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Age and Secretagogue Type Jointly Determine Dynamic Growth Hormone Responses to Exogenous Insulin-Like Growth Factor-Negative Feedback in Healthy Men

Division of Endocrinology and Metabolism, Department of Internal Medicine (J.D.V.), Mayo Medical and Graduate Schools of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905; Exercise Physiology Laboratory (J.Y.W., A.L.W.), General Clinical Research Center, University of Virginia Health System, Charlottesville, Virginia 22908; Endocrine Service, Medical Section (A.I.), Salem Veterans Affairs Medical Center, Salem, Virginia 24153; Department of Pharmacology/Chemical Toxicology (E.E.M.), University of Milan, Milan, Italy; and Division of Endocrinology and Metabolism, Department of Internal Medicine (C.Y.B.), Tulane University Medical Center, New Orleans, Louisiana 70112-2699

Address all correspondence and requests for reprints to: Johannes D. Veldhuis, Division of Endocrinology and Metabolism, Department of Internal Medicine, Mayo Medical and Graduate Schools of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905. E-mail: veldhuis.johannes{at}mayo.edu.

The primary cause of waning GH and IGF-I concentrations in healthy aging adults is not established. To test the postulate that age influences negative feedback by IGF-I in a secretagogue-specific fashion, 17 normal men (nine young and eight older) each completed eight randomly ordered injections of placebo or recombinant human (rh) IGF-I (20 µg/kg sc), followed by saline/rest, aerobic exercise, GHRH (1 µg/kg iv bolus), or GH-releasing peptide-2 (1 µg/kg iv bolus) stimulation. GH secretion was monitored by sampling blood every 10 min for 7 h, high-sensitivity immunochemiluminometric assay, and deconvolution analysis conditioned on prior pulse-onset times and biexponential kinetics. Analysis of covariance showed that age (P = 0.028), secretagogue (P < 0.001), and rhIGF-I (P < 0.005) individually determine pulsatile GH secretion and exhibit a strong 3-fold interaction (P < 10^–5). Post hoc comparisons revealed that elderly subjects manifest less IGF-I inhibition of a maximal GHRH stimulus (P = 0.013 vs. young), blunted initial IGF-I suppression of fasting GH release (P = 0.038), and impaired IGF-I feedback on the regularity of GH secretion (P = 0.023). Age stratum did not influence peak IGF-I and nadir GH concentrations or rhIGF-I-induced inhibition of GH secretion stimulated by exercise or GH-releasing peptide-2.

In summary, experimental elevation of IGF-I concentrations unmasks reduced rhIGF-I-dependent feedback inhibition of fasting and GHRH-stimulated GH secretion in healthy older men, indicating that aging selectively modulates the autoinhibition process.

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