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From the Clinical Research Centers |
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
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Abstract |
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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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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In light of the foregoing issues, the present studies evaluated GH secretion in healthy prepubertal and late adolescent boys and girls using 1) repetitive (10-min) blood sampling; 2) a high sensitivity chemiluminescence GH assay (sensitivity, 0.005 µg/L); 3) deconvolution analysis to estimate both basal and pulsatile GH secretion; 4) the approximate entropy (ApEn) statistic to quantify the regularity of GH release patterns, which is strongly gender dependent at least in the adult (21, 22); and 5) cosine regression to assess overnight rhythmic variations in GH secretory burst mass and frequency (i.e. rhythmic-episodic GH coupling). These neuroendocrine analyses unmask prominent interactive effects of gender and sexual maturation on each primary regulated facet of GH secretion.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The 4 study groups comprised a total of 58 healthy children:
i.e. prepubertal boys (n = 17) and girls (n = 11),
and late adolescent males (n = 13) and females (n = 17).
Corresponding ages are given in Table 1
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The height and weight of each subject fell between the 5th and 95th
percentiles for age based on standards from the National Center for
Health Statistics. In prepubertal children, the bone age was within 2
SD of values predicted for chronological age.
Prepuberty was defined in boys as stage I genitalia and pubic hair, and
in girls as stage I breasts and pubic hair, as described by Tanner.
Late adolescence was defined by pubertal developmental stage IV or V
for genitalia in boys and for breasts in girls. A nonoverlapping
description of the serum GH concentration peak characteristics in some
of these profiles was included in a previous body compositional
analysis (23).
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Clinical protocol
Volunteers were unmedicated with a normal medical history, physical examination, and screening blood tests of hematological, renal, metabolic, electrolytic, and hepatic function. No volunteers had acute illness, chronic disease, psychiatric disorder, recent medication use (within five biological half-lives), transmeridian travel (within 2 weeks), or significant weight changes (e.g. 1 kg or more within 10 days).
The sampling protocol consisted of repetitive blood removal overnight at 10-min intervals (1.5 mL each) for 12 h beginning at 1800 h. To allow adaptation, volunteers were admitted to the General Clinical Research Center in the morning (0800 h). A constant diet was given, beginning with breakfast. An iv catheter was inserted in a forearm vein at least 1 h before blood sampling began. Sleep monitoring was not performed, but lights were put out at 2000 h.
Screening endocrine measurements were made by RIA or immunoradiometric assay (IRMA) of (morning) serum concentrations of testosterone, estradiol, FSH, LH, PRL, insulin-like growth factor I (IGF-I), T4, and TSH (6, 17), all of which were appropriate to maturational state and gender.
Assays
GH concentrations were measured in each serum sample in duplicate by an automated ultrasensitive chemiluminescence-based assay (modified Nichols Luma Tag hGH assay; sensitivity, 0.005 µg/L) using human recombinant GH (22 kDa) as the assay standard, as described previously (17, 18, 19). The median inter- and intraassay coefficients of variation were less than 6.5% and 8.5%, respectively. All 73 serum samples from each admission were assayed together. Unknown sample values were interpolated from GH standard curves along with their joint variances, as described recently using a four- or five-parameter best-fit monotonic sigmoidal function (24).
Serum estradiol was measured by RIA using solid phase RIA (Coat-A-Count, Diagnostic Products, Los Angeles, CA) with a sensitivity of 10 pg/mL (17, 18). Undetectable sample values were arbitrarily assigned this threshold for statistical purposes.
Deconvolution analysis
Deconvolution analysis was applied to estimate basal and pulsatile GH secretion jointly (17, 25, 26). Total pulsatile GH secretion is calculated as the product of secretory burst frequency and the mean mass of GH released per pulse. Basal secretion represents time-invariant (interpulse) GH release (26). Overall GH production is the sum of these components. Deconvolution analysis was carried out using 95% statistical confidence intervals to define significant (nonzero amplitudes of) calculated GH secretory bursts (17, 27). The technician was blinded to study design.
Overnight (12-h) rhythmicity
Cosine regression with a 720-min periodicity was used to quantify the inherent overnight rhythms in deconvolution-calculated GH secretory burst mass and intersecretory pulse intervals in each of the four study groups (27, 28). Only rhythms with significantly nonzero (P < 0.05) amplitudes were considered further.
ApEn
ApEn was applied as a scale- and model-independent statistic to quantify the orderliness or regularity of GH release patterns. Normalized ApEn parameters of m = 1 (series length) and r = 20% (threshold) of the intraseries SD were applied, as previously described (6, 22). This ApEn statistic is thus designated ApEn (1, 20%). ApEn evaluates the consistency of recurrence of subpatterns in the data. For a neuroendocrine axis, ApEn is an indirect barometer of feedback activity. Higher absolute ApEn values given the same series lengths and ApEn parameter values as those used here denote greater disorderliness of subordinate patterns in the time series.
Statistical analysis
Because of nonnormal distributions, measures derived by deconvolution, entropy, and cosinor analyses were compared by ANOVA after logarithmic transformation (1). Mean and integrated (12-h) serum GH concentrations were compared by ANOVA of untransformed data. Computed data are presented as the mean ± SEM. Statistical significance was construed for P < 0.05.
Linear regression analysis was applied to test for correlations between
GH secretory pulse mass and serum IGF-I or sex steroid hormone
concentrations. To allow for multiple comparisons, we used a protected
P value of 
0.01, which, on the average, would yield only
one false positive inference for each 100 regressions carried out.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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, overnight
frequently sampled serum GH concentration profiles in prepubertal boys
and girls and late adolescents of both sexes were visibly pulsatile.
Figure 1A shows the observed and deconvolution-predicted fits of the
serial serum GH concentrations. Figure 1B shows the calculated
underlying GH secretory bursts, highlighting the episodicity of release
in males and females.
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summarizes the mean and
integrated (12-h) serum GH concentrations in the total of 58
prepubertal and late adolescent girls and boys studied. There were 2-
to 2.5-fold increases in the mean and integrated serum GH
concentrations in late puberty (P <
10-6), which were gender
independent (Fig. 2).
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illustrates that the mass of GH
secreted per burst (integral of the calculated GH secretory event) was
maturation (but not gender) dependent, whereas GH burst frequency was
not (Table 2). There were 2.2- to
2.3-fold elevations in GH secretory burst mass in adolescent males and
females compared with values in prepubertal children of either gender.
The amplification of GH secretory burst mass in adolescents reflected a
1.5-fold augmentation of GH secretory burst amplitude (calculated
maximal rate of GH secretion attained within a release episode) and a
concomitant 1.5-fold prolongation of the GH secretory burst
half-duration (computed duration of the underlying secretory pulse at
half-maximal amplitude; P < 0.01). In contrast, GH
half-life, secretory burst duration, frequency, and interburst
interval were invariant of either gender or maturational status (Table 2).
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Prepubertal boys and girls had similar pulsatile GH secretion rates, as
did adolescent males and females. Basal GH secretion did not vary
significantly (Table 2
). The mean percentage of GH secretion that was
pulsatile was invariant across the four study groups, as follows:
96 ± 11% (girls) and 91 ± 9.3% (boys), 96 ± 8.9%
(female adolescents), and 97 ± 13% (male adolescents;
P = NS).
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, mean GH ApEn was significantly higher
in adolescent females than in prepubertal girls, prepubertal boys, or
adolescent males (P = 0.00074). These differences
signify that adolescent girls (only) maintain a more irregular GH
release process.
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. The mass of GH secreted per burst
varied significantly overnight by a mean amplitude of approximately
35% of the mesor in all four study groups. The absolute amplitude of
this variation was greater in late adolescents of both genders than in
prepubertal boys (but not girls). There was no other sex difference
either before puberty or in late adolescence. GH interpulse intervals
also maintained significant overnight rhythmicity, albeit at a slightly
lower fractional amplitude than pulse mass (i.e. by a mean
amplitude of 
21% of the mesor). The mesor of this rhythm was higher
in adolescents of both genders than in prepubertal girls (but not
boys).
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. Strongly positive linear correlations
were evident between 1) the serum estradiol concentration and the ApEn
(irregularity) of GH secretion (P <
10-4) as well as basal GH
secretion (P = 0.013), 2) the serum testosterone
concentration and GH secretory burst mass (P = 0.001)
and GH half-life (P = 0.0025), and 3) the plasma IGF-I
concentration and GH secretory burst mass (P <
10-5).
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Discussion |
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The present investigation in healthy children reveals that GH secretory burst mass is sex independent before puberty. In contrast, in young and midadulthood, GH secretory pulse mass is strongly (1.5- to 2.0 fold) gender dependent (27). However, male and female adolescents exhibited a prominent amplification of GH pulse mass compared with prepubertal children. The difference was mechanistically specific, as the basal GH secretion rate, burst frequency, interpulse interval and GH half-life were not affected by pubertal status. Deconvolution analysis attributed the elevation in GH pulse mass to a combined (1.5-fold) greater secretory burst duration and amplitude (maximal rate of GH secretion attained within a secretory pulse). We are unaware of any prior recognition of the latter dual mechanism of physiological regulation of pulsatile GH secretion in puberty. Indeed, previous application of a 20-min blood sampling regimen and a lower sensitivity GH IRMA identified only an increase in GH secretory burst amplitude in pubertal boys (4), most likely reflecting the dual technical constraints of limited sampling frequency and imperfect assay sensitivity (see the introduction).
According to current neuroregulatory concepts, GH secretory pulses are evoked when an adequate hypothalamic (GHRH) stimulus is delivered via the hypothalamo-pituitary portal microvasculature to responsive somatotrope in the absence of excessive restraint by somatostatin (1). Single hypothalamo-pituitary portal venous blood samples in urethane-anesthetized adult male rats disclosed simultaneous somatostatin withdrawal and GHRH release during a pulse of GH secretion (29). In other mammals, such as the sheep and pig, high frequency repeated portal blood sampling in conscious animals has unveiled a wider variety of somatostatin-GHRH interactions (30, 31). This disparity may reflect technical differences, species distinctions, and/or modulatory signaling by other putative coregulators of GH secretion (1). Considering the simplest model of reciprocal release of GHRH and somatostatin, our finding of an elevated mass of GH secreted per burst in late adolescence would probably reflect enhanced competing pituitary actions of GHRH over somatostatin. Inferred GHRH predominance could be mediated, in turn, via an absolute increase in hypothalamic GHRH release or action and/or a reduction in somatostatin restraint. In the present analysis the unchanging GH secretory burst frequency would speak against a mechanism that involves solely a reduction in hypothalamic somatostatin secretion in late puberty. This reasoning follows from analyses in other clinical states marked by presumptive somatostatin withdrawal, e.g. fasting, type I diabetes mellitus, and sleep, wherein the same sampling and analytical techniques readily detect accelerated GH secretory burst frequency (17, 27, 32). Conversely, GH peak frequency falls in response to short-term iv infusion of somatostatin in young men (20). The present new data thus favor (but do not prove) an interpretation of amplified endogenous GHRH release and/or actions in late adolescence, rather than exclusively or predominantly somatostatin withdrawal during the nighttime phase of GH release. To our knowledge, analogous data are not available for the daytime fed state.
Although the identities of postulated endogenous (non-GHRH) cosecretogogues of GH remain unknown in the human, constant iv infusion of GH-releasing peptide-2 (GHRP-2), a novel (non-GHRH) synthetic hexapeptide stimulus of GH release selectively amplifies GH secretory burst mass and concurrently elevates the plasma IGF-I concentration without altering the half-life of GH, the interpulse interval, or the pulse frequency (33). These GHRP-2-driven dynamics in the adult closely emulate the foregoing physiology of the maturing GH axis in adolescents of both sexes. Thus, albeit unproven, the present clinical data do not exclude a possible role for (putative) endogenous GHRP-like cosecretagogues in augmenting pulsatile GH secretion in late puberty.
Deconvolution analysis and an ultrasensitive GH assay here predicted equivalent basal (interpulse) GH secretion in prepubertal and late adolescent girls and boys. Whereas analysis of basal hormone release is technically difficult, especially if there are few interpulse measurements of serum hormone concentrations (34), the present 12-h GH profiles typically displayed intervals of secretory quiescence at the onset (1800 h) and/or offset (0600 h) of the blood-sampling session. Basal GH secretion in puberty is of interest, because virtually nothing is known about its physiological regulation in the human. Indeed, until recently, interpulse serum GH concentrations often remained undetectable in both the experimental animal (e.g. adult male rat as studied by RIA) and human (e.g. adults and children evaluated in the daytime fed state using earlier IRMAs). The present analysis unexpectedly demonstrated apparently unchanging basal GH secretion rates in pre- and late puberty. This finding is probably not artifactual, as the same deconvolution technique disclosed severalfold elevated basal GH release in premenopausal women compared with similarly aged men (27, 35). On the other hand, considering the entire group of 58 volunteers, the present study in prepubertal and late adolescent children revealed a strongly positive linear relationship between estradiol and the basal GH secretion rate (P = 0.013). This observation in children should be distinguished from an earlier reported weakly negative correlation between estradiol and basal GH secretion in a cohort of 26 healthy men across a wide span of ages and body composition (see below) (17).
Recent clinical application of ultrasensitive GH assays has revealed that (basal) interpulse GH release persists in hypopituitary patients (36), somatostatin-infused men (20), estrogen-withdrawn postmenopausal women (37), and hypothyroid, obese, and older volunteers (17, 18). The origin and regulation of nonpulsatile GH secretion are poorly understood. However, in one recent study, repeated pulsatile iv infusions of GHRH (0.33 µg/kg bolus every 90 min for 3 days) in healthy men significantly increased basal GH secretion, as estimated by deconvolution analysis (38). Continuous infusion of GHRP-2 (1 µg/kg·h, iv, for 24 h) in postmenopausal women also elevated basal GH secretion (39). In contrast, in a similar population, oral estrogen administration raised interpulse serum GH concentrations solely by augmenting GH secretory pulse mass (37). In the latter context, we emphasize that increases in interpeak serum GH concentrations can arise from one of several distinguishable secretory mechanisms, e.g. more frequent GH secretory bursts, a higher burst mass, a prolonged hormone half-life, and/or greater basal secretion (25, 26, 40). Thus, appropriate analytical tools must be applied to dissect the individual contributions of the foregoing mechanisms.
As a complementary, but statistically independent, measure of neuroregulation within the GH axis, we used the ApEn statistic. This new regularity metric quantifies the reproducibility or orderliness of biological time series, such as hormone release patterns, and can serve as a barometer of feedback activity within an axis (41, 42, 43). The ApEn measure showed that neither gender nor pubertal maturation singly controls the orderliness of GH release, as only late adolescent girls exhibited more disorderly GH secretory patterns (P = 0.00074). Elevated ApEn values in older girls are consistent with the emergence of new or stronger feedback interactions within the adolescent female GH-IGF-I axis (6). More intense interactions could reflect changing patterns of hypothalamic somatostatin and GHRH release, altered intrapituitary (paracrine or autocrine) regulation of somatotrope function, and/or reduced negative feedback effects of GH or IGF-I on the hypothalamo-pituitary unit. The available clinical data cannot yet distinguish definitively among these primary hypotheses. However, experiments in the rodent have unmasked consistently attenuated GH autonegative feedback in the female compared with the male animal (44). In thematic analogy, a recent clinical study showed that young women are relatively resistant (compared with young men) to the GH-suppressing effect of peripherally infused IGF-I (45). Thus, we can suggest that the elevated ApEn of GH profiles in late adolescent girls may mirror reduced GH and/or IGF-I autonegative feedback at this time (6, 17, 21). This change could be due to relative estrogen predominance, as gonadectomy or GnRH agonist-induced down-regulation of the reproductive axis in the immature rat blunts the vivid gender contrast in GH release patterns otherwise evident in the adult (21). In corollary, in clinical studies, the administration of estrogen (or aromatizable androgen) elicits more irregular patterns of GH release (6, 37, 46), and thereby mimics the foregoing greater disorderliness of GH evident in late pubertal girls. Thus, we speculate that heightened irregularity of GH release patterns in women (22) and late adolescent girls (present data) originates from estrogen-dependent regulation of GH and/or IGF-I feedback control mechanisms. Further interventional experiments will be needed to confirm or refute this clinical hypothesis.
Diurnal rhythms in serum concentrations in the adult can be ascribed to corresponding 24-h variations in (ultradian) secretory burst amplitude (mass) and/or frequency (28). With respect to both sleep and the smaller circadian contribution (17), nyctohemeral rhythmicity of GH release is probably under the supervision of one or more central nervous system (CNS) regulatory centers (1). Here, we applied cosine regression analysis to evaluate overnight rhythmic variations in GH secretory pulse mass and interpulse interval. Thereby, we could assess the degree of coupling of the rhythmic and episodic modes of GH secretion in children of both sexes before and during late puberty. GH secretory burst mass and interpulse interval both varied significantly (respectively, by 35% and 21% of their mean values) overnight in prepubertal and adolescent males and females. The mass of GH secreted per burst was maximal (acrophase) at approximately midnight. Although sleep monitoring was not performed in these children, the acrophase mirrors the expected rise in GH secretion during first onset deep (slow wave) sleep (47). The amplitude as well as the cosine mean of the nighttime variation in the mass of GH secreted per burst increased by 2-fold in adolescents of both sexes compared with prepubertal boys (but not girls, who showed intermediate values). GH interpulse interval values likewise exhibited a significant nighttime rhythmicity in all four study groups, with an estimated nadir (corresponding to the time of the maximum in GH secretory burst frequency) at approximately 0645 h. This acrophase was independent of gender and maturation. On the other hand, the cosine mean of the rhythm in interpulse intervals was higher in adolescents of both sexes than in prepubertal girls (but not prepubertal boys). The foregoing sex-distinctive variations in GH secretory burst mass and frequency in puberty may reflect developmental modulation of GH pulsatility via a combination of relevant CNS inputs, e.g. neural signals originating in the suprachiasmatic nucleus, and other inputs associated with the sleep-wake activity cycle (1). Additional clinical experiments will be required to identify the nature of CNS pathways that confer these gender and maturation-dependent changes in rhythmic-pulsatile GH coupling.
In summary, the present multifold analyses of GH secretory dynamics in 58 prepubertal and late adolescent healthy boys and girls indicate that 1) basal GH secretion is evident before puberty in both sexes; 2) GH half-life, pulse frequency, interburst interval, pulse duration, burst amplitude and mass, and the ApEn of GH release patterns are gender independent before puberty; 3) the ApEn of GH secretory patterns increases significantly in the late adolescent female compared with the late pubertal male and prepubertal children of both genders; 4) basal GH secretion, GH half-life, and GH pulse frequency do not differ before and after puberty; 5) GH secretion is predominantly pulsatile (global mean, 95% of total secretion) in both prepuberty and late puberty in both sexes; and 6) the overnight rhythms in GH secretory burst mass and frequency are amplified in late adolescents compared with prepubertal boys and girls, respectively. Correlation analysis reveals that both basal GH secretion and the irregularity of GH release patterns relate positively to the serum estradiol concentration, whereas plasma IGF-I and GH secretory burst mass vary directly with the serum testosterone concentration. These different statistical associations point to differential roles of estrogen and androgen in mediating developmental changes in the pubertal GH-IGF-I axis. Although we did not correlate the dynamic measure of GH release with linear growth velocities in this cross-sectional study, an earlier longitudinal assessment across male pubertal development revealed a marked rise in 24-h GH ApEn approximately 4 months before attainment of maximal height velocity (48). Other cross-sectional analyses of normal growing children also relate GH pulse mass to plasma IGF-I levels and height increments (1, 2, 4, 5, 8, 9, 10, 11). We conclude that gender and sexual maturation jointly modulate specific facets of neuroregulatory control of the human GH-IGF-I axis via preferential sex hormone drive of the basal, pulsatile, entropic, and rhythmic modalities of GH secretion.
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Acknowledgments |
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Footnotes |
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Received December 2, 1999.
Revised March 10, 2000.
Accepted April 1, 2000.
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