Uterine leiomyomas are common, nonmalignant, gonadal steroid-dependent, monoclonal neoplasms that occur in 70–80% of premenopausal women.1 Although many women with uterine leiomyomas are asymptomatic, approximately 25% develop symptoms requiring treatment.2–4 The two most common symptoms associated with uterine leiomyomas are heavy menstrual bleeding and pain.5–9 One epidemiologic study reported that heavy menstrual bleeding was experienced by 86% and pain by 49% of women with symptomatic uterine leiomyomas.9
Women's experience with uterine leiomyoma–associated pain is diverse: symptoms may include menstrual and pelvic pain,6 abdominal or pelvic pressure, low back pain, painful intercourse, and pain with defecation.5,9–11 Three quarters of women with uterine leiomyomas experience menstrual-associated pain and nonmenstrual pain is reported by up to a third of women.7 Despite the high prevalence of pain associated with uterine leiomyomas, few clinical trials have assessed the effect of treatments on uterine leiomyoma–associated pain in a rigorous, prespecified manner. Given the potentially debilitating effects and severity of pain in uterine leiomyomas, an in-depth assessment of a potentially effective treatment strategy is warranted.
Relugolix combination therapy (relugolix-CT), an oral once-daily nonpeptide, gonadotropin-releasing hormone receptor antagonist (relugolix 40 mg) with estradiol 1 mg and norethindrone acetate 0.5 mg, has been approved for management of uterine leiomyoma–associated heavy menstrual bleeding for up to 2 years (U.S.) or moderate-to-severe uterine leiomyoma symptoms without limitation on duration of use (E.U.). In the LIBERTY 1 and 2 phase 3 studies, relugolix-CT significantly improved heavy menstrual bleeding, with reduction of 84.3% in menstrual blood loss volume from baseline to week 24 in both studies compared with 23.2% and 15.1%, respectively, in the placebo groups.12 Additionally, relugolix-CT provided high rates of amenorrhea, correction of anemia if present at baseline, improved pelvic discomfort, and maintained bone density, with a similar incidence of adverse events with placebo treatment.12 Because pain is the second most bothersome symptom for women with uterine leiomyomas,7 an important secondary objective of the LIBERTY trials was to comprehensively assess the effect of relugolix-CT on uterine leiomyoma–associated pain.
LIBERTY 1 and 2 (NCT03049735 and NCT03103087) were two large, replicate, multinational, double-blind, randomized, phase 3 studies designed to determine the efficacy and safety of 24 weeks of relugolix-CT compared with placebo in women with heavy menstrual bleeding associated with uterine leiomyomas (Appendix 1, available online at https://links.lww.com/AOG/C704; details regarding the study design, eligibility criteria, participant disposition, and safety results have been reported elsewhere).12 The LIBERTY studies were approved by independent international review boards (Appendix 2, available online at https://links.lww.com/AOG/C704) and conducted in accordance with International Conference on Harmonization guidelines and ethical principles of the Declaration of Helsinki. Both studies were registered at ClinicalTrials.gov before enrollment of any study participants and are reported using CONSORT (Consolidated Standards of Reporting Trials) guidelines.
Both studies enrolled women in North and South America, Europe, and Africa. LIBERTY 1 enrolled 388 women at 80 sites (April 2017–October 2018); LIBERTY 2 enrolled 382 women at 99 sites (June 2017–December 2018). Premenopausal women aged 18–50 years with an ultrasonographically confirmed diagnosis of uterine leiomyomas and heavy menstrual bleeding documented by the alkaline hematin method13 who met all other entry criteria were eligible. Heavy menstrual bleeding was defined as menstrual blood loss volume of 80 mL or greater per cycle for two cycles or 160 mL or greater during one cycle. Exclusion criteria included a medical history indicating other causes of heavy menstrual bleeding14 and contraindications to treatment with low-dose estradiol and norethindrone acetate.
Because the prevalence and severity of uterine leiomyoma symptoms varies by race,3,15 race and ethnicity were recorded in LIBERTY 1 and LIBERTY 2. Participants reported their race and ethnicity using categories predefined by the study protocol.
Women were randomized 1:1:1 to receive relugolix-CT (relugolix 40 mg, estradiol 1 mg, norethindrone acetate 0.5 mg), delayed relugolix-CT (relugolix 40 mg monotherapy followed by relugolix-CT, each for 12 weeks) or placebo, taken orally once-daily for a study duration of 24 weeks. Randomization was stratified by geographic region (North America vs Rest of World) and mean screening menstrual blood loss volume at baseline (less than 225 mL vs 225 mL or greater). The purpose of the delayed relugolix-CT group was to evaluate the safety of relugolix monotherapy12; because this regimen was not intended for use in clinical practice, only results on pain endpoints for the relugolix-CT and placebo groups are reported here.
The primary endpoint for the LIBERTY studies was the proportion of women who achieved both a menstrual blood loss volume of less than 80 mL and a 50% or higher reduction from the baseline menstrual blood loss over the last 35 days of treatment. The results from the primary endpoint analysis were previously reported.12
A key predefined secondary objective was the assessment of uterine leiomyoma–associated pain. The studies were designed a priori so that women recorded their worst uterine leiomyoma–associated pain in the preceding 24 hours, for both menstrual and nonmenstrual days. Uterine leiomyoma–associated pain is variable, with experience ranging from chronic dull pain to acute, severe pain during menstruation.5 Because greater pain intensity is more likely to have a negative effect on women's daily life and to require pain medications, a measure of worst pain was included to document the frequency of moderate-to-severe uterine leiomyoma–associated pain over the menstrual cycle. As such, the daily assessment of pain at its worst allows for the evaluation of variability of worst pain of both chronic pain (including pain during nonmenstrual days) and acute pain (menstrual days). Women reported on pain experience daily using an electronic diary (eDiary) and scored their worst pain using a numerical rating scale (Appendix 3, available online at https://links.lww.com/AOG/C704). The numerical rating scale is a validated, single-item, self-reported measure that asks respondents to rank their pain on an 11-point scale from 0 to 10, with anchors described as “no pain” (0) and “pain as bad as you can imagine” (10).9,16 Women also recorded daily any menstrual bleeding (yes or no) that they experienced, allowing for the determination of pain response during menstrual and nonmenstrual days. Any use of medication for the treatment of uterine leiomyoma–associated pain also was collected using the eDiary daily.
Daily pain evaluation began during the screening period (Appendix 1, https://links.lww.com/AOG/C704). Women were asked to begin eDiary entries after returning the first collection of feminine products and at least 7 days before initiation of study drug. The majority of women needed only one or two collections, but several women required as many as four collections to confirm heavy menstrual bleeding. Therefore, the number of pain score days obtained from each woman during the screening phase (serving also as the baseline) was variable and could be shorter than 7 days or as long as 70 days, but fewer than 4% of women had 7 days or fewer and more than half of women had at least 35 days of baseline pain collection. Once women met the heavy menstrual bleeding target for enrollment, daily pain collection continued during the treatment phase using the eDiary (Fig. 1).
The effect of relugolix-CT on uterine leiomyoma–associated pain was assessed in women who met study pain-evaluation requirements; ie, women with moderate-to-severe pain (maximum numerical rating scale score 4 or higher) on at least 1 day during the screening phase and with at least 80% compliance rate in daily eDiary entries over the last 35 days of treatment. To fully characterize the effect of relugolix-CT on pain, multiple pain endpoints were analyzed. A key secondary endpoint in the trials was the proportion of women who achieved minimal-to-no pain (maximum numerical rating scale score 1 or lower) during the last 35 days of treatment, comparing relugolix-CT with placebo.12 Additional prespecified secondary pain endpoints included the proportions of women with minimal-to-no pain on menstrual and on nonmenstrual days, and the proportion of women who achieved at least a 30% reduction in maximum numerical rating scale pain score (a traditional threshold for clinically meaningful improvement17,18) from baseline to week 24. Ad hoc analyses included mean maximum numerical rating scale pain scores (summarized per visit; every 4 weeks) over time and the percent reduction in proportion of days with use of analgesics from baseline to week 24.
Pain medication was allowed per study protocol: first line: ibuprofen; second line: nonibuprofen nonsteroidal antiinflammatory drug (NSAID) or acetaminophen; third line: opioid or opioid-acetaminophen combination; fourth line: investigator discretion. The proportion of days women used any analgesic was calculated based on daily eDiary entries and was used to define the reduction from baseline in pain medication use during menstrual and nonmenstrual days. The assessment was defined as greater than 0 change in percentage of days with pain medication use from baseline to week 24 (ie, in the last 35 days of treatment).
Because the demographic and baseline characteristics of the pain subpopulations were comparable for LIBERTY 1 and 2, and comparisons of the pain secondary endpoint between relugolix-CT and placebo groups showed consistent results and a statistically significant difference in both studies (Appendix 4, available online at https://links.lww.com/AOG/C704), the data were pooled for this comprehensive assessment of the effect of relugolix-CT on pain associated with uterine leiomyomas. The maximum numerical rating scale score for uterine leiomyoma–associated pain at week 24 was calculated as the maximum numerical rating scale score of all nonmissing scores reported during the last 35 days of treatment. For the prespecified pain endpoint, (ie, the proportion of women experiencing minimal-to-no uterine leiomyoma–associated pain (numerical rating scale score 1 or lower) over the last 35 days of treatment) the study would have 90% power to detect a treatment difference of 30% at a two-sided, 0.05 significance level with a sample size of about 65 patients per group, assuming that approximately 50% of patients would be in the pain evaluable subpopulation and that responder rates would be 10% for placebo and 40% for relugolix-CT.
Treatment comparison between relugolix-CT and placebo groups was performed using a stratified Cochran-Mantel-Haenszel test with the randomization stratification factors (region and baseline menstrual blood loss volume less than 225 vs 225 mL or greater) as strata.12 Point estimates and two-sided 95% CIs were provided for treatment differences in proportions as well as for each treatment group. A sensitivity analysis without requiring 80% or greater compliance with eDiary entries was conducted to allow evaluation of the endpoint in all women with moderate or severe pain at baseline (with maximum numerical rating scale score 4 or higher).
The proportion of women who achieved a maximum numerical rating scale score of 1 or lower for uterine leiomyoma–associated pain over the last 35 days of treatment during menstrual days (menstrual pain subpopulation) and nonmenstrual days (nonmenstrual pain subpopulation) also were analyzed using a stratified Cochran-Mantel-Haenszel test comparing relugolix-CT with placebo. The “last observation carried forward” approach was used to derive the maximum numerical rating scale score among the pain scores recorded during the last 35 days of treatment (ie, either using the week 24 scores for week 24 completers or using the scores recorded over the last 35 days of treatment before discontinuation of treatment for early terminated patients) to determine their responder status (maximum numerical rating scale score 1 or lower). To account for the potential effect of analgesic use, a post hoc sensitivity analysis was performed assessing the proportions of women with minimal-to-no pain during the last 35 days of treatment and without any increased use of analgesics in the menstrual pain and nonmenstrual pain subpopulations. Increased use of analgesics was defined as a larger proportion of days with use of analgesics for uterine leiomyoma–associated pain during the last 35 days of treatment compared with baseline and was analyzed in the menstrual pain and nonmenstrual pain subpopulations as post hoc analyses.
The proportion of women who achieved at least a 30% reduction in maximum numerical rating scale score for uterine leiomyoma–associated pain from baseline to the last 35 days of treatment also was determined in the pain subpopulation using a stratified Cochran-Mantel-Haenszel test. To describe pain over time, mean maximum numerical rating scale scores were summarized by treatment and visit using descriptive statistics for overall pain as well as for menstrual and nonmenstrual bleeding pain subpopulations. The maximum numerical rating scale score for each woman at a visit was defined as the highest numerical rating scale score reported in the visit window, defined as a period between adjacent visit dates.
Subgroup analyses of the key secondary pain endpoint (proportion of women within the pain subpopulation who achieved minimal-to-no pain during the last 35 days of treatment) were performed to assess whether treatment effects were consistent across clinically important subgroups (age, race, ethnicity, region, body mass index [BMI, calculated as weight in kilograms divided by height in meters squared], menstrual blood loss, uterine leiomyoma volume, and uterine volume). The odds ratio and its 95% CI for each subgroup based on a logistic regression model are displayed in a forest plot. The logistic regression model included treatment group, baseline menstrual blood loss volume value, and geographic region as covariates.
Between April 2017 and July 2019, a total of 509 women were enrolled and treated in the relugolix-CT and placebo groups of the two phase 3 LIBERTY trials (Fig. 1). In the overall population, 69.9% (177/253) and 74.2% (190/256) of women in the relugolix-CT and placebo groups, respectively, reported moderate-to-severe pain at baseline. Of these, 277 were also at least 80% compliant with eDiary completion and therefore met study pain-evaluation requirements: 49.8% (126/253) and 59.0% (151/256) in the relugolix-CT and placebo groups, respectively (Table 1). These women comprised the pain subpopulation and had a mean (SD) age of 42.5 (4.9) years for relugolix-CT and 42.4 (5.5) years for placebo, BMI of 32.0 (8.0) for relugolix-CT and 32.0 (7.5) for placebo, and menstrual blood loss volume of 245.4 (186.4) mL for relugolix-CT and 207.4 (114.3) mL for placebo. There were no notable differences in demographic or clinical characteristics between treatment groups in the pain subpopulation, between the pain subpopulation and the overall population, or between the menstrual pain and nonmenstrual pain subpopulations and the overall population (Table 1).
At baseline, most of the women in both the relugolix-CT and placebo groups of the pain subpopulation (92.9% and 96.0%, respectively) reported moderate-to-severe menstrual pain, with corresponding mean maximum numerical rating scale scores of 7.2 and 6.9, respectively. Approximately half of the women (51.6% and 49.0%, respectively), reported moderate-to-severe nonmenstrual pain, with mean maximal numerical rating scale scores of 6.7 and 6.3, respectively (Table 1). In the relugolix-CT and placebo groups, 44.4% and 45.0% of women, respectively, had moderate-to-severe pain on both menstrual and nonmenstrual days.
The proportion of women in the pain subpopulation achieving minimal-to-no uterine leiomyoma–associated pain (maximum numerical rating scale score 1 or lower) during the last 35 days of treatment was significantly higher in the relugolix-CT group (45.2%; 95% CI 36.4–54.3) than in the placebo group (13.9%; 8.8–20.5; nominal P<.001; Fig. 2A). Similarly, assessment of pain in the menstrual pain and nonmenstrual pain subpopulations showed that 65.0% (55.6–73.5) and 44.6% (32.3–57.5) of women who received relugolix-CT reported minimal-to-no pain in the last 35 days of treatment compared with 19.3% (13.2–26.7) and 21.6% (12.9–32.7) of women who received placebo, respectively (nominal P<.001 and P=.004, Fig. 2B). Adjusting for analgesic use did not meaningfully change these results. Treating patients who had an increase in percentage of days with pain medication use from baseline to the last 35 days of treatment as nonresponders resulted in responder rates of 63.2% (53.8–72.0) for relugolix-CT compared with 18.6% (12.6–25.9) for placebo in the menstrual pain subpopulation and 44.6% (32.3–57.5) compared with 21.6% (12.9–32.7) in the nonmenstrual pain subpopulation.
A sensitivity analysis was conducted that included all women with moderate-to-severe pain at baseline without being required to have 80% or greater compliance with eDiary entries. There were no differences in demographic or baseline characteristics between women in the pain subpopulation and those excluded from the analyses owing to insufficient compliance with eDiary (data not shown). This sensitivity analysis demonstrated that 37.9% (95% CI 30.7–45.4) compared with 14.7% (10.0–20.6) of women achieved minimal-to-no uterine leiomyoma–associated pain (maximum numerical rating scale score 1 or lower) during the last 35 days of treatment in the relugolix-CT and placebo groups, respectively, supporting findings from the predefined key secondary pain endpoint analysis.
At baseline, 72.5% of women in the pain subpopulation used medication for uterine leiomyoma–associated pain; the most commonly used was ibuprofen (50.0%), followed by nonibuprofen NSAIDs or acetaminophen (30.8%). Opioid use at baseline was low (4.0%). During the last 35 days of treatment, overall use of pain medications was reduced to 26.0% and 43.0% of women in the relugolix-CT and placebo groups, respectively, with most frequent use of ibuprofen (19.7% vs 29.8%), followed by nonibuprofen NSAIDs or acetaminophen (5.5% vs 15.2%); opioids were used by 1.6% compared with 3.3%, respectively (Table 2).
Assessment of analgesic use for uterine leiomyoma–associated pain in the pain subpopulation showed that the proportion of days with pain medication use in the menstrual pain and nonmenstrual pain subpopulations were comparable between treatment groups at baseline (Table 3). The mean proportion of days with pain medication use in the menstrual pain subpopulation decreased from 35.9% at baseline to 7.2% at week 24 for women treated with relugolix-CT compared with placebo (34.7–25.5%, Table 3). Fewer women used analgesics in the nonmenstrual pain subpopulation at baseline (10.4% vs 16.0%, for relugolix-CT and placebo groups, respectively), and reduction in the proportion of days with pain medication use was observed in both the relugolix-CT and placebo groups, with similar proportions at week 24 (3.4% vs 3.8%, Table 3).
The majority of women in the pain subpopulation in the relugolix-CT group (71.4%; 95% CI 62.7–79.1) achieved a 30% or greater reduction17,18 in maximum numerical rating scale score from baseline to the last 35 days of treatment, compared with 40.4% (32.5–48.7) in the placebo group (nominal P<.001; Fig. 3). Assessment of mean maximum numerical rating scale score by visit from baseline to week 24 showed that most of the effect of relugolix-CT was observed by week 4 for the pain, menstrual pain, and nonmenstrual pain subpopulations, with maximal reduction by week 8 that was sustained through week 24 (Fig. 4A–C).
Figure 5 displays the subgroup analyses of the proportion of women who achieved minimal-to-no pain (numerical rating scale score 1 or lower) during the last 35 days of treatment in the pain subpopulation. All subgroups favored relugolix-CT relative to placebo (odds ratio greater than 1), suggesting that treatment effects are consistent across demographic and clinically important subgroups.
Pain is an undertreated aspect of the burden of uterine leiomyomas,7,19 despite studies reporting its importance second only to heavy menstrual bleeding.5–9 The LIBERTY trials include a robust, prospective daily assessment of uterine leiomyoma–associated pain. The threshold of the key secondary pain endpoint was high, requiring women to achieve minimal-to-no pain (numerical rating scale score 1 or lower) after 24 weeks of treatment. This threshold was chosen because it represents a clinically relevant improvement in pain, that was anticipated to be associated with reduced analgesic use and increased ability of the woman to perform daily activities. This high bar exceeds the traditional 30% improvement threshold reported to be clinically meaningful,17,18 which was included as another secondary endpoint in the LIBERTY trials for completeness. Additional outcomes addressed pain experienced in the menstrual pain and nonmenstrual pain subpopulations, as well as pain medication use, to ensure adequate characterization of uterine leiomyoma–associated pain.
Both LIBERTY studies enrolled women who had a high level of pain burden, with approximately 70% having at least 1 day of moderate-to-severe pain associated with uterine leiomyomas in the baseline period.12 The pain subpopulation, which reported moderate-to-severe pain at baseline and high compliance with eDiary completion during the last 35 days of treatment, represented approximately half of the study participants; their demographic and baseline characteristics were representative of the general population enrolled in the studies. Most women in the pain subpopulation (about 95%) reported moderate-to-severe pain during menstrual days; however, about half also reported nonmenstrual pain, and approximately 45% reported both menstrual and nonmenstrual pain. Women treated with relugolix-CT had significant improvement in uterine leiomyoma–associated pain compared with women receiving placebo, with the greatest improvement in menstrual pain. However, relugolix-CT also reduced uterine leiomyoma–associated nonmenstrual pain. Improvements in pain associated with uterine leiomyomas were accompanied by reductions in analgesic use; of note, improvement in pain remained unchanged after adjustment for analgesic use. These data reflect a robust treatment effect of relugolix-CT on uterine leiomyoma–associated pain.
Studies of relugolix monotherapy in Japanese women with uterine leiomyomas have previously demonstrated reductions in pain with treatment. A phase two dose-finding study found a significantly higher proportion of women with moderate-to-severe uterine leiomyoma–associated pain (numerical rating scale score 4 or higher) at baseline achieved no or minimal pain by the end of the 12-week treatment period with relugolix 40 mg than with placebo.20 In a phase 3 study evaluating uterine leiomyoma–associated pain with an 11-point numerical rating scale as in the LIBERTY trials, the proportion of women with maximum numerical rating scale scores of 1 or lower during the last 28 days was significantly higher with relugolix monotherapy than placebo.21 Data from the LIBERTY program together with results from the Japanese trials—representing three adequate and well-controlled studies—support that relugolix 40 mg provides consistent, clinically meaningful reductions in pain associated with uterine leiomyomas as monotherapy and in combination with estradiol and norethindrone acetate. However, relugolix monotherapy is associated with a hypoestrogenic state22 with declines in bone mineral density and vasomotor symptoms, including hot flashes.23 The combination of relugolix, estradiol, and norethindrone acetate was designed to reduce leiomyoma symptoms while minimizing hypoestrogenic side effects. Achievement of the latter goal was demonstrated in LIBERTY 1 and LIBERTY 2, with significant improvement of uterine leiomyoma–associated symptoms and health-related quality of life, as well as reduction of uterine volume compared with placebo, while preserving bone mineral density and minimizing vasomotor symptoms.12
Strengths of the analyses include the rigorous predefined responder threshold applied in the LIBERTY program, reflecting minimal-to-no pain, which is highly clinically relevant. The daily eDiary assessment of worst pain, on both menstrual and nonmenstrual days, allowed for women's pain experience to be comprehensively assessed, thereby avoiding potential issues due to recall bias. This comprehensive assessment of pain is unique and has not been reported in previous uterine leiomyoma trials.24 Additional strengths of the study include the use of a general measure of uterine leiomyoma–associated pain, allowing all types of uterine leiomyoma–associated pain experienced by women to be considered,25 and the fact that pain was attributed to uterine leiomyomas by the patient herself.
There are limitations to these analyses. Potential effects of comorbidities, including adenomyosis or endometriosis, were not assessed. The effect of relugolix-CT on pain in women with mild pain at baseline was not evaluated because the focus of the assessment was on women who would benefit most from a treatment that reduced pain in uterine leiomyomas; ie, those with moderate-to-severe pain.
There remains a high unmet need for effective treatments, especially nonsurgical interventions, for women with uterine leiomyomas.26,27 The consistent and significant reduction in measures of pain with relugolix-CT observed in the LIBERTY program is clinically meaningful, patient-relevant, and together with an improvement of heavy menstrual bleeding and other uterine leiomyoma–associated symptoms, is likely to have a substantial effect on the life of women with symptomatic uterine leiomyomas. Relugolix-CT is an option for the treatment of moderate-severe uterine leiomyoma–associated symptoms in women with symptomatic uterine leiomyomas, improving heavy menstrual bleeding and pain, the two most common uterine leiomyoma symptoms.
Authors' Data Sharing Statement
- Will 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 available.
- By what access criteria will data be shared (including with whom, for what types of analyses, and by what mechanism)? Not available.
1. Stewart EA. Clinical practice. Uterine fibroids. N Engl J Med 2015;372:1646–55. doi: 10.1056/NEJMcp1411029
2. Perez-Lopez FR, Ornat L, Ceausu I, Depypere H, Erel CT, Lambrinoudaki I, et al. EMAS position statement: management of uterine fibroids. Maturitas 2014;79:106–16. doi: 10.1016/j.maturitas.2014.06.002
3. Wise LA, Laughlin-Tommaso SK. Epidemiology of uterine fibroids: from menarche to menopause. Clin Obstet Gynecol 2016;59:2–24. doi: 10.1097/GRF.0000000000000164
4. Laughlin SK, Stewart EA. Uterine leiomyomas: individualizing the approach to a heterogeneous condition. Obstet Gynecol 2011;117:396–403. doi: 10.1097/AOG.0b013e31820780e3
5. Zimmermann A, Bernuit D, Gerlinger C, Schaefers M, Geppert K. Prevalence, symptoms and management of uterine fibroids: an international internet-based survey of 21,746 women. BMC Womens Health 2012;12:6. doi: 10.1186/1472-6874-12-6
6. David M, Pitz CM, Mihaylova A, Siedentopf F. Myoma-associated pain frequency and intensity: a retrospective evaluation of 1548 myoma patients. Eur J Obstet Gynecol Reprod Biol 2016;199:137–40. doi: 10.1016/j.ejogrb.2016.02.026
7. Fuldeore MJ, Soliman AM. Patient-reported prevalence and symptomatic burden of uterine fibroids among women in the United States: findings from a cross-sectional survey analysis. Int J Womens Health 2017;9:403–11. doi: 10.2147/IJWH.S133212
8. Foth D, Rohl FW, Friedrich C, Tylkoski H, Rabe T, Romer T, et al. Symptoms of uterine myomas: data of an epidemiological study in Germany. Arch Gynecol Obstet 2017;295:415–26. doi: 10.1007/s00404-016-4239-y
9. Monleon J, Canete ML, Caballero V, Del Campo M, Domenech A, Losada MA, et al. Epidemiology of uterine myomas and clinical practice in Spain: an observational study. Eur J Obstet Gynecol Reprod Biol 2018;226:59–65. doi: 10.1016/j.ejogrb.2018.05.026
10. Maruo T, Ohara N, Wang J, Matsuo H. Sex steroidal regulation of uterine leiomyoma growth and apoptosis. Hum Reprod Update 2004;10:207–20. doi: 10.1093/humupd/dmh019
11. Myers ER, Goodwin S, Landow W, Mauro M, Peterson E, Pron G, et al. Prospective data collection of a new procedure by a specialty society: the FIBROID registry. Obstet Gynecol 2005;106:44–51. doi: 10.1097/01.AOG.0000165827.66541.dd
12. Al-Hendy A, Lukes AS, Poindexter AN 3rd, Venturella R, Villarroel C, Critchley HOD, et al. Treatment of uterine fibroid symptoms with relugolix combination therapy. N Engl J Med 2021;384:630–42. doi: 10.1056/NEJMoa2008283
13. Hallberg L, Hogdahl AM, Nilsson L, Rybo G. Menstrual blood loss--a population study. Variation at different ages and attempts to define normality. Acta Obstet Gynecol Scand 1966;45:320–51. doi: 10.3109/00016346609158455
14. Munro MG, Critchley HOD, Fraser IS, Committee FMD. The two FIGO systems for normal and abnormal uterine bleeding symptoms and classification of causes of abnormal uterine bleeding in the reproductive years: 2018 revisions. Int J Gynaecol Obstet 2018;143:393–408. doi: 10.1002/ijgo.12666
15. Baird DD, Dunson DB, Hill MC, Cousins D, Schectman JM. High cumulative incidence of uterine leiomyoma in Black and White women: ultrasound evidence. Am J Obstet Gynecol 2003;188:100–7. doi: 10.1067/mob.2003.99
16. Ameade EPK, Mohammed BS. Menstrual pain assessment: comparing verbal rating scale (VRS) with numerical rating scales (NRS) as pain measurement tools. Int J Womens Health Wellness 2016;2:017. doi: 10.23937/2474-1353/1510017
17. Farrar JT, Young JP Jr., LaMoreaux L, Werth JL, Poole RM. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain 2001;94:149–58. doi: 10.1016/s0304-3959(01)00349-9
18. Dworkin RH, Turk DC, Farrar JT, Haythornthwaite JA, Jensen MP, Katz NP, et al. Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain 2005;113:9–19. doi: 10.1016/j.pain.2004.09.012
19. Soliman AM, Margolis MK, Castelli-Haley J, Fuldeore MJ, Owens CD, Coyne KS. Impact of uterine fibroid symptoms on health-related quality of life of US women: evidence from a cross-sectional survey. Curr Med Res Opin 2017;33:1971–8. doi: 10.1080/03007995.2017.1372107
20. Hoshiai H, Seki Y, Kusumoto T, Kudou K, Tanimoto M. Relugolix for oral treatment of uterine leiomyomas: a dose-finding, randomized, controlled trial. BMC Womens Health 2021;21:375. doi: 10.1186/s12905-021-01475-2
21. Osuga Y, Enya K, Kudou K, Hoshiai H. Relugolix, a novel oral gonadotropin-releasing hormone antagonist, in the treatment of pain symptoms associated with uterine fibroids: a randomized, placebo-controlled, phase 3 study in Japanese women. Fertil Steril 2019;112:922–9 e2. doi: 10.1016/j.fertnstert.2019.07.013
22. Osuga Y, Enya K, Kudou K, Tanimoto M, Hoshiai H. Oral gonadotropin-releasing hormone antagonist relugolix compared with leuprorelin injections for uterine leiomyomas: a randomized controlled trial. Obstet Gynecol 2019;133:423–33. doi: 10.1097/AOG.0000000000003141
23. Friedman AJ, Lobel SM, Rein MS, Barbieri RL. Efficacy and safety considerations in women with uterine leiomyomas treated with gonadotropin-releasing hormone agonists: the estrogen threshold hypothesis. Am J Obstet Gynecol 1990;163:1114–9. doi: 10.1016/0002-9378(90)90667-v
24. Schlaff WD, Ackerman RT, Al-Hendy A, Archer DF, Barnhart KT, Bradley LD, et al. Elagolix for heavy menstrual bleeding in women with uterine fibroids. N Engl J Med 2020;382:328–40. doi: 10.1056/NEJMoa1904351
25. Deal LS, Williams VS, Fehnel SE. Development of an electronic daily uterine fibroid symptom diary. Patient 2011;4:31–44. doi: 10.2165/11537290-000000000-00000
26. Al-Hendy A, Myers ER, Stewart E. Uterine fibroids: burden and unmet medical need. Semin Reprod Med 2017;35:473–80. doi: 10.1055/s-0037-1607264
27. Fortin C, Flyckt R, Falcone T. Alternatives to hysterectomy: the burden of fibroids and the quality of life. Best Pract Res Clin Obstet Gynaecol 2018;46:31–42. doi: 10.1016/j.bpobgyn.2017.10.001