By Anna Rozzi, BA, and Maria I. Rodriguez, MD, MPH
Anna Rozzi is an MD candidate, Oregon Health & Science University, Portland. Dr. Rodriguez is Professor, Obstetrics & Gynecology, Division of Complex Family Planning, Department of Obstetrics & Gynecology, Oregon Health & Science University, Portland.
This multicenter, placebo-controlled, double-blind randomized clinical trial was conducted in 10 hospitals in China and enrolled 134 patients with diagnosed adenomyosis to evaluate mifepristone as an effective treatment for adenomyosis pain symptoms. Among the intervention group, 98.1% had total remission of adenomyosis pain symptoms as well as improved secondary outcomes with no serious adverse events. Mifepristone is promising for treating pain from adenomyosis.
Che X, Wang J, Sun W, et al. Effect of mifepristone vs placebo for treatment of adenomyosis with pain symptoms: A randomized clinical trial. JAMA Netw Open 2023;6:e2317860.
Adenomyosis, also known as internal endometriosis, is defined by the presence of ectopic endometrial glands and stroma in the myometrium and affects approximately 20% of people of reproductive age with a uterus. The prevalence of adenomyosis is estimated to range from 5% to 70%.1,2 Adenomyosis proves a challenge in gynecology and healthcare economics, with serious health problems ranging from dysmenorrhea, menorrhagia, and secondary anemia to subfertility, miscarriage, and obstetric complications.3 Healthcare costs for long-term treatment are on par with chronic, high-impact diseases such as diabetes and rheumatoid arthritis.3 There are no approved clinical guidelines for the medical treatment of adenomyosis. Drug research and development in adenomyosis has been slow, and treatment options are limited in terms of effectiveness, tolerability, and costs. Current medical options include gonadotropin-releasing hormone agonist (GnRH-a), oral contraceptives, and progestins. Although GnRH-a is efficient in controlling dysmenorrhea and menorrhagia and reducing uterine size for adenomyosis, the adherence to GnRH-a treatment is much lower than expected because of its high cost and high rates of adverse effects and bone resorption. A majority of adenomyosis patients (82%) choose hysterectomy to cure their adenomyosis-related symptoms.
The interest in mifepristone as a potential treatment for adenomyosis stems from previous research and medical applications of mifepristone to treat gynecologic conditions. Mifepristone was reported as the first selective progesterone receptor modulator in 1982, and new research on the mechanisms of action of mifepristone are shifting our views on how the drug can be broadened as a medical treatment beyond use as an abortifacient. Mifepristone has been found to have possible clinical applications in the treatment of endometriosis and uterine fibroids. Previous studies have indicated that mifepristone treatment halted the development of adenomyosis in mice, decreased uterine volume and increased hemoglobin, and downregulated the expression of genes that are associated with endometrial epithelial cell proliferation, migration, and invasion of primary endometrial cells as seen in adenomyosis.4
This trial studied the effect of 10 mg of mifepristone or placebo treatment taken orally once per day for 12 weeks on adenomyosis-associated dysmenorrhea intensity as evaluated by the visual analog scale (VAS, range of 0-10, with a higher score representing greater pain intensity). The trial was completed in 10 hospitals in China, and participants were enrolled by their clinicians. Patients eligible for participation were premenopausal patients with a uterus, between ages 18 and 50 years, with a confirmed diagnosis of adenomyosis via ultrasonography or magnetic resonance imaging. All patients with a VAS score > 0 points were included with or without menorrhagia (as measured by Pictorial Blood Loss Assessment Chart [PBAC] score ≥ 100 points, equivalent to 80 mL of blood loss). Patients with severe anemia, a history of undiagnosed vaginal bleeding, endometrial malignant tumors, uterine fibroids, endometriosis, and any patients unwilling to use nonhormonal contraceptives were excluded from participation.
Participating patients were screened initially for four weeks, then randomly assigned at a 1:1 ratio to receive mifepristone (10 mg) or placebo during the double-blind period, with regular trial visits performed every four weeks for 12 weeks, and an additional four weeks post-treatment. Patients were not allowed to use other drugs or treatment methods that affected efficacy evaluation. However, because of ethical standards, patients were allowed to receive analgesics in placebo-controlled trials with the use of indomethacin suppositories as recommended to avoid trial bias. The primary measure of mifepristone efficacy for the treatment of adenomyosis was the change in adenomyosis-associated dysmenorrhea intensity, which was measured from baseline to 12 weeks of treatment using the VAS. Complete remission (defined as the proportion of patients who achieved complete remission of dysmenorrhea) and total efficacy rates (defined as the proportion of patients with a VAS score reduced by at least 30% from baseline) for dysmenorrhea were evaluated.
This trial explored two key secondary endpoints: heavy menstrual bleeding as assessed by the validated, highly specific and sensitive PBAC and mean change in hemoglobin levels. A complete remission rate for heavy menstrual bleeding (80 mL+ blood loss/PBAC score of 100) was defined as the proportion of patients who had amenorrhea at 12 weeks. A total efficacy rate for menstrual blood loss was defined as the proportion of patients with PBAC scores reduced by at least 30% from baseline to the end of treatment. Additional secondary endpoints included changes in CA125 levels, platelet counts, and uterine volume.
A total of 194 patients were screened, with 134 patients eligible for participation, who were enrolled and randomized between May 2018 and April 2019. Of these, 66 patients were assigned to the mifepristone group and 68 patients were assigned to the placebo group; each group demonstrated similar baseline characteristics. Sixty-one patients (mean [standard deviation (SD)] age, 40.2 [4.6] years) in the mifepristone group and 65 patients (mean [SD] age, 41.7 [5.0] years) in the placebo group were included in the final analysis. After 12 weeks, there was a statistically significant improvement in VAS scores from baseline in the mifepristone group, with a mean (SD) change in VAS scores from baseline of -6.63 (1.92), and only -0.95 (1.75) points in the placebo group (between-group difference, -5.68; 95% confidence interval, -6.37 to -4.99; P < 0.001). It is important to observe that improvement in pain was noted by four weeks after mifepristone treatment. Both the complete remission and total efficacy rates for dysmenorrhea in the mifepristone group were significantly greater than those in the placebo group at week 12 (complete remission: 54 patients [88.5%] vs. four patients [6.2%]; P < 0.00; total efficacy: 56 patients [91.8%] vs. 15 patients [23.1%]; P < 0.001). Results included sensitivity analysis to adjust for missing data.
All secondary endpoint outcomes showed significant improvements in the mifepristone group compared to the placebo group, with significant improvement in complete remission for heavy menstrual bleeding (36 patients [90.00%] vs. two patients [5.41%]) and total efficacy for heavy menstrual bleeding (38 patients [95.00%] vs. 14 patients [37.84%]) at 12 weeks of treatment. Mifepristone treatment resulted in significant improvements in hemoglobin levels in patients with anemia (complete remission rates were 28 patients [7.78%] in the mifepristone group and eight patients [22.85%] in the placebo group [P < 0.001]). In patients with anemia, hemoglobin levels increased by a mean (SD) of 2.13 (1.38) g/dL in the mifepristone group and 0.48 (0.97) g/dL in the placebo group at week 12 (P < 0.001). No serious adverse events were reported.
COMMENTARY
The results of this double-blind, placebo-controlled, randomized trial demonstrate that mifepristone has strong potential as an effective medical treatment option for adenomyosis. Adenomyosis is a highly prevalent disease with a history of very little research.5 The results showed that mifepristone can serve as a low-cost, highly efficacious treatment of both dysmenorrhea and menorrhagia as evidenced by a high complete remission rate of pain and a significant reduction in bleeding. Although the data suggest that mifepristone could be considered as an off-label use for adenomyosis treatment, restrictions on medical abortion medications in the United States may limit the ability to access mifepristone for adenomyosis treatment. The dose of adenomyosis is much smaller (10 mg vs. 200 mg) than that used in medical abortion; however, a pending lawsuit against the U.S. Food and Drug Administration jeopardizes mifepristone use for many gynecologic considerations.
Adenomyosis is a high-impact disease diagnosis, significantly affecting an individual’s quality of life and future.3 While continued research on the long-term safety and efficacy of mifepristone for adenomyosis treatment is necessary, this study demonstrates the importance of mifepristone in a range of gynecologic conditions.
REFERENCES
- Di Donato N, Montanari G, Benfenati A, et al. Prevalence of adenomyosis in women undergoing surgery for endometriosis. Eur J Obstet Gynecol Reprod Biol 2014;181:289-293.
- Naftalin J, Hoo W, Pateman K, et al. How common is adenomyosis? A prospective study of prevalence using transvaginal ultrasound in a gynaecology clinic. Hum Reprod 2012;27:3432-3439.
- Guo SW, Groothuis PG. Is it time for a paradigm shift in drug research and development in endometriosis/adenomyosis? Hum Reprod Update 2018;24:577-598.
- Che X, Wang J, He J, et al. A new trick for an old dog: The application of mifepristone in the treatment of adenomyosis. J Cell Mol Med 2020;24:1724-1737.
- Cope AG, Ainsworth AJ, Stewart EA. Current and future medical therapies for adenomyosis. Semin Reprod Med 2020;38:151-156.
