A C TA Obstetricia et Gynecologica
AOGS M A I N R E SE A RC H A R TI C LE
Desogestrel-only contraceptive pill versus sequential contraceptive vaginal ring in the treatment of rectovaginal endometriosis infiltrating the rectum: a prospective open-label comparative study UMBERTO LEONE ROBERTI MAGGIORE, VALENTINO REMORGIDA, CAROLINA SCALA, EMANUELA TAFI, PIER L. VENTURINI & SIMONE FERRERO Department of Obstetrics and Gynecology, San Martino Hospital and National Institute for Cancer Research, University of Genoa, Genoa, Italy
Key words Bowel endometriosis, desogestrel, endometriosis, hormonal therapy, vaginal ring Correspondence Umberto Leone Roberti Maggiore, Department of Obstetrics and Gynecology, San Martino Hospital and National Institute for Cancer Research, University of Genoa, Largo Rosanna Benzi 1, 16132 Genoa, Italy. E-mail: [email protected] Conflicts of interest The authors have stated explicitly that there are no conflicts of interest in connection with this article. Please cite this article as: Leone Roberti Maggiore U, Remorgida V, Scala C, Tafi E, Venturini PL, Ferrero S. Desogestrel-only contraceptive pill versus sequential contraceptive vaginal ring in the treatment of rectovaginal endometriosis infiltrating the rectum: a prospective open-label comparative study. Acta Obstet Gynecol Scand 2014; 93:239–247. Received: 20 March 2013 Accepted: 19 December 2013
Abstract Objective. To compare the efficacy of two hormonal therapies in treating symptoms caused by bowel endometriosis. Design. Patient preference study. Setting. University hospital. Population. A total of 143 women with rectovaginal endometriosis infiltrating the rectum. Methods. This study was performed between January 2008 and June 2011. Patients were treated with a desogestrelonly contraceptive pill or with the sequential combined contraceptive vaginal ring for 12 months. Main outcome measures. The primary endpoint of the study was the rate of satisfied patients at 12-month follow up. The changes in symptoms and in the volume of the nodules were secondary endpoints. Results. At 12-month follow up, the rate of satisfied patients was higher in the group treated with the desogestrel-only contraceptive pill than in the group treated with the sequential combined contraceptive vaginal ring (p = 0.004). When only changes in gastrointestinal symptoms were considered, 50% of patients treated with the desogestrel-only contraceptive pill and 31.3% of those treated with the sequential combined contraceptive vaginal ring were satisfied (p = 0.037). The reduction in the volume of the nodules, the percentages of patients who discontinued the therapy after the completion of the study and of those who decided to undergo surgery were similar between the two groups. Conclusions. Both hormonal therapies are efficacious in treating symptoms caused by rectovaginal endometriosis infiltrating the rectum. Patient satisfaction is higher with the desogestrel-only pill than with a vaginal ring. Abbreviations:
D, desogestrel; SN, sequential Nuvaring.
DOI: 10.1111/aogs.12326
Introduction Bowel endometriosis is defined as endometriotic nodules infiltrating at least the muscularis propria of the bowel. A recent epidemiological study identified a crude incidence of all endometriosis of 10.0/10 000 person-years and an
Key Message Both a desogestrel-only contraceptive pill and a sequential combined contraceptive vaginal ring are effective for the management of bowel endometriosis-related symptoms. The decrease in the volume of the nodules, the adherence to therapy and the rate of patients requiring surgery were similar between the two study groups. More women treated with a desogestrel-only contraceptive pill are satisfied with their treatment compared with those using a sequential combined contraceptive vaginal ring.
ª 2013 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 93 (2014) 239–247
239
Medical therapies in bowel endometriosis
incidence of histologically verified endometriosis of 5.7/ 10 000 person-years (1). It causes pain and a wide range of gastrointestinal symptoms including diarrhea, constipation, abdominal bloating, passage of mucus in the stools, rectal bleeding and symptoms mimicking irritable bowel syndrome (2,3). Bowel endometriotic nodules can be excised by either nodulectomy or segmental bowel resection; surgery significantly improves pain, gastrointestinal complaints, sexual function and quality of life (4–9). However, it is associated with the risk of severe complications (in particular, ureteral damage and dehiscence of the suture). Furthermore, women with endometriosis are of reproductive age and no information is available on the long-term follow up (over 10 years) of young patients undergoing bowel surgery. When endometriotic nodules infiltrate the colorectal wall determining a stenosis of the bowel lumen, sub-occlusive symptoms may be present and, therefore, surgery is required to treat symptoms and to avoid the risk of bowel occlusion. However, in most of the patients, colorectal nodules do not cause bowel stenosis and, therefore, the treatment should aim to ameliorate pain and gastrointestinal symptoms and improve quality of life rather than to eradicate the disease. Hormonal therapies are an established therapeutic option in patients with deep endometriosis (10,11). Recently, some studies showed the efficacy of hormonal therapies in treating pain and intestinal symptoms caused by bowel endometriosis (12–15). However, no study compared the efficacy of progestin and estroprogestin contraceptive therapy in the treatment of symptoms caused by bowel endometriosis. This patient preference prospective study was designed to compare patients’ satisfaction in women with rectovaginal endometriosis infiltrating the rectum treated either by a desogestrel-only contraceptive pill or with a combined sequential contraceptive vaginal ring.
Material and Methods This patient preference prospective study included women of reproductive age with rectovaginal endometriotic nodules infiltrating the rectum. Patients were recruited between January 2008 and June 2011. The study protocol was approved by the Hospital Research Review Committee (432/09 April 2007). Women were informed that there is limited evidence on the effects of hormonal treatments on the symptoms caused by bowel endometriosis (12–15). They were informed that, in some patients, the volume of the intestinal nodule may increase during treatment and that therapy should not be considered curative (16,17). Women participated in the study after an informed written consent was obtained.
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Patients eligible for the study were recruited among women referred to our centre because of pain and gastrointestinal symptoms of more than 6 months duration. The diagnosis of rectovaginal endometriosis was made by vaginal and rectal examinations; the presence of rectal infiltration was assessed by magnetic resonance imaging. Participation in the study was offered only to women unwilling to undergo surgery and who did not desire pregnancy in the year after inclusion in the study. Only women with endometriotic nodules infiltrating at least the muscular layer of the rectal wall and with an estimated colorectal stenosis 3 cm; use of hormonal therapies in the 6 months before study entry; typical contraindications for estrogens and progestogens; use of drugs that interfere with contraceptive steroid metabolism; abnormal findings at breast examination and mammary ultrasound scan; psychotic disturbances; history of drug or alcohol abuse. Patients accepting to participate in the study were submitted to one of the following treatments: continuous oral treatment with desogestrel 75 lg/day [Cerazette, Organon, Rome, Italy; group desogestrel (D)], or combined sequential contraceptive vaginal ring [Nuvaring, 15 lg ethinylestradiol and 120 lg etonogestrel, Organon, Rome, Italy; through days 1–21 of the menstrual cycle – group sequential Nuvaring (SN)]. The choice of the treatment was decided on the basis of the preference of the patient. The duration of treatment was 12 months. Before starting the treatment, at 6 and 12 months of treatment the presence and severity of dysmenorrhea, deep dyspareunia, non-menstrual pelvic pain and dyschezia were evaluated by using a 10-cm visual analogue scale. Patients completed a symptom analogue scale questionnaire (1 indicated absence of the symptom; 10 indicated the highest score) regarding each gastrointestinal symptom. The volume of the nodules was estimated by using virtual organ computer-aided analysis. After the completion of treatment, patients rated the overall degree of satisfaction with their treatment by answering the following question: “Taking into consideration the variations in pain symptoms, in overall well-being and quality of life, as well as the adverse effects experienced, if any, how would you define the level of satisfaction with your treatment?” as previously described (12,18,19). Answers were based on a five-point Likert scale (very satisfied, satisfied, uncertain, dissatisfied, and very dissatisfied).
ª 2013 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 93 (2014) 239–247
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Patients were also asked whether gastrointestinal symptoms changed during the treatment. Adverse effects experienced during treatment were recorded daily by participants on diary cards. In the 3 months before starting the treatment and during the therapy, patients were allowed to take non-steroidal antiinflammatory drugs for the treatment of pain and lactulose for the treatment of constipation. The primary endpoint of the study was the rate of satisfied patients (very satisfied and satisfied) at 12-month follow up. The secondary endpoint of the study was the evaluation of changes in symptoms and in the volume of the nodules during treatment. Women who discontinued the treatment before the end of the study were considered as being not satisfied with treatment (primary endpoint), but were excluded from the evaluation of symptom course during treatment (secondary endpoint).
Statistical analysis In calculating the sample size required, the primary objective was the rate of satisfied patients (very satisfied and satisfied) at 12-month follow up. Based on previous data investigating the effects of progestins on pain and intestinal symptoms of patients with colorectal endometriosis (12), we hypothesized that about 60% of the patients treated with desogestrel would be satisfied. We considered a difference of 25% in satisfaction rate between the study groups as clinically relevant. To have an 80% change of detecting such a difference at an overall statistical significance level of 5%, it was estimated that about 50 patients per group were required. Considering that treatment allocation was based on patient preference, the recruitment continued until the planned sample-size was reached in the least numerous group. Categorical variables were compared by using the chisquared test and the Fisher exact test. Changes in severity of symptoms and volume of the nodules during treatment in each study group were analyzed by using the paired t-test and the signed rank test according to data distribution. The comparisons in the changes of intensity of the symptoms and volume of the nodules during treatment between the two study groups were performed by using the t-test or Mann–Whitney U-test according to data distribution. Data were analyzed using the SIGMA STAT software version 3.5 (Systat Software Inc., San Jose, CA, USA) and the SPSS software version 13.0 (SPSS Science, Chicago, IL, USA).
Results One hundred and sixty-two patients were invited to participate to the study and 143 agreed. Table 1 summarizes
Medical therapies in bowel endometriosis
the characteristics of the women enrolled in the study. Figure 1 shows the diagrammatic flow of the participants. The number of patients who withdrew from the study between 6- and 12-month follow-up was higher in group SN than in group D (p < 0.001; Figure 1). The mean (SD) time of withdrawal was similar in the two study groups (group D, 7.5 0.5 months; group SN, 7.0 2.3 months; p = 0.591). At 12-month follow up, in group D, 16.7% of women were very satisfied, 45.0% were satisfied, 16.7% were uncertain and 21.6% were dissatisfied. In group SN, 8.4% of women were very satisfied, 27.7% were satisfied, 42.2% were uncertain and 21.7% were dissatisfied. Therefore, the rate of satisfied patients (very satisfied and satisfied) at 12-month follow up was higher in group D (61.7%) than group SN (36.1%; p = 0.004). However, a similar percentage of patients was dissatisfied in both study groups (p = 0.998). When only the changes in gastrointestinal symptoms were considered, 50.0% of patients in group D and 31.3% of those in group SN were satisfied (significantly improved, improved and slightly improved) at 12-month follow up (p = 0.037).
Table 1. Demographic and clinical characteristics of the patients included in the study.
Age (years, mean SD) Smokers, n (%) Parity, n (%) Previous surgery for endometriosis, n (%) Ovarian endometriotic cysts, n (%) Dysmenorrhea, n (%) Chronic pelvic pain, n (%) Dyschezia, n (%) Sexually active, n (%) Dyspareunia,a n (%) Previous hormonal treatments, Combined oral contraceptive pill Contraceptive vaginal ring Contraceptive patch Levonorgestrel-releasing intrauterine device Progestin-only pill (desogestrel)
Group D (n = 60)
Group SN (n = 83)
p
34.7 3.3
33.8 4.8
0.474
6 (10.0) 15 (25.0) 27 (45.0)
12 (14.4) 25 (30.1) 32 (38.6)
0.591 0.628 0.548
12 (20.0)
25 (30.1)
0.006
54 (90.0) 45 (75.0)
79 (95.2) 67 (80.7)
0.386 0.539
39 (65.0) 57 (95.0) 39 (68.4) n (%) 47 (78.3)
58 (69.9) 75 (90.4) 62 (82.7)
0.664 0.478 0.284
59 (71.1)
0.433
12 (20.0)
20 (24.1)
0.706
2 (3.3) 2 (3.3)
3 (3.6) 0 (0)
0.711 0.340
3 (5.0)
14 (16.9)
0.057
a
Percentage of sexually active population.
ª 2013 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 93 (2014) 239–247
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Figure 1. Flow chart showing recruitment and women’s progress through the study. D, desogestrel; SN, sequential Nuvaring.
Table 2 shows the changes in pain and gastrointestinal symptom scores during treatment. Obviously, in group D, symptoms associated with menstruation (such as dysmenorrhea, constipation during menstruation, diarrhea during menstruation and cyclical rectal bleeding) disappeared during treatment. At 12-month follow up, there was a significant amelioration in the intensity of all pain and gastrointestinal symptoms (except abdominal bloating) compared with baseline (Table 2). In group SN, at 12-month follow up, the severity of all pain and gastrointestinal symptoms (except diarrhea during menstruation and passage of mucus) significantly decreased compared with baseline (Table 2). The changes in the severity of pain and gastrointestinal symptoms at baseline, and at 6 and 12 months of treatment in the two study groups are shown in Figures 2 and 3. At baseline, there was no significant difference in the severity of pain and gastrointestinal symptoms between the two study groups (Table 2). At 12-month follow up the intensity of chronic pelvic pain, dyschezia, deep dyspareunia, diarrhea, intestinal cramping, feeling of incomplete evacuation and passage of mucus was significantly lower in group D than in group SN; there was no significant difference in the intensity of constipation and abdominal bloating between the two study groups (Table 2). At baseline, there was no significant difference in the mean (SD) volume of the endometriotic nodules between group D (5.4 2.6 cm3) and group SN (5.5 2.3 cm3; p = 0.345). At the 6-month follow up there was a 20.5% (19.1%) reduction in the mean
242
(SD) volume of the nodule in group D (4.1 1.8 cm3) compared with baseline (p < 0.001). In group SN, the mean (SD) reduction in the volume of the nodule at 6-month follow up was 18.5% (16.1%; 4.3 1.5 cm3; p < 0.001). Similarly, at the 12-month follow up there was a significant reduction in the mean (SD) volume of the nodule compared with baseline both in group D (28.0 25.6%; 3.7 2.0 cm3; p < 0.001) and in group SN (27.2 24.8%; 3.8 1.6 cm3; p < 0.001). The reduction of the volume of the endometriotic nodules between 6- and 12-month follow up was significant in both group D and group SN (p < 0.001, respectively). The two hormonal therapies did not cause a significantly different change in the volume of the endometriotic nodules at 6-month follow up (p = 0.155) and 12-month follow up (p = 0.237). Despite the hormonal therapies, an increase in the volume of the endometriotic nodules was observed in 11.1% of patients in group D and in 8.5% of those in group SN (p = 0.846). In both study groups, no significant difference was observed in patient satisfaction and judgment of changes in gastrointestinal symptoms between patients with increase in the volume of the nodules and those with a decrease in the volume of the nodule (data not shown). The changes in the use of drugs (naproxen sodium and lactulose) during treatment are described in Table 3. Fifty-four patients completed the study protocol in group D. Among these, 10 (18.5%) underwent surgery after completion of treatment; the presence of colorectal endometriosis was always confirmed by surgery and histology. Twenty-seven patients (50.0%) continued the
ª 2013 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 93 (2014) 239–247
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Medical therapies in bowel endometriosis
Table 2. Comparison of the changes in pain and gastrointestinal symptoms during treatment in each group and between the two study groups. Symptom
Baseline
Dysmenorrhea Group D 6.7 1.6 Group SN 6.4 1.7 p 0.317 Chronic pelvic pain Group D 5.7 0.9 Group SN 5.6 1.2 p 0.854 Dyschezia Group D 5.1 1.4 Group SN 5.3 1.5 p 0.077 Deep dyspareunia Group D 5.4 1.9 Group SN 5.8 1.2 p 0.837 Constipation Group D 6.9 1.3 Group SN 7.0 1.1 p 0.529 Constipation during menstruation Group D 7.8 1.1 Group SN 6.6 1.5 p 0.060 Diarrhea Group D 7.8 1.5 Group SN 7.3 1.4 p 0.424 Diarrhea during menstruation Group D 7.9 0.9 Group SN 8.2 0.7 p 0.196 Intestinal cramping Group D 6.9 2.2 Group SN 5.9 1.7 p 0.067 Abdominal bloating Group D 6.4 1.9 Group SN 6.9 1.6 p 0.152 Feeling of incomplete evacuation Group D 4.6 1.8 Group SN 4.5 0.5 p 0.940 Passage of mucus Group D 5.6 1.4 Group SN 5.5 1.5 p 0.755 Cyclical rectal bleeding Group D 4.8 0.9 Group SN 5.3 0.5 p 0.077
6-month
12-month
(n = 54) (n = 79)
NA 4.1 1.6 (n = 79) p < 0.001* NA
NA 3.1 1.4 (n = 71) p < 0.001* p < 0.001† NA
(n = 45) (n = 67)
3.3 1.3 (n = 45) p < 0.001* 4.1 1.2 (n = 67) p < 0.001* 0.004
2.9 1.3 (n = 42) p < 0.001* p = 0.004† 3.5 1.3 (n = 59) p < 0.001* p < 0.001† 0.040
(n = 39) (n = 58)
2.2 1.7 (n = 39) p < 0.001* 5.1 1.7 (n = 58) p < 0.001*
AOGS M A I N R E SE A RC H A R TI C LE
Desogestrel-only contraceptive pill versus sequential contraceptive vaginal ring in the treatment of rectovaginal endometriosis infiltrating the rectum: a prospective open-label comparative study UMBERTO LEONE ROBERTI MAGGIORE, VALENTINO REMORGIDA, CAROLINA SCALA, EMANUELA TAFI, PIER L. VENTURINI & SIMONE FERRERO Department of Obstetrics and Gynecology, San Martino Hospital and National Institute for Cancer Research, University of Genoa, Genoa, Italy
Key words Bowel endometriosis, desogestrel, endometriosis, hormonal therapy, vaginal ring Correspondence Umberto Leone Roberti Maggiore, Department of Obstetrics and Gynecology, San Martino Hospital and National Institute for Cancer Research, University of Genoa, Largo Rosanna Benzi 1, 16132 Genoa, Italy. E-mail: [email protected] Conflicts of interest The authors have stated explicitly that there are no conflicts of interest in connection with this article. Please cite this article as: Leone Roberti Maggiore U, Remorgida V, Scala C, Tafi E, Venturini PL, Ferrero S. Desogestrel-only contraceptive pill versus sequential contraceptive vaginal ring in the treatment of rectovaginal endometriosis infiltrating the rectum: a prospective open-label comparative study. Acta Obstet Gynecol Scand 2014; 93:239–247. Received: 20 March 2013 Accepted: 19 December 2013
Abstract Objective. To compare the efficacy of two hormonal therapies in treating symptoms caused by bowel endometriosis. Design. Patient preference study. Setting. University hospital. Population. A total of 143 women with rectovaginal endometriosis infiltrating the rectum. Methods. This study was performed between January 2008 and June 2011. Patients were treated with a desogestrelonly contraceptive pill or with the sequential combined contraceptive vaginal ring for 12 months. Main outcome measures. The primary endpoint of the study was the rate of satisfied patients at 12-month follow up. The changes in symptoms and in the volume of the nodules were secondary endpoints. Results. At 12-month follow up, the rate of satisfied patients was higher in the group treated with the desogestrel-only contraceptive pill than in the group treated with the sequential combined contraceptive vaginal ring (p = 0.004). When only changes in gastrointestinal symptoms were considered, 50% of patients treated with the desogestrel-only contraceptive pill and 31.3% of those treated with the sequential combined contraceptive vaginal ring were satisfied (p = 0.037). The reduction in the volume of the nodules, the percentages of patients who discontinued the therapy after the completion of the study and of those who decided to undergo surgery were similar between the two groups. Conclusions. Both hormonal therapies are efficacious in treating symptoms caused by rectovaginal endometriosis infiltrating the rectum. Patient satisfaction is higher with the desogestrel-only pill than with a vaginal ring. Abbreviations:
D, desogestrel; SN, sequential Nuvaring.
DOI: 10.1111/aogs.12326
Introduction Bowel endometriosis is defined as endometriotic nodules infiltrating at least the muscularis propria of the bowel. A recent epidemiological study identified a crude incidence of all endometriosis of 10.0/10 000 person-years and an
Key Message Both a desogestrel-only contraceptive pill and a sequential combined contraceptive vaginal ring are effective for the management of bowel endometriosis-related symptoms. The decrease in the volume of the nodules, the adherence to therapy and the rate of patients requiring surgery were similar between the two study groups. More women treated with a desogestrel-only contraceptive pill are satisfied with their treatment compared with those using a sequential combined contraceptive vaginal ring.
ª 2013 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 93 (2014) 239–247
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incidence of histologically verified endometriosis of 5.7/ 10 000 person-years (1). It causes pain and a wide range of gastrointestinal symptoms including diarrhea, constipation, abdominal bloating, passage of mucus in the stools, rectal bleeding and symptoms mimicking irritable bowel syndrome (2,3). Bowel endometriotic nodules can be excised by either nodulectomy or segmental bowel resection; surgery significantly improves pain, gastrointestinal complaints, sexual function and quality of life (4–9). However, it is associated with the risk of severe complications (in particular, ureteral damage and dehiscence of the suture). Furthermore, women with endometriosis are of reproductive age and no information is available on the long-term follow up (over 10 years) of young patients undergoing bowel surgery. When endometriotic nodules infiltrate the colorectal wall determining a stenosis of the bowel lumen, sub-occlusive symptoms may be present and, therefore, surgery is required to treat symptoms and to avoid the risk of bowel occlusion. However, in most of the patients, colorectal nodules do not cause bowel stenosis and, therefore, the treatment should aim to ameliorate pain and gastrointestinal symptoms and improve quality of life rather than to eradicate the disease. Hormonal therapies are an established therapeutic option in patients with deep endometriosis (10,11). Recently, some studies showed the efficacy of hormonal therapies in treating pain and intestinal symptoms caused by bowel endometriosis (12–15). However, no study compared the efficacy of progestin and estroprogestin contraceptive therapy in the treatment of symptoms caused by bowel endometriosis. This patient preference prospective study was designed to compare patients’ satisfaction in women with rectovaginal endometriosis infiltrating the rectum treated either by a desogestrel-only contraceptive pill or with a combined sequential contraceptive vaginal ring.
Material and Methods This patient preference prospective study included women of reproductive age with rectovaginal endometriotic nodules infiltrating the rectum. Patients were recruited between January 2008 and June 2011. The study protocol was approved by the Hospital Research Review Committee (432/09 April 2007). Women were informed that there is limited evidence on the effects of hormonal treatments on the symptoms caused by bowel endometriosis (12–15). They were informed that, in some patients, the volume of the intestinal nodule may increase during treatment and that therapy should not be considered curative (16,17). Women participated in the study after an informed written consent was obtained.
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Patients eligible for the study were recruited among women referred to our centre because of pain and gastrointestinal symptoms of more than 6 months duration. The diagnosis of rectovaginal endometriosis was made by vaginal and rectal examinations; the presence of rectal infiltration was assessed by magnetic resonance imaging. Participation in the study was offered only to women unwilling to undergo surgery and who did not desire pregnancy in the year after inclusion in the study. Only women with endometriotic nodules infiltrating at least the muscular layer of the rectal wall and with an estimated colorectal stenosis 3 cm; use of hormonal therapies in the 6 months before study entry; typical contraindications for estrogens and progestogens; use of drugs that interfere with contraceptive steroid metabolism; abnormal findings at breast examination and mammary ultrasound scan; psychotic disturbances; history of drug or alcohol abuse. Patients accepting to participate in the study were submitted to one of the following treatments: continuous oral treatment with desogestrel 75 lg/day [Cerazette, Organon, Rome, Italy; group desogestrel (D)], or combined sequential contraceptive vaginal ring [Nuvaring, 15 lg ethinylestradiol and 120 lg etonogestrel, Organon, Rome, Italy; through days 1–21 of the menstrual cycle – group sequential Nuvaring (SN)]. The choice of the treatment was decided on the basis of the preference of the patient. The duration of treatment was 12 months. Before starting the treatment, at 6 and 12 months of treatment the presence and severity of dysmenorrhea, deep dyspareunia, non-menstrual pelvic pain and dyschezia were evaluated by using a 10-cm visual analogue scale. Patients completed a symptom analogue scale questionnaire (1 indicated absence of the symptom; 10 indicated the highest score) regarding each gastrointestinal symptom. The volume of the nodules was estimated by using virtual organ computer-aided analysis. After the completion of treatment, patients rated the overall degree of satisfaction with their treatment by answering the following question: “Taking into consideration the variations in pain symptoms, in overall well-being and quality of life, as well as the adverse effects experienced, if any, how would you define the level of satisfaction with your treatment?” as previously described (12,18,19). Answers were based on a five-point Likert scale (very satisfied, satisfied, uncertain, dissatisfied, and very dissatisfied).
ª 2013 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 93 (2014) 239–247
U. Leone Roberti Maggiore et al.
Patients were also asked whether gastrointestinal symptoms changed during the treatment. Adverse effects experienced during treatment were recorded daily by participants on diary cards. In the 3 months before starting the treatment and during the therapy, patients were allowed to take non-steroidal antiinflammatory drugs for the treatment of pain and lactulose for the treatment of constipation. The primary endpoint of the study was the rate of satisfied patients (very satisfied and satisfied) at 12-month follow up. The secondary endpoint of the study was the evaluation of changes in symptoms and in the volume of the nodules during treatment. Women who discontinued the treatment before the end of the study were considered as being not satisfied with treatment (primary endpoint), but were excluded from the evaluation of symptom course during treatment (secondary endpoint).
Statistical analysis In calculating the sample size required, the primary objective was the rate of satisfied patients (very satisfied and satisfied) at 12-month follow up. Based on previous data investigating the effects of progestins on pain and intestinal symptoms of patients with colorectal endometriosis (12), we hypothesized that about 60% of the patients treated with desogestrel would be satisfied. We considered a difference of 25% in satisfaction rate between the study groups as clinically relevant. To have an 80% change of detecting such a difference at an overall statistical significance level of 5%, it was estimated that about 50 patients per group were required. Considering that treatment allocation was based on patient preference, the recruitment continued until the planned sample-size was reached in the least numerous group. Categorical variables were compared by using the chisquared test and the Fisher exact test. Changes in severity of symptoms and volume of the nodules during treatment in each study group were analyzed by using the paired t-test and the signed rank test according to data distribution. The comparisons in the changes of intensity of the symptoms and volume of the nodules during treatment between the two study groups were performed by using the t-test or Mann–Whitney U-test according to data distribution. Data were analyzed using the SIGMA STAT software version 3.5 (Systat Software Inc., San Jose, CA, USA) and the SPSS software version 13.0 (SPSS Science, Chicago, IL, USA).
Results One hundred and sixty-two patients were invited to participate to the study and 143 agreed. Table 1 summarizes
Medical therapies in bowel endometriosis
the characteristics of the women enrolled in the study. Figure 1 shows the diagrammatic flow of the participants. The number of patients who withdrew from the study between 6- and 12-month follow-up was higher in group SN than in group D (p < 0.001; Figure 1). The mean (SD) time of withdrawal was similar in the two study groups (group D, 7.5 0.5 months; group SN, 7.0 2.3 months; p = 0.591). At 12-month follow up, in group D, 16.7% of women were very satisfied, 45.0% were satisfied, 16.7% were uncertain and 21.6% were dissatisfied. In group SN, 8.4% of women were very satisfied, 27.7% were satisfied, 42.2% were uncertain and 21.7% were dissatisfied. Therefore, the rate of satisfied patients (very satisfied and satisfied) at 12-month follow up was higher in group D (61.7%) than group SN (36.1%; p = 0.004). However, a similar percentage of patients was dissatisfied in both study groups (p = 0.998). When only the changes in gastrointestinal symptoms were considered, 50.0% of patients in group D and 31.3% of those in group SN were satisfied (significantly improved, improved and slightly improved) at 12-month follow up (p = 0.037).
Table 1. Demographic and clinical characteristics of the patients included in the study.
Age (years, mean SD) Smokers, n (%) Parity, n (%) Previous surgery for endometriosis, n (%) Ovarian endometriotic cysts, n (%) Dysmenorrhea, n (%) Chronic pelvic pain, n (%) Dyschezia, n (%) Sexually active, n (%) Dyspareunia,a n (%) Previous hormonal treatments, Combined oral contraceptive pill Contraceptive vaginal ring Contraceptive patch Levonorgestrel-releasing intrauterine device Progestin-only pill (desogestrel)
Group D (n = 60)
Group SN (n = 83)
p
34.7 3.3
33.8 4.8
0.474
6 (10.0) 15 (25.0) 27 (45.0)
12 (14.4) 25 (30.1) 32 (38.6)
0.591 0.628 0.548
12 (20.0)
25 (30.1)
0.006
54 (90.0) 45 (75.0)
79 (95.2) 67 (80.7)
0.386 0.539
39 (65.0) 57 (95.0) 39 (68.4) n (%) 47 (78.3)
58 (69.9) 75 (90.4) 62 (82.7)
0.664 0.478 0.284
59 (71.1)
0.433
12 (20.0)
20 (24.1)
0.706
2 (3.3) 2 (3.3)
3 (3.6) 0 (0)
0.711 0.340
3 (5.0)
14 (16.9)
0.057
a
Percentage of sexually active population.
ª 2013 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 93 (2014) 239–247
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Figure 1. Flow chart showing recruitment and women’s progress through the study. D, desogestrel; SN, sequential Nuvaring.
Table 2 shows the changes in pain and gastrointestinal symptom scores during treatment. Obviously, in group D, symptoms associated with menstruation (such as dysmenorrhea, constipation during menstruation, diarrhea during menstruation and cyclical rectal bleeding) disappeared during treatment. At 12-month follow up, there was a significant amelioration in the intensity of all pain and gastrointestinal symptoms (except abdominal bloating) compared with baseline (Table 2). In group SN, at 12-month follow up, the severity of all pain and gastrointestinal symptoms (except diarrhea during menstruation and passage of mucus) significantly decreased compared with baseline (Table 2). The changes in the severity of pain and gastrointestinal symptoms at baseline, and at 6 and 12 months of treatment in the two study groups are shown in Figures 2 and 3. At baseline, there was no significant difference in the severity of pain and gastrointestinal symptoms between the two study groups (Table 2). At 12-month follow up the intensity of chronic pelvic pain, dyschezia, deep dyspareunia, diarrhea, intestinal cramping, feeling of incomplete evacuation and passage of mucus was significantly lower in group D than in group SN; there was no significant difference in the intensity of constipation and abdominal bloating between the two study groups (Table 2). At baseline, there was no significant difference in the mean (SD) volume of the endometriotic nodules between group D (5.4 2.6 cm3) and group SN (5.5 2.3 cm3; p = 0.345). At the 6-month follow up there was a 20.5% (19.1%) reduction in the mean
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(SD) volume of the nodule in group D (4.1 1.8 cm3) compared with baseline (p < 0.001). In group SN, the mean (SD) reduction in the volume of the nodule at 6-month follow up was 18.5% (16.1%; 4.3 1.5 cm3; p < 0.001). Similarly, at the 12-month follow up there was a significant reduction in the mean (SD) volume of the nodule compared with baseline both in group D (28.0 25.6%; 3.7 2.0 cm3; p < 0.001) and in group SN (27.2 24.8%; 3.8 1.6 cm3; p < 0.001). The reduction of the volume of the endometriotic nodules between 6- and 12-month follow up was significant in both group D and group SN (p < 0.001, respectively). The two hormonal therapies did not cause a significantly different change in the volume of the endometriotic nodules at 6-month follow up (p = 0.155) and 12-month follow up (p = 0.237). Despite the hormonal therapies, an increase in the volume of the endometriotic nodules was observed in 11.1% of patients in group D and in 8.5% of those in group SN (p = 0.846). In both study groups, no significant difference was observed in patient satisfaction and judgment of changes in gastrointestinal symptoms between patients with increase in the volume of the nodules and those with a decrease in the volume of the nodule (data not shown). The changes in the use of drugs (naproxen sodium and lactulose) during treatment are described in Table 3. Fifty-four patients completed the study protocol in group D. Among these, 10 (18.5%) underwent surgery after completion of treatment; the presence of colorectal endometriosis was always confirmed by surgery and histology. Twenty-seven patients (50.0%) continued the
ª 2013 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 93 (2014) 239–247
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Medical therapies in bowel endometriosis
Table 2. Comparison of the changes in pain and gastrointestinal symptoms during treatment in each group and between the two study groups. Symptom
Baseline
Dysmenorrhea Group D 6.7 1.6 Group SN 6.4 1.7 p 0.317 Chronic pelvic pain Group D 5.7 0.9 Group SN 5.6 1.2 p 0.854 Dyschezia Group D 5.1 1.4 Group SN 5.3 1.5 p 0.077 Deep dyspareunia Group D 5.4 1.9 Group SN 5.8 1.2 p 0.837 Constipation Group D 6.9 1.3 Group SN 7.0 1.1 p 0.529 Constipation during menstruation Group D 7.8 1.1 Group SN 6.6 1.5 p 0.060 Diarrhea Group D 7.8 1.5 Group SN 7.3 1.4 p 0.424 Diarrhea during menstruation Group D 7.9 0.9 Group SN 8.2 0.7 p 0.196 Intestinal cramping Group D 6.9 2.2 Group SN 5.9 1.7 p 0.067 Abdominal bloating Group D 6.4 1.9 Group SN 6.9 1.6 p 0.152 Feeling of incomplete evacuation Group D 4.6 1.8 Group SN 4.5 0.5 p 0.940 Passage of mucus Group D 5.6 1.4 Group SN 5.5 1.5 p 0.755 Cyclical rectal bleeding Group D 4.8 0.9 Group SN 5.3 0.5 p 0.077
6-month
12-month
(n = 54) (n = 79)
NA 4.1 1.6 (n = 79) p < 0.001* NA
NA 3.1 1.4 (n = 71) p < 0.001* p < 0.001† NA
(n = 45) (n = 67)
3.3 1.3 (n = 45) p < 0.001* 4.1 1.2 (n = 67) p < 0.001* 0.004
2.9 1.3 (n = 42) p < 0.001* p = 0.004† 3.5 1.3 (n = 59) p < 0.001* p < 0.001† 0.040
(n = 39) (n = 58)
2.2 1.7 (n = 39) p < 0.001* 5.1 1.7 (n = 58) p < 0.001*
