical Therapies: rectal/bowel endometriosis. in Endometriosis science and 812
practice (eds Giudice LC, Johannes LH & Healy DL) 19–26 (Wiley-Blackwell Publishing, 2012). 813
89. Brosens IA, Fusi L, Brosens JJ. Endometriosis is a risk factor for spontaneous 814
hemoperitoneum during pregnancy. Fertil Steril. 2009;92:1243–5. 815
MANUSCRIP
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34
90. O'Leary SM. Ectopic decidualization causing massive postpartum intraperitoneal 816
hemorrhage. Obstet Gynecol. 2006;108:776–9. 817
91. Setubal A, Sidiropoulou, Z, Torgal M, Casal E, Lourenc o,C, Koninckx P. Bowel 818
complications of deep endometriosis during pregnancy or in vitro fertilization. Fertil Steril, 2014; 819
101:442-6. 820
92. Bashir RM, Montgomery EA, Gupta PK, et al. Massive gastrointestinal hemorrhage during 821
pregnancy caused by ectopic decidua of the terminal ileum and colon. Am J Gastroenterol. 822
1995;90:1325–7. 823
93. Stephansson O, Kieler H, Granath F, Falconer H. Endometriosis, assisted reproduction 824
technology, and risk of adverse pregnancy outcome. HumReprod. 2009;24:2341–7. 825
94. Healy DL, Breheny S, Halliday J, et al. Prevalence and risk factors for obstetric 826
haemorrhage in 6730 singleton births after assisted reproductive technology in Victoria Australia. 827
Hum Reprod. 2010;25:265–74. 828
95. Hadfield RM, Lain SJ, Raynes-Greenow CH, Morris JM, Roberts CL. Is there an association 829
between endometriosis and the risk of pre-eclampsia? A population based study. Hum Reprod. 830
2009;24:2348–52. 831
96. Naples JD, Batt RE, Sadigh H. Spontaneous abortion rate in patients with endometriosis. 832
Obstet Gynecol. 1981;57:509–12. 833
97. Jacobson TZ, Duffy JM, Barlow D, Farquhar C, Koninckx PR, Olive D. Laparoscopic 834
surgery for subfertility associated with endometriosis. Cochrane Database Syst Rev 835
2010:CD001398. 836
837
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