107
Psychiatry Research, 33:107-l 12 Elsevier
Endocrine Responses to Growth Hormone Releasing Hormone and Corticotropin Releasing Hormone in Early-Onset Alzheimer’s Disease K. Peter Lesch, Ralph Ihl, Lutz Friilich, Rainer Heinrich M. Schulte, and Konrad Maurer Received 1989.
February
Rupprecht,
Ulrich
Miiller,
7, 1989; revised version received August IO, 1989; accepted November
9,
Abstract. In a study of the hypothalamic-pituitary-somatotropic (HPS) and the hypothalamic-pituitary-adrenal (HPA) systems in early-onset Alzheimer’s disease (AD), 10 drug-naive patients and matched controls were given 50 pg growth hormone releasing hormone (GHRH) at 9 a.m. and 100 pg corticotropin releasing hormone (CRH) at 6 p.m. as an i.v. bolus dose. Compared with controls, patients with AD showed attenuated GHRH-induced growth hormone (GH) responses and decreased adrenocorticotropic hormone (ACTH) but normal cortisol secretion following CRH. GH responses to GHRH were negatively correlated with the plasma insulin-like growth factor (IGF-I) concentrations and the severity of dementia. A positive correlation was found between GHRH-evoked GH release and ACTH responses to CRH. The results suggest a pathological process at the level of the pituitary or the hypothalamus, possibly involving a cholinergic, monoaminergic, or peptidergic imbalance in AD, and support the view that altered HPS and HPA secretory dynamics in AD are related to the underlying brain dysfunction. Key
Words.
somatotropic
Dementia, insulin-like growth factor, hypothalamic-pituitaryaxis, hypothalamic-pituitary-adrenal axis.
Post-mortem examinations of brain specimens from patients with Alzheimer’s disease (AD) reveal marked cholinergic, monoaminergic, and peptidergic deficiencies not only in the cerebral cortex but also in subcortical structures, including the hypothalamus (Greenwald et al., 1983; Perry, 1987). In particular, irreversibly decreased neuronal tissue and cerebrospinal fluid somatostatin (SRIH) concentrations in AD are widely replicated findings (Davies and Terry, 1981; Wood et al., 1982), with the significance of these observations being further suggested by the identification of the SRIH neurons as a major locus of development of neurofibrillary tangles and plaques. Hypothalamic regions receiving cholinergic and monoaminergic input are also the major sources of peptide-releasing/ inhibiting hormones. Since growth hormone (GH) secretion is principally regulated through
K. Peter Lesch, M.D., Ralph Ihl, M.D., Lutz Friilich, M.D., Rainer Rupprecht, M.D., and Ulrich Miiller, B.A., are Research Assistants, and Konrad Maurer, M.D., is Professor, Department of Psychiatry, University of Wiirzburg, Wiirzburg, FRG. Heinrich M. Schulte, M.D., is Assistant Professor, Department of Medicine I, University of Kiel, Kiel, FRG. (Reprint requests to Dr. K.-P. Lesch, Laboratory of Clinical Science, NIMH, Bldg. 10/3D41, 9000 Rockville Pike, Bethesda, MD 20892, USA.) 0165-1781/90/$03.50
@ 1990 Elsevier Scientific
Publishers
Ireland
Ltd.
108 altered hypothalamic SRIH or GH releasing hormone (GHRH) output, distorted GH secretory dynamics associated with AD, as detected by reduced sleep-related secretion of GH (Davis et al., 1982), diurnal GH hypersecretion (Christie et al., 1987), and blunted GH responses to the cholinesterase inhibitor edrophonium (Thienhaus et al., 1987), are believed to reflect deficient release of SRIH resulting in hyperactivity of the hypothalamic-adrenal-somatotropic (HPS) system. In addition, a variety of neuroendocrine derangements involving the hypothalamic-pituitaryadrenal (HPA) axis have been described in AD. These abnormalities include decreased corticotropin releasing hormone (CRH) concentrations and reciprocal changes in CRH receptors in the cortex (Bissette et al., 1985; DeSouza et al., 1986), increased nocturnal cortisol secretion (Davis et al., 1986), and nonsuppression of plasma cortisol concentrations after dexamethasone administration (Raskind et al., 1982; Balldin et al., 1983). To explore HPS and HPA system integrity in AD, GHRH and CRH stimulation tests were carried out in patients with early-onset AD and matched controls.
Methods Ten drug-naive, nondepressed patients (7 women, 3 men), aged 49-66years (mean Ifr SD = 58.6f 6.3)and with a body mass index (BMI) of 23.1 * 2.6 kg/m*, met DSM-III-Rcriteria (American Psychiatric Association, 1987) for primary degenerative dementia and NINCDSADRDA criteria (McKhann et al., 1984) for probable AD. All investigations were performed after the patients’ admission to the Department of Psychiatry, University of Wiirzburg. Patients were evaluated by physical examination, routine laboratory screening, and various imaging techniques including event related potentials (ERP), brain electrical activity mapping (BEAM), computed tomography (CT) or magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and positron emission tomography (PET). The severity of dementia was assessed with Folstein’s Mini-Mental State (FMMS) examination (Folstein et al., 1975) and the Brief Cognitive Rating Scale (BCRS; Reisberg et al., 1983). The mean (+ SD) BCRS and FMMS scores were 4.1 f 1.5 and 16.3 Ifr 10.0, respectively. Ten controls were matched for age (55.2 + 4.6 years), gender (7 women, 3 men), and BMI (23.6 & 2.9 kg/m*). All subjects received 5Opg synthetic human GHRH-44 amide at 9 a.m. and 100 pugsynthetic human CRH-41 at 6 p.m. as an i.v. bolus dose at rest in bed. GH was measured at -15, 0, 15, 30,45,60,90, and 120 min and insulin-like growth factor (IGF-I) was determined at -15 min. Adrenocorticotropic hormone (ACTH) and cortisol were measured at -15,0, 5, 15, 30,60,90, and 120 min. GH, IGF-I, ACTH, and cortisol analyses employed standard radioimmunoassay (RIA) techniques as previously described (Lesch et al., 19890). Hormone responses were calculated as net areas under the curve (AUC), using trapezoidal integration. The data were analyzed using Mann-Whitney’s U test and Spearman’s rank order correlation.
Results Compared with controls, the patients with AD showed attenuated (mean + SD) GH responses to GHRH (851 & 734 vs. 361 * 666 ng * min/ ml; p < 0.05)(Fig. 1, Table 1A) and decreased ACTH (3 136 + 2798 vs. 1431 f 825 pg * min/ml; p < 0.05) but normal cortisol release (12.9 * 4.4 vs. 13.9 f 7.3 X 103 ng * min/ml; NS) following CRH (Fig. 1, Table 1B). No difference was found in basal GH and IGF-I concentrations. The GHRH-induced GH responses and IGF-I concentrations were negatively correlated in the AD patients (r, -0.58, p < 0.05) and across the entire sample
Fig. 1. Time course curves of GH responses to GHRH and CRH-induced ACTH/cortisol release in 10 Alzheimer’s disease patients and 10 normal controls
-30
0
30
60
90
120 min
GH = growth hormone. GHRH = growth hormone releasing hormone. CRH = corticotropin releasing hormone. ACTH = adrenocorticotropic hormone. Subjects were matched for age, gender, and body mass index. Alzheimer’s disease = open symbols. Normal controls = solid symbols.
Table 1A. Baseline growth hormone (GH), GH responses to GH releasing hormone, and insulin-like growth factor I (IGF-I) in patients with Alzheimer’s disease (n = 10) and matched controls IGF-I AUC GH Basal GH (U/ml) (ng minImI) (ng/mt) l
Alzheimer’s
disease
Controls
1.8 f 2.2
361 k 666’
0.74 f 0.31
1.7 k 1.6
651 + 734
0.73 f 0.36
Note. AUC = area under the curve. 1. p < 0.05, Mann-Whitney
U test, P-tailed
Table 1B. Baseline cortisol, ACTH, and cortisol responses to corticotropin releasing hormone in patients with Alrheimer’s disease (n = 10) and matched controls
Alzheimer’s
Basal cortisol (WW
AUC ACTH (pg . min/ml)
AUC cortisol (ng min/ml X 103)
78.6 f 50.0
1431 IIZ 825’
13.9 f 7.3
50.6 k 23.7
3136 f 2798
12.9 * 4.4
disease
Controls Note. ACTH = adrenocorticotropic 1, p < 0.05, Mann-Whitney
hormone. AUC = area under the curve.
U test, P-tailed.
l
110
(r,= -0.39, p < 0.05).While baseline ACTH values were not different, the blunted ACTH response was associated with increased basal cortisol concentrations. A positive correlation was found between GHRH-evoked GH release and ACTH responses to CRH across the entire sample (r, = 0.45, p < 0.05).This relationship persisted only in the patient group when AD patients and controls were tested separately (r, = 0.67, p < 0.05).GH and cortisol responses were not correlated. In the patients with AD, a correlation was found between GH responses to GHRH and severity of dementia as assessed by the BCRS (rs = -0.56, p < 0.05) and the FMMS (r, = 0.50, p < 0.1).The magnitude of GH responses to GHRH and CRH-induced ACTH/cortisol secretion did not differ between men and women and was not significantly correlated with age and BMI.
Discussion Our data indicate that GH responses after GHRH administration are attenuated in patients with early-onset AD as compared to normal controls. The impaired pituitary response could have resulted from diurnal GH hypersecretion, previously demonstrated in Alzheimer-type dementia (Christie et al., 1987). Although exaggerated GH output may reflect increased release of endogenous GHRH (Lesch et al., 1989a), it is more likely to be due to a cholinergic or SRIH-ergic deficiency. This hypothesis is supported by the observation that cholinergic and SRIH-ergic deficits are particularly pronounced in patients with early-onset AD (Rossor et al., 1984). Since feedback inhibition of GH secretion is mediated by peripheral GHdependent IGF-I production and by a direct effect of GH, diminished GHRHinduced GH responses may be a consequence of HPS hyperactivity. Although there is no compelling evidence of diurnal GH hypersecretion in our patient sample, as reflected by elevated basal GH levels or increased IGF-I concentrations, the diminished GH responses to GHRH may indicate a pathological process at the level of the pituitary or the hypothalamus. Recently, several studies demonstrated abnormal GH release in response to GHRH in depression (Lesch et al., 1987; Risch et al., 1988; Neuhauser and Laakmann, 1988; Krishnan et al., 1988) and panic disorder (Rapaport et al., 1989), thus indicating the limitations and low specificity of this challenge paradigm. Further studies are necessary to clarify HPS axis dysregulation and the relevance of GHRH stimulation tests in psychiatric illness. The discordance in ACTH and cortisol responses to CRH stimulation in AD patients indicates that the pituitary corticotroph cells respond to the negative feedback of increased baseline cortisol and that the abnormal HPA activity reflects a suprapituitary disturbance. Accordingly, the apparently normal functioning of the ACTH-secreting cells and the presumed integrity of the glucocorticoid-dependent negative feedback regulation suggest that mild hypercortisolism in patients with AD reflects an abnormality at or above the level of the hypothalamus that may lead to a hypersecretion of endogenous CRH (or vasopressin). Hyperactivity of CRH-containing neurons may be due to alterations in the hypothalamic, limbic, and other subcortical structures where cholinergic, monoaminergic, and peptidergic interactions are known to have important modulatory influences on hormonal release (Lesch et al., 1989~).
111 Our results, therefore, provide functional evidence of disturbed HPS and HPA axis regulation in AD that appears to be related to underlying brain dysfunction. Further study of neurotransmitter-mediated HPS and HPA dysregulation using selective pharmacological challenge compounds such as m-chlorophenylpiperazine (Mueller et al., 1985) or ipsapirone (Lesch et al., 1989b; Lesch et al., 1990) combined with peripheral measures may allow a clearer understanding of the pathophysiology of neuroendocrine dysfunction in AD.
References American Psychiatric Association. DSM-III-R: Diagnostic and Statistical Manual of Mental Disorders. Washington, DC: American Psychiatric Press, 1987. Balldin, J.; Gottfries, C.G.; Karlsson, I.; Lindstedt, G.; Langstrom, G.; and Walinder, J. Dexamethasone suppression test and serum prolactin in dementia disorders. British Journal of Psychiatry, 143:277-28 1, 1983. Bissette, G.; Reynolds, G.P.; Kilts, C.D.; Widerliiv, E.; and Nemeroff, C.B. Corticotropinreleasing factor-like immunoreactivity in senile dementia of the Alzheimer type. Journal of the American Medical Association, 254:3067-3069, 1985. Christie, J.E.; Whalley, L.J.; Bennie, J.; Dick, H.; Blackburn, I.M.; and Fink, G. Characteristic plasma hormone changes in Alzheimer’s disease. British Journal of Psychiatry, 150:674-681, 1987. Davies, P., and Terry, R.D. Reduced cortical somatostatin-like immunoreactivity in cerebral cortex cases from Alzheimer’s disease and senile dementia of the Alzheimer type. Neurobiology of Aging, 2:9-14, 1981. Davis, B.M.; Levy, M.I.; Rosenberg, G.S.; Math& A.; and Davis, K.L. Relationship between growth hormone and cortisol and acetylcholine: A possible neuroendocrine strategy for assessing the cholinergic deficit. In: Corkin, S.; Davis, K.L.; Growdon, J.H.; Usdin, E.; and Wurtman, J., eds. Alzheimer’s Disease: Report of Progress in Research. New York: Raven Press, 1982. Davis, K.L.; Davis, B.M.; Greenwald, B.S.; Mohs, R.C.; Math& A.A.; Johns, C.A.; and Horvath, T.B. Cortisol and Alzheimer’s disease: Basal studies. American Journal of Psychiatry, 143:300-305, 1986. De Souza, E.B.; Whitehouse, P.J.; Kuhar, M.J.; Price, D.L.; and Vale, W.W. Reciprocal changes in corticotropin-releasing factor (CRF)-like immunoreactivity and CRF receptors in cerebral cortex of Alzheimer’s disease. Nature, 319:593-595, 1986. Folstein, M.F.; Folstein, SE.; and McHugh, P.R. “Mini-Mental State”: A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research, 12:189-198, 1975. Greenwald, B.S.; Mohs, R.C.; and Davis, K.L. Neurotransmitter deficits in Alzheimer’s disease: Criteria for significance. Journal of the American Geriatric Society, 3 1:3 10-3 16, 1983. Krishnan, K.R.R.; Manepalli, A.N.; Richie, J.C.; Rayasam, K.; Melville, M.L.; Daughtry, G.; Thorner, M.O.; Rivier, J.E.; Vale, W.W.; Nemeroff, C.B.; and Carroll, B.J. Growth hormone-releasing factor stimulation test in depression. American Journal of Psychiatry, 145:90-92, 1988. Lesch, K.P.; Laux, G.; Erb, A.; Pfiiller, H.; and Beckmann, H. Attenuated growth hormone response to growth hormone-releasing hormone in major depressive disorder. Biological Psychiatry, 22:1495-1499, 1987. Lesch, K.P.; Mayer, S.; Disselkamp-Tietze, J.; Hoh, A.; Schoellnhammer, G.; and Schulte, H.M. Subsensitivity of the 5-hydroxytryptamine-1A (5-HTIA) receptor-mediated hypothermic response to ipsapirone in unipolar depression. Life Sciences, 46:1271-1277, 1990. Lesch, K.P.; Miiller, U.; Rupprecht, R.; Kruse, K.; and Schulte, H.M. Endocrine responses to growth hormone-releasing hormone, thyrotropin-releasing hormone and corticotropinreleasing hormone in depression. Acta Psychiatrica Scandinavica, 79:597-602, 1989a.
112 Lesch, K.P.; Rupprecht, R.; Poten, B.; Miiller, U.; Siihnle, K.; Fritze, J.; and Schulte, H.M. Endocrine responses to S-hydroxytryptamine-1A receptor activation in ipsapirone in humans. Biological Psychiatry, 26:203-205, 1989b. McKhann, G.; Drachman, D.; Folstein, M.; Katzman, R.; Price, D.; and Stadlam, E.M. Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA work group under the auspices of the Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology, 34:939-944, 1984. Mueller, E.A.; Murphy, D.L.; and Sunderland, T. Neuroendocrine effects of m-chlorophenylpiperazine, a serotonin agonist, in humans. Journal of Clinical Endocrinology and Metabolism, 61:1179-l 184, 1985. Neuhauser, H., and Laakmann, G. Stimulation of growth hormone by GHRH as compared to DMI in depressed patients. Pharmacopsychiatry, 21443-444, 1988. Perry, E.K. Cortical neurotransmitter chemistry in Alzheimer’s disease. In: Meltzer, H., ed. Psychopharmacology: The Third Generation of Progress. New York: Raven Press, 1987. pp. 568-575. Rapaport, M.H.; Risch, S.C.; Gillin, J.C.; Golshan, S.; and Janowsky, D.S. Blunted growth hormone response to peripheral infusion of human growth hormone-releasing factor in patients with panic disorder. American Journal of Psychiatry, 146:92-95, 1989. Raskind, M.; Peskind, E.; Rivard, M.F.; Veith, R.; and Barnes, R. Dexamethasone suppression test and cortisol circadian rhythm in primary degenerative dementia. American Journal of Psychiatry, 139: 1468- 147 1, 1982. Reisberg, B.; London, E.; Ferris, S.H.; Borenstein, J.; Scheier, L.; and de Leon, M.J. The Brief Cognitive Rating Scale: Language, motoric and mood, concomitants in primary degenerative dementia (PDD). Psychopharmacology Bulletin, 19:702-708, 1983. Risch, S.C.; Ehlers, C.; Janowsky, D.S.; Judd, L.; Gillin, J.C.; Dana, R.; and McAdams, L.A. Human growth hormone releasing factor infusion effects on plasma growth hormone in affective disorder patients and normal controls. Peptides, 9:45-48, 1988. Rossor, M.N.; Iversen, L.L.; Reynolds, G.P.; Mountjoy, C.Q.; and Roth, M. Neurochemical characteristics of early and late onset types of Alzheimer’s disease. British Medical Journal, 288:961-969, 1984. Thienhaus, O.J.; Zemlan, F.P.; Bienenfeld, D.; Hartford, J.T.; and Bosmann, H.B. Growth hormone response to edrophonium in Alzheimer’s disease. American Journal of Psychiatry, 144:1049-1059, 1987. Wood, P.L.; Etienne, P.; Lal, S.; Gauthier, S.; Cajal, S.; and Nair, N.P.V. Reduced lumbar CSF somatostatin levels in Alzheimer’s disease. Life Sciences, 31:2073-2079, 1982.
Psychiatry Research, 33:107-l 12 Elsevier
Endocrine Responses to Growth Hormone Releasing Hormone and Corticotropin Releasing Hormone in Early-Onset Alzheimer’s Disease K. Peter Lesch, Ralph Ihl, Lutz Friilich, Rainer Heinrich M. Schulte, and Konrad Maurer Received 1989.
February
Rupprecht,
Ulrich
Miiller,
7, 1989; revised version received August IO, 1989; accepted November
9,
Abstract. In a study of the hypothalamic-pituitary-somatotropic (HPS) and the hypothalamic-pituitary-adrenal (HPA) systems in early-onset Alzheimer’s disease (AD), 10 drug-naive patients and matched controls were given 50 pg growth hormone releasing hormone (GHRH) at 9 a.m. and 100 pg corticotropin releasing hormone (CRH) at 6 p.m. as an i.v. bolus dose. Compared with controls, patients with AD showed attenuated GHRH-induced growth hormone (GH) responses and decreased adrenocorticotropic hormone (ACTH) but normal cortisol secretion following CRH. GH responses to GHRH were negatively correlated with the plasma insulin-like growth factor (IGF-I) concentrations and the severity of dementia. A positive correlation was found between GHRH-evoked GH release and ACTH responses to CRH. The results suggest a pathological process at the level of the pituitary or the hypothalamus, possibly involving a cholinergic, monoaminergic, or peptidergic imbalance in AD, and support the view that altered HPS and HPA secretory dynamics in AD are related to the underlying brain dysfunction. Key
Words.
somatotropic
Dementia, insulin-like growth factor, hypothalamic-pituitaryaxis, hypothalamic-pituitary-adrenal axis.
Post-mortem examinations of brain specimens from patients with Alzheimer’s disease (AD) reveal marked cholinergic, monoaminergic, and peptidergic deficiencies not only in the cerebral cortex but also in subcortical structures, including the hypothalamus (Greenwald et al., 1983; Perry, 1987). In particular, irreversibly decreased neuronal tissue and cerebrospinal fluid somatostatin (SRIH) concentrations in AD are widely replicated findings (Davies and Terry, 1981; Wood et al., 1982), with the significance of these observations being further suggested by the identification of the SRIH neurons as a major locus of development of neurofibrillary tangles and plaques. Hypothalamic regions receiving cholinergic and monoaminergic input are also the major sources of peptide-releasing/ inhibiting hormones. Since growth hormone (GH) secretion is principally regulated through
K. Peter Lesch, M.D., Ralph Ihl, M.D., Lutz Friilich, M.D., Rainer Rupprecht, M.D., and Ulrich Miiller, B.A., are Research Assistants, and Konrad Maurer, M.D., is Professor, Department of Psychiatry, University of Wiirzburg, Wiirzburg, FRG. Heinrich M. Schulte, M.D., is Assistant Professor, Department of Medicine I, University of Kiel, Kiel, FRG. (Reprint requests to Dr. K.-P. Lesch, Laboratory of Clinical Science, NIMH, Bldg. 10/3D41, 9000 Rockville Pike, Bethesda, MD 20892, USA.) 0165-1781/90/$03.50
@ 1990 Elsevier Scientific
Publishers
Ireland
Ltd.
108 altered hypothalamic SRIH or GH releasing hormone (GHRH) output, distorted GH secretory dynamics associated with AD, as detected by reduced sleep-related secretion of GH (Davis et al., 1982), diurnal GH hypersecretion (Christie et al., 1987), and blunted GH responses to the cholinesterase inhibitor edrophonium (Thienhaus et al., 1987), are believed to reflect deficient release of SRIH resulting in hyperactivity of the hypothalamic-adrenal-somatotropic (HPS) system. In addition, a variety of neuroendocrine derangements involving the hypothalamic-pituitaryadrenal (HPA) axis have been described in AD. These abnormalities include decreased corticotropin releasing hormone (CRH) concentrations and reciprocal changes in CRH receptors in the cortex (Bissette et al., 1985; DeSouza et al., 1986), increased nocturnal cortisol secretion (Davis et al., 1986), and nonsuppression of plasma cortisol concentrations after dexamethasone administration (Raskind et al., 1982; Balldin et al., 1983). To explore HPS and HPA system integrity in AD, GHRH and CRH stimulation tests were carried out in patients with early-onset AD and matched controls.
Methods Ten drug-naive, nondepressed patients (7 women, 3 men), aged 49-66years (mean Ifr SD = 58.6f 6.3)and with a body mass index (BMI) of 23.1 * 2.6 kg/m*, met DSM-III-Rcriteria (American Psychiatric Association, 1987) for primary degenerative dementia and NINCDSADRDA criteria (McKhann et al., 1984) for probable AD. All investigations were performed after the patients’ admission to the Department of Psychiatry, University of Wiirzburg. Patients were evaluated by physical examination, routine laboratory screening, and various imaging techniques including event related potentials (ERP), brain electrical activity mapping (BEAM), computed tomography (CT) or magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and positron emission tomography (PET). The severity of dementia was assessed with Folstein’s Mini-Mental State (FMMS) examination (Folstein et al., 1975) and the Brief Cognitive Rating Scale (BCRS; Reisberg et al., 1983). The mean (+ SD) BCRS and FMMS scores were 4.1 f 1.5 and 16.3 Ifr 10.0, respectively. Ten controls were matched for age (55.2 + 4.6 years), gender (7 women, 3 men), and BMI (23.6 & 2.9 kg/m*). All subjects received 5Opg synthetic human GHRH-44 amide at 9 a.m. and 100 pugsynthetic human CRH-41 at 6 p.m. as an i.v. bolus dose at rest in bed. GH was measured at -15, 0, 15, 30,45,60,90, and 120 min and insulin-like growth factor (IGF-I) was determined at -15 min. Adrenocorticotropic hormone (ACTH) and cortisol were measured at -15,0, 5, 15, 30,60,90, and 120 min. GH, IGF-I, ACTH, and cortisol analyses employed standard radioimmunoassay (RIA) techniques as previously described (Lesch et al., 19890). Hormone responses were calculated as net areas under the curve (AUC), using trapezoidal integration. The data were analyzed using Mann-Whitney’s U test and Spearman’s rank order correlation.
Results Compared with controls, the patients with AD showed attenuated (mean + SD) GH responses to GHRH (851 & 734 vs. 361 * 666 ng * min/ ml; p < 0.05)(Fig. 1, Table 1A) and decreased ACTH (3 136 + 2798 vs. 1431 f 825 pg * min/ml; p < 0.05) but normal cortisol release (12.9 * 4.4 vs. 13.9 f 7.3 X 103 ng * min/ml; NS) following CRH (Fig. 1, Table 1B). No difference was found in basal GH and IGF-I concentrations. The GHRH-induced GH responses and IGF-I concentrations were negatively correlated in the AD patients (r, -0.58, p < 0.05) and across the entire sample
Fig. 1. Time course curves of GH responses to GHRH and CRH-induced ACTH/cortisol release in 10 Alzheimer’s disease patients and 10 normal controls
-30
0
30
60
90
120 min
GH = growth hormone. GHRH = growth hormone releasing hormone. CRH = corticotropin releasing hormone. ACTH = adrenocorticotropic hormone. Subjects were matched for age, gender, and body mass index. Alzheimer’s disease = open symbols. Normal controls = solid symbols.
Table 1A. Baseline growth hormone (GH), GH responses to GH releasing hormone, and insulin-like growth factor I (IGF-I) in patients with Alzheimer’s disease (n = 10) and matched controls IGF-I AUC GH Basal GH (U/ml) (ng minImI) (ng/mt) l
Alzheimer’s
disease
Controls
1.8 f 2.2
361 k 666’
0.74 f 0.31
1.7 k 1.6
651 + 734
0.73 f 0.36
Note. AUC = area under the curve. 1. p < 0.05, Mann-Whitney
U test, P-tailed
Table 1B. Baseline cortisol, ACTH, and cortisol responses to corticotropin releasing hormone in patients with Alrheimer’s disease (n = 10) and matched controls
Alzheimer’s
Basal cortisol (WW
AUC ACTH (pg . min/ml)
AUC cortisol (ng min/ml X 103)
78.6 f 50.0
1431 IIZ 825’
13.9 f 7.3
50.6 k 23.7
3136 f 2798
12.9 * 4.4
disease
Controls Note. ACTH = adrenocorticotropic 1, p < 0.05, Mann-Whitney
hormone. AUC = area under the curve.
U test, P-tailed.
l
110
(r,= -0.39, p < 0.05).While baseline ACTH values were not different, the blunted ACTH response was associated with increased basal cortisol concentrations. A positive correlation was found between GHRH-evoked GH release and ACTH responses to CRH across the entire sample (r, = 0.45, p < 0.05).This relationship persisted only in the patient group when AD patients and controls were tested separately (r, = 0.67, p < 0.05).GH and cortisol responses were not correlated. In the patients with AD, a correlation was found between GH responses to GHRH and severity of dementia as assessed by the BCRS (rs = -0.56, p < 0.05) and the FMMS (r, = 0.50, p < 0.1).The magnitude of GH responses to GHRH and CRH-induced ACTH/cortisol secretion did not differ between men and women and was not significantly correlated with age and BMI.
Discussion Our data indicate that GH responses after GHRH administration are attenuated in patients with early-onset AD as compared to normal controls. The impaired pituitary response could have resulted from diurnal GH hypersecretion, previously demonstrated in Alzheimer-type dementia (Christie et al., 1987). Although exaggerated GH output may reflect increased release of endogenous GHRH (Lesch et al., 1989a), it is more likely to be due to a cholinergic or SRIH-ergic deficiency. This hypothesis is supported by the observation that cholinergic and SRIH-ergic deficits are particularly pronounced in patients with early-onset AD (Rossor et al., 1984). Since feedback inhibition of GH secretion is mediated by peripheral GHdependent IGF-I production and by a direct effect of GH, diminished GHRHinduced GH responses may be a consequence of HPS hyperactivity. Although there is no compelling evidence of diurnal GH hypersecretion in our patient sample, as reflected by elevated basal GH levels or increased IGF-I concentrations, the diminished GH responses to GHRH may indicate a pathological process at the level of the pituitary or the hypothalamus. Recently, several studies demonstrated abnormal GH release in response to GHRH in depression (Lesch et al., 1987; Risch et al., 1988; Neuhauser and Laakmann, 1988; Krishnan et al., 1988) and panic disorder (Rapaport et al., 1989), thus indicating the limitations and low specificity of this challenge paradigm. Further studies are necessary to clarify HPS axis dysregulation and the relevance of GHRH stimulation tests in psychiatric illness. The discordance in ACTH and cortisol responses to CRH stimulation in AD patients indicates that the pituitary corticotroph cells respond to the negative feedback of increased baseline cortisol and that the abnormal HPA activity reflects a suprapituitary disturbance. Accordingly, the apparently normal functioning of the ACTH-secreting cells and the presumed integrity of the glucocorticoid-dependent negative feedback regulation suggest that mild hypercortisolism in patients with AD reflects an abnormality at or above the level of the hypothalamus that may lead to a hypersecretion of endogenous CRH (or vasopressin). Hyperactivity of CRH-containing neurons may be due to alterations in the hypothalamic, limbic, and other subcortical structures where cholinergic, monoaminergic, and peptidergic interactions are known to have important modulatory influences on hormonal release (Lesch et al., 1989~).
111 Our results, therefore, provide functional evidence of disturbed HPS and HPA axis regulation in AD that appears to be related to underlying brain dysfunction. Further study of neurotransmitter-mediated HPS and HPA dysregulation using selective pharmacological challenge compounds such as m-chlorophenylpiperazine (Mueller et al., 1985) or ipsapirone (Lesch et al., 1989b; Lesch et al., 1990) combined with peripheral measures may allow a clearer understanding of the pathophysiology of neuroendocrine dysfunction in AD.
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