Effects of Growth Hormone–Releasing Hormone on Cognitive Function in Adults With Mild Cognitive Impairment and Healthy Older Adults

Growth hormone–releasing hormone (GHRH), growth hormone, and insulinlike growth factor 1 have potent effects on brain function, their levels decrease with advancing age, and they likely play a role in the pathogenesis of Alzheimer disease. Previously, we reported favorable cognitive effects of short-term GHRH administration in healthy older adults and provided preliminary evidence to suggest a similar benefit in adults with mild cognitive impairment (MCI).

Randomized, double-blind, placebo-controlled trial.

A total of 152 adults (66 with MCI) ranging in age from 55 to 87 years (mean age, 68 years); 137 adults (76 healthy participants and 61 participants with MCI) successfully completed the study.

Primary cognitive outcomes were analyzed using analysis of variance and included 3 composites reflecting executive function, verbal memory, and visual memory. Executive function was assessed with Stroop Color-Word Interference, Task Switching, the Self-Ordered Pointing Test, and Word Fluency, verbal memory was assessed with Story Recall and the Hopkins Verbal Learning Test, and visual memory was assessed with the Visual-Spatial Learning Test and Delayed Match-to-Sample.

Twenty weeks of GHRH administration had favorable effects on cognition in both adults with MCI and healthy older adults. Longer-duration treatment trials are needed to further examine the therapeutic potential of GHRH administration on brain health during normal aging and “pathological aging.”

Participants were randomly assigned to either group using a 1:1 ratio in blocks of 4 to receive 1.0 mg/d of tesamorelin (hereafter referred to as GHRH) or placebo as a subcutaneous injection 30 minutes before bedtime for 20 weeks. Treatment allocation was stratified by diagnosis, sex, and estrogen use. Outcomes were assessed between 8 and 10 AM at baseline, at weeks 10 and 20, and again 10 weeks after treatment was discontinued (week 30). Before and after treatment, participants received an oral glucose tolerance test (OGTT) and a dual-energy x-ray absorptiometry scan. Participants and study personnel involved in data collection were blinded to treatment assignment.

Story Recall and the Hopkins Verbal Learning Test were administered to assess verbal memory, and the Visual-Spatial Learning Test 53 , 54 and Delayed Match-to-Sample 55 were administered to assess visual memory. For Story Recall, participants heard a narrative containing 40 informational bits and then re-called as much as possible immediately and after a 25-minute delay. Credit was awarded for verbatim recall and accurate paraphrases. For the Hopkins Verbal Learning Test, participants heard 16 words and recalled as many items as possible across 3 learning trials and then again after a 25-minute delay. For both verbal memory tests, total recall (immediate + delayed) was analyzed. For the Visual-Spatial Learning Test, a visual analog of the Hopkins Verbal Learning Test, participants viewed 8 designs that were placed on a 5 × 6 array for 10 seconds. The designs were then removed and mixed with 8 distractors, and participants selected the 8 studied designs and placed them in their correct positions on the array; this procedure was repeated 2 additional times. After a 25-minute delay, participants again selected the 8 designs from the distractors and placed them in their remembered locations on the array, and total recall of correct design paired with correct location was recorded. For Delayed Match-to-Sample, 20 abstract geometric designs were presented in series for 10 seconds on a touch-screen monitor. Following a 25-minute delay, 20 design triplets were displayed in series, and participants touched the single design per set that was previously studied.

Insulin sensitivity, glucose tolerance, and adiposity were measured in light of well-established GH effects on energy metabolism. Participants completed an OGTT during screening and at week 20. Following a 12-hour fast, blood samples were collected for glucose and insulin measurements; participants then consumed a 75-g dextrose solution, and blood samples were obtained 60 and 120 minutes later. At screening, participants meeting the American Diabetes Association standard glycemic criterion for diabetes, which is indicated by a fasting plasma glucose level greater than 125 mg/dL (to convert to millimoles per liter, multiply by 0.0555) or a 2-hour OGTT glucose level exceeding 199 pg/mL, were excluded from enrollment. At baseline and week 20, dual-energy x-ray absorptiometry scans were performed to quantify body fat and lean muscle mass.

Circulating levels of IGF-1 were measured before study entry at screening and baseline. At weeks 2, 4, 8, 10, 16, and 20, IGF-1 was measured to ensure levels were within the physiologic range, adverse events were assessed, a brief physical examination was performed, and changes in medications, exercise regime, or health status were recorded. When an adverse event became problematic for a participant, the dose was reduced by 0.25 mg/d by a physician investigator blinded to treatment group assignment. A separate, unblinded physician investigator (G.R.M.) with no direct contact with participants or psychometrists adjusted the dose either when achieved IGF-1 exceeded physiologic levels or when IGF-1 failed to increase by at least 15% over baseline for participants in the active group. Each of these GHRH dose adjustments was yoked with a similar adjustment for a placebo-treated participant to maintain the blind for participants, staff, and other investigators. Compliance was monitored during study visits via the number of returned vials and the number of entries in a self-reported log.

COGNITION For the intent-to-treat analysis, the omnibus multivariate analysis of variance on the 3 composite scores indicated favorable effects on cognitive function at week 20 over baseline for adults allocated to receive GHRH vs placebo ( F 3,133 = 3.11, P = .03). Although overall cognitive performance differed by diagnosis, as expected ( F 3,133 = 5.97, P < .001), GHRH had comparable beneficial effects both in healthy older adults and in adults with MCI (no treatment × diagnosis interaction; P = .22), consistent with predictions based on our earlier work (ie, comparable GHRH effects observed for participants with higher and lower MMSE scores). 31 For the completer analysis, missing data did not exceed 5%, and the omnibus multivariate analysis of variance produced a similar but more robust pattern of results. Treatment with GHRH had a favorable effect on cognition ( F 3,125 = 5.26, P = .002), and even though the healthy adults outperformed those with MCI overall ( F 3,125 = 11.15, P < .001), the cognitive benefit relative to placebo was comparable for both groups (no treatment × diagnosis interaction; P = .57). The results of the completer analysis indicated similar GHRH benefits at weeks 10 and 20 (no interaction involving week on treatment). Education was included as a covariate in the intent-to-treat and completer analyses (together with age and baseline MMSE score), whereas sex was not. Separate univariate analyses on the constituent composites scores indicated a GHRH-related improvement in normal controls and attenuation of decline in adults with MCI for executive function (effect size: f = 0.37, F 1,127 = 8.34, P = .005; Figure 2A ) and a trend showing the same pattern of results for verbal memory (effect size: f = 0.24, F 1,130 = 3.09, P = .08; Figure 2B ). For both analyses, favorable effects were comparable in adults with MCI and in normal controls (no treatment × diagnosis interaction; P > .27). Visual memory was not reliably affected by treatment with GHRH in our study ( P > .15), likely in part owing to the high variability in scores and the near-chance performances on the Delayed Match-to-Sample. For the executive function and verbal memory composites, further inspection of the mean change z scores for the constituent tests indicated a positive influence of GHRH on all but Word Fluency ( Table 2 ). Exploratory analyses of week-30 washout data (change scores relative to baseline) using analysis of variance suggested a lingering GHRH-related benefit for executive function ( P = .08) but not verbal memory ( P = .32).

Serum levels of IGF-1 increased by 117% with GHRH administration ( F 1,131 = 109.73, P < .001), with no interaction involving week on treatment or diagnosis ( Figure 3 ) indicating comparable effects at weeks 10 and 20 in adults with MCI and normal controls. The IGF-1 response to GHRH did not differ by sex ( P = .69). Ten weeks after termination of treatment (week 30), IGF-1 concentration returned to basal levels. For the entire sample, treatment-related increases in serum IGF-I were associated with higher executive function composite change scores ( r = 0.2, P = .03), but there were no other associations involving cognition and IGF-1. Treatment with GHRH increased fasting plasma insulin levels in adults with MCI but not in normal controls (treatment × diagnosis interaction, F 1,128 = 6.94, P = .005; the mean [SD] values were −0.20 [1.2] ng/mL for normal controls who received placebo and −0.02 [0.9] ng/mL for normal controls who received GHRH [ P = .95], and the mean [SD] values were −1.91 [10.5] ng/mL for adults with MCI who received placebo and 2.32 [12.5] ng/mL for adults with MCI who received GHRH [ P < .001]). Fasting plasma glucose, glycosylated hemoglobin A 1c , and 2-hour OGTT glucose and insulin responses were not affected by treatment. Treatment with GHRH reduced body fat by 7.4% ( F 1,129 = 41.30, P < .001) and increased lean muscle mass by 3.7% ( F 1,129 = 27.60, P < .001), and these effects were similar in adults with MCI and normal controls, and in both men and women. The GHRH-related changes in fasting plasma insulin level and body composition were not correlated with the treatment-related change in cognition for the entire group or within subgroups defined by diagnosis. To examine potential moderators of cognitive response, analyses of composites were rerun, including treatment-related changes in fasting insulin level, body composition, and IGF-1 level as covariates. When the omnibus models were adjusted for IGF-1 concentration, the GHRH effect on cognition was no longer apparent; treatment effects on fasting insulin level or body composition were not contributory. In the executive function analysis of variance, a similar pattern of results was observed, whereas, for verbal memory, the treatment effect was equally attenuated when the analysis of variance was adjusted for IGF-1 level or for insulin level.

We examined the effects of treatment with GHRH on cognition and serum IGF-1 level in healthy older adults and adults with amnestic MCI in light of our previous findings showing treatment benefits for those with lower baseline MMSE scores and reports by others linking lower IGF-1 levels with poorer cognitive performance. 11 , 13 , 32 – 34 Five months of daily subcutaneous injections of GHRH increased circulating IGF-1 to young adult normal levels and had a favorable effect on executive function in adults with MCI and healthy older adults. A trend indicated a positive GHRH effect on verbal memory. Although treatment with GHRH reduced body fat and increased lean muscle mass, these effects did not modulate cognitive response. To our knowledge, there are only 2 other randomized controlled studies examining the cognitive effects of an intervention that promotes natural stimulation of GH secretion in older adults: our first 5-month trial of GHRH administration in cognitively normal adults 31 and a large, multisite 12-month trial of a ghrelin mimetic in patients with mild to moderate AD. 59 In the present study, we used a different GHRH analog than that administered in our previous trial 31 in light of its preferred safety profile and robust IGF-1–elevating effect, we refined the cognitive battery to better assess executive function and episodic memory, and we expanded the sample to include older adults with MCI. Although we cannot make head-to-head comparisons of GHRH effects on specific cognitive tests across our 2 trials, the therapeutic promise of GHRH is strengthened by the consistency of overall findings. In the AD trial, 59 the hormone administered was an orally active GH secretagogue (MK-677) and biologically similar to ghrelin, which is produced by the stomach. MK-677 increased serum IGF-1 concentrations by 73% at 12 months, but the results of the primary analyses indicated no treatment effects on disease progression as measured by standard outcomes in AD clinical trials. The results of the clinician-based assessment at 12 months, however, indicated a trend for improvement ( P = .06) in the MK-677 group, particularly for noncarriers of the apolipoprotein E (APOE) ε4 allele (ie, ε4-negative adults). Although APOE genotyping was not performed in our study, it is possible that a high proportion of our participants were noncarriers of the ε4 allele, given the inclusion of a sizeable group of well-characterized cognitively normal participants who are less likely to be ε4 carriers. 60 Other differences between our study and the MK-677 study relate to the specific hormone administered (GHRH vs ghrelin mimetic), with different physiological effects (MK-677 increased blood glucose levels and hemoglobin A 1c levels, and GHRH did not), treatment efficacy on serum IGF-1 level (117% with GHRH vs 73% with MK-677), and sensitivity of cognitive outcomes to treatment effects on executive function and episodic memory. Despite methodological dissimilarities in the 2 trials, it may be that the key difference is the timing of the intervention relative to stage of disease, such that stimulation and restoration of GH and IGF-1 activities result in beneficial effects but only when pathologic processes that cause decline in cognitive function can still be prevented, delayed, or reversed. In our study, treatment with GHRH increased fasting plasma insulin levels in adults with MCI but not in normal controls. Insulinlike growth factor 1 and insulin have similar metabolic effects, 61 and IGF-1 is a potent insulin sensitizer. 62 Early AD pathology is linked to subclinical changes in insulin activity in the periphery and in the central nervous system 63 , 64 such that adults with amnestic MCI may be particularly sensitive to metabolic changes affecting insulin availability. 28 , 65 Our data suggest that IGF-1 plays a role in treatment response on executive function, whereas, for verbal memory, both IGF-1 and insulin are likely to contribute. Although speculative, GHRH-stimulated increases in circulating insulin may help to override the early negative effects of AD pathology to boost performance on abilities (such as declarative memory) that are particularly sensitive to insulin-related dysfunction. 47 Although somatotrophic hormone levels decrease with advancing age, 5 , 6 with a potential adverse effect on cognition, 5 , 6 , 11 – 13 lower GH and IGF-1 levels are not always associated with negative consequences. In animal models of GH and IGF-1 deficiency and in studies of caloric restriction, reduced GH and IGF-1 levels and activity are associated with a longer life span. 66 , 67 Moreover, transgenic mice that produce abnormally high levels of GH and IGF-1 have a shorter life span and early age-related cognitive changes. 68 The relationship between lower levels of IGF-1 and “delayed aging,” attributed to improved insulin signaling and glucose metabolism, 66 contrasts with reports in human studies indicating no effect of caloric restric