Ahmed Mahmoud Abdou is a Lecturer and Consultant of Obstetrics and Gynecology, Faculty of Medicine, Zagazig University, Egypt. He has Bachelor degree (M.B. Bch) in Medicine and Surgery, Master (M.Sc.) and Doctorate degrees (M.D. degree) in Obstetrics and Gynecology from the previously mentioned institute. His field of interest is reproductive endocrinology and gynecological endoscopy.
Objective: To compare the efficacy and safety of dienogest (DNG) with depot leuprolide acetate (LA) in patients with recurrent pelvic pain following laparoscopic surgery for endometriosis.
Design: Prospective randomized trial.
Setting: Zagazig University hospitals, Egypt.
Patients: Two hundred and forty-two patients with recurrent pelvic pain following laparoscopic surgery for endometriosis.
Intervention: Dienogest (2 mg/day, orally) or depot LA (3.75 mg/4 weeks, intramuscularly) for 12 weeks. Main Outcome Measures A visual analogue scale was used to test the intensity of pain before and after the end of treatment.
Results: There was highly significant reduction in pelvic pain, back pain and dyspareunia in both groups with mean of difference in dienogest group (28.7 ± 5.3, 19.0 ± 4.3 and 20.0 ± 3.08 mm, respectively) and in LA group (26.2 ± 3.01, 19.5 ± 3.01 and 17.9 ± 2.9 mm, respectively). The most frequent drug-related adverse effects indienogest group were vaginal bleeding and weight gain (64.5 and 10.8%, respectively) which were significantly higher than LA group (21.5 and 3.3%, respectively). While the most frequent drug-related adverse effects in LA group were hot flushes and vaginal dryness (46.3 and 15.7%, respectively) which were significantly higher than dienogest group (15.7 and 3.3%, respectively).
Conclusion: Daily dienogest is as effective as depot LA for relieving endometriosis-associated pelvic pain, low back pain and dyspareunia. In addition, dienogest has acceptable safety, tolerability and lower incidence of hot flushes. Thus, it may offer an effective and well-tolerated treatment in endometriosis.
Keywords : Endometriosis, Pelvic pain, Leuprolide acetate, Dienogest
Endometriosis is defined as the presence of ectopic endometrial tissue outside the uterine cavity inducing a chronic inflammatory reaction [1].
It is a common condition affecting adult women, and the exact prevalence of which is unknown but estimated to range from 2 to 10% of the general female population and up to 50% of infertile women [2]. The prevalence of endometriosis in adolescents undergoing laparoscopy for pelvic pain was reported to be 47% [3]. Although some patients with endometriosis suffer from painful symptoms and/or infertility, others are asymptomatic. Diagnosis is made by physical examination, imaging techniques, and finally proved by histopathology [1].
There is no cure for endometriosis up till now. Surgery is a commonly used treatment option, but the recurrence is high: approximately 40–50% after 5 years [4–6]. Laparoscopic surgery may reduce painful symptoms and improve quality of life in 67–80% of patients [7], but lesions and symptoms frequently recur within 2–5 years [8, 9]. Repeated surgery is associated with increased morbidity, health care costs and reduction in the ovarian reserve in patients with ovarian endometriosis [4].
Medical treatment can alleviate the pelvic pain, but unfortunately the relief is for a limited duration, and symptoms often recur after cessation of treatment. The most widely used therapies are progestins, combined oral contraceptives (COCs), GnRH agonists [10]. GnRH agonists induce a hypoestrogenic state causing menopausal symptoms such as hot flushes, and reduced bone mineral density. Their use is therefore limited to short-term use [11].
Dienogest is a derivative of 19-nortestosterone with a high selectivity for the progesterone receptors. The oral use has been approved for medical treatment of endometriosis in Europe, Japan, and Australia. It has the ability of creating a hypoestrogenic and hyperprogestogenic environment, which causes decidualization of the ectopic endometrium [12].
To compare the efficacy of DNG with depot leuprolide acetate (LA) in patients with recurrent pelvic pain following laparoscopic surgery for endometriosis.
The study was conducted in the Department of Obstetrics and Gynecology, Faculty of medicine, Zagazig University hospitals, Egypt, between May 2014 and December 2016.
The study was a 12-week prospective randomized trial of dienogest versus depot LA. After approval of the local ethics committee, a written informed consent was obtained from all patients before starting. The flowchart of the participants is shown in Fig. 1.
The study included 242 women aged 20–45 years with
recurrent pelvic pain within 1 year following laparoscopic
surgery for histopathologically proven endometriosis in
revised-American Fertility Society (r-AFS, 1985) stages I–
IV based on the total surface size of the lesions, presence of
adhesions, and ovarian lesions [13]. Endometriosis had to
be confirmed by either diagnostic laparoscopy within
3 months or by therapeutic laparoscopy within 12 months
of enrollment into the study with subsequent recurrence of
pain
Exclusion criteria were pregnancy, breast feeding,
amenorrhea within 3 months of enrollment, previous use of
hormonal agents (e.g., GnRH agonists, progestins, danazol
or oral contraceptives) following laparoscopy, undiagnosed
genital bleeding, history of severe adverse drug reactions or
hypersensitivity to steroid hormones or GnRH agonists,
history of thrombosis/embolism or depression and patients
at risk of decreased bone mineral density (BMD) (e.g., a
family history of osteoporosis or use of corticosteroids).
The indication for laparoscopy, in all included patients, was chronic pelvic pain, and there were no cases concerned with fertility.
The study protocol, the intervention involved, possible early and long-term side effects of interventions were explained to the patients. Those who were willing to participate in the study and consented for participation were subjected to the following:
Patients were divided randomly by using random number
table (computer), software Open Epi version 3.21 into
two groups (A and B). Patients were assigned to either
group by the randomization known, while allocation concealment
concentrated on preventing selection and confusing
biases. In group A, patients received dienogest at adose of 2 mg given orally once daily at the same time for
12 weeks with the first tablet taken on the first day after
onset of menstrual bleeding. In group B, patients received
leuprolide acetate at a standard dose of 3.75 mg as a depot
intramuscular injection every 4 weeks for 12 weeks with
the first injection given during the first 3 days of menstrual
bleeding.
Patients were followed up during the treatment period;
they were asked about the compliance of drug intake,
assessment of pain improvement using visual analogue
score at 12 weeks, also they were asked about development
of side effects. Patients initially diagnosed to have
endometriomas at enrollment had ultrasonography for
assessment of the size of endometriomas after 12 weeks of
treatment.
The primary outcome measured was the change of severity of pelvic pain, back pain and dyspareunia from the baseline to the end of treatment (12 weeks after administration of dienogest or LA), as assessed by a visual analogue scale (VAS; 0 mm = absence of pain, 100 mm = unbearable pain).
Collected data were coded, entered and analyzed using Microsoft Excel software. Data were then imported into Statistical Package for the Social Sciences (SPSS) version 20.0 software for analysis. Data were expressed as number and percentage for qualitative variable while they were expressed as mean ± SD for quantitative variables. The following tests were used to test differences for significance; differences between frequencies (qualitative variables) and percentages in groups were compared by Chi square test and differences between parametric quantitative independent groups by t test in paired by paired t. p value was set at \0.05 for significant results & \0.001 for high significant result.
Total of 317 new cases attended the outpatient clinic in the Department of Obstetrics and Gynecology, Faculty of medicine, Zagazig University hospitals, during the study period and were assessed for eligibility, and 284 patients met requirements of inclusion criteria. The study protocol, the intervention involved, possible early and long-term side effects of interventions were explained to the patients. Out of which, 261 patients were willing to participate in thestudy and consented for participation. Simple randomiza-tion of those 261 patients was done and 130 cases were allocated in group A (dienogest 2 mg oral tablet once daily for 12 weeks) and 131 cases in group B (leuprolide acetatedepot 3.75 mg intramuscular injection every 4 weeks for12 weeks). Patients who dropped from follow-up were excluded from the study statistics and results (9 patients from group A and 10 patients from group B). So, finally242 patients were analyzed (121 patients from group A and121 patients from group B). Study flowchart is shown in Fig.1.
There were no statistically significant differences(p[0.05) between the two studied groups regarding the demographic parameters as shown in Table1. Patients were of comparable age (29.52±3.32 years in dienogest group and 29.77±3.09 years in leuprolide acetate group), weight (67.55±6.65 kg in dienogest group and67.19±6.97 kg in leuprolide acetate group) and bodymass index (25.03±1.45 kg/m2in dienogest group and24.84±1.47 kg/m2in leuprolide acetate group) in bothgroups. There was no significant difference between thevisual analogue score in both groups before the study asregards pelvic pain (59.27±11.02 in dienogest group and58.73±11.01 in leuprolide acetate group), back pain(45.91±3.33 in dienogest group and 46.68±3.29 in leuprolide acetate group) and dyspareunia (36.53±3.87 indienogest group and 34.98±4.96 in leuprolide acetate group) (Table1).
Both dienogest and leuprolide acetate were associated with highly significant reduction in VAS for pelvic pain by the end of the study. At baseline, the mean VAS was59.27±11.02 mm in the dienogest group and58.73±11.01 mm in the leuprolide acetate group. By12 weeks, mean VAS for pelvic pain had decreased to30.61±10.65 mm in the dienogest group and to32.53±8.74 mm in the leuprolide acetate group. There was no significant difference between both groups by12 weeks (p= 0.17) (Table2).
Regarding back pain, both dienogest and leuprolideacetate were associated with highly significant reductions in VAS by the end of the study (12 weeks). In dienogest group, the mean VAS was 45.91±3.33 mm at the base-line which decreased to 26.92±4.40 mm by 12 weeks.While in leuprolide acetate group, the mean VAS was46.68±3.29 mm at the baseline which decreased to27.22±1.79 mm by 12 weeks. There was no significant difference between both groups by 12 weeks (p= 0.597)(Table3).
Also, VAS for dyspareunia was highly significantly reduced in both dienogest and leuprolide acetate groups by the end of the study. At baseline, the mean VAS in the dienogest and the leuprolide acetate groups was36.53±3.87 and 34.98±4.96 mm, respectively, which was reduced to 16.53±3.10 and 17.11±2.53 mm,respectively, by 12 weeks. There was no significant difference between both groups by 12 weeks (p= 0.263) (Table4).
At the beginning of the study, 23 patients of the dienogest group and 19 patients of leuprolide acetate group were diagnosed to have endometrioma. The mean size of endometriomas was 32.48±4.93 and 33.00±5.29 mm,respectively. By 12 weeks, endometrioma size was reduced to 28.74±6.39 and 30.11±5.48 mm, respectively There was no significant difference between both groups by12 weeks (p= 0.467) (Table5).
The most frequent drug-related adverse effects in die-nogest group were vaginal bleeding and weight gain (64.5and 10.8%, respectively) which were significantly higher than leuprolide acetate group (21.5 and 3.3%, respec-tively),pvalue was (0.000 and 0.020, respectively). While the most frequent drug-related adverse effects in leuprolideacetate group were hot flushes and vaginal dryness (46.3and 15.7%, respectively) which were significantly higher than dienogest group (15.7 and 3.3%, respectively), p value was (0.000 and 0.001, respectively) (Table6).
There was highly significant reduction in pelvic pain,back pain and dyspareunia in both groups with mean of difference in dienogest group (28.7±5.3, 19.0±4.3 and20.0±3.08 mm, respectively) and in leuprolide acetategroup (26.2±3.01, 19.5±3.01 and 17.9±2.9 mm,respectively).
This study was an attempt to find the best treatment forrecurrent pelvic pain following laparoscopic surgery forhistopathologically proven endometriosis, comparing theeffect of dienogest and leuprolide acetate.
Recurrence is a major concern after surgical excision ofovarian endometriomas especially in patients wishing topreserve the ovarian function. The recurrence rate isreported to be as high as 50% at 5 years [6].
There is worldwide concern regarding the risk of repe-ated operations for endometriosis [15].
Gonadotrophin-releasing hormone analogues or pro-gestins are the options most usually adopted.
In recent years, the attention of clinicians has beenfocused on dienogest, which is currently the only steroidaldrug marketed in most of Europe. Dienogest reducesendometriotic lesions by creating a local progestogenicenvironment, suppressing the systemic estrogen levelmoderately [16].
Pain was evaluated with a VAS score, one of the mostutilized tests in clinical research even if it is a subjectivemeasure [17]; it has, however, the advantage of simplicity,is language independent and is easily understood by mostpatients. The VAS score was assessed at the beginning ofthe study and again at 12 weeks.
In the current study, both dienogest and leuprolideacetate were associated with highly significant reductionsin VAS for pelvic pain, back pain and dyspareunia by12 weeks. There was no significant difference betweenboth groups.
This result was in agreement with Strowitzki et al., whostudied 252 Patients with confirmed endometriosis thatwere randomized to treatment with dienogest (2 mg/day,orally) or LA (3.75 mg, depot i.m. injection, every4 weeks) for 24 weeks and found that both dienogest andLA were associated with substantial reductions in VASscore between baseline and week 24. At baseline, the mean(±SD) VAS score was 60.2 (±24.2) mm in the dienogestgroup and 57.9 (±21.0) mm in the LA group. By week 24,mean VAS scores had decreased to 12.7 (±20.3) mm inthe dienogest group and to 11.9 (±16.9) mm in the LAgroup [17].
Harada et al. in 2009 compared dienogest (2 mg/day,orally) to buserelin acetate (BA) (900lg/day, intranasally)for 24 weeks in 271 patients with endometriosis com-plaining of at least one of five subjective symptoms (lowerabdominal pain, lumbago, defecation pain, dyspareunia, nd pain on internal examination) and concluded thatdienogest reduced the scores of all symptom at the end oftreatment that were comparable to those obtained with BA[18].
Caruso et al. in 2015 studied the effect of dienogest2 mg on quality of life and sexual function in women withendometriosis-associated pelvic pain. Pain improvementwas observed in the study group at 3 (p\0.05) and6 months (p\0.001) of treatment, and no change wasobserved in the control group (p= NS) [19].
The most frequent drug-related adverse effect in die-nogest group was vaginal bleeding (64.5%) which wassignificantly higher than leuprolide acetate group (21.5%).None of the patients in either group had discontinued themedication due to abnormal uterine bleeding which sug-gests that the break through bleeding had a minimal impacton the drug compliance especially with the concomitantimprovement in pelvic pain associated with treatment.Informing the patients about this possible adverse effect ofdienogest therapy may enhance further compliance.
Many studies reported that dienogest is associated withirregular uterine bleeding in the short-term therapy[20–22]. Dienogest-induced genital bleeding originatedmainly from breakthrough bleeding from pseudodeciduathat occurs commonly with progestational agents. Theincidence of genital bleeding decreased with continuedtreatment and resolved after the end of treatment [23].
There were minimal changes in the body weight whichoccurred in 10.8% of dienogest-treated cases. This wasconsistent with previous studies [24,25].
The most frequent drug-related adverse effects inleuprolide acetate group were hot flushes and vaginaldryness (46.3 and 15.7%, respectively) which were sig-nificantly higher than dienogest group (15.7 and 3.3%,respectively). Consistent with this observation, GnRHagonists are associated with estrogen deprivation symp-toms (hot flushes, vaginal dryness, headache and decreasedlibido) and bone demineralization which limits the durationof treatment to 6 months in the absence of add-back ther-apy [17]. The European Society for Human Reproductionand Embryology (ESHRE) guideline recommends carefuluse of GnRH agonists in younger women who have not yetachieved the maximum bone density [1].
The safety profile of dienogest in treatment ofendometriosis that was reported in this study is supportedby previous studies [26–28].
In this study, there was highly significant reduction inthe endometrioma size in both dienogest and leuprolideacetate groups which may offer a new treatment option incases with pelvic pain and endometrioma. Unfortunately,there was a small number of cases having endometrioma inthis study.
A potential limitation of the study was the relatively shortduration of treatment which was restricted to 12 weeks. Alonger study duration on a larger number of patients istherefore recommended to properly assess the long-termefficacy and safety of dienogest. Another limitation was theVAS scoring for pain which is unfortunately a subjectivemeasure, so the process of obtaining patients’ scores by theinvestigators could have been biased.
Conflict of interest: All authors declare that there is no conflict ofinterest with other people or organizations that could inappropriatelyinfluence or bias the content of the paper.
Ethical approval: All procedures performed in this study involvinghuman participants (administration of oral dienogest 2 mg once dailyor intramuscular leuprolide acetate depot 3.75 mg injection every4 weeks for 12 weeks for patients with recurrent pelvic pain fol-lowing laparoscopy for endometriosis) were in accordance with theethical standards of the Faculty of Human Medicine—ZagazigUniversity and with the 1964 Declaration of Helsinki and its lateramendments and were approved by the IRB (Institutional ReviewBoard). The study protocol, the intervention involved, possible earlyand long-term side effects of interventions were explained to thepatients. After approval of the local ethics committee, a writteninformed consent was obtained from all patients before participatingin the study.
Informed Consent: Written informed consent was obtained from allpatients before participating in the study.
