Uterine leiomyomas are the most common benign tumors among reproductive-age women.1 Uterine leiomyoma prevalence has been found to be higher among black women.2 There are several ways of treating leiomyomas, the most common being surgery. Gonadotropin-releasing hormone analogs have been widely used as adjuvant therapy to surgery, but their high costs limit the extent of their use.3 Uterine artery embolization is an efficient treatment but is invasive and is not free of complications.4
The exact mechanism of the genesis of uterine leiomyomas remains unknown, but it is accepted that estrogens and progestins influence its development, and estrogen and progestin receptors have been detected in leiomyomas.5–7 The antiprogestogen mifepristone has been proven to have similar or higher efficacy to the gonadotropin-releasing hormone analogs in the treatment of leiomyoma.8,9 Murphy et al10,11 (1993 and 1995) reported 44% and 51% regressions of the uterine leiomyomas when participants received daily 25-mg and 50-mg doses, respectively, of mifepristone for a period of 3 months. Eisinger et al12 (2003), obtained similar results using daily 5-mg and 10-mg doses of mifepristone for a period of 6 months but reported a high rate of endometrial hyperplasia. Steinauer et al13 (2004), in a systematic review of the literature, concluded that administering mifepristone decreased the volume of the uterine leiomyomas with symptomatic improvement but warned of its adverse effects: endometrial hyperplasia. In a continuation of their 2003 study, Eisinger et al14 (2005), administered the same 5-mg and 10-mg doses for a period of 12 months, with no additional benefits being noted with respect to the first 6 months of treatment, although there was a marked reduction in the number of simple endometrial hyperplasia stemming from a second diagnostic examination of the hyperplasias. Gommier et al (2007), using 10-mg doses of mifepristone, reported similar findings to those of Eisinger’s 2005 study, with 10% simple endometrial hyperplasias (Gommier B, Magning G. Mifepristone for treatment of myomas [meeting abstract]. Third Symposium. Misoprostol and mifepristone in obstetrics and gynecology. Valencia, Spain, October 4–5, 2007). Fiscella et al15 (2006) noted a discernible improvement in the quality of life in women treated for a period of 6 months with daily 5-mg doses of mifepristone, recording no cases of simple endometrial hyperplasia. The objective of this study was to estimate the efficacy of the 3-month daily administration of 5 mg compared with 10 mg of mifepristone for the treatment of uterine leiomyomas.
MATERIALS AND METHODS
The study consists of a double-blind randomized clinical trial with two treatment groups. The study was approved by the Scientific Committee of the Teaching Hospital “Eusebio Hernández” in Havana City, Cuba. Women were recruited by primary health care units and the classification consultancy department of the hospital where the research took place.
Inclusion criteria were 1) symptomatic uterine leiomyomas, 2) of reproductive age or premenopausal, 3) agreement to use a nonhormonal method of contraception, 4) agreement to keep a monthly log of all episodes of vaginal bleeding and adverse effects of mifepristone during treatment, 5) agreement to undergo ultrasound examinations in every follow-up or evaluation visit, and 6) agreement to undergo two endometrial biopsies: the first before treatment start and the second 10 days after treatment termination. Exclusion criteria were 1) pregnancy or active attempts to become pregnant, 2) breastfeeding, 3) hormonal contraception or any hormonal therapy in the previous 3 months, 4) pelvic inflammatory disease, 5) adnexal masses, 6) abnormal or unexplained vaginal bleeding, 7) diagnosed or suspected malignant neoplastic disease, 8) signs or symptoms of mental illness, 9) adrenal disease, 10) sickle cell anemia, 11) liver disease, 12) kidney disease, 13) bleeding disorders, or 14) other health problems contraindicating the use of antiprogestogens. Once prospective participants had been fully informed as to the nature and requirements of the study, Informed consent forms were duly signed. The study did not make use of a placebo control group so as not to deprive participants of potentially positive therapeutic effects—studies have shown that low doses of mifepristone help reduce leiomyoma volume, relieve associated symptoms, and improve the woman’s general condition.
We used mifepristone from Zizhu Pharmaceutical Co. Ltd., Beijing, China. Mifepristone 5 mg and 10 mg capsules were prepared by the study pharmacist (Valencia, Spain). Group 1 (n=50) received oral administration of mifepristone (5 mg) for 3 months. Group 2 received daily oral 10 mg of mifepristone for 3 months.
Abdominal uterine ultrasonography was performed before the start of treatment, at 45 days, and at the end of treatment (Fig. 1). Leiomyoma volume was calculated using the following formula: 4πabc/3 where a, b, and c are the radii of the sphere in each of the three planes, expressed in cm3.16 When more than one leiomyoma was present, the biggest was measured and the variations of that leiomyoma were controlled to estimate the efficacy of treatment. The total uterine volume was measured using the formula described above. The endometrial thickness was measured in millimeters using ultrasonography. All measurements were taken using an Aloka Co. Ltd. Ultrasound Diagnostic Equipment SSD-4000, Mitaka-SHI, Tokyo, Japan.
To determine hemoglobin values and liver transaminases, blood samples were taken before treatment start, at 45 days, and at treatment termination. It was decided beforehand that any participant showing significant changes in liver transaminases would be removed from the trial.
Endometrial biopsies were done before treatment start and 3 months after treatment termination. The biopsy was performed using metallic curettes under general sedation. The endometrial samples were examined by three hospital pathologists. The posttreatment biopsies were interpreted with no prior knowledge of either the initial results or the mifepristone dose. Histologic interpretation of the endometrial samples used the findings of previous studies on the changes that occur in the endometrium due to the action of mifepristone as guidelines.17,18 The endometrial biopsy sample was classified as normal if the endometrium was in secretory or proliferative phase of the normal menstrual cycle. Hyperplasia was determined using World Health Organization criteria.19,20 Pathologic endometrial biopsy samples were evaluated for the presence of endometrial intraepithelial neoplasia using the criteria proposed by Mutter.21 For both treatment groups, the primary efficacy variable was the posttreatment percentage reduction in leiomyoma volume, whereas the secondary efficacy variable was the posttreatment percentage reduction in uterine volume.
Other efficacy variables were 1) changes in the prevalence of symptoms attributable to uterine leiomyomas: pelvic pain, lower back pain, rectal pain, pelvic pressure, urinary symptoms, dyspareunia, hypermenorrhea and metrorrhagia. Their prevalence was measured at treatment start, at 45 days and at 3 months. 2) Changes of hemoglobin and liver transaminases at the end of treatment, and 3) adverse effects of mifepristone: amenorrhea, hot flushes, nausea, vomiting, weakness/fatigue, others.
Women were assigned to one or other of the treatment groups by way of a random computer-generated list. Staff not involved in the study prepared sealed opaque envelopes containing cards with either “mifepristone A” or “mifepristone B” on them. These referred to either 5-mg or 10-mg doses of mifepristone. The sealed envelope corresponding to the woman’s entry number in the trial was opened by one of the research doctors, and she was subsequently included into the corresponding treatment group. Only the study monitor knew the corresponding dosage of each participant, and this information was kept secret until the data processing was complete. Researchers and participants did not know which dosage the participants received. Stopping rules for the study were considered unwarranted, and no interim analysis was envisaged.
The expected reduction in leiomyoma volume was used to estimate the sample size for the study. To calculate sample size, we took Eisinger et al,12 as a reference point and assumed that 5-mg and 10-mg doses of mifepristone would give similar results of leiomyoma size reduction (40% with respect to the pretreatment value) based on the uterine volume reduction figures reported in the 4th month of treatment. A preliminary power analysis suggested that a sample of 40 participants in each treatment group would provide a minimal 85% power to detect a 40% difference in change in the leiomyoma volume at a significance level of 0.05 after 3 months of treatment using mifepristone 5 mg compared with 10 mg.22 The sample size for the study was increased by approximately 20% (50 women in each treatment group, totaling 100 for the entire trial), to compensate for possible dropouts or protocol violations.
Results are presented in percentages, means, and standard deviations with 95% confidence intervals for mean. The assumption of a normal distribution for continuous variables was verified using graphic tests and the Kolmogorov-Smirnov test with a Lilliefors significance correction test. When normality was assumed, the t test was used to compare the means of the quantitative variables. When the hypothesis of normality was not accepted, the nonparametric Mann-Whitney U test was used. Pearson’s χ2 and t test for independent samples were used to assess homogeneity between treatment groups. Analysis of variance was used for comparing leiomyoma and uterine volumes between groups, before treatment, at 45 days, and at 90 days. Changes in the uterine and leiomyoma volumes, within groups, at 45 and 90 days were analyzed using a random effects model that did not include covariates. Using Dunnett’s test, mean leiomyoma and uterine volume values at 45 days and 3 months were compared with values before treatment in each treatment group. The normal approximation for proportions was used for comparing symptoms and adverse effects between treatment groups. All tests were two-tailed, and P<.05 was considered significant. Statistical analysis was performed using the SPSS 10.5 for Windows (SPSS Inc., Chicago, IL) statistical package.
Between January 2007 and January 2008, 123 participants were sent to the consultative research center. Twenty-three did not fulfill inclusion criteria, thus 100 of 123 (81.3%) participants were recruited. Analysis was performed on an intention-to–treat basis. There were no dropouts and no losses to follow-up. There were no cases of simple endometrial hyperplasia in the endometrial biopsy taken before treatment start. One participant from the mifepristone 10 mg group with a submucosal leiomyoma presented heavy bleeding and intense low abdominal pain at 45 days was admitted to hospital and expelled a myoma. The participant was removed from the study but the information corresponding to her while she was in the study was included in data analysis.
The general characteristics of participants are presented in Table 1. It was found that mean ages of participants differed significantly between treatment groups. Three women presented infertility associated with or attributable to the uterine leiomyomas, one in the 10-mg mifepristone group and two in the 5-mg group.
There was a single myoma in 23 of 50 (46.0%) women from the mifepristone 10 mg group and in 27 of 50 (54.0%) participants from the mifepristone 5 mg group; this difference was not statistically significant (P=.212). In total, 28% of uterine leiomyomas were subserosal; 57% were intramural, and 15% were submucosal. There were no statistically significant differences between treatment groups with regard to localization of the uterine leiomyomas (P=.331).
In the mifepristone 10 mg group, a 17% (95% confidence interval [CI] –11 to 74) and 45% (95% CI 37–54) leiomyoma volume reduction was obtained after 45 and 90 days, with values of P=.143 and P<.001, respectively. In the 5-mg group the reduction was 39% (95% CI 18–118) and 57% (95% CI 48–67), with values of P=.009 and P<.001, respectively. There was no reduction in the uterine leiomyoma volumes when compared with their initial values in 9 of 49 (18.4%) cases from the 10-mg group and in 7 of 50 (14.0%) participants from the 5-mg group, respectively. These proportions did not differ significantly (P=.278) (Table 2). In the 10-mg group a 23% (95% CI –9 to 270) and 40% (95% CI 34 to –46) reduction in uterine volume was obtained after 45 and 90 days, with P=.061 and P=.002, respectively. In the 5-mg group the reduction was 28% (95% CI 18–45) and 36% (95% CI 31 to –40), with P<.001 in both groups. There was no reduction in the uterine volumes when compared with their initial values in 10 of 49 (20.4%) cases from the 10-mg group and in 8 of 50 (16.0%) participants from the 5-mg group, respectively. The proportions did not differ significantly (P=.285) Table 3.
At the evaluation visit, 90 days after treatment start, 44 of 49 (89.8%) women from the mifepristone 10 mg group and 45 of 50 (90.0%) participants from the 5-mg group, respectively, were amenorrheic. The difference was not significant (P=.487). In this visit, hot flushes were reported by 10 of 49 (20.40%) participants from the group of 10 mg of mifepristone, and in the mifepristone 5 mg group, this was reported by 5 of 50 (10.0%) women. The difference was not statistically significant (P=.074).
Regarding adverse effects attributable to mifepristone, at 3 months there were no statistically significant differences between the groups, although nausea was more frequent in the 10 mg mifepristone group P=.02). Table 4 contains the prevalence of symptoms by treatment groups. In both groups, the prevalence of all symptoms at the end of treatment was much less than at the beginning, and these differences were statistically highly significant.
In total, five participants (5%) presented elevated liver transaminases at the end of treatment, with values that were between 55 and 63 international units (normal values: 46 and 49 international units for the aspartate aminotransferase and alanine aminotransferase, respectively). Three of these five participants had been administered mifepristone 10 mg.
In total, 19% of participants had hemoglobin below 10.0 g/dL at inclusion. Once the treatment period was finished only one participant had a hemoglobin value of 9.6 g/dL; at inclusion, this patient had a 9.3 g/dL hemoglobin value. In total, at inclusion, 63% of the participants had hemoglobin values below 12.0 g/dL; when the study concluded, 44% of the total remained with hemoglobin values inferior to 12.0 g/dL, and this difference was significant, P=.003.
At 3 months, 99 endometrial biopsies were performed, two of which did not provide sufficient material; one participant from the mifepristone 10 mg group was removed from the study because she expelled a myoma at day 45. There were 52 participants with secretory endometria: 28 (57.1%) in the 10-mg group and 24 (48.0%) in the 5-mg group. There were 44 participants with proliferative endometria: 20 (40.8%) in the mifepristone 10 mg group and 24 (48.0%) in the mifepristone 5 mg group. One simple hyperplasia was diagnosed (2.0%) from the mifepristone 10 mg group.
Between 1.5 and 2 months after treatment termination, two women from the mifepristone group experienced heavy vaginal bleeding, and hysterectomies were performed on both participants. The first was 39 years old with two previous children. Before treatment start, an intramural leiomyoma of 161 cm3, hypermenorrhea and metrorrhagia accompanied by pelvic pain, with a hemoglobin value of 9.3 g/dL, had been recorded; at treatment termination, the leiomyoma had decreased to 120 cm3, and the symptoms had disappeared, with a hemoglobin value of 11.1 g/dL. The second was 30 years old with one previous child. Before treatment start, a submucosal myoma of 144 cm3 with pelvic pain and hypermenorrhea, with a hemoglobin level of 12. 6 g/dL, had been recorded; at treatment termination, the myoma had decreased to 70 cm3, and symptoms had disappeared, with a hemoglobin level was 13.5 g/dL.
Once the treatment was over, two participants with leiomyoma-related infertility who had been treated with mifepristone 5 mg became pregnant. At the time of writing this report, one of them was 22 weeks pregnant and became pregnant 1 month after terminating treatment with mifepristone; in the case of other woman, a 7-week pregnancy was diagnosed by ultrasonography three months after the end of treatment; her pregnancy was being supervised in her health area, and no more information on her could be obtained.
The absence of a placebo group seriously limits the methodology of this study; however, an 81.3% participant participation implies an acceptable external validity. There were no statistically significant differences between the two treatment groups with regard to any of the following variables: 1) reduction in the leiomyoma volume, 2) reduction in the uterine volume, 3) reduction in uterine leiomyoma symptom prevalence, and 4) adverse effects attributable to mifepristone, with the exception of hot flushes and nausea that were more frequent in the 10-mg group.
Reductions in uterine leiomyoma volumes are comparable with the results of certain studies using similar doses of mifepristone,8,23 but greater than those of others.11 The uterine volume reduction percentages are similar to those reported by Fiscella et al15 administering doses of mifepristone 5 mg with twice as long treatment periods but are slightly lower than those obtained by Eisinger et al using the same doses but with two to four times longer treatment periods, namely 6 and 12 months.12,14
Most participants noted a marked improvement in the major symptoms of uterine leiomyomas: pelvic, lower back, and rectal pain, uterine bleeding, etc, and these are comparable with those reported in other studies with an extended treatment period of between 6 and 12 months.10–12,14,15 Moreover, the decrease in both symptom prevalence and severity was detected very early on in the course of treatment, becoming apparent in the clinical control at 45 days, earlier than in other studies.12,14 Although the intensity of the symptoms was not measured, this should be done in future studies, at least in participants who continue to present symptoms at the end of treatment. However, we must insist once again that with the exception of cases of pelvic pain, which continued to be present in reasonably high percentages (20.4% and 12.0%) in the 10- and 5-mg groups, respectively, all other symptoms, including some of the major ones such as metrorrhagia and hypermenorrhea, had very low posttreatment prevalence percentages, lower than 6.1%. So although the intensity of symptoms was not measured at the end of treatment, and therefore no statistical affirmation can be made, we can say that our clinical impression was that the pelvic pain and the other symptoms still present were of a much lower intensity. In other words, there was a clinical improvement. In our opinion, the evident symptomatic improvement should outweigh increases or reductions in leiomyoma or uterine volumes. Expulsion of submucous myoma by one participant 1.5 months after treatment can be interpreted as a spontaneous or accidental occurrence or can be attributed to the effect of mifepristone. Regarding the most frequent adverse effects of mifepristone, our data concur with the results of other similar studies using mifepristone 5 mg and 10 mg.12,15
High percentages of amenorrhea in both treatment groups are responsible, clinically speaking, for the improvement of hemoglobin values in practically all participants, with the exception of one woman who began with a 9.3-g/dL hemoglobin value and who, when the treatment concluded, had a hemoglobin value of 9.6 g/dL. The elevated percentages of amenorrhea observed here, 89.8% and 90.0%, for groups of mifepristone 10 mg and 5 mg, respectively, is comparable with other studies using similar dose and treatment intervals.8,9,23
Judging by the decrease in uterine and leiomyoma volume and the symptomatic improvement in the study published by Eisinger et al,12 where they administered the treatment up to 6 months, the added benefit of extending treatment for more than 3 months does not seem to be great, because the percentages of uterine volume reduction percentages are very similar to those obtained with only 3 months treatment; the symptomatic improvement reported by Eisinger et al was practically the same as ours, with the exception of amenorrhea: in the study by Eisinger et al its frequency began to diminish starting from 85% at 3 months to 61–65% at 6 months of treatment.
The elevated transaminases found in five women (5%) are comparable with results of other studies.10,12,23 In our study, the minimal elevated transaminases have little clinical significance—between 55 and 63 international units. Fiscella et al15 did not report any alteration in this measure in their study. Some of these alterations of the transaminases obtained in our study are probably accidental or due to causes not related with mifepristone.
In this trial, although we did not set out to explicitly study the acceptability of the method, we observed a high degree of adherence to treatment, as evidenced by the participants’ desire to continue once treatment had concluded. It is worth noting that two of the 5-mg mifepristone participants, formerly diagnosed with infertility problems associated with the uterine myoma, became pregnant between 1 and 3 months after concluding the treatment. Two other participants underwent hysterectomies, some 1.5 months after finishing treatment when symptoms, particularly uterine bleeding, became intense again.
Attention should be drawn to the fact that in the 10-mg treatment group, a single simple hyperplasia was diagnosed, with no hyperplasia in the 5-mg group. In this sense, the zero hyperplasia observed in the 5-mg group in our study reflects the results of earlier studies using mifepristone 5 mg.14,15,17
One of the principal shortcomings of this study is the absence of a participant follow-up period. This would allow us to evaluate the longevity of symptomatic improvements and volume reductions, thus determining the treatment repetition interval. Five-milligram doses of mifepristone produce leiomyoma and uterine volume reduction and a symptomatic improvement similar to 10-mg doses, with zero hyperplasia, and future studies should include longer treatment periods and posttreatment participant evolution follow-up.
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