IN ADULTS, GH deficiency (GHD) is the most common

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1 X/98/$03.00/0 Vol. 83, No. 9 Journal of Clinical Endocrinology and Metabolism Printed in U.S.A. Copyright 1998 by The Endocrine Society Effects of Physiological Growth Hormone (GH) Therapy on Cognition and Quality of Life in Patients with Adult- Onset GH Deficiency* HOWARD B. A. BAUM, LAURENCE KATZNELSON, JANET C. SHERMAN, BEVERLY M. K. BILLER, DOUGLAS L. HAYDEN, DAVID A. SCHOENFELD, KRISTIN E. CANNISTRARO, AND ANNE KLIBANSKI Neuroendocrine Unit (H.B.A.B., L.K., B.M.K.B., K.E.C., A.K.), Department of Medicine, Psychology Assessment Center (J.C.S.), and General Clinical Research Center (D.L.H., D.A.S.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts ABSTRACT GH replacement of adults with acquired GH deficiency (GHD) results in body composition changes including increases in lean mass and bone mineral density. However, the effects of long-term GH therapy on cognitive function are largely unknown, and there are conflicting data regarding quality of life. We performed a randomized, double-blind, placebo-controlled study of GH replacement in adults with GHD and measured cognition and sense of well-being using standardized psychometric tests before and after therapy. Forty men (median age 51 yr, range yr) with a history of pituitary disease were randomized to GH therapy (starting dose, g/kg per day: mean treatment dose, 4 2 g/kg per day) vs. placebo for 18 months, and GH doses were adjusted according to serum insulin growth factor-i levels. At baseline, the patients displayed a full-scale intelligence quotient (IQ) score nearly 1 SD above the normal mean. IN ADULTS, GH deficiency (GHD) is the most common endocrine deficiency associated with pituitary disease, affecting % of individuals with pituitary macroadenomas (1, 2). GHD has been associated with changes in body composition including a decrease in lean body mass, increase in percent body fat, and a decrease in bone mineral density (3 7). Recent investigations have demonstrated that GH replacement in adults with GHD results in improvements in bone density and lean muscle mass indicating a therapeutic benefit of GH on body composition (8 10). Children diagnosed with GHD often experience academic difficulty, and, although such patients display a normal intelligence quotient (IQ) distribution, they may display behavioral problems consistent with attention-deficit disorder (11 14). It is unknown whether the observed effects are caused by GHD or are attributable to childhood illness or other associated factors. As adults, these patients have been reported to have psychosocial problems and experience decreased rates of employment and marriage (15, 16). Patients who acquire GHD as adults have been reported to have Received March 16, Revision received May 28, Accepted June 2, Address all correspondence and requests for reprints to: Anne Klibanski, Neuroendocrine Unit, Bulfinch 457, Massachusetts General Hospital, 32 Fruit Street, Boston, Massachusetts * This work was supported in part by NIH Grant M01-RR and a research grant from Genentech. Mean scores on all cognitive tests fell within normal limits, and on many tests, fell above the mean. On tests of verbal learning and delayed visual memory, mean test scores fell below the mean (although within normal limits), suggestive of a relative compromise in the area of memory performance. Following 18 months of GH replacement therapy, there were no significant changes in cognitive function or quality of life. We conclude that acquired GHD in adult men is not associated with significant alterations in cognitive function as assessed by standardized tests, and chronic low-dose GH replacement therapy does not result in significant beneficial effects on cognitive function or quality of life. Although previous studies have suggested that GH replacement in adults with acquired GHD may improve quality of life, our data do not support the use of physiological GH replacement in GHD men for this indication. (J Clin Endocrinol Metab 83: , 1998) diminished perceived quality of life and level of general health (17, 18). Therefore, potential cognitive and quality of life changes that may accompany this disorder in adults are important issues. In several short-term studies, GH administration has led to improved mood and sense of well-being in patients with acquired GHD (17, 19, 20). However, these studies were limited by factors including use of pharmacological GH doses and short-term controlled treatment duration. In addition, there have been no long-term controlled studies that have assessed the benefits of GH therapy on cognitive function. To assess the long-term effects of GH therapy on cognitive function and sense of well-being, we used a battery of standardized psychometric tests and standardized personality and quality of life questionnaires to determine cognitive function and sense of well-being in adult men with GHD at baseline and following 18 months of GH replacement. Subjects Subjects and Methods Forty men (ages yr, median 51 yr) with a history of pituitary disease were recruited from the Massachusetts General Hospital Neuroendocrine Clinical Center and from area physicians. Baseline hormone evaluation and response of bone density and body composition to GH administration in a subset of these patients have been previously reported (21). Inclusion criteria included: 1) normal growth and development; 2) a diagnosis after age 18 yr of benign sellar neoplasm, pituitary 3184

2 GH AND COGNITION 3185 apoplexy, or idiopathic hypopituitarism; and 3) peak serum GH levels less than 5 g/l in response to two pharmacological stimuli (insulin, clonidine, and/or arginine) administered on separate mornings after an overnight fast. Clinical characteristics of the patients are described in Table 1. None of the patients received psychiatric medications at baseline or at any time during the study. Patients were excluded if they had a history of acromegaly, diabetes mellitus, or malignancy; were not receiving standard thyroid or adrenal hormone replacement therapy if deficient in those hormones; or had initiated adrenal, gonadal, or thyroid hormone replacement therapy within 6 months of entry. The study was approved by the Subcommittee on Human Studies of the Massachusetts General Hospital, and all patients gave written informed consent. Psychometric testing Testing was performed at the same time of day for all patients on all occasions and took approximately 2.5 h. All testing and scoring of tests was performed by a neuropsychologist or psychometrician, and patients received the tests in the same order. Cognitive function Tests of cognitive function were administered, including: Wechsler Adult Intelligence Scale-Revised (WAIS-R) (22), a test of general level of intellectual functioning that yields IQ scores for adults, including Verbal IQ (a measure of verbal abilities), Performance IQ (a measure of visual-spatial and motor functions), and Full-Scale IQ; Peabody Picture Vocabulary Test-Revised (23), a test of receptive vocabulary knowledge; Raven s Standard Progressive Matrices (24), a test of visual pattern completion that depends on physical matching for the easier patterns, and on more abstract problem-solving based on analogy for the more difficult problems; Controlled Oral Word Association Test (F-A-S) (25), a test requiring subjects to rapidly generate words beginning with particular letters that depends on control aspects of executive function (including attention, initiation, and retrieval processes) and on working memory; Wechsler Memory Scale- Revised (selected subtests) (26), a test that assesses ability to remember verbal (story) and visual (design) information and tests recall of information in immediate, delayed, and recognition memory formats; California Verbal Learning Test (27), a test of word list learning in which the individual is presented with the word list to learn over repeated trials, and for which memory for the list is tested in free and cued recall conditions after short and long delays and in a recognition memory format; Continuous Recognition Test (28), a test that requires the individual to view 120 drawings, many of which are repeated, and assesses attention to detail and visual memory; Trail Making Test (Parts A and B) (29), a test that involves attention and motor speed and, for Part B, the ability to shift-set (on Part A, the individual rapidly connects numbers that are randomly arrayed on a page, whereas on Part B, the individual rapidly connects the numbers and letters in alternating fashion, e.g. 1-A-2-B, etc.); and, Stroop Color and Word Test (30), a test that measures selective attention. On TABLE 1. Clinical descriptions of patients with GHD Diagnosis a Treatment b Other hormone deficiencies c NFA (n 19) S,R (n 13) A,T,G (n 24) PRL (n 11) S (n 14) T,G (n 6) Cranio (n 5) S,B (n 3) G (n 4) Cushing s (n 2) R,B (n 3) T (n 2) Idiopathic (n 2) S,R,B (n 2) A,T (n 1) Apoplexy (n 1) B (n 2) A,G (n 1) None (n 3) None (n 2) Total (n 40) Total (n 40) Total (n 40) a NFA, clinically nonfunctioning pituitary adenoma; PRL, prolactinoma; Cranio, craniopharyngioma; Idiopathic, idiopathic hypopituitarism. b S, surgery; R, radiation therapy; B, bromocriptine. c A, adrenal; T, thyroid; G, gonadal. this test, the individual s response rate is measured in three trials: color word naming, color naming, and an interference trial, in which the individual must name the color of ink that a conflicting color word is printed in (e.g. respond green when the word blue is printed in green ink). Sense of well-being Sense of well-being was assessed with four self-rating questionnaires, including Part 1 of the Nottingham Health Profile (NHP), the Psychological General Well-Being Schedule (PGWB), the General Health Questionnaire (GHQ), and the Minnesota Multiphasic Personality Inventory-2 (MMPI-2). The NHP (Galen Research, London, U.K.) assesses physical, emotional and social distress (31). Six subscales including emotions, pain, physical mobility, sleep, energy, and social isolation were derived. Analysis was based on the percentage of positive answers in each subscale, with a score higher than 0 indicating a compromised state. The PGWB is a self-assessed inventory concentrating on general well-being and included 22 items that regard anxiety, depressed mood, positive well-being, self-control, general health, and vitality (32). A total score is derived, and, the higher the score, the better the well-being. The GHQ elicits a response of 0 3 on each of 60 items and is designed to screen for and quantify changes in psychological status (33). The MMPI-2 is the most widely used of all written personality tests (34). It was constructed on principles of actuarial prediction, and rigorous statistical discrimination techniques were used to select the test items. The clinical scales were recently normalized on 2600 individuals representing a range of ages, ethnicity, education, income status, and geographic location in the United States (35, 36). We focused on three clinical scales, Hypochondriasis, Depression, and Hysteria, because elevated scores on these scales correlate with complaints of moderate emotional distress and multiple somatic complaints such as headache and insomnia. GH administration protocol After baseline psychometric testing, subjects were randomly assigned in a double-blind, placebo-controlled trial to receive daily recombinant human GH injections (Nutropin; Genentech, South San Francisco, CA) or placebo for 18 months as previously described (8). Neither the patients nor the psychologist administering the psychometric testing were aware of the treatment assignment. The initial starting dose was 10 g/kg per day self-administered at night sc. Patients returned at 1 week, 1 month, and 3, 6, and 12 months for outpatient measurement of serum insulin growth factor-i (IGF-I). The GH dose was reduced by 25% after any visit at which the serum IGF-I was found to be elevated. Each patient receiving placebo was asked to reduce his dose by 25% during the first 6 months of the study to maintain patient blinding. The mean GH dose at 18 months was 4 2 g/kg per day. Drug compliance was assessed by vial count. Psychometric and quality of life testing was repeated at the 18-month visit. The WAIS-R, Peabody Picture Vocabulary Test, Raven s Standard Progressive Matrices, and the California Verbal Learning Test were performed at 18 months on the first 24 subjects only. The other studies were performed on all subjects at 18 months. Biochemical assays Serum IGF-I was measured by RIA kit after acid-alcohol extraction (Nichols Institute, San Juan Capistrano, CA). The age-adjusted normal ranges for this assay were g/l for men aged yr and for men more than 40 yr. Interassay coefficients of variation were 5.2% and 8.4% at g/l and g/l, respectively. Changes from baseline to 18 months were compared between groups using a two-tailed Student s t test. P 0.05 was considered significant. For analysis of the NHP, changes in scores from baseline to 18 months were compared between groups using the Wilcoxon test. For analysis of the cognitive function tests, raw scores were converted to z-scores in order to use a standardized score. All data are presented as mean sem unless otherwise stated.

3 3186 BAUM ET AL. JCE&M 1998 Vol 83 No 9 Results Baseline evaluation Results of the baseline evaluation are presented in Table 2. There were no significant differences between the scores for men randomized to GH compared with placebo. Based on administration of the WAIS-R, the patient population displayed an overall mean Full-Scale IQ score of (z-score, ). With all subjects combined, mean scores on all cognitive tests fell within normal limits (defined as between 1 sd above and below the mean). As shown in Table 2, many of the mean scores on cognitive tests fell above the mean. In contrast, on the California Verbal Learning Test, mean learning and memory scores consistently fell below the mean, with generally higher recall errors than normal. In subjects with a history of radiation therapy, mean baseline scores on the cognitive tests were within normal limits (see Table 3). Cognitive test scores in patients with a history of radiation treatment were similar to those not treated with radiation except on the Controlled Oral Word Association Test, where patients with a history of radiation scored higher (see Table 3). As shown in Table 4, subscale scores for quality of life assessment using the NHP were similar between the GH and placebo groups at baseline except in the pain subscale, where the placebo subjects described more distress. Scores for the PGWB, GHQ, and MMPI-2 were similar between the GH and placebo groups at baseline. Biochemical results and side effects Serum IGF-I levels were similar in the GH group and the placebo group at baseline ( vs g/l) as previously reported (8). The mean IGF-I level increased significantly in patients receiving GH ( g/l, P ) and was significantly different from that in the patients receiving placebo at 18 months ( g/l, P ). Compliance with GH administration, based on vial count, was clinically evident, because all patients in the GH group required dose reductions caused by elevated IGF-I levels (8). Three patients receiving GH for 18 months experienced GH-related side effects: two patients developed edema, and one patient developed myalgias. All side effects occurred at a time when the serum IGF-I level was above the normal range and resolved with dose reduction. These adverse effects have been previously described (8). Five patients randomized to GH dropped out of the study. One patient dropped out at 3 months because of a seizure (his internist had stopped anticonvulsant therapy). Another subject dropped out after less than 1 month after starting the TABLE 2. Neurocognitive tests at baseline Test GH Placebo WAIS Full Scale IQ (standard score) Peabody Picture Vocabulary Test Revised Raven s Standard Progressive Matrices Controlled Oral Word Association Test (F-A-S) Wechsler Memory Scale Digit Span Forward Digit Span Backward Logical Memory I Logical Memory II Visual Memory Span Forward Visual Memory Span Backward Visual Reproduction I Visual Reproduction II California Verbal Learning Test Recall Measures: Overall Learning Score List A: Trial List A: Trial List B (Interference List) Short Delay Free Recall Short Delay Cued Recall Long Delay Free Recall Long Delay Cued Recall Recognition Measures: Recognition Hits Discriminability False Positives Response Bias Recall Errors: Perseverations Intrusions (Free Recall) Intrusions (Cued Recall) Continuous Recognition Test: Correct Response (std score) Stroop Color and Word Test: Interference Trail Making Tests Trails A Trails B Data are presented as z-scores ( SEM).

4 GH AND COGNITION 3187 TABLE 3. Effects of previous radiation therapy (RT) on neurocognitive function Test RT No RT WAIS Full Scale IQ (standard score) Peabody Picture Vocabulary Test Revised Raven s Standard Progressive Matrices Controlled Oral Word Association Test (F-A-S) a Wechsler Memory Scale Digit Span Forward Digit Span Backward Logical Memory I Logical Memory II Visual Memory Span Forward Visual Memory Span Backward Visual Reproduction I Visual Reproduction II California Verbal Learning Test Recall Measures: Overall Learning Score List A: Trial List A: Trial List B (Interference List) Short Delay Free Recall Short Delay Cued Recall Long Delay Free Recall Long Delay Cued Recall Recognition Measures: Recognition Hits Discriminability False Positives Response Bias Recall Errors: Perseverations Intrusions (Free Recall) Intrusions (Cued Recall) Continuous Recognition Test: Correct Response (std score) Stroop Color and Word Test: Interference Trail Making Tests Trails A Trails B Z-scores ( SEM). P TABLE 4. Results of self-assessements of NHP at baseline and after 18 months of GH or placebo administration in patients with GHD Subscales GH group Placebo group Baseline 18 months Baseline 18 months Emotional reactions ( ) ( ) Energy ( ) ( ) Pain a b ( ) ( ) Sleep ( ) ( ) Social Isolation ( ) ( ) Physical mobility ( ) ( ) Data are expressed as mean SEM. a P 0.05 compared with baseline value for placebo group. b P 0.05 for change from baseline to 18 months compared with placebo. Parentheses, mean change at 18 months SEM. study because of tachycardia. Another subject discontinued the study because of a cerebrovascular accident at 15 months. The other two were discontinued for nonmedical reasons. A subject randomized to placebo dropped out of the study at 3 months because of pneumonia. Testing of cognitive function and sense of well-being at 18 months Neurocognitive tests showed no significant changes in the z-scores tests following 18 months of GH administration compared with placebo.

5 3188 BAUM ET AL. JCE&M 1998 Vol 83 No 9 As shown in Table 4, there was no change in the quality of life subscales for emotional reactions, energy, sleep, social isolation, and physical mobility assessed by the NHP between GH and placebo groups following 18 months GH therapy. There was a significant difference between the groups at 18 months in the pain subscale (P 0.05), with a decrease in the description of pain in the placebo group and an increase in pain in the GH group. Scores for the PGWB and GHQ did not change significantly during the study compared with placebo (see Table 5). MMPI-2 scores did not significantly change, but, on the Hysteria scale, there was a small increase in report of adverse symptoms in the GH group that was significant when compared with the placebo group (P 0.03, Table 5). Discussion We assessed cognitive function and quality of life in men with adult-onset GHD both before and following GH replacement therapy for 18 months. We are unaware of previous controlled long-term studies that have evaluated cognitive function extensively in GH-treated patients with adult-onset GHD. Performance on all tests at baseline in the 40 GHD patients, which included tests of intelligence, language, memory, attention, and abstract reasoning, as well as personality and perceived health and quality of life, fell within normal limits, and, on many tests, above the mean. On a test of verbal learning and memory and on two tests of visual memory, mean level of performance fell slightly below the mean as compared with a standardized population, although within normal limits. In this randomized, placebocontrolled study of GH therapy in GHD adult men, 18 months of GH administration was not associated with cognitive improvements compared with placebo. Similarly, administration of physiological GH therapy did not alter quality of life assessment compared with controls. Our data do not demonstrate a significant beneficial effect of GH therapy on cognitive function and sense of well-being in men with adult-onset GHD. Baseline cognitive testing showed a relative impairment in TABLE 5. Results of self-assessements of sense of well-being using Psychological General Well-Being Schedule, General Health Questionnaire, and MMPI at baseline and after 18 months of GH or placebo administration in patients with GHD Test GH group Placebo group Baseline 18 Months Baseline 18 Months Psychological General Well-Being Schedule (maximum 110) General Health Questionnaire (maximum 180) MMPI-2 (T-scores: mean 50, SD 10) Hypochondriasis Depression Hysteria a Data are presented as mean SD. a P 0.03 for change from baseline to 18 months compared with placebo. performance on tests of verbal learning and visual memory compared with performance on all other cognitive tests administered. This finding suggests that in adult men with GHD, the ability to learn and remember new information may be mildly compromised. In a previous study of 104 community-dwelling men over 69 yr old, serum IGF-I levels correlated with performance on the Digital Symbol Substitution test (37) but not with other cognitive tests. In our study, a previous history of radiation therapy to the sella was not associated a deleterious effect on cognitive function. GH replacement therapy for 18 months at physiological doses did not lead to an overall improvement in cognitive function in our patients, who were already performing generally at or above the mean on most cognitive measures. In a study by Papadakis et al. (38), GH was administered at a dose of 0.03 mg/kg to older men with low serum IGF-I levels. Following 6 months of therapy, there was a significant increase only in the Trails B Test, a test of attention and motor speed. Of note, in this study there was a significant occurrence of adverse effects. The lack of improvement in our subjects may reflect the fact that GH, when administered at replacement, physiological doses, either does not significantly affect the cognitive state or requires a longer duration of administration. Previous studies have suggested that GHD is associated with a reduced quality of life. In studies using the NHP to assess quality of life, patients with GHD scored higher than normals, suggesting that such patients perceive themselves as being more emotionally labile, more socially isolated, and less energetic than controls (17, 18) In another study of 36 men and women with GHD, subjects significantly deviated from the reference population in energy and emotional reaction using the NHP (39). In that study, there was a trend for worse scores for women. It is therefore possible that there is a gender-specific effect of GHD on quality of life, and that men may demonstrate more subtle or no alterations. Quality of life did not improve in our subjects following administration of GH therapy at physiological doses for 18 months. Previous studies, which were all shorter than 1 year and which used higher doses of GH than given in our study, have shown a benefit of GH therapy on sense of well-being. McGauley (17) administered GH (0.025 mg/kg) in a doubleblind, placebo-controlled trial to 24 GHD subjects (gender unspecified) for 6 months. Scores on the NHP and the Psychological General Well-Being Schedule improved significantly in these patients. Bengtsson et al. (20) administered GH at a dose of mg/kg in a double-blind, cross-over, placebo-controlled trial for 6 months to 9 GHD subjects, including 8 men, and showed an improvement on the Comprehensive Psychological Rating Scale in 7 men. In contrast, Burman et al. (39) administered GH (2 U/m 2 ) for 9 months in a double-blind, placebo-controlled trial to 36 GHD subjects, including 21 men. NHP scores were higher than normal, and there was a tendency toward higher ratios in women than men. The group did not demonstrate improvement on the NHP compared with placebo. Because studies that have demonstrated a benefit in sense of well-being used much higher doses of GH than used in the present study, it is possible that the psychological benefits seen in these previous studies are pharmacological effects, or may reflect the fact that patients on the drug may know that they are re-

6 GH AND COGNITION 3189 ceiving the medication, with resultant bias. In the current study, doses of GH were adjusted to maintain IGF-I levels in the normal, physiological range. As a result, only 3 of 20 patients randomized to GH experienced transient side effects, thereby minimizing this concern. Several recent randomized, placebo-controlled studies for 6 months have shown no consistent GH treatment effect on sense of wellbeing as assessed by NHP. In the study by Cuneo et al. (40), mean baseline NHP scores in a study group of 166 patients were low, indicating little or no impairment. Although during the initial controlled 6-month period there was a suggested decrease in perceived pain in the GH group, no treatment effect on the emotional reactions subscale was demonstrated. In contrast, NHP scores in the study by Attanasio et al. (41) were higher in GHD adults compared with controls. Significant improvements in physical mobility and energy were only seen at 18 months, following a 12-month, open-label treatment period. Therefore, in a number of studies, a consistent positive effect of GH therapy on quality of life was demonstrated primarily following an open-label treatment period. Our study shows no indication that in a controlled study prolonged therapy with GH for up to 18 months has any additional, beneficial effect on quality of life. It is also possible that the instruments used in our study to assess quality of life may have been relatively insensitive in demonstrating minor beneficial effects of GH administration on sense of well-being. These data demonstrate that men with adult-onset GHD perform normally on tests of IQ and cognitive functioning. The performance of our patients on particular tests of memory and learning, although normal, were low relative to performance on other cognitive tests. 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