Continuous estetrol/drospirenone regimen for the treatment of endometriosis-related pain: preliminary results

Purpose Endometriosis is a chronic inflammatory condition that causes significant physical and psychological distress. This study aimed to evaluate the therapeutic efficacy and safety of a combined oral contraceptive containing estetrol (E4, 14 mg) and drospirenone (DRSP, 3 mg) in managing endometriosis-related pain.

A retrospective cohort study was carried out at the Endometriosis Center, Federico II University Hospital, Naples, from January 2024 to November 2024. Forty patients with diagnosis of endometriosis and significant pain symptoms (VAS > 6) were included and received E4/DRSP under a continuous regimen for 6 months. Chronic pelvic pain, dyspareunia, dysmenorrhea, and patient quality of life were assessed at baseline, after 3 and 6 months. In the group of patients with endometrioma, reduction in size was evaluated.

E4/DRSP significantly reduced chronic pelvic pain and dyspareunia. Dysmenorrhea was resolved entirely due to amenorrhea induction. Endometriomas decreased in size by 30% on average after 6 months. Adverse effects were mild and occurred in 13/40 of patients (32.5%).

E4/DRSP demonstrated efficacy and tolerability for managing endometriosis-related pain, offering a promising option for long-term treatment. Further research is needed to confirm its impact on lesion regression and disease progression.

Endometriosis is a chronic inflammatory disease affecting up to 15% of women of reproductive age, with an estimated 176 million women affected worldwide. It is a chronic and recurrent disease with adverse effects on patients' physical and psychological well-being and therefore requires a long-term management and the administration of pharmacological therapies over long periods of time to have good control of symptoms [Citation1,Citation2]. The most recent guidelines from ESHRE recommend the use of nonsteroidal anti-inflammatory drugs (NSAIDs) or other analgesics to reduce endometriosis-related pain; alternatively, hormone treatment, such as combined hormonal contraceptives (CHCs), progestogens, GnRH agonists, or GnRH antagonists, should be prescribed [Citation3]. Hormonal treatment for endometriosis aims to suppress menstruation either by inhibiting the hypothalamic‒pituitary‒ovarian axis or by inducing pseudo-decidualization of the ectopic endometrial tissue, leading to amenorrhea and thereby hindering the progression of endometriotic lesions. The result is a reduction of pain and other symptoms associated with endometriosis owing to the minimization or elimination of the growth and bleeding of endometrial-like tissue [Citation4,Citation5]. The choice among the different treatments should consider individual preferences, side effects, individual efficacy, costs, and availability, while, nowadays, there is insufficient evidence of the superiority of one hormonal treatment compared to others. In fact, as reported in the literature, many treatments show comparable effects in terms of efficacy and tolerability [Citation6,Citation7]. Over the years, there has been an evolution in the use of CHC from the administration of the synthetic estrogen ethinylestradiol to the use of the natural estrogen estradiol (E2), valerate, or micronized. The same innovation has been observed with progestins by the introduction of different generations [Citation8,Citation9]. Recently, some studies in the literature have focused on new hormonal agents, such as estrogen estetrol and progestin drospirenone (DRSP), initially testing their molecular and biochemical effects on endometriotic cells in vitro [Citation10]. Only subsequently, their effects on clinical endometriosis-related symptoms have been evaluated, but data are still limited. Estetrol (E4) is a natural estrogen that is normally produced by the fetal liver, and it binds to estrogen receptors (ER) with greater affinity for ERα compared to ERβ. Considering that endometriotic cells have pathologically higher expression of ERβ and considering that the stimulation of ERα naturally increases the expression of progestin receptors (PRs) in endometrial tissue, increasing sensitivity to progesterone, E4 could be a winning molecule for restoring progesterone sensitivity [Citation10]. While both E2 and E4 exert a proliferative action on endometrial cells in vitro, the effect of E4 is ∼100-fold less potent than E2 and this could be an advantage in patients with endometriosis. Additionally, the combination of E4 and DRSP achieves adequate ovulation suppression with a good tolerance profile [Citation11]. Despite all these theoretical advantages, there are still few data in the literature on using the combination of E4 and DRSP for the treatment of endometriosis-related pain. Therefore, in the present study, we evaluated the therapeutic effects and safety of a new CHC containing E4 (14 mg) and DRSP (3 mg) on endometriosis-related symptoms. A continuous regimen, consisting of the administration of the therapy daily without a hormone-free interval, was chosen in order to maintain steady hormone levels, preventing fluctuations that can trigger menstrual bleeding or pain.

A retrospective cohort study was carried out at the Endometriosis Center of Federico II University Hospital in Naples, Italy, from January 2023 to November 2024. Among the clinical records of patients diagnosed with painful symptoms related to endometriosis, we selected the first 40 patients who had been prescribed treatment with the CHC containing E4 and DRSP on a continuous schedule. All the patients had to have completed 6 months of treatment. The selection criteria were as follows: age between 18 and 40 years; a diagnosis of endometriosis strongly supported by ultrasound evaluation according to the consensus opinion from the IDEA group, which requires four key steps for pelvic examination (progressive analysis of the uterus, ovaries, pouch of Douglas and mobility and deep infiltrating endometriosis) [Citation12] or MRI examination in complex or uncertain cases. Moreover, the patients needed to have reported, for at least 6 months, one or more of the following symptoms with a severity >6 on the visual analog scale (VAS): dysmenorrhea, dyspareunia, chronic pelvic pain; patients should not have received hormonal therapy within the last 18 months. Prescription of treatment and all the evaluations at the different times were performed before the start of our retrospective study, as routine in our clinic. According to the protocol of our clinic, evaluation of pain is generally carried out through the VAS for pain every three months for the first six months and every six months thereafter. The cutoff for the recruitment of symptomatic patients was a VAS score equal to or greater than 6. Therefore, a reduction in symptoms to a VAS score equal to or less than 5 was considered clinically significant. For patients affected by endometriomas, a transvaginal ultrasound scan was performed at every visit. Patients were prescribed one tablet containing 15 mg of E4 and 3 mg of DRSP daily (Drovelis, Gedeon-Richter, Italy) for 6 months. Patients had been instructed to discard the last 4 tablets of each package in order to avoid the placebo phase, which would lead to menstrual bleeding. Patient satisfaction and quality of life were assessed at the beginning of the therapy and after six months using the EQ-5D questionnaire. The EQ-5D is a generic instrument that includes five dimensions: mobility, self-care, daily activities, pain, and emotional well-being (depression or anxiety). Each item is scored based on a three-point scale, and the EQ-5D score is calculated by their sum, resulting in scores ranging from 0 (best possible status) to 10 (worst possible status) [Citation13]. Finally, the patients self-reported any adverse effects; they had been informed only about the most common one, which was spotting. The primary endpoint was to assess the efficacy of the administration of E4/DRSP in terms of improvement of endometriosis-related pain, including dysmenorrhea, chronic pelvic pain, and dyspareunia. The secondary outcomes included the (potential) reduction in the size of endometriomas when present and the improvement in quality of life. Statistical analysis Statistical analysis was performed using the Statistical Package for Social Science, version 17.0 (SPSS, Chicago, IL). The data distribution for continuous variables was assessed with the Shapiro–Wilk's test. Student's t-test for paired and unpaired samples was used to compare parametric variables at different times in the same group and between groups, respectively. The Mann‒Whitney test was used to analyze differences in nonparametric parameters between groups. Differences in proportions between groups were analyzed with the X2 test.

Clinical characteristics of patients Forty patients who met the inclusion criteria were included. The clinical characteristics are reported in . The mean age was 25.1 ± 5.0 years (mean ± SD), the mean body mass index (BMI) was 22.2 kg/m² ± 2.7, and the majority of patients, 29 patients (72.5%), were nulliparous. Regarding gynecological conditions, ovarian endometrioma was the most common diagnosis and was observed in 30 (75%) out of 40 patients, followed by deep infiltrating endometriosis (DIE) in 14 patients (35%), adenomyosis in 7 patients (17.5%), and fibroids in 2 (5%). In terms of comorbidities, 62.5% of patients reported no associated conditions. Gastrointestinal disorders were present in 17.5% of cases, thyroid disease in 15%, and diabetes in 2.5%. No cases of hypertension were reported, and 2.5% of patients had other unspecified comorbidities (). Efficacy E4/DRSP administered in a continuous regimen induced amenorrhea in all patients and, therefore, practically eliminated dysmenorrhea. The mean VAS score for chronic pelvic pain significantly reduced after 3 and 6 months, from 6 [5–7] at baseline to 2 [2–6] at 3 months to 0 [0–3] at 6 months (). The mean VAS score for dyspareunia also reduced from 8 [6–8] at baseline to 4 [3–6] at 3 months to 2 [1–6] at 6 months (). The responder rate of patients achieving >50% reduction for chronic pelvic pain VAS scores and dyspareunia VAS score from baseline to the sixth cycle was 92.5% and 67.5%, respectively. In the subgroup of 30 patients with ovarian endometriomas, the size was assessed at each follow-up examination by ultrasonography: the maximum diameter and the volume of endometrioma were reported. The diameters decreased on average from 4.3 ± 1.7 cm (mean ± SD) at baseline to 3.8 ± 1.3 cm (mean ± SD) at 3 months and to 3.1 ± 1.9 cm at six months of follow-up. After six months of study, the maximum diameter was reduced by 30%, and in 4 patients (10%), the endometriomas disappeared (). Similarly, the volume changed from 47.4 ± 26.1 cm3 (mean ± SD) at baseline to 47.9 ± 24.5 cm3 at three months to 25.9 ± 28.3 cm3 at six months. The quality of life of patients was assessed using the EQ-5D questionnaire [Citation10] both at baseline and after six months of therapy. The score significantly decreased from a median value of 7 [4-8] (median [range]) at baseline to 4 [3–7] after six months, indicating an improvement in patients' overall health status ().Adverse effects and safety profile Adverse events were common. Spotting was the predominant event, and 31 out of 40 (77.5%) patients experienced spotting mixed with frank bleeding. It occurred for <1 day. The other drug-related adverse effects were similar to those reported in the literature for CHCs: 3 patients (7.5%) experienced headache, 6 patients (15%) had a feeling of swelling along with breast tenderness, and 4 (10%) patients developed asthenia with somnolence. No other serious adverse events or clinically relevant changes occurred during treatment.

Findings and interpretation Endometriosis is a complex and challenging condition that often requires a multifaceted approach to treatment. Hormonal therapies are essential for managing symptoms and progression of the disease, as they can help regulate the hormonal environment that drives the growth of endometrial-like tissue outside the uterus. Hormonal drugs, which work by suppressing menstruation, are the most effective treatment for endometriosis-related pain, regardless of the disease phenotype (ovarian, deeply infiltrative, or superficial endometriosis) [Citation14]. To date, the ESHRE guidelines strongly recommend the use of hormonal therapy, including combined oral contraceptives, progestins, GnRH analogs, and others, for the management of endometriosis-related pain, and a recent study comparing the effects of CHCs ethinyl estradiol/drospirenone (0.03 mg/3 mg) and progestins Dienogest (2 mg), has found them to be largely comparable [Citation3,Citation15]. The use of CHCs in the treatment of endometriosis offers several advantages, including good tolerability and low cost. CHCs work by reducing menstrual flow and promoting decidualization of endometriotic implants, as well as decreasing the proliferation of cells. They inhibit ovarian function and the metabolism of arachidonic acid into prostaglandins, resulting in the overall alleviation of pelvic pain. Although combined hormonal contraceptives have been used for decades in clinical practice to effectively manage dysmenorrhea, evidence regarding the use and impact of the new E4/DRSP formulation remains limited [Citation16,Citation17]. Recently, Harada et al., in trying to evaluate the effect of E4/DRSP on endometriosis symptoms, demonstrated improvements for the most severe pelvic pain from baseline to the end of 6 months of treatment, albeit with a cyclic administration regimen [Citation18]. Endometriotic lesions are characterized by an overexpression of ERβ and a lower representation of ERα and progestin receptors (PRs). In this way, the pathological tissue becomes highly sensitive to estrogenic stimulation while concurrently resistant to progestins. Additionally, considering that ERα can stimulate the transcription and activation of PRs in endometrial tissue, it is easy to understand that its lower expression further contributes to the phenomenon of progesterone resistance typical of endometriosis [Citation19–21]. As E4 binds to estrogen receptors (ERs) α and β with a higher affinity for estrogen receptor alpha (ERα) than estrogen receptor beta (ERβ), it could be the ideal estrogen to be used in the treatment of endometriosis [Citation22]. Moreover, in the last few years, some authors have demonstrated that E4 does not induce the proliferation or migration of endometriotic cells in vitro and increases the levels of PRs, enhancing and restoring the response to progesterone (P4) in patients who have previously developed resistance [Citation10]. On the other hand, DRSP is a synthetic progestin, comparable to human progesterone, and a strong inhibitor of mineralocorticoid activity [Citation23]. Some authors tried to clarify the mechanism and first confirmed that it reduces the expression and secretion of inflammatory cytokines (IL-6 and IL-8) and growth factors (VEGF and NGF) mRNA from endometriotic cells. Further, DRSP's effects are mediated by PRs, not mineralocorticoid receptors (MRs), indicating that it acts on human endometriotic tissue by stimulating the PR, similar to the actions of natural progesterone and other progestins [Citation24,Citation25]. In the present study, E4/DRSP, administered on a continuous schedule results more effective in the treatment of dysmenorrhea, chronic pelvic pain, and dyspareunia. This approach not only alleviates symptoms but also targets the hormonal drivers of endometriosis, potentially slowing lesion progression. Inducing amenorrhea through continuous use has been proposed as a superior strategy to cyclic regimens, as it may stabilize the hormonal environment and enhance therapeutic outcomes [Citation26]. As a matter of fact, in the 30 patients presenting with an endometrioma, we observed a 30% reduction in the maximum diameter of the lesion after 6 months of treatment. This agrees with other studies suggesting that hormonal therapy can reduce the size of endometriomas or prevent their growth. A meta-analysis by Thiel et al. supported that in patients treated with CHC, a reduction in endometrioma size is present, albeit less pronounced compared to other treatments, such as dienogest, letrozole, relugolix, and leuprolide acetate. These findings indicate that CHCs may somewhat contribute to stabilizing or slightly reducing endometrioma size [Citation27]. E4/DRSP also appears to have a safer long-term side effect profile, making it more suitable for chronic management. E4/DRSP has shown favorable ‘hemostatic’ effects in healthy women in clinical trials [Citation28]. Douxfls et al. confirmed that at 15 mg/3 mg dosage, the combination E4/DRSP had a significantly lower change from baseline activated protein C resistance (APCr) and prothrombin fragment 1 and 2 levels compared respectively with ethinylestradiol/levonorgestrel and ethinylestradiol/drospirenone, thus confirming a better profile of the risk of deep venous thrombosis and pulmonary embolisms [Citation29–31]. In addition, the antimineralocorticoid effect of DRSP helps to decrease fluid retention and bloating, making it a more tolerable choice for women who are susceptible to these side effects. However, common side effects may occur, such as headaches, mood changes, and breast tenderness, as experienced by 13/40 patients in the present study. study. Our data confirm the good tolerability of this drug according to the EQ-5D questionnaire. Clinical and research implications Concerning the treatment regimen, in this study, a continuous administration of E4/DRSP was preferred over cyclic administration for better control of dysmenorrhea, as this scheme seems to be favorable for controlling pain [Citation32]. The totality of patients experienced the complete resolution of dysmenorrhea, as amenorrhea was induced. A systematic review and meta-analysis by Muzii et al. compared continuous versus cyclic CHC use for the treatment of endometriosis-related pain and reported that the continuous regimen appeared to be more effective in reducing dysmenorrhea, but no differences were observed for the relief of chronic pelvic pain and dyspareunia, although there was a trend toward lower cyst recurrence rates with continuous CHC use [Citation33]. Our study demonstrated a significant decrease in dyspareunia, which was already evident after three months of therapy, and in chronic pelvic pain after six months of therapy, thus confirming the findings reported in the review by Jensen et al., which observed a clinically significant reduction in both dyspareunia and noncyclic pelvic pain, resulting in a definitive improvement in quality of life [Citation34,Citation35]. Strengths and limitations Although the consistency of our results, our study has certain limitations: the retrospective nature, the small sample size, and the absence of endometriomas in some patients. Another limitation is the criterion of choosing CHCs, instead of progestin-only treatment, not to deprive patients of the benefits of estrogen and the contraceptive effect, which was requested by the patients themselves. Moreover, the last limitation could be the lack of stratification of the population by disease stage. However, we do not believe this could alter the preliminary data, given that endometriosis symptoms are common in all stages.

Our results suggest that CHC containing E4/DRSP might represent a well-accepted treatment for women with endometriosis, reducing dysmenorrhea, chronic pelvic pain, and dyspareunia. Furthermore, the success in reducing endometriomas, although not significant, drove us to propose administering the therapy for a longer time so as to be fully conscious of the benefits of this hormonal therapy, even in patients with ovarian endometriosis. The observational and retrospective design and the small size of our samples make our results preliminary; therefore, further studies are needed to validate them. However, we believe that this CHC containing E4/DRSP could be a valid alternative for symptomatic patients with endometriosis. Short condensation This study assesses the impact of estrogen/drospirenone on chronic pelvic pain and endometriosis symptoms. Results reveal significant reductions in dysmenorrhea and dyspareunia, along with improved quality of life, underscoring its potential as a novel therapeutic option. Disclosure statement No potential conflict of interest was reported by the author(s). Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Data availability statement The datasets generated during the study are available from the corresponding author upon reasonable request.

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