Evaluation of the long-term efficacy and safety of dydrogesterone in the treatment of endometriosis/dysmenorrhea

A total of 45 patients had endometriotic lesions (including patients who did not complete 12 cycles of treatment and follow-up), and the endometriotic lesion volume decreased in 28 patients (62.22%, 28/45), remained unchanged in 10 patients (22.22%, 10/45), and increased in 7 patients (15.56%, 7/45). 40% of the patients had reduced lesions after 3 cycles of treatment, and nearly 60% of the patients had reduced lesions after 6 cycles of treatment. There was no significant difference in the initial lesion volume between the increased, decreased, and unchanged groups ( p  = 0.082) (Table 2 ; Fig. 2 ). Table 2 Changes in endometriotic lesion volume during treatment Cycle Endometriotic lesion volume (cm 3 ) Increased ( n %) Unchanged ( n %) Decreased ( n %) n P Initial 65.73 ± 67.89 - - - 45 - Cycle 3 59.06 ± 65.02 8 (17.78%) 19 (42.22%) 18 (40.00%) 45 0.008 Cycle 6 47.26 ± 56.46 8 (18.18%) 10 (22.73%) 26 (59.09%) 44 0.001 Cycle 9 27.54 ± 23.53 7 (19.44%) 10 (27.78%) 19 (52.78%) 36 0.001 Cycle 12 24.83 ± 21.60 6 (17.14%) 6 (17.14%) 23 (65.71%) 35 < 0.001 (Paired Wilcoxon signed-rank test.) Fig. 2 Changes in endometriotic lesion mean volume during treatment Changes in endometriotic lesion volume during treatment (Paired Wilcoxon signed-rank test.) Changes in endometriotic lesion mean volume during treatment The mean volume (SD) of the ovarian endometriomas ranged from 50.08 (± 41.74) cm 3 before treatment ( n  = 39) to 22.20 (± 14.37) cm 3 after 12 cycles ( n  = 31). From baseline to the end of 12 cycles, the cyst volume decreased in 18 patients (51.34%). (Supplementary Table 2, Supplementary Fig. 1). The mean volume (SD) of adenomyoma lesions ranged from 100.47 (± 91.47) cm 3 before treatment ( n  = 10) to 30.15 (± 34.96) cm 3 at cycle 12 ( n  = 6). More than 60% of the patients had reduced adenomyoma lesion volume after 6 cycles of treatment. The adenomyoma lesion volume at the 6th treatment cycle significantly differed from that before treatment ( p  = 0.031) (Supplementary Table 3). As shown in Supplementary Table 4, patients with larger initial endometriotic lesion volumes were more likely to withdraw from treatment ( p  = 0.031). The VAS score tended to decrease throughout the study ( p  < 0.001). The mean VAS score ranged from 4.83 (± 1.94) before treatment to 2.13 (± 1.82) after 12 cycles ( n  = 46). More than 80% ( n  = 37, 80.43%) of patients experienced relief of dysmenorrhea after 2 cycles of treatment, and more than 75% ( n  = 35, 76.09%) of patients did not need analgesics during menstruation after 3 cycles of treatment. The baseline VAS scores of the cured and remitted patients were 3.21 (± 1.19) and 5.53 (± 1.78), respectively, and the difference was statistically significant ( p  < 0.001) (Table 3 ; Fig. 3 ). There was no significant difference in the initial VAS score between patients who completed treatment and those who withdrew from treatment ( p  = 0.124) (Supplementary Table 4). Table 3 Changes in VAS score and analgesic use during treatment Cycle VAS Analgesic use No Remission ( n %) Partial Remission ( n %) Complete Remission ( n %) n P Initial 4.83 ± 1.94 39 - - - 46 - Cycle 1 4.37 ± 1.88 39 25 (54.35%) 21 (45.65%) 0 (0%) 46 < 0.001 Cycle 2 4.02 ± 1.90 36 9 (19.57%) 37 (80.43%) 0 (0%) 46 < 0.001 * Cycle 3 2.13 ± 1.82 11 3 (6.52%) 41 (89.13%) 2 (4.35%) 46 < 0.001 * Cycle 6 1.30 ± 1.01 0 0 (0%) 35 (81.40%) 8 (18.60%) 43 < 0.001 * Cycle 9 0.45 ± 0.99 0 0 (0%) 10 (27.78%) 26 (72.22%) 36 < 0.001 Cycle 12 0.28 ± 0.57 0 0 (0%) 6 (17.14%) 29 (82.86%) 33 < 0.001 (Note: * paired Student’s t test, others paired Wilcoxon signed-rank test.) Fig. 3 Changes in the mean VAS score during treatment Changes in VAS score and analgesic use during treatment (Note: * paired Student’s t test, others paired Wilcoxon signed-rank test.) Changes in the mean VAS score during treatment The mean Ca125 concentration ranged from 27.98 (± 15.13) U/mL before treatment to 22.66 (± 6.17) U/mL at cycle 12 ( n  = 38). There was no significant difference in CA125 levels before and after treatment ( p  > 0.05) (Table 4 ). Table 4 Ca125 levels during treatment Ca125 Mean(± SD) IU/mL P Initial 27.98 ± 15.13 0.191 Cycle 3 27.35 ± 12.89 0.225 Cycle 6 26.94 ± 12.23 0.137 Cycle 9 24.08 ± 8.09 0.090 Cycle 12 22.66 ± 6.17 0.286 (Paired Wilcoxon signed-rank test.) Ca125 levels during treatment (Paired Wilcoxon signed-rank test.) Forty-eight patients completed the SF-36 questionnaire. After treatment, the quality of life scores in 7 dimensions of the SF-36 were significantly greater than those before treatment ( p  < 0.001), except for mental health ( p  = 0.054). Body pain improved the most. The mean BP score ranged from 47.29 (± 18.65) before treatment to 85.63 (± 7.41) after 12 cycles ( n  = 46) (Table 5 ). Table 5 SF-36 scores before and after treatment SF-36 subscales Before Treatment After Treatment P Physical Functioning (PF) 80.83 ± 11.36 92.5 ± 6.27 < 0.001 Role limitations due to physical problems (RP) 52.60 ± 18.76 80.21 ± 16.27 < 0.001 Body Pain (BP) 47.29 ± 18.65 85.63 ± 7.41 < 0.001 General Health (GH) 54.38 ± 12.53 65.83 ± 9.75 < 0.001 Vitality (VT) 62.08 ± 11.66 68.69 ± 7.68 < 0.001 Social Function (SF) 71.88 ± 14.70 86.20 ± 9.38 < 0.001 Role limitations due to emotional problems (RE) 75 ± 26.18 85.41 ± 18.07 0.001 Mental Health (MH) 65.58 ± 10.16 66.67 ± 8.63 0.054 (Paired Wilcoxon signed-rank test.) SF-36 scores before and after treatment (Paired Wilcoxon signed-rank test.) After 3 menstrual cycles of treatment, anaemia significantly improved compared with that before treatment, haemoglobin levels significantly increased compared with before treatment ( p  < 0.0010), and the menstrual period significantly decreased compared with that before treatment ( p  < 0.001) (Supplementary Table 5). AEs, including breast pain (14.6%), irregular bleeding (10.42%), drowsiness (4.17%), and dizziness (2.08%), occurred in 15 patients (31.25%) (Supplementary Table 6). All of these were mild to moderate and occurred mainly during the first 3 cycles of treatment and gradually decreased with increasing medication duration. No serious adverse drug events or adverse reactions, such as thrombosis, occurred. Two patients became pregnant during treatment, and one patient successfully delivered a female infant at term.

This was a retrospective study in which patients with endometriosis or dysmenorrhea (including postoperative recurrence) who strongly needed drug therapy from May 2020 to October 2021 at Shaanxi Provincial People’s Hospital were included. The protocol was approved by the ethics committee of Shaanxi Provincial People’s Hospital (IRB No. R182). The inclusion criteria were as follows: (1) Patients with endometriosis between the ages of 14 and 50 years who had been clinically diagnosed or who had been diagnosed after surgery and who needed medical treatment; (2) who had not taken combined OCs, pregnancy hormone medications, GnRH-a, the levonorgestrel-releasing intrauterine system, androgen derivative sedatives, analgesics, or Chinese herbal medicine during the previous three menstrual cycles; and (3) who were willing to use dydrogesterone for endometriosis treatment after being fully informed and able to clearly assess the level of pain. All patients provided informed verbal consent to participate in the study. The exclusion criteria were clinical suspicion or surgical pathological diagnosis of malignancy, pregnancy or breastfeeding, severe liver or kidney disease, allergy to any component of the study drug, severe cardiovascular disease, hormone-dependent tumour, history of thrombotic disease, or contraindication to the use of the study drug. Dydrogesterone (Duphaston ® ) was used at 10 mg per 12 h daily for 21 days/cycle (5 to 25 days of each menstrual cycle) for a total of 12 cycles. Follow-up administration: The patients were followed up per menstrual cycle after taking medication during the first 3 cycles and after cycles 6, 9, and 12. Changes in endometriosis and adverse reactions were recorded. Changes in endometriotic lesions by transvaginal ultrasound, conducted by an ultrasonographer with extensive experience in gynaecologic sonography, particularly in the field of endometriosis, according to the ultrasound diagnostic criteria and classification of endometriosis reported in previous literature [ 20 , 21 ]. Routine blood tests were performed using the electrical impedance flow method. Serum carbohydrate antigen 125 (Ca125) was detected using a chemiluminescence immunoassay. The Medical Outcomes Study 36-item short-form survey (SF-36) [ 22 ] was administered before and at the end of treatment. The patients were followed up per menstrual cycle after taking medication during the first 3 cycles and after cycles 6, 9, and 12. Changes in endometriosis and adverse reactions were recorded. Changes in endometriotic lesions by transvaginal ultrasound, conducted by an ultrasonographer with extensive experience in gynaecologic sonography, particularly in the field of endometriosis, according to the ultrasound diagnostic criteria and classification of endometriosis reported in previous literature [ 20 , 21 ]. Routine blood tests were performed using the electrical impedance flow method. Serum carbohydrate antigen 125 (Ca125) was detected using a chemiluminescence immunoassay. The Medical Outcomes Study 36-item short-form survey (SF-36) [ 22 ] was administered before and at the end of treatment. Endometriotic lesions (including ovarian endometriotic cysts and adenomyomas) were examined by transvaginal ultrasound from baseline to every 3 menstrual cycles. The maximum diameter of the endometriotic lesion (D1) and the diameter orthogonal to D1 (D2) were measured. The endometriotic lesion was assumed to be spherical, its volume was calculated using the equation [(D1 + D2) ×1/2] 3 × 0.52 cm 3 , and the total volume was recorded for multiple lesions. The volume change was calculated as follows: [(baseline lesion volume–lesion volume at follow-up)/baseline lesion volume]*100%. The patients were divided into three groups: reduced (>+ 15%), unchanged (± 15%), and increased (> −15%), with the number of patients in each group being counted [ 23 ]. Dysmenorrhea was assessed by means of visual analogue scale (VAS) scores [ 24 ]. SF-36 scores were recorded at baseline and at the end of treatment. Ca-125 levels were measured during the nonmenstrual period at baseline and at follow-up during treatment. The patients’ menstrual cycles, menstrual periods, and haemoglobin levels were recorded on the medical records form (routine clinical documentation) before treatment and at each follow-up visit. All the changes were compared between each follow-up visit during treatment and before treatment. The drug safety indicators of this study included the occurrence and incidence of adverse events (AEs) and adverse drug reactions (ADRs) among the study subjects during treatment. An adverse reaction was defined as any adverse or unexpected sign (including laboratory outliers), symptom, or illness that was transiently associated with the use of a drug, whether or not it was considered causally related to the drug. An adverse effect was defined as any adverse drug event that could not be ruled out as causal. Adverse drug events and adverse reactions were recorded separately by type, severity, and incidence throughout the study. The data were analysed using IBM SPSS Statistics v25.0 (IBM Inc., Chicago, IL). Descriptive data are represented as the means (± SD), skewed data are expressed as the medians and ranges, and categorical data are described as percentages. Parametric tests were used for normally distributed data, whereas nonparametric tests were used for data that did not fit a normal distribution. To determine if the data followed a normal distribution, the K‒S test was used. The paired Wilcoxon signed-rank test or paired Student’s t test was used to compare pre- and postoperative paired data. All the statistical tests were two-sided, with P values at the 5% level considered significant.

The process of patient enrolment in this study is shown in Fig. 1 . The efficacy and safety analysis set included 48 of the 50 recruited individuals. Subjects who received further endometriosis-related medications and one who was lost to follow-up were not included. Fig. 1 Study flowchart Study flowchart During the observation period, 10 patients (20.83%) discontinued treatment at different times. The reasons for discontinuation were as follows: AEs occurred in 2 patients (4.17%, breast pain and irregular bleeding), and 8 patients (16.67%) were unwilling to continue taking the drug for their own reasons, including 3 patients (6.25%) who planned to undergo artificial assisted reproduction, 3 patients (6.25%) who planned to undergo surgery, and 2 patients (4.17%) who became pregnant during treatment. A total of 38 subjects completed 12 cycles of medication and follow-up. The characteristics of the 48 patients and 10 patients who discontinued treatment analysed in the study are shown in Table 1 and Supplementary Table 1, respectively. Table 1 Demographic and clinical characteristics of the study patients Parameter Mean ± SD or number Age (years) (Median, Mean ± SD) 33, 34.04 ± 6.09 Age range (years) 25–47 ≥ 20, < 30 (n%) 15 (31.25%) ≥ 30, <40 (n%) 24 (50%) ≥ 40, <50 (n%) 9 (18.75%) Height (cm) (Median, Mean ± SD) 161.08 ± 3.91 Weight (kg) (Median, Mean ± SD) 59.73 ± 5.69 BMI (Median, Mean ± SD) 23.06 ± 2.50 Menstrual cycle length (d) (n, Range, Median, Mean ± SD) n  = 48, 20–70, 28, 32.44 ± 10.06 Regular menstrual cycle (d) (n, Range, Median, Mean ± SD) n  = 40, 25–35, 27, 27.85 ± 2.51 Irregular menstrual cycle (d) (n, Range, Median, Mean ± SD) n  = 8, 20–70, 50, 49.38 ± 14.25 With endometrial abnormal uterine bleeding (AUB) 5 With endometrial polyp 3 Types of disease 48 Ovarian endometriotic cysts 35 Adenomyosis or adenomyoma 6 Ovarian endometriotic cysts with adenomyosis or adenomyoma 4 Dysmenorrhoea 3 Dysmenorrhoea condition (Yes/No) 46/2 Mild 11 Moderate 24 Severe 11 History of allergy (Yes/No) 25/23 Dyspareunia (Yes/No) 11/37 Fertility requirements (Yes/No) 22/26 History of previous treatment for endometriosis (Primary treatment/Operation/Medicine/Operation + medicine) 24/10/11/3 (Note: The menstrual cycle length of patients with irregular menstruation was taken as the average of the three menstrual cycles before treatment. Demographic and clinical characteristics of the study patients History of previous treatment for endometriosis (Primary treatment/Operation/Medicine/Operation + medicine) (Note: The menstrual cycle length of patients with irregular menstruation was taken as the average of the three menstrual cycles before treatment.

Endometriosis (EMT) is a prevalent disease in women of childbearing age. Approximately 10% of women of childbearing age [ 1 ], 20%−50% of infertile women [ 2 ], and 71%−87% of women with chronic pelvic pain have EMT [ 3 , 4 ]. EMT not only has negative effects on patients’ sexual function, social activities, work ability, and quality of life but also places a significant burden on financial costs and healthcare utilization [ 5 – 8 ]. Owing to the lack of specific symptoms and accurate and effective imaging detection methods (MRI or transvaginal ultrasound) for early or minor lesions and biomarkers, the diagnosis of EMT is frequently delayed [ 9 – 13 ]. The latest ESHRE guidelines suggest the start of empirical drug therapy as early as possible on the basis of clinical diagnosis [ 9 ]. Owing to the high recurrence rate of EMT, postoperative management via drug treatment is typically implemented for long durations. Therefore, the choice of long-term maintenance drugs is particularly important for symptom control and recurrence prevention. In recent years, low-dose oestrogen/progestin oral contraceptives (OCs) and low-dose progestin dienogest have gradually become the first-line drug choices for the treatment of endometriosis-associated dysmenorrhea because of their good tolerance. However, because of their effects on the hypothalamus‒pituitary‒ovary (HPO) axis and their ability to inhibit ovulation, they cannot address the treatment and pregnancy requirements of patients with EMT [ 11 , 14 ]. Dydrogesterone has gained attention as a treatment for endometriosis. Because its molecular structure is closest to that of natural progesterone, the regimen does not contain oestrogen, androgen, or mineralocorticoid activity, and its long-term use has a low risk of thrombosis, does not affect bone metabolism, and does not inhibit ovulation or affect the basal body temperature. This regimen seems to be the best choice for women with fertility requirements, EMT, and dysmenorrhea [ 14 – 17 ]. Although it did cause certain side effects, such as drip bleeding and breast swelling, these effects were all temporary, moderate, and acceptable for the vast majority of patients. However, clinical data on its efficacy in treating EMT are limited [ 18 , 19 ]. The aim of this retrospective observational study was to evaluate the efficacy and safety of long-term dydrogesterone treatment in Chinese women with EMT in a real-world setting and to provide clinical data for the long-term management of medical treatment for EMT.

This retrospective study assessed the clinical efficacy and safety of long-term dydrogesterone treatment in Chinese women with endometriosis and dysmenorrhea in a real-world setting. Approximately 80% of patients had reduced or unchanged endometriotic lesion volumes after 6 cycles of dydrogesterone treatment; more than 80% of the patients experienced partial relief of dysmenorrhea after two cycles of treatment, and the therapeutic effect increased with the extension of the treatment cycle. These findings align with those of previous research, although notable differences emerged [ 25 – 29 ]. However, the following points differ from those of previous studies: (1) Several earlier retrospective studies have shown that dydrogesterone does not improve the appearance of ectopic lesions under laparoscopy. However, the results of this study revealed that after dydrogesterone treatment, not only was dysmenorrhea relieved, but the endometrioid lesions in most patients also regressed or were maintained, as measured by transvaginal ultrasound, with these observations likely due to different detection methods and evaluation criteria [ 9 , 16 , 17 ]. Although laparoscopic exploration is the gold standard for the diagnosis of endometriosis, it is not the first choice for diagnosis or follow-up. Transvaginal ultrasound detection is more beneficial for clinical diagnosis, timely treatment, and posttreatment follow-up. The sensitivity and specificity for the diagnosis of endometriotic cysts are 93% and 95%, respectively, and the sensitivity and specificity for the diagnosis of adenomyosis are 82.5% and 84.6%, respectively [ 30 ]. Compared with laparoscopy, transvaginal ultrasonography may decrease the specificity for some lesion types. In accordance with the current guidelines, transvaginal ultrasound was the first recommended method for diagnosing endometriosis, and this study also conforms to the concept of providing drug treatment as soon as possible on the basis of clinical diagnosis [ 9 ]. (2) Most of the previous studies involved short- and intermediate-term treatments ranging from 2 to 6 months [ 18 , 19 , 23 , 29 ], while more than half of the patients in this study received treatment for as long as 1 year. Some patients may not experience obvious effects at the initial stage of treatment, with efficacy observed only after prolonged treatment. In addition, early randomized controlled studies were mostly used to evaluate the effect of postoperative maintenance treatment for endometriosis, but this study included some patients who were initially treated without surgery and found a positive effect with respect to this population. Previous studies focused mostly on ovarian endometriotic cysts or simple dysmenorrhea [ 23 , 25 , 28 , 29 ] and did not address the treatment of adenomyomas. This study also included some patients with adenomyosis, and more than 60% of the patients had significantly reduced adenomyoma lesion volume after 6 cycles of treatment ( p = 0.031). Additionally, the initial lesion volume did not significantly differ between the groups of patients who had reduced, increased, or unchanged lesions following treatment. This suggests that our conservative treatment may not be restricted to patients with small lesions, but this is still preliminary and needs more research. The Ca125 concentration slightly decreased during follow-up, but the change in the Ca125 concentration did not significantly differ from that before treatment in our study. The reason may be that the degree of the increase in the Ca125 concentration varies among different diseases, including pelvic inflammation, merged endometriotic cyst rupture, or uterine glandular myopathy. However, most of the patients in this study had simple endometriotic cysts, and the overall Ca125 level was normal or slightly increased. In addition, several studies have shown that the Ca125 level is not completely consistent with the changes in endometriotic lesions [ 31 – 33 ]. This study revealed that dydrogesterone improved quality of life in 7 dimensions of the SF-36 scale, except for mental health. Among the changes in the 7 dimensions, the improvement in the bodily pain score was the most significant (47.29 ± 18.65 vs. 85.63 ± 7.41, p  < 0.001). Additionally, both RP and GH significantly improved (52.60 ± 18.76 vs. 80.21 ± 16.27 and 54.38 ± 12.53 vs. 65.83 ± 9.75, respectively; p  < 0.001). This could be because dysmenorrhea and general health are intimately linked to these conditions. This study also revealed that the use of dydrogesterone in the treatment of dysmenorrhea can promote a trend towards normal menstruation with reduced menstrual volume and can mitigate anaemia in patients. These findings suggest that dydrogesterone may confer dual effects on endometriosis patients with abnormal menstruation. Several studies have shown that dydrogesterone at therapeutic doses does not inhibit ovulation but has a slight inhibitory effect on the H‒P‒O axis. Therefore, dydrogesterone offers unique advantages for patients with dysmenorrhea during adolescence, fertility requirements, and perimenopausal endometriosis. In this study, two patients conceived naturally during treatment, and one patient delivered normally. Despite the limited number of patients, the results provide an early indication of the treatment’s influence on the H‒P‒O axis and reproductive function. This study has several limitations. First, this study included some newly treated patients who were diagnosed only through clinical diagnosis rather than surgical diagnosis; thus, the ideal accuracy of surgical staging may not be achieved in judging the severity of the disease. Second, owing to ethical requirements and the limitations of retrospective studies, no control group was used in this study because the placebo control group was obviously not in line with the humanitarian spirit for patients with symptoms or lesions. However, rather than serving as the primary treatment of choice, other drugs in China at that time were generally only used for postoperative treatment for women of childbearing age because of their side effects, such as perimenopausal symptoms and ovulation inhibition. This does, in fact, undermine the credibility and evidence of the advantages of this treatment method. As treatment options for endometriosis have improved, some patients with endometriosis who do not require immediate fertility treatment have chosen COC or other medicines following clinical diagnosis. We intend to perform prospective, clinically controlled studies in the future to investigate potential long-term maintenance treatment options for endometriosis. Third, owing to the limited duration, the number of included patients, especially patients with adenomyosis who completed 12 cycles of treatment, was only 38. The endometriotic lesion volume changed from 65.73 ± 67.89 cm 3 to 24.83 ± 21.60 cm 3 . According to the PASS calculation, the power (1-β) was 99%, with a sample size of 38 and a significance level of α = 5% [ 34 , 35 ]. Furthermore, we referred to previous similar studies [ 23 , 29 ] and included a total of 31 to 52 cases for the effectiveness analysis, which was similar to the number of cases in our study. Therefore, the sample size of this study could reflect the therapeutic effect of dydrogesterone on a large sample population to a certain extent.

This study provides limited clinical data on the efficacy and safety of dydrogesterone in the long-term treatment of endometriosis in Chinese women. The results of this study suggest that long-term use of dydrogesterone can effectively control endometriotic lesions in most women and significantly improve dysmenorrhea and quality of life. Dydrogesterone may be a suitable conservative and long-term maintenance treatment option for endometriosis patients, especially for those with fertility requirements, adolescents, and perimenopausal patients.

Supplementary Material 1 Supplementary Material 1 Supplementary Material 2 Supplementary Material 2 Supplementary Material 3. Supplementary tables. Supplementary Material 3. Supplementary tables. Supplementary Material 4. Fig. S1 Changes in endometriotic cyst mean volume during treatment. Supplementary Material 4. Fig. S1 Changes in endometriotic cyst mean volume during treatment.