How We Can Optimize Dysmenorrhea Treatment: Real-World Results from a Cross-Sectional, Multi-Center Study

A total of 969 subjects responded to the questionnaire and 821 subjects stated dysmenorrhea (all women, mean age 30.68 ± 6.92 years, range 15–54 years). Further details of the study participants are shown in Fig. 1 . A total 266 patients had no surgical treatment of endometriosis (no-STE) (all women, mean age 28.10, range 15–43). Among them, 42 patients (7%) underwent surgery for endometriosis symptoms, but endometriosis diagnosis could not be made surgically. Ninety-five subjects (35.7%) were currently receiving EDT. Of these, nine reported that their hormonal therapy was not prescribed for dysmenorrhea or endometriosis, although the treatment may still alleviate dysmenorrhea symptoms. 171 subjects (64.3%) were currently not using EDT. The sociodemographic data are shown in Table 1 . Subjects receiving EDT were significantly younger than patients not receiving EDT (mean age 26.58 [95% CI 25.22–27.94] vs. 28.95 [95% CI 28.08–29.82] years; p = 0.003). Patients not receiving EDT did not significantly differ from patients who received EDT in terms of intensity of dysmenorrhea (7.35 [95% CI 7.08–7.62] vs. 7.52 [95% CI 7.18–7.87] VAS), degree of impairment caused by dysmenorrhea and restrictions in work, family and leisure time (see Table 1 ). In the group not receiving EDT, 149 subjects (87.1%) did not undergo surgery due to dysmenorrhea (see Table 1 ). Patients taking pain medication (n = 241; 90.6%) for the treatment of dysmenorrhea had a significantly higher VAS pain level in comparison to those not taking pain medication (mean pain level of patients using pain medication 7.61 (95% CI 7.41–7.80) versus non-users 5.15 (95% CI 4.00–6.30), F = 45.961, p < 0.001). Pain medication is taken by 87 (91.6%) subjects using EDT and by 154 subjects (90.1%) not using EDT during menstruation due to dysmenorrhea, with no significant difference between the groups (F = 0.165; p > 0.05; see Table 1 ). Taking pain medication resulted in a lower VAS score of dysmenorrhea in both groups (5.06 [95% CI 4.58–5.55] VAS vs. 4.63 [95% CI 4.29–4.98] VAS). There was no significant difference in VAS score when treated with pain medication treatment within groups (F = 2.073; p > 0.05; see Table 1 ). The EDT types used are listed in Table 2 . The active ingredients used are displayed in Table 3 . 63 of the subjects (66.3%) who used EDT reported that they had no amenorrhea during the last three months. Of these 63 subjects who menstruated or reported vaginal bleeding, 14 subjects were on cyclical combined hormonal contraceptives (100% of cyclical users) and 16 subjects were on long-term/continuous combined hormonal contraceptives (59.2% of long-term/continues users). Nineteen patients were on long-term progestogen contraceptives including long-term dienogest intake (n = 9). Accordingly, 36% of dienogest users reported vaginal bleeding within the last three months, while 76.9% of patients taking other progestogens experienced vaginal bleeding within the last three months (F = 7.943, p < 0.001). 87.5% (n = 14) of LNG-IUD patients reported vaginal bleeding. The comparison of the different treatment groups is shown in Supplementary Table S1 (online). 86 subjects who do not currently use EDT have used it in the past (90.5%). The most frequently reported reasons for rejecting endocrine therapy were side effects (n = 70; 40.9%) and a general refusal to take synthetic hormones (n = 68; 39.8%). Concerns about thrombosis were mentioned by 29 patients (17.0%). Migraine with aura was reported as a reason without prior physician advice by 16 patients (9.4%), and an additional 16 patients (9.4%) stated that their physician recommended avoiding hormonal treatment due to migraine with aura. Fourteen patients (8.2%) reported a desire for childbearing as the main reason for declining therapy. Previous thrombosis (n = 2; 1.2%) and migraine without aura without physician suggestion (n = 1; 0.6%) were mentioned less frequently. Other reasons were cited by 11 patients (6.4%). Multiple reasons could be reported (see Fig. 2 ). Reasons given by patients for refusing hormone treatment. Multiple answers were possible. The prevalence of migraine with and without aura as a secondary diagnosis is shown in Table 1 . Migraine with never-occurring aura was a secondary diagnosis in 26 patients who did not use an EDT. The risk of migraine with never-occurring aura was not increased in the subgroup of patients who did not use EDT. Migraine with aura was present in 29 patients who did not use EDT. The risk of migraine with aura was not increased in the subgroup of subjects without EDT compared to those with EDT. Four migraine patients with migraine without aura (15.4%) reported that their physician had not prescribed hormonal treatment due to their migraine, while 19 migraine patients with aura (65.6%) stated that their physician had not prescribed them hormonal treatment due to their migraine.

A cross-sectional multi-center study was conducted from May to November 2023 via an online survey platform ( https://www.umfrageonline.com ). Patients were recruited via an e-mail invitation to patients from two university hospital endometriosis centers with patient visits between January 2017 and March 2023 and permission for e-mail follow-up in May 2023 (UKSH Kiel, UKSH Lübeck, Germany). Further recruitment was carried out by the German Endometriosis Association via the homepage and social media channels. Inclusion criteria for the survey were postmenarcheal and premenopausal women with a history of menstrual pain or endometriosis – regardless of severity, as assessed by self-report –, who were able to understand German language. The study questionnaire was developed by the research team, pilot-tested in a sample of patients for clarity. The survey assessed sociodemographic and clinical characteristics, comorbidities, menstrual and endometriosis-related symptoms, quality of life, surgical diagnosis/treatment, and hormonal and analgesic management, including type and regimen of hormone therapy. Premenopausal status was defined as self-reported time between menarche and menopause, confirmed by current menstruation or ongoing hormonal treatment; other causes of amenorrhea, such as previous hysterectomy or current pregnancy, were also assessed in this context. However, in this analysis we focus only on subjects with dysmenorrhea and non-surgically treated endometriosis (no-STE). Surgical treatment of endometriosis was defined as removal of at least some endometriosis tissue. Subjects with incomplete questionnaires and/or who did not fulfil the inclusion criteria were excluded from the analysis. Only patients who completed and submitted the full online questionnaire were included; however, single unanswered items were left blank and excluded from analysis on a per-item basis. Patients with no-STE and no menstrual bleeding within the last three months, which could not be explained with an active hormonal treatment were excluded (see Fig. 1 ). Flowchart of participant enrolment and analysis. Before participation in the study, information was provided on the average expected response time, the objectives of the study and the voluntary nature of participation. In order to start the survey, the subjects had to agree on study participation and anonymized data storage. Ethics approval for this study was issued by the Ethics Committee of University of Lübeck (AZ2023–287) prior to recruitment in 2023. For statistical analysis Statistical Package for Social Sciences (IBM SPSS Statistics for MAC, Version 22.0. Armonk, NY: IBM Corp) was used. Statistical significance was set at p < 0.05 (two-sided). One-way analysis of variance (one-way ANOVA) was used for comparisons between groups who utilized endocrine dysmenorrhea treatment (EDT) and those that were not using EDT. Descriptive analyses were expressed as mean ± standard deviation (SD). Absolute numbers and percentages are additionally stated. The Shapiro-Wilk test was performed to determine whether variables were normally distributed.

As dysmenorrhea and endometriosis have a high prevalence and cause high socioeconomic costs and reduced quality of life, appropriate treatment of these patients is essential. Our study demonstrates that endocrine therapy for dysmenorrhea is underutilized, despite its role as guideline-recommended first-line treatment. Patient attitudes towards artificial female sex hormones and concerns regarding side effects, thrombosis and migraine substantially influence treatment choices and highlight the need for structured counselling and shared decision-making. Many patients therefore refrain from using endocrine therapy, while surgical treatment should be reserved for selected cases or when medical management fails.

Our real world data show important potential to improve the management of women with clinical dysmenorrhea, which have not received surgical treatment either because no endometriotic lesions have been found and removed surgically – or because they never have received surgery. Many of our participants with no-STE do not use EDT (64.3%) and 87.1% of those have not received surgery for diagnosis and possible treatment of endometriosis. Although pain medication for dysmenorrhea is used very frequently, pain levels are still high, so the overall treatment cannot be considered ideal. Patients undergoing EDT sometimes use it cyclically (14.7% of subjects on EDT). Induced amenorrhea and thus prevention of menstruation and dysmenorrhea as result of prolonged/continuous use of EDT only applies to 65.9% of combined hormonal contraceptive users. A small subgroup of patients reported using hormonal therapy not primarily for dysmenorrhea or endometriosis (n = 9). Nevertheless, as such treatments may still alleviate menstrual pain, their inclusion reflects real-world treatment patterns in which hormonal preparations often serve multiple indications. The main reasons for refusing EDT are (fear of) negative side effects, refusal to take synthetic hormones, comorbidity with migraine with or without aura, fear of thrombosis or the desire to become pregnant. The treatment of dysmenorrhea may, in selected cases, include surgery to locate, visualize, and remove endometriotic lesions, which can potentially improve symptoms 7 . According to current ESHRE guidelines, both diagnostic laparoscopy with surgical removal of lesions and an empirical approach with EDT (combined oral contraceptives or progestogens) are acceptable options in women suspected of endometriosis and are known to be an effective treatment for dysmenorrhea 7 13 . Surgery should therefore be considered as one possible option to reduce endometriosis-associated pain, taking into account its invasive nature, potential morbidity, and the need for individualized counselling of patients regarding benefits and risks 7 . Patients receiving hormonal therapy were younger (mean 26.58 vs. 28.95 years, p = 0.003), which may reflect treatment patterns rather than symptom severity alone. Younger women typically more often attend gynecological consultations, for example also for contraception purposes, which may contribute to the prescription of hormonal therapy 19 Combined oral contraceptives (COCs) are usually used to reduce menstrual pain 13 , but progestogens are also an option for empirical first-line treatment of women with suspected endometriosis 7 20 . In the case of endometriosis, progestogens as the first-line treatment are recommended, as they effectively suppress endometriosis-associated pain and avoid the potential risk of hidden disease progression that may occur under estrogen-containing combined oral contraceptives 21 22 . Overexpression of the estrogen receptor and underexpression of the progesterone receptor in ectopic endometrial implants are possible causes 21 22 . Dienogest as a progestogen monotherapy which inhibits ovulation at a dose of 2 mg is not officially a contraceptive pill but is an approved treatment for endometriosis 23 . It is effective in inhibiting/reducing symptoms associated with endometriosis 24 25 . In the past, dienogest has not been used primarily for dysmenorrhea without proven endometriosis because of the high cost of treatment 22 . Our study now shows that dienogest as a monotherapy appears to be the main progestogen used to treat dysmenorrhea today. It is known that continuous use of COCs leads to a greater reduction in pain than standard use 13 . This was also seen in our study. 100% of the patients using standard hormonal contraceptives reported dysmenorrhea and menstruation within the last 3 months, compared with 59.2% of patients on continuous/extended use. COCs in the treatment of dysmenorrhea also have the advantage that the tailored cycle in the continuous cycle (4-days treatment break after 3 consecutive days of vaginal bleeding or spotting) may lead to shorter periods of bleeding and pain than in those using dienogest 22 26 . Continuous/extended use of COCs is considered safe 27 28 29 . Some preparations have been approved for extended use (91 days to 120 days) 30 31 . A preparation containing 90 µg levonorgestrel and 20 µg ethinylestradiol is approved for 365 days 27 28 , but is not currently available in some countries. However, off-label continuous use of COCs is conceivable and is even recommended by the British FSRH guideline 29 . Although EDT is effective in reducing dysmenorrhea and improving quality of life and reducing absenteeism from work/school 13 , women of reproductive age are known to refuse endocrine treatment of endometriosis symptoms because of side effects, fear of possible side effects, and the desire to live without synthetic hormones 14 15 32 33 . In addition, women with known ovarian endometriosis have been shown to refuse endocrine therapy putting their reproductive health at unnecessary risk 16 . Interestingly, it has also been shown that endometrioma patients were significantly less likely to take hormone therapy in the past and in the present, so the use of EDT could reduce the risk of ovarian endometriosis formation 16 . Moreover, women with ovarian endometriosis reported in the present comparable levels of dysmenorrhea and analgesic consumption as those with other forms of the disease but no endometriomas, indicating that the overall symptom burden does not explain their lower acceptance of endocrine treatment, as they also take significantly less hormone therapy in the present 16 . COCs have been reported to increase the likelihood of thrombosis (relative risk 3.5, 95% CI 2.9–4.3) 34 . However, the background risk of thromboembolism in premenopausal women is low (5/10000 per women-year) 35 . Some data show that arterial or venous thrombosis is not significantly increased using progestin-only hormone therapy compared with no use 36 . However recent data reported that progestin-only pills were associated with a slightly increased risk of ischemic stroke (adjusted rate ratio 1.6; about 15 extra cases per 100000 person-years) and myocardial infarction (adjusted rate ratio 1.5; about 4 extra cases per 100000 person-years), while the levonorgestrel-IUD showed no excess risk 37 . The observed increase in arterial thrombotic risk with progestin-only pills, implants, and injections in this study should be interpreted with caution, as the number of events in these subgroups was low and the estimates therefore remain subject to statistical uncertainty 37 . However also depot medroxyprogesterone acetate (DMPA) is known to increase the risk of thrombosis 36 . Even in the presence of a history of thromboembolism, the use of progestin-only hormones does not significantly increase the incidence rate of recurrent venous thromboembolism 38 . Despite the potential benefits of EDT, patients appear to overestimate the risk of thrombosis. When discussing this with patients, clinicians should put this into perspective and remember that progestin-only therapy remains an option in all cases. Importantly, given the rarity of arterial thrombotic events and the high burden of dysmenorrhea symptoms, the overall benefit–risk profile remains favorable 37 . Potential adverse effects such as mood changes, depressive symptoms, and libido alterations must be considered when counseling women with dysmenorrhea regarding hormonal therapy. While randomized trial evidence does not confirm a causal link with depressive symptoms 39 , large-scale registry data indicate an increased risk of antidepressant use with several hormonal methods, including combined oral contraceptives (RR 1.23), progestin-only pills (RR 1.34), and the levonorgestrel IUD (RR 1.4) 40 . Regarding sexual function, data from the Contraceptive CHOICE Project suggest that lack of sexual desire was more frequently reported with depot medroxyprogesterone acetate, the vaginal ring, and implants, but not with oral contraceptives or the levonorgestrel IUD 41 . A meta-analysis investigating treatment of adenomyosis patients showed that dienogest has a side effect profile comparable to the levonorgestrel IUD 42 . These potential side effects, together with other tolerability concerns, need to be carefully weighed against the substantial analgesic and overall therapeutic benefits of hormonal treatment. Other reasons why patients refused EDT were migraine with and without aura. Screening instruments, such as the ID Migraine or MS-Q questionnaires, can facilitate the initial differentiation of migraine with versus without aura based on patient self-reports, as highlighted in expert consensus guidelines on migraine diagnosis 43 . Migraines with and without aura are known to be associated with an increased risk of stroke with an incidence of 5.9/100000 and 4.0/100000 per year respectively 44 . Individuals with migraine with aura have a two-fold increased risk of ischemic stroke compared to those without migraine 45 , although the absolute risk remains low 46 . However, some studies cannot confirm increased risk in individuals with migraine without aura 45 . The different risk may be explained by biological mechanisms, since migraine aura may change vascular reactivity and endothelial dysfunction by cortical spreading depression, while migraine without aura does not feature the same vascular and cortical disruptions 47 . The risk of stroke in migraineurs appears to be further increased by the use of COCs compared with non-users: 25.4/100000 per year versus 4/100000 for migraine without aura and 36.9/100000 versus 5.9/100000 for migraine with aura 44 . The consensus working group of the European Headache Federation (EFH) and the European Society of Contraception and Reproductive Health (ESCRH) stated that – also in the case of migraine with and without aura – either progestin-only or COCs can be used for the treatment of endometriosis symptoms on “clinical grounds” 44 . Progestin-only pills are safe in patients with a history of migraine with or without aura in terms of stroke risk. One of the solutions to overcome hormone phobia and refusal to use EDT could be that EDT could be offered to patients with the option to stop or switch immediately if intolerable side effects occur and the risk-benefit ratio is not positive from the patient’s perspective. In all cases where further endocrine treatment is not desired or is not as effective as intended and there is no immediate desire to become pregnant, surgery for dysmenorrhea should be offered with the intention of diagnosing and treating endometriosis. Adequate counselling has been shown to significantly reduce anxiety levels in women with suspected endometriosis, emphasizing the need for structured patient education to overcome hormone-related concerns 48 . In women who wish to become pregnant, within six months (depending on the patient’s age and other factors), diagnostic and therapeutic surgery could be offered with the aim of improving the likelihood of pregnancy, diagnosing infertility and reducing pain. Early intervention is critical, as a prolonged duration of infertility prior to surgery significantly reduces postoperative pregnancy rates if endometriosis is present 49 . In the case of endometriosis diagnosis by imaging and gynecological examination with suspected infertility a referral to an IVF center should be also discussed 7 . Strengths of our study include its large, multicenter real-world cohort of German-speaking women with dysmenorrhea and the comprehensive documentation of treatment patterns, symptom burden, and patient-reported barriers to endocrine therapy. This real-world perspective highlights discrepancies between guideline recommendations and patient decision-making. However, several limitations must be acknowledged. Due to the anonymous nature of the online survey, patient responses could not be validated against medical records, and the self-reported information may therefore be subject to recall bias or individual perception influenced by dysmenorrhea symptoms or prior hormone use. Furthermore, selection bias is likely, as participation was voluntary and recruitment occurred mainly via endometriosis centers and the German Endometriosis Association, potentially attracting women with a higher symptom burden, health awareness or educational level.

Painful menstruation cramps (dysmenorrhea) are common in women. Prevalence rates of women with dysmenorrhea in studies with representative samples range from 16.8 to 81% 1 2 3 , with a meta-analysis showing an estimated overall prevalence of 71.1% 4 . Chronic pelvic pain (which is often associated with endometriosis and includes dysmenorrhea in particular) can severely affect women’s health and have a negative impact on quality of life. Labor productivity/absenteeism also causes costs with a socioeconomic burden on the healthcare system and society 1 5 6 . Therefore, appropriate treatment of severe, disruptive and disabling dysmenorrhea is crucial for society. Differential diagnoses for dysmenorrhea include primary dysmenorrhea, endometriosis, adenomyosis, pelvic inflammatory disease, and uterine fibroids. Endometriosis, a chronic, hormone-dependent condition, often requires long-term management. Signs of endometriosis can be detected by gynecological examination and imaging techniques such as transvaginal ultrasound. However, the histological diagnosis of endometriosis is made by surgery, particularly laparoscopy 7 . Literature shows that endometriosis is confirmed by surgery in about 70% of the patients with endometriosis symptoms 8 9 . Surgery is invasive and may be associated with morbidity and mortality, but the removal of endometriosis lesions may be associated with a reduction of overall pain 7 10 . Especially if hydronephrosis is present due to compression/infiltration of the ureter by deep infiltrating endometriosis, surgical treatment is required to prevent kidney damage. Surgical detection, resection, histological proof of endometriosis and the resulting visualization of this hidden disease can further be an important psychological factor for these patients and their environment 7 . However, a risk/benefit assessment should always be carried out before surgery 7 10 11 12 . Residual dysmenorrhea after endometriosis surgery or prophylaxis for endometriosis/pain recurrence can be treated with endocrine therapy e.g. dienogest, hormonal contraceptives or GNRH-analogues and antagonists in combination with estrogen add-back. Pragmatic empirical treatment of dysmenorrhea can be carried out with hormonal contraceptives or progestogens when clinical and sonographic evaluation suggests endometriosis or in the absence of other identifiable pathology 7 13 . It is known that hormonal contraceptives can reduce dysmenorrhea, especially when taken continuously compared to standard cyclical usage 13 . Despite the potential benefits of hormonal contraceptives or progestogens in endometriosis and dysmenorrhea, many patients show a negative attitude towards these therapies, which leads to lower compliance 14 15 . Notably, hormonal treatment is also frequently rejected in the presence of endometriomas, although this refusal is not consistent with current medical evidence, as it entails a considerable risk of recurrence and, in young women, may compromise future fertility 16 . Negative associations and a decline in the use of oral contraception are also observed in patients without endometriosis 17 18 . In this analysis of a cross-sectional study, we investigate the prevalence of endocrine treatment of dysmenorrhea and the use of pain medication in a cohort of dysmenorrhea patients without a history of surgical endometriosis treatment and histologically proven diagnosis of endometriosis.

Supplementary Table S1 : Endocrine dysmenorrhea treatment; comparison of cyclical use, extended/continuous use, long term progestogen intake, LNG-IUD.