Stimulation of the growth hormone (GH)-insulin-like growth factor I axis by daily oral administration of a GH secretogogue (MK-677) in healthy elderly subjects

Ian M. Chapman, Mark A. Bach, Eve Van Cauter, Mildred Farmer, David Krupa, Alice M. Taylor, Lisa M. Schilling, Katrina Y. Cole, Emily H. Skiles, Suzan S. Pezzoli, Mark L. Hartman, Johannes D Veldhuis, Glenn J. Gormley, Michael O. Thorner

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Abstract

Aging is associated with declining activity of the GH axis, possibly contributing to adverse body composition changes and increased incidence of cardiovascular disease. The stimulatory effects on the GH-insulin-like growth factor I (IGF-I) axis of orally administered MK-677, a GH-releasing peptide mimetic, were investigated. Thirty-two healthy subjects (15 women and 17 men, aged 64- 81 yr) were enrolled in a randomized, double blind, placebo- controlled trial. They received placebo or 2, 10, or 25 mg MK-677, orally, once daily for 2 separate study periods of 14 and 28 days. At baseline and on day 14 of each study period, blood was collected every 20 min for 24 h to measure GH, PRL, and cortisol. Attributes of pulsatile GH release were assessed by 3 independent algorithms. MK-677 administration for 2 weeks increased GH concentrations in a dose-dependent manner, with 25 rag/day increasing mean 24-h GH concentration 97 ± 23% (mean ± SE; P < 0.05 vs. baseline). This increase was due to an enhancement of preexisting pulsatile GH secretion. GH pulse height and interpulse nadir concentrations increased significantly without significant changes in the number of pulses. With 25 mg/day MK-677 treatment, mean serum IGF-I concentrations increased into the normal range for young adults (141 ± 21 μg/L at baseline, 219 ± 21 μg/L at 2 weeks, and 265 ± 29 μg/L at 4 weeks; P < 0.05). MK-677 produced significant increases in fasting glucose (5.4 ± 0.3 to 6.8 ± 0.4 mmol/L at 4 weeks; P < 0.01 vs. baseline) and IGF-binding protein-3. Circulating cortisol concentrations did not change, and PRL concentrations increased 23%, but remained within the normal range. Once daily treatment of older people with oral MK-677 for up to 4 weeks enhanced pulsatile GH release, significantly increased serum GH and IGF-I concentrations, and, at a dose of 25 mg/day, restored serum IGF-I concentrations to those of young adults.

Original languageEnglish (US)
Pages (from-to)4249-4257
Number of pages9
JournalJournal of Clinical Endocrinology and Metabolism
Volume81
Issue number12
DOIs
StatePublished - 1996
Externally publishedYes

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ibutamoren mesylate
Insulin-Like Growth Factor I
Growth Hormone
Oral Administration
Healthy Volunteers
Hydrocortisone
Young Adult
Reference Values
Serum
Placebos
Insulin-Like Growth Factor Binding Protein 3

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

Stimulation of the growth hormone (GH)-insulin-like growth factor I axis by daily oral administration of a GH secretogogue (MK-677) in healthy elderly subjects. / Chapman, Ian M.; Bach, Mark A.; Van Cauter, Eve; Farmer, Mildred; Krupa, David; Taylor, Alice M.; Schilling, Lisa M.; Cole, Katrina Y.; Skiles, Emily H.; Pezzoli, Suzan S.; Hartman, Mark L.; Veldhuis, Johannes D; Gormley, Glenn J.; Thorner, Michael O.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 81, No. 12, 1996, p. 4249-4257.

Research output: Contribution to journalArticle

Chapman, IM, Bach, MA, Van Cauter, E, Farmer, M, Krupa, D, Taylor, AM, Schilling, LM, Cole, KY, Skiles, EH, Pezzoli, SS, Hartman, ML, Veldhuis, JD, Gormley, GJ & Thorner, MO 1996, 'Stimulation of the growth hormone (GH)-insulin-like growth factor I axis by daily oral administration of a GH secretogogue (MK-677) in healthy elderly subjects', Journal of Clinical Endocrinology and Metabolism, vol. 81, no. 12, pp. 4249-4257. https://doi.org/10.1210/jc.81.12.4249
Chapman, Ian M. ; Bach, Mark A. ; Van Cauter, Eve ; Farmer, Mildred ; Krupa, David ; Taylor, Alice M. ; Schilling, Lisa M. ; Cole, Katrina Y. ; Skiles, Emily H. ; Pezzoli, Suzan S. ; Hartman, Mark L. ; Veldhuis, Johannes D ; Gormley, Glenn J. ; Thorner, Michael O. / Stimulation of the growth hormone (GH)-insulin-like growth factor I axis by daily oral administration of a GH secretogogue (MK-677) in healthy elderly subjects. In: Journal of Clinical Endocrinology and Metabolism. 1996 ; Vol. 81, No. 12. pp. 4249-4257.
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abstract = "Aging is associated with declining activity of the GH axis, possibly contributing to adverse body composition changes and increased incidence of cardiovascular disease. The stimulatory effects on the GH-insulin-like growth factor I (IGF-I) axis of orally administered MK-677, a GH-releasing peptide mimetic, were investigated. Thirty-two healthy subjects (15 women and 17 men, aged 64- 81 yr) were enrolled in a randomized, double blind, placebo- controlled trial. They received placebo or 2, 10, or 25 mg MK-677, orally, once daily for 2 separate study periods of 14 and 28 days. At baseline and on day 14 of each study period, blood was collected every 20 min for 24 h to measure GH, PRL, and cortisol. Attributes of pulsatile GH release were assessed by 3 independent algorithms. MK-677 administration for 2 weeks increased GH concentrations in a dose-dependent manner, with 25 rag/day increasing mean 24-h GH concentration 97 ± 23{\%} (mean ± SE; P < 0.05 vs. baseline). This increase was due to an enhancement of preexisting pulsatile GH secretion. GH pulse height and interpulse nadir concentrations increased significantly without significant changes in the number of pulses. With 25 mg/day MK-677 treatment, mean serum IGF-I concentrations increased into the normal range for young adults (141 ± 21 μg/L at baseline, 219 ± 21 μg/L at 2 weeks, and 265 ± 29 μg/L at 4 weeks; P < 0.05). MK-677 produced significant increases in fasting glucose (5.4 ± 0.3 to 6.8 ± 0.4 mmol/L at 4 weeks; P < 0.01 vs. baseline) and IGF-binding protein-3. Circulating cortisol concentrations did not change, and PRL concentrations increased 23{\%}, but remained within the normal range. Once daily treatment of older people with oral MK-677 for up to 4 weeks enhanced pulsatile GH release, significantly increased serum GH and IGF-I concentrations, and, at a dose of 25 mg/day, restored serum IGF-I concentrations to those of young adults.",
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AU - Farmer, Mildred

AU - Krupa, David

AU - Taylor, Alice M.

AU - Schilling, Lisa M.

AU - Cole, Katrina Y.

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AU - Pezzoli, Suzan S.

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AU - Veldhuis, Johannes D

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AU - Thorner, Michael O.

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N2 - Aging is associated with declining activity of the GH axis, possibly contributing to adverse body composition changes and increased incidence of cardiovascular disease. The stimulatory effects on the GH-insulin-like growth factor I (IGF-I) axis of orally administered MK-677, a GH-releasing peptide mimetic, were investigated. Thirty-two healthy subjects (15 women and 17 men, aged 64- 81 yr) were enrolled in a randomized, double blind, placebo- controlled trial. They received placebo or 2, 10, or 25 mg MK-677, orally, once daily for 2 separate study periods of 14 and 28 days. At baseline and on day 14 of each study period, blood was collected every 20 min for 24 h to measure GH, PRL, and cortisol. Attributes of pulsatile GH release were assessed by 3 independent algorithms. MK-677 administration for 2 weeks increased GH concentrations in a dose-dependent manner, with 25 rag/day increasing mean 24-h GH concentration 97 ± 23% (mean ± SE; P < 0.05 vs. baseline). This increase was due to an enhancement of preexisting pulsatile GH secretion. GH pulse height and interpulse nadir concentrations increased significantly without significant changes in the number of pulses. With 25 mg/day MK-677 treatment, mean serum IGF-I concentrations increased into the normal range for young adults (141 ± 21 μg/L at baseline, 219 ± 21 μg/L at 2 weeks, and 265 ± 29 μg/L at 4 weeks; P < 0.05). MK-677 produced significant increases in fasting glucose (5.4 ± 0.3 to 6.8 ± 0.4 mmol/L at 4 weeks; P < 0.01 vs. baseline) and IGF-binding protein-3. Circulating cortisol concentrations did not change, and PRL concentrations increased 23%, but remained within the normal range. Once daily treatment of older people with oral MK-677 for up to 4 weeks enhanced pulsatile GH release, significantly increased serum GH and IGF-I concentrations, and, at a dose of 25 mg/day, restored serum IGF-I concentrations to those of young adults.

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