Varelas, Fotios K. MD1; Papanicolaou, Alexis N. MD1; Vavatsi-Christaki, Norma MD2; Makedos, Georgios A. MD1; Vlassis, Georgios D. MD1
Uterine leiomyomata are the most common benign tumors of the female reproductive tract, affecting approximately 30% of women of reproductive age, and are responsible for 33% of hysterectomies performed in the United States.1 Despite the fact that the exact pathogenesis of uterine leiomyomata remains unknown, there is plenty of evidence linking their growth to sex steroids.2 Their incidence increases during the reproductive age, whereas deprivation of ovarian steroids, as seen in women after menopause or during gonadotrophin-releasing hormone (GnRH) agonist treatment leads to reduction of leiomyoma volume.3 Circulating ovarian estrogen represents the major source of leiomyoma growth. In addition, many researchers have demonstrated the ability of leiomyomata to synthesize estrogen in situ.4 The treatment of leiomyomata is mainly surgical. Numerous hormonal agents have been used for the management of uterine leiomyomata and the associated symptomatology.5 Gonadotrophin-releasing hormone agonists effectively reduce the size of leiomyomata,6 but their use is limited by significant hypoestrogenic adverse effects.7 Furthermore, discontinuation of treatment leads to regrowth of leiomyomata. Thus, only a limited number of patients can benefit from a short course of GnRH agonist therapy either before surgical management or before menopause.
Aromatase P450 is an estrogen synthetase that catalyzes the conversion of androstenedione and testosterone by hydroxylation to estrone and estradiol. The presence of aromatase in leiomyoma tissue has been shown by previous researchers.8 Estrogens produced in situ by leiomyomata could possibly promote cell proliferation and, consequently, their own growth.4 Anastrazole is a potent, third-generation, nonsteroidal aromatase inhibitor used for the treatment of advanced breast cancer in menopausal patients. One case report in the literature described a perimenopausal patient suffering from a symptomatic leiomyoma treated successfully with the nonsteroidal aromatase inhibitor, fadrozole.9 The aim of this study was to investigate the effect of anastrazole on uterine leiomyomata in symptomatic premenopausal women.
MATERIALS AND METHODS
This prospective intervention study was conducted between September 2003 and May 2005 in the 4th University Department of Obstetrics and Gynaecology, Aristotle University of Thessaloniki, Greece. We enrolled in the study 41 Caucasian symptomatic premenopausal women attending the outpatient clinic having no more than two leiomyomata of at least 35 mm diameter. A total of 45 leiomyomata were finally assessed. Excluded from the study were women with neoplastic, metabolic, endocrine, renal, liver, hematologic, and infectious diseases; history of acute, recurrent, or past thromboembolic disease; history of osteopenia or osteoporosis; current or previous use of drugs interfering with bone metabolism; or presence of hypoechoic or calcified leiomyomata detected at ultrasonography or magnetic resonance imaging scan. In addition, patients requiring or requesting immediate surgical treatment and women with a desire for childbearing in the next year were not included. Prior hormonal therapy had to be completed at least 6 months before trial entry. All participants underwent dilation and curettage before entering the study. Endometrial pathology as documented by endometrial biopsy was also considered an exclusion criterion. None of the women studied entered menopause 1 year after the end of the trial. At trial entry all women were prescribed anastrazole (Arimidex, Astra-Zeneca, Maccelsfield, UK), 1 mg daily for three 28-day cycles. Women were instructed to ensure adequate dietary calcium intake and agreed to use barrier contraception.
The study protocol was in accordance with the latest revision of the Helsinki Declaration on human experimentation and was approved by the Scientific Committee of Hippokrates General Hospital. The aim and the potential risks were explained to all women before entering the study. All patients signed an informed consent.
Number, size, and location of leiomyomata, uterine size, and endometrial thickness were assessed either by ultrasonography or by magnetic resonance imaging at the beginning of the study, at the end of the first treatment cycle, and at the end of the third cycle. All ultrasound scans were performed by the first author using either a General Electric Logiq 400 Pro (GE Healthcare Ultrasound, Solingen, Germany) equipped with a broadband 4.5–9 MHz transvaginal probe and a 2–5 MHz abdominal probe with harmonic imaging or a Siemens Sonoline SI 450 (Tokyo, Japan) real-time scan system equipped with a high definition endocavity probe 5–7.5 MHz and a 3.5 MHz abdominal probe. Magnetic resonance imaging scans were performed using a Siemens Vision 1.5 (1.5 tesla) by an experienced operator who was unaware of the treatment protocol.
All dimension measurements (D1, D2, D3) were repeated twice, and the arithmetic mean was calculated and recorded. Leiomyoma and uterine volumes were calculated by applying the ellipsoid formula (D1×D2×D3×0.52) and using the integrated machine software. To evaluate the effect of anastrazole on normal myometrium we calculated the difference between uterine and leiomyoma volumes in each patient, as described by previous researchers.10
Laboratory analyses included hematological, biochemical, serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol measurements at trial entry and at the end of the first and third treatment cycle. The first hormonal and imaging assessments were performed randomly during the menstrual cycle. At trial entry a urine β-hCG test was also performed. Follicle-stimulating hormone and LH were measured with immunoradiometric assay (IRMA) using commercial kits (125I–hFSH and 125I–hLH IRMA kits, Institute of Isotopes Company, Ltd, Budapest, Hungary). Estradiol concentrations were measured with radioimmunoassay (RIA) using commercial kits (Ultra-Sensitive Estradiol RIA, DSL-4800, Diagnostic Systems Laboratories, Webster, TX).
We asked all women to describe their menstrual patterns and keep a menstrual calendar over the three cycles of treatment. At trial entry and at the end of treatment, participants scored the severity of leiomyoma-related symptomatology, such as menorrhagia, pelvic pressure or pain, urinary frequency, and constipation, using a visual analog scale from 0 to 10, with 10 corresponding to maximal severity, as described by previous researchers.11
The change in leiomyoma volume was set as the primary end point. A minimal required sample size of 33 leiomyomata was calculated to achieve 85% power at an alpha level of 1%, in detecting a 50% change in the volume of uterine leiomyomata, with an anticipated mean volume of 160 mL and standard deviation of 120 mL. These values were based on unpublished data from our department, since the anticipated variance was much greater, compared with the majority of published reports. Changes in the uterine volume, difference between uterine and leiomyoma volumes, endometrial thickness, hematocrit, gonadotrophins, estradiol, self-reported severity of leiomyoma-associated symptoms, menstrual pattern, and adverse effects were also considered, as secondary end points. All analyses included the women who completed the study; a last-value-carried-forward intention-to-treat analysis (Fig. 1) was also performed with regard to the primary end point.
The normality of values and their differences were assessed by using the one-sample Kolmogorov-Smirnoff test. All scale variables were found to be normally distributed. Comparison of means at baseline was performed with the Student t test for independent samples. The effect of treatment was evaluated by means of general linear model–based repeated measures analysis of (co)variance, with time/treatment as the within-groups factor. Between-groups factors of no statistical significance were excluded from the model. Within-groups pairwise comparisons were performed after Bonferroni adjustment for repeated measures.
Values that were not normally distributed were compared by using nonparametric tests, namely the Mann-Whitney (two independent samples) and Wilcoxon (two related samples) tests. Proportions were compared with the Friedman, Cochran, and McNemar tests. Two-tailed statistical significance was set at 5% (.05). We performed all statistical analyses with SPSS 13.0 (SPSS Inc, Chicago, IL). The sample size was calculated with NCSS-PASS 2005 (Number Cruncher Statistical Systems, Kaysville, UT).
A total of 35 patients with 39 leiomyomata completed the study (Fig. 1). No statistically significant difference in baseline characteristics was observed between dropouts and completers (Table 1). It should be noted, however, that dropouts tended to be older, with smaller leiomyomata and less severe leiomyoma-associated symptoms, especially pelvic pressure or pain (Table 1, Figs. 1 and 2).
The mean volume of uterine leiomyomata decreased significantly (F=28.38, P<.001), after the first (P<.001) and the last two (P=.001) cycles of treatment with anastrazole (Table 2, Fig. 2). This difference remained statistically significant at the .001 level after last-value-carried-forward intention-to-treat analysis (Figs. 1 and 2). At the end point, anastrazole resulted in a mean 55.74% reduction of original leiomyoma volume (90.66 mL, standard deviation [SD] 97.46, 95% confidence interval [CI] 58.921–122.105). Two of the 39 treated leiomyomata increased in size, whereas one of the 39 remained unchanged at the end of the three-cycle treatment.
Leiomyoma location did not have a significant effect on their volume decrease. However, a significant interaction between age (40 years or younger and older than 40 years) and treatment was observed (F=3.32, P=.042) (Fig. 3). Thus, leiomyoma volume was significantly decreased, after both the first (P<.001) and the last two (P=.002) cycles of treatment with anastrazole in women aged older than 40 years, whereas no significant difference was found in women aged younger than 40 years (Fig. 3). The interaction term was of borderline significance after intention-to-treat analysis (F=2.38, P=.099).
Α significant interaction between leiomyoma size (50 mm or less and more than 50 mm) and treatment was observed (F=4.10, P=.021), especially concerning the first month of treatment (P=.065) (Fig. 4). Thereby, the size of large (greater than 50 mm) leiomyomata was significantly decreased, after both the first (P<.001) and the last 2 months (P=.004) of treatment with anastrazole, whereas a less significant difference was observed in small (50 mm or less) leiomyomata (P=.031 at 3 months, compared with baseline) (Fig. 4).
The mean uterine volume decreased significantly at the end of treatment (t=5.00, P<.001) (Table 2). At the end point, anastrazole resulted in a mean 29.85% reduction of original uterine volume (83.02 mL, SD 98.72, 95% CI 53.01–126.66). No interaction with leiomyoma location or age was observed, whereas a borderline interaction (P=.062) with uterine size was found. Treatment had no significant effect on the size of normal myometrium (difference between uterine and leiomyoma volumes) and endometrial thickness (Table 2). No new tumors were detected during the study.
The hematocrit significantly increased by 11.3% at the end of treatment (t=4.60, P<.001) (Table 2). No interaction with leiomyoma location or age was observed. No significant changes in FSH, LH, or estradiol levels were observed (Table 2).
Our participants demonstrated a significant decrease in the self-reported score concerning severity of vaginal bleeding (Wilcoxon z=5.05, P<.001) and pelvic pressure or pain (Wilcoxon z=3.77, P<.001), and a borderline decrease with respect to urinary frequency (Wilcoxon z=1.73, P=.083) and constipation (Wilcoxon z=1.84, P=.066) (Table 2).
Overall, the menstrual pattern improved significantly (Friedman χ2=35.35, P<.001). Specifically, the percentage of women with regular cycles increased from 17.1% at baseline to 34.3% at the end of the first month (McNemar P=.031) and 51.4% at the end of the third month (McNemar P=.065 compared with first month, P<.001 compared with baseline; Cochran Q=16.93, P<.001). Compared with baseline when no woman reported hypo-, oligo-, or amenorrhea, such menstrual patterns were observed in 31.4% of women at the end of the first month (McNemar P=.001) and 28.6% at the end of the third month (McNemar P=.774 compared with first month, P=.001 compared with baseline; Cochran Q=16.33, P<.001). Amenorrhea was induced in 8.6% of women at the end of third month. Overall, 63% of women reported an improvement in menstrual pattern, while in the remaining 37% the menstrual pattern remained unaltered (Wilcoxon z=4.41, P<.001).
There were no serious adverse effects reported. One woman (3%) reported vaginal dryness, and one woman (3%) reported dyspareunia at the end of the first and third treatment cycles.
We demonstrated in this study a significant reduction of uterine leiomyoma volume in premenopausal women after a three-cycle treatment with the aromatase inhibitor anastrazole. The observed reduction is comparable with GnRH agonist12 and antagonist13 administration in premenopausal women. Anastrazole resulted in a significant reduction of leiomyoma size at the end of the first treatment cycle, thus suggesting an almost immediate start of anastrazole action, with a further reduction during the next two cycles. Gonadotrophin-releasing hormone agonists induce an initial flare-up effect. As a result, maximum leiomyoma size reduction is achieved within 3–6 months. In contrast, GnRH antagonists induce an immediate hypoestrogenic state resulting in maximum leiomyoma reduction within 3 weeks of treatment.13 Anastrazole induced a significant reduction of total uterine volume that is similar to that observed with GnRH agonists14 and antagonists.13 In contrast to GnRH analogues,15 anastrazole was not found to affect the volume of nonleiomyomatous uterus, implying a minimal effect on the normal myometrium.
High-dose raloxifene has inhibited the growth of asymptomatic leiomyomata in premenopausal women without a significant effect on normal myometrium, whereas growth of new leiomyomata has been observed during low-dose raloxifene or placebo.11 In our study anastrazole induced a reduction of leiomyoma volume similar to that observed with mifepristone treatment in premenopausal women. The antiprogestin mifepristone has been studied in different doses and resulted in a significant decrease of leiomyoma volume.16 Whether the volume reduction observed with anastrazole is sustained after discontinuation of treatment needs to be examined.
The significant increase of the hematocrit observed in this study was obviously due to the improved menstrual pattern. However, the observed increase is not as high as with GnRH analogues17 that usually induce amenorrhoea.
Unlike GnRH analogues, which cause a profound decline in gonadotrophins and estrogens,7,13 usually below levels of detection, we have not detected any significant differences in FSH, LH, and estradiol during treatment. As a result, only a small proportion of patients reported mild adverse effects such as dyspareunia and vaginal dryness during anastrazole treatment, whereas the use of GnRH agonists and antagonists is related to significant hypoestrogenic adverse effects, affecting practically all patients treated. Raloxifene exhibits a favorable adverse effect profile when used in premenopausal women with asymptomatic leiomyomata. As in our study, raloxifene in high doses does not significantly affect the endocrine function,18 while it prevents the growth of leiomyomata. In contrast, mifepristone treatment of uterine leiomyomata results in a high rate of ovarian inhibition and subsequent amenorrhea and hot flushes.19
In this study we observed an alleviation of leiomyoma-related symptomatology. A reduction in leiomyoma-related symptoms has been reported after using either GnRH agonists alone15 or in combination with raloxifene.20 Reduced bleeding patterns and pelvic pain have also been noted with mifepristone treatment.21 It is interesting that the baseline characteristics showed that women who dropped out tended to be older, had smaller leiomyomata, and had reported less severe leiomyoma-associated symptoms, possibly implying a lower interest for a novel pharmaceutical therapy.
Leiomyomata are heterogeneous clinical entities, with dissimilar patterns of growth, development, and clinical presentation. It has been shown that leiomyomata exhibit different percentages of cytogenetic abnormalities according to their location and size.22 In this study we did not observe a significant effect of leiomyoma location on tumor volume reduction. On the other hand, leiomyomata smaller than 5 cm in their greatest diameter showed a smaller volume reduction after treatment. A significant positive correlation between initial leiomyoma volume and subsequent regression, with larger tumors being more likely to shrink than smaller ones, has been reported by other researchers using GnRH agonists.12 It should be noted that our findings could also be due to the relatively limited number of small leiomyomata because our study was not powered to detect differences in this specific subgroup.
In contrast to previous researchers who have used GnRH agonists,12 we reported a different efficacy of anastrazole in different age groups. Anastrazole resulted in a significant leiomyoma volume reduction in premenopausal women aged older than 40 years, leading to the hypothesis of a more pronounced effect on this age group. Our finding that not all leiomyomata decrease in volume after medical treatment has already been noted with both GnRH agonists23 and antagonists.13
In addition, the fact that gonadotrophins and estradiol remained unchanged during treatment leads to the hypothesis that anastrazole in such a low dose acts primarily by inhibition of estrogens produced in situ by leiomyomata. This is further supported by the very small proportion of patients reporting mild adverse effects, suggesting a minimal effect of continuous anastrazole administration on the hypothalamic pituitary axis and no subsequent ovarian stimulation.
A limitation of our study is that it is not blinded and placebo controlled. This is a common limitation with studies on medical therapies of uterine leiomyomata. Because of the heterogeneity of leiomyoma volume, location, age presentation, and related symptomatology, one study cannot accurately control all these parameters. The absence of blinding introduces potential bias of the investigators in assessing the results of treatment and of the patients in reporting leiomyoma-related symptomatology and possible adverse effects of treatment. Another limitation of our study that merits comment is that it might be underpowered with respect to some secondary end points and subgroup analysis.
In conclusion, anastrazole seems to be a promising option in the treatment of uterine leiomyomata for the following reasons. Anastrazole induces a reduction of leiomyoma volume similar to that of GnRH analogues, it improves the hematocrit, and it could be used in the preoperative and perimenopausal period. It exhibits rare and less severe hypoestrogenic adverse effects and can be administered orally. The experience obtained with long-term anastrazole administration in postmenopausal women with breast cancer indicates a favorable safety profile, enabling us to consider long-term administration in premenopausal women with leiomyomata. Further studies are needed to confirm our findings in larger cohorts of patients in a carefully designed, placebo-controlled randomized clinical trial to establish the duration of response and the risks associated with prolonged anastrazole use in premenopausal women.
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