Growth hormone releasing hormone improves the cognition of healthy older adults

Abstract

Declines in the activity of the somatotrophic axis have been implicated in the age-related changes observed in a number of physiological functions, including cognition. Such age-related changes may be arrested or partially reversed by hormonal supplementation. We examined the effect of 6 months treatment with daily growth hormone releasing hormone (GHRH) or placebo on the cognition of a group of 89 healthy older (68.0 ± 0.7) adults. GHRH resulted in improved performance on WAIS-R performance IQ (p < 0.01), WAIS-R picture arrangement (p < 0.01), finding A's (p < 0.01), verbal sets (p < 0.01) and single–dual task (p < 0.04). GHRH-based improvements were independent of gender, estrogen status or baseline cognitive capacity. These results demonstrate that the age-related decline in the somatotrophic axis may be related to age-related decline in cognition. Further they indicate that supplementation of this neuro-hormonal axis may partially ameliorate such cognitive declines in healthy normal older adults and potentially in individuals with impaired cognitive function (i.e., mild cognitive impairment and Alzheimer's disease).

Introduction

It has been suggested that the declines in growth hormone (GH) and insulin-like growth factor I (IGF-I) observed with advancing age may contribute to the impaired cognitive function associated with aging [2], [17], [26] and perhaps to that seen in neurodegenerative diseases such as Alzheimer's disease [4], [5], [9]. GH and IGF-I are present in the plasma and the cerebrospinal fluid, and both have binding sites in the CNS, including in the choroid plexus and particularly in the hippocampus, a brain structure crucial to learning and memory [1], [8], [14]. Significant negative correlations have been observed between advancing age and the density of GH binding sites, especially in the pituitary, hypothalamus and hippocampus [10], [15].

Sonntag has recently reviewed the interactions of GH, IGF-I and brain aging [21], [22]. He noted that studies in aged rodents have demonstrated that administration of GH, IGF-I or GHRH results in: (1) increased cortical microvascular density and inferred cerebral blood flow [23]; (2) increased cortical glucose metabolism [12]; (3) amelioration of age-related declines in hippocampal neurogenesis [11]; and (4) reversal of age-related declines of spatial and reference memory [24], [25].

GH deficient (GHD) children have significant cognitive deficits, which may be moderated by GH treatment [19], [27]. Cognitive deficits are also seen in GH deficient adults [6], [7], [19], [20] and can be normalized by GH therapy [7], [20]. Several studies have reported positive correlations between IGF-I and cognition in the healthy elderly [2], [18], [28], particularly those involving processing speed. While there have been no previous direct examinations of the effect of GHRH treatment on cognitive function, aside from the current study, the effect of somatotrophic axis supplementation by GH treatment has been explored. Three recent, placebo-controlled trials [7], [16], [18] of GH, rather than GHRH treatment, of 6–24 months duration in GHD adults reported improved cognitive function; although a fourth, similar, placebo-controlled GH treatment study [3] observed no such improvement after 18 months of treatment.

Given the emerging evidence in support of the likelihood that stimulating the somatotrophic axis can influence cognition, an obvious and important question that the current study seeks to answer is whether somatotrophic supplementation can improve cognitive function in healthy older adults. The current study employs GHRH rather than GH to augment the somatotrophic axis. This use of GHRH has several advantages [13]. For one, GHRH, depending on its exact formulation, produces either a brief pulse of GH secretion, or a train of pulses, generally resembling physiological pulsatile GH secretion, rather than a prolonged rise in GH levels as seen with GH supplementation. This is important since, in other contexts, the pattern as well as the quantity of GH delivered has been found to modulate its effects. Also, when a secretagogue such as GHRH is used, the normal negative feedback regulation by IGF-I on pituitary GH secretion is preserved, offering at least some relative buffering against overdosing. Thus, GHRH provides a more “normal physiologic” boost to GH secretion than GH itself, which is potentially important in any study population but perhaps more so in the senior population where somatotrophic axis activity is compromised [13].

Here we report the results of a prospective, randomized, placebo-controlled, double-blinded study of the effects of 6 months of GHRH treatment on the cognitive function of healthy older men and women.