Long-term growth hormone treatment preserves GH-induced memory and mood improvements: a 10-year follow-up study in GH-deficient adult men
Introduction
The condition of growth hormone deficiency in adults is accepted as a clinical syndrome involving physical and psychological symptoms (Cuneo et al., 1992). The most apparent symptoms include altered body composition (low lean body mass, low muscle mass and high fat mass), low bone mineral density (BMD), altered lipid profile, as well as reduced sense of psychological well-being, including impaired cognitive functioning (De Boer et al., 1995). Replacement with recombinant human growth hormone (GH) has been shown to reduce or even counteract these physical, mood, and cognitive impairments (Baum et al., 1996, Johannsson et al., 1996).
The level of insulin-like growth factor I (IGF-I), a serum marker for GH status, appears to be positively related to mood and cognitive functioning. The activity of the GH-IGF-I axis declines with aging. Studies in healthy elderly subjects reveal a positive correlation between IGF-I levels and scores for the Mini Mental State Examination (MMSE) (Rollero et al., 1998) for short-term memory tasks and for cognitive flexibility tasks (Aleman et al., 2000). GH substitution in GH-deficient (GHD) patients and healthy men appears to be beneficial for cognitive functioning, as assessed by tasks measuring attention, memory, and perceptual motor skill (Almqvist et al., 1986, Deijen et al., 1998, Papadakis et al., 1996). In addition, GH treatment is associated with lower stress levels during intellectual performance (Sartorio et al., 1995). These findings indicate that patients with GHD exhibit an impaired Quality of Life (QoL) and that GH substitution improves this condition (Björk et al., 1989, Degerblad et al., 1990, McGauley, 1989). QoL relates to social and psychological well-being, as assessed from the patient's perspective. Elements that contribute to an individual's QoL, with particular relevance to patients with GH deficiency, are their levels of emotional, cognitive, and social functioning (McGauley et al., 1996).
Patients with GHD can be divided in two different groups based on the extent of pituitary failure: isolated GH-deficient (IGHD), in which only the GH secretion is insufficient, and multiple pituitary-hormone-deficient (MPHD), in which there is impaired GH secretion and also an impaired secretion of other pituitary hormones (i.e., ACTH, TSH, gonadotropins). While both groups are cognitively impaired, they have been shown to be quite distinct with respect to psychological functioning, since MPHD patients are also impaired in terms of their psychological well-being (Deijen et al., 1996).
As yet, the exact mechanism behind the relation between GH and cognitive functioning is not understood. However, there are indications that both GH and IGF-I can cross the blood–brain barrier (Han, 1995, Johansson and Bengtsson, 1997) and binding sites for GH and IGF-I have been shown to be present in the choroid plexus, hypothalamus, putamen, thalamus, and the hippocampus (Adem et al., 1989, Nyberg, 2000). Moreover, GH treatment has been found to reduce the concentration of a dopamine (DA) metabolite, homovanillic acid (HVA), in cerebrospinal fluid (Burman et al., 1993). The hippocampus is known to contain high levels of DA (Lloyd and Hornykiewicz, 1972). As both the hippocampus and DA are involved in learning and memory (Beninger, 1989), a change in the availability of GH in the hippocampus may influence memory processes by altering the DA turnover in that area of the brain (Deijen et al., 1996).
With respect to the psychological effects of GH replacement, at least 6 months of such treatment is known to induce positive effects on QoL (Deijen et al., 1998). Furthermore, a decrease in QoL is seen 6 months after the discontinuation of GH, and this effect disappears again after at least 6 months of renewed GH treatment (Sartorio et al., 1995, Stouthart et al., 2003). Mood in particular is improved after 6 months of treatment, whereas an improvement in cognitive functions seems to require a longer period of treatment of at least 1 year (Deijen et al., 1998, Stouthart et al., 2003).
Long-term studies are important in terms of defining the safety limits and long-term effects of GH replacement. Experience with long-term GH therapy in adults is limited, and only one 10-year follow-up study has been published to date. This study, carried out in 10 GHD adults, indicated that a decade of GH treatment increases lean body mass and muscle mass while reducing atherogenic lipid profile and carotid intima media thickness. Well-being also improved, as measured by the Nottingham Health Profile (Gibney et al., 1999). However, cognitive functioning was not measured in this study.
The objective of the present study was to determine the effects of 10 years of GH therapy on memory and mood in GHD patients and to determine whether normalization of IGF-I levels during this 10-year period is associated with changes in the indices for mood and cognition. Our hypothesis is that GH substitution in childhood-onset GHD patients will improve mood and memory. We expected to observe mood improvements before the improvement of memory and that these psychological improvements would stabilize and be maintained during the long-term treatment period.
Section snippets
Design
The study, which was initially started as a 6-month placebo-controlled trial, continued as an open-label study (Deijen et al., 1996). For the placebo group, the starting point of the study was at 6 months. GH substitution continued and psychological functions were assessed during 10 years of follow-up. Fifty adult men with childhood-onset GHD were included at the start of the study as described previously (De Boer et al., 1996). Thirty-eight patients were studied for a follow-up period of 39–69
GH status
Mean serum IGF-I levels were the same in the IGHD and MPHD group at all time points. Mean values of the total group are shown in Table 1. All IGF-I measurements were significantly higher than those at baseline, F(6,189) = 24.14, P < 0.0005. IGF-I values at 10 years were lower than those at 5 years, F(1) = 15.28, P = 0.001.
Mood and memory
Compared to the pre-treatment scores, the following treatment effects were found for mood and memory. Mean values (±SEM) of the different test scores are shown in Table 2.
Discussion
In the present study, the effects of 10 years of GH substitution on mood and memory were studied in 23 childhood-onset GHD men. From this long-term follow-up study, it can be concluded that cognitive functioning and mood state improved over time throughout the 10-year follow-up period. Post-treatment health status parameters had improved relative to the pre-treatment situation. These improvements concern mood parameters such as psychic complaints, anxiety, tension, and vigor. Short-term and
References (40)
- et al.
Insulin-like growth factor 1 (IGF-1) receptors in the human brain: quantitative autoradiographic localization
Brain Res.
(1989) - et al.
Effects of growth hormone substitution on mental performance in adults with growth hormone deficiency: a pilot study
Psychoneuroendocrinology
(1986) Dissociating the effects of altered dopaminergic function on performance and learning
Brain Res. Bull.
(1989)- et al.
Effect of growth hormone on brain neurotransmitters
Lancet
(1993) - et al.
Cognitive impairments and mood disturbances in growth hormone deficient men
Psychoneuroendocrinology
(1996) - et al.
Cognitive changes during growth hormone replacement in adult men
Psychoneuroendocrinology
(1998) Growth hormone in the brain: characteristics of specific brain targets for the hormone and their functional significance
Front. Neuroendocrinol.
(2000)- et al.
Quality of life of growth hormone (GH) deficient young adults during discontinuation and restart of GH therapy
Psychoneurendocrinology
(2003) - et al.
Bidirectional modulation of basal forebrain N-methyl-d-aspertate receptor function differentially affects visual attention but not visual discrimination performance
Neuroscience
(2001) - et al.
Age-sensitive cognitive function, growth hormone and insulin-like growth factor 1 plasma levels in healthy older men
Neuropsychobiology
(2000)
One-year follow-up of quality of life in adults with untreated growth hormone deficiency
Clin. Endocrinol.
Effects of physiologic growth hormone therapy on bone density and body composition in patients with adult-onset growth hormone deficiency: a randomized, placebo-controlled trial
Ann. Intern. Med.
Quality of life of adults with growth hormone deficiency: a controlled study
Acta Paediatr. Scand.
Growth hormone treatment affects brain neurotransmitters and thyroxine
Clin. Endocrinol.
The growth hormone deficiency syndrome in adults
Clin. Endocrinol.
Clinical aspects of growth hormone deficiency in adults
Endocr. Rev.
Monitoring of growth hormone replacement therapy in adults, based on measurement of serum markers
J. Clin. Endocrinol. Metab.
Physical and psychological capabilities during substitution therapy with recombinant growth hormone in adults with growth hormone deficiency
Acta Endocrinol.
The Hopkins Symptom Checklist (HSCL): a self-report symptom inventory
Behav. Sci.
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