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Gender and Sexual Maturation-Dependent Contrasts in the Neuroregulation of Growth Hormone Secretion in Prepubertal and Late Adolescent Males and Females—A General Clinical Research Center-Based Study¹

Division of Endocrinology and Metabolism, Departments of Internal Medicine and Pediatrics, Center for Biomathematical Technology, University of Virginia Health Sciences Center (J.D.V., J.N.R., A.D.R.), and Department of Pharmacology (A.D.R.), University of Virginia, Charlottesville, Virginia 22908

Address all correspondence and requests for reprints to: Dr. J. D. Veldhuis, Division of Endocrinology, Department of Internal Medicine, Box 202, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908. E-mail: jdv{at}virginia.edu

Although numerous studies have delineated an impact of gender on the neuroendocrine control of GH secretion in the adult, few investigations have defined the nature and extent of sex differences before puberty. This deficit reflects jointly the sensitivity limitations of earlier GH assays and the paucity of intensive sampling protocols in healthy children. Here we have applied a chemiluminescence-based GH assay (sensitivity, 0.005 µg/L) to study GH release in blood sampled every 10 min for 12 h from 1800–0600 h in 58 healthy children. Males and females were evaluated in prepuberty (n = 17 boys; n = 11 girls) and late adolescence (n = 13 males; n = 17 females). We quantitated the principal regulated facets of GH release by 1) deconvolution analysis to assess basal vs. pulsatile GH secretion, 2) approximate entropy to compute the regularity of GH release patterns, and 3) cosine regression analysis to evaluate the overnight rhythmic release of GH. Gender by maturation analysis of variance revealed a mean 2.3-fold increase in the integrated serum GH concentration between prepuberty and late adolescence (P < 10^-6). Deconvolution analysis disclosed that 91–97% of total GH secretion was pulsatile. Pulsatile, but not basal, GH release showed marked sexual maturation dependence (P < 10^-5). Pulsatile GH release rose in adolescents due to a 2.25-fold greater GH secretory burst mass (P = 0.00011), which reflected joint 1.5-fold increases in GH secretory pulse amplitude and duration (P < 0.01). Pulse-mass enhancement across puberty was gender independent, but mechanistically specific, as GH pulse frequency, intersecretory burst interval, and half-life were invariant of pubertal status. The approximate entropy statistic identified more disorderly GH secretion patterns in adolescent females compared with prepubertal children and adolescent males (P = 0.00074). Cosinor analysis unmasked elevated overnight rhythms in GH secretory burst mass and interburst intervals in late adolescents of both genders compared with prepubertal boys (for burst mass) or girls (for interburst intervals). Linear regression analysis disclosed strong correlations among 1) the plasma insulin-like growth factor I concentration and GH secretory burst mass (P < 10^-3), 2) the GH pulse mass and the serum testosterone concentration (P = 10^-3), 3) the irregularity (entropy) of GH secretory patterns and the serum estradiol concentration (P < 10^-4), and 4) the basal GH secretion rate and the serum estradiol concentration (P = 10^-2).

In summary, healthy prepubertal children and late adolescent boys and girls manifest distinctive mechanisms controlling GH release, as appraised for all three of the pulsatile, entropic, and 12-h rhythmic modes of GH neuroregulation. The major maturational contrast in the pulsatile mode of GH secretion is amplified secretory burst mass in adolescents due to jointly heightened GH pulse amplitude and duration. The dominant gender distinction lies in the reduced orderliness of GH release patterns in late adolescent girls. Overnight rhythms in GH secretory burst mass and interburst intervals enlarge in both sexes at adolescence, thus signaling enhanced coupling between the rhythmic and pulsatile control of GH release at this time. At the extrema of pubertal development, sex steroid hormones are associated differentially with specific facets of GH release, e.g. an elevated basal GH secretion rate (estrogen), greater irregularity of GH release patterns (estrogen), and amplified GH secretory burst mass and higher plasma insulin-like growth factor I concentrations (testosterone). Accordingly, we postulate that sex steroids supervise selectively each of the dominant facets of GH neurosecretory control across human puberty.

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