Increased Growth Hormone Response to Apomorphine in Parkinson Disease Compared with Multiple System Atrophy

ORIGINAL CONTRIBUTION 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

Background: Parkinson disease (PD) is often difficult to Results: The GH response to the low dose of apomor- distinguish from parkinsonian syndromes of other causes phine was significantly increased in patients with PD when in early stages of the disease. In search of a suitable endo- compared with patients with multiple system atrophy or crinologic challenge test, we investigated dopaminergic sen- the control subjects (multivariate analyses of covari- sitivity in patients with de novo parkinsonian syndromes. ance; univariate F test, all PϽ.05). In contrast, there were no significant group differences with use of the higher Objective: We measured the growth hormone (GH) re- dose of apomorphine or in the somatorelin-induced GH sponse to a subthreshold dose of the dopamine 1–dopa- release. mine 2 receptor agonist apomorphine hydrochloride to differentiate parkinsonian syndromes from PD. Conclusions: The GH response to a subthreshold dose of apomorphine appears to be a useful tool to identify Patients and Methods: Seventeen patients with a clini- patients with PD vs multiple system atrophy. The en- cal diagnosis of PD, 16 patients with a clinical diagnosis hanced GH response to a subthreshold dopaminergic of multiple system atrophy, and 11 healthy controls. The stimulus may reflect a hypersensitivity of the extrastria- GH response to a subthreshold dosage of apomorphine tal dopamine receptors in PD. 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. Arch Neurol. 2001;58:241-246

HE CLINICAL differentia- tients with PD and healthy subjects.2 How- tion of patients with par- ever, an attempt to replicate these findings kinsonian syndromes (PSs) was unsuccessful.3 involves a high risk of false- The GH response to dopaminergic positive diagnosis of Par- substances is a well-established neuroen- kinson disease (PD), particularly in early docrine test to investigate the sensitivity of T 4 stages of the disease. Twenty-five per- the overall central dopaminergic system. cent of patients with clinically diagnosed The present study aimed to distinguish PD PD had clear evidence of a multiple sys- from nonidiopathic PS, particularly MSA, tem atrophy (MSA) at postmortem exami- with an endocrinologic challenge test re- nation.1 With respect to appropriate treat- flecting the central dopamine receptor func- ment regimens, the distinction of PD from tion. We therefore investigated the GH re- MSA is of increasing importance. The out- sponse to the strong dopamine 1–dopamine come of treatment studies using possibly 2 receptor agonist apomorphine hydro- “neuroprotective” drugs is weakened by chloride in patients with new clinical di- the inclusion of patients with nonidio- agnoses of PD or MSA and compared the pathic PS, especially when patients with results with those for a healthy control de novo cases are investigated. group matched for age. In search of a reliable and practi- cable method for differentiating PD from RESULTS PS of other causes, a recent study by Kim- ber et al2 focused on the dysregulation of LOW-APOMORPHINE TEST the central noradrenergic pathways in pa- From the Neurology Section, tients with MSA. The blunted response of The analysis of covariance showed both Max Planck Institute of growth hormone (GH) to clonidine dif- a significant time main effect and Psychiatry, Munich, Germany. ferentiated patients with MSA from pa- groupϫtime interaction effect (Wilks mul-

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 PATIENTS AND METHODS [sensitivity, 4160 pmol/L]; corticotropin: Nichols Insti- tute [sensitivity, 0.22 pmol/L]). The interassay and intra- assay variation coefficients of the radioimmunoassays were PATIENTS all less than 8%. All samples from a given subject were measured in duplicate in 1 assay. The study design, experimental procedure, and recruit- The experimental protocol was approved by the Eth- ment of patients are diagrammed in Figure 1. ics Committee for Human Experiments of the Bayerische We recruited 38 patients with PS who had never been Landesa¨rztekammer (Munich, Germany). treated with dopaminergic agents. Before participating in the experiments, all subjects gave informed consent. The CLINICAL DIAGNOSES clinical classification was made by experienced neurolo- gists who were unaware of the results of the endocrino- Parkinson disease was diagnosed according to the United logic tests. The results of only the 33 patients diagnosed Kingdom Parkinson’s Disease Society Brain Bank criteria.8 as having PD or MSA were included in the subsequent data We diagnosed PD if the patient showed a positive or equivo- analysis and compared with an age-matched healthy con- cal response in the high-apomorphine test and a clear mo- trol group. The patients with vascular PS or with progres- tor improvement after 3 months of the dopaminergic treat- sive supranuclear palsy were excluded (see Figure 1). ment. We diagnosed MSA according to the consensus statement of the American Autonomic Society and Ameri- EXPERIMENTAL PROCEDURE can Academy of Neurology.9 The clinical features included (1) a PS with autonomic failure proved by either The tests with somatorelin (GH-releasing factor), a low dose tilt-table test10 or clinically relevant urinary dysfunction; of apomorphine (low-apomorphine test), or a high dose (2) negative dopaminergic treatment response in the high- of apomorphine (high-apomorphine test) were per- apomorphine test and a negative or equivocal response to formed on 3 consecutive days. The somatorelin test and a 3-month dopaminergic treatment period; (3) presence of the low-apomorphine test were performed on the first 2 days additional pyramidal tract signs, cerebellar signs, predomi- (randomized schedule). On the third day, the patients par- nant gait disorder, falling, and dizziness (Table 1). All pa- ticipated only in the high-apomorphine test. Eleven patients underwent magnetic resonance imaging to detect vas- tients with PD and 14 patients with MSA participated in cular lesions and atrophy. the somatorelin test. According to the protocol described by Corn et al,5 the subjects received either apomorphine STATISTICAL ANALYSIS hydrochloride, 0.005 mg/kg of body weight subcutaneously (Teclapharm GmbH, Lu¨ neburg, Germany), or so- The statistical differences in hormone responses were tested matorelin, 1 µg/kg of body weight subcutaneously (Fer- for significance by a 2-factorial multivariate analysis of co- ring Arzneimittel GmbH, Kiel, Germany). The high- variance (MANCOVA, Wilks multivariate test of signifi- apomorphine test6,7 (3 mg subcutaneously) was performed cance) for repeated measures with time as a within- with a pretreatment of domperidone, 20 mg 3 times daily subject factor and group (PD, MSA, and control group) as orally (Motilium; Byk Gulden Lomberg Chemische Fab- a between-subject factor. Age, sex, and hormone concen- rik GmbH, Konstanz, Germany), that started after the trations at time 0 (baseline) were entered as covariates in completion of the preceding endocrine challenge. The re- all subjects, and duration (in years) and the severity of the sponse to the high-apomorphine injection was evaluated disease (in Hoehn and Yahr stages11) only when the pa- by a clinical rating according to the Unified Parkinson’s Dis- tient groups were compared. The MANCOVAs were ap- ease Rating Scale, Part III (motor examination), before and plied for the hormone levels at single time points and ad- 20 minutes after the injection: a score of 30% or more was ditionally with the use of 2 robust profile characteristics: rated as positive; 10% to 30%, equivocal; and 10% or less the area under the time course curve of the hormone con- or an increase, negative.6 All patients were treated subse- centration (trapezoidal integration) and the ⌬ values (dif- quently with levodopa at a dosage of at least 400 mg 3 times ferences between baseline and maximum values). The lat- daily or an equivalent dose of a dopamine agonist (caber- ter MANCOVA was done with a 1-factorial MANCOVA for goline or pergolide mesylate, at least 3 mg 3 times daily). each experimental condition, with group as the only be- A positive levodopa response included a subjective and ob- tween-subject factor. In case of a significant main or inter- jective change in the clinical symptoms within a period of action effect of group and/or time, post hoc tests (univari- at least 3 months (improvement of the Unified Parkin- ate F tests and tests with contrasts) were performed to son’s Disease Rating Scale, Part III, score Ն30%). identify the pairs of groups or time points with significant The blood specimens were analyzed with commer- differences. To approach normality and homogeneity, all cially available radioimmunoassay kits (Figure 1) (GH: Ni- variables entered in the MANCOVAs were log n–trans- chols Institute, San Juan Capistrano, Calif [sensitivity, 8.8 formed. As a nominal level of significance, ␣=.05 was ac- pmol/L]; prolactin: ICN Pharmaceuticals, Costa Mesa, Calif cepted and corrected (post hoc tests) according to the Bon- [sensitivity, Ͻ87 pmol/L]; cortisol: ICN Pharmaceuticals ferroni procedure to keep the type I error at .05 or less.

Ͻ tivariate tests of significance; time: F20,442=8.28, P .001; jects at 30, 45, and 60 minutes after the subthreshold dose ϫ Ͻ group time: F20,483=2.96, P .001), which were mainly of apomorphine (Figure 2). attributed to the time and group differences of GH and The prolactin secretion was lower in the patients with prolactin responses. The GH response differed signifi- PD than in those with MSA or the control subjects, al- cantly between the patients with PD and MSA and be- though the group differences were not statistically sig- tween the patients with PD and the healthy control sub- nificant (Figure 3).

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Neuroendocrine Testing

9:30 AM Overnight Fast/Cannulation Day 1 APO 0.005 mg/kg SC 10 AM Day 2 GHRH 1 µg/kg BW IV Day 3 APO 3 mg SC Figure 1. Study design and the flow diagram of the patients who completed the UPDRS Before/After Treatment neuroendocrine testing before entering the diagnostic procedure. Values are given as mean ± SD unless otherwise specified. APO indicates apomorphine Blood samples at –30, 0, 15, 30, 45, 60, 90, 120 min to Measure Growth Hormone, Prolactin, Cortisol, hydrochloride; SC, subcutaneously; GHRH, somatorelin; BW, body weight; IV, Corticotropin by RIAs 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. Clinical Diagnosis

17 Patients With PD 16 Patients With MSA 4 Patients With Vascular PS Age, 64 ± 12 y Age, 64 ± 7 y 1 Patient With PSP Sex, 5 F/12 M Sex, 12 F/4 M Age Range, 36-81 y Age Range, 56-77 y 11 Healthy Controls Duration, 3.1 ± 1.8 y Duration, 2.7 ± 2.0 y Age, 58 ± 11 y H&Y Score, 3.3 ± 2.1 H&Y Score, 2.7 ± 1.0 Sex, 5 F/6 M Age Range, 36-73 y

Table 1. Clinical and Demographic Characteristics of Patients With PD and MSA*

Age, y Patient No./ Additional Sex At Sampling At Disease Onset Type of PS H&Y Gait Neurologic Signs Diagnosis 1/M 43 39 AR 2.0 GD NA PD 2/F 74 66 AR 4.0 GD, gait initiation failure NA PD 3/F 60 60 AR 2.0 NA NA PD 4/M 75 71 TD 1.0 NA NA PD 5/M 63 60 AR 1.5 NA NA PD 6/M 56 54 TD 1.5 NA NA PD 7/M 72 69 Equiv 1.5 NA NA PD 8/M 69 65 TD 1.0 NA NA PD 9/M 74 72 TD 1.5 NA Facial palsy PD 10/M 63 58 TD 2.5 NA Stereotactic surgery PD 11/F 59 57 AR 2.5 Gait initiation failure NA PD 12/M 76 75 Equiv 2.0 NA NA PD 13/M 36 33 Equiv 1.5 NA Torticollis PD 14/M 55 54 Equiv 2.5 NA NA PD 15/F 73 70 Equiv 1.5 NA NA PD 16/M 63 60 TD 2.0 NA Hemianopia† PD 17/M 81 73 TD 3.0 NA NA PD 18/F 56 52 NA 3 GD, balance impaired VGP, spasticity MSA-CEREB 19/F 56 54 NA 2.5 Mild gait ataxia Dysarthria MSA-CEREB 20/F 58 58 NA 2.0 Balance impaired Myoclonus MSA-SN 21/F 72 70 NA 2.5 Severe GD, falling Spasticity MSA-SN 22/M 58 56 NA 2.5 NA VGP MSA-SN 23/F 76 74 NA 3.0 Severe GD NA MSA-SN 24/M 62 61 NA 2.5 Balance impaired NA MSA-SN 25/F 60 58 NA 2.0 Balance impaired Myoclonus MSA-SN 26/F 77 74 NA 4.0 Severe GD, falling Spasticity MSA-SN 27/F 68 66 NA 4.0 Balance impaired, ataxia VGP MSA-CEREB 28/M 56 54 NA 2.5 NA Vertigo MSA-SN 29/F 65 57 NA 4.0 Retropulsion, falling Spasticity MSA-SN 30/F 66 65 NA 1.0 NA NA MSA-SN 31/F 68 66 NA 1.0 NA REM disorder MSA-SN 32/F 60 53 NA 4.0 Gait ataxia Spasticity MSA-CEREB 33/M 65 63 NA 3.0 Gait ataxia Nystagmus, spasticity MSA-SN

*PD indicates Parkinson disease; MSA, multiple system atrophy; PS, parkinsonian syndrome; H&Y, Hoehn and Yahr score; AR, akinetic-rigid; TD, tremor dominant; Equiv, equivalence type; GD, gait disorder; VGP, vertical gaze palsy; REM, rapid eye movement; CEREB, cerebellar type; NA, not applicable; and SN, striatonigral type. †Patient had a hemianopia after stroke.

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530 520

∗ ∗

260 ∗ 260 ∗

0 0

B B

530 Prolactin, pmol/L 2610 Growth Hormone, pmol/L

1740

260

870

0 0 –30 +30 +60 +120 –30 +30 +60 +120 Time, min Time, min

Figure 2. Growth hormone (GH) response to testing with high and low doses Figure 3. Prolactin response in the low- and high-dose apomorphine of apomorphine hydrochloride (arrows indicate time of drug administration). hydrochloride test (arrows indicate time of drug administration). A, Prolactin A, Mean (SE) GH secretion before and after a low dose of apomorphine secretion (mean±SE) in response to a low dose of apomorphine hydrochloride (0.005 mg/kg of body weight subcutaneously) in patients with hydrochloride (0.005 mg/kg of body weight subcutaneously) in patients with idiopathic Parkinson disease (PD) or with multiple system atrophy (MSA) and idiopathic Parkinson disease (PD; n=17) or with multiple system atrophy an age-matched healthy control group (HC; n=11). Significant differences in (MSA; n=16) and an age-matched healthy control group (HC; n=11). the GH concentration between PD and MSA at different time points are B, Prolactin response to a high dose of apomorphine hydrochloride indicated by asterisks (univariate F tests and tests with contrasts, PϽ.05; see (3 mg subcutaneously) in patients with PD (n=17) and MSA (n=16). “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). P=.003), where only the area under the curve and ⌬ values of the GH responses contributed significantly to this Ͻ HIGH-APOMORPHINE TEST group effect (univariate F test; P .05). The covariance analysis showed a significant time effect COVARIATE EFFECTS (Wilks multivariate test of significance; effect of time: Ͻ F20,256=7.08, P .001). The high dose of apomorphine re- There was no significant influence of the covariates age sulted in a marked increase in cortisol, corticotropin, and and sex on the hormone responses in any of the experi- GH concentrations (univariate F test; PϽ.05). How- mental conditions. The covariates duration and severity of ever, there were no significant differences between the disease had no significant effect on the hormone secre- groups (Table 2). tion courses. However, the patients with MSA exhibited a higher mean (±SD) Hoehn and Yahr score than those SOMATORELIN TEST 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, After administration of somatorelin (Figure 4), the con- 2.7 [2.0]; PD, 3.3 [2.1]). A significant influence of the base- centration of almost all hormones showed a time- line values was found only for prolactin in both the low- dependent course (Wilks multivariate test of signifi- and high-apomorphine tests. Ͻ cance; effect of time: F20,372=2.43, P .001), which was similar for all groups. The only non–time-dependent hor- COMMENT mone was prolactin. We investigated the extrastriatal dopaminergic sensitiv- AREA UNDER THE CURVE AND ⌬ VALUES ity of patients with PSs by measuring the GH response to a subthreshold dose of the dopamine 1–dopamine 2 The analysis of the concentration-curve characteristics receptor agonist apomorphine. The enhanced GH re- between the group and the experimental conditions lease found in the low-apomorphine test significantly dif- showed a significant group effect in the low- ferentiated the patients with clinically diagnosed PD from apomorphine condition (Wilks multivariate test of sig- those with clinically diagnosed MSA and from an age- nificance; effect of group for low apomorphine: F16,34=3.05, matched healthy control group. The prolactin response

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 Table 2. Concentrations of Plasma GH, Prolactin, Cortisol, and Corticotropin in Response to Low and High Doses of Apomorphine and Somatorelin

Mean (SD)

PD MSA HC

AUC ⌬ AUC ⌬ AUC ⌬ Somatotropin, pmol/L Low-dose apomorphine 1170 (893) 295 (238) 383 (361) 79 (101) 462 (242) 88 (66) Somatorelin 1276 (118) 290 (264) 717 (796) 128 (207) 933 (444) 180 (110) High-dose apomorphine 2055 (1584) 466 (339) 1346 (893) 330 (264) NA NA Prolactin, pmol/L Low-dose apomorphine 2017 (1457) 4 (117) 2478 (1530) 65 (126) 2617 (1152) 30 (48) Somatonelin 2070 (1135) 91 (157) 3465 (2561) 143 (187) 3504 (1652) 117 (104) High-dose apomorphine 10 491 (6561) 191 (257) 10 939 (8074) 43 (65) NA NA Cortisol, nmol/L Low-dose apomorphine 2615 (1273) 123 (201) 2345 (1052) 77 (134) 2340 (752) 103 (125) Somatorelin 2306 (745) 49 (86) 2251 (923) 53 (95) 2390 (874) 38 (69) High-dose apomorphine 4112 (1798) 407 (297) 3864 (1738) 368 (271) NA NA Corticotropin, pmol/L Low-dose apomorphine 60 (62) 5 (12) 110 (211) 26 (61) 32 (22) 3 (5) Somatorelin 34 (9) 1 (12) 30 (13) 1 (1) 25 (11) 1 (1) High-dose apomorphine 85 (57) 23 (25) 97 (90) 25 (34) NA NA

*GH indicates growth hormone; PD, Parkinson disease; MSA, multiple system atrophy; HC, healthy controls; AUC, area under the curve; ⌬, difference between baseline and maximum values after injection; and NA, not applicable; and boldface type, significant value.

tended to be lower in the patients with PD than in the other 2 groups. The cortisol and corticotropin concen- PD HC MSA

tration did not distinguish among the 3 groups. 440 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 220 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 Growth Hormone, pmol/L MSA groups disappeared when a high dose of apomor- 0 phine was given to test the dopaminergic treatment re- –30 +30 +60 +120 sponse. Time, min We speculate that both the dopamine-induced in- Figure 4. Growth hormone (GH) response to somatorelin (GH-releasing crease in GH secretion and decrease in prolactin secre- factor; 1 µg/kg of body weight intravenously). Data represent mean (±SE) GH tion result from a hypothalamic dopaminergic hypersen- concentrations in response to somatorelin in patients with Parkinson disease sitivity in PD. This was investigated in a recent positron (PD; n=11), multiple system atrophy (MSA; n=14), and an age-matched emission tomographic study that used fluorodopa F 18 healthy control group (HC; n=11). and demonstrated significant changes in the dopamin- ␣ ergic metabolism in patients with PD within extrastria- A recent study using the 2-adrenoceptor agonist tal structures.12 clonidine as a stimulus for GH release focused on the cen- The neurophysiologic mechanisms mediating the do- tral autonomic deficit as a condition pathognomonic for paminergic control of the GH release are still unclear. MSA. The clonidine-induced GH response separated these There is some evidence that dopamine 2 receptors in- patients with MSA from those with PD.2 However, these fluence the M1 cholinergic control of somatostatin, and results have not yet been replicated by other authors.3 thus GH release, since the dopamine-induced GH re- Llau et al17 compared the response of GH and prolactin lease is antagonized by pirenzepine hydrochloride.13 In with apomorphine in patients with PD before and after addition, dopamine is known to stimulate somatorelin a dopaminergic treatment. They failed to detect any sig- secretion,2,14 although dopaminergic receptors have not nificant differences between the groups and concluded yet been demonstrated on the somatorelin-secreting neu- that hypothalamic dopaminergic sensitivity is normal in rons in humans. Dopamine 1 and 2 receptors have been PD. We found comparable absolute values for the GH re- characterized on pituitary somatotrophs in animal ex- sponse in the low-apomorphine test in our patients with periments15 and in neuroimaging studies in patients with PD. Therefore, other factors, such as the patients’ clini- pituitary adenomas,16 which also suggests a direct mecha- cal classification, may explain the observed differences nism at the pituitary cell level. between Llau and coworkers’ study and our results.

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 To exclude major abnormalities in the regulation of REFERENCES the somatotropic system, we investigated the somatorelin- induced GH response, which was comparable in all 3 1. Colosimo C, Albanese A, Hughes AJ, de Bruin VM, Lees AJ. Some specific clini- groups. The subemetic dose of apomorphine did not af- cal features differentiate multiple system atrophy (striatonigral variety) from Par- fect the hormones of the hypothalamic-pituitary-adrenal kinson’s disease. Arch Neurol. 1995;52:294-298. 2. Kimber JR, Watson L, Mathias CJ. Distinction of idiopathic Parkinson’s disease system. In contrast, the high dose of apomorphine from multiple-system atrophy by stimulation of growth-hormone release with resulted in an immediate and marked rise in the circu- clonidine. Lancet. 1997;349:1877-1881. lating corticotropin and cortisol levels in all patients, 3. 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