Uterine leiomyomas impose a significant burden on women,1,2 health care systems,3–5 and society.6 About 20–40% of women will be diagnosed with uterine leiomyomas.7 Persistent heavy menstrual bleeding, a symptom of uterine leiomyomas, can induce anemia with fatigue and reduce quality of life (QOL).8,9
Gonadotropin-releasing hormone (GnRH) agonists (eg, leuprorelin) are common preoperative therapies for uterine leiomyoma-related symptoms. They suppress sex hormones via a negative feedback loop.10 Gonadotropin-releasing hormone agonists produce an initial transient increase in gonadotropin levels, called the flare effect. However, continued GnRH agonist therapy induces down-regulation and desensitization of GnRH receptors, producing a hypogonadotrophic state and a reduction in sex hormones. Thus, therapeutic benefit can take approximately 6 weeks to achieve.11,12 Furthermore, GnRH agonists are peptides and oral formulations are unavailable.
Relugolix (TAK-385), an oral nonpeptide GnRH-receptor antagonist, promptly suppresses pituitary gonadotropin by GnRH-receptor competition, lowering estradiol (E2) and progesterone levels within days, without the symptom flare associated with GnRH agonists (Hoshiai H, Seki Y, Kusumoto T, Kudou K, Komura E, Tanimoto M. Phase 2 study of relugolix vs placebo in heavy menstrual bleeding associated with uterine fibroids [abstract]. Obstet Gynecol 2017;129:86S.). A previous study has shown that discontinuation of relugolix leads to more rapid and predictable recovery of the pituitary-gonadal axis compared with leuprorelin injection (Osuga Y, Seki Y, Tanimoto M, Kusumoto T, Kudou K, Terakawa N. Relugolix, an oral gonadotropin-releasing hormone (GnRH) receptor antagonist, in women with endometriosis (EM)-associated pain: phase 2 safety and efficacy 24-week results [abstract]. Endocrine Abs 2017; GP134.).
A phase 2, randomized, double-blind study in women with uterine leiomyomas and heavy menstrual bleeding showed that relugolix 10–40 mg once daily for 12 weeks resulted in significant dose-dependent reductions in menstrual blood loss compared with placebo (Hoshiai et al. Obstet Gynecol 2017.). The phase 3 confirmatory study reported here enrolled women with uterine leiomyomas and heavy menstrual bleeding in Japan, and evaluated noninferiority of oral relugolix 40 mg once daily for 12 weeks, compared with monthly leuprorelin injections (primary endpoint), and efficacy, pharmacodynamics, and safety for 24 weeks.
This phase 3, multicenter, randomized, double-blind, double-dummy, parallel-group, noninferiority study evaluated the efficacy and safety of relugolix 40 mg administered orally once daily compared with a monthly leuprorelin injection in women with symptomatic uterine leiomyomas. Leuprorelin acetate is currently one of the most common treatment options in the preoperative therapy of women with uterine leiomyoma-related symptoms or signs.13 The study was conducted at 34 centers in Japan in compliance with the institutional review board regulations and all applicable local regulations. The study was approved by the Institutional Review Board at each study site. All patients provided informed consent before enrollment.
We enrolled premenopausal women who were at least 20 years of age with uterine leiomyomas and heavy menstrual bleeding as assessed by a score of at least 120 on the pictorial blood loss assessment chart for one cycle during the run-in period (Fig. 1). Other inclusion criteria included confirmed (transvaginal ultrasound scan or other methods) noncalcified uterine leiomyomas with no prior surgical treatment, at least one myoma of at least 3 cm, and confirmed regular menstrual cycles (25–38 days with menstrual bleeding for at least three consecutive days). Exclusion criteria included markedly abnormal uterine bleeding, anovulatory bleeding, or nondiagnosable abnormal genital bleeding; history of thyroid gland disorder with irregular menstruation; history of blood disorders; osteoporosis, osteopenia, or other metabolic bone diseases; history of hysterectomy or bilateral oophorectomy; abdominal pain related to irritable bowel syndrome or interstitial cystitis; pelvic inflammatory disease; malignant tumor; pregnant or lactating; active liver disease, jaundice, or with alanine aminotransferase, aspartate aminotransferase, or bilirubin (total bilirubin) greater than 1.5 times the upper limit of normal; and treatment with any of the following drugs within the 16 weeks before initiation of the screening period: oral contraceptive or sex hormone preparations, GnRH analogues, dienogest, danazol, or aromatase inhibitors. Abnormal uterine bleeding and anovulatory bleeding were not defined in the study protocol.
Patients underwent a screening period, followed by a placebo run-in period, before randomization to study drug at visit 3 (Fig. 1). Study drug treatment consisted of a daily relugolix 40 mg tablet with a placebo injection every 4 weeks or a leuprorelin acetate injection (1.88 mg or 3.75 mg) every 4 weeks with a daily placebo tablet, in a double-blind manner for a treatment period of 24 weeks, and a follow-up period of 4 weeks. The dose of leuprorelin (or leuprorelin placebo) was determined by the investigator at visit 2 in accordance with the approved dosage and administration in Japan, which recommends the 3.75 mg dose for patients with heavy body weight or markedly enlarged uterus; the leuprorelin dose was not changed during the study. Administration at visits 2 and 3 was initiated on days 1–5 of the first menstruation after participation in the screening and run-in periods, respectively. Patients were followed-up until the first posttreatment menstruation occurred.
Use of sex hormone preparations was prohibited during the study. Use of oral iron preparations was permitted without changing the dose and regimen during the treatment period in patients whose blood hemoglobin level was less than 10.0 g/dL when enrolled or those taking iron before enrollment. Analgesics were only permitted for severe pain associated with uterine leiomyomas and as treatment for adverse events.
At initiation of treatment (Fig. 1), patients were randomized (1:1) to relugolix or leuprorelin. The blocked randomization scheme was computer-generated by an independent statistician, and investigators obtained randomization numbers for eligible patients via a web-based program. All randomization information was stored in a secured area accessible only to authorized personnel. All study personnel involved in the treatment or assessment of patients were blinded to treatment allocation. Blind maintenance was achieved by concealment of the pharmacodynamics test results from all external parties and personnel involved in the conduct of the study until the randomization code was opened.
The primary objective was to evaluate the efficacy (noninferiority) of oral relugolix 40 mg administered once-daily for 12 weeks, compared with a leuprorelin injection every 4 weeks. Twelve weeks reflects the usual presurgical treatment period for uterine leiomyomas.8 The volume of menstrual blood loss was measured daily using the pictorial blood loss assessment chart score, a semi-objective method for evaluating menstrual blood loss.14 Patients were required to use the menstrual products designated by the sponsor and record in a paper diary the number of tampons or pads used, as well as clots and flooding during the screening and treatment periods. Patients were asked to complete the diary on a daily basis. At each study visit, diary entries were reviewed and any unclear or insufficient information in the diary was queried with the patient. The primary efficacy endpoint of the study was the proportion of patients with a total pictorial blood loss assessment chart score of less than 10 for weeks 6–12, calculated as the sum of the daily scores over the 6-week period. The 6-week duration encompassed the maximum menstrual cycle of eligible patients.
Secondary efficacy endpoints were defined as the proportion of patients with a total pictorial blood loss assessment chart score of less than 10 for weeks 2–6, for weeks 18–24, and for the 6 weeks before each patient's final dose of study drug; myoma and uterine volumes measured by transvaginal ultrasound scan at each study visit at weeks 2–12 and 24; hemoglobin levels at weeks 2–24 visits; pain assessed daily by the numerical rating scale score for weeks 2–6, weeks 18–24, and 6 weeks before each patient's final dose; and the Uterine Fibroid Symptom Health-Related Quality of Life Questionnaire score at weeks 4–24 visits (study visits are shown in Table 1). Safety assessments included adverse events and clinical hematology, chemistry, and urinalysis laboratory tests at every visit, vital signs and weight at weeks 4–24 visits, standard 12-lead electrocardiograms at week 24, and bone mineral density (BMD), as measured by dual-energy X-ray absorptiometry, and biochemical bone metabolism markers (serum N-telopeptide and bone-specific alkaline phosphatase) at weeks 12 and 24 (Table 1).
Additional endpoints included amenorrhea (proportion of patients with a total pictorial blood loss assessment chart score of 0), pharmacodynamic effects on the blood concentrations of luteinizing hormone, follicle-stimulating hormone, E2, and progesterone, and the time from the last dose of study drug to the return of the menstrual cycle.
Two analysis sets were defined: full analysis set and safety analysis set. The full analysis set was used for the primary and all other efficacy analyses, and was defined as all patients randomized and who received at least one dose of the study drug. The safety analysis set was defined as all patients who received at least one dose of the study drug. All efficacy and safety analyses were conducted on an intention-to-treat basis.
A sample size of 288 patients (144 per group) was estimated to provide at least 90% power to demonstrate noninferiority of relugolix to leuprorelin at a one-sided 0.025 level of significance (nQuery Advisor 6.01), using a noninferiority margin of −15%, assuming that approximately 10% of patients would not be evaluable for the primary endpoint. Based on the results of previous studies (Hoshiai et al. Obstet Gynecol 2017.),11 the point estimate (95% CI) of the proportion of patients with a total pictorial blood loss assessment chart score of less than 10 for weeks 6–12 in both the relugolix and leuprorelin groups was estimated to be 83.6% (71.2–92.2%). Assuming leuprorelin would have a comparable effect to relugolix 40 mg, a noninferiority margin of 15% was set, which was considered smaller than the smallest effect size expected for relugolix compared with leuprorelin (Hoshiai et al. Obstet Gynecol 2017.). For the primary endpoint, the point estimate and two-sided 95% CI for the difference in proportions were calculated using the Farrington and Manning method. If the lower bound of the 95% CI was greater than or equal to the noninferiority margin of −15%, noninferiority of relugolix 40 mg to leuprorelin was concluded. Descriptive or summary statistics were provided for secondary and other endpoints and, where appropriate, mean differences between the treatment groups and the two-sided 95% CIs were determined. No imputation of values for missing primary efficacy endpoint data was performed. Analyses were performed using SAS version 9.4.
ROLE OF THE FUNDING SOURCE
This study was sponsored by Takeda Pharmaceutical Company Limited, manufacturer and licensee of relugolix (TAK-385), under the codevelopment agreement with an affiliate of NovaQuest Capital Management L.L.C. Medical writing assistance was provided by Tania Dickson, PhD, CMPP, and Serina Stretton, PhD, CMPP of ProScribe—Envision Pharma Group, and was funded by Takeda Pharmaceutical Company Limited. ProScribe's services complied with international guidelines for Good Publication Practice (GPP3).
Takeda Pharmaceutical Company Limited was involved in the study design, data collection, data analysis, and preparation of the manuscript. The authors had access to relevant aggregated study data and other information (such as study protocol, analytic plan and report, validated data table, and clinical study report) required to understand and report research findings. The authors take responsibility for the presentation and publication of the research findings, have been fully involved at all stages of publication and presentation development, and are willing to take public responsibility for all aspects of the work. All individuals included as authors and contributors who made substantial intellectual contributions to the research, data analysis, and publication or presentation development are listed appropriately. The role of the sponsor in the design, execution, analysis, reporting, and funding is fully disclosed. The authors' personal interests, financial or nonfinancial, relating to this research and its publication have been disclosed.Authors' Data Sharing StatementWill individual participant data be available (including data dictionaries)? No.What data in particular will be shared: Not available.What other documents will be available? Not available.When will data be available (start and end dates)? Not applicable.By what access criteria will data be shared (including with whom, for what types of analyses, and by what mechanism)? Not applicable.
A total of 429 patients signed the informed consent and were screened (Fig. 2). Of these, 281 were randomized to either relugolix (n=139) or leuprorelin (n=142). The most common reason for ineligibility, in 139 patients, was failure to meet the entry criteria.
There were no clinically significant differences in any demographic or baseline characteristics between treatment groups (Table 2). The mean age of the patients was 42.9±5.13 years, and 53% of patients were parous. The most common type of uterine leiomyoma was intramural (81.5%), followed by subserosal (38.1%) and submucosal (11.7%); no patient had a cervical-type uterine leiomyoma. Mean pictorial blood loss assessment chart score was 259.1±163.39. Of patients randomized to leuprorelin, 87.3% received the 1.88 mg dose.
The primary endpoint, the proportion of patients with a total pictorial blood loss assessment chart score of less than 10 for weeks 6–12, was 82.2% in the relugolix group and 83.1% in the leuprorelin group (Table 3). The inter-group difference (relugolix group−leuprorelin group) in the proportions of patients with a total pictorial blood loss assessment chart score of less than 10 for weeks 6–12 was −0.9% (95% CI: −10.10 to 8.35). As the lower boundary of the 95% CI was greater than −15%, the noninferiority of relugolix 40 mg to leuprorelin was demonstrated (P=.001). When summarized by leuprorelin dose, the proportion of patients with a total pictorial blood loss assessment chart score of less than 10 for weeks 6–12 was 80.6% (100/124 patients) with the 1.88 mg dose and 100% (18/18 patients) with the 3.75 mg dose.
More patients in the relugolix group than in the leuprorelin group achieved a total pictorial blood loss assessment chart score of less than 10 for weeks 2–6 (64.2% vs 31.7% [relugolix−leuprorelin difference 32.5; 95% CI: 20.95 to 44.13]). Menses occurred in 15 of 139 patients in the relugolix group and 43 of 142 patients in the leuprorelin group for weeks 2–6 (3 vs 13 patients at week 2–3; 8 vs 19 patients at week 3–4; 4 vs 9 patients at week 4–5; and 0 vs 2 patients at week 5–6). The treatment effect of relugolix was maintained until the last study period (weeks 18–24) (Table 3). For weeks 18–24, more patients in the leuprorelin group (94.7%) than in the relugolix group (84.1%) achieved a total pictorial blood loss assessment chart score of less than 10 (relugolix−leuprorelin difference −10.6; 95% CI: −18.34 to −2.88). The majority of nonresponders in the relugolix group who completed week 24 had at least one E2 level greater than 20 pg/mL for weeks 16–24. Amenorrhea (total pictorial blood loss assessment chart score of 0) was achieved by more patients in the relugolix group than in the leuprorelin group for weeks 2–6 (52.6% vs 21.8% [relugolix−leuprorelin difference 30.7; 95% CI: 19.45 to 42.00]). There was no difference between groups for rates of amenorrhea at weeks 6–12, with both at about 73% (relugolix−leuprorelin difference −0.6; 95% CI: −11.04 to 9.82) (Table 3). For the 6 weeks before each patient's final dose, more patients in the leuprorelin group (88.7%) than in the relugolix group (75.4%) achieved amenorrhea (relugolix−leuprorelin difference −13.4; 95% CI: −22.27 to −4.48).
Both treatments reduced myoma and uterine volumes, with median (Q1, Q3) reductions for relugolix and leuprorelin at week 12 of −51% (−65.1, −26.3) and −48% (67.1, −33.2) in myoma volumes and −45% (−54.8, −31.8) and −43% (−53.7, −31.0) in uterine volumes (Table 4). Myoma and uterine volumes decreased more rapidly in the relugolix group than in the leuprorelin group, with median reductions in myoma volumes from baseline to week 2 of −23% and −8%, respectively, for relugolix and leuprorelin [relugolix−leuprorelin difference −12.1%; 95% CI: −19.78 to −4.33; Wilcoxon rank sum test P<.001] and median reductions in uterine volumes of −24% and −10%, respectively [relugolix−leuprorelin difference −15.2%; 95% CI: −20.79 to −9.51; P<.001].
In both treatment groups, hemoglobin levels increased from baseline to week 4 and subsequently continued to increase depending on the duration of treatment (Table 4). A subgroup analysis showed that the increase in both groups was independent of iron supplementation (Appendix 1, available online at http://links.lww.com/AOG/B286). Both groups showed similar improvements in pain assessed by numerical rating scale score and symptom severity and QOL assessed by the Uterine Fibroid Symptom Health-Related Quality of Life Questionnaire (Table 4).
The overall incidence of treatment-emergent adverse events was similar in both groups and most treatment-emergent adverse events were mild or moderate (Table 5). Two serious treatment-emergent adverse events occurred in the leuprorelin group, a large intestinal polyp and an ulnar fracture, and were considered unrelated to study drug. No deaths occurred during the study.
Treatment-emergent adverse events with an incidence of 10% or more in either treatment group included intermenstrual bleeding (coded as metrorrhagia using Medical Dictionary for Regulatory Activities version 20.0), hot flushes, viral upper respiratory tract infection, heavy menstrual bleeding (Medical Dictionary for Regulatory Activities term menorrhagia), headache, and hyperhidrosis. These treatment-emergent adverse events were mild or moderate in intensity. The overall incidence of treatment-emergent adverse events leading to study drug discontinuation was 6.5% for relugolix and 4.9% for leuprorelin (Table 5). The most frequently reported event leading to study drug discontinuation was hot flush (relugolix: four patients, leuprorelin: one patient).
The incidence of patients with abnormal liver tests (alanine aminotransferase or aspartate aminotransferase elevated to more than three times the upper limit of normal) was comparable in the two treatment groups, with three patients (2.2%) in the relugolix group and two patients (1.4%) in the leuprorelin group. No cases of abnormal liver tests were associated with elevated bilirubin, and all resolved while continuing or after completing or discontinuing study drug administration. No clinically significant changes from baseline were noted for the clinical laboratory tests, vital signs, weight, or 12-lead electrocardiogram (data not shown).
A decrease in BMD was observed in both groups. The median (Q1, Q3) percent changes of BMD from baseline at weeks 12 and 24 were −1.7% (−3.1, −0.3) and −4.4% (−6.4, −2.5), respectively, in the relugolix group, and −2.1% (−3.8, −0.6) and −4.4% (−6.1, −3.0), respectively, in the leuprorelin group. No differences in N-telopeptide levels or bone-specific alkaline phosphatase levels were noted between groups (Appendix 2, available online at http://links.lww.com/AOG/B286).
Almost all patients resumed menses after treatment discontinuation in both groups, and menses returned earlier in the relugolix group than in the leuprorelin group. The median (Q1, Q3) time from the last dose of study drug to the return of menstrual cycles was 37.0 (32.0, 46.0) days in the relugolix group and 65.0 (54.0, 77.0) days in the leuprorelin group.
Median E2 levels decreased from baseline in both groups (Fig. 3). By week 2, E2 levels were decreased from baseline to below postmenopausal levels in the relugolix group, whereas it took 4 weeks to reach the same serum E2 levels in the leuprorelin group. The very low median serum E2 levels were maintained until week 24 and recovered within 4 weeks after the last dose for the relugolix group, but median serum E2 levels did not recover within 4 weeks after the last dose in the leuprorelin group. Reductions were also observed in luteinizing and follicle-stimulating hormones and progesterone (Appendix 3, available online at http://links.lww.com/AOG/B286).
This phase 3 study demonstrated oral relugolix was noninferior to leuprorelin depot injections in reducing heavy menstrual bleeding at 6–12 weeks of treatment. The safety profile of relugolix was comparable with leuprorelin. These data replicate results from a phase 2 study of relugolix in a similar patient population.
Depot formulations of GnRH agonists are used to treat heavy menstrual bleeding and reduce leiomyoma size, but have a delayed onset and must be given by monthly injection.15,16 Oral, once-daily relugolix, a nonpeptide GnRH-receptor antagonist, achieved a similar proportion of heavy menstrual bleeding responders at 6–12 weeks to a monthly leuprorelin injection (82.2% vs 83.1%) and was statistically noninferior to leuprorelin. Importantly, to be a responder in this study, women had to have a pictorial blood loss assessment chart score of at least 120 at enrollment and achieve the very high hurdle of a total score of less than 10 for weeks 6–12.
Uterine leiomyoma symptoms and patient-reported QOL substantially improved with relugolix and leuprorelin. These improvements could be related to the reductions in heavy menstrual bleeding and rise in low hemoglobin levels which contribute to fatigue and deteriorating QOL.17 Relugolix-treated patients achieved amenorrhea more rapidly than those on leuprorelin, although the incidence of amenorrhea was higher in the leuprorelin group towards the end of the treatment period. Both groups had increased hemoglobin levels as early as 4 weeks. Hemoglobin levels continued to increase during treatment independent of iron supplementation, likely reflecting the significant reductions in heavy menstrual bleeding.
Myoma and uterine volumes are linked to pain and discomfort in women with uterine leiomyomas. Myoma and uterine volumes at week 2 showed a more rapid decrease in the relugolix group than in the leuprorelin group. By 12 weeks, relugolix and leuprorelin both reduced myoma and uterine volumes by more than 40% from baseline, with reductions in numerical rating scale pain scores. These benefits are expected to be clinically relevant in the management of uterine leiomyoma symptoms. In addition, for patients who do require hysterectomy, the decrease in leiomyoma size may decrease blood loss, need for blood transfusion, duration and route of hysterectomy, and postoperative complications.18
Estradiol concentrations decreased rapidly from week 2 in the relugolix group without an initial flare; increases in E2 levels occurred in approximately 40% of leuprorelin-treated patients. Relugolix showed a faster onset than leuprorelin, as evidenced by the greater proportion of patients with a total pictorial blood loss assessment chart score of less than 10 by weeks 2–6 and greater decreases in myoma and uterine volumes by week 2.
The primary endpoint was measured at weeks 6–12. At weeks 2–6, relugolix showed an earlier effect on menstrual bleeding compared with leuprorelin. By weeks 18–24, the proportion of responders increased further to 94.7% in the leuprorelin arm and to 84.1% in the relugolix arm, which was inconsistent with the primary endpoint result at weeks 6–12. The majority of nonresponders in the relugolix arm had E2 levels that were greater than 20 pg/mL, despite reported study drug compliance in both groups of more than 99%. The reason remains unclear why this further increase in responders by weeks 18–24 was not seen in the relugolix group, although it is possible that the high patient-reported compliance did not always reflect actual compliance. Ongoing studies are evaluating relugolix in combination with low-dose E2 and progestin for the longer-term treatment of heavy menstrual bleeding.
Another limitation of depot GnRH agonists is delayed return of menses after treatment discontinuation. Estradiol levels and menses resumed more quickly after relugolix discontinuation than after leuprorelin discontinuation. Rapid return of hormone levels to baseline and earlier restoration of menstruation could be beneficial in managing concurrent illness and restoring fertility for women planning pregnancy.
Oral relugolix 40 mg once daily during a 24-week period was well tolerated with a safety profile comparable with leuprorelin. The overall incidence of adverse events was similar between the treatment groups and most adverse events were mild or moderate in intensity. Similar decreases in BMD observed with relugolix and leuprorelin were attributed to their hypoestrogenic effects. Further phase 3 investigation is underway to evaluate the coadministration of relugolix 40 mg with low-dose hormonal add-back therapy to mitigate the hypoestrogenic effects of relugolix without substantial reduction of the benefits.
The strengths of this study include its prospective, multicenter, randomized, double-blind, leuprorelin-controlled design. Although the study enrolled a Japanese-only population, the similarity in pharmacokinetics of relugolix between Japanese and Caucasian women was confirmed in a phase 1 study and the underlying driver mutations for the majority of uterine leiomyomas are similar in black, Caucasian, Hispanic, and Asian women.19–22 Direct comparisons to GnRH agonists and antagonists other than leuprorelin and relugolix cannot be made.
Once-daily oral relugolix was noninferior to a leuprorelin monthly injection in improving heavy menstrual bleeding at 6–12 weeks of treatment, and provided more rapid reduction of heavy menstrual bleeding, and myoma and uterine volume. Both relugolix and leuprorelin increased hemoglobin levels and improved QOL. Menses returned earlier after cessation of relugolix than leuprorelin, and relugolix had a safety profile comparable with leuprorelin. Data from this phase 3 study suggest that relugolix has promise as a novel treatment for women with heavy menstrual bleeding associated with uterine leiomyomas.
The authors thank all investigators for their assistance with this study and the women who participated in this study. The authors also thank the sponsor for assistance with data monitoring and gathering, and for funding the writing support that was provided by ProScribe—Envision Pharma Group.
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