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Contrasting Negative-Feedback Control of Endogenously Driven and Exercise-Stimulated Pulsatile Growth Hormone Secretion in Women and Men

Department of Internal Medicine (J.D.V.), Division of Endocrinology and Metabolism, Mayo Medical and Graduate Schools of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905; and Departments of Health Evaluation Sciences (J.P.), Human Services (L.W., M.P., A.W.), and Medicine (J.Y.W., A.W.), General Clinical Research Center, University of Virginia, Charlottesville, Virginia 22908

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.

GH represses its own secretion via rapid and reversible feedback exerted at key hypothalamic loci. The primary mechanisms include stimulation of somatostatin release and inhibition of GHRH outflow. Autoinhibition is prominent in the adult male rat but diminutive in the female animal. The sex contrast reflects important differences in central neuropeptide signaling in this species. No comparable insights into gender-specific control of GH autofeedback are available in the human. To examine this issue, we quantitated acute recombinant human (rh)GH-induced inhibition of baseline (resting) and aerobic exercise-stimulated GH secretion in healthy young men (n = 8) and early follicular-phase women (n = 6). Each subject underwent four fasting, morning inpatient infusion studies in a prospectively randomized, placebo-controlled, double-blind, within-subject cross-over design. The feedback paradigm comprised 6-min bolus iv infusion of saline or rhGH (10 µg/kg) followed in 120 min by rest or submaximal aerobic (individually calibrated) bicycle ergometry for 30 min. Concomitantly, blood was sampled every 10 min for 6 h, and sera were submitted to immunochemiluminometric GH assay (sensitivity 0.005 µg/liter). Biexponential deconvolution analysis was applied to estimate stimulated GH secretory-burst mass (µg/liter per 90 min after onset of exercise or rest). Women and men had statistically comparable serum estradiol but unequal testosterone concentrations. Repeated-measures ANOVA documented a significant three-way interaction among gender, stimulus type (rest or exercise), and feedback status (saline or rhGH injection) in determining GH secretory-burst mass (P = 0.008). There were prominent two-factor interactions among gender and exercise (P < 0.001); gender and rhGH-induced negative feedback (P = 0.002); and exercise and rhGH feedback (P = 0.006). Gender comparisons disclosed that women, compared with men, maintain 20-fold higher GH secretory-burst mass at rest (P < 0.001); 40-fold less stimulation of pulsatile GH release by exercise than rest (P < 0.001); and 20-fold greater inhibition of GH secretory-burst mass by rhGH than saline at rest (P < 0.05). Observed feedback contrasts by sex were specific, inasmuch as gender did not affect absolute estimates of exercise-stimulated GH secretion (µg/liter/90 min); nadir GH concentrations (µg/liter) enforced by rhGH infusion; and the time latency (min) to manifest maximal inhibition after rhGH injection.

In summary, the present clinical investigation unmasks: 1) markedly greater fractional feedback inhibition of pulsatile GH secretion by rhGH in young women than men; and 2) partial resistance of the aerobic-exercise stimulus to GH autofeedback in both women and men. We postulate that sex-steroid-specific control of somatostatin and GHRH outflow may mediate the former gender contrasts, whereas unknown (gender-independent) factors may determine the capability of exercise to significantly antagonize GH autoinhibition.

Current address for L.W.: Department of Exercise and Sport Science, University of North Carolina-Greensboro, Greensboro, North Carolina 27410.

This work was supported in part by Grants O1 RR00847 and RR00585 from the National Center for Research Resources (Rockville, MD) to the General Clinical Research Centers of the University of Virginia and Mayo Clinic; and Grants R01 AG 19695 and AG 14799 (to J.D.V.) from the National Institutes of Health (Bethesda, MD).

Abbreviations: GHRP, GH-releasing peptide; rh, recombinant human; S, saline; VO₂ peak, peak oxygen consumption.

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