Original Paper Gynecol Obstet I nvest 1992;34:102-104
Paolo Vercellini Nicoletta Vendola Alberto Colombo Cristina Passadore Laura Trespidi Pier Giorgio Crosignani
Veralipride for Hot Flushes during Gonadotropin-Releasing Hormone Agonist Treatment
L. Mangiagalli Department of Obstetrics and Gynecology, University of Milano School of Medicine, Milano, Italy
Abstract Hot flushes are the commonest symptom induced by gonadotropin-releasing hormone agonists (GnRHa). We performed an open observational trial to evaluate the efficacy of veralipride, an antidopaminergic drug, in reducing hot flushes in 25 premenopausal women treated with a GnRHa for endometriosis (8 subjects) or menorrhagia (17 subjects). The patients received goserelin depot for 6 months and veralipride was added for the third month. Hot flushes, severe in all women at 2 months, improved in both frequency and intensity in 92% of the subjects during veralipride administration. The benefit obtained persisted until the end of the GnRHa treatment.
Introduction Veralipride, a benzamide derivative with antidopa minergic action [1], has been shown to be significantly more effective than placebo in reducing the frequency and severity of hot flushes associated with postmenopausal hypoestrogenism [1-3]. We performed a pilot study to evaluate the therapeutic efficacy of veralipride for hy poestrogenism induced by a gonadotropin-releasing hor mone agonist (GnRHa) in premenopausal women.
Material and Methods In the period from July 1990 to June 1991 we recruited patients with endometriosis or menorrhagia for a combined treatment with a GnRHa and veralipride. We considered subjects who were premeno pausal (FSH < 30 mlU/ml) with normal serum prolactin (PRL) lev
Received: February 3,1992 Accepted: February 24, 1992
els (< 25 ng/ml), and without galactorrhea, visual field defects or extrapyramidal symptoms. Breast examination was negative in all the women, and none had received hormonal treatment in the pre vious 6 months. The patients were treated with the GnRHa goserelin (Zoladcx, 1CI Pharmaceuticals, Macclesfield, Cheshire, UK), administered as a 28-day subcutaneous depot formulation for 6 months, and they were requested to fill in a chart reporting both the daily frequency and severity of hot flushes scored from 0 to 3, according to the scheme shown in table 1. Severity of hot flushes was defined as mild, moderate and severe based on limitation of daily activity: mild if there was no interfer ence, moderate if there was limitation without complete interference, and severe if patients were forced to withdraw from usual occupa tion. Values of both frequency and severity were totalled to give a vasomotor score. Subjects reporting a daily score > 3 at the time of the third goser elin injection were offered treatment with veralipride 100 mg/day per os continuously for 28 days (from day 56 to day 84 after the first goserelin injection). They were asked to continue filling in the symp tom chart until the end of the 6 months of GnRHa treatment.
Paolo Vercellini, MD L. Mangiagalli Department of Obstetrics and Gynecology University of Milano School of Medicine Via Commenda 12 1-20122 Milano (Italy)
€> 1992 S. Karger AG. Basel 0378-7346/92/0342-0102 $2.75/0
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Key Words Veralipride Hot flushes Gonadotropin-releasing hormone agonists Antidopaminergic drugs
Plasma levels of FSH. LH, 17p-estradiol (17pE2) and PRL were determined at 2, 3 and 4 months of GnRHa administration (before and at the end of veralipride treatment and 1 month later). Quantita tive determinations of serum hormones were performed by immunoradiometric assay for LH and FSH (Maiaclone, Serono Diagnostici, Milano, Italy) and radioimmunoassay for 17pE2 and PRL (Estradiol 125I ter. Prolactin d.a. kit. Biodata, Milano, Italy). The significance of differences was evaluated using analysis of variance for repeated measurements and fc-test as appropriate. The protocol had institutional approval, and informed consent to the study was obtained from each subject.
Results Twenty-five women with mean age 43 years (range 2551) met the inclusion criteria, 8 with endometriosis and 17 with menorrhagia. They all completed the study. During veralipride administration, hot flushes were abolished, reduced or unchanged in 9 (36%), 14 (56%) or 2 (8%) women, respectively. The corresponding figures at both 1 and 3 months after withdrawal of this drug were 4 (16%), 14 (56%), and 7 (28%), without significant differ ences versus veralipride treatment values. Variations in the mean vasomotor score during the study period are shown in table 2, as are variations in serum hormone lev els. The secretion of gonadotropins was markedly re duced, and 17pEi fell to postmenopausal levels, except for a flare up in 3 women at 3 months and in 2 at 4 months. PRL concentrations, which were considerably increased by veralipride, returned to basal values in all cases at sus pension of this drug. During its administration, breast tension was reported by 5 women (20%), asthenia by 3 (12%), drowsiness by 3 (12%), and galactorrhea by 1 (4%). All side effects subsided when veralipride was with drawn.
Table 2. Variations of serum hormone levels and vasomotor score (VS) during the study period (data expressed as mean ± SD) FSH LH 17ßE: PRL VS
Discussion GnRHa are currently widely employed in numerous estrogen-dependent disorders [4], The hypoestrogenism induced by them causes hot flushes and bone deminerali zation. Combining progestins with GnRHa reduces these side effects but limits the therapeutic efficacy of the ana logues [5] and causes irregular uterine bleeding [6], In the absence of valid ‘add-back’ regimens which allow long term treatments, GnRHa are usually used singly for few months. In this way, bone resorption is limited and reversible [7], but hot flushes persist and affect patient compliance. Randomized, double-blind, clinical trials have shown that veralipride is significantly more effective than pla cebo in reducing vasomotor symptoms in postmeno pausal women [1, 3], The drug’s effects on hot flushes have been attributed to its antidopaminergic properties and the related increase in opioidergic tone, which can lead to inhibition of tonic LH release [1]. Unlike postmenopausal women, the patients treated with GnRHa present a continuous, profound inhibition
Table 1. Scoring scheme for the evalua tion of the frequency and severity of hot flushes Score
Frequency
Severity
0 1 2 3
0 < 5/day > 5, < 10/day > 10/day
0 mild moderate severe
Pretreatment
At 2 months (GnRHa)
At 3 months (GnRHa+ veralipride)
At 4 months (GnRHa)
At 6 months (GnRHa)
9.5 ± 4.1 14.5 ±4.6 133.7 ± 65.4 12.5 ± 8.3 -
5.5 ± 2.0 3.5± 1.3