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.

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 mg/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 microgram/L at baseline, 219 +/- 21 micrograms/L at 2 weeks, and 265 +/- 29 micrograms/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.

[1]  M. Thorner,et al.  Enhancement of pulsatile growth hormone secretion by continuous infusion of a growth hormone-releasing peptide mimetic, L-692,429, in older adults--a clinical research center study. , 1996, The Journal of clinical endocrinology and metabolism.

[2]  M. Thorner,et al.  Once daily subcutaneous growth hormone-releasing hormone therapy accelerates growth in growth hormone-deficient children during the first year of therapy. Geref International Study Group. , 1996, The Journal of clinical endocrinology and metabolism.

[3]  M L Johnson,et al.  Differential impact of age, sex steroid hormones, and obesity on basal versus pulsatile growth hormone secretion in men as assessed in an ultrasensitive chemiluminescence assay. , 1995, The Journal of clinical endocrinology and metabolism.

[4]  F. Casanueva,et al.  Absence of growth hormone (GH) secretion after the administration of either GH-releasing hormone (GHRH), GH-releasing peptide (GHRP-6), or GHRH plus GHRP-6 in children with neonatal pituitary stalk transection. , 1995, The Journal of clinical endocrinology and metabolism.

[5]  R. Fahlbusch,et al.  The growth hormone secretagogue, L-692,429, induces phosphatidylinositol hydrolysis and hormone secretion by human pituitary tumors. , 1995, Biochemical and biophysical research communications.

[6]  F. Casanueva,et al.  Blocked growth hormone-releasing peptide (GHRP-6)-induced GH secretion and absence of the synergic action of GHRP-6 plus GH-releasing hormone in patients with hypothalamopituitary disconnection: evidence that GHRP-6 main action is exerted at the hypothalamic level. , 1995, The Journal of clinical endocrinology and metabolism.

[7]  H. de Boer,et al.  Clinical aspects of growth hormone deficiency in adults. , 1995, Endocrine reviews.

[8]  C. Diéguez,et al.  Growth hormone secretion after the administration of GHRP‐6 or GHRH combined with GHRP‐6 does not decline in late adulthood , 1995, Clinical endocrinology.

[9]  M. Thorner,et al.  Neuroendocrine responses to a novel growth hormone secretagogue, L-692,429, in healthy older subjects. , 1994, The Journal of clinical endocrinology and metabolism.

[10]  M L Johnson,et al.  Enhanced basal and disorderly growth hormone secretion distinguish acromegalic from normal pulsatile growth hormone release. , 1994, The Journal of clinical investigation.

[11]  V. Lenaerts,et al.  Growth hormone (GH)-releasing hormone secretion is stimulated by a new GH-releasing hexapeptide in sheep. , 1994, Endocrinology.

[12]  R. Marcus,et al.  Effects of recombinant human growth hormone on metabolic indices, body composition, and bone turnover in healthy elderly women. , 1994, The Journal of clinical endocrinology and metabolism.

[13]  M. Straume,et al.  Enhanced sensitivity growth hormone (GH) chemiluminescence assay reveals lower postglucose nadir GH concentrations in men than women. , 1994, The Journal of clinical endocrinology and metabolism.

[14]  A. O’Sullivan,et al.  Diagnosis of growth-hormone deficiency in adults , 1994, The Lancet.

[15]  K. Katoh,et al.  Effects in vitro of New Growth Hormone Releasing Peptide (GHRP‐1) on Growth Hormone Secretion from Ovine Pituitary Cells in Primary Culture , 1994, Journal of neuroendocrinology.

[16]  A. Barkan,et al.  Effects of a prolonged growth hormone (GH)-releasing peptide infusion on pulsatile GH secretion in normal men. , 1993, The Journal of clinical endocrinology and metabolism.

[17]  B. Bengtsson,et al.  Effects of treatment with recombinant human growth hormone on insulin sensitivity and glucose metabolism in adults with growth hormone deficiency. , 1993, Metabolism: clinical and experimental.

[18]  S. Pong,et al.  A nonpeptidyl growth hormone secretagogue. , 1993, Science.

[19]  M. Thorner,et al.  Twenty-four-hour growth hormone (GH)-releasing peptide (GHRP) infusion enhances pulsatile GH secretion and specifically attenuates the response to a subsequent GHRP bolus. , 1993, The Journal of clinical endocrinology and metabolism.

[20]  D. Schade,et al.  Anthropometric, metabolic, and immunological effects of recombinant human growth hormone in AIDS and AIDS-related complex. , 1993, Journal of acquired immune deficiency syndromes.

[21]  I. Robinson,et al.  Systemic administration of growth hormone-releasing peptide activates hypothalamic arcuate neurons , 1993, Neuroscience.

[22]  M. Blackman,et al.  Human growth hormone and human aging. , 1993, Endocrine reviews.

[23]  D. Clemmons,et al.  The insulin-like growth factors. , 1993, Annual review of physiology.

[24]  R. Smith,et al.  Evidence for a role of protein kinase-C in His-D-Trp-Ala-Trp-D-Phe-Lys-NH2-induced growth hormone release from rat primary pituitary cells. , 1991, Endocrinology.

[25]  J. Jørgensen.  Human growth hormone replacement therapy: pharmacological and clinical aspects. , 1991, Endocrine reviews.

[26]  D. Clemmons,et al.  The effect of growth hormone on weight gain and pulmonary function in patients with chronic obstructive lung disease. , 1991, Chest.

[27]  T. Badger,et al.  On the actions of the growth hormone-releasing hexapeptide, GHRP. , 1991, Endocrinology.

[28]  B. Bengtsson,et al.  Premature mortality due to cardiovascular disease in hypopituitarism , 1990, The Lancet.

[29]  D. Rudman,et al.  Effects of human growth hormone in men over 60 years old. , 1990, The New England journal of medicine.

[30]  M. Thorner,et al.  Growth hormone (GH)-releasing peptide stimulates GH release in normal men and acts synergistically with GH-releasing hormone. , 1990, The Journal of clinical endocrinology and metabolism.

[31]  D. Wilmore,et al.  Low‐Dose Growth Hormone and Hypocaloric Nutrition Attenuate the Protein‐Catabolic Response After Major Operation , 1989, Annals of surgery.

[32]  E. Convey,et al.  The synergistic effects of His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 on growth hormone (GH)-releasing factor-stimulated GH release and intracellular adenosine 3',5'-monophosphate accumulation in rat primary pituitary cell culture. , 1989, Endocrinology.

[33]  O. Butenandt.  Diagnostic Value of Growth Hormone‐Releasing Hormone Tests in Short Children , 1989, Acta paediatrica Scandinavica. Supplement.

[34]  E. Cauter,et al.  Estimating false-positive and false-negative errors in analyses of hormonal pulsatility , 1988 .

[35]  M L Johnson,et al.  The pituitary gland secretes in bursts: appraising the nature of glandular secretory impulses by simultaneous multiple-parameter deconvolution of plasma hormone concentrations. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[36]  Johannes D. Veldhuis,et al.  The pituitary gland secretes in bursts , 1987 .

[37]  A. Rogol,et al.  Effects of sex and age on the 24-hour profile of growth hormone secretion in man: importance of endogenous estradiol concentrations. , 1987, The Journal of clinical endocrinology and metabolism.

[38]  M L Johnson,et al.  Cluster analysis: a simple, versatile, and robust algorithm for endocrine pulse detection. , 1986, The American journal of physiology.

[39]  D. Rudman.  Growth Hormone, Body Composition, and Aging , 1985, Journal of the American Geriatrics Society.

[40]  R. McCARTER,et al.  The influence of age on the 24-hour integrated concentration of growth hormone in normal individuals. , 1985, The Journal of clinical endocrinology and metabolism.

[41]  Andrée Tixier-Vidal,et al.  The anterior pituitary , 1975 .

[42]  A. Jost.  [The anterior pituitary of the fetus]. , 1962, Biologie medicale.

[43]  E. Pearson,et al.  THE EFFECT OF GROWTH HORMONE ON NITROGEN BALANCE AT VARIOUS LEVELS OF INTAKE IN BURNED PATIENTS , 1960 .