Effetto dell’applicazione di diversi agonisti ed antagonisti della dopamina nelle vampate post-menopausali
Maturitus, 8 (1986) 229-237 229ElsevierMAT 00399 Effects of different dopamine agonists and antagonists on post-menopausal hot flushes L. Zichella ‘ P. Falaschi *, P. Fioretti 3, G.B. Melis 3, A. Cagnacci 3, , M. Gambacciani 3 and S. Mancini 3 ’I Clinicu Ostetrica e Ginecologica ‘L.u Sapienra ‘ Policlinico , Umberto J, Department of Obstetrics and Gynaecologv I, and ’ Department of Internal Medicine V, Unioersitv of Rome; and -’Department of Obstetrics and Qnaecologv, Unioersiti degli Studi, Pisu. Jta!v (Received 14 May 1985; revision received 30 December 1985; accepted 13 June 1986) The dopaminergic system seems to be involved in both pulsatile luteinizing hormone (LH) secretionand hot flushes in post-menopausal women. With the aim of further clarifying its role, the effectivenessof dopaminergic and antidopaminergic drugs in the treatment of hot flushes was studied. Self-assessedscores for vasomotor symptoms were evaluated in 5 groups of 15 patients treated for 20 days with one ofthe following agents: placebo; the dopamine receptor agonist, bromocriptine; the indirect dopaminergicagent, Liposom: the antidopaminergic drug, veralipride or the peripheral antidopaminergic agent,domperidone. All of these treatment regimens were effective in alleviating hot flushes, but the pharmaco-logical agents proved to be more effective than the placebo. A direct dopaminergic action is hypothesizedin the case of bromocriptine and Liposom, while the antidopaminergic drugs might act through differentindirect mechanisms such as the short-loop feedback exerted by hyperprolactinaemia on tuberoinfundib-ular dopamine (TIDA) neurons with a secondary dopamine-like activity, or stimulation of the opioidsystem.(Key words: Dopamine, Agonists, Antagonists, Hot flushes)Introduction Hot flushes are perhaps the most common of all the vasomotor symptomsexperienced by post-menopausal women, occurring in about 80% of cases. They aredescribed as an intense feeling of heat centred on the upper body, often associatedwith a visible reddening of the face and neck. This feeling of heat rapidly becomesgeneralised, and is accompanied by palpitations and profuse sweating. It has been established objectively that there is a clear correlation between hotflushes and an elevation of finger temperature, as well as a reduction in skinresistance [ 1,2].Correspondence to: Dr. G.B. Melis. Clinica Ostetrica e Ginecologica, Universita degii Studi, via Roma 37.56100 Pisa, Italy.0378-5122/86/$03.50 0 1986 Elsevier Science Publishers B.V. (Biomedical Division)
230 Various neuroendocrine changes have also been observed during hot flushes ,but the main accompanying neuroendocrine event manifests itself as luteinizinghormone (LH) pulses [4,5]. Pulsatile LH secretion is enhanced in post-menopausalwomen and almost 85% of pulses correlate temporally with hot flushes [5,6].However, it has been clearly established that LH pulses alone cannot induce hotflushes, but are more probably the hormonal expression of the altered neurotrans-mitter functions within the hypothalamus which are mainly responsible for vasomo-tor symptoms in post-menopausal subjects [7,8]. Modifications in the hypothalamic neurotransmitter system are present in hypo-gonadal animals [9,10] and, in particular, an increased norepinephrine/dopamine(NE/DA) ratio has been reported in the hypothalamus of ovariectomised rats [ll].Despite the conflicting data [12,13], dopamine and dopaminergic drugs wouldappear to reduce LH pulsatility and secretion in both animals and humans [14,15].Although a pituitary site of action cannot be completely excluded in humans, thiseffect is probably exerted on hypothalamic LH releasing factor (LHRF) secretingcells, as has been demonstrated in animals [14,15]. These data suggest that a reduction in endogenous dopaminergic tone may beone .of the possible mechanisms involved in both the enhanced pulsatile LHsecretion and the pathogenesis of hot flushes in post-menopausal women. Some investigators, however, maintain that the intrahypothalamic dopaminergictone is enhanced in post-menopausal women, suggesting that the administration ofantidopaminergic drugs could be useful in the treatment of hot flushes . In view of these conflicting data, we evaluated the clinical changes in vasomotorsymptoms which follow pharmacological manipulation of the dopaminergic systemwith both agonist and antagonist drugs.Subjects and methods Twenty-five women aged 45-55 yr volunteered to participate in the study. Thepatients had all undergone physiological menopause l-2 yr before the start of thestudy and were experiencing severe vasomotor symptoms. They had not receivedendocrinologically active drugs for at least the preceding 6 mth. The patients were randomly divided into 5 groups of 15 subjects and receivedeither placebo or drug treatment for 20 days. The following drugs were adminis-tered: bromocriptine (BCT, 3.75 mg/day per OS) as a direct dopamine receptoragonist ; Liposom (40 mg/day intramuscularly), an extract of hypothalamicphospholipids, as an indirect dopamine receptor stimulating agent [17,18]; veralipride(VER, 100 mg/day per OS), as a specific dopamine receptor blocking agent withcentral effects ; and domperidone (DOM, 10 mg/day per OS), as a specificdopamine receptor blocking agent with no central effects, since it does not cross theblood-brain barrier . The severity of the vasomotor symptoms was self-assessed before and aftertreatment. The patients were required to fill in a chart reporting both the frequencyand intensity of hot flushes, scored from O-3 according to the scheme shown in
231TABLE ISCORING SCHEME FOR THE EVALUATION OF THE FREQUENCY AND INTENSITY OFPOST-MENOPAUSAL VASOMOTOR SYMPTOMS Hot flushes Frequency Intensity 0 0 < S/day Slight > 5, < lo/day Moderate > lo/day SevereTable I. The values for both frequency and intensity were totalled and thepretreatment mean was compared with that after each treatment using Student’st-test for paired data. The differences between the pharmacological treatments and the placebo werealso evaluated by means of the r-test. In addition, the statistical significance of thedifferences between the efficacy of the drug treatments and that of the placebo wereevaluated using the Fisher test. The mean vasomotor symptom scores computed for each group of patientsbefore and after treatment are set out in Table II. No significant differencesbetween the groups were detected before treatment. A significant improvement inthe mean vasomotor score was observed in all groups at the end of treatment(P < 0.05 with placebo, P -c 0.001 with BCT, Liposom, VER and DOM). However,comparison of the scores at the end of the treatment revealed that all drugs usedhad reduced the scores more than the placebo (P -c 0.05). *TABLE IIMEAN VASOMOTOR SYMPTOMS SCORES BEFORE AND AFTER TREATMENT WITH DIF-FERENT COMPOUNDSCompound a Before After Significance (paired f-test)Placebo 3.0+0.2 2.4 +O.l P < 0.05BCT 3.4 f 0.4 * 0.85 +O.l ** P < 0.001Liposom 3.0+0.3 * 1.0 kO.1 ** P i 0.001VER 3.5*0.3 * 1.2 +0.1 ** P < 0.001DOM 3.6kO.5 * 1.2 io.3 ** P i 0.001 * No significant difference in relation to placebo group.** P i 0.05 in relation to placebo group. a BCT, bromocriptine; VER, veralipride: DOM, domperidone.
232TABLE IIICOMPARISON OF THE EFFICACY OF DIFFERENT DRUGS AND PLACEBO IN THE TREAT-MENT OF POST-MENOPAUSAL HOT FLUSHESCompound ’ Number of patients Significance Improvement No improvement (Fisher test)Placebo 6 9 _BCT 14 1 P i 0.01Liposom 13 2 P < 0.05VER 14 1 P < 0.01DOM 13 2 P < 0.05a BCT, bromocriptine; VER, veralipride; DOM, domperidone. Moreover, a significantly greater number of patients experienced an improvementin vasomotor symptoms after pharmacological treatment than after placebo admin-istration (P < 0.01 with BCT and VER, P < Cr.05 with Liposom and DOM) (TableIII). Indeed, the placebo was completely ineffective in 9 patients, even though itmarkedly reduced hot flushes in 3 patients and completely abolished them inanother 3 (Table III). BCT and VER, on the other hand, were each ineffective inonly one patient, and Liposom and DOM in only two. Complete disappearance of hot flushes was observed in 6 subjects treated withLiposom or DOM, in 5 patients treated with BCT and in 3 patients treated withVER. The remaining patients experienced a marked reduction in vasomotor symp-toms (9 on BCT, 7 on Liposom, 11 on VER and 7 on DOM) (Table III). No side-effects were reported with either the placebo or Liposom. BCT inducednausea, constipation and hypotension in 13 patients, but these side-effects disap-peared in all but two of the patients within the first week of treatment. DOM andVER caused mastodynia in 6 and 10 patients, respectively, while galactorrhoea wasobserved in 2 patients after VER treatment.Discussion Hot flushes are a common symptom caused by reduced oestrogen secretion inwomen mainly after the menopause . Although oestrogen replacement therapy isthe most effective treatment for this complaint , other drugs are also able toalleviate or to abolish hot flushes [l&21-23]. Indeed, some investigators maintainthat placebos are more effective in the treatment of vasomotor symptoms than inother conditions [21,22]. Current data confirms these results and it has been shown in a group of 15post-menopausal subjects that placebo treatment induced a slight but significantdecrease in the intensity and frequency of hot flushes. It is difficult to explain theso-called placebo effect completely, but some data clearly demonstrate that aplacebo exerts its effects, or at least its analgesic effect, through an increase inendogenous opioid activity .
233 It has also been shown that clonidine treatment improves neurovegetative symp-toms in post-menopausal women . Although clonidine’ main pharmacological saction seems to be its alpha-receptor blocking activity, its therapeutic effect mightalso be explained through the enhancement of endogenous opioid activity that itproduces [20,21,25,26]. These observations led some workers to formulate the opioid-adrenergic explana-tion of the origin of hot flushes . The involvement of opioids in the control of the thermoregulatory system hasbeen demonstrated in animals [27-291. Opioid or opiate administration reducesthermic sensitivity in animals [27,29]. The acute morphine withdrawal syndromeinduced by naloxone administration is followed by changes in skin temperature andconductance similar to those observed during hot flushes . On the other hand,there are many similarities between the clinical manifestations of heroin withdrawalsyndrome in humans and the neurovegetative post-menopausal syndrome [20,30]. A direct correlation exists between peripheral and central opioid levels andcirculating oestrogen levels in both animals and humans [31-331. In post-menopausalwomen peripheral opioid levels are low, as is central opioid activity [33-351. Inhypogonadal subjects, exogenous steroid administration can increase peripheralopioid levels, restore central opioid activity and alleviate subjective hot flushes120,361. All these data suggest that hot flushes could be the main symptom of oestrogenwithdrawal and the consequent endogenous opioid withdrawal that this causes . Different neuroactive drugs that are able to influence the central opioid system might therefore be effective in the treatment of hot flushes. We have shown that antidopaminergic drugs, such as VER or DOM, are able to relieve vasomotor symptoms in post-menopausal subjects. Their efficacy was found to be significantly greater than that of placebo, as indeed had previously been shown by ourselves and other investigators [16,22]. Antidopaminergic drugs are able to increase plasma levels and hypothalamic concentrations of opioid peptides when injected into animals [37,38]. They also increase circulating opioid levels in humans [40,41]. This action could be exerted through direct blocking of the dopamine receptors present in hypothalamic-pituitary opiodergic cells , but an indirect effect exerted through hyperprolactinaemia has been reported to enhance central opioid tonus in animals [42-441. Increased opioid neuroendocrine activity has also been demonstrated in women suffering from hyperprolactinaemia due to pituitary adenoma . All these findings may explain how the hyperprolactinaemia induced by VER and DOM administration is in itself able to increase endogenous opioid tonus in post-menopausal subjects and consequently to reduce neurovegetative symptoms, these effects being similar to what is seen during treatment with oestrogens [16,20,22,23]. On the basis of these data it may be postulated that pharmacological hyperpro- lactinaemia may correct the endogenous opioid withdrawal syndrome that results from oestrogen lack in post-menopausal women [20,42-441. Similarly, in other hypo-oestrogenic conditions, such as those in patients with amenorrhoea or pitui-
234tary adenoma, the presence of hyperprolactinaemia could explain the absence of hotflushes even though the levels of circulating oestrogens are very low . Anotherpossible explanation of the efficacy of antidopaminergic drugs in the treatment ofhot flushes that merits consideration could be a pharmacological effect mediatedthrough the blocking of central dopaminergic receptors. Buvat et al., who maintain that hot flushes are due to the increase in centraldopaminergic tone that follows the decrease in oestrogen concentrations, claimedthat VER might reduce dopaminergic tone at the anterior hypothalamic level, wherethe main thermoregulatory centres are located . This explanation is at variancewith the fact that castration has been shown to reduce rather than increasehypothalamic dopaminergic activity in rats [46,47]. In addition, VER should exert acentral action at the brain level and it is known that benzamides easily cross theblood-brain barrier . Moreover, DOM is also able to exert therapeutic effectssimilar to those obtained with VER even though its antidopaminergic activity isonly peripheral . All these data suggest that the therapeutic effect of these drugsis not mediated through their central antidopaminergic properties. However, it cannot be completely excluded that antidopaminergic drugs mightparadoxically exert a dopaminergic action indirectly; hyperprolactinaemia inducedby peripherally-acting antidopaminergic drugs might increase TIDA neuron-activityvia a short-loop feedback mechanism [23,48]. Previous studies in ovariectomisedwomen have demonstrated that BCT, which exerts direct and potent dopaminergiceffects, is able to reduce pulsatile LH secretion-the main endocrine event corre-lated with hot flushes [4-8,151. Since the major thermoregulatory nucleus and themedial preoptic area involved in pulsatile LRF secretion are closely related anatomi-cally within the hypothalamus and can be affected by the same neurotransmitteralterations, it has been hypothesised that the reduction in hypothalamic dopaminergictone might also be involved in the pathogenesis of hot flushes [6,10]. The presentstudy shows that the administration of dopaminergic drugs such as BCT or Liposomis able to reduce vasomotor symptoms. These findings confirm previous results obtained in our laboratory with BCTshowing that this drug was more effective than placebo in improving vasomotor symptoms in a group of post-menopausal women [22,23]. Moreover, in a previouscross-over study in which we analyzed endocrine and clinical responsiveness to BCTand VER administration in 10 post-menopausal women, we observed that the twodrugs have opposite endocrine effects . BCT reduces prolactin plasma levels tovalues lower than 5 ng/ml and decreases pulsatile LH secretion from about 1.8pulses/h to about 1.1 pulses/h. In constrats, VER markedly increases prolactinlevels to values of about 120 ng/ml after 3 weeks of treatment, but has no effect on LH secretion. Paradoxically, both drugs show similar therapeutic efficacy in the treatment of hot flushes . It is known that BCT has some alphalytic properties and it has been suggested that it might influence LH secretion and hot flushes by directly decreasing the activity of the noradrenergic system . The present data indicate that thishypothesis seems very unlikely. Indeed, the administration of Liposom, whichincreases the activity of the endogenous dopaminergic system and has no alphalytic
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