Effects of growth hormone–releasing hormone on cognitive function in adults with mild cognitive impairment and healthy older adults: results of a controlled trial

Abstract

Background: Growth hormone–releasing hormone(GHRH), growth hormone, and insulin like 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).

Objective: To examine the effects of GHRH on cognitive function in healthy older adults and in adults with MCI.

Design: Randomized,double-blind,placebo-controlled trial.

Setting: Clinical Research Center, University of Washington School of Medicine in Seattle.

Participants: 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.

Intervention: Participants self-administered daily subcutaneous injections of tesamorelin (Theratechnologies Inc),a stabilized analog of human GHRH (1 mg/d), or placebo 30 minutes before bedtime for 20 weeks. At baseline, at weeks 10 and 20 of treatment, and after a 10-week washout(week 30), blood samples were collected, and parallel versions of a cognitive battery were administered. Before and after the 20-week intervention, participants completed an oral glucose tolerance test and a dual-energy x-ray absorptiometry scan to measure body composition.

Main outcome measures: 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.

Results: The intent-to-treat analysis indicated a favorable effect of GHRH on cognition (P=.03), which was comparable in adults with MCI and healthy older adults.The completer analysis showed a similar pattern, with a more robust GHRH effect (P=.002). Subsequent analyses indicated a positive GHRH effect on executive function (P=.005) and a trend showing a similar treatment-related benefit in verbal memory(P=.08). Treatment with GHRH increased insulin like growth factor 1 levels by 117 %(P.001), which remained within the physiological range, and reduced percent body fat by 7.4%(P.001). Treatment with GHRH increased fasting insulin levels within the normal range by 35%in adults with MCI (P.001) but not in healthy adults. Adverse events were mild and were reported by 68%of GHRH treated adults and 36% of those who received placebo.

Conclusions: 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.”

Trial registration: clinicaltrials.gov Identifier: NCT00257712

Figure 1

Consolidated Standards of Reporting Trials flow diagram of healthy older adults and adults with mild cognitive impairment (MCI). AE indicates adverse event; GHRH, growth hormone–releasing hormone; and IGF-1, insulinlike growth factor 1.

Figure 2

Cognitive response to growth hormone–releasing hormone (GHRH). Mean z scores representing change from baseline in composites of executive function (A) and verbal memory (B), expressed as residualized change scores. Treatment with GHRH had favorable effects on executive function (P = .005) as measured by Task Switching accuracy, Stroop Color-Word Interference reaction time (voice onset latency) on “interference” trials, Self-Ordered Pointing Test accuracy, and Word Fluency. A similar trend was observed for verbal memory (P = .08) as measured by total recall (immediate + delayed) on the Hopkins Verbal Learning Test and total Story Recall. Pairwise comparisons between subgroups defined by diagnosis are not presented because the main finding indicates a treatment effect for the groups combined and no treatment × diagnosis interaction. Visual memory did not benefit from GHRH administration. Error bars indicate standard error of the mean. MCI indicates mild cognitive impairment.

Figure 3

Mean serum insulinlike growth factor 1 (IGF-1) levels at baseline (week 0) and at weeks 10 and 20 (to convert to nanomoles per liter, multiply by 0.131). The IGF-1 levels increased with the administration of growth hormone–releasing hormone (GHRH) (P < .001), with no differences observed as a function of time (week 10 vs week 20) or diagnosis (healthy vs mild cognitive impairment [MCI]). Error bars indicate standard error of the mean.