Three types of endometriosis have been described: peritoneal endometriosis, ovarian endometriosis (known as endometrioma) and deep infiltrating endometriosis (DIE) (
Despite the limits of the ASRM classification, two
randomized studies (
The aims of this study were therefore to evaluate the impact on pregnancy rate of endometrioma associated with DIE after a first ICSI-IVF cycle and to evaluate determinant factors to establish a pragmatic approach.
We retrospectively identified 104 women with endometrioma who had undergone ICSI-IVF treatment
after at least 1 year of infertility in the Department of
Gynecology-Obstetrics at Tenon hospital (France)
from January 2007 to June 2010. The investigation
of fertility included a hormonal blood test in the third
day of the cycle [serum level measurements of estradiol (E2), follicle stimulating hormone (FSH), inhibin
B and anti-mullerian hormone (AMH)], a hysterosalpingography, transvaginal sonography and semen
analysis for the partner. The diagnosis of endometriosis was made with physical examination, transvaginal
sonography and magnetic resonance imaging (MRI)
using previously published imaging criteria (
The patients were divided into two groups; the endometrioma group (37 women) consisting of patients with proved endometrioma without DIE and the endometrioma-DIE group (67 women) consisting of patients with endometrioma and DIE.
Three different forms of down regulation were used:
a long gonadotropin-releasing hormone (GnRH) agonist, a short agonist or an antagonist protocol. Ovarian
stimulation was done with doses of recombinant FSH
between 75 and 450 IU/d depending on patient age,
body mass index (BMI), antral follicle count (AFC),
AMH, size and number of follicles, and E2 levels.
This stimulation was begun once pituitary desensitization (E2 level <50 pg/mL) had been achieved.
Transvaginal oocyte retrieval was scheduled 35-36
hours after hCG injection and embryo transfer (ET)
was performed 2-3 days later. On day 2, individually
cultured embryos were evaluated on the basis of the
number of blastomeres, blastomere size, fragmentation rate and presence of multinucleated blastomeres
For embryo transfer, a soft catheter was used which is inserted through the cervical canal into the uterine cavity. Ultrasound guidance and anesthesia was not required.
Univariate analysis was performed using Student’s t test or Wilcoxon test for continuous variables and Chi-square test or Fisher’s exact test for qualitative variables. We tested epidemiological, biological and radiological characteristics in a multivariate analysis for association with pregnancy rate. A p value of less than 0.05 was considered significant.
Recursive partitioning (RP) was used to determine cut-offs for each variable predicting an improvement in pregnancy rate. RP is a technique which can be applied to examine large datasets to uncover hidden patterns within the data and to elucidate statistically significant sub-groupings within the data. RP is non-parametric in nature, imposing no a priori restrictions on the distributional forms of the predictor variables. The central result is a simple and intuitive RP algorithm. At each step, the RP program determines for each variable cut-points that optimally separate patients into homogeneous groups. A multiple logistic regression (MLR) was performed; including all variables that were correlated to the conception rate. Only independent factors of pregnancy rate were included in a RP model. All analyses were performed using the R package with the Verification, Design, Hmisc, DiagnosisMed, ROCR and Presence Absence libraries.
All the patients gave informed consent to participate in the study. The protocol was approved by the Ethics Committee of the Collège National des Gynécologues et Obstétriciens Français (CNGOF).
One hundred and four women with endometrioma and proved infertility who had undergone ICSI-IVF cycles were included with only the first cycles being analyzed. The epidemiological characteristics of the whole population are summarized in table 1. The median age of the population study was 32 years and the median BMI was 22.4 kg/m2. The median duration of infertility was 3 years.
Epidemiological characteristics of the 104 patients with endometrioma with or without DIE
|Characteristics||Patients Number n=104|
Endometriomas were unilateral and associated with DIE in 55.7 and 64.4% of cases respectively. The median number of endometriomas was two and the median size of the largest endometrioma was 33 mm. The proportion of patients with a major endometrioma measuring less than 3 cm, between 3-5 cm and more than 5 cm was 36.5, 51 and 12.5% respectively. Before the ICSI-IVF cycle, AMH serum levels were 4 ng/ml in women with an endometrioma diameter size lower than 3 cm or between 3-5 cm and 3 ng/ml in those with an endometrioma diameter size over 5 cm. No difference in AMH serum levels according to endometrioma sizes was observed. AMH serum levels in patients with or without prior surgery for endometrioma were 2.7 ng/ml and 3.9 ng/ml respectively (p=0.2) and in those with or without prior surgery for DIE were 2.9 and 3 ng/ml respectively (p=0.9).
The epidemiological characteristics of patients with endometrioma with or without DIE are summarized in table 2. No difference in the median age, smoking, duration of infertility or rate of associated tubal and male infertility was found. BMI was higher in the group of patients with endometrioma and DIE (p=0.01). AMH serum levels in patients with endometrioma with or without DIE were 3.2 and 3.4 ng/ml respectively. No difference in AMH serum levels was found between the groups.
Comparison of epidemiological characteristics of patients with endometrioma with or without DIE
|Patients with endometrioma and DIE n=67||Patients with endometrioma without DIE n=37||P value|
|32 (24-42)||33 (24-41)||0.2|
|23.12 (17.2-35.4)||21.3 (17.9-29.9)||0.01|
|12 (17.9%)||8 (21.6%)||0.84|
|3 (1-9)||4 (1-7)||0.25|
|40 (59.7%)||16 (43.2%)||0.16|
|28 (41.8%)||15 (40.5%)||0.93|
|7 (10.5%)||15 (40.5%)||0.0008|
The pre ICSI-IVF biological characteristics and responses to hormonal ovarian stimulation of the patients with endometrioma with or without DIE are summarized in table 3. No differences in the AMH, inhibin B, E2, AFC, number of ICSI or IVF procedures, types of ovarian stimulation, total dose of gonadotrophin used, number of mature follicles >14 mm, total number of oocytes retrieved, total number of day-2 fresh embryos, number of top day-2 fresh embryos, thickness of endometrium, number of top day-2 embryos transferred and number of embryos cryopreserved were found between the groups. An association between the requirement for ICSI and male infertility was observed (p<0.0001).
Comparison of epidemiological characteristics of patients who conceived and those who did not is given in table 4. Using univariable analysis, the number of patients who conceived was lower in the group of patients with endometrioma and DIE (in the group of patients with endometrioma and DIE: patients who conceived n=22 (51.1%) vs. patients who did not conceive n=45 (73.8%); p=0.03).
Biological characteristics and responses to ovarian stimulation of patients with endometriomas with or without DIE
|Patients with endometrioma and DIE n=67||Patients with endometrioma without DIE n=37||P value|
|2.8 (0.2-12.4)||2.5 (0.5-14.2)||0.6|
|56 (15-125)||49 (15-278)||0.9|
|1765 (295-5460)||1802 (520-4185)||0.5|
|12 (2-60)||12 (2-28)||0.2|
|2400 (1100-7650)||2250 (1350-7200)||0.76|
|8 (1-21)||7 (2-16)||0.65|
|8 (1-26)||8 (2-19)||0.24|
|4 (0-16)||5 (0-14)||0.29|
|1 (0-8)||1 (0-4)||0.48|
|10 (5-27)||10 (7-16)||0.74|
|1 (0-2)||1 (0-2)||0.93|
|1 (0-12)||1 (0-10)||0.97|
Characteristics of patients who conceived and who did not conceive
|Patients with endometrioma and DIE n=43||Patients with endometrioma without DIE n=61||P value|
|32 (26-39)||33 (24-42)||0.4|
|11 (25.6%)||9 (14.8%)||0.26|
|22.1 (17.9-31.1)||22.6 (17.2-35.4)||0.85|
|3 (1-9)||3 (1-8)||0.25|
|11 (26%)||11 (18%)||0.49|
|24 (55.8%)||32 (52.4%)||0.89|
|13 (30.2%)||30 (49.1%)||0.08|
|ICSI||10 (23.2%)||26 (42.6%)|
|IVF||33 (76.8%)||35 (57.4%)|
|19 (44%)||39 (64%)||0.07|
|24 (56%)||22 (36%)|
|34.5 (10-90)||33 (10-100)||0.84|
|22 (51.1%)||45 (73.8%)||0.03|
|31 (72%)||41 (67%)||0.75|
|36 (92.3%)||45 (76.3%)||0.07|
Multivariable analysis identified three independent factors of pregnancy rate. A lower
rate was associated with the presence of DIE
(OR=0.24, 95% CI: 0.085-0.7, p=0.009) and
the use of ICSI (OR=0.23, 95% CI: 0.07-0.8,
p=0.02) and higher rate with an AMH serum
level above 1 ng/ml (OR=4.3, 95% CI: 1.1-
19, p=0.049). After RP, the presence of DIE
emerged as the most likely determinant factor
of pregnancy (
Recursive partitioning model to predict pregnancy rate.
Calibration of the model with an ROC AUC.
This study demonstrates that the presence of DIE in patients with endometrioma requiring an ICSI-IVF for infertility has a negative impact on pregnancy rate.
Indications to treat endometrioma before
ICSI-IVF in infertile patients have been the
source of controversy. A recent meta-analysis including four trials (
Using multivariable analysis, the present study has demonstrated that endometrioma associated
DIE, AMH serum levels and the type of ART (IVF
or ICSI) were independent prognostic factors of
pregnancy. In a study comparing conservative surgery for rectovaginal endometriosis with expectant management, Vercellini et al. (3) reported a
12-month and a 24-month cumulative probability
of conception of 20.5 and 44.9% respectively in the
former group and 34.7 and 46.8% respectively in
the latter (not significant) suggesting that excision
of rectovaginal endometriosis does not improve
the likelihood of pregnancy nor reduce time-toconception. In a review of the literature, these
authors concluded that the purported benefit of
excision of rectovaginal endometriosis in infertile patients reported by several authors may be
attributed to treatment of co-existing peritoneal
and ovarian endometriosis (
A few studies have focused on patient and
endometriosis characteristics that may be useful to evaluate the individual probability of
pregnancy in infertile patients. Younis et al.
Some limitations of the present study have to be underlined. First, the retrospective nature of this study cannot exclude all potential biases. Secondly, the true impact of DIE in patients with infertility associated with endometrioma can only be truly assessed by a prospective trial comparing fertility results of ART in patients with DIE compared to those after removal of DIE. Third, the higher BMI in patients with endometrioma and DIE in our study constitutes a compounding factor. However, the number of obese patients (BMI >30 kg/m²) was low (2.6%) and no difference in response to hormonal ovarian stimulation was observed among the groups. Fourth, we used only the data from the first ICSI-IVF cycle of each patient to develop the model which means that the cumulative pregnancy rate after several cycles could not be evaluated. Finally, further external validation studies are required before the use of the presented model in clinical practice.
The data in this study support that DIE associated with endometrioma in infertile patients has a negative impact on the pregnancy rate in first cycle ICSI-IVF. Moreover, the resultant predictive model of pregnancy rate could provide better prediction for couples about the chances of conceiving, thereby contributing to a comprehensive strategy of infertility management.