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Growth hormone responses to growth hormone releasing factor in primary degenerative dementia
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Growth Hormone Responses to Growth Hormone Releasing Factor in Primary Degenerative Dementia Roger Thomas, Peter Williams, Rhys
and Maurice Scanlon
The growth hormone (GH), thyroid-stimulating hormone (TSH), and prolactin (PRL) responses to growth hormone releasing factor (GRF) were investigated in 18 patients suffering from primary degenerative dementia (PDD) and in 20 age- and sex-matched normal elderly controls. There was no significant difference in the growth hormone response to GRF stimulation between patients and controls, and in neither subject group was there a demonstrable TSH or prolactin response to GRF. These jindings indicate that the pathophysiology underlying the blunted growth hormone response to pharmacological challenge in PDD must lie at a suprapituita~ level.
Many patients with primary degenerative dementia (PDD), particularly of the Alzheimer type, exhibit abnormal growth hormone secretory patterns, as detected by a reduction in sleep-induced growth hormone (GH) response when compared to normal controls (Davis et al. 1982) and a blunting of the GH response following the administration of a cholinesterase inhibitor when compared to a matched control group (Thienhaus et al. 1987). The pathophysiology of these abnormalities, however, remains controversial. The release of GH from the anterior pituitary gland is controlled by two major hypothalamic peptide releasing factors-growth hormone releasing factor (GRF), which is localized primarily in the arcuate nucleus and stimulates the release of GH, and somatostatin, which is localized p~rn~ly in the p~av~n~cul~ nucleus and inhibits GH release (Finley et al. 1981; Bloch et al. 1984). The neuroregulation of GFW-induced GH release is complex and involves many neurotransmitter systems, such as dopamine, acetylcholine, and serotonin (Konlu and Lamruintausta 1978; Checkley 1980), and also possibly other agents, such as melatonin (Smythe and Lazarus 1973). Although there is clear evidence that cholinergic mechanisms operate at a suprapituitary or hypothalamic level in the control of GH release, probably through the modulation of hypothalamic somatostatinergic neurons, it is unclear whether or not there are also direct anterior pituitary cholinergic actions (Dieguez et al. 1987). Although many abnormalities of neurotransmitter activity have been described in dementia of the Alzheimer type (DAT), it is the cholinergic system that has been most
From the Depatments of Psychological Medicine (R.T., P.W.), Medical Biochemistry (R.J.), and Medicine (M.S.), University of Wales College of Medicine, Cardiff, Wales. Address reprint requests to Dr. Roger Thomas, Consultant Psychiatrist, Whitchurch Hospital, Cardiff CF4 7=, Wales. Received May 24, 1988; revised November 26, 1988.
0 1989 Society of Biological
Psychiatry
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strongly implicated, and there is now compelling evidence for a central cholinergic deficit in DAT (David et al. 1979; Coyle et al. 1983). It is thought that the cholinergic cell groups that innervate the hippocampus and temporal neocortex are also responsible for the innervation of those regions of the hypothalamus that are the major sources of peptide releasing factors (lshii 1965; Rossor et al. 1980; McDuff and Sumi 1983). A neuroendocrine strategy for assessing the cholinergic deficit in DAT. such as the GH response to a cholinesterase inhibitor, might have diagnostic and prognostic importance (particularly with regard to treatments that enhance cholinergic activity). However, until the pituitary response to exogenous GRF is assessed. it cannot be stated with confidence that the defect is suprapituitary, and therefore, also a measure of central cholinergic activity. The advent of GRF for clinical use allows hypothalamic mechanisms to be bypassed, and an uncomplicated assessment of control at the pituitary level to be made. Some studies have demonstrated blunted pituitary responses to other hypothalamic releasing factors in DAT [e.g., thyrotrophin (TSH) response to thyrotrophin releasing hormone (TRH)], but the magnitude of these changes was small and of little biological significance (Thomas et al. 1987). To our knowledge, no other group has yet investigated the pituitary GH response to GRF in DAT. Two principal peptides with GRF activity exist, namely, GRF 1-44 and GRF l-40. and both are potent stimulators of GH secretion. In our study, GRF l-44 was used. The GRF challenge test is now a well-established procedure (Shibasaki et al. 1984). The thyrotrophin (TSH) and prolactin (PRL) responses to GRF were also measured.
Methods Eighteen patients ( 12 women and 6 men) who had been diagnosed as suffering from DA’I by the responsible consultant psychiatrist, were drawn from psychogeriatric units in South Glamorgan. Patients were included if they met the criteria of the Diagnostic and Srutistical Manual of Mental Disorders (DSM-III) (American Psychiatric Association 1980) for primary degenerative dementia. Secondary causes of dementia were excluded by taking a detailed history and by physical and mental state examination. Routine electrocardiogram (EKG), chest x-rays, and skull x-rays were normal, and routine biochemical and hematological values were within normal limits. The electroencephalogram (EEG) showed a diffuse abnormality that was compatible with a diagnosis of DAT. Patients who were thought, on clinical assessment, to have a concurrent depressive illness, who had a past history of psychiatric disorder, or who scored 4 or more on the Hachinski scale for multiinfarct dementia (Rossen et al. 1980) were excluded. Patients were questioned using the Geriatric Mental State Schedule (Copeland et al. 1976) in order to establish symptomatology for the inclusion criteria. All patients had been ill for at least 1 year (range l-l 1 years, mean 3.4 years). They were severely demented as assessed by a modified version of the 37-item test of Blessed et al. (1968), all scoring less than 10, and all showed prominent signs of parietal lobe dysfunction on formal testing of their mental state. Within our group of patients with PDD, the majority are likely to have Alzheimer pathology. Twenty age- and sex-matched normal controls (13 women and 7 men) were selected by advertising in a local newspaper. The control subjects were active, ambulant, had no past history of neuropsychiatric disorder, were free of serious medical illness, and had biochemical and hematological values within normal limits. Their cognitive function was normal, as assessed by the Kendrick Battery for the detection of dementia in the elderly
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Table 1. Matching of Patients with DAT and Controls in Terms of Six Variables
Age @==.I
Weight (kg) Total serum protein (g/liter) Serum albumin (g/liter) Serum free Ts (pmouliter) tSerum free T4 (pmoVliter) IS. notsigniticant. ?tT, is expressed on a logarithmic “Means + SE.
Patients (n = 18)
Controls (n = 20)
P
76.62 -L i.lln
73.42 rt 1.24
NS
60.91 rt 64.84 2 39.12 ir 3.81 t 1.09[12.57] rt
1.93 1.57 1.34 0.21 0.03
64.86 _c 1.91 66.57 2 1.25 39.52 ZL0.83 5.16 a 0.21 1.16[17.00] * 0.04
NS NS NS 0.001 NS
scale, with the arithmetic mean in brackets
(Gibson and Kendrick 1979). For all subjects, weight, serum albumin, and total serum protein values were recorded. Unfortunately, height was not routinely measured, so that
body mass quotients are not available. All control subjects were drug-free, and all patients had been free of medication for at least 6 weeks, with the exception of very occasional small doses of ~nzodi~epines at night (and not even these were administered in the week prior to testing). Subjects did not smoke or consume alcohol on a regular basis. Informed consent was obtained from the controls, but in the case of the patients, all of whom were too demented to understand the research nature of the test, consent was obtained from the nearest relative. After an overnight fast from midnight, an indwelling iv catheter was positioned at 9:30 AM. At 10:00 AM, 10 ml of blood was sampled for estimation of baseline levels of GH, PRL, TSH, free triiodothyroxine (a,), and free thyroxine (f&). An iv bolus of GRF was then given (in a dosage of 1 pglkg body weight), and 10 ml of blood was again sampled at 15 min, 30 min, 45 min, 60 min, 90 min, and 120 min after the injection. All subjects were recumbent during the test. Serum samples were stored at - 20°C. GH was measured by double-antibody assay as previously described (Rodriguez-Amao et al. 1981). The intraassay coefficient of variation for GH was 9%, 5%, and 4% at dose levels of 2.8, 14, 24 mu/liter, respectively. The interassay coefficient of variation was 13%, 5%, and 5% at the same dose levels. Prolactin was measured by double-antibody radioi~unoassay. The intraassay coefficient of variation of the PRL assay was 6% at a dose level of 480 mu/liter, and the interassay coefficient of variation of the PRL assay was 9% at the same dose level. TSH was measured using an immunoradiometric assay as described recently (John and Jones 1984). This assay has a working range from 0.5 to greater than 30 mu/liter, with a coefficient of variation of less than 10%.
Results The dis~bution of values for GH, PRL, TSH, and fI”_+were highly ~sitively skewed and required log-transformation. Other variables were analyzed untransformed. The two subject groups were compared by the two-sample unpaired t-test and by multiple regression analysis. Table 1 illustrates the mean values ( + SEM) and the significance of the differences between patients and controls for the following parameters: age, weight, serum albumin, total serum protein, ff3, and log ffd. It can be seen that there is a significant difference between the two groups only for fT3, with the patients having a significantly lower value (p < 0.001). All other variables matched closely.
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Table 2. Mashing of Patients and Controls in Termsof Basal and Stimulated Values of GH, PRL, and TSH Patients (n = 18) GH basal GH 15 min GH 30 min
GH 45 min GH 60 min GH 90 min GH 120 min PRL basal PRL 15min
PRL 30min PRL45 min PRL 60 min PRL 90 min PRL 120min TSH basal TSH 1.5 min TSH TSH TSH TSH TSH
30 min 4.5 min 60 min 90 min 120 min
(~/liter) (k/liter) (p/liter) (~/liter) (p/liter) (p/liter) t @liter) (p/liter) (p/liter) ( pAiter)
1 (pJW~f (pliter
(@liter)
(~/liter) @./liter) (p,/literl (pAiter) (w/liter) (p/liter) (p/liter) (pdliter)
AI1GH, PRL, and TSH values are Op. uncorrected value. “p<. corrected for baseline value. NS,no~5igni~cant.
0.27 0.69 0.83 0.71 0.71 0.51 0.38 2.29 2.32 2.30 2.31 2.30 2.28 2.29 0.06 0.1 I 0.18 0.14 0.15 0.13 0.08
E2.971 [IO.691 113.831 [9.92] [9.10] l-4.741 [3.02] f222.71 [236.1] (229.2] 1245.41 [237.3] [219.4] f223.61 [I.711 [1.98] [2.16] 12.141 [2.0.5] [1.X7] [I.711
-t 2 it t ir k -+ -r it * r+ * k t t t i 5 t lr: -+
0.07 0.12 0.12 0.12 0.11 0.09 0.07 0.06 0.06 0.06 0.06 0.06 0.05 0.05 0.09 0.09 0.09 0.10 0.09 0.08 0.09
Controls (n = 20) 0.18 0.49 0.61 0.63 0.64 0.55 0.51 2.02 2.06 2.05 2.04 2.03 2.02 2.00 0.09 0.14 0.16 0.15 0.12 0.06 0.08
[I.781 16.131 [7.35] [7.31] [7.44] 15.771 i4.21) 1114.1] 1125.61 [120.0] !I 18.0] fIlS.l] f112.3] 1107.61 [I.511 [l&o] [1.75] [1.66] [1.63] 1I.471 [ I.481
t t rt t -+ c +2 t k A rtr I 2 Lt -+ c + A tit
0.05 0.10 0.10 0.09 0.09 0.09 0.07 0.04 O.@+ o.u3 0.04 0.04 0.03 0.03 0.06 0.06 0.07 0.06 0.07 0.07 0.06
P” NS NS NS NS NS NS NS 0.001 0.001 0.001 O.Ool 0.001 0.001 0.01 NS NS NS NS NS NS NS
P‘
‘.
NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS 0.05 NS
expressed on a logartthmic scale as means i FE, with the arithmetic mean in brackets
Table 2 illustrates the mean values ( t SEM) and significance of the difference between patients and controls for baseline and stimulated values of GH, PRL, and TSH. For all three hormones, the logarithmic values are shown, with the arithmetic means in brackets. For the stimulated hormone levels p-values are shown uncorrected and corrected for the corresponding baseline value. For GH, there is no significant difference between the two groups with regard to basal or stimulated values, although there is a trend for the patients with PDD to have the higher values. For TSH, there is also no significant difference between the two groups for basal or stimulated values (except at one time p=oint). No significant stimulation of TSH by GRF occurs in either the patients or controls. For PRL, there is a highly significant difference (p < O.oOl), at all time points, between the two groups, with patients having the higher values. However, when a correction for baseline value is applied, the differences between the two groups at the post-zero times disappear. The highly significant difference between the patient and control groups is due to a difference in baseline values only, and there is no significant PRL response, in either group, to GRF stimulation. In the regression analysis, age correlated inversely with flY3, but did not correlate with any other variable. r)iscussion In this study both healthy elderly subjects and patients with PDD dernonstrat~ a GH of the response was not significantly different between the two groups, aIthough a trend was noted for higher GH levels in the patients. Other responseto GRF. The magnitude
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research groups have found that the GH response to challenge with a cholinesterase inhibitor (e.g., edrophonium) is blunted in patients with Alzheimer’s disease when compared to matched normal controls (Thienhaus et al. 1987), and it has been suggested that this reduction in GH response is due to deficient cholinergic input at the hypothalamic level. This input arises from areas known to undergo degeneration in DAT (Rossor et al. 1980). However, a more critical review of the study by Thienhaus et al. (1987) shows that this entire effect may have been due to the very different baseline growth hormone levels in the two groups. Furthermore, it has been reported recently that patients with DAT and normal controls do not differ on the growth hormone response to edrophonium (Davidson et al. 1987). Another problem with the interpretation of edrophonium-induced increase in growth hormone is that the effects may be mediated entirely in the periphery, through the indirect effects of increasing noradrenergic activity, which in turn feeds back to the pituitary. Further investigation is therefore needed to clarify the GH response to cholinesterase inhibitors. There is also evidence that cholinesterase inhibitors that can cross the blood-brain barrier, e.g., physostigmine, can temporarily alleviate memory deficits in some patients with DAT (Mohs et al. 1985), providing in vivo support for the functional relevance of cortical cholinergic depletion as a factor in the illness. As our present study demonstrates that the pituitary GH response to GRF in PDD is normal, abnormalities in neurotransmitter function, which may in turn result in abnormalities in GH secretion, must lie at a suprapituitary level. The trend for higher GH responses to GRF in the patient group might be a reflection of reduced secretion of hypothalamic somatostatin, which has been postulated to occur in DAT (Rossor and Iversen, 1986). There was no significant TSH response to GRF in patients or controls and also no significant difference in TSH values between the two subject groups. This inability of GRF to stimulate TSH release is in keeping with previous studies (Jordan et al. 1986). The control of TSH secretion by neuropeptide releasing factors is complex and can be influenced by many hormones and neurotransmitter systems (Besses et al. 1975; Tanjasini et al. 1976; Gold et al. 1977; Martin et al. 1977; Loosen et al. 1978) that may be disrupted in DAT (Bowen et al. 1979; Terry and Davies 1980; Bondareff et al. 1981; Raskin et al. 1984). There was no PRL response to GRF in patient or control groups, and again, this is in keeping with previous studies (Jordan et al. 1986). The highly significant difference in PRL concentration (p < 0.001) between the two groups, at all time points, was due to a higher baseline value in the subjects with PDD. This is in keeping with our previous study (Thomas et al. 1987). PRL is normally under dopaminergic inhibitory control (La1 et al. 1973; De Rivera et al. 1976), and as dopaminergic activity is decreased in DAT (Gottfries 1981), this might account for the raised PRL level seen in the patients when compared to controls. Others have also documented raised PRL in dementia (Samorajski 1985) and in Parkinson’s disease (Agnoli et al. 1981), a condition that shares many biochemical abnormalities with DAT (Roth 1986). However, some studies have found no difference in values, or even lower values, of PRL in their Alzheimer patients when compared to controls (Balldin et al. 1983; Peabody et al. 1986). Assay differences or demographic variations might account for this confusing picture. Another interesting and important finding is that of a low serum ff 3 level in the patient group as compared to the control group (p < O.OOl), and which is consistent with results of our previous study (Thomas et al. 1987). This was not accompanied by a significantly
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lower fT4 value, nor by a significantly higher TSH value in the patient group. The likely explanation of this is a reduced conversion of T4 to TS, as observed in the low TX syndrome (Hersman et al. 1983), which is associated with acute and chronic illness (Braverman and Vagenakis 1979). Although others have also demonstrated low T3 levels in patients with psychiatric disorders when compared with normal controls (Spratt et al. 1982; Orsulak et al. 1985), it must be emphasized that values are still within the euthyroid range of the laboratory. We would like to express our thanks to Sanofi for providing the GRF and to Robert Newcombe advice,
for his statistical
References Agnoli A, Baldassarre M, Ruggieri S, Falaschi P, Urso RD, Rocco A (1981): Prolactin response as an index of dopaminergic receptor function in Parkinson’s disease. Correlation findings and therapeutic response. J Neural Transm 5 1:123- 134.
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ageing or selective neuronal loss as
Braverman LE, Vagenakis AG (1979): The thyroid. Clin Endocrinol Metab 8:621. Checkley SA (1980): Neuroendocrine tests of monoamine function in man: A review of basic theory in its application to the study of depressive illness. Psycho1 Med 10:35-53. Copeland JRM, Kelleher MJ, Kellet JM, Gourlay AJ (1976): A semi-structured clinical interview for the assessment of diagnosis and mental state in the elderly: The Geriatric Mental State Schedule. Psycho1 Med 61439-419. JT, Price DL, De Long MR (1983): Alzheimer’s innervation. Science 219:1184-l 190.
Coyle
disease: A disorder of cortical cholinergic
J, et al (1987): Effects of Tensilon on GH secretion in A.D. patients. ACNP Annual Meeting, San Juan.
Davidson
Presented
at the
Davis BM, Brown GM, Miller N, Friesen HG, Kastin AJ, Davies KL (1982): Effects of cholinergic stimulation in pituitary hormonal release. Psychoneuroendocrinology 7:347-354. Davis KL, Mohs RS, Tinkle&erg J Med 30:946.
JR (1979): Enhancement
of memory by physostigmine.
N Engl
De Rivera JL, La1 S, Eltigi P, Hontela S, Muller HF, Friesen HE (1976): Effect of acute and chronic neuroleptic therapy on serum prolactin levels in men and women of different age groups. Clin Endocrinol 51273.
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Dieguez C, Page MD, Scanlon MF (1987): Growth hormone neuroregulation and its alteration in disease states. Clin Endocrinol 27:109-143. Finley JCW, Maderdrut JL, Roger LJ, et al (1981): The immunocytochemical localization of somatostatin-containing neurones in the rat central nervous system. Neuroscience 6:2173-2192. Gibson AJ, Kendrick DC (1979): The Kendrick Batteryfor the Detection of Dementia in the Elderly. NFER Nelson Publications Company Ltd. Gold PW, Goodwin FK, Wehr T, Rebar R (1977): Pituitary thyrotrophin releasing hormone in affective illness: Relationship to spinal and fluid amine metabolites. Am J Psychiatry 134: 1028. Gottfries CG (1981): Biochemical aspects of dementia. In van Praag H, Cader M, Rafaelson OJ, Sachar EJ (eds), Handbook of Biological Psychiatry. New York: Marcel Dekker.
Hersman JM, Partridge WM, Nicoloff JT (1983): Thyroid function in nonthyroidal illness. Ann Intern Med 98:946-957.
Ishii T (1965): Distribution of Alzheimer’s neurofibrillary changes on the brain stem and hypothalamus of senile dementia. Acta Neuropathol6: 18 1-187. John R, Jones K (1984): An automated immunoradiometric assay for human thyrotrophin. Clin Chem 30:13961398. Jordan V, Dieguez C, Lafaffian I, Rodrigues-Amao MD, Gomez-Pan A, Hall R, Scanlon MF (1986): Influence of dopaminergic, adrenergic and cholinergic blockade and TRH administration on GH response to GRF l-29. Clin Endocrinol 24:291-298. Konlu M, Lamruintausta R (1978): Effect of melatonin on L-tryptophan and apomorphine-stimulated GH secretion in man. J Clin Exp Med 49:70-72. La1 S, de la Vega CE, Souskes TL, Friesen HE (1973): Effect of apomorphine on growth hormone, prolactin, luteinizing hormone and follicle-stimulating hormone levels in human serum. J Clin Endocrinol Metab 37:719-724.
Loosen PT, Prange AJ, Wilson IC (1978): The TSH response to TRH in psychiatric patients. Relation to serum cortisol. Progr Neuropsychpharmacol2:479. McDuff T, Sumi SM (1983): Subcortical degeneration in Alzheimer’s disease. Neurology 33(Suppl 2): 159. Martin JB, Reichlon S, Brown GM (1977): Clinical Neuroendocrinology. Philadelphia: F.A. Davies . Mohs RC, Davis BM, Johns CA, et al (1985): Oral physostigmine treatment of patients with Alzheimer’s disease. Am J Psychiatty 142:28-33. Grsulak PJ, Cronley G, Schlesser MA, Gibs D, Fairchild C, Rush AJ (1985): Free thiodothyronine (T3) and thyroxine (T4) in a group of unipolar depressed patients and normal subjects. Biol Psychiatry 20: 1047-1054.
Peabody CA, Minkoff JR, Davies I-ID, Winograd CH, Yesavage J, Tinklenberg JR (1986): Thyrotrophin-releasing hormone stimulation test and Alzheimer’s disease. Biol Psychiatry 21:553556.
Raskin MA, Raskind AE, Halter JB, Jimerson DC (1984): Norepinephrine and MHPE levels in CSF and plasma in Alzheimer’s Disease. Arch Gen Psychiatry 41:343. Rodrigues-Amao MD, Gomez-Pan A, Rainbow SJ, Woodhead S, Coman-Schally AV, Schally CA, Meyers DH, Hall R (1981): Effects of prosomatostatin on growth hormone and prolactin response to arginine in man. Lancet ii:353-356. Rossen WG, Terry RD, Field PA, Katzman R, Peck A (1980): Pathological verification of ischaemic score in differentiation of dementia. Ann Neural 7:486-488. Rossor MN, Iversen LL (1986): Noncholinergic neurotransmitter abnormalities in Alzheimer’s disease. Br Med Bull 42~70-74. Rossor MN, Iversen LL, Mountjoy CQ, et al (1980): Arginine vasopressin and choline ace@transferase in brains of patients with Alzheimer’s type senile dementia. Lancet ii:1367-1368. Roth M (1986): The association of clinical and neurological findings and its bearing on the classification and aetiology of Alzheimer’ disease. Br Med Bull 41:42-50.
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Samorajski T (1985): Prolactin studies in senile dementia of the Alzheimer type. In Gaitz CM, Samorajski T (eds), Ageing 2ooO: Our exalts Care Destiny: I, New York: Springer-Verlag. pp 155-167. Shibosaki T, Shizume K, Nakahara M, Masuda A, Jibiki K, Demura H, Wakabayaski 1, Ling N (1984): Age-related changes in plasma growth hormone response to growth ho~one-releasing factor in man. J Clin Endocrinol ~etab 58212-214. Smythe GA, Lazarus L (1973): Suppression of LGH secretion by melatonin and cyproheptadine. J CZin Invest 57: 117-121. Spratt Dl, Pont A, Miller MB, et al (1982): Hyperthyroxinemia in patients with acute psychiatric disorders. Am J Med 73:41-47. Tanjasiri P, Kosdur X, Rorsheim W (1976): Somatostatin in the physiologic feedback control of thyroptropin secretion. Lije Sri 6:656. Terry R, Davies P (1980): Dementia of the Alzheimer type. Ann Rev Neurosci 3:77. Thienhaus OJ, Zemlan FP, Bienenfeld D, Hartford JT, Bosmann HB (1987): Growth hormone response to edrophonium in Alzheimer’s disease. Am J Psychiatry 144:1049-1052. Thomas DR, Hailwood R, Harris B, Williams PA, Scanlon MF, John R ( 1987): Thyroid status in senile dementia of the Alzheimer type (SDAT). Actu Psych&r Scund 76: 158-l 63.
389
Growth Hormone Responses to Growth Hormone Releasing Factor in Primary Degenerative Dementia Roger Thomas, Peter Williams, Rhys
and Maurice Scanlon
The growth hormone (GH), thyroid-stimulating hormone (TSH), and prolactin (PRL) responses to growth hormone releasing factor (GRF) were investigated in 18 patients suffering from primary degenerative dementia (PDD) and in 20 age- and sex-matched normal elderly controls. There was no significant difference in the growth hormone response to GRF stimulation between patients and controls, and in neither subject group was there a demonstrable TSH or prolactin response to GRF. These jindings indicate that the pathophysiology underlying the blunted growth hormone response to pharmacological challenge in PDD must lie at a suprapituita~ level.
Many patients with primary degenerative dementia (PDD), particularly of the Alzheimer type, exhibit abnormal growth hormone secretory patterns, as detected by a reduction in sleep-induced growth hormone (GH) response when compared to normal controls (Davis et al. 1982) and a blunting of the GH response following the administration of a cholinesterase inhibitor when compared to a matched control group (Thienhaus et al. 1987). The pathophysiology of these abnormalities, however, remains controversial. The release of GH from the anterior pituitary gland is controlled by two major hypothalamic peptide releasing factors-growth hormone releasing factor (GRF), which is localized primarily in the arcuate nucleus and stimulates the release of GH, and somatostatin, which is localized p~rn~ly in the p~av~n~cul~ nucleus and inhibits GH release (Finley et al. 1981; Bloch et al. 1984). The neuroregulation of GFW-induced GH release is complex and involves many neurotransmitter systems, such as dopamine, acetylcholine, and serotonin (Konlu and Lamruintausta 1978; Checkley 1980), and also possibly other agents, such as melatonin (Smythe and Lazarus 1973). Although there is clear evidence that cholinergic mechanisms operate at a suprapituitary or hypothalamic level in the control of GH release, probably through the modulation of hypothalamic somatostatinergic neurons, it is unclear whether or not there are also direct anterior pituitary cholinergic actions (Dieguez et al. 1987). Although many abnormalities of neurotransmitter activity have been described in dementia of the Alzheimer type (DAT), it is the cholinergic system that has been most
From the Depatments of Psychological Medicine (R.T., P.W.), Medical Biochemistry (R.J.), and Medicine (M.S.), University of Wales College of Medicine, Cardiff, Wales. Address reprint requests to Dr. Roger Thomas, Consultant Psychiatrist, Whitchurch Hospital, Cardiff CF4 7=, Wales. Received May 24, 1988; revised November 26, 1988.
0 1989 Society of Biological
Psychiatry
ooo6-3223/891$03.50
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I‘homas et al
strongly implicated, and there is now compelling evidence for a central cholinergic deficit in DAT (David et al. 1979; Coyle et al. 1983). It is thought that the cholinergic cell groups that innervate the hippocampus and temporal neocortex are also responsible for the innervation of those regions of the hypothalamus that are the major sources of peptide releasing factors (lshii 1965; Rossor et al. 1980; McDuff and Sumi 1983). A neuroendocrine strategy for assessing the cholinergic deficit in DAT. such as the GH response to a cholinesterase inhibitor, might have diagnostic and prognostic importance (particularly with regard to treatments that enhance cholinergic activity). However, until the pituitary response to exogenous GRF is assessed. it cannot be stated with confidence that the defect is suprapituitary, and therefore, also a measure of central cholinergic activity. The advent of GRF for clinical use allows hypothalamic mechanisms to be bypassed, and an uncomplicated assessment of control at the pituitary level to be made. Some studies have demonstrated blunted pituitary responses to other hypothalamic releasing factors in DAT [e.g., thyrotrophin (TSH) response to thyrotrophin releasing hormone (TRH)], but the magnitude of these changes was small and of little biological significance (Thomas et al. 1987). To our knowledge, no other group has yet investigated the pituitary GH response to GRF in DAT. Two principal peptides with GRF activity exist, namely, GRF 1-44 and GRF l-40. and both are potent stimulators of GH secretion. In our study, GRF l-44 was used. The GRF challenge test is now a well-established procedure (Shibasaki et al. 1984). The thyrotrophin (TSH) and prolactin (PRL) responses to GRF were also measured.
Methods Eighteen patients ( 12 women and 6 men) who had been diagnosed as suffering from DA’I by the responsible consultant psychiatrist, were drawn from psychogeriatric units in South Glamorgan. Patients were included if they met the criteria of the Diagnostic and Srutistical Manual of Mental Disorders (DSM-III) (American Psychiatric Association 1980) for primary degenerative dementia. Secondary causes of dementia were excluded by taking a detailed history and by physical and mental state examination. Routine electrocardiogram (EKG), chest x-rays, and skull x-rays were normal, and routine biochemical and hematological values were within normal limits. The electroencephalogram (EEG) showed a diffuse abnormality that was compatible with a diagnosis of DAT. Patients who were thought, on clinical assessment, to have a concurrent depressive illness, who had a past history of psychiatric disorder, or who scored 4 or more on the Hachinski scale for multiinfarct dementia (Rossen et al. 1980) were excluded. Patients were questioned using the Geriatric Mental State Schedule (Copeland et al. 1976) in order to establish symptomatology for the inclusion criteria. All patients had been ill for at least 1 year (range l-l 1 years, mean 3.4 years). They were severely demented as assessed by a modified version of the 37-item test of Blessed et al. (1968), all scoring less than 10, and all showed prominent signs of parietal lobe dysfunction on formal testing of their mental state. Within our group of patients with PDD, the majority are likely to have Alzheimer pathology. Twenty age- and sex-matched normal controls (13 women and 7 men) were selected by advertising in a local newspaper. The control subjects were active, ambulant, had no past history of neuropsychiatric disorder, were free of serious medical illness, and had biochemical and hematological values within normal limits. Their cognitive function was normal, as assessed by the Kendrick Battery for the detection of dementia in the elderly
BIOL PSYCHIATRY
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1989;26:389-396
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Table 1. Matching of Patients with DAT and Controls in Terms of Six Variables
Age @==.I
Weight (kg) Total serum protein (g/liter) Serum albumin (g/liter) Serum free Ts (pmouliter) tSerum free T4 (pmoVliter) IS. notsigniticant. ?tT, is expressed on a logarithmic “Means + SE.
Patients (n = 18)
Controls (n = 20)
P
76.62 -L i.lln
73.42 rt 1.24
NS
60.91 rt 64.84 2 39.12 ir 3.81 t 1.09[12.57] rt
1.93 1.57 1.34 0.21 0.03
64.86 _c 1.91 66.57 2 1.25 39.52 ZL0.83 5.16 a 0.21 1.16[17.00] * 0.04
NS NS NS 0.001 NS
scale, with the arithmetic mean in brackets
(Gibson and Kendrick 1979). For all subjects, weight, serum albumin, and total serum protein values were recorded. Unfortunately, height was not routinely measured, so that
body mass quotients are not available. All control subjects were drug-free, and all patients had been free of medication for at least 6 weeks, with the exception of very occasional small doses of ~nzodi~epines at night (and not even these were administered in the week prior to testing). Subjects did not smoke or consume alcohol on a regular basis. Informed consent was obtained from the controls, but in the case of the patients, all of whom were too demented to understand the research nature of the test, consent was obtained from the nearest relative. After an overnight fast from midnight, an indwelling iv catheter was positioned at 9:30 AM. At 10:00 AM, 10 ml of blood was sampled for estimation of baseline levels of GH, PRL, TSH, free triiodothyroxine (a,), and free thyroxine (f&). An iv bolus of GRF was then given (in a dosage of 1 pglkg body weight), and 10 ml of blood was again sampled at 15 min, 30 min, 45 min, 60 min, 90 min, and 120 min after the injection. All subjects were recumbent during the test. Serum samples were stored at - 20°C. GH was measured by double-antibody assay as previously described (Rodriguez-Amao et al. 1981). The intraassay coefficient of variation for GH was 9%, 5%, and 4% at dose levels of 2.8, 14, 24 mu/liter, respectively. The interassay coefficient of variation was 13%, 5%, and 5% at the same dose levels. Prolactin was measured by double-antibody radioi~unoassay. The intraassay coefficient of variation of the PRL assay was 6% at a dose level of 480 mu/liter, and the interassay coefficient of variation of the PRL assay was 9% at the same dose level. TSH was measured using an immunoradiometric assay as described recently (John and Jones 1984). This assay has a working range from 0.5 to greater than 30 mu/liter, with a coefficient of variation of less than 10%.
Results The dis~bution of values for GH, PRL, TSH, and fI”_+were highly ~sitively skewed and required log-transformation. Other variables were analyzed untransformed. The two subject groups were compared by the two-sample unpaired t-test and by multiple regression analysis. Table 1 illustrates the mean values ( + SEM) and the significance of the differences between patients and controls for the following parameters: age, weight, serum albumin, total serum protein, ff3, and log ffd. It can be seen that there is a significant difference between the two groups only for fT3, with the patients having a significantly lower value (p < 0.001). All other variables matched closely.
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Table 2. Mashing of Patients and Controls in Termsof Basal and Stimulated Values of GH, PRL, and TSH Patients (n = 18) GH basal GH 15 min GH 30 min
GH 45 min GH 60 min GH 90 min GH 120 min PRL basal PRL 15min
PRL 30min PRL45 min PRL 60 min PRL 90 min PRL 120min TSH basal TSH 1.5 min TSH TSH TSH TSH TSH
30 min 4.5 min 60 min 90 min 120 min
(~/liter) (k/liter) (p/liter) (~/liter) (p/liter) (p/liter) t @liter) (p/liter) (p/liter) ( pAiter)
1 (pJW~f (pliter
(@liter)
(~/liter) @./liter) (p,/literl (pAiter) (w/liter) (p/liter) (p/liter) (pdliter)
AI1GH, PRL, and TSH values are Op. uncorrected value. “p<. corrected for baseline value. NS,no~5igni~cant.
0.27 0.69 0.83 0.71 0.71 0.51 0.38 2.29 2.32 2.30 2.31 2.30 2.28 2.29 0.06 0.1 I 0.18 0.14 0.15 0.13 0.08
E2.971 [IO.691 113.831 [9.92] [9.10] l-4.741 [3.02] f222.71 [236.1] (229.2] 1245.41 [237.3] [219.4] f223.61 [I.711 [1.98] [2.16] 12.141 [2.0.5] [1.X7] [I.711
-t 2 it t ir k -+ -r it * r+ * k t t t i 5 t lr: -+
0.07 0.12 0.12 0.12 0.11 0.09 0.07 0.06 0.06 0.06 0.06 0.06 0.05 0.05 0.09 0.09 0.09 0.10 0.09 0.08 0.09
Controls (n = 20) 0.18 0.49 0.61 0.63 0.64 0.55 0.51 2.02 2.06 2.05 2.04 2.03 2.02 2.00 0.09 0.14 0.16 0.15 0.12 0.06 0.08
[I.781 16.131 [7.35] [7.31] [7.44] 15.771 i4.21) 1114.1] 1125.61 [120.0] !I 18.0] fIlS.l] f112.3] 1107.61 [I.511 [l&o] [1.75] [1.66] [1.63] 1I.471 [ I.481
t t rt t -+ c +2 t k A rtr I 2 Lt -+ c + A tit
0.05 0.10 0.10 0.09 0.09 0.09 0.07 0.04 O.@+ o.u3 0.04 0.04 0.03 0.03 0.06 0.06 0.07 0.06 0.07 0.07 0.06
P” NS NS NS NS NS NS NS 0.001 0.001 0.001 O.Ool 0.001 0.001 0.01 NS NS NS NS NS NS NS
P‘
‘.
NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS 0.05 NS
expressed on a logartthmic scale as means i FE, with the arithmetic mean in brackets
Table 2 illustrates the mean values ( t SEM) and significance of the difference between patients and controls for baseline and stimulated values of GH, PRL, and TSH. For all three hormones, the logarithmic values are shown, with the arithmetic means in brackets. For the stimulated hormone levels p-values are shown uncorrected and corrected for the corresponding baseline value. For GH, there is no significant difference between the two groups with regard to basal or stimulated values, although there is a trend for the patients with PDD to have the higher values. For TSH, there is also no significant difference between the two groups for basal or stimulated values (except at one time p=oint). No significant stimulation of TSH by GRF occurs in either the patients or controls. For PRL, there is a highly significant difference (p < O.oOl), at all time points, between the two groups, with patients having the higher values. However, when a correction for baseline value is applied, the differences between the two groups at the post-zero times disappear. The highly significant difference between the patient and control groups is due to a difference in baseline values only, and there is no significant PRL response, in either group, to GRF stimulation. In the regression analysis, age correlated inversely with flY3, but did not correlate with any other variable. r)iscussion In this study both healthy elderly subjects and patients with PDD dernonstrat~ a GH of the response was not significantly different between the two groups, aIthough a trend was noted for higher GH levels in the patients. Other responseto GRF. The magnitude
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research groups have found that the GH response to challenge with a cholinesterase inhibitor (e.g., edrophonium) is blunted in patients with Alzheimer’s disease when compared to matched normal controls (Thienhaus et al. 1987), and it has been suggested that this reduction in GH response is due to deficient cholinergic input at the hypothalamic level. This input arises from areas known to undergo degeneration in DAT (Rossor et al. 1980). However, a more critical review of the study by Thienhaus et al. (1987) shows that this entire effect may have been due to the very different baseline growth hormone levels in the two groups. Furthermore, it has been reported recently that patients with DAT and normal controls do not differ on the growth hormone response to edrophonium (Davidson et al. 1987). Another problem with the interpretation of edrophonium-induced increase in growth hormone is that the effects may be mediated entirely in the periphery, through the indirect effects of increasing noradrenergic activity, which in turn feeds back to the pituitary. Further investigation is therefore needed to clarify the GH response to cholinesterase inhibitors. There is also evidence that cholinesterase inhibitors that can cross the blood-brain barrier, e.g., physostigmine, can temporarily alleviate memory deficits in some patients with DAT (Mohs et al. 1985), providing in vivo support for the functional relevance of cortical cholinergic depletion as a factor in the illness. As our present study demonstrates that the pituitary GH response to GRF in PDD is normal, abnormalities in neurotransmitter function, which may in turn result in abnormalities in GH secretion, must lie at a suprapituitary level. The trend for higher GH responses to GRF in the patient group might be a reflection of reduced secretion of hypothalamic somatostatin, which has been postulated to occur in DAT (Rossor and Iversen, 1986). There was no significant TSH response to GRF in patients or controls and also no significant difference in TSH values between the two subject groups. This inability of GRF to stimulate TSH release is in keeping with previous studies (Jordan et al. 1986). The control of TSH secretion by neuropeptide releasing factors is complex and can be influenced by many hormones and neurotransmitter systems (Besses et al. 1975; Tanjasini et al. 1976; Gold et al. 1977; Martin et al. 1977; Loosen et al. 1978) that may be disrupted in DAT (Bowen et al. 1979; Terry and Davies 1980; Bondareff et al. 1981; Raskin et al. 1984). There was no PRL response to GRF in patient or control groups, and again, this is in keeping with previous studies (Jordan et al. 1986). The highly significant difference in PRL concentration (p < 0.001) between the two groups, at all time points, was due to a higher baseline value in the subjects with PDD. This is in keeping with our previous study (Thomas et al. 1987). PRL is normally under dopaminergic inhibitory control (La1 et al. 1973; De Rivera et al. 1976), and as dopaminergic activity is decreased in DAT (Gottfries 1981), this might account for the raised PRL level seen in the patients when compared to controls. Others have also documented raised PRL in dementia (Samorajski 1985) and in Parkinson’s disease (Agnoli et al. 1981), a condition that shares many biochemical abnormalities with DAT (Roth 1986). However, some studies have found no difference in values, or even lower values, of PRL in their Alzheimer patients when compared to controls (Balldin et al. 1983; Peabody et al. 1986). Assay differences or demographic variations might account for this confusing picture. Another interesting and important finding is that of a low serum ff 3 level in the patient group as compared to the control group (p < O.OOl), and which is consistent with results of our previous study (Thomas et al. 1987). This was not accompanied by a significantly
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lower fT4 value, nor by a significantly higher TSH value in the patient group. The likely explanation of this is a reduced conversion of T4 to TS, as observed in the low TX syndrome (Hersman et al. 1983), which is associated with acute and chronic illness (Braverman and Vagenakis 1979). Although others have also demonstrated low T3 levels in patients with psychiatric disorders when compared with normal controls (Spratt et al. 1982; Orsulak et al. 1985), it must be emphasized that values are still within the euthyroid range of the laboratory. We would like to express our thanks to Sanofi for providing the GRF and to Robert Newcombe advice,
for his statistical
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