1. Maturitus, 8 (1986) 229-237 229
Elsevier
MAT 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) secretion
and hot flushes in post-menopausal women. With the aim of further clarifying its role, the effectiveness
of dopaminergic and antidopaminergic drugs in the treatment of hot flushes was studied. Self-assessed
scores for vasomotor symptoms were evaluated in 5 groups of 15 patients treated for 20 days with one of
the following agents: placebo; the dopamine receptor agonist, bromocriptine; the indirect dopaminergic
agent, 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 hypothesized
in the case of bromocriptine and Liposom, while the antidopaminergic drugs might act through different
indirect 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 opioid
system.
(Key words: Dopamine, Agonists, Antagonists, Hot flushes)
Introduction
Hot flushes are perhaps the most common of all the vasomotor symptoms
experienced by post-menopausal women, occurring in about 80% of cases. They are
described as an intense feeling of heat centred on the upper body, often associated
with a visible reddening of the face and neck. This feeling of heat rapidly becomes
generalised, and is accompanied by palpitations and profuse sweating.
It has been established objectively that there is a clear correlation between hot
flushes and an elevation of finger temperature, as well as a reduction in skin
resistance [ 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)

2. 230
Various neuroendocrine changes have also been observed during hot flushes [3],
but the main accompanying neuroendocrine event manifests itself as luteinizing
hormone (LH) pulses [4,5]. Pulsatile LH secretion is enhanced in post-menopausal
women and almost 85% of pulses correlate temporally with hot flushes [5,6].
However, it has been clearly established that LH pulses alone cannot induce hot
flushes, 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 would
appear 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, this
effect is probably exerted on hypothalamic LH releasing factor (LHRF) secreting
cells, as has been demonstrated in animals [14,15].
These data suggest that a reduction in endogenous dopaminergic tone may be
one .of the possible mechanisms involved in both the enhanced pulsatile LH
secretion and the pathogenesis of hot flushes in post-menopausal women.
Some investigators, however, maintain that the intrahypothalamic dopaminergic
tone is enhanced in post-menopausal women, suggesting that the administration of
antidopaminergic drugs could be useful in the treatment of hot flushes [16].
In view of these conflicting data, we evaluated the clinical changes in vasomotor
symptoms which follow pharmacological manipulation of the dopaminergic system
with both agonist and antagonist drugs.
Subjects and methods
Twenty-five women aged 45-55 yr volunteered to participate in the study. The
patients had all undergone physiological menopause l-2 yr before the start of the
study and were experiencing severe vasomotor symptoms. They had not received
endocrinologically active drugs for at least the preceding 6 mth.
The patients were randomly divided into 5 groups of 15 subjects and received
either 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 receptor
agonist [15]; Liposom (40 mg/day intramuscularly), an extract of hypothalamic
phospholipids, as an indirect dopamine receptor stimulating agent [17,18]; veralipride
(VER, 100 mg/day per OS), as a specific dopamine receptor blocking agent with
central effects [16]; and domperidone (DOM, 10 mg/day per OS), as a specific
dopamine receptor blocking agent with no central effects, since it does not cross the
blood-brain barrier [19].
The severity of the vasomotor symptoms was self-assessed before and after
treatment. The patients were required to fill in a chart reporting both the frequency
and intensity of hot flushes, scored from O-3 according to the scheme shown in

3. 231
TABLE I
SCORING SCHEME FOR THE EVALUATION OF THE FREQUENCY AND INTENSITY OF
POST-MENOPAUSAL VASOMOTOR SYMPTOMS
Hot flushes
Frequency Intensity
0 0
< S/day Slight
> 5, < lo/day Moderate
> lo/day Severe
Table I. The values for both frequency and intensity were totalled and the
pretreatment mean was compared with that after each treatment using Student’s
t-test for paired data.
The differences between the pharmacological treatments and the placebo were
also evaluated by means of the r-test. In addition, the statistical significance of the
differences between the efficacy of the drug treatments and that of the placebo were
evaluated using the Fisher test.
The mean vasomotor symptom scores computed for each group of patients
before and after treatment are set out in Table II. No significant differences
between the groups were detected before treatment. A significant improvement in
the 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 used
had reduced the scores more than the placebo (P -c 0.05).
*
TABLE II
MEAN VASOMOTOR SYMPTOMS SCORES BEFORE AND AFTER TREATMENT WITH DIF-
FERENT COMPOUNDS
Compound a Before After Significance
(paired f-test)
Placebo 3.0+0.2 2.4 +O.l P < 0.05
BCT 3.4 f 0.4 * 0.85 +O.l ** P < 0.001
Liposom 3.0+0.3 * 1.0 kO.1 ** P i 0.001
VER 3.5*0.3 * 1.2 +0.1 ** P < 0.001
DOM 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.

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TABLE III
COMPARISON OF THE EFFICACY OF DIFFERENT DRUGS AND PLACEBO IN THE TREAT-
MENT OF POST-MENOPAUSAL HOT FLUSHES
Compound ’ Number of patients Significance
Improvement No improvement (Fisher test)
Placebo 6 9 _
BCT 14 1 P i 0.01
Liposom 13 2 P < 0.05
VER 14 1 P < 0.01
DOM 13 2 P < 0.05
a BCT, bromocriptine; VER, veralipride; DOM, domperidone.
Moreover, a significantly greater number of patients experienced an improvement
in vasomotor symptoms after pharmacological treatment than after placebo admin-
istration (P < 0.01 with BCT and VER, P < Cr.05 with Liposom and DOM) (Table
III). Indeed, the placebo was completely ineffective in 9 patients, even though it
markedly reduced hot flushes in 3 patients and completely abolished them in
another 3 (Table III). BCT and VER, on the other hand, were each ineffective in
only one patient, and Liposom and DOM in only two.
Complete disappearance of hot flushes was observed in 6 subjects treated with
Liposom or DOM, in 5 patients treated with BCT and in 3 patients treated with
VER. 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 induced
nausea, 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 and
VER caused mastodynia in 6 and 10 patients, respectively, while galactorrhoea was
observed in 2 patients after VER treatment.
Discussion
Hot flushes are a common symptom caused by reduced oestrogen secretion in
women mainly after the menopause [20]. Although oestrogen replacement therapy is
the most effective treatment for this complaint [20], other drugs are also able to
alleviate or to abolish hot flushes [l&21-23]. Indeed, some investigators maintain
that placebos are more effective in the treatment of vasomotor symptoms than in
other conditions [21,22].
Current data confirms these results and it has been shown in a group of 15
post-menopausal subjects that placebo treatment induced a slight but significant
decrease in the intensity and frequency of hot flushes. It is difficult to explain the
so-called placebo effect completely, but some data clearly demonstrate that a
placebo exerts its effects, or at least its analgesic effect, through an increase in
endogenous opioid activity [24].

5. 233
It has also been shown that clonidine treatment improves neurovegetative symp-
toms in post-menopausal women [21]. Although clonidine’ main pharmacological
s
action seems to be its alpha-receptor blocking activity, its therapeutic effect might
also be explained through the enhancement of endogenous opioid activity that it
produces [20,21,25,26].
These observations led some workers to formulate the opioid-adrenergic explana-
tion of the origin of hot flushes [20].
The involvement of opioids in the control of the thermoregulatory system has
been demonstrated in animals [27-291. Opioid or opiate administration reduces
thermic sensitivity in animals [27,29]. The acute morphine withdrawal syndrome
induced by naloxone administration is followed by changes in skin temperature and
conductance similar to those observed during hot flushes [28]. On the other hand,
there are many similarities between the clinical manifestations of heroin withdrawal
syndrome in humans and the neurovegetative post-menopausal syndrome [20,30].
A direct correlation exists between peripheral and central opioid levels and
circulating oestrogen levels in both animals and humans [31-331. In post-menopausal
women peripheral opioid levels are low, as is central opioid activity [33-351. In
hypogonadal subjects, exogenous steroid administration can increase peripheral
opioid levels, restore central opioid activity and alleviate subjective hot flushes
120,361.
All these data suggest that hot flushes could be the main symptom of oestrogen
withdrawal and the consequent endogenous opioid withdrawal that this causes [20].
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 [41], 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 [45].
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-

6. 234
tary adenoma, the presence of hyperprolactinaemia could explain the absence of hot
flushes even though the levels of circulating oestrogens are very low [45]. Another
possible explanation of the efficacy of antidopaminergic drugs in the treatment of
hot flushes that merits consideration could be a pharmacological effect mediated
through the blocking of central dopaminergic receptors.
Buvat et al., who maintain that hot flushes are due to the increase in central
dopaminergic tone that follows the decrease in oestrogen concentrations, claimed
that VER might reduce dopaminergic tone at the anterior hypothalamic level, where
the main thermoregulatory centres are located [16]. This explanation is at variance
with the fact that castration has been shown to reduce rather than increase
hypothalamic dopaminergic activity in rats [46,47]. In addition, VER should exert a
central action at the brain level and it is known that benzamides easily cross the
blood-brain barrier [16]. Moreover, DOM is also able to exert therapeutic effects
similar to those obtained with VER even though its antidopaminergic activity is
only peripheral [19]. All these data suggest that the therapeutic effect of these drugs
is not mediated through their central antidopaminergic properties.
However, it cannot be completely excluded that antidopaminergic drugs might
paradoxically exert a dopaminergic action indirectly; hyperprolactinaemia induced
by peripherally-acting antidopaminergic drugs might increase TIDA neuron-activity
via a short-loop feedback mechanism [23,48]. Previous studies in ovariectomised
women have demonstrated that BCT, which exerts direct and potent dopaminergic
effects, 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 the
medial preoptic area involved in pulsatile LRF secretion are closely related anatomi-
cally within the hypothalamus and can be affected by the same neurotransmitter
alterations, it has been hypothesised that the reduction in hypothalamic dopaminergic
tone might also be involved in the pathogenesis of hot flushes [6,10]. The present
study shows that the administration of dopaminergic drugs such as BCT or Liposom
is able to reduce vasomotor symptoms.
These findings confirm previous results obtained in our laboratory with BCT
showing that this drug was more effective than placebo in improving vasomotor
symptoms in a group of post-menopausal women [22,23]. Moreover, in a previous
cross-over study in which we analyzed endocrine and clinical responsiveness to BCT
and VER administration in 10 post-menopausal women, we observed that the two
drugs have opposite endocrine effects [23]. BCT reduces prolactin plasma levels to
values lower than 5 ng/ml and decreases pulsatile LH secretion from about 1.8
pulses/h to about 1.1 pulses/h. In constrats, VER markedly increases prolactin
levels 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 [23].
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 [49]. The present data indicate that this
hypothesis seems very unlikely. Indeed, the administration of Liposom, which
increases the activity of the endogenous dopaminergic system and has no alphalytic

7. 235
action, also alleviates vasomotor symptoms [17,18]. It is accordingly suggested that
the fall in steroid plasma levels in hypogonadal subjects induces a reduction in the
hypothalamic dopaminergic tone which is responsible for both increased pulsatile
LH secretion and hot flushes [10,14,15].
In conclusion, it is suggested that the fall in steroid plasma levels in post-
menopausal women may induce a reduction in both the hypothalamic dopaminergic
tone and the opioidergic tone. These neurotransmitter changes are probably in-
volved in the pathogenesis of hot flushes. We consider that any drug that is able to
substitute or restore dopamine and opioid activity is also capable of alleviating the
post-menopausal vasomotor syndrome.
Acknowledgements
This research was supported by the Cons&ho Nazionale delle Ricerche (CNR)
through the ‘ Endocrinology Group’ and the ‘Mechanisms of Ageing’ project.
We also wish to thank Emilio Madrigali, Gino Narducci and Silvano Orcesi for
their technical assistance.
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