To Evaluate the Efficacy and Safety of Mifepristone in Reducing the Size & Symptoms of Uterine Leiomyoma/Fibroids

Abstract

Background and Study Objective

Uterine leiomyomas, or fibroids, are prevalent benign gynecological tumors affecting many women during their reproductive years. While surgical excision has long been the gold standard for fibroid treatment, the pharmacological management, including progesterone receptor modulators like mifepristone (RU 486), has garnered attention due to the reduced surgical approaches. However, there is a notable paucity of research on the effectiveness of mifepristone, on the same. This study seeks to evaluate the safety and efficacy of mifepristone in reducing uterine leiomyoma size and alleviating associated symptoms.

Methodology

Conducted prospectively, the study enrolled 20 pre-menopausal women, aged 18 years or older, from Nanavati Max Super Speciality Hospital Mumbai, Maharashtra, India. Participants were selected based on specific inclusion criteria, including the presence of at least one uterine myoma with a minimum diameter of 2.5 cm as confirmed by ultrasound. Participants had an average age of 39.75 years and an average BMI of 27.58 kg/m².

Results

The study found that mifepristone significantly reduced uterine volume by 75%, with hemoglobin levels substantially improving from 9 gm/dL initially to 12.51 gm/dL after six months. Pain intensity, assessed using the Visual Analog Scale (VAS) score, gradually decreased from baseline to three-month, with all 20 patients reporting the complete absence of pelvic pain by six months.

Conclusion

This prospective study highlights mifepristone’s promise as a non-surgical approach to effectively reduce uterine fibroid volume, improve hemoglobin levels, and mitigate uterine blood loss in patients.

Introduction

Leiomyomas are the most prevalent benign uterine tumors, afflicting up to 30% of women in their reproductive years, typically between the ages of 35 and 45. These growths often lead to symptoms like excessive menstrual bleeding, abdominal pain, and the presence of a palpable abdominal mass. The severity of these symptoms is typically linked to factors such as the number, size, structure, and location of the myomas [1].

A considerable portion of women in their reproductive years need surgical interventions to address symptomatic myomas, accounting for approximately 40% of all hysterectomies performed in pre-menopausal women in the USA. Notably, this places a substantial economic burden on healthcare systems and results in increased rates of morbidity and mortality [2].

Additional treatment alternatives encompass invasive interventions such as 1) embolization targeting the blood supply to the fibroids and 2) myolysis, which involves the destruction of muscle tissue within smaller fibroids. However, it is crucial to note that myolysis is not recommended for women who aspire to become pregnant due to its potential to lead to significant pregnancy-related complications, and it also lacks FDA approval. Furthermore, existing medical management options include the utilization of selective estrogen receptor modulators (SERMs), GnRH agonists, GnRH antagonists, progesterone receptor modulators (SPRMs), aromatase inhibitors, danazol, gestrinone, anti-progestogens, and more [3].

Hysterectomies continue to serve as a fundamental and widely employed surgical approach for addressing myomas, while non-surgical treatment alternatives possess specific constraints [4].

Specific pharmaceuticals like danazol are linked to significant androgenic side effects and potential liver dysfunction. Danazol has been observed to lead to an approximate reduction of 18–23% in uterine volume [5]. Gonadotropin-releasing hormone agonist (GnRH) medications like Goserelin Acetate are associated with a higher cost and can induce hypoestrogenism, resulting in symptoms resembling menopause, including vaginal dryness, hot flashes, and bone loss. However, they have demonstrated efficacy in reducing myoma size by approximately 50% within a three-month timeframe [6]. Using these medications in women of reproductive age is discouraged due to the onset of significant menopausal-like symptoms. Additionally, uterine artery embolization, although effective in reducing leiomyoma size by a range of 35–69%, carries potential risks, including uterine synechia and premature ovarian failure. It is important to note that this procedure lacks FDA approval [7].

Several hypotheses and emerging evidence suggest that progesterone plays a significant role in the development and sustenance of uterine leiomyoma [8]. It is imperative to assess the impact of progesterone receptor modulators such as mifepristone (RU 486) in non-surgical approaches to managing myomas [9]. Mifepristone (RU 486) is a synthetic steroid with dual attributes, exhibiting both anti-glucocorticoid and anti-progesterone activities. This pharmaceutical primarily exerts its effects through antagonistic actions, with a strong binding affinity to endometrial progesterone receptors and a weaker interaction with estrogen receptors. Additionally, it has been observed to upregulate androgen receptors. A placebo-controlled study conducted by Bagara et al. in 2009 provided evidence that low-dose mifepristone effectively reduced the size of myomas and mitigated associated symptoms [10].

Hence, the previous study endeavored to assess the effectiveness and safety of mifepristone in reducing the size and symptoms associated with Uterine Leiomyoma/Fibroids.

Materials and Methods

This was a prospective study done at Nanavati Max Super Speciality Hospital, Mumbai, Maharashtra, India. The study was commenced after the ethical clearance and was according to the principles of Helsinki.

The study subjects were selected from the outpatient Department of Obstetrics and Gynecology. For the selection of the subjects, specific inclusion criteria were applied, including pre-menopausal women over 18 years of age, women with at least one uterine myoma measuring a minimum of 2.5 cm in diameter, and no myoma larger than 15 cm in diameter, as diagnosed by ultrasound. These patients experienced clinical symptoms associated with the fibroids, such as uterine bleeding and pain. They were willing to use non-hormonal contraception, and they were eligible for either hysterectomy or myomectomy. A consent letter was obtained from all study participants.

Women who desired pregnancy or were nursing, had received hormonal contraception or any hormonal therapy within the last 3 months, showed signs or symptoms of pelvic inflammatory disease, had a history of or were presently diagnosed with uterine, cervical, ovarian, or breast cancer, had abnormal hepatic function or renal function at the time of the study, experienced abnormal or unexplained vaginal bleeding, had known severe coagulation disorders or sickle cell disease, were diagnosed with adenomyosis, had current genital infections, or had any contraindications to receiving anti-progestins were excluded.

A total of 20 patients, who met the inclusion and exclusion criteria were enrolled for the study. Demographic information was gathered, and clinical assessments were conducted at baseline, 3 months, and 6 months. In addition to this, the Visual Analog Scale (VAS) score was used to evaluate improvements in pelvic pain at different time points. The administration of mifepristone commenced during the first week of menstruation. Concomitant medications such as iron therapy, thyronorm & warfarin were used by 8 patients. Iron therapy was not required in 5 patients at the end of the treatment.

The primary endpoints for this study included assessing the time it took to achieve amenorrhea from the initiation of therapy, changes in the size of the largest fibroid in centimeters, alterations in the total uterine volume in cubic centimeters, and shifts in the size of the three largest fibroids in cubic centimeters.

The secondary outcome of interest was the measurement of hemoglobin levels in grams per deciliter (g/dL) to determine significant improvements.

Adverse events related to the drug intervention were also monitored throughout the study. The drug used in the intervention was Fibroease™ Mifepristone, administered at a dosage of 25 mg once daily for either 3 or 6 months.

Statistical Analysis

All the statistical analysis was conducted using STATA v15.0 software. The differentiation between parameters in the two groups was assessed through the application of a paired t-test. A significance level of a p-value less than 0.005 was considered as significant.

Results

The mean age of the 20 patients was 39.75 years, and their average BMI was 27.58 kg/m². Notably, only significant co-morbidities were recorded, which included two individuals who were potential kidney donors, and one patient who had experienced severe anemia alongside cardiac disease and hypertension. Table 1 shows the demographic status of the patients.

Table 1.

Summary statistics of demographics of all subjects

Parameter	Count (N = 20)
Age (years)
N	20
Mean	39.75
Height (cm)
Mean	155.77
Maximum	182.88
Weight (kg)
Mean	65.90
BMI (kg/m2)
Mean	27.58
Marital Status, n (%)
Married	16 (80.00%)
Co-morbidities, n (%)
Severe Anemia	1 (5.00%)
Hypertension	1 (5.00%)
Potential kidney doner	2 (10.00%)
Cardiac disease	1 (5.00%)
Others	15 (75.00%)

The mean fibroid volume at baseline was compared to the mean fibroid volume at subsequent visits (3rd and 6th month, as available). Additionally, the mean fibroid volume at subsequent visits was compared to that of the same patients from the baseline visit. The variations in fibroid volume were presented along with the corresponding p values obtained by applying a paired t test to the findings. Table 2 shows the mean change in the size of fibroids from baseline to 3 months and 6 months.

Table 2.

Summary statistics of change in the size of fibroids

Parameter	Count (N = 20)
Baseline visit
N	20
Mean	13.49
3rd Month (12 vs. 12 comparison)
N	12
Mean	19.81
Mean change from baseline visit	4.33
P-value	0.5001
6th Month (5 vs. 5 comparison)
N	5
Mean	15.78
Mean change from baseline visit	4.94
P-value	0.6120

The number of fibroids that had completely reduced at 6 months was 15. Table 3 shows visit wise Size of fibroid Counts.

Table 3.

Summary statistics of visit wise size of fibroid counts

Parameter	Count (N = 20)
No. of fibroids at baseline visit	20 (100.00%)
No. of fibroids at 3rd Month	12 (60.00%)
No. of fibroids completely reduced at 3rd Month	8 (40.00%)
No. of fibroids at 6th month	5 (25.00%)
No. of fibroids completely reduced at 6th, month	15 (75.00%)

A significant improvement in hemoglobin levels, from 9 to 12.51 gm/dL, was observed when compared with the reduction in fibroid size from baseline to 6 months. Figure 1 shows the hemoglobin levels at base line, 3 months, and 6 months.

Fig. 1.

Mean hemoglobin levels at different visits

A gradual reduction in the VAS score was noted from baseline to 3 months and further to 6 months. By the conclusion of the study, at 6 months, pelvic pain had completely disappeared in all 20 patients. Figure 2 shows the VAS SCORE of pelvic pain from baseline to 6 months, and Fig. 3 shows the pressure symptoms in which the results are similar to VAS score symptoms, while Tables 4 and 5 show the VAS score of dyspanuria and urinary complaints. The results were similar for both the VAS scores at baseline. 3 months and 6 months.

Fig. 2.

VAS score of pelvic pain at different visits

Fig. 3.

VAS score of pressure symptoms at different visits

Table 4.

Summary statistics of concomitant medication

Parameter	Count N (%)
Concomitant medications, n (%)
Homeopathic RX	1 (5.00%)
Iron	2 (10.00%)
NIL	2 (10.00%)
Thyronorm	1 (5.00%)
Warfarin	1 (5.00%)
Syrup Duphalac	1 (5.00%)
Concomitant iron therapy, n (%)
Yes	6 (30.00%)
No	11 (55.00%)
Did not require iron treatment	3 (15.00%)

Discussion

Previous evidence indicated that the size and growth of myomas in humans depended on progesterone levels and various medications. These medications encompassed selective progesterone receptor modulators (SPRMs, such as Asoprisnil) and anti-progestins (Mifepristone). Murphy et al. reported in 1993 that mifepristone could serve as a treatment option for uterine myoma [11].

Management with low-dose mifepristone was observed to reduce volume, size, and bleeding while contributing to an improvement in hemoglobin levels. The use of mifepristone, which possesses both antiprogesterone and anti-glucocorticoid properties in a dose-dependent manner, could also potentially forestall or delay the need for surgical procedures like hysterectomies [12].

Several prior studies have reported outcomes similar to our own investigation. For instance, Kettle et al. found a mean reduction in myoma volume of 46% with a 25 mg dose and a 49% decrease with a 100 mg dose over a three-month period. They documented a decrease in amenorrhea ranging from 40 to 70% within one year at doses of 5–10 mg, while 100 mg led to 100% amenorrhea [13]. Engman et al. noted a 28% reduction with a 50 mg dose within three months [14].

These findings were in line with several other investigations that assessed a range of mifepristone doses, administered for varying durations, typically spanning three to six months [14]. Dosages as low as 5 mg and as high as 50 mg were found to be effective in reducing myoma volume by 26–57% and alleviating myoma-related symptoms, including menorrhagia, dysmenorrhea, and pelvic pressure, as well as inducing amenorrhea in 41–100% of cases [15, 16]. Yang et al. observed that 87.8% of women experienced a substantial reduction in the need for hysterectomy procedures after receiving a daily 25 mg dose of mifepristone for three months [17]. Reinsch et al. reported that RU 486 (Mifepristone) improved uterine blood flow and expedited uterine fibroid improvement in 1994 [18].

Even ultra-low doses, such as 2.5 mg, led to an 11% reduction in uterine volume and provided significant relief from symptoms, suggesting a potential dose–response relationship, which was also associated with improved VAS scores and quality of life [19, 20]. It is worth noting that the growth of fibroids increased, and the recurrence rate doubled after the abrupt or gradual discontinuation of treatment.

Eisinger et al. documented a 48% reduction in mean uterine volume and a 61% reduction in amenorrhea with a 10 mg mifepristone dosage [19]. Various mifepristone dosages were compared by Murphy et al., who concluded that a 25 mg dose was effective in causing a clinically significant decrease in leiomyoma volume [11].

The mechanism of reduced bleeding and myoma size is likely to be due to the structural, functional, and microvascular effects of mifepristone on the endometrium and uterine musculature in a dose and duration-dependent manner. In our study, 25 mg Mifepristone reduced uterine size to a mean value of 8.55% (4.94) from baseline to 6 months while Bagaria et al. had 26.6% reduction with 10 mg over 3 months [10].

This short-term treatment was well tolerated; although large studies are needed to add safety information, about endometrial long-term follow-up after discontinuing treatment. Peri-menopausal women with anemia who are not willing for surgical procedures are definitely ideal candidates for this treatment [20]. It can be used in preoperative cases to reduce the size and buildup hemoglobin levels to have better surgical outcomes [21].

Notably, the study experienced no dropouts, underscoring the high level of acceptance among participants for this cost-effective treatment, which also holds the potential to obviate the need for hysterectomy procedures [15, 22].

Presently, clinical trials are underway, investigating the use of mifepristone at doses ranging from 5 to 50 mg over different durations, spanning from 3 to 12 months. The precise dose and duration for optimal results are yet to be conclusively determined.

Conclusion

In summary, this study highlights mifepristone’s potential as a non-surgical solution for uterine myomas. Our results demonstrate a substantial reduction in uterine volume, improved hemoglobin levels, and overall patient well-being. Mifepristone also enhanced VAS scores and quality of life. These findings underscore mifepristone’s promise as an effective treatment option, with further research needed to optimize dosing and duration parameters.

Abbreviations

VAS

Visual Analog Scale

BMI

Body Mass Index

FDA

Food and Drug Administration

GnRH

Gonadotropin-Releasing Hormone

SPGRMs

Selective Progesterone Receptor Modulators

Funding

Nil.

Declarations

Conflict of interest

No conflict of interest.

Ethical Approval

This is an observational study. The study conduct was approved by an Institutional Ethics Committee.