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Increased Growth Hormone Response to Apomorphine in Parkinson Disease Compared With Multiple System Atrophy
Elisabeth Friess, MD;
Tania Kuempfel, MD;
Juliane Winkelmann, MD;
Dagmar Schmid, MD;
Manfred Uhr, MD;
Rainer Rupprecht, MD;
Florian Holsboer, MD, PhD;
Claudia Trenkwalder, MD
Arch Neurol. 2001;58:241-246.
ABSTRACT
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Background Parkinson disease (PD) is often difficult to distinguish from parkinsonian
syndromes of other causes in early stages of the disease. In search of a suitable
endocrinologic challenge test, we investigated dopaminergic sensitivity in
patients with de novo parkinsonian syndromes.
Objective We measured the growth hormone (GH) response to a subthreshold dose
of the dopamine 1–dopamine 2 receptor agonist apomorphine hydrochloride
to differentiate parkinsonian syndromes from PD.
Patients and Methods Seventeen patients with a clinical diagnosis of PD, 16 patients with
a clinical diagnosis of multiple system atrophy, and 11 healthy controls.
The GH response to a subthreshold dosage of apomorphine and to somatorelin
(GH-releasing factor) was tested in a randomized order; on the third day the
protocol was repeated with a clinically effective dose of apomorphine.
Results The GH response to the low dose of apomorphine was significantly increased
in patients with PD when compared with patients with multiple system atrophy
or the control subjects (multivariate analyses of covariance; univariate F
test, all P<.05). In contrast, there were no significant
group differences with use of the higher dose of apomorphine or in the somatorelin-induced
GH release.
Conclusions The GH response to a subthreshold dose of apomorphine appears to be
a useful tool to identify patients with PD vs multiple system atrophy. The
enhanced GH response to a subthreshold dopaminergic stimulus may reflect a
hypersensitivity of the extrastriatal dopamine receptors in PD.
INTRODUCTION
THE CLINICAL differentiation of patients with parkinsonian syndromes
(PSs) involves a high risk of false-positive diagnosis of Parkinson disease
(PD), particularly in early stages of the disease. Twenty-five percent of
patients with clinically diagnosed PD had clear evidence of a multiple system
atrophy (MSA) at postmortem examination.1 With
respect to appropriate treatment regimens, the distinction of PD from MSA
is of increasing importance. The outcome of treatment studies using possibly
"neuroprotective" drugs is weakened by the inclusion of patients with nonidiopathic
PS, especially when patients with de novo cases are investigated.
In search of a reliable and practicable method for differentiating PD
from PS of other causes, a recent study by Kimber et al2
focused on the dysregulation of the central noradrenergic pathways in patients
with MSA. The blunted response of growth hormone (GH) to clonidine differentiated
patients with MSA from patients with PD and healthy subjects.2
However, an attempt to replicate these findings was unsuccessful.3
The GH response to dopaminergic substances is a well-established neuroendocrine
test to investigate the sensitivity of the overall central dopaminergic system.4 The present study aimed to distinguish PD from nonidiopathic
PS, particularly MSA, with an endocrinologic challenge test reflecting the
central dopamine receptor function. We therefore investigated the GH response
to the strong dopamine 1–dopamine 2 receptor agonist apomorphine hydrochloride
in patients with new clinical diagnoses of PD or MSA and compared the results
with those for a healthy control group matched for age.
PATIENTS AND METHODS
PATIENTS
The study design, experimental procedure, and recruitment of patients
are diagrammed in Figure 1.
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Figure 1. Study design and the flow diagram
of the patients who completed the neuroendocrine testing before entering the
diagnostic procedure. Values are given as mean ± SD unless otherwise
specified. APO indicates apomorphine hydrochloride; SC, subcutaneously; GHRH,
somatorelin; BW, body weight; IV, intravenously; UPDRS, Unified Parkinson's
Disease Rating Scale; RIA, radioimmunoassay; PD, Parkinson disease; H&Y,
Hoehn and Yahr; MSA, multiple system atrophy; PS, parkinsonian syndrome; and
PSP, progressive supranuclear palsy.
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We recruited 38 patients with PS who had never been treated with dopaminergic
agents. Before participating in the experiments, all subjects gave informed
consent. The clinical classification was made by experienced neurologists
who were unaware of the results of the endocrinologic tests. The results of
only the 33 patients diagnosed as having PD or MSA were included in the subsequent
data analysis and compared with an age-matched healthy control group. The
patients with vascular PS or with progressive supranuclear palsy were excluded
(see Figure 1).
EXPERIMENTAL PROCEDURE
The tests with somatorelin (GH-releasing factor), a low dose of apomorphine
(low-apomorphine test), or a high dose of apomorphine (high-apomorphine test)
were performed on 3 consecutive days. The somatorelin test and the low-apomorphine
test were performed on the first 2 days (randomized schedule). On the third
day, the patients participated only in the high-apomorphine test. Eleven patients
with PD and 14 patients with MSA participated in the somatorelin test. According
to the protocol described by Corn et al,5 the
subjects received either apomorphine hydrochloride, 0.005 mg/kg of body weight
subcutaneously (Teclapharm GmbH, Lüneburg, Germany), or somatorelin,
1 µg/kg of body weight subcutaneously (Ferring Arzneimittel GmbH, Kiel,
Germany). The high-apomorphine test6, 7
(3 mg subcutaneously) was performed with a pretreatment of domperidone, 20
mg 3 times daily orally (Motilium; Byk Gulden Lomberg Chemische Fabrik GmbH,
Konstanz, Germany), that started after the completion of the preceding endocrine
challenge. The response to the high-apomorphine injection was evaluated by
a clinical rating according to the Unified Parkinson's Disease Rating Scale,
Part III (motor examination), before and 20 minutes after the injection: a
score of 30% or more was rated as positive; 10% to 30%, equivocal; and 10%
or less or an increase, negative.6 All patients
were treated subsequently with levodopa at a dosage of at least 400 mg 3 times
daily or an equivalent dose of a dopamine agonist (cabergoline or pergolide
mesylate, at least 3 mg 3 times daily). A positive levodopa response included
a subjective and objective change in the clinical symptoms within a period
of at least 3 months (improvement of the Unified Parkinson's Disease Rating
Scale, Part III, score  30%).
The blood specimens were analyzed with commercially available radioimmunoassay
kits (Figure 1) (GH: Nichols Institute,
San Juan Capistrano, Calif [sensitivity, 8.8 pmol/L]; prolactin: ICN Pharmaceuticals,
Costa Mesa, Calif [sensitivity, <87 pmol/L]; cortisol: ICN Pharmaceuticals
[sensitivity, 4160 pmol/L]; corticotropin: Nichols Institute [sensitivity,
0.22 pmol/L]). The interassay and intra-assay variation coefficients of the
radioimmunoassays were all less than 8%. All samples from a given subject
were measured in duplicate in 1 assay.
The experimental protocol was approved by the Ethics Committee for Human
Experiments of the Bayerische Landesärztekammer (Munich, Germany).
CLINICAL DIAGNOSES
Parkinson disease was diagnosed according to the United Kingdom Parkinson's
Disease Society Brain Bank criteria.8 We diagnosed
PD if the patient showed a positive or equivocal response in the high-apomorphine
test and a clear motor improvement after 3 months of the dopaminergic treatment.
We diagnosed MSA according to the consensus statement of the American Autonomic
Society and American Academy of Neurology.9
The clinical features included (1) a PS with autonomic failure proved by either
tilt-table test10 or clinically relevant urinary
dysfunction; (2) negative dopaminergic treatment response in the high-apomorphine
test and a negative or equivocal response to a 3-month dopaminergic treatment
period; (3) presence of additional pyramidal tract signs, cerebellar signs,
predominant gait disorder, falling, and dizziness (Table 1). All patients underwent magnetic resonance imaging to detect
vascular lesions and atrophy.
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Table 1. Clinical and Demographic Characteristics of Patients With
PD and MSA*
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STATISTICAL ANALYSIS
The statistical differences in hormone responses were tested for significance
by a 2-factorial multivariate analysis of covariance (MANCOVA, Wilks multivariate
test of significance) for repeated measures with time as a within-subject
factor and group (PD, MSA, and control group) as a between-subject factor.
Age, sex, and hormone concentrations at time 0 (baseline) were entered as
covariates in all subjects, and duration (in years) and the severity of the
disease (in Hoehn and Yahr stages11) only when
the patient groups were compared. The MANCOVAs were applied for the hormone
levels at single time points and additionally with the use of 2 robust profile
characteristics: the area under the time course curve of the hormone concentration
(trapezoidal integration) and the  values (differences between baseline
and maximum values). The latter MANCOVA was done with a 1-factorial MANCOVA
for each experimental condition, with group as the only between-subject factor.
In case of a significant main or interaction effect of group and/or time,
post hoc tests (univariate F tests and tests with contrasts) were performed
to identify the pairs of groups or time points with significant differences.
To approach normality and homogeneity, all variables entered in the MANCOVAs
were log n–transformed. As a nominal level of significance, 
= .05 was accepted and corrected (post hoc tests) according to the Bonferroni
procedure to keep the type I error at .05 or less.
RESULTS
LOW-APOMORPHINE TEST
The analysis of covariance showed both a significant time main effect
and group x time interaction effect (Wilks multivariate tests of significance;
time: F20,442 = 8.28, P<.001; group
x time: F20,483 = 2.96, P<.001),
which were mainly attributed to the time and group differences of GH and prolactin
responses. The GH response differed significantly between the patients with
PD and MSA and between the patients with PD and the healthy control subjects
at 30, 45, and 60 minutes after the subthreshold dose of apomorphine (Figure 2).
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Figure 2. Growth hormone (GH) response to
testing with high and low doses of apomorphine hydrochloride (arrows indicate
time of drug administration). A, Mean (SE) GH secretion before and after a
low dose of apomorphine hydrochloride (0.005 mg/kg of body weight subcutaneously)
in patients with idiopathic Parkinson disease (PD) or with multiple system
atrophy (MSA) and an age-matched healthy control group (HC; n = 11). Significant
differences in the GH concentration between PD and MSA at different time points
are indicated by asterisks (univariate F tests and tests with contrasts, P<.05; see "Results" section for the results of the multivariate
analyses of variance). B, Growth hormone response to a high dose of apomorphine
hydrochloride (3 mg subcutaneously) in patients with PD (n = 17) and MSA (n
= 16).
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The prolactin secretion was lower in the patients with PD than in those
with MSA or the control subjects, although the group differences were not
statistically significant (Figure 3).
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Figure 3. Prolactin response in the low-
and high-dose apomorphine hydrochloride test (arrows indicate time of drug
administration). A, Prolactin secretion (mean ± SE) in response to
a low dose of apomorphine hydrochloride (0.005 mg/kg of body weight subcutaneously)
in patients with idiopathic Parkinson disease (PD; n = 17) or with multiple
system atrophy (MSA; n = 16) and an age-matched healthy control group (HC;
n = 11). B, Prolactin response to a high dose of apomorphine hydrochloride
(3 mg subcutaneously) in patients with PD (n = 17) and MSA (n = 16).
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HIGH-APOMORPHINE TEST
The covariance analysis showed a significant time effect (Wilks multivariate
test of significance; effect of time: F20,256 = 7.08, P<.001). The high dose of apomorphine resulted in a marked increase
in cortisol, corticotropin, and GH concentrations (univariate F test; P<.05). However, there were no significant differences
between the groups (Table 2).
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Table 2. Concentrations of Plasma GH, Prolactin, Cortisol, and Corticotropin
in Response to Low and High Doses of Apomorphine and Somatorelin
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SOMATORELIN TEST
After administration of somatorelin (Figure 4), the concentration of almost all hormones showed a time-dependent
course (Wilks multivariate test of significance; effect of time: F20,372 = 2.43, P<.001), which was similar for
all groups. The only non–time-dependent hormone was prolactin.
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Figure 4. Growth hormone (GH) response to
somatorelin (GH-releasing factor; 1 µg/kg of body weight intravenously).
Data represent mean (±SE) GH concentrations in response to somatorelin
in patients with Parkinson disease (PD; n = 11), multiple system atrophy (MSA;
n = 14), and an age-matched healthy control group (HC; n = 11).
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AREA UNDER THE CURVE AND VALUES
The analysis of the concentration-curve characteristics between the
group and the experimental conditions showed a significant group effect in
the low-apomorphine condition (Wilks multivariate test of significance; effect
of group for low apomorphine: F16,34 = 3.05, P = .003), where only the area under the curve and values of
the GH responses contributed significantly to this group effect (univariate
F test; P<.05).
COVARIATE EFFECTS
There was no significant influence of the covariates age and sex on the hormone responses in any
of the experimental conditions. The covariates duration and severity of disease had no significant
effect on the hormone secretion courses. However, the patients with MSA exhibited
a higher mean (±SD) Hoehn and Yahr score than those with PD (MSA, 2.7
[1.0]; PD, 2.0 [0.8]), while the duration of the disease was comparable in
the 2 groups (MSA, 2.7 [2.0]; PD, 3.3 [2.1]). A significant influence of the
baseline values was found only for prolactin in both the low- and high-apomorphine
tests.
COMMENT
We investigated the extrastriatal dopaminergic sensitivity of patients
with PSs by measuring the GH response to a subthreshold dose of the dopamine
1–dopamine 2 receptor agonist apomorphine. The enhanced GH release found
in the low-apomorphine test significantly differentiated the patients with
clinically diagnosed PD from those with clinically diagnosed MSA and from
an age-matched healthy control group. The prolactin response tended to be
lower in the patients with PD than in the other 2 groups. The cortisol and
corticotropin concentration did not distinguish among the 3 groups.
We hypothesized that previously untreated patients with PD would show
an increased sensitivity of the hypothalamic receptors because of a nigrostriatal
dopaminergic deficit. To reveal the putative hypersensitivity of the GH-controlling
hypothalamic dopaminergic pathways, we used a subthreshold dose of apomorphine
that did not induce adverse effects. The difference in the apomorphine-induced
GH release between the PD and MSA groups disappeared when a high dose of apomorphine
was given to test the dopaminergic treatment response.
We speculate that both the dopamine-induced increase in GH secretion
and decrease in prolactin secretion result from a hypothalamic dopaminergic
hypersensitivity in PD. This was investigated in a recent positron emission
tomographic study that used fluorodopa F 18 and demonstrated significant changes
in the dopaminergic metabolism in patients with PD within extrastriatal structures.12
The neurophysiologic mechanisms mediating the dopaminergic control of
the GH release are still unclear. There is some evidence that dopamine 2 receptors
influence the M1 cholinergic control of somatostatin, and thus GH release,
since the dopamine-induced GH release is antagonized by pirenzepine hydrochloride.13 In addition, dopamine is known to stimulate somatorelin
secretion,2, 14 although dopaminergic
receptors have not yet been demonstrated on the somatorelin-secreting neurons
in humans. Dopamine 1 and 2 receptors have been characterized on pituitary
somatotrophs in animal experiments15 and in
neuroimaging studies in patients with pituitary adenomas,16
which also suggests a direct mechanism at the pituitary cell level.
A recent study using the 2-adrenoceptor agonist clonidine
as a stimulus for GH release focused on the central autonomic deficit as a
condition pathognomonic for MSA. The clonidine-induced GH response separated
these patients with MSA from those with PD.2
However, these results have not yet been replicated by other authors.3 Llau et al17 compared
the response of GH and prolactin with apomorphine in patients with PD before
and after a dopaminergic treatment. They failed to detect any significant
differences between the groups and concluded that hypothalamic dopaminergic
sensitivity is normal in PD. We found comparable absolute values for the GH
response in the low-apomorphine test in our patients with PD. Therefore, other
factors, such as the patients' clinical classification, may explain the observed
differences between Llau and coworkers' study and our results.
To exclude major abnormalities in the regulation of the somatotropic
system, we investigated the somatorelin-induced GH response, which was comparable
in all 3 groups. The subemetic dose of apomorphine did not affect the hormones
of the hypothalamic-pituitary-adrenal system. In contrast, the high dose of
apomorphine resulted in an immediate and marked rise in the circulating corticotropin
and cortisol levels in all patients, which is probably related to the physical
stress induced by the side effects of apomorphine. The pretreatment with domperidone
increased the baseline prolactin levels in both patient groups, most likely
because of the blockade of pituitary dopamine 2 receptors.
We could not find a significant influence of sex; however, this may
have been masked by the unequal sex distribution in our study sample. Other
influences such as age and duration and severity of the disease did not account
for the observed differences in the GH response to the subthreshold dose of
apomorphine.
In summary, the GH response to a subthreshold dose of apomorphine could
be a simple and clinically useful additional tool for the differential diagnosis
of patients with PS. This challenge test is easy to standardize, inexpensive,
and without any adverse effects for the participants. Future studies using
larger samples may evaluate the influence of age, sex, and pretreatment with
dopaminergic agents.
AUTHOR INFORMATION
Accepted for publication November 2, 2000.
Presented in part at the meeting of the European Neurological Society,
Milan, Italy, June 9, 1999.
We thank Elisabeth Kappelmann for her excellent technical assistance,
Alexander Yassouridis for his helpful comments on the statistical analysis,
and Susanne Heim for secretarial services.
From the Neurology Section, Max Planck Institute of Psychiatry, Munich,
Germany.
Corresponding author and reprints: Elisabeth Friess, MD, Max Planck
Institute of Psychiatry, Kraepelinstr 10, D-80804 Munich, Germany (e-mail: friess{at}mpipsykl.mpg.de).
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