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doi: 10.1097/01.NT.0000420995.78613.fe
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Can a Growth Hormone-Stimulating Drug Improve Cognitive Function?

Fitzgerald, Susan

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ARTICLE IN BRIEF

Investigators reported that study participants (including both healthy participants and those with mild cognitive impairment) that took growth hormone-releasing hormone showed improvements in executive function — primarily in areas of planning, focus, and selective attention.

A once-a-day injection of a hormone-stimulating drug could help improve cognitive function in both healthy older people and those who have mild cognitive impairment (MCI), according to a new study by University of Washington researchers.

Study participants who gave themselves a daily shot of growth hormone-releasing hormone (GHRH) for 20 weeks showed improvement on tests to measure executive function and verbal memory.

The findings, published in the Aug. 6 online edition of the Archives of Neurology, might sound as if researchers found a way to slow the ravages of aging. But the research team cautioned that GHRH needs to be further tested.

“GHRH administration has favorable effects on cognitive function not only in healthy older adults but in adults at increased risk of cognitive decline and dementia,” they concluded. “Larger and long-duration treatment trials are needed to firmly establish the therapeutic potential of GHRH administration to promote brain health in normal aging and ‘pathological aging.’”

Laura D. Baker, PhD, the study's lead author, told Neurology Today that her group now plans to test GHRH in older adults with MCI and in healthy older adults who have a first-degree relative with Alzheimer's dementia.

“We're not there yet,” Dr. Baker, associate professor of psychiatry and behavioral science, said of the study's clinical implications. “We need longer-term administration of the drug to test efficacy and safety.”

Heather Snyder, PhD, senior associate director of medical and scientific relations at the Alzheimer's Association, said the new research on GHRH is interesting, but she agreed that additional research is needed to determine whether the drug could be clinically useful to patients.

“This research is too preliminary to have an impact on clinical practice,” Dr. Snyder told Neurology Today. “This is a single study that we need to see replicated in a larger, more diverse population to better understand the possible benefits or side effects — either or both of which may emerge with further testing. There is not enough evidence or data yet to comment on what these may be.”

In the medical literature, there have been long-term risks associated with and reported with use of GHRH — particularly, in children being treated for idiopathic short stature, Turner's syndrome, and pediatric Crohn's disease, for example — including insulin resistance, intracranial hypertension, increased mortality, and bone and other tumors.[See “References.”]

Some so-called anti-aging experts and clinics have also prescribed human growth hormone off-label — it is not FDA-approved for “anti-aging” — with unproven claims that the products reverse age-related deterioration.

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RATIONALE FOR STUDY

Why did the investigators focus on GHRH? In the new report, the study authors explained that GHRH stimulates the release of growth hormone from the pituitary, which in turn stimulates an increase in the production and release of insulin-like growth factor 1 (IGF-1) from the liver. The three hormones “have potent effects on brain function, their levels decrease with age, and they likely play a role in the pathogenesis of Alzheimer disease,” the researchers wrote.

The research team previously reported short-term benefits from a controlled study designed to test the effects of GHRH on cognitive function in healthy older adults. Those prior results, coupled with reports by other groups that link lower IGF-1 levels with poorer cognitive function, provided a rationale for this larger study.

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STUDY METHODOLOGY

DR. LAURA D. BAKER s...
DR. LAURA D. BAKER s...
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The current study involved 152 people ranging in age from 55 to 87, including 82 participants with normal cognitive status and 66 participants who met the published diagnostic guidelines for amnestic MCI (single or multiple domain). They were all given baseline tests to measure their cognitive status. Participants were randomly assigned to a group that self-administered a daily injection of tesamorelin, a stabilized analog of human GHRH (1 mg/daily), or to a control group that administered a placebo (sterile water) 30 minutes before bedtime. The injections were administered subcutaneously in the abdomen using a small needle similar to what is used by diabetics, Dr. Baker said. Tesamorelin is licensed for use in the US for reducing abdominal fat in HIV patients, who can acquire belly fat as a consequence of their medication regimens.

A battery of cognitive and executive function tests was administered at baseline, 10 weeks, 20 weeks and 30 weeks (after the drug washout phase). Researchers developed composite scores of executive function, verbal memory, and visual memory for each participant based on their performance on the tests, and then compared how they fared from the start to the finish of the trial.

The researchers reported that the group (including both healthy participants and those with MCI) that took GHRH showed improvements in executive function — primarily in areas of planning, focus, and selective attention, Dr. Baker said. There was also improvement in verbal memory, though the effect was more modest. There did not appear to be any effect on visual memory.

The researchers also measured circulating levels of IGF-1, and the participants who took GHRH had a 117 percent increase in the hormone, Dr. Baker said.

“What we wanted to do was get IGF-1 levels to the level we would see in a 30-year-old adult and that's what we saw,” she said. Those who took GHRH also had a decrease in body fat, but the cognitive benefits remained even after taking this into account in the statistical analysis.

Adverse events were mild, including redness or stinging at the injection site, gastrointestinal upset, and fluid retention. About 68 percent of those in the GHRH group had an adverse event, compared with 36 percent of the controls.

Dr. Baker said her group has concluded that the cognitive findings associated with GHRH were positive enough to move forward with more testing.

The big caveat is, “[Is] it possible to translate these findings into everyday life and if so, how?” she said.

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WHAT ABOUT EVERYDAY FUNCTION?

Dr. Baker said the next study will include adults with MCI and healthy older adults with a first-degree relative with Alzheimer's dementia. The benefits of the hormone treatment will be measured using tests of everyday function — such as the ability to look up a phone number and read the dosing on a bottle of medicine.

“The potential to preserve, or even enhance, cognitive function in normal aging and in populations where cognitive functions are already failing rapidly owing to neurodegenerative disease clearly has important implications not only for the affected individual but also for the support system that bears the social and financial burden of long-term caregiving.”

The Alzheimer's Association estimated that by the midpoint of this century, more than $1 trillion will be spent to care for person with Alzheimer's disease.

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MECHANISM NOT UNDERSTOOD

Adam Boxer, MD, PhD, associate professor of neurology at University of California, San Francisco, said the study “produced interesting results and raises some important questions, but I don't think enough is known about the mechanism at this point to pursue a larger efficacy study.”

Dr. Boxer, who directs the Alzheimer's Disease and Frontotemporal Dementia Clinical Trials Program at the Memory and Aging Center at UCSF, said he believed more needs to be understood about the underlying biological mechanism at work with GHRH and IGF-1. He said the study results lead to the assumption that boosting circulating levels of IGF-1 has a positive effect on cognition, but he said that idea runs counter to research in animals models that shows that lower levels of IGF-1 and IGF-related signaling are associated with increased longevity.

DR. ADAM BOXER said ...
DR. ADAM BOXER said ...
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“Why then should increasing IGF-1 improve cognitive function?” he asked. “Perhaps IGF-1 is a marker for a more complicated process that is altering cognitive function. More information about the mechanism could help us understand whether there is a biology of aging that is separate from the biology of cognitive decline and Alzheimer's or whether this is all one continuum.”

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REFERENCES:

• Baker LD, Barsness SM, Vitiello MV, et al. Effects of growth hormone-releasing hormone on cognitive function in adults with mild cognitive impairment and healthy older adults: Results of a controlled trial. Arch Neurol 2012; E-pub 2012 Aug. 6.
• Rosenfeld RG, Cohen P, Wit JM, et al. Long-term surveillance of growth hormone therapy. J Clin Endocrinol Metabol 2012;97(1):68–72.

• Craig ME, Cowell CT, Price DA, et al, on behalf of the KIGS International Board. Growth hormone treatment and adverse events in Prader-Willi syndrome: Data from KIGS (the Pfizer International Growth Database); Clin Endocrinol 2006:65(2):178–185.
• Liu H, Bravata DM, Hoffman AR, et al. Systematic review: The safety and efficacy of growth hormone in the healthy elderly. Ann Intern Med 2007;14 (2): 104–115.
• Cutfield WS, Wilton P, Price DA, et al. Incidence of diabetes mellitus and impaired glucose tolerance in children and adolescents receiving growth-hormone treatment: Lancet 2000;355(9204):610–613.

©2012 American Academy of Neurology

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