Pain and ovarian endometrioma recurrence after laparoscopic treatment of endometriosis: a long-term prospective study

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Pain and ovarian endometrioma recurrence after

laparoscopic treatment of endometriosis: a long-term prospective study

Maria Grazia Porpora, M.D., Debora Pallante, M.D., Annamaria Ferro, M.D., Brenda Crisafi, M.D., Filippo Bellati, M.D., Ph.D., and Pierluigi Benedetti Panici, M.D.

Department of Gynecology and Obstetrics, University of Rome ‘‘Sapienza,’’ Rome, Italy

Objective: To identify prognostic factors for pain and endometrioma recurrence after complete laparoscopic excision of endometrioma(s).

Design: Prospective observational study.

Setting: Tertiary care university hospital.

Patient(s): One-hundred sixty-six consecutive women affected by uni- or bilateral ovarian endometrioma(s).

Intervention(s): Laparoscopic conservative treatment of endometriosis.

Main Outcome Measure(s): Patient demographic characteristics, surgical findings, and surgical results were pro- spectively recorded. Postoperative follow-ups were carried out every 3 months to identify pain and/or endometrioma recurrence for a minimum of 3 years.

Result(s): Dysmenorrheal, dyspareunia, and chronic pelvic pain recurred in 14.5%, 6%, and 5.4% of women, respectively. Prior surgery for endometriosis, adhesion extension, and use of ovarian stimulation drugs (OSD) were unfavorable prognostic factors for pain symptoms. Ovarian endometrioma recurred in 9.6% of cases; negative factors were prior surgery for endometriosis, OSD, pelvic adhesions, and high American Society for Reproductive Medicine disease scores. Postoperative pregnancy showed a significant protective effect on pain and disease recurrences.

Conclusion(s): Prior surgery, presence of adhesions, and ovulation drugs are negative prognostic factors. Preg- nancy has a protective effect on disease and pain recurrence. (Fertil Steril^Ò2010;93:716–21. Ó2010 by American Society for Reproductive Medicine.)

Key Words: Endometrioma recurrence, endometriosis, laparoscopy, pelvic pain, risk factors

Endometriosis affects approximately 5%–12% of women in their reproductive years(1, 2). In infertile women, the prevalence may rise to 50% (3). Laparoscopy is an effective technique for the treatment of endometriosis and related symptoms, and most authors agree that it should be considered to be the gold standard(4–7).

Endometrioma recurrence affects between 8% and 32%

of women (8–13), and pain recurs in 10%–40% of cases (8, 10, 13, 14). Risk factors for endometriomas and pain recurrence are continuously under evaluation to help physi- cians improve preoperative and postoperative treatment.

Only a few prospective studies have attempted to identify the factors responsible for disease and pain recurrence.

The objective of the present study was to identify prognostic factors for both pain and ovarian endometrioma recurrence.

MATERIALS AND METHODS

Between May 1998 and June 2004, 219 patients undergoing laparoscopy for adnexal mass with the presumed diagnosis of ovarian endometriomas were enrolled in this prospective observational longitudinal study. The protocol of this study was approved by the local ethics committee. Fifty-three patients with associated gynecologic and nongynecological pa- thologies requiring additional surgical treatment (i.e., hysterectomy, oophorectomy, etc.) or in whom laparoscopic findings and pathologic analyses did not confirm endometriosis were excluded from the present analysis. One hundred sixty-six women met all of the selection criteria. Informed consent to the study and follow-up was obtained, and patients were preoperatively subjected to a detailed medical and gynecologic history and pelvic examination. Two consecutive abdominal and vaginal ultrasounds, at three menstrual cycles from each other, were performed before carrying out surgery.

Dysmenorrhea, deep dyspareunia, and chronic pelvic pain (CPP), defined as noncyclic pelvic pain, were evaluated by a visual analog scale (VAS) with zero representing no pain and 10 representing the worst imaginable pain (15–17).

Intensity of symptoms were classified as none (0), mild (1–4), moderate (5–7), or severe (8–10). Blood chemistries were routinely carried out before surgery. Surgical proce- dures were performed in the Department of Gynecology

Received July 29, 2008; revised October 6, 2008; accepted October 9, 2008; published online December 4, 2008.

M.G.P. has nothing to disclose. D.P. has nothing to disclose. A.F. has nothing to disclose. B.C. has nothing to disclose. F.B. has nothing to disclose. P.B. has nothing to disclose.

Reprint requests: Maria Grazia Porpora, M.D., Department of Gynecology and Obstetrics, University of Rome ‘‘Sapienza,’’ Viale Regina Elena, 324–00161—Roma, Italy (FAX: þ39 06 4450368; E-mail:mgporpor@

tin.it).

Fertility and Sterility^âVol. 93, No. 3, February 2010 0015-0282/10/$36.00

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and Obstetrics of the University of Rome ‘‘Sapienza’’ by the same senior surgeon (M.G.P.).

During surgery, the presence, localization, and extent of typical powder-burn and subtle lesions, adhesions, and deep infiltrating implants were recorded. Disease was classified according to the revised American Society for Reproductive Medicine (rASRM) score(18). After adhesiolysis, all lesions were treated as follows: complete removal of ovarian endometriomas by stripping, excision of deep endometriosis, and coagulation of peritoneal implants with bipolar forceps.

Specimens underwent thorough histologic analysis. Clinical and ultrasound examinations, pain, and occurrence of pregnancy were assessed at 3-month intervals for 3 years and, in the absence of new symptoms, once yearly thereafter. Fol- low-up was closed in June 2007.

Pain recurrence was defined on the basis of a postoperative VAS pain score of R5 in women with preoperative pain symptoms. The recurrence of ovarian endometrioma was defined as the presence of a cyst with a typical aspect, as detected by transvaginal ultrasonography, characterized by a round, homogeneous, hypoechoic, low-level echo cyst or with thin internal heterogeneous trabeculation, with or without internal septa, no or poor vascularization of capsule, and septa(19). When the cyst was indistinguishable from a tran- sient corpus luteum cyst or hemorrhagic cyst, the diagnosis of recurrence was made only when the cyst persisted after suc- cessive menstrual cycles.

Patient characteristics are reported inTable 1. Briefly, all women were in their fertile years and most complained of pain. Primary infertility was recorded in 17 women; approximately one-third of the patients suffered from deep endometriosis and/or bilateral ovarian cysts. Sixteen women had undergone previous surgery for endometriosis.

Statistical Analysis

Parametric tests were carried out after having examined the normal distribution of the data to be analyzed. Intensity of symptoms were classified as none (0), mild (1–4), moderate (5–7), or severe (8–10). When assessing the intensity of symptoms, these were combined as none/mild and moder- ate/severe. The Student t test was used for continuous para-

metric variables. Fisher exact test and the chi-squared test were used for categoric variables. Statistical significance was set at P<.05. Relative risks and 95% confidence interval (CI) were calculated for the studied variables.

RESULTS

Before surgery, one-hundred twenty-seven women (76.5%) had at least one pain symptom R5. Dysmenorrhea was absent in 22.3% of cases (37 women), mild in 7.3% (12 women), moderate in 24.1% (40 women), and severe in 46.4% (77 women); deep dyspareunia was absent in 57.2%

of cases (95 women), mild in 4.2% (7 women), moderate in 15.6% (26 women), and severe in 22.8 % (38 women); CPP was absent in 47.6% (79 women), mild in 5.4% (9 women), moderate in 21.6% (36 women), and severe in 25.3% (42 women). Abdominal and vaginal ultrasound revealed the presence of ovarian endometriomas in all cases (218 cysts, bilateral, in 52 women).

At laparoscopy, ovarian cystic endometriosis was confirmed in all women, with mean size 4.89 2.4 cm (range 1–15 cm). Bilateral ovarian endometriomas were present in 52 cases, peritoneal lesions in 110, deep lesions in 57, and adnexal adhesions in 141; 37 patients had partial and 18 total cul-de-sac obliteration (Table 2). According to the rASRM

TABLE 1

Patient characteristics.

Factor No. of cases (%)

Age, yrs (mean SD) 31.5 6.46

Infertility 17 (10.2)

Pain 127 (76.5)

Previous surgery

for ovarian endometrioma

16 (9.6)

Pregnancy desire 52 (31.3)

Porpora. Pain and ovarian endometrioma recurrence. Fertil Steril 2010.

TABLE 2

Laparoscopic findings.

No. of cases (%) Ovarian endometriomas

Overall 218

Bilateral 52 (31.3)

Mean size SD (cm) 4.9 2.4 Peritoneal lesions

Overall 110 (66.3)

Typical 61 (55.4)

Atypical 17 (15.4)

Both 32 (29.2)

Deep endometriosis (uterosacral ligaments)

57 (34.3) Adnexal adhesions

Absent 25 (15.0)

1/3 47 (28.3)

2/3 44 (26.6)

3/3 50 (30.1)

Cul de sac obliteration

Absent 111 (66.8)

Partial 37 (22.4)

Complete 18 (10.8)

Stage

I 0

II 0

III 94 (56.6)

IV 72 (43.4)

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classification, 94 women had stage III (56.6%) and 72 stage IV (43.4%) disease. All endometriomas were completely ex- cised by stripping, deep lesions removed, adhesions lysed, and peritoneal lesions coagulated with bipolar forceps. Postoper- ative therapy was chosen on the basis of individual characteristics and after careful counseling with the patient as follows:

no therapy for 103 women (62.6%); oral contraceptives (OC;

desogestrel 0.15 mg/ethinyl estradiol 0.02 mg for at least 1 year) for 18 women (28.6%); GnRH analogue (GnRHa; trip- torelin 3.75 mg once a month for 3 months) for 30 women (47.6%); and GnRHa followed by OC for 15 women (23.8%).

Eight women desiring pregnancy, who had bilateral tubal occlusion or where there was a problem of male infertility, underwent assisted reproductive techniques (IVF) and received recombinant FSH for ovarian stimulation; none of them achieved a pregnancy.

After a minimum of 3 years of follow-up, 140 women (84.3%) had no dysmenorrhea, 7 women had mild symptoms (4.2%), 11 women (6.6%) had moderate pain, and 8 women (4.8%) suffered from severe dysmenorrhea. Dyspareunia was absent in 160 women (96.4%), mild in 3 (4.2%), moderate in 2 (1.2 %), and severe in 1 (0.6 %). Chronic pelvic pain was absent in 161 women (97%), mild in 3 (3.4%), moderate in 1 (0.6 %), and severe in 1 (0.6%) (Table 3).

The use of ovulation induction drugs was an unfavorable factor for recurrence of dysmenorrhea (relative risk [RR] 4; 95%

CI 1.4–10.9; P<.001) and CPP (RR 9.9; 95% CI 1–97; P<.05). Adnexal adhesions score at laparoscopy was as- sociated with recurrence of CPP (RR 2.6; 95% CI 0.4–18.7;

P¼.025). Prior surgery for endometriosis was a risk factor of dyspareunia recurrence (RR 3.7; 95% CI 0.8–17.7; P¼.003), CPP (RR 4.7; 95% CI 0.5–48.8; P¼.02), and dysmenorrhoea recurrence (RR 2.7, 95% CI 1–7.1; P¼.04). No significant as- sociation was found between postoperative pain and the pa-

tient’s age, number and size of ovarian endometriomas, presence of deep endometriosis, and disease stage (Table 4).

Recurrences of ovarian endometriomas were diagnosed by ultrasounds in 15 cases (9.6%): six (40%) on the same ovary, three (20%) on the opposite ovary, and six (40%) on both ova- ries. In three cases, the recurrence occurred within the first year, in six at the 2-year follow-up, in two within 5 years, and in four 5 years after surgery. In three cases it was associated with pain recurrence. Ten patients (62.5%) underwent a reoperation which confirmed the endometriotic nature of the lesions. Six women (40%) had been subjected to prior surgery for endometriosis, which was found to be a negative prognostic factor (RR 6.25; 95% CI 2.5–15.3; P<.001). A significant association was also found between endometriomas recurring and the presence and the score of adnexal ad- hesions (P<.001) and the adhesions in the cul-de-sac (RR 3.02; 95% CI 1.13–8.01; P¼.025). In particular, no recur- rences occurred in women without any adnexal adhesion.

Administration of ovulation induction drugs (RR 4.9; 95%

CI 1.7–14.03; P¼.004) and high disease score (P¼.014) at rASRM classification were also associated with recurrence.

The number, size, and site of endometriomas and the presence, type, and extent of peritoneal lesions did not seem to affect ovarian endometrioma recurrence (Table 4).

Regarding the role of postoperative medical treatment, there were recurrences in five women who did not receive any treatment, in two who received only OC, in six who took GnRHa alone, and in two who took GnRHa followed by OC. No recurrences occurred during the administration of low-dose cyclic OC; neither was its use associated with a significant increased risk after treatment ended. The use of GnRHa did not seem to influence the endometrioma recurrence rate.

Out of 52 women who desired to become pregnant, 28 obtained a spontaneous pregnancy within 2 years. These women

TABLE 3

Pain symptoms before and after treatment.

Symptom Before laparoscopy,% (n) >3 yrs follow-up,% (n)

No dysmenorrhea 22.3 (37) 84.3 (140)

Mild dysmenorrhea 9.3 (12) 5.4 (7)

Moderate dysmenorrhea 31 (40) 8.5 (11)

Severe dysmenorrhea 59.7 (77) 6.2 (8)

No CPP 47.6 (79) 97 (161)

Mild CPP 10.3 (9) 3.4 (3)

Moderate CPP 41.4 (36) 1.1 (1)

Severe CPP 48.3 (42) 1.1 (1)

No dyspareunia 57.2 (95) 96.4 (160)

Mild dyspareunia 9.8 (7) 4.2 (3)

Moderate dyspareunia 36.6 (26) 2.8 (2)

Severe dyspareunia 53.5 (38) 1.4 (1)

Note:CPP ¼ chronic pelvic pain.

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had partners with no male infertility factors, had at least one patent fallopian tube, and were significantly younger than those undergoing IVF (mean age 30.4 4.5 years vs. 34.7

4.2 years; P¼.02). None of them had ovarian endome- trioma or pain recurrences after delivery. Indeed, pregnancy appeared to have a protective effect against endometriosis (P¼.04) and pain recurrence (P¼.01).

DISCUSSION

One of the most frustrating aspects of the surgical treatment of endometriosis is the high recurrence of pain and ovarian endometriomas. Laparoscopy is the best treatment for ovarian endometriomas because of the low morbidity, high tolerance, and overall low costs. The aim of the present study was to analyze the effectiveness of laparoscopic treatment of endometriosis and the risk factors that might influence the recurrence rate of endometriomas and pain symptoms. The real incidence of endometriosis recurrence is uncertain because of the variety of criteria used to define it. Some authors have considered the recurrence of symptoms to be recurrence of the disease, whereas in most studies, such as the present one, only ultrasonographic or surgical findings of ovarian endometrioma have been taken into account (19–22).

We observed a high effectiveness of treatment over the long term, in terms of both pain and ovarian endometriosis:

the improvement in pain being seen in 84.5% of cases and endometrioma recurring in only 9.6%. In a previously reported

study(23), we showed that different types of pelvic pain were associated with specific locations of the disease: Deep endometriosis in the uterosacral ligament correlated with deep dyspareunia and CPP, which was also related to the presence and the extent of pelvic adhesions, whereas the intensity of dysmenorrhea was associated with adnexal and cul de sac adhesions. After laparoscopy, we observed a significant reduc- tion in dysmenorrhea, dyspareunia, and CPP; dysmenorrhoea remained the most common symptom after surgery, with higher pain scores.

Ovarian stimulation was a risk factor for the recurrence of dysmenorrhea and chronic pelvic pain, which was also related to the adhesions score at laparoscopy and a prior oper- ation for endometriosis. The latter was also a risk factor for the recurrence of deep dyspareunia. These factors may indi- cate a more aggressive disease and/or a tendency to adhesion reformation, but also the need of a complete removal of all visible lesions and adhesions when pain is the major symptom complained of by the patient. Controlled ovarian hyperstimulation temporarily increases circulating estrogens and may worsen symptoms related to the disease.

In the present study, the trend in the cumulative recurrence rate of ovarian endometrioma was dependent on the months elapsed since treatment and increased over time, in line with earlier observations (9, 12). The number and size of the cysts removed did not influence the recurrence of endometriosis, in line with Xishi et al.(13)but in contrast with other authors(8, 9, 11).

TABLE 4

Correlation between selected factors and recurrence of pain symptoms and ovarian endometrioma.

Dysmenorrhea Dyspareunia CPP Endometrioma recurrence

Age NS NS NS NS

Peritoneal lesions^a NS NS NS NS

Adnexal adhesions^a NS NS <.025; 2.6

(0.4–18.7)

<.001

Adhesions in the cul-de sac^a NS NS NS <.05; 3.02

(1.13–8.01) Size of ovarian

endometriomas

NS NS NS NS

Stage of disease^a(rASRM) NS NS NS NS

Deep lesions^a NS NS NS NS

Previous surgery <.05; 2.7 (1–7.1)

<.005 ; 3.7 (0.8–17.7)

<.02; 4.7 (0.5–48.8)

<.001; 6.25 (2.5–15.3) Ovarian stimulation <.001; 4

(1.4–10.9)

NS <.05; 9.9 (1–97)

<.005; 4.9 (1.7–14.03)

Postoperative GnRHa NS NS NS NS

Postoperative OC NS NS NS NS

Note:Values presented are by univariate analysis: P value; relative risk (95% confidence interval). CPP ¼ chronic pelvic pain; GnRHa ¼ GnRH agonist; NS, not significant; OC ¼ oral contraceptives; rASRM ¼ revised American Society for Reproductive Medicine.

aAt laparoscopy, before surgical treatment.

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In the present study, prior surgery for endometriosis, high score at rASRM classification, as reported by Xishi et al. and Abbot et al.(13, 24), and the presence and extent of adnexal and cul de sac adhesions seemed to increase the risk of endometrioma recurrence. In particular, no recurrences were observed in patients without any adnexal adhesions. These factors can reflect a more aggressive disease or incomplete surgery regarding small endometriotic lesions hidden by adhesions. In fact, even if a careful adhesiolysis that appeared complete at the end of surgery was performed in all cases, it is possible that small undetectable adhesions can persist when extensive adhesions are present. Ovarian stimulation was also a negative prognostic factor; it is possible that exposure to high levels of estrogens may stimulate the growth of endometriotic lesions(25). The impact of gonadotropin stimulation and associated high E2levels on endometriosis still remains unclear. D’Hooghe et al.(26)were the first to retro- spectively examine the recurrence rate of endometriosis after surgical treatment for moderate to severe endometriosis in patients who underwent ovarian hyperstimulation for either an insemination or an IVF cycle. Those investigators were not able to conclude that higher levels of estrogen exposure led to a higher recurrence rate of this disease. However, a re- cent paper describes five patients who developed significant pelvic pain, requiring narcotics, during a controlled ovarian hyperstimulation cycle who were surgically diagnosed with endometriosis (27). The risk of recurrence might increase with the number of stimulation cycles, but the small number of our series did not permit such correlation.

Postoperative pregnancy was identified as a favorable prognostic factor; no endometrioma recurrences occurred in patients who achieved pregnancy within 2 years after surgery.

These women—who achieved a spontaneous conception, had at least one patent fallopian tube, for whom no male infertility factors were present, and who were younger than those who attempted IVF—did not differ regarding other prognostic factors. In our experience, recurrences were not related to age. The benefit of pregnancy on the development and recurrence of endometriosis has recently been observed in other series (9, 12). Moreover, laparoscopic excision of endometrioma is known to improve fertility when it is carried out in infertile women (28). For these reasons, gynecologists should optimize the timing of laparoscopy according to the patient’s age and desire for pregnancy.

Only a minority of patients had both pain and endometrioma recurrence. Future studies are necessary to clarify whether there is a correlation between pain and the recurrence of ovarian endometriosis. In this study, postoperative medical therapy did not reduce the risk of pain and disease recurrence. However, this result may be related to the fact that the medical treatment was given to women with more ad- vanced disease, severe pain symptoms, and no desire for pregnancy and for a short period of time. Nevertheless, the present results are in line with earlier observations that postoperative medical treatment did not significantly influence disease recurrence (29–31). Three-month GnRH analogue

or danazol therapy after laparoscopy was demonstrated to provide no significant advantage in preventing disease recurrence(29–30). Postoperative administration of low-dose cyclic OCs for 6 months also had no significant effect on the long-term recurrence rate of endometrioma (31). However, the treatment period of those studies was <1 year. It is there- fore possible that medical treatments >1 year may be effective in preventing endometrioma recurrence. Further studies are needed to determine the effectiveness of these therapies.

The present study indicates that there is a highly significant improvement in pain symptoms, dysmenorrhea remaining the most common symptom observed after surgery. Adhe- sions, previous surgery for endometriosis, and the use of ovulation drugs seem to be unfavorable prognostic factors.

Postoperative pregnancy shows a protective effect against both pain and endometrioma recurrence.

In conclusion, history of surgery for endometriosis, adhesions, and medical treatment of infertility all increase the risk of unfavorable outcome in the long term. Pregnancy shows a protective effect against pain and endometrioma recurrence. Minimally invasive surgeons should carefully tailor treatment strategies and timing to each individual case.

Acknowledgments:The authors thank Emanuela Forcella and Carla Sorren- tino from Istituto Superiore di Sanita for the statistical analyses.

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