Impact of estetrol and drospirenone combination therapy on alleviation of the pelvic pain of endometriosis: a randomized control trial

The first visit of the first participant was on March 5, 2020. From the 18 clinical sites, 88 eligible participants were randomized. Two subjects did not receive the study drug because of predose discontinuation. The full analysis set population consisted of 86 participants: 45 in the E4/DRSP group and 41 in the EE/DRSP group. Early termination occurred in one participant because of “Withdrawal by Participant” in the E4/DRSP group, and one because of “Adverse Event” and four because of “Investigator’s decision” reasons in the EE/DRSP group ( Fig. 1 ). Participants’ background characteristics were comparable between the E4/DRSP and EE/DRSP groups, with age of 34.9 ± 7.61 years and a body mass index of 20.8 ± 2.44 kg/m 2 . Of the 86 participants, 30 (34.9%) and 22 (25.6%) presented with adenomyosis and uterine fibroids as comorbidities, respectively. Both adenomyosis and uterine fibroids were observed in six participants (7.0%). At baseline, the mean and standard deviation of the most severe VAS scores were 71.5 ± 14.50 mm, and those of the nonmenstrual EAPP VAS score were 45.3 ± 26.23 mm. All participants had dysmenorrhea. There were no statistically significant differences in baseline characteristics between the groups (all P values>.15), indicating that the groups were well balanced. The P value for dysmenorrhea could not be calculated because all subjects had it ( Table 1 ). Figure 1 Participant flow. Investigator’s decision: The principal investigators determined that there was a breach of the study protocol and decided that premature termination was appropriate because of poor compliance with the study protocol. E4/DRSP = estetrol 15 mg/drospirenone 3 mg; EE/DRSP = ethinyl estradiol 20 μg/drospirenone 3 mg; FAS = full analysis set. Table 1 Demographics and baseline characteristics (FAS). Characteristic E4/DRSP EE/DRSP Total P value a n=45 n=41 n=86 Age, year 34.4 ± 7.15 b [22–49] c 35.3 ± 8.16 [20–48] 34.9 ± 7.61 [20–49] .5984 Height, cm 161.49 ± 4.763 160.47 ± 4.804 161.00 ± 4.782 .3246 Weight, kg 54.19 ± 5.892 53.73 ± 7.956 53.97 ± 6.915 .7637 BMI, kg/m 2 20.72 ± 1.921 20.81 ± 2.931 20.76 ± 2.440 .8688 Menstrual cycle, days 28.58 ± 2.350 28.40 ± 2.555 28.49 ± 2.437 .7411 Most severe VAS score, mm 69.61 ± 14.039 73.52 ± 14.828 71.48 ± 14.469 .2120 Nonmenstrual EAPP VAS score, mm 43.78 ± 25.280 46.94 ± 27.565 45.28 ± 26.285 .5805 eGFR (ml/min/1.73 m 2 ) 96.66 ± 17.112 [74.2–146.1] 93.53 ± 17.764 [61.1–156.8] 95.17 ± 17.394 [61.1–156.8] .4077 Dysmenorrhea, n (%) 45 (100) 41 (100) 86 (100) NC Endometrioma, n (%) 44 (97.8) 41 (100) 85 (98.8) 1.0000 Age category, n (%) .3847  20–29 (y) 14 (31.1) 13 (31.7) 27 (31.4)  30–39 (y) 20 (44.4) 13 (31.7) 33 (38.4)  40–49 (y) 11 (24.4) 15 (36.6) 26 (30.2) Smoking Status, n (%) .3070  Never 31 (68.9) 34 (82.9) 65 (75.6)  Former 8 (17.8) 5 (12.2) 13 (15.1)  Current 6 (13.3) 2 (4.9) 8 (9.3) Comorbidity, n (%) .9861  Uterine fibroids / adenomyosis 3 (6.7) 3 (7.3) 6 (7.0)  Uterine fibroids 9 (20.0) 7 (17.1) 16 (18.6)  Adenomyosis 12 (26.7) 12 (29.3) 24 (27.9)  None 21 (46.7) 19 (46.3) 40 (46.5) BMI = body mass index; E4/DRSP = estetrol 15 mg/drospirenone 3 mg; EE/DRSP = ethinyl estradiol 20 μg/drospirenone 3 mg; eGFR = estimated glomerular filtration rate; FAS = full analysis set; VAS = visual analog scale. a Statistical comparisons were performed using the two-sample t -test for continuous variables and Fisher’s exact test for categorical variables. b Mean ± standard deviation. c Range (min–max). Participant flow. Investigator’s decision: The principal investigators determined that there was a breach of the study protocol and decided that premature termination was appropriate because of poor compliance with the study protocol. E4/DRSP = estetrol 15 mg/drospirenone 3 mg; EE/DRSP = ethinyl estradiol 20 μg/drospirenone 3 mg; FAS = full analysis set. Demographics and baseline characteristics (FAS). BMI = body mass index; E4/DRSP = estetrol 15 mg/drospirenone 3 mg; EE/DRSP = ethinyl estradiol 20 μg/drospirenone 3 mg; eGFR = estimated glomerular filtration rate; FAS = full analysis set; VAS = visual analog scale. Statistical comparisons were performed using the two-sample t -test for continuous variables and Fisher’s exact test for categorical variables. Mean ± standard deviation. Range (min–max). Changes in the most severe EAPP VAS scores from baseline to weeks 4, 8, and 12 were −12.6 ± 15.48, −29.0 ± 20.14, and −32.5 ± 19.57 mm in the E4/DRSP group and −12.8 ± 17.21, −35.4 ± 24.77, and −33.9 ± 27.02 mm in the EE/DRSP group, respectively ( Supplemental Fig. 1 , available online). This would suggest that the changes from baseline in the most severe EAPP VAS over time profiles were quite similar between the E4/DRSP and EE/DRSP groups. Furthermore, the spline function curves inferred on the basis of the individual daily VAS scores showed that E4/DRSP suppressed the nonmenstrual pain more than EE/DRSP ( Fig. 2 ). Figure 2 Spline function curves on the basis of the individual VAS scores over time profiles. Treatment period is from day 1 to day 84. The best fit curves were developed using the Akaike information criterion, varying the degrees of freedom for each treatment group. E4/DRSP = estetrol 15 mg/drospirenone 3 mg; EE/DRSP = ethinyl estradiol 20 μg/drospirenone 3 mg; VAS = visual analogue scale. Spline function curves on the basis of the individual VAS scores over time profiles. Treatment period is from day 1 to day 84. The best fit curves were developed using the Akaike information criterion, varying the degrees of freedom for each treatment group. E4/DRSP = estetrol 15 mg/drospirenone 3 mg; EE/DRSP = ethinyl estradiol 20 μg/drospirenone 3 mg; VAS = visual analogue scale. Supplemental Figure 2 , available online shows the percentages of participants who responded “very much improved”, “much improved”, or “minimally improved” on the CGI-I and “very much satisfied”, “much satisfied”, or “minimally satisfied” on the PGI-I. Supplemental Figure 2 shows that responders were significantly more likely to give answers in the top 3 response levels on both the CGI-I and PGI-I than nonresponders (Fisher’s exact test: P =.006, P =.006, respectively). The sum of the percentages of participants rating the highest three grades on the CGI-I was estimated to be 95.2% and 57.7% in the responders and nonresponders, respectively. On the PGI-I, a similarly larger portion of participants rated the highest three grades in responders (95.2%) than in nonresponders (57.7%). Ultimately, significantly higher responder rates were observed in the E4/DRSP group (61.9%) than in the EE/DRSP group (30.8%, P =.043) ( Fig. 3 ). Figure 3 Proportion of responders after 12-week E4/DRSP or EE/DRSP treatment. P value was estimated by Fisher’s exact test. Error bars show two-sided 95% confidence intervals inferred by the Clopper-Pearson method. E4/DRSP = estetrol 15 mg/drospirenone 3 mg, EE/DRSP = ethinyl estradiol 20 μg/drospirenone 3 mg. Proportion of responders after 12-week E4/DRSP or EE/DRSP treatment. P value was estimated by Fisher’s exact test. Error bars show two-sided 95% confidence intervals inferred by the Clopper-Pearson method. E4/DRSP = estetrol 15 mg/drospirenone 3 mg, EE/DRSP = ethinyl estradiol 20 μg/drospirenone 3 mg. The incidence of adverse events (AEs) among the 86 participants was 88.9% (40/45) in the E4/DRSP group and 92.7% (38/41) in the EE/DRSP group. The incidence of adverse drug reactions was 77.8% (35/45) in the E4/DRSP group and 90.2% (37/41) in the EE/DRSP group. The high incidence of AEs was primarily because of intermenstrual bleeding, which occurred in 68.9% of participants in the E4/DRSP group and 73.2% in the EE/DRSP group. Of them, 26 out of 31 participants in the E4/DRSP group and 23 out of 30 participants in the EE/DRSP group experienced intermenstrual bleeding before day 28 of treatment, indicating that these events were mainly observed during the initial phase of hormonal adjustment. Other frequently reported AEs included headache (E4/DRSP: 17.8%, EE/DRSP: 26.8%) and nausea (E4/DRSP: 6.7%, EE/DRSP: 22.0%). In terms of severity, most AEs were mild (E4/DRSP: 66.7%, EE/DRSP: 70.7%), whereas over the moderate AEs occurred in 22.2% of E4/DRSP and 21.9% of EE/DRSP participants. Regarding study discontinuation because of an AE, this was attributed to two events (malaise and decreased appetite) reported in the same participant in the EE/DRSP group. Furthermore, E4/DRSP had less effect on hemostasis than EE/DRSP ( 15 ). Kobayashi et al. ( 15 ) provide a detailed report of the coagulation and fibrinolytic parameters assessed in the same clinical trial described in the present manuscript.

This study used a multicenter, randomized, open-label, active-controlled, parallel-group design and included Japanese patients diagnosed with endometriosis. The objective of the study was to clarify the association of EAPP alleviation with improvement in QOL-related questionnaires after 12-week treatment with either E4/DRSP or EE/DRSP. This study was conducted in accordance with the Declaration of Helsinki and good clinical practice protocols and met all local legal and regulatory requirements. The protocol was reviewed and approved by the institutional review board of each study site, and written informed consent was obtained from all participants (study registration code: jRCT2080225090). Patients aged ≥20 and <50 years who were diagnosed with endometriosis were enrolled in this study. The clinical diagnoses were on the basis of laparotomy/laparoscopy, transvaginal ultrasonography, or magnetic resonance imaging (i.e., the presence of ovarian endometriomas). For surgically diagnosed cases, endometriosis was confirmed by direct visualization of lesions during laparotomy or laparoscopy. Specifically, transvaginal ultrasound and magnetic resonance imaging findings used for diagnosis included the identification of ovarian endometriomas (chocolate cysts). Another eligibility criterion was an EAPP score ≥40 mm on the visual analogue scale (VAS) during two consecutive menstrual cycles in the baseline observation period. Additional eligibility criteria are provided in the Supplemental Materials . Eligible participants were randomly allocated to either the E4 15 mg/DRSP 3 mg group or the EE 20 μg/DRSP 3 mg group in a 1:1 ratio using stratification factors, i.e., baseline VAS scores (<60 mm or ≥60 mm) and complications (none, uterine fibroids, or adenomyosis), to eliminate potential biases between groups. Rescue medications (loxoprofen, ibuprofen) were allowed as needed throughout the study in both groups. Stratified randomization codes were developed by the interactive web response system using a permuted-block design managed by an office independent of the clinical investigators and other stakeholders. Immediately after randomization, the participants took one tablet per day at a consistent time of day from the first day of menstruation. In the E4/DRSP group, participants were treated with one tablet daily (24-day oral administration of E4/DRSP tablets, followed by a 4-day hormone-free interval per cycle) for three consecutive cycles over 12 weeks. In the EE/DRSP group, one tablet was administered daily for 84 days according to the dosage and administration that received regulatory approval for EAPP treatment in Japan ( 31 ). The dosing regimens were selected on the basis of the approved indications and available formulations at the time of study initiation. Although E4/DRSP was originally developed as a contraceptive, its use in endometriosis-associated pain is supported by clinical guidelines recommending COCs as first-line therapy. At the time of protocol development, the cyclic (24/4) regimen was the only dosing schedule available for E4/DRSP in clinical practice. In contrast, EE/DRSP was administered as a flexible extended regimen, which is the only COC currently approved in Japan specifically for the treatment of EAPP. These choices ensured both regulatory alignment and clinical relevance within the Japanese context. In both groups, a 56-day follow-up period was scheduled after the treatment. The participants were requested to visit the clinical sites every 4 weeks during the baseline observation and treatment periods. During the study, participants were asked to assess and report EAPP intensity on a 100 mm VAS scale (0: no pain to 100: worst possible pain) and bleeding events using the patients’ daily diary. The investigator confirmed the bleeding events to determine the menstrual period for each participant. Seven-point QOL-related questionnaires, clinician’s global impression of improvement (CGI-I) and patient’s global impression of improvement (PGI-I), were scored after 12 weeks of treatment. The CGI-I was rated by investigators in the following seven categories: “1, Very much improved”; “2, Much improved”; “3, Minimally improved”; “4, No change”; “5, Minimally worse”; “6, Much worse”; and “7, Very much worse”. The PGI-I was rated by participants in the following seven categories: “1, Very much satisfied”; “2, Much satisfied”; “3, Minimally satisfied”; “4, Neither satisfied nor dissatisfied”; “5, Minimally dissatisfied”; “6, Much dissatisfied”; and “7, Very much dissatisfied”. As safety endpoints, treatment-emergent adverse events were monitored throughout the study. Statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC). No formal sample size estimation was conducted because of the exploratory nature of this study; however, assuming a moderate effect size of 0.5 and a dropout rate of 15%, 40 participants per group were required to ensure statistical power ≥80%. The most severe EAPP scores were based on daily VAS scores every 4 weeks over the course of the study. Changes in the VAS score of the most severe EAPP from baseline to week 12 were expressed as mean ± standard deviation values every 4 weeks. A spline function was applied to depict the EAPP VAS scores over time profiles during the treatment periods using the entire set of individual data. On the basis of the time profiles, steadily alleviating pain was identified as a “≥70 mm VAS decrease from baseline lasting ≥80% days of the nonmenstrual periods after treatment from day 29 to day 84”. The 1st cycle treatment (day 1 to day 28) was not included in the evaluation because of the unstable hormonal condition. Participants who met the criteria were defined as “responders”; the others were “nonresponders”. Data obtained after E4/DRSP and EE/DRSP treatment were consolidated, the 7-point CGI-I and PGI-I scores were collapsed into the top 3 and bottom 4 response levels, respectively, and Fisher’s exact tests were performed comparing responders and nonresponders. Finally, responder rates were compared between E4/DRSP and EE/DRSP treatment groups using Fisher’s exact test.

Both E4/DRSP and EE/DRSP alleviated the most severe EAPP similarly at week 12; however, nonmenstrual pain intensities were decreased more with E4/DRSP than with EE/DRSP. Features of nonmenstrual pain intensities could be proposed to define responders who achieve significantly greater improvement in global impression scores. Significantly higher responder rates were achieved in the E4/DRSP group than in the EE/DRSP group. Consequently, this study showed that E4/DRSP has the potential to improve QOL in patients with endometriosis, with greater amelioration of nonmenstrual EAPP than EE/DRSP.

This study revealed that E4/DRSP was as effective as EE/DRSP in reducing the most severe EAPP after 12 weeks of treatment. Additionally, pain intensity in the nonmenstrual period appeared to influence global impressions, and E4/DRSP was found to decrease the pain intensity more than EE/DRSP. As a result, a significantly higher proportion of participants in the E4/DRSP group experienced an improvement in their global impressions compared with those in the EE/DRSP group. Endometriosis is a complex gynecological disease that presents with a wide range of pain symptoms, including dysmenorrhea, intermenstrual lower abdominal and back pain, defecation pain, and dyspareunia, as well as infertility ( 1 , 2 ). These symptoms extend beyond physical complaints and have significant socioeconomic impacts, negatively affecting patients’ QOL ( 2 , 4 , 5 , 6 ). Facchin et al. ( 26 ) showed that pelvic pain in endometriosis is associated with poor QOL, and that nonmenstrual pelvic pain had a higher impact on physical and mental QOL, anxiety, and depression. However, amelioration of EAPP has not been found to translate into improvement of QOL even after treatment with estrogen-progestin combination products. Grandi et al. ( 27 ) reported that the reduction of both menstrual pain and nonmenstrual pain improved QOL in their systematic review; however, there was no perception of how closely the two are inter-linked. The present study, therefore, aimed to give due consideration to better QOL by ameliorating EAPP experienced during the nonmenstrual periods after E4/DRSP treatment compared with EE/DRSP treatment. In the present study, steadily alleviating pain was defined as VAS reduced ≥70 mm from baseline during ≥80% of days in the nonmenstrual period; participants with such steadily alleviating pain were considered “responders”. The baseline VAS value was approximately 70 mm; thus, the definition would translate into a health condition that was relieved from painful symptoms for approximately 6 days in a week. The present study proposes that the intensity of nonmenstrual pain relief was significantly associated with improvement of both CGI-I and PGI-I in responders and nonresponders; however, E4/DRSP led to significantly higher responder rates than EE/DRSP. This provides new insights into the management of EAPP, although these findings warrant further exploration in future studies. The dosing regimens differed between the two groups, with cyclic administration including hormone-free intervals in the E4/DRSP group and continuous administration in the EE/DRSP group. Although this difference in dosing regimens may have affected the outcomes, previous studies have suggested that both cyclic and continuous administration of low-dose estrogen-progestin combinations can improve pain symptoms and QOL in women with endometriosis ( 30 ). Therefore, although variations in bleeding patterns may have occurred, the impact on pain relief and overall patient impressions is likely minimal. Nonetheless, further research is warranted to clarify the potential influence of dosing schedules on pain-related outcomes. The mechanism by which endometriosis causes chronic pain remains unclear; however, endometriosis is a chronic inflammatory condition, and proinflammatory responses translate into sensory nerve activation and alteration of nociceptive pathway activation ( 32 ). Menstrual debris results in recruiting immune cells such as neutrophils, macrophages, and natural killer cells, resulting in several mediators such as prostaglandin E2, nerve growth factor, interleukin (IL)-8, IL-1β, and so forth being elevated. Eventually, the enhanced inflammatory response leads to the interaction of the immune cells with sensory nerves, inducing chronic pelvic pain (CPP). Immune cells also regulate neuroangiogenesis, which promotes the blood supply for lesion growth, as well as the density of unmyelinated nerve fibers, C-fibers, which strongly generate CPP. The difference in the pharmacological mode of action in the management of endometriosis between E4 and EE remains unknown, although it has been intensively investigated; however, it was recently reported that E4 inhibited E2-induced invasion and migration of human endometrial stromal cells ( 33 ). In that study, E4 was found to downregulate Wiskott-Aldrich syndrome protein family member 1, the expression of which may contribute to the alleviation of endometriotic lesions. In addition, Patiño-García et al. ( 34 ) showed that E4 did not affect cell growth or migration, but increased ERα and progesterone receptors, and reduced ERβ, which translated into improvement of the ERα-to-ERβ ratio and progestin resistance. It was also reported that the regulatory mechanism via G protein-coupled estrogen receptor 1 (GPER-1) was predominantly expressed on the endoplasmic reticulum in the migration and invasion of ectopic endometrial stromal cells ( 35 , 36 ). Zhang et al. ( 37 ) found that GPER-1 was profoundly expressed in endometrial stromal cells. Therefore, the interplay between E4 and GPER-1 would be of interest. Further investigations are required to elucidate the different features of pain alleviation during the nonmenstrual period between E4/DRSP and EE/DRSP. This study has several limitations. First, this study was not blinded because of the different manners of dosage and administration, i.e., E4/DRSP in a cyclic regimen and EE/DRSP in a flexible extended regimen. Second, no formal sample size estimation was considered; however, the sample size was large enough to detect a medium effect size of 0.5 with a statistical power of 0.8.

T.H. reports medical writing and clinical trial advisory fee payment was made to me based on medical expert contract from Fuji Pharma Co., Ltd. for the submitted work; Case study meeting fee payment was made to me based on medical expert contracts from Fuji Pharma Co., Ltd; Medical writing fees for other clinical trials other than this manuscript were paid to me in accordance with the Medical Expert Contract from Fuji Pharma Co., Ltd. M.N. report this study was sponsored by Fuji Pharma Co., Ltd. All funds for study and my salary and article processing charges are paid by Fuji Pharma Co., Ltd.; Fuji Pharma Co., Ltd. and Mithra Pharmaceuticals. A patent has been filed with regard to the improvement of cul-de sac induration, pelvic tenderness and uterine mobility in subjects with endometriosis complicated by adenomyosis. M.I. reports this study was sponsored by Fuji Pharma Co., Ltd. All funds for study and my salary and article processing charges are paid by Fuji Pharma Co., Ltd. T.H. reports medical writing and clinical trial advisory fee payment was made to me based on medical expert contract from Fuji Pharma Co., Ltd. for the submitted work; Case study meeting fee payment was made to me based on medical expert contracts from Fuji Pharma Co., Ltd; Medical writing fees for other clinical trials other than this manuscript were paid to me in accordance with the Medical Expert Contract from Fuji Pharma Co., Ltd. K.M. reports this study was sponsored by Fuji Pharma Co., Ltd. All funds for study and my salary and article processing charges are paid by Fuji Pharma Co., Ltd. T.H. reports medical writing and clinical trial advisory fee payment was made to me based on medical expert contract from Fuji Pharma Co., Ltd. for the submitted work; Case study meeting fee payment was made to me based on medical expert contracts from Fuji Pharma Co., Ltd; Medical writing fees for other clinical trials other than this manuscript were paid to me in accordance with the Medical Expert Contract from Fuji Pharma Co., Ltd. C.M. has nothing to disclose. M.H. has nothing to disclose. T.K. reports medical writing and clinical trial advisory fee payment was made to me based on medical expert contract from Fuji Pharma Co., Ltd. for the submitted work; Case study meeting fee payment was made to me based on medical expert contracts from Fuji Pharma Co., Ltd