Treatment of Cachexia With Ghrelin in
Patients With COPD*
Noritoshi Nagaya, MD; Takefumi Itoh, MD; Shinsuke Murakami, MD;
Hideo Oya, MD; Masaaki Uematsu, MD; Kunio Miyatake, MD; and
Kenji Kangawa, PhD
Study objectives: Ghrelin is a novel growth hormone (GH)-releasing peptide that also induces a
positive energy balance by decreasing fat utility and stimulating feeding through GH-indepen-
dent mechanisms. We investigated whether ghrelin improves cachexia and functional capacity in
patients with COPD.
Methods: This is an open-label pilot study. Human ghrelin (2 ?g/kg bid) was IV administered to
seven cachectic patients with COPD for 3 weeks. Food intake, body composition, muscle strength,
exercise capacity, pulmonary function, and sympathetic nerve activity were examined before and
after ghrelin therapy.
Results: A single administration of ghrelin markedly increased serum GH (21-fold). Three-week
treatment with ghrelin resulted in a significant increase in mean (? SEM) body weight
(49.3 ? 3.6 to 50.3 ? 3.8 kg; p < 0.05). Food intake was significantly increased during ghrelin
therapy. Ghrelin increased lean body mass and peripheral and respiratory muscle strength.
Ghrelin significantly increased Karnofsky performance status score and the distance walked in 6
min (370 ? 30 to 432 ? 35 m; p < 0.05), although it did not significantly alter pulmonary
function. Ghrelin attenuated the exaggerated sympathetic nerve activity, as indicated by a
marked decrease in plasma norepinephrine level (889 ? 123 to 597 ? 116 pg/mL; p < 0.05).
Conclusions: These preliminary results suggest that repeated administration of ghrelin improves
body composition, muscle wasting, functional capacity, and sympathetic augmentation in cachec-
tic patients with COPD.
(CHEST 2005; 128:1187–1193)
Key words: cachexia; chronic obstructive; exercise capacity; ghrelin; nutrition
Abbreviations: GH ? growth hormone; IGF ? insulin-like growth factor
quently in patients with COPD and is a strong
independent risk factor for mortality.1–4Cachexia
achexia, which is a catabolic state characterized
by weight loss and muscle wasting, occurs fre-
also impacts not only the respiratory musculature,
but also the peripheral skeletal muscle function,
which impairs the quality of life in patients with
COPD. However, there have been no promising
drugs to improve pulmonary cachexia.
Ghrelin is a novel growth hormone (GH)-releasing
peptide that was isolated from the stomach and has
been identified as an endogenous ligand for the GH
secretagogue receptor.5Therefore, ghrelin may in-
duce beneficial effects on muscle strength and en-
ergy metabolism via a GH-dependent mechanism.
For editorial comment see page 1084
On the other hand, ghrelin induces a positive energy
balance and weight gain by decreasing fat utility6and
stimulating food intake7through GH-independent
mechanisms. Interestingly, ghrelin has been shown
to act directly on the CNS to decrease sympathetic
nerve activity,8,9which may attenuate the exagger-
ated energy expenditure in patients with COPD. An
*From the Department of Internal Medicine (Drs. Nagaya, Itoh,
Murakami, Oya, and Miyatake), National Cardiovascular Center,
Osaka, Japan; Cardiovascular Division (Dr. Uematsu), Kansai
Rosai Hospital, Hyogo, Japan; and Department of Biochemistry
(Dr. Kangawa), National Cardiovascular Center Research Insti-
tute, Osaka, Japan.
This study was supported by the Research Grant for Cardiovas-
cular Disease (16C-6) from the Ministry of Health, Labor and
Welfare; the Mochida Memorial Foundation for Medical and
Pharmaceutical Research; and the Promotion of Fundamental
Studies in Health Science of the Organization for Pharmaceutical
Safety and Research of Japan.
Manuscript received August 12, 2004; revision accepted Febru-
ary 15, 2005.
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
Correspondence to: Noritoshi Nagaya, MD, Department of In-
ternal Medicine, National Cardiovascular Center, 5–7-1 Fujishi-
rodai, Suita, Osaka 565-8565, Japan; e-mail: firstname.lastname@example.org.
www.chestjournal.orgCHEST / 128 / 3 / SEPTEMBER, 2005
17 Shimizu Y, Nagaya N, Isobe T, et al. Increased plasma ghrelin
level in lung cancer cachexia. Clin Cancer Res 2003; 9:774–
18 Takaya K, Ariyasu H, Kanamoto N, et al. Ghrelin strongly
stimulates growth hormone (GH) release in humans. J Clin
Endocrinol Metab 2000; 85:4908–4911
19 Amato G, Carella C, Fazio S, et al. Body composition, bone
metabolism, heart structure and function in growth hormone
deficient adults before and after growth hormone replace-
ment therapy at low doses. J Clin Endocrinol Metab 1993;
20 Bark TH, McNurlan MA, Lang CH, et al. Increased protein
synthesis after acute IGF-I or insulin infusion is localized to
muscle in mice. Am J Physiol 1998; 275:E118–E123
21 Shintani M, Ogawa Y, Ebihara K, et al. Ghrelin, an endoge-
nous growth hormone secretagogue, is a novel orexigenic
peptide that antagonizes leptin action through the activation
of hypothalamic neuropeptide Y/Y1 receptor pathway. Dia-
betes 2001; 50:227–232
22 Wren AM, Small CJ, Ward HL, et al. The novel hypothalamic
peptide ghrelin stimulates food intake and growth hormone
secretion. Endocrinology 2000; 141:4325–4328
23 Anker SD, Chua TP, Ponikowski P, et al. Hormonal changes
and catabolic/anabolic imbalance in chronic heart failure and
their importance for cardiac cachexia. Circulation 1997;
24 Anderson P, Saltin B. Maximal perfusion of skeletal muscle in
man. J Appl Physiol 1985; 366:233–249
25 Nagaya N, Miyatake K, Uematsu M, et al. Hemodynamic,
renal and hormonal effects of ghrelin infusion in patients with
chronic heart failure. J Clin Endocrinol Metab 2001; 86:
26 Pape GS, Friedman M, Underwood LE, et al. The effect of
growth hormone on weight gain and pulmonary function in
patients with chronic obstructive lung disease. Chest 1991;
27 Papadakis MA, Grady DG, Black D, et al. Growth hormone
replacement in healthy older men improves body composition
but not functional ability. Ann Intern Med 1996; 124:708–
28 Pichard C, Kyle U, Chevrolet JC, et al. Lack of effects of
recombinant growth hormone on muscle function in patients
requiring prolonged mechanical ventilation: a prospective.
Crit Care Med 1996; 24:403–413
29 Burdet L, de Muralt B, Schutz Y, et al. Administration of growth
hormone to underweight patients with chronic obstructive pul-
monary disease: a prospective, randomized, controlled study.
Am J Respir Crit Care Med 1997; 156:1800–1806
www.chestjournal.org CHEST / 128 / 3 / SEPTEMBER, 2005