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Complementary Secretagogue Pairs Unmask Prominent Gender-Related Contrasts in Mechanisms of Growth Hormone Pulse Renewal in Young Adults

Division of Endocrinology and Metabolism, Departments of Internal Medicine (C.S.-W., K.L.M., J.M.M., J.D.V.) and Pediatrics (F.H.M.), Mayo School of Graduate Medical Education, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905; Division of Endocrinology and Metabolism (L.F.), Department of Internal Medicine, School of Medicine, University of Virginia, Charlottesville, Virginia 22908; and Division of Endocrinology and Metabolism (C.Y.B.), Department of Internal Medicine, 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, Departments of Internal Medicine and Pediatrics, Mayo School of Graduate Medical Education, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905. E-mail: veldhuis.johannes{at}mayo.edu.

The present study examines the thesis that pulsatile GH secretion is controlled simultaneously by three principal signals; viz., GHRH, GH-releasing peptide (GHRP, ghrelin), and somatostatin (SS). According to this ensemble notion, no single regulatory peptide acts alone or can be interpreted in isolation. Therefore, to investigate gender-specific control of pulsatile GH secretion, we designed dual-effector stimulation paradigms in eight young men and six women as follows: 1) L-arginine/GHRH (to clamp low SS and high GHRH input); 2) L-arginine/GHRP-2 (to clamp low SS and high GHRP drive); 3) GHRH/GHRP-2 (to clamp high GHRH and high GHRP feedforward); vs. 4) saline (unclamped). Statistical comparisons revealed that: 1) fasting pulsatile GH secretion was 7.6-fold higher in women than men (P < 0.001); 2) L-arginine/GHRH and L-arginine/GHRP-2 evoked, respectively, 4.6- and 2.2-fold greater burst-like GH release in women than men (P < 0.001 and P = 0.015); and 3) GHRH/GHRP-2 elicited comparable GH secretion by gender. In the combined cohorts, estradiol concentrations positively predicted responses to L-arginine/GHRP-2 (r² = 0.49, P = 0.005), whereas testosterone negatively predicted those to L-arginine/GHRH (r² = 0.56, P = 0.002). Based upon a simplified biomathematical model of three-peptide control, the current outcomes suggest that women maintain greater GHRH potency, GHRP efficacy, and opposing SS outflow than men. This inference upholds recent clinical precedence and yields valid predictions of sex differences in self-renewable GH pulsatility.

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