"This study is an initial proof of principal that augmenting low growth hormone levels in this way has the potential to reverse the abnormal body composition seen in these individuals," says Steven Grinspoon, MD, of the MGH Neuroendocrine Unit and Program in Nutritional Metabolism, the report's senior author. "At the current time, there is no established treatment for this syndrome."
The combination drug strategy known as highly active antiretroviral therapy (HAART) can significantly reduce virus levels and help maintain health in HIV-infected individuals, but more than half may develop lipodystrophy. Typical symptoms of the syndrome include a loss of subcutaneous fat in the face, arms, and legs and increased fat deposits in the abdomen and upper back. The metabolic aspects of the syndrome – changes in cholesterol and other blood lipids, and development of insulin resistance – could also increase the risk of cardiovascular disease.
It recently has been discovered that men with lipodystrophy do not secrete normal levels of growth hormone. Although growth-hormone (GH) injections can reduce fat deposits that develop in other GH-deficiency situations, high-dose injections have a number of significant side effects, including insulin resistance, already a problem for lipodystrophy patients.
In a healthy body, secretion of GH is controlled by a feedback mechanism, which shuts down the process if hormone concentrations exceed normal blood levels. Directly injecting GH could bypass this natural control mechanism, allowing blood levels to rise too high. In an attempt to raise GH levels in a more natural manner, the MGH team devised a strategy using growth-hormone-releasing hormone (GHRH).
They enrolled 31 men with HIV lipodystrophy for a 12-week, randomized, double-blinded study. Participants injected themselves twice daily with either GHRH or a placebo injection. To track GH secretion, the researchers measured blood levels of insulin-like growth factor-1 (IGF-1). As part of the natural feedback system, IGF-1 levels rise in response to GH blood levels, which turns off further hormone secretion. Body composition was measured by x-ray and CT scan studies, and blood tests followed other metabolic markers.
At the end of the study period, participants in the GHRH group had significant increases in their IGF-1 levels compared with the placebo group, indicating more normal GH production and regulation. In addition, body composition of those in the GHRH group returned to a more normal pattern, with increases in subcutaneous fat in the extremities and less fat deposited deep within the abdomen. Although there were no significant differences in total fat mass, those in the GHRH group had significant increases in lean body mass.
As the reseachers hoped, the increased GH levels resulting from GHRH therapy did not significantly change blood levels of insulin and glucose. Cholesterol and triglyceride levels also remained stable. In addition, both participants and their physicians noted improvement in lipodystrophy symptoms in the GHRH group, and those participants also expressed significantly greater satisfaction with their overall appearance.
"The novel part of this study was use of a natural secretion inducer to produce normal hormone levels," Grinspoon says. "The significant redistribution of fat away from the abdomen reflects a change toward a more healthy cardiovascular profile, an important health benefit with minimal risk due to the achievement of normal growth hormone levels." Grinspoon is an associate professor of Medicine at Harvard Medical School.
The researchers note that further studies should investigate longer-term therapy in a larger, more diverse population. They also are studying other GH-secretion inducers and theorize that this approach could be useful for other GH-deficiency syndromes. Although GHRH remains investigational for lipodystrophy, the study was performed with the approval of the Food and Drug Administration.
The study's first author is Polyxeni Koutkia, MD, of the MGH Neuroendocrine Unit and Program in Nutritional Metabolism. Co-authors are Bridget Canavan, Martin Torriani, MD, and John Kissko, all of the MGH; and Jeff Breau of Massachusetts Institute of Technology. The research was supported by grants from the National Institute for Diabetes, Digestive and Kidney Diseases, and the study drug was provided by Serono, Inc., which had no additional input into the study.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $400 million and major research centers in AIDS, cardiovascular research, cancer, cutaneous biology, medical imaging, neurodegenerative disorders, transplantation biology and photomedicine. In 1994, MGH and Brigham and Women's Hospital joined to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups, and nonacute and home health services.
Journal
JAMA