European Journal of Obstetrics & Gynecology and Reproductive Biology 183 (2014) 188–192
Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Dienogest in women with persistent endometriosis-related pelvic pain during norethisterone acetate treatment Matteo Morotti *, Fausta Sozzi, Valentino Remorgida, Pier Luigi Venturini, Simone Ferrero Department of Obstetrics and Gynaecology, IRCCS Azienda Ospedaliera Universitaria San Martino – IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
A R T I C L E I N F O
A B S T R A C T
Article history: Received 1 August 2014 Received in revised form 8 October 2014 Accepted 22 October 2014
Objective: To evaluate patient satisfaction at 6-months dienogest (DNG) treatment in women with symptomatic rectovaginal endometriosis who had pain persistence and were unsatisfied after 6-months of norethisterone acetate (NETA) therapy. Study design: This 24-weeks pilot open-label prospective study enrolled 25 women. The main outcome was the degree of patient satisfaction measured by using a Likert scale. Secondary outcomes were to evaluate differences in endometriosis-related pain, quality of life, sexual function changes and volumetric nodules changes during DNG compared to NETA treatment. Results: Patient satisfaction improved at 3- and 6-months (p < 0.001, respectively) treatment with DNG compared with baseline treatment with NETA. Six months DNG treatment decreased the intensity of all the endometriosis-associated pain (chronic pelvic pain, dyspareunia, dyschezia) compared to baseline (p < 0.001 for all comparisons). Quality of life and quality of sexual life evaluated with the EHP-30 and FSFI, respectively, increased after 6 months treatment. The volume of the endometriotic nodules did not significantly change during treatment. Conclusions: This study confirms the efficacy of DNG in treating symptomatic women with rectovaginal endometriosis even in a particular endometriotic subpopulation of NETA ‘‘resistant’’ patients. Further randomized clinical trials comparing these two progestins both in first than second line are warranted. ß 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Endometriosis Dienogest Norethisterone acetate Pain Progestins
Introduction Rectovaginal endometriosis is one of the more common pelvic localizations of this disease and it usually causes pain symptoms including dysmenorrhea, chronic pelvic pain, dyschezia and deep dyspareunia. When pregnancy is not desired, hormonal therapies may be administered to symptomatic patients who decline surgery or to patients who previously underwent incomplete excision of deep endometriotic lesions and wish to avoid further surgery [1]. Current medical therapies (including progestins) do not eradicate endometriotic lesions but they are efficacious and safe in relieving pain symptoms associated with rectovaginal endometriosis [2].
* Corresponding author at: Department of Obstetrics and Gynaecology, IRCCS Azienda Ospedaliera Universitaria San Martino – IST Istituto Nazionale per la Ricerca sul Cancro, Largo R. Benzi 1, 16132 Genoa, Italy. Tel.: +39 010511525; fax: +39 010511525. E-mail address: [email protected] (M. Morotti). http://dx.doi.org/10.1016/j.ejogrb.2014.10.036 0301-2115/ß 2014 Elsevier Ireland Ltd. All rights reserved.
Several progestins have been demonstrated to be safe end efficacious in controlling endometriosis associated pain-symptoms and they can be recommended as first-line therapy in this setting [3,4]. Amongst progestins, norethisterone acetate is one of the most commonly used medical treatment for pelvic endometriosis and it was demonstrated to be safe and efficacious in relieving pain symptoms [5–9]. However, a percentage of patients ranging from 20% to 37% is dissatisfied after 6-months NETA treatment in different studies, suggesting that NETA is not efficacious or not well tolerated in around one over 3 patients treated [6–9]. In the last years several research efforts has been focused on DNG, an oral derivative of 19-nortestosterone, specifically designed for the treatment of endometriosis. This compound slightly differs from other progestins for the presence of a cyanometilic group in place of an ethinyl group in position 17alpha, thus combining the advantages of nortestosterone derivatives with the benefits of progesterone derivatives [10]. DNG has been shown to be effective in reducing pain symptoms associated with endometriosis thus representing an important option in the medical treatment of this disease
M. Morotti et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 183 (2014) 188–192
[11–19]. Its pharmacological mechanism slightly differs from other progestins; it appears to involve not only PR activation but also regulation of PR subtypes [10], suggesting a possible role of DNG in patient unsatisfied/resistant to NETA treatment. Given this background we planned a 24-week prospective open-label study evaluating the efficacy and tolerability of DNG in women with rectovaginal endometriosis who were unsatisfied with previous 6months NETA treatment. Materials and methods Study population This 6-months prospective, open-label trial was performed in an academic centre for the diagnosis and treatment of endometriosis. Criteria for inclusion in the study were: patients treated with NETA (2.5–5 mg/day, Primolut-Nor1; Schering, formerly NV Organon, Oss, the Netherlands) for 6 months who had pain persistence (at least one symptom with intensity >8 on a visual analogue scale) and were unsatisfied (Likert scale of 4) or very unsatisfied (Likert scale of 5) with the treatment. Patients had to be treated in our clinic with the charts included in our electronic database. The electronic database contains demographic and clinical records of all the patients who attend our clinic; it records each type of medication administered and it also serves as a repository for laboratory data and to assess clinical outcome for audit purposes (adverse effects of the treatment, acceptance of therapy, quality of life and quality of sexual life during treatment and general feedbacks). This database is always filled by the specialty registrars attending the clinic. The endometriosis patients in our clinic keep diaries including information regarding pain changes (every 3 months) throughout a 10-cm visual analogue scale (VAS); the left extreme of the scale indicating the absence of pain and the right indicating the worst pain possible. The validated language versions of the Endometriosis Health Profile-30 (EHP-30) core questionnaire and Female Sexual Index (FSFI) questionnaire, which we routinely administer to all endometriosis patients after 6 months therapy, was extracted from the database and used to measure quality of life and quality of sexual life changes, respectively [20,21]. Other inclusion criteria were: diagnosis of rectovaginal endometriosis based on vaginal and rectal examinations and confirmed by rectal water contrast transvaginal ultrasonography (RWC-TVS) [22,23] and desire to avoid surgery. RWC-TVS is a classic TVS ultrasound technique plus the injection of saline solution into the rectal lumen up to a 20-cm under ultrasonographic control through a 6-mm catheter [22]. Exclusion criteria for the study were: desire to conceive and information missing from the electronic database. Eligible patients were offered dienogest (Visanne1; Bayer, Milan, Italy, group DNG) at the dose of 2 mg/day for 6 months. Patients were informed that DNG is chemically similar to NETA and that both treatments have previously been shown to significantly decrease the intensity of pain symptoms caused by endometriosis [5–9,11–19] but no previous studies compared these two progestins. Patient satisfaction was the primary endpoint. Secondary endpoints were: changes in pain symptoms, volume of the nodules, changes in quality of life and quality of sexual life assessed with the EHP-30 and FSFI questionnaire and adverse effects. The local Institutional Review Board approved the study protocol. Patients enrolled in the study signed a written informed consent.
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Assessment of symptoms during follow-up The intensity of pain symptoms was evaluated before starting the therapy, after 3 and 6 months of treatment using a 10-cm VAS scale given to the patients before the visit in the clinic. A validated language version of the EHP-30 core questionnaire was used to evaluate the quality of life. The EHP-30 core instrument consists of five dimensions – pain, control and powerlessness, social support, emotional well-being and selfimage, all of which are scored from 0 to 100. Lower scores indicate better health status [20]. A validated language version of the FSFI, a multidimensional self-assessment questionnaire consisting of 19 questions, was used to evaluate sexual function. The questions are grouped for domains of libido, arousal, lubrication, orgasm, satisfaction, and pain; higher scores reflect better sexual function (maximum score 36). The FSFI has been validated based on the Diagnostic and Statistical Manual of Mental Disorders IV diagnoses of desire disorder, arousal disorder, and orgasmic dysfunction [21]. The volume of the nodules was estimated by using virtual organ computer-aided analysis (VOCAL, GE Healthcare, Little Chalfont, UK). Vaginal bleeding was defined as follow: spotting (scanty bleeding not requiring usual sanitary protection), breakthrough bleeding (light or moderate bleeding requiring sanitary protection) and metrorrhagia (more than normal menstruation). After the completion of treatment, the women 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 [24]. Answers were based on a 5-point Likert scale (very satisfied, satisfied, uncertain, dissatisfied, very dissatisfied). Statistical analysis The comparison of pain intensity during the treatment and between two different treatments was performed by using the paired Student’s t-test and the Mann–Whitney U-test according to the data distribution and one-way ANOVA with Dunnett’s multiple comparisons test according to data distribution when comparing three or more categories. Categorical variables were compared by using the chi-square test. p < 0.05 was considered statistically significant. Data were analyzed using the PRISM software version 6 (GraphPad Software, La Jolla, CA, USA). Results Out of thirty-six patients fitting the inclusion criteria during the study period, six were excluded for incomplete diaries during the NETA treatment (6/36, 16.7%). Five patients did not accept the treatment (5/30, 16.7%) and one patient was lost to follow-up, thus 25 patients were evaluable for the intention-to-treat analysis (ITT). The demographic characteristics and baseline data of the patients included in the study are presented in Table 1. At the 6-month assessment in the ITT analysis, 3 (3/25, 12.0%) women in group DNG were very satisfied with their treatment, 10 (10/25, 40.0%) were satisfied, 10 (10/25, 40.0%) were uncertain, 1 (1/25, 4.0%) was dissatisfied and 1 (1/25, 4.0%) was very dissatisfied. Overall, 52.0% (13/25) of the women in group DNG were satisfied or very satisfied after 6 months of treatment compared with 16.0% (4/25) at 3 months (p < 0.001) and no patient (was the inclusion criteria) at the baseline (p < 0.001). Interestingly, we noted also a statistical improvement in patients’ satisfaction between 3 and 6 months of DNG treatment
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Table 1 Demographic characteristics of patients included in the study. Patients included (n = 25) Age (years, mean SD) BMI (kg/m2, mean SD) Previous hormonal treatment (n, %) oral contraceptive pill vaginal ring GnRH analogues vaginal danazol Previous surgery for endometriosis (n, %) Concomitant uterine fibroids (n, %) Concomitant adenomyosis (n, %) Concomitant ovarian endometriosis (n, %)
33.4 3.8 21.7 2.3 13 (61.9%) 5 (23.8%) 3 (14.2%) 1 (4.8%) 13/25 (52.0%) 6/25 (24%) 3/25 (12%) 5/25 (20%)
(p = 0.016). Eight women with concomitant uterine fibroids or ovarian endometriosis or adenomyosis were very satisfied or satisfied with the treatment (8/13, 61.5%) compared to 5 patients with rectovaginal endometriosis only (5/13, 48.5%, p = 0.434). At univariate analysis only adenomyosis showed a trend towards the significance (p = 0.083) but at the multivariate analysis none of these factors was significant correlated with improved patient’ satisfaction after 6 months DNG treatment. DNG treatment was effective in controlling endometriosis related pain (Fig. 1). When compared with baseline values, the intensity of chronic pelvic pain and dyspareunia, were significantly decreased at 3-month and 6 months in both groups (ANOVA, p < 0.001) while the intensity of dyschezia decreased only at 6 months (p < 0.001). Changes in self-assessment of quality of life and quality of sexual life are shown in Fig. 2. After 6 months DNG treatment we noted a decrease in several subdomains of the EHP-30 (pain, control and powerlessness and self-image) respect to baseline that led to an overall improvement in quality of life (57.68 5.94 vs. 54.10 6.73, in group NETA and DNG respectively, p < 0.001, Fig. 2A). Women after 6-months DNG therapy had increased FSFI values compared to women at the end of 6-months NETA treatment (23.08 1.69 vs. 21.80 1.31; p = 0.001) (Fig. 2B). All women had sexual intercourse during the study. Regarding each subdomain, we found a statistical increase in lubrification and pain (p = 0.325 and p = 0.002, respectively). There was no significant change in the volume of the endometriotic nodules between baseline and 6 months DNG treatment (3.02 1.14 cm3 and 2.92 0.98 cm3, p = 0.213) (Fig. 3).
Fig. 1. Intensity of pain symptoms at baseline and at 3 months and 6 months follow-up.
DNG was generally well tolerated, with no reported serious adverse events. More common adverse effects in DNG cohort included headache (n = 4, 4/25, 16.0%), nausea (n = 2, 2/25, 8.0%), breast tenderness (n = 1, 1/25, 4.0%). During the previous 6 months NETA treatment five women reported breakthrough bleeding (20.0%) and the dose of norethisterone acetate was increased to 5 mg/day, two (8.0%) weight gain, one nausea (4.0%) and one (4.0%) decrease of libido. No significant difference was observed in the percentage of patients who experienced at least one adverse event between NETA (9/25, 36.0%) and DNG treatment (7/25, 28.0%, p = 0.762). The number of spotting days after 6 months of therapy was 4.09 1.8 days without significative difference with the 4.48 1.5 days to 6 months NETA treatment (p = 0.083). DNG did not modify consistently the biochemical profile after 6 months NETA treatment (Table 2). Comments In this 24-week, open-label prospective study, DNG 2 mg daily orally was associated with increased patient satisfaction, quality of
Fig. 2. Quality of life and quality of sexual life changes in women undergoing DNG treatment compared to baseline (6-months NETA treatment). (A, B) Graphic representation of global EHP-30 and FSFI scores differences between 6-months DNG treatment and 6 months NETA treatment, respectively.
M. Morotti et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 183 (2014) 188–192
Fig. 3. Changes in the volume of the endometriotic nodules during DNG therapy.
Table 2 Serum lipid values at the baseline, 6 months NETA treatment and 6 months DNG treatment according to treatment allocation.
Total fasting cholesterol (mg/dL) High-density lipoprotein cholesterol (mg/dL) Low-density lipoprotein cholesterol (mg/dL) Triglycerides (mg/dL) *
Baseline (n = 25)
6-months NETA (n = 25)
6-months DNG (n = 24)
177.5 19.1
179.1 13.69
174.2 23.1
58.4 6.0
51.5 7.0*
56.6 5.9
107.9 19.5
111.8 15.3
90.4 14.3
78.8 11.2
101.9 24.4 *
83.3 12.2
p < 0.05 compared to the baseline.
sexual life and significant reductions in pain symptoms in patients with rectovaginal endometriosis who were unsatisfied with previous 6 months treatment with NETA. The improvement in endometriosis-associated pain with DNG was accompanied by an acceptable safety and tolerability profile in term of clinical and biochemical features, consistent with observations in previous reports (Fig. 2, Table 2) [11–19]. In the last years several studies showed that DNG, a progestin specifically studied for endometriosis is efficacious in controlling pain symptoms in patients with endometriosis with a good tolerability in term of bleeding pattern and lipid profile [10]. DNG action mechanism slightly differs from other progestins as NETA, as it is highly selective for progesterone receptors and acts directly reducing proliferation and cytokine production in endometriotic stromal cells [25,26]. These molecular mechanisms might explain the good clinical results of this drug after a recent switch from a similar drug, in term of pharmacological class, as NETA. Furthermore, we showed that the quality of life, evaluated with the EHP-30, increase after 6 months of DNG treatment (Fig. 2A and B). Also the quality of sexual life, evaluated with the FSFI, ameliorates after 6 months of DNG treatment compared with the baseline (in particular libido and pain). In particular, we found interesting that the pain subdomain in the FSFI questionnaire ameliorated significantly at 6 months treatment, although we did not find any volumetric change of the endometriotic nodules compared to the baseline (Fig. 3). These
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findings might suggest a direct or indirect effect of DNG on pain modulation and transmission. Progestins and DNG have pronounced anti-inflammatory effects on the pelvic environment in women with endometriosis [27], we hypothesized that DNG might also act with other mechanism as a direct effect on the peripheral neuroinflammation [28,29] and thus to the central sensization mechanism, that are of paramount importance in generating and modulating the endometriosis-associated pain perception [30,31]. This study confirms that DNG has little effect on plasma lipid levels, consistent with other studies [11–19] and tend to stabilize the lipid patterns respect to 6 months NETA treatment (Table 2). This is clinically important, as it is beneficial for any medication, particularly when used for long-term, to display neutral effects on plasma lipids [17]. This study does not confirm clinically that DNG reduces the volumetric changes of rectovaginal nodules that were indirectly theorized by the increased apoptotic rates seen in preclinical models during DNG treatment [32]. However, the study population was highly selected and did not benefit from NETA treatment; therefore, there patients might represent a clinical progesterone resistant population, that might be refractory to progestin-induced apoptosis [33]. This study present several pitfalls. The most relevant limitation is that this study is not randomized. In fact, we compared a 6 months of prospective treatment with the previous 6 months of retrospectively evaluated charts. Indeed, the good results shown in this trial might present an intrinsic bias as the patients switched from a not tolerated drug towards a ‘‘new’’ drug and this might have highlighted the patient perception regarding the treatment. However, we believe that this clinical scenario (dynamic monitoring of patient response to treatment and drug switching to another) is what happens during the daily practice, and thus this study might still have a role in the clinical practice. Another limitation is that, in the current study, the diagnosis of rectovaginal endometriosis was based on RWC-TVS and not on diagnostic laparoscopy and histology, therefore we cannot exclude that patients with rectovaginal endometriosis and concomitant uterine fibroids, adenomyosis or other endometriotic localizations might have benefit from DNG treatment. In conclusion, this is the first study evaluating the use of DNG in a pre-treated NETA population and it represents an useful contribution to evidence-based prescribing, as it shows that DNG 2 mg/day was associated with significant improvements in patient satisfaction, endometriosis-associated pain symptoms and quality of life and quality of sexual life, in this specific setting. Randomized clinical trials comparing these two progestins in first and second lines are warranted. Conflict of interest None. References [1] Johnson NP, Hummelshoj L, World Endometriosis Society Montpellier Consortium. Consensus on current management of endometriosis. Hum Reprod 2013;28:1552–68. [2] Vercellini P, Crosignani PG, Somigliana E, Berlanda N, Barbara G, Fedele L. Medical treatment for rectovaginal endometriosis: what is the evidence. Hum Reprod 2009;24:2504–14. [3] Brown J, Kives S, Akhtar M. Progestagens and anti-progestagens for pain associated with endometriosis. Cochrane Database Syst Rev 2012;(3): CD002122. [4] Dunselman GA, Vermeulen N, Becker C, et al. ESHRE guideline: management of women with endometriosis. Hum Reprod 2014;29:400–12. [5] Muneyyirci-Delale O, Karacan M. Effect of norethindrone acetate in the treatment of symptomatic endometriosis. Int J Fertil Womens Med 1998;43:24–7.
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[6] Vercellini P, Pietropaolo G, De Giorgi O, Pasin R, Chiodini A, Crosignani PG. Treatment of symptomatic rectovaginal endometriosis with an estrogen– progestogen combination versus low-dose norethindrone acetate. Fertil Steril 2005;84:1375–87. [7] Ferrero S, Camerini G, Seracchioli R, Ragni N, Venturini PL, Remorgida V. Letrozole combined with norethisterone acetate compared with norethisterone acetate alone in the treatment of pain symptoms caused by endometriosis. Hum Reprod 2009;24:3033–41. [8] Ferrero S, Camerini G, Ragni N, Venturini PL, Biscaldi E, Remorgida V. Norethisterone acetate in the treatment of colorectal endometriosis: a pilot study. Hum Reprod 2010;25:94–100. [9] Ferrero S, Remorgida V, Venturini PL, Leone Roberti Maggiore U. Norethisterone acetate versus norethisterone acetate combined with letrozole for the treatment of ovarian endometriotic cysts: a patient preference study. Eur J Obstet Gynecol Reprod Biol 2014;174:117–22. [10] Bizzarri N, Remorgida V, Leone Roberti Maggiore U, et al. Dienogest in the treatment of endometriosis. Expert Opin Pharmacother 2014;15:1889–902. [11] Harada T, Momoeda M, Taketani Y, et al. Dienogest is as effective as intranasal buserelin acetate for the relief of pain symptoms associated with endometriosis-a randomized, double-blind, multicenter, controlled trial. Fertil Steril 2009;91:675–81. [12] Ko¨hler G, Faustmann TA, Gerlinger C, Seitz C, Mueck AO. A dose-ranging study to determine the efficacy and safety of 1, 2, and 4 mg of dienogest daily for endometriosis. Int J Gynaecol Obstet 2010;108:21–5. [13] Strowitzki T, Marr J, Gerlinger C, Faustmann T, Seitz C. Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24week, randomized, multicentre, open-label trial. Hum Reprod 2010;25:633–41. [14] Strowitzki T, Faustmann T, Gerlinger C, Seitz C. Dienogest in the treatment of endometriosis-associated pelvic pain: a 12-week, randomized, double-blind, placebo-controlled study. Eur J Obstet Gynecol Reprod Biol 2010;151:193–8. [15] Kitawaki J, Kusuki I, Yamanaka K, Suganuma I. Maintenance therapy with dienogest following gonadotropin-releasing hormone agonist treatment for endometriosis-associated pelvic pain. Eur J Obstet Gynecol Reprod Biol 2011; 157:212–6. [16] Petraglia F, Hornung D, Seitz C, et al. Reduced pelvic pain in women with endometriosis: efficacy of long-term dienogest treatment. Arch Gynecol Obstet 2012;285:167–73. [17] Strowitzki T, Marr J, Gerlinger C, Faustmann T, Seitz C. Detailed analysis of a randomized, multicenter, comparative trial of dienogest versus leuprolide acetate in endometriosis. Int J Gynaecol Obstet 2012;117:228–33. [18] Harada M, Osuga Y, Izumi G, et al. Dienogest, a new conservative strategy for extragenital endometriosis: a pilot study. Gynecol Endocrinol 2011;27: 717–20. [19] Hirata T, Izumi G, Takamura M, et al. Efficacy of dienogest in the treatment of symptomatic adenomyosis: a pilot study. Gynecol Endocrinol 2014;30:726–9.
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Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Dienogest in women with persistent endometriosis-related pelvic pain during norethisterone acetate treatment Matteo Morotti *, Fausta Sozzi, Valentino Remorgida, Pier Luigi Venturini, Simone Ferrero Department of Obstetrics and Gynaecology, IRCCS Azienda Ospedaliera Universitaria San Martino – IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
A R T I C L E I N F O
A B S T R A C T
Article history: Received 1 August 2014 Received in revised form 8 October 2014 Accepted 22 October 2014
Objective: To evaluate patient satisfaction at 6-months dienogest (DNG) treatment in women with symptomatic rectovaginal endometriosis who had pain persistence and were unsatisfied after 6-months of norethisterone acetate (NETA) therapy. Study design: This 24-weeks pilot open-label prospective study enrolled 25 women. The main outcome was the degree of patient satisfaction measured by using a Likert scale. Secondary outcomes were to evaluate differences in endometriosis-related pain, quality of life, sexual function changes and volumetric nodules changes during DNG compared to NETA treatment. Results: Patient satisfaction improved at 3- and 6-months (p < 0.001, respectively) treatment with DNG compared with baseline treatment with NETA. Six months DNG treatment decreased the intensity of all the endometriosis-associated pain (chronic pelvic pain, dyspareunia, dyschezia) compared to baseline (p < 0.001 for all comparisons). Quality of life and quality of sexual life evaluated with the EHP-30 and FSFI, respectively, increased after 6 months treatment. The volume of the endometriotic nodules did not significantly change during treatment. Conclusions: This study confirms the efficacy of DNG in treating symptomatic women with rectovaginal endometriosis even in a particular endometriotic subpopulation of NETA ‘‘resistant’’ patients. Further randomized clinical trials comparing these two progestins both in first than second line are warranted. ß 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Endometriosis Dienogest Norethisterone acetate Pain Progestins
Introduction Rectovaginal endometriosis is one of the more common pelvic localizations of this disease and it usually causes pain symptoms including dysmenorrhea, chronic pelvic pain, dyschezia and deep dyspareunia. When pregnancy is not desired, hormonal therapies may be administered to symptomatic patients who decline surgery or to patients who previously underwent incomplete excision of deep endometriotic lesions and wish to avoid further surgery [1]. Current medical therapies (including progestins) do not eradicate endometriotic lesions but they are efficacious and safe in relieving pain symptoms associated with rectovaginal endometriosis [2].
* Corresponding author at: Department of Obstetrics and Gynaecology, IRCCS Azienda Ospedaliera Universitaria San Martino – IST Istituto Nazionale per la Ricerca sul Cancro, Largo R. Benzi 1, 16132 Genoa, Italy. Tel.: +39 010511525; fax: +39 010511525. E-mail address: [email protected] (M. Morotti). http://dx.doi.org/10.1016/j.ejogrb.2014.10.036 0301-2115/ß 2014 Elsevier Ireland Ltd. All rights reserved.
Several progestins have been demonstrated to be safe end efficacious in controlling endometriosis associated pain-symptoms and they can be recommended as first-line therapy in this setting [3,4]. Amongst progestins, norethisterone acetate is one of the most commonly used medical treatment for pelvic endometriosis and it was demonstrated to be safe and efficacious in relieving pain symptoms [5–9]. However, a percentage of patients ranging from 20% to 37% is dissatisfied after 6-months NETA treatment in different studies, suggesting that NETA is not efficacious or not well tolerated in around one over 3 patients treated [6–9]. In the last years several research efforts has been focused on DNG, an oral derivative of 19-nortestosterone, specifically designed for the treatment of endometriosis. This compound slightly differs from other progestins for the presence of a cyanometilic group in place of an ethinyl group in position 17alpha, thus combining the advantages of nortestosterone derivatives with the benefits of progesterone derivatives [10]. DNG has been shown to be effective in reducing pain symptoms associated with endometriosis thus representing an important option in the medical treatment of this disease
M. Morotti et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 183 (2014) 188–192
[11–19]. Its pharmacological mechanism slightly differs from other progestins; it appears to involve not only PR activation but also regulation of PR subtypes [10], suggesting a possible role of DNG in patient unsatisfied/resistant to NETA treatment. Given this background we planned a 24-week prospective open-label study evaluating the efficacy and tolerability of DNG in women with rectovaginal endometriosis who were unsatisfied with previous 6months NETA treatment. Materials and methods Study population This 6-months prospective, open-label trial was performed in an academic centre for the diagnosis and treatment of endometriosis. Criteria for inclusion in the study were: patients treated with NETA (2.5–5 mg/day, Primolut-Nor1; Schering, formerly NV Organon, Oss, the Netherlands) for 6 months who had pain persistence (at least one symptom with intensity >8 on a visual analogue scale) and were unsatisfied (Likert scale of 4) or very unsatisfied (Likert scale of 5) with the treatment. Patients had to be treated in our clinic with the charts included in our electronic database. The electronic database contains demographic and clinical records of all the patients who attend our clinic; it records each type of medication administered and it also serves as a repository for laboratory data and to assess clinical outcome for audit purposes (adverse effects of the treatment, acceptance of therapy, quality of life and quality of sexual life during treatment and general feedbacks). This database is always filled by the specialty registrars attending the clinic. The endometriosis patients in our clinic keep diaries including information regarding pain changes (every 3 months) throughout a 10-cm visual analogue scale (VAS); the left extreme of the scale indicating the absence of pain and the right indicating the worst pain possible. The validated language versions of the Endometriosis Health Profile-30 (EHP-30) core questionnaire and Female Sexual Index (FSFI) questionnaire, which we routinely administer to all endometriosis patients after 6 months therapy, was extracted from the database and used to measure quality of life and quality of sexual life changes, respectively [20,21]. Other inclusion criteria were: diagnosis of rectovaginal endometriosis based on vaginal and rectal examinations and confirmed by rectal water contrast transvaginal ultrasonography (RWC-TVS) [22,23] and desire to avoid surgery. RWC-TVS is a classic TVS ultrasound technique plus the injection of saline solution into the rectal lumen up to a 20-cm under ultrasonographic control through a 6-mm catheter [22]. Exclusion criteria for the study were: desire to conceive and information missing from the electronic database. Eligible patients were offered dienogest (Visanne1; Bayer, Milan, Italy, group DNG) at the dose of 2 mg/day for 6 months. Patients were informed that DNG is chemically similar to NETA and that both treatments have previously been shown to significantly decrease the intensity of pain symptoms caused by endometriosis [5–9,11–19] but no previous studies compared these two progestins. Patient satisfaction was the primary endpoint. Secondary endpoints were: changes in pain symptoms, volume of the nodules, changes in quality of life and quality of sexual life assessed with the EHP-30 and FSFI questionnaire and adverse effects. The local Institutional Review Board approved the study protocol. Patients enrolled in the study signed a written informed consent.
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Assessment of symptoms during follow-up The intensity of pain symptoms was evaluated before starting the therapy, after 3 and 6 months of treatment using a 10-cm VAS scale given to the patients before the visit in the clinic. A validated language version of the EHP-30 core questionnaire was used to evaluate the quality of life. The EHP-30 core instrument consists of five dimensions – pain, control and powerlessness, social support, emotional well-being and selfimage, all of which are scored from 0 to 100. Lower scores indicate better health status [20]. A validated language version of the FSFI, a multidimensional self-assessment questionnaire consisting of 19 questions, was used to evaluate sexual function. The questions are grouped for domains of libido, arousal, lubrication, orgasm, satisfaction, and pain; higher scores reflect better sexual function (maximum score 36). The FSFI has been validated based on the Diagnostic and Statistical Manual of Mental Disorders IV diagnoses of desire disorder, arousal disorder, and orgasmic dysfunction [21]. The volume of the nodules was estimated by using virtual organ computer-aided analysis (VOCAL, GE Healthcare, Little Chalfont, UK). Vaginal bleeding was defined as follow: spotting (scanty bleeding not requiring usual sanitary protection), breakthrough bleeding (light or moderate bleeding requiring sanitary protection) and metrorrhagia (more than normal menstruation). After the completion of treatment, the women 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 [24]. Answers were based on a 5-point Likert scale (very satisfied, satisfied, uncertain, dissatisfied, very dissatisfied). Statistical analysis The comparison of pain intensity during the treatment and between two different treatments was performed by using the paired Student’s t-test and the Mann–Whitney U-test according to the data distribution and one-way ANOVA with Dunnett’s multiple comparisons test according to data distribution when comparing three or more categories. Categorical variables were compared by using the chi-square test. p < 0.05 was considered statistically significant. Data were analyzed using the PRISM software version 6 (GraphPad Software, La Jolla, CA, USA). Results Out of thirty-six patients fitting the inclusion criteria during the study period, six were excluded for incomplete diaries during the NETA treatment (6/36, 16.7%). Five patients did not accept the treatment (5/30, 16.7%) and one patient was lost to follow-up, thus 25 patients were evaluable for the intention-to-treat analysis (ITT). The demographic characteristics and baseline data of the patients included in the study are presented in Table 1. At the 6-month assessment in the ITT analysis, 3 (3/25, 12.0%) women in group DNG were very satisfied with their treatment, 10 (10/25, 40.0%) were satisfied, 10 (10/25, 40.0%) were uncertain, 1 (1/25, 4.0%) was dissatisfied and 1 (1/25, 4.0%) was very dissatisfied. Overall, 52.0% (13/25) of the women in group DNG were satisfied or very satisfied after 6 months of treatment compared with 16.0% (4/25) at 3 months (p < 0.001) and no patient (was the inclusion criteria) at the baseline (p < 0.001). Interestingly, we noted also a statistical improvement in patients’ satisfaction between 3 and 6 months of DNG treatment
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Table 1 Demographic characteristics of patients included in the study. Patients included (n = 25) Age (years, mean SD) BMI (kg/m2, mean SD) Previous hormonal treatment (n, %) oral contraceptive pill vaginal ring GnRH analogues vaginal danazol Previous surgery for endometriosis (n, %) Concomitant uterine fibroids (n, %) Concomitant adenomyosis (n, %) Concomitant ovarian endometriosis (n, %)
33.4 3.8 21.7 2.3 13 (61.9%) 5 (23.8%) 3 (14.2%) 1 (4.8%) 13/25 (52.0%) 6/25 (24%) 3/25 (12%) 5/25 (20%)
(p = 0.016). Eight women with concomitant uterine fibroids or ovarian endometriosis or adenomyosis were very satisfied or satisfied with the treatment (8/13, 61.5%) compared to 5 patients with rectovaginal endometriosis only (5/13, 48.5%, p = 0.434). At univariate analysis only adenomyosis showed a trend towards the significance (p = 0.083) but at the multivariate analysis none of these factors was significant correlated with improved patient’ satisfaction after 6 months DNG treatment. DNG treatment was effective in controlling endometriosis related pain (Fig. 1). When compared with baseline values, the intensity of chronic pelvic pain and dyspareunia, were significantly decreased at 3-month and 6 months in both groups (ANOVA, p < 0.001) while the intensity of dyschezia decreased only at 6 months (p < 0.001). Changes in self-assessment of quality of life and quality of sexual life are shown in Fig. 2. After 6 months DNG treatment we noted a decrease in several subdomains of the EHP-30 (pain, control and powerlessness and self-image) respect to baseline that led to an overall improvement in quality of life (57.68 5.94 vs. 54.10 6.73, in group NETA and DNG respectively, p < 0.001, Fig. 2A). Women after 6-months DNG therapy had increased FSFI values compared to women at the end of 6-months NETA treatment (23.08 1.69 vs. 21.80 1.31; p = 0.001) (Fig. 2B). All women had sexual intercourse during the study. Regarding each subdomain, we found a statistical increase in lubrification and pain (p = 0.325 and p = 0.002, respectively). There was no significant change in the volume of the endometriotic nodules between baseline and 6 months DNG treatment (3.02 1.14 cm3 and 2.92 0.98 cm3, p = 0.213) (Fig. 3).
Fig. 1. Intensity of pain symptoms at baseline and at 3 months and 6 months follow-up.
DNG was generally well tolerated, with no reported serious adverse events. More common adverse effects in DNG cohort included headache (n = 4, 4/25, 16.0%), nausea (n = 2, 2/25, 8.0%), breast tenderness (n = 1, 1/25, 4.0%). During the previous 6 months NETA treatment five women reported breakthrough bleeding (20.0%) and the dose of norethisterone acetate was increased to 5 mg/day, two (8.0%) weight gain, one nausea (4.0%) and one (4.0%) decrease of libido. No significant difference was observed in the percentage of patients who experienced at least one adverse event between NETA (9/25, 36.0%) and DNG treatment (7/25, 28.0%, p = 0.762). The number of spotting days after 6 months of therapy was 4.09 1.8 days without significative difference with the 4.48 1.5 days to 6 months NETA treatment (p = 0.083). DNG did not modify consistently the biochemical profile after 6 months NETA treatment (Table 2). Comments In this 24-week, open-label prospective study, DNG 2 mg daily orally was associated with increased patient satisfaction, quality of
Fig. 2. Quality of life and quality of sexual life changes in women undergoing DNG treatment compared to baseline (6-months NETA treatment). (A, B) Graphic representation of global EHP-30 and FSFI scores differences between 6-months DNG treatment and 6 months NETA treatment, respectively.
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Fig. 3. Changes in the volume of the endometriotic nodules during DNG therapy.
Table 2 Serum lipid values at the baseline, 6 months NETA treatment and 6 months DNG treatment according to treatment allocation.
Total fasting cholesterol (mg/dL) High-density lipoprotein cholesterol (mg/dL) Low-density lipoprotein cholesterol (mg/dL) Triglycerides (mg/dL) *
Baseline (n = 25)
6-months NETA (n = 25)
6-months DNG (n = 24)
177.5 19.1
179.1 13.69
174.2 23.1
58.4 6.0
51.5 7.0*
56.6 5.9
107.9 19.5
111.8 15.3
90.4 14.3
78.8 11.2
101.9 24.4 *
83.3 12.2
p < 0.05 compared to the baseline.
sexual life and significant reductions in pain symptoms in patients with rectovaginal endometriosis who were unsatisfied with previous 6 months treatment with NETA. The improvement in endometriosis-associated pain with DNG was accompanied by an acceptable safety and tolerability profile in term of clinical and biochemical features, consistent with observations in previous reports (Fig. 2, Table 2) [11–19]. In the last years several studies showed that DNG, a progestin specifically studied for endometriosis is efficacious in controlling pain symptoms in patients with endometriosis with a good tolerability in term of bleeding pattern and lipid profile [10]. DNG action mechanism slightly differs from other progestins as NETA, as it is highly selective for progesterone receptors and acts directly reducing proliferation and cytokine production in endometriotic stromal cells [25,26]. These molecular mechanisms might explain the good clinical results of this drug after a recent switch from a similar drug, in term of pharmacological class, as NETA. Furthermore, we showed that the quality of life, evaluated with the EHP-30, increase after 6 months of DNG treatment (Fig. 2A and B). Also the quality of sexual life, evaluated with the FSFI, ameliorates after 6 months of DNG treatment compared with the baseline (in particular libido and pain). In particular, we found interesting that the pain subdomain in the FSFI questionnaire ameliorated significantly at 6 months treatment, although we did not find any volumetric change of the endometriotic nodules compared to the baseline (Fig. 3). These
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findings might suggest a direct or indirect effect of DNG on pain modulation and transmission. Progestins and DNG have pronounced anti-inflammatory effects on the pelvic environment in women with endometriosis [27], we hypothesized that DNG might also act with other mechanism as a direct effect on the peripheral neuroinflammation [28,29] and thus to the central sensization mechanism, that are of paramount importance in generating and modulating the endometriosis-associated pain perception [30,31]. This study confirms that DNG has little effect on plasma lipid levels, consistent with other studies [11–19] and tend to stabilize the lipid patterns respect to 6 months NETA treatment (Table 2). This is clinically important, as it is beneficial for any medication, particularly when used for long-term, to display neutral effects on plasma lipids [17]. This study does not confirm clinically that DNG reduces the volumetric changes of rectovaginal nodules that were indirectly theorized by the increased apoptotic rates seen in preclinical models during DNG treatment [32]. However, the study population was highly selected and did not benefit from NETA treatment; therefore, there patients might represent a clinical progesterone resistant population, that might be refractory to progestin-induced apoptosis [33]. This study present several pitfalls. The most relevant limitation is that this study is not randomized. In fact, we compared a 6 months of prospective treatment with the previous 6 months of retrospectively evaluated charts. Indeed, the good results shown in this trial might present an intrinsic bias as the patients switched from a not tolerated drug towards a ‘‘new’’ drug and this might have highlighted the patient perception regarding the treatment. However, we believe that this clinical scenario (dynamic monitoring of patient response to treatment and drug switching to another) is what happens during the daily practice, and thus this study might still have a role in the clinical practice. Another limitation is that, in the current study, the diagnosis of rectovaginal endometriosis was based on RWC-TVS and not on diagnostic laparoscopy and histology, therefore we cannot exclude that patients with rectovaginal endometriosis and concomitant uterine fibroids, adenomyosis or other endometriotic localizations might have benefit from DNG treatment. In conclusion, this is the first study evaluating the use of DNG in a pre-treated NETA population and it represents an useful contribution to evidence-based prescribing, as it shows that DNG 2 mg/day was associated with significant improvements in patient satisfaction, endometriosis-associated pain symptoms and quality of life and quality of sexual life, in this specific setting. Randomized clinical trials comparing these two progestins in first and second lines are warranted. Conflict of interest None. References [1] Johnson NP, Hummelshoj L, World Endometriosis Society Montpellier Consortium. Consensus on current management of endometriosis. Hum Reprod 2013;28:1552–68. [2] Vercellini P, Crosignani PG, Somigliana E, Berlanda N, Barbara G, Fedele L. Medical treatment for rectovaginal endometriosis: what is the evidence. Hum Reprod 2009;24:2504–14. [3] Brown J, Kives S, Akhtar M. Progestagens and anti-progestagens for pain associated with endometriosis. Cochrane Database Syst Rev 2012;(3): CD002122. [4] Dunselman GA, Vermeulen N, Becker C, et al. ESHRE guideline: management of women with endometriosis. Hum Reprod 2014;29:400–12. [5] Muneyyirci-Delale O, Karacan M. Effect of norethindrone acetate in the treatment of symptomatic endometriosis. Int J Fertil Womens Med 1998;43:24–7.
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