J Neurol (1991) 238 : 19-22

Journal of

Neurology © Springer-Verlag 1991

Plasma profiles of adrenocorticotropic hormone, cortisol, growth hormone and prolactin in patients with untreated Parkinson's disease G. Bellomo 1, L. Santambrogio 1, M. Fiacconi 2, A . M . Scarponi 1, and G. Ciuffetti 1 111Department of Internal Medicine and 2Department of Nuclear Medicine, University of Perugia Medical School, 1-06100 Perugia, Italy Received February 22, 1990 / Received in revised form July 26, 1990 / Accepted September 3, 1990

Summary. Plasma profiles of prolactin, growth h o r m o n e , a d r e n o c o r t i c o t r o p i c h o r m o n e ( A C T H ) and cortisol were evaluated in a group of u n t r e a t e d patients with idiopathic P a r k i n s o n ' s disease and a g r o u p o f healthy a g e - m a t c h e d controls. Plasma integrated concentrations o f all horm o n e s except prolactin were significantly lower in the patients as c o m p a r e d with the controls; h o w e v e r , prolactin nocturnal p e a k c o n c e n t r a t i o n was significantly elevated in the patients; nocturnal g r o w t h h o r m o n e levels were significantly reduced in the Parkinson group; A C T H and cortisol plasma concentrations were also consistently lower during most of the day in the patients with Parkinson's disease. These data confirm the presence of a h y p o t h a l a m i c disturbance in patients with idopathic Parkinson's disease, which can affect pituitary function.

Key words: P a r k i n s o n ' s disease - A d r e n o c o r t i c o t r o p i c h o r m o n e - Cortisol - G r o w t h h o r m o n e - Prolactin

Introduction Substantial evidence a c c u m u l a t e d during the last two decades has d o c u m e n t e d that idiopathic P a r k i n s o n ' s disease ( I D P ) is associated with d e g e n e r a t i o n of dopaminergic n e u r o n s in the substantia nigra and nigro-striatal pathways [2, 12] and also with abnormalities of adrenergic, cholinergic, serotoninergic and peptidergic pathways [4, 12, 13, 16]. A deficit of d o p a m i n e and possibly o f o t h e r n e u r o t r a n s m i t t e r s has b e e n d e m o n s t r a t e d not only in the substantia nigra but also in the h y p o t h a l a m u s o f patients with I P D at p o s t m o r t e m examination [2, 3, 13]. In view of the i m p o r t a n c e of d o p a m i n e and related neurotransmitters in the regulation of pituitary function t h r o u g h the h y p o t h a l a m u s , it is conceivable that alterations of h o r m o n e levels can be detected in patients with I P D . I n d e e d , studies have b e e n c o n d u c t e d investigating Offprint requests to: G. Bellomo, II Department of Internal Medicine, University of Perugia, Policlinico Monteluce, 1-06100 Perugia, Italy

the basal m o r n i n g values as well as the r e s p o n s e of plasm a prolactin ( P R L ) , cortisol, g r o w t h h o r m o n e ( G H ) , thyroid stimulating h o r m o n e and g o n a d o t r o p h i n s to various stimuli [5, 7, 17, 19, 24] or the response of P R L to t r e a t m e n t with l e v o d o p a [8], a l t h o u g h at times with disc o r d a n t results. H o w e v e r , no data are available regarding the circadian p a t t e r n of such h o r m o n e s in u n t r e a t e d patients with I P D . F o r this r e a s o n we have studied the plasma profiles of P R L , G H , a d r e n o c o r t i c o t r o p i c horm o n e ( A C T H ) and cortisol during a whole day in patients with I P D w h o h a d never received any specific t h e r a p y c o m p a r e d with a g r o u p of healthy a g e - m a t c h e d controls.

Patients and methods A group of 15 patients with IPD (8 men and 7 post-menopausal women) and a group of 12 healthy controls (6 men and 6 postmenopausal women), whose relevant clinical parameters are summarized in Table 1, participated in the study (which was approved by the hospital ethics committee) after being fully informed about the procedures and giving their consent. All of them were admitted to our hospital at least 48 h prior to the beginning of the investigation and were submitted to routine blood and urine analyses, including tests of renal and liver function, which all gave normal results; a chest radiograph, electrocardiogram and CT of the brain, which did not show any abnormalities, were also performed. All the patients had been recently seen by the same neurologist, who rated their degree of disability according to different scales (Table 1). The diagnosis of Parkinson's disease was established based on the presence (at least) of typical tremor on one or both sides and extrapyramidal rigidity; all the patients but one were rated at stage 2 of the Hoehn and Yahr scale; physical examination was otherwise unremarkable. Neither the patients nor the controls had taken any medications during the 2 weeks preceding the study, and in particular the patients with IPD had never been given any specific treatment for their disease. The patients and controls were also subjected to tests of autonomic function, which included the following, performed as described elsewhere [9, 10]: R-R variations with deep breathing, Valsalva ratio, heart rate and blood pressure response to standing, sustained handgrip. All the tests results were within normal limits in all the controls and in 10 of the patients: 2 of these showed an abnormal response to sustained handgrip, 3 a borderline deep breathing test, and 1 a fall in diastolic blood pressure after standing greater than 20 mm Hg.

20 1. Clinical features of a group (n = 14) of patients with idiopathic Parkinson's disease (IPD) and a group of healthy agematched controls (n = 12)

30.

Table

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IPD ~' Age (years) Blood pressure (mmHg) Blood glucose (mg/dl) Creatinine clearance (ml/min) Duration of disease (months) Columbia University rating scale Northwestern rating scale Webster rating scale Hoehn and Yahr rating scale ~'

C on trois ~'

63.3 131/82 83.1 99.4 13.2 25 42 8 1.8

(6.4) (6/4) (4.7) (5.9) (4.3) (3) (2) (2.5) (0.3)

64.5 133/76 87.0 101.8 -

(5.9) (5/3) (4.4) (5.5)

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Fig. 1. Plasma prolactin concentrations (mean, SEM) in a group of patients with idiopathic Parkinson's disease (IPD, n = 14) and a group of healthy controls (n = 12). * P < 0.001: o - - © , controls; e - - e , IPD patients

Values given are mean (SD)

Oll the day of the study, after an overnight fast, an indwelling catheter was inserted into a forearm vein, and beginning at 8 a.m. blood samples (5 ml) were collected every 4h until the following morning. Meals (of the same composition for the two groups) were served at 8.30 a.m., 12.30 p.m. and 8 p.m. Blood was centrifuged immediately after collection at 4°C, the supernatant aspirated and stored at - 4 0 ° C until the time of assy. Whenever possible a patient and a control were studied on the same day. Hormones were measured in triplicate by radioimmunoassay using commercial kits: G H was determined according to Langston and Forno [16] and A C T H according to Ewing et al. [10], with slight modifications. Quality control of A C T H assays (as well as the others) was assessed according to the method of Rodbard [23]. The coefficient of variation between ten assays was 11.1%, within assay 7.9%, with a detection limit of 3.5 ng/1. Repeated assays after 3 months showed a decrease of the measured A C T H concentration approximately equal to 9-12%. All the radioimmunoassays were performed at the end of the study, using the same kit for the assay of the patients' and control sera. Statistical analysis was carried out using the Student's t-test for unpaired samples and hormone plasma integrated concentrations were computed using Simpson's algorithm. One patient was later shown to have an empty sella syndrome and her data were excluded from the analysis.

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Fig.2. Plasma growth hormone levels (mean. SEM) in a group of patients with IPD (n - 14) and a group of healthy controls (n = 12). * P < 0.01; o - - o , controls: e - - e , IPD patients 25-

20Results

T

H o r m o n e p r o f i l e s d i f f e r e d in t h e t w o g r o u p s : i n t e g r a t e d p l a s m a c o n c e n t r a t i o n s o f all h o r m o n e s b u t P R L w e r e s i g n i f i c a n t l y l o w e r in t h e p a t i e n t s w i t h I P D ( T a b l e 2). P R L p e a k p l a s m a c o n c e n t r a t i o n (Fig. 1) was o b s e r v e d at 4 a . m . in t h e I P D g r o u p a n d it d i f f e r e d s i g n i f i c a n t l y f r o m

2. Integrated plasma concentration (mean, SD) of A C T H , cortisol, GH and prolactin in a group of patients with IPD (n = 14) and a group of healthy controls (n = 12)

Table

Hormone

IPD ~

A C T H (ng/l*24 h) Cortisol (i,tg/dl*24 h) GH(ng/ml*24h) Prolactin (ng/ml*24h)

80.9 168.3 3.9 221.2

(35.4) (39.8) (2.7) (45.6)

Controls"

P

202.1 249.1 14.1 207.4

0.00005 0.004 0.0008 NS

(84.5) (61.0) (7.4) (42.6)

A C T H , Adrenocorticotropic hormone: GH, growth hormone ~' Values given are mean (SD)

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Fig. 3. Plasma adrenocorticotropic hormone levels (mean, SEM) in a group of patients with IPD (n = 14) and a group of healthy controls (n = 12). * P < 0.01; o - - o , controls; e - - e , IPD patients t h e c o n t r o l v a l u e (21.9, S D 2.1 vs 13.9, S D 1 . 1 n g / m l , P < 0.01). N o c t u r n a l l e v e l s o f G H (Fig. 2) w e r e signific a n t l y l o w e r in t h e p a t i e n t s w i t h I P D (0.205, S D 0.18 vs 1.008, S D 0 . 2 3 9 n g / m l , P < 0 . 0 1 at 8 p . m . ; 1.008, S D 0.24 vs 1.74, S D 0.39 n g / m l , P < 0.1 at m i d n i g h t ; 0.31,

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Fig. 4. Plasma cortisol levels (mean, SEM) in a group of patients with IPD (n = 14) and a group of healthy controls (n = 12). * P < 0.05; o - - o , controls; O--O, IPD patients SD 0.17 vs 1.76, SD 0.26ng/ml, P < 0 . 0 1 at 4 a.m.). Plasma A C T H levels were consistently lower throughout the day in the patients with IPD (Fig. 3) with respect to the control group; plasma cortisol (Fig. 4) followed a similar pattern. Discussion

Our study shows that plasma nocturnal peak P R L concentration was significantly higher in patients with IPD as compared with controls; such a finding might be dependent on the fact that Parkinson's disease is associated with a defective neural transmission at synapses probably involving the D-2 dopamine receptors [8, 15], which are known to mediate suppression of P R L secretion [15]. The dopamine deficit might not be so complete as to cause also diurnal hyperprolactinaemia, in view of the fact that all the patients were studied at an early stage of their disease. Other investigators have shown either normal, slightly decreased or slightly increased P R L levels [7, 17, 19, 24]; however, nocturnal plasma concentrations either were not studied or they were measured in patients treated pharmacologically. G H secretion also appeared to be abnormal in patients with IPD, only during the night hours; as G H secretion is stimulated in vivo by catecholamines and also by dopamine [10], a hypothalamic deficit of the latter, which has been shown to be present in IPD, may account for the decreased nocturnal levels of G H observed in our study. Diurnal G H levels did not differ between patients with IPD and controls; this finding is consistent with reports from other authors who measured basal G H levels [7, 19]. A recent carefully conducted study has shown that age alone can affect G H secretion both in normal subjects and patients with autonomic failure [25], as the administration of an opioid antagonist (naloxone) induced an increased secretion of G H in elderly subjects, whereas it had not effect on the younger group. We were not able to ascertain age induced effects in our study, as the patients and controls were quite homogeneous with respect to age, and stimulation/inhibition studies were not performed.

The reduced plasma concentration of cortisol found in the IPD group occurred in parallel with a similar decrease in A C T H levels and was clearly dependent on it. These findings cannot be explained on the basis of a dopamine deficit alone, as dopamine exerts no influence on (does not even inhibit) corticotropin releasing hormone (CRH) secretion by the paraventricular nucleus in the hypothalamus [11, 14, 20, 21]; however, a depletion of other neurotransmitters such as norepinephrine, which is known to cause the release of C R H in man probably acting through a-l-adrenoceptors [1, 20], has been demonstrated at postmortem examination of the hypothalamus of patients with IPD [2, 3, 16]. The findings of our study seem to indicate the presence of subtle subclinical abnormalities in nocturnal secretion of some pituitary hormones, which might be caused by hypothalamic dysfunction; indeed, the biochemistry of the hypothalamus in Parkinson's disease is still a matter of controversy. There is general agreement that the hypothalamic dopamine content is reduced in patients ith IPD at postmortem examination [2, 6, 13, 16], but studies regarding the concentrations of other neurotransmitters have yielded conflicting results. In earlier studies a decreased noradrenaline content in the parkinsonian hypothalamus had been found [2, 3, 22]; but later studies [6, 13] have not confirmed this finding. The explanation for such a discrepancy is not clear as yet; it can be hypothesized that in some of the earlier studies patients with multisystem atrophy had been included in the analysis. Also, duration of disease, the type and duration of pharmacological treatment may influence the biochemistry of hypothalamus in patients with IPD. Finally, it is known that sleep may be disturbed in patients with IPD, which could influence the rhythmicity of hormone secretion; however, we did not find any differences in the quality and duration of sleep between the patients and controls. Furthermore, only 4 of the patients and 3 of the controls reported occasional use of sleeping pills. In conclusion, our data show that the plasma profiles of PRL, G H , A C T H and cortisol differ in patients with IPD from those observed in healthy controis; the clinical significance of such abnormalities is not clear as yet, though they might play a contributory role in the abnormal postprandial and orthostatic adaptation of blood pressure which is often found [18] in subjects with IPD.

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