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1 Guilford, Connecticut 06437; 2 Department of Internal Medicine, General Clinical Research Center, Center for Biomathematical Technology, 3 National Science Foundation Center for Biological Timing, and 4 Department of Pediatrics, University of Virginia, Charlottesville 22908; and 5 INSMED Pharmaceuticals, Richmond, Virginia 23219
Clarifying the time
evolution, and underlying neuroendocrine regulation, of hormone
secretion during puberty is of pivotal importance both physiologically
and clinically. We sought to determine whether clinical growth and
elevated growth hormone (GH) release in pubertal boys are associated
with shifts in the irregularity of GH secretory patterns. We studied GH
release in 23 healthy boys longitudinally at ~4-mo intervals over a
6-yr period throughout puberty, by repetitive blood sampling at 20-min
intervals for 24 h on each study date. To quantify serial
irregularity in the GH profiles, we utilized approximate entropy
(ApEn), a scale- and model-independent quantification of the extent of
sequential "randomness." Complementary statistical analyses
establish that on a per-subject basis, serum GH concentration-time
series show greatest secretory disorderliness (maximal ApEn) in
prepuberty and mid-to-late puberty, followed by a steep decline in ApEn
to maximal orderliness in postpubertal adolescence (P < 0.0001, ANOVA). Pooling all subject comparisons, we observed a
persistent positive correlation between ApEn and growth velocity
(GrVel), Pearson r = 0.467 (P < < 10
10). Moreover, in general, ApEn(GH) preceded GrVel
evolution, with a time frame lead of 4-8 mo providing the most
pronounced correlations between ApEn and GrVel. In the setting of low
postpubertal growth, per-subject ApEn values fell to approximately
one-half of maximal ApEn values and, on average, were in the 13th
percentile from minimal (P < < 10
10)
for fully mature boys. Thus, in a longitudinal transpubertal analysis,
greater irregularity in GH secretion corresponds to greater linear
growth in boys, which culminates in highly regular GH secretory
dynamics after sexual maturity. In addition to clinical utility, there
may be added experimental merit in knowing that GH dynamics typically
predict accelerated linear growth in 4-8 mo.
approximate entropy; pulsatility; growth rate; somatotropic axis; humans
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