1 Department of Obstetrics & Gynecology, University Magna Graecia of Catanzaro, Catanzaro, 2 Department of Endocrinology and Experimental Oncology and 3 Department of Gynecology, Obstetrics and Human Reproduction, University of Naples Federico II, Naples, 4 Department of Obstetrics and Gynecology, University Tor Vergata of Rome, and 5 Department of Obstetrics and Gynecology, University of Rome Campus Biomedico, Rome, Italy
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Abstract |
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Key words: add-back therapy/fibroids/GnRH analogue/leiomyomas/raloxifene
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Introduction |
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Several medical therapies have been proposed for the treatment of uterine leiomyomas, such as gestrinone, danazol, RU486, estroprogestins, tamoxifene, analogue of somatostatin, or interferon alpha (Coutinho, 1989; Coutinho and Goncalves, 1989
; Lumsden et al., 1989
; Murphy et al., 1993
; Kertel et al., 1994
; Barbieri, 1997
; Marshall et al., 1998
; Friedman and Thomas, 1999
; De Leo et al., 1999
, 2001
; Minakuchi et al., 1999
; Sadan et al., 2001
). GnRH analogue administration has been considered to be more effective medical therapy for uterine leiomyomas (Filicori et al., 1983
; Steward, 2001
).
The hypoestrogenic state induced by GnRH analogue causes climacteric-like symptoms, such as hot flushes, vaginal dryness, reduction of libido, and bone loss, which may be reduced or prevented with the administration of sex hormones (add-back therapy) (Friedman et al., 1990; Adashi, 1994
; Surrey, 1995
; Pickersgill, 1998
). Furthermore, the addition of progestins or estroprogestins at the start of the GnRH analogue administration reduces the effectiveness of the analogue on the uterine and leiomyoma size (Carr et al., 1993
; Friedman et al., 1994
; Nakayama et al., 1999
). At present, only the addition of tibolone, a steroid compound structurally related to 19-nortestosterone derivatives, which exhibits a concomitant weak estrogenic, progestinic, and androgenic activity (Modelska and Cummings, 2002
), is an effective add-back therapy for GnRH analogue treatment if administered with the analogue (Palomba et al., 1998
, 1999
, 2001a
).
Raloxifene hydrochloride is a synthetic non-steroidal drug derived from benzothiophene and afferent to selective estrogen receptor modulators (SERM), a group of compounds that interact with estrogen receptors eliciting tissue-specific responses (Kuiper et al., 1997; Paech et al., 1997
; Khovidhunkit and Shoback, 1999
). It is known that raloxifene acts on the metabolism, the central nervous system, the skeleton and the cardiovascular system as a estrogenic agonist (Walsh et al., 1998
; Ettinger et al., 1999
; Mosca, 2001
; Barrett-Connor et al., 2002
), whereas it shows a weak estrogenic antagonist effect on reproductive organs, including the breast and the uterus (Cummings et al., 1999
; Cohen et al., 2000
; Goldstein et al., 2000
).
Pre-clinical data (Black et al., 1994; Bryant et al., 1996
; Fuchs-Young et al., 1996
; Porter et al., 1998
; Walker et al., 2000
) have suggested that raloxifene may have a beneficial effect on leiomyomas. In a recent clinical study (Palomba et al., 2001b
), we observed a significant reduction in leiomyoma size after 1 year of treatment with raloxifene 60 mg daily in post-menopausal women. On the contrary, the administration of raloxifene at standard and high dose, in pre-menopausal women affected by uterine leiomyomas, did not induce any reduction in uterine and leiomyoma sizes (Palomba et al., 2002a
).
Based on these considerations, the present study was designed to investigate the effect of adding 60 mg raloxifene daily on both uterine and leiomyoma size, and also on leiomyoma-related symptoms in symptomatic pre-menopausal women treated with GnRH analogue.
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Materials and methods |
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Subjects
Between June 2000 and January 2001, 100 pre-menopausal women affected by symptomatic uterine leiomyomas were enrolled in the study.
Exclusion criteria were: neoplastic, metabolic, endocrine, liver, haematological and infectious diseases; active rheumatoid arthritis; history of acute or recurrent vascular thrombosis; a bone mineral density (BMD) value <1.0 SD of the mean peak BMD for sex-matched healthy young adults (1.0 T-score) at posterioranterior lumbar spine; a body mass index (BMI) <18 or >30 kg/m2; previous or current treatment with bisphosphonates, sodium fluoride, calcitonin, estroprogestins or anabolic steroids, corticosteroids, calcium or vitamin D, phosphate, thiazidic diuretics or other drugs interfering with bone metabolism; abnormal serum levels of creatinine and parathyroid hormone (PTH). Women smoking >20 cigarettes per day and drinking more than three alcoholic beverages per day were also excluded. The presence of hypoechoic or calcified leiomyomas, or endometrial abnormalities detected at transvaginal ultrasonography (TV-USG) was also considered an exclusion criterion.
Treatment protocol
At trial entry, all subjects were randomized in single blocks into a single-blind, placebo-controlled study design using a computer-generated randomization list. The subjects were assigned to one of two groups of 50 women each. All women received leuprolide acetate depot (LAD) (Enantone; Takeda, Rome, Italy) at a dose of 3.75 mg/28 days combined with raloxifene hydrochloride (Evista; Eli Lilly, Sesto Fiorentino, Italy) at a dose of 60 mg/day p.o. (group A) or placebo tablets (1 tablet/day; group B).
The duration of the study was six cycles of 28 days each and for this period the single-blinding was maintained in the two groups. After the six cycles, the women of group A continued the treatment for another 12 cycles.
Study protocol
At the beginning of the study and after six cycles of treatment, uterine and leiomyoma sizes, the number of tumours, and endometrial thickness were measured by TV-USG. At the same time, bone metabolism was measured, and calcium intake, alcohol consumption, and physical activity were evaluated (Palomba et al., 2002b).
No dietary restriction or changes were implemented during the study. To ensure adequate calcium intake, all patients with an intake <1000 mg received daily supplements of elemental calcium in the form of an effervescent tablet composed of calcium carbonate (Cacit; Procter & Gamble, Rome, Italy) to achieve a total daily intake of 1000 mg.
All women agreed to use barrier contraception throughout the study.
Ultrasonographic scans were performed by the same experienced operator using a Toshiba PowerVision 6000 (Toshiba Medical System, Rome, Italy) equipped with a 7.5 MHz transvaginal probe. The operator was unaware of treatment assignment. Uterine and leiomyoma sizes were evaluated measuring the three main diameters (D1, D2, D3) and applying the formula of the ellipsoid (D1xD2xD3x0.52). An arithmetic mean of the sizes was used where two leiomyomas were present. As previously described (Palomba et al., 2001b), to evaluate the effect of treatments on the non-leiomyoma tissue, the difference between uterine and leiomyoma volumes (
size) was calculated in each subject. The data were expressed as percentage change of baseline values. Endometrial thickness was also measured.
The subjects were instructed to maintain a personal daily diary of the severity of leiomyoma-related symptoms, such as menorrhagia, pelvic pressure and pain, urinary frequency, and constipation. The severity of symptoms was carefully recorded by each woman using a rank scale ranging from 1 to 10, with 1 being the least and 10 being the most severe (Palomba et al., 1998, 2002a
). The women recorded in the diary the number of uterine vaginal bleeding episodes and of hot flushes.
The bone metabolism was evaluated measuring the BMD and the bone turnover markers. The BMD was determined by dual energy X-ray absorptiometry (Dexa QDR 1000; Hologic, Waltham, MA, USA) at posterior-anterior lumbar spine (vertebrae L1L4) and at hip (trochanter and femoral neck) (Palomba et al., 2002b). The bone metabolism was evaluated at entry and after six cycles by determining the serum levels of osteocalcin and bone alkaline phosphatase levels, and urinary creatinine-corrected free deoxypyridinoline and pyrilinks-D (Palomba et al., 2002b
).
Standard clinical evaluations and laboratory analyses, including haematological, renal function and liver function tests, measurements of serum calcium and phosphate concentrations, and microscopic examinations of sediment from midstream urine specimens were performed before treatment, and after three and six cycles of treatment.
The subjects were also instructed to report in the daily diary the appearance of adverse experiences (AE). The AE were defined as any undesirable clinical experience occurring to patients during the study, whether or not related to the drugs administered. A serious AE was defined as death, overdose, diagnosis of cancer, or any event that was life-threatening, permanently disabling or requiring hospitalization. From the time the patients received the first dose of the drugs all subjects were seen every 3 months to check the personal diary. All patient data were carefully considered to establish the severity, duration, seriousness, and a possible causeeffect relationship.
Statistical analysis
Using previous studies (Sener et al., 1996; Palomba et al., 2001b
, 2002a
) a sample of 30 subjects per group would be necessary to detect an effect on the size of one SD with an
value of 0.05 (two-sided) and a power 1
of 0.8. Furthermore, because the primary end-point of our protocol study was lumbar spine BMD changes, the sample size studied was 50 subjects/group (Palomba et al., 2002b
,c
).
All data shown in this paper were analysed by intention-to-treat method.
Statistical analysis was performed using the SPSS 9.0 (SPSS Inc., Chicago, IL, USA) package. Data are expressed as mean ± SD. Analysis of the variance was used to evaluate differences between the two groups in age, BMI, BMD, parity, number of cigarettes smoked per day, endometrial thickness, uterine and leiomyoma sizes, and size between groups at entry and after six cycles of treatment. Wilcoxons signed-rank test was used to compare parity, cigarettes smoked, alcohol consumption, calcium intake and physical activity. The proportion of women receiving calcium supplements in the two groups of treatment was compared using the
2-test. The differences in length and severity of menstrual cycles between and within groups were compared at entry and after six cycles of treatment using analysis of variance and Wilcoxons signed rank tests, respectively. Fishers exact test was used to compare the incidence of AE between treatment groups.
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Results |
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In group A, two women dropped out for lack of compliance to the treatment (one subject did not take only raloxifene at the second month and one GnRH analogue and raloxifene at the start), and three because of missed BMD and TV-USG examinations after 6 months (two did not perform the BMD measurements and one the TV-USG evaluation).
In group B, one woman dropped out for lack of compliance to the treatment (she did not take GnRH analogue and raloxifene at the start of the study), and three because of missed BMD examinations at the sixth month.
Uterine, leiomyoma and sizes
After randomization, no difference in uterine, leiomyoma, and sizes was detected between the two groups at entry (Table I
). After six cycles of treatment, a significant (P < 0.05) decrease in uterine and leiomyoma size was obtained in both groups (Figure 1
). No significant difference was observed in percentage of change in uterine size between groups (Figure 1
). Furthermore, in group A, a significant decrease (P < 0.05) in leiomyoma size was observed between baseline and group B (Figure 1
). After treatment, a significant (P < 0.05) change in
sizes was observed in the two groups in comparison with baseline without differences between groups (Figure 1
).
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Vasomotor symptoms
In both groups, the mean number of hot flushes per day increased significantly (P < 0.05) after 15 days from the start of the treatment and remained constant for all six cycles of treatment. No significant differences were observed between the two groups (Figure 3).
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There was also no significant difference in the incidence of clinical effects and/or laboratory abnormalities between the two groups of treatment.
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Discussion |
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In guinea-pigs, a fast regression of abdominal wall estrogen-induced leiomyomas was observed after raloxifene administration (Porter et al., 1998). A more recent study in the rat (Walker et al., 2000
) has confirmed that raloxifene analogue inhibits the cell proliferation in leiomyoma tissue, reducing their size and incidence by 4060%.
Our previous clinical data (Palomba et al., 2001b) have shown that 1 year of raloxifene administration at doses of 60 mg daily significantly reduces the uterine and leiomyoma sizes in post-menopausal women. A relevant finding of this study was the selective action of raloxifene on the leiomyoma tissue. In particular, in post-menopausal women the raloxifene administration seems to induce a significant reduction of leiomyoma sizes, without any significant action on normal myometrium. No significant effect on uterine and leiomyoma sizes, furthermore, was observed after six cycles of raloxifene administration at standard and/or high doses in pre-menopausal women affected by asymptomatic uterine leiomyomas (Palomba et al., 2002a
). These findings may have a 2-fold explanation. First, it is possible that the raloxifene doses were too low to reduce or revert the proliferative effect of serum estradiol in normal ovulatory women. In fact, in post-menopausal women the serum estradiol levels are
10-fold lower in comparison with normally cycled pre-menopausal women. Second, in post-menopausal women estrogen receptors could have a different intra-tumoral pattern in terms of concentration, expression and affinity in comparison with pre-menopausal women (Brandon et al., 1995
; Lessl et al., 1997
).
Based on these considerations, we designed this prospective, randomized, single-blind, placebo-controlled clinical trial in order to confirm the beneficial effect of raloxifene administration on uterine leiomyomas in women with low levels of sex hormones during GnRH analogue treatment.
The main outcome measure of our study was to demonstrate the effectiveness of raloxifene administration on bone metabolism during GnRH analogue treatment. Indeed, no negative effects of GnRH analogue on BMD and bone turnover markers were observed during the administration of analogues plus raloxifene at standard doses (Palomba et al., 2002c).
Our data confirm (Carr et al., 1993; Friedman et al., 1994
; Palomba et al., 1998
, 1999
, 2001a
; Nakayama et al., 1999
) that GnRH analogue administration is effective for the treatment of symptomatic uterine leiomyomas in terms of reduction in uterine and leiomyoma sizes, and of leiomyoma-related symptomatology. Raloxifene addition induced a reduction in leiomyoma dimensions, which was significantly higher than that observed after treatment with placebo. Moreover, this reduction did not lead to any significant further reduction in leiomyoma-related symptoms.
The raloxifene-related reduction in leiomyoma dimensions observed in the present study was higher and more rapid in comparison with that obtained in post-menopausal women (Palomba et al., 2001b). These data were probably due to the profound hypoestrogenism achieved after GnRH analogue administration. In both groups the decrease in leiomyoma size was higher in comparison with that obtained in
size, confirming that GnRH analogue seems to act more on tumoral than on non-leiomyoma tissue as previously observed (Carr et al., 1993
) using magnetic resonance imaging. In addition, after 6 months of treatment, whereas the leiomyoma size decreased more significantly in women treated with raloxifene, no significant difference was detected in non-leiomyoma size (
size) between groups, showing that (as is the case in pre-menopausal women during GnRH analogue administration) raloxifene acts selectively on leiomyoma tissue.
During our study period, few side-effects were detected and the raloxifene treatment was tolerated as well as the placebo. In particular, no significant difference in mean hot flushes per day and in uterine bleedings was observed between the two treatment groups.
Unfortunately, raloxifene administration did not reduce the GnRH analogue-related vasomotor symptoms. On the contrary, a significant reduction in mean number of hot flushes per day was observed when adding tibolone to GnRH analogue treatment (Palomba et al., 1998, 1999
, 2001a
; Di Carlo et al., 2000
).
Raloxifene and tibolone are two compounds that did not induce endometrial proliferation in post-menopausal women with a high percentage of non-bleeding cycles (Goldstein et al., 2000; Modelska and Cummings, 2002
); our study confirms these data. In fact, tibolone (Palomba et al., 1998
) or raloxifene addition to GnRH analogue treatment in women with uterine leiomyomas did not increase the percentage of women with uterine bleedings in comparison with analogue alone.
In conclusion, the administration of GnRH analogue plus raloxifene in pre-menopausal women with symptomatic uterine leiomyomas is effective in reducing uterine and leiomyoma size with a strong effect on leiomyoma tissue. It is possible to envisage the use of raloxifene as an add-back therapy in women treated with GnRH analogue during the first months of treatment to preserve bone mass and to achieve the maximal reduction in leiomyoma sizes, using successively tibolone or estroprogestin addition for a long-term treatment.
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Acknowledgements |
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Notes |
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References |
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Submitted on June 13, 2002; accepted on August 25, 2002.