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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 6 2140-2150
Copyright © 1999 by The Endocrine Society

Original Studies

Tripartite Neuroendocrine Activation of the Human Growth Hormone (GH) Axis in Women by Continuous 24-Hour GH-Releasing Peptide Infusion: Pulsatile, Entropic, and Nyctohemeral Mechanisms1

N. Shah2, W. S. Evans, C. Y. Bowers and J. D. Veldhuis

Division of Endocrinology, Department of Internal Medicine (N.S., W.S.E., J.D.V.), National Science Foundation Center for Biological Timing, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908; the Division of Endocrinology and Metabolism, Tulane University Medical Center (C.Y.B.), New Orleans, Louisiana 70112-2699

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


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Despite the discovery of potent GH-releasing peptides (GHRPs) more than 15 yr ago and the recent cloning of human, rat, and pig GHRP receptors in the hypothalamus and pituitary gland, the neuroregulatory mechanisms of action of GHRP agonists on the human hypothalamo-somatotroph unit are not well delineated. To gain such clinical insights, we evaluated the ultradian (pulsatile), entropic (pattern orderliness), and nyctohemeral GH secretory responses during continuous 24-h iv infusion of saline vs. the most potent clinically available hexapeptide, GHRP-2 (1 µg/kg·h) in estrogen-unreplaced (mean serum estradiol, 12 ± 2.4 pg/mL) postmenopausal women (n = 7) in a paired, randomized design. Blood was sampled every 10 min for 24 h during infusions and was assayed by ultrasensitive GH chemiluminescence assay. Pulsatile GH secretion was quantitated by deconvolution analysis, orderliness of GH release patterns by the approximate entropy statistic, and 24-h GH rhythmicity by cosinor analysis. Statistical analysis revealed that GHRP-2 elicited a 7.7-fold increase in (24-h) mean serum (±SEM) GH concentrations, viz. from 0.32 ± 0.042 (saline) to 2.4 ± 0.34 µg/L (GHRP-2; P = 0.0006). This occurred via markedly stimulated pulsatile GH release, namely a 7.1-fold augmentation of GH secretory burst mass: 0.87 ± 0.18 (control) vs. 6.3 ± 1.3 µg/L (GHRP-2; P = 0.0038). Enhanced GH pulse mass reflected a commensurate 10-fold (P = 0.023) rise in GH secretory burst amplitude [maximal GH secretory rate (micrograms per L/min) attained within a secretory pulse] with no prolongation in event duration. GH burst frequency, interpulse interval, and calculated GH half-life were all invariant of GHRP-2 treatment. Concurrently, as detected in the ultrasensitive GH assay, GHRP-2 augmented deconvolution-estimated interpulse (basal) GH secretion by 4.5-fold (P = 0.025). The approximate entropy of 24-h serum GH concentration profiles rose significantly during GHRP-2 infusion; i.e. from 0.592 ± 0.073 (saline) to 0.824 ± 0.074 (GHRP-2; P = 0.0011), signifying more irregular or disorderly GH release patterns during secretagogue stimulation. Cosinor analysis of 24-h GH rhythms disclosed a significantly earlier (daytime) acrophase at 2138 h (±140 min) during GHRP-2 stimulation vs. 0457 h (±42 min) during saline infusion (P = 0.013). Concomitantly, the cosinor amplitude rose 6-fold (P = 0.018), and the mesor (cosine mean) rose 5-fold (P = 0.003). Fasting (0800 h) plasma insulin-like growth factor (IGF-I) concentrations rose by -11 ± 12 µg/L during saline infusion and by 102 ± 18 µg/L during GHRP-2 infusion (P = 0.0036). GHRP-2 infusion did not modify (24-h pooled) serum LH, FSH, or TSH concentrations and minimally increased serum (pooled) daily PRL (6.8 ± 0.83 vs. 12 ± 1.2 µg/L; P < 0.05) and cortisol (5.3 ± 0.59 to 7.0 ± 0.74; P < 0.05) concentrations.

In summary, 24-h constant iv GHRP-2 infusion in the gonadoprival female neurophysiologically activates the GH-IGF-I axis by potentiating GH secretory burst mass and amplitude by 7- to 10-fold and augmenting the basal (nonpulsatile) GH secretion by 4.5-fold. GHRP-2 action is highly selective, as it does not alter GH secretory burst frequency, interpulse interval, event duration, or GH half-life. GHRP-2 effectively elevates IGF-I concentrations, unleashes greater disorderliness of GH release patterns, and heightens the 24-h rhythmicity of GH secretion. These tripartite features of GHRP-2’s action in estrogen-withdrawn (postmenopausal) women also characterize normal human puberty and/or sex steroid regulation of the GH-IGF-I axis. However, how or whether GHRP-2 interacts further with sex hormone modulation of GH neurosecretory control in older women and men is not yet known.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
NOVEL GH-releasing peptides (GHRPs) and nonpeptidyl GHRP mimetics can potently activate GH secretion in experimental animals and the human (1, 2, 3, 4, 5). Recent cloning of GHRP receptors in several species (6) has prompted a continuing search for a corresponding putative endogenous GHRP-like ligand(s) (7). The GHRP receptor gene encodes type 1a and 1b transcripts, the former serving as an effective ligand-activated, G protein-coupled, transmembrane-expressed transducer of intracellular calcium, inositol phosphate, and protein kinase C second messenger signals (7, 8, 9). The GHRP receptor is structurally and functionally distinct from that of either GHRH or somatostatin by way of ligand binding specificity, second messengers, desensitization profile, and somatotroph cell distribution (10, 11). Multiple hypothalamic and pituitary sites of GHRP receptor expression are evident (11, 12, 13, 14). Nonetheless, to date, the precise in vivo neuroregulatory actions of GHRP agonists in the human remain poorly defined (15).

Several plausible neuroendocrine mechanisms may subserve the actions of GHRPs. First, GHRPs can stimulate pituitary GH secretion directly (albeit relatively modestly, by 2- to 3-fold) in studies using in vitro perifusion, monolayer culture, or single somatotroph cells in the rat, sheep, cow, and human (1, 4, 14). Secondly, GHRPs act on the central nervous system (CNS) to evoke sleep in the human, increase appetite in rats, trigger hypothalamic electrophysiological activity, stimulate c-fos gene and protein expression in the ventromedial and arcuate nuclei of the rat and hamster, and elicit GHRH release into hypothalamo-pituitary portal blood of sheep (4, 12, 16, 17, 18, 19). Thirdly, GHRPs can partially oppose somatostatin’s actions both in the brain, where somatostatin otherwise inhibits GHRH release, and on (pituitary) somatotrophs, where somatostatin exerts countervailing effects on calcium influx and membrane depolarization (8, 12, 16). Fourth GHRPs synergize with GHRH (4, 15, 20, 21, 22). Lastly, GHRPs may release a putative hypothalamic U (unknown) factor that would in part explicate their typically greater in vivo than in vitro potency (20). Indeed, maximal GHRP stimulation in the human requires an intact hypothalamo-pituitary unit (23), consistent with the importance of one or more hypothalamic mechanisms of action of GHRPs (4).

The pulsatile, entropic, and 24-h rhythmic modes of GH secretion are believed to be endowed, respectively, by 1) the coordinate actions of hypothalamic GHRH and somatostatin to control GH pulsatility; 2) multiple intra- and extrapituitary regulatory signals converging on somatotroph cells to dictate entropic measures, and 3) diurnally varying neuronal inputs from the suprachiasmatic nuclei and sleep/activity centers to supervise 24-h rhythms (4, 24). Given the potentially confounding actions of sex hormones on one or more of these distinct neuroregulatory mechanisms (5), here we initially investigate GHRP’s actions on the GH-insulin-like growth factor I (IGF-I) axis in the gonadoprival state. To this end, we have infused continuously for 24 h in estrogen-withdrawn postmenopausal women the most potent GHRP effector clinically available, viz. GHRP-2, which can activate GH secretion at doses even lower than those of GHRP-6 (25). We hypothesized that a GHRP receptor agonist would drive enhanced GH secretion via native GHRP receptors expressed in the human hypothalamo-pituitary unit (4) and thereby help to unmask specific neuroregulatory mechanisms of action of this family of secretagogue molecules.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Clinical protocol

Seven healthy postmenopausal women (aged 58–68 yr), each of whom had experienced clinical menopause at least 2 yr before the study, provided written informed consent approved by the human investigation committee of the University of Virginia Health Sciences Center. The (mean ± SEM) body mass index was 27 ± 1.4 kg/m2. All volunteers were unmedicated, had received no hormone replacement therapy for at least 4 weeks, and had a normal medical history, physical examination, and screening blood chemistry tests of hematological, renal, electrolytic, metabolic, and hepatic function. There were no acute illnesses, chronic diseases, psychiatric disorders, recent use of medications (within five biological half-lives), transmeridian travel within 2 weeks, or significant weight changes (2 kg or more within 10 days).

The blood-sampling protocol consisted of blood removal from a forearm vein at 10-min intervals (2 mL) for 24 h beginning at 0800 h after admission to the General Clinical Research Center the evening before. The iv catheter was inserted at least 2 h before blood sampling began. Volunteers received an isocaloric diet consisting of three meals provided at 0800, 1200, and 1700 h.

Assays

Serum GH concentrations were measured in each sample in duplicate by a fully automated ultrasensitive GH chemiluminescence assay (modified Nichols Luma Tag hGH assay, Nichols Institute Diagnostics, San Juan Capistrano, CA; sensitivity, 0.005 µg/L) using human recombinant GH (22 kDa) as assay standard (26, 27). The median inter- and intraassay coefficients of variation were both less than 7.5%. All 145 serum samples from each admission were assayed together. Serum IGF-I, estradiol, cortisol, TSH, LH, FSH, and PRL concentrations were measured in a single 24-h pool of serum from each subject in duplicate by RIA, immunoradiometric assay (IRMA), or chemiluminescence assay (26, 27).

Deconvolution analysis

Deconvolution analysis was applied to estimate pulsatile GH secretion and the GH half-life (27, 28, 29). Daily pulsatile GH secretion is the product of secretory burst frequency and the (mean) mass of GH released per pulse. Basal secretion represents the time-invariant interpulse component of the GH release profile (29). Analysis was carried out requiring 95% joint statistical confidence intervals for all GH secretory burst amplitudes (27, 30).

Nyctohemeral (24-h) rhythmicity

Diurnal rhythmicity of serum GH concentrations was appraised by cosinor analysis (31). Separately, the 24-h rhythms of calculated GH secretory burst mass and interpulse intervals were quantitated in each of the two sessions.

Approximate entropy (ApEn)

ApEn was used as a scale- and model-independent statistic that is complementary to (and distinct from) pulse detection and cosinor analyses (32). ApEn quantifies the serial orderliness or pattern regularity of the (hormone) release process over 24 h. Normalized ApEn parameters of m = 1 (series length) and r = 20% (threshold) of the intraseries SD were used, as previously described (33). This statistic is thus designated ApEn (1, 20%). Other thresholds of 10% and 30% were also tested. ApEn quantifies the reproducibility of subordinate (nonpulsatile) patterns in serial hormone measurements. A higher absolute ApEn value (at equal series lengths and parameter values as those used here) denotes greater disorderliness (randomness) of moment to moment hormone release, as observed previously for GH in acromegaly (34), aging men (27), and women compared to men (33).

Statistical analyses

Because of nonnormal distributions, the various deconvolution, entropy, and cosinor measures were compared using a paired two-tailed nonparametric (Wilcoxon) test. Mean and integrated (24-h) serum GH, LH, FSH, TSH, cortisol, estradiol, and PRL concentrations were assessed by a paired two-tailed Student’s t test. Computed data are presented as the mean ± SEM (median). Statistical significance was construed for P < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Figure 1AGo illustrates 24-h serum GH concentration profiles obtained by 10-min blood sampling during saline vs. GHRP-2 infusions (assigned in randomized order) in three (of seven) postmenopausal women. The corresponding deconvolution-calculated GH secretory profiles are presented in Fig. 1BGo. All profiles exhibited visually evident pulsatile GH release over 24 h in both the saline- and GHRP-2-stimulated sessions.




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  		Figure 1. Illustrative profiles of serum GH concentrations obtained by sampling every 10 min for 24 h in three (of seven) healthy postmenopausal women during randomly ordered continuous iv saline (control) or GHRP-2 (1 µg/kg·h) infusions. A, Serum GH concentrations and deconvolution-predicted (fitted) curves. B, Calculated GH secretory profiles logarithmically displayed. Arrows mark significant GH secretory bursts. Insets show expanded scale views.

 
Figure 2Go depicts the increases (average, 7.7-fold) in 24-h mean and integrated serum GH concentrations elicited in the seven individual women given GHRP-2 vs. saline infusions.



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  		Figure 2. Individual postmenopausal women’s 24-h mean (top) and integrated (bottom) serum GH concentrations during continuous iv saline vs. GHRP-2 (1 µg/kg·h) infusions. Numerical values are the mean ± SEM (n = 7 women). The P value was determined by paired two-tailed Student’s t testing. Volunteers were studied as described in Fig. 1Go and Materials and Methods.

 
Deconvolution analysis was used to quantitate the mass, amplitude, frequency, and duration of GH secretory bursts over 24 h. Figure 3AGo depicts the individual data underlying the 7.1-fold mean augmentation of GH secretory burst mass achieved by GHRP-2 infusion and the commensurate rise in GH secretory burst amplitude (Fig. 3BGo). In contrast, calculated GH secretory burst duration, GH half-life, secretory burst frequency, and interpulse interval were all independent of treatment (see Table 1Go). In addition, serum (24-h pooled) TSH, estradiol, LH, and FSH concentrations remained unaffected by continuous 24-h iv secretagogue administration (Table 1Go).



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  		Figure 3. Individual women’s deconvolution-calculated GH secretory burst mass (top panel) and amplitude (maximal rate of GH secretion attained within each secretory pulse; bottom panel) during continuous iv saline (control) vs. GHRP-2 infusions over 24 h (see Fig. 2Go). The P value is nonparametric.

 

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  		Table 1. Selected end points not influenced by continuous GHRP-2 infusions in the ovariprival state

 
As summarized in Fig. 4Go, GHRP-2 infusion significantly enhanced basal GH secretion over 24 h, viz. by 4.5-fold (P = 0.025). As 24-h pulsatile GH secretion rose by 8.3-fold (P = 0.0057) in response to GHRP-2 stimulation, calculated total (pulsatile plus basal) 24-h GH secretion also rose significantly, viz. by a mean 8-fold (P = 0.0053).



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  		Figure 4. Partitioning of total daily GH secretion (micrograms per L; top panel) into pulsatile (middle panel), and basal (bottom panel) production in seven individual postmenopausal women infused iv with saline (control) or GHRP-2 for 24 h (see Fig. 3Go).

 
Figure 5Go shows the significant rise in ApEn values of 24-h GH profiles evoked by continuous GHRP-2 infusion in the group of seven postmenopausal women. An elevated ApEn during GHRP-2 infusion was also evident at either lower or higher thresholds (10%, and 30% thresholds, P = 0.0005 and P = 0.014, respectively; see Materials and Methods). Higher entropy values denote greater irregularity, inconsistency, or disorderliness of moment to moment GH release patterns over the 24 h.



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  		Figure 5. ApEn (1, 20%) of 24-h serum GH concentration profiles in seven individual women administered saline (control) or GHRP-2 iv continuously for 24 h. Higher ApEn (see Materials and Methods for technical definition) denotes greater process randomness or disorderliness of GH release patterns. Data are presented otherwise as described in the legend of Figure 3Go.

 
Figure 6Go depicts the GHRP-2-induced changes in 24-h rhythmicity of serum GH concentrations, as assessed by cosinor analysis. GHRP-2 significantly increased the amplitude (by 6-fold; P = 0.018) and mesor (mean value about which the 24-h GH rhythm oscillates, by 5-fold, P = 0.003), and shifted the acrophase (time of the maximal GH concentration) from 0457 h (±42 min) to 2138 h (±140 min; P = 0.013).



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  		Figure 6. Cosinor analysis of 24-h rhythmicity of serum GH concentrations during continuous iv saline (control) or GHRP-2 infusions in seven individual postmenopausal women. Acrophase, Time of maximal serum GH concentrations (minutes before 0800 h); amplitude, half the maximal excursion in the 24-h rhythm; mesor, cosine mean. Data are individual values with group mean ± SEM, which are presented otherwise as described in Fig. 3Go.

 
Figure 7Go illustrates the 24-h rhythms in deconvolution-calculated GH secretory burst mass and interpulse interval in the saline vs. GHRP-2 infusion sessions. Quantitative results are summarized in Table 2Go. GHRP-2 infusion markedly (by 9-fold) stimulated the 24-h rhythm in GH secretory burst mass and abolished the 24-h rhythm in GH secretory burst frequency.



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  		Figure 7. Twenty-four-hour variations in deconvolution-calculated GH secretory burst mass (A) and intersecretory burst interval (B). Burst mass units are micrograms per L, and interpulse interval units are minutes. Data are from all seven women during control (saline) vs. GHRP-2 infusions. The continuous curves plotted through the individual data points are best-fit (24-h) cosinor rhythms. See Table 2Go for quantitative values of amplitude, acrophase, and mesor (mean) of fitted curves.

 

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  		Table 2. Cosinor analysis of 24-h rhythmicity of deconvolution-estimated GH interpulse interval and GH secretory burst mass

 
Figure 8Go gives the individual serum (24-h pooled) concentrations of cortisol and PRL, both of which exhibited small, but statistically consistent, increases during GHRP-2 infusions. Figure 9Go shows that 24-h incremental serum IGF-I concentrations (algebraic difference between value at 0800 h after the infusion vs. 0800 h at the start of the infusion) rose significantly during GHRP-2 infusion; namely, by 102 ± 18 vs. by -11 ± 12 µg/L during saline infusion (P = 0.0036).



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  		Figure 8. Individual women’s serum (24-h pooled) concentrations of cortisol (top) and PRL (bottom) in the control (saline/placebo) vs. GHRP-2 infusion sessions. Data are presented otherwise as described in Fig. 2Go.

 


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  		Figure 9. Twenty-four-hour incremental serum IGF-I concentrations in seven individual women in response to iv saline vs. GHRP-2 (1 µg/kg·h) infusions. The incremental serum IGF-I concentration was defined as the algebraic difference in each women between the 0800 h values at the end vs. the beginning of the infusion. Data are presented as defined in Fig. 2Go.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The specific short term (24-h) neuroregulatory actions of sustained GHRP-2 stimulation in healthy gonadoprival women impact three major categories of GH-IGF-I axis dynamics, with correspondingly distinctive physiological implications. First, GHRP-2 prominently potentiated pulsatile (ultradian) GH release, namely by 7- to 10-fold, which presumptively reflects enhancement of GHRH/somatostatin interactions. Secondly, GHRP-2 elevated the ApEn of serial GH release patterns over 24 h, indicating heightened disorderliness of GH secretion, and thereby probably reflecting augmentation of multiple convergent inputs to somatotrophs. And, thirdly, GHRP-2 amplified the 24-h rhythmicity of serum GH concentrations, consistent with greater diurnal hypothalamo-pituitary drive by neural signals from the suprachiasmatic (circadian) nucleus and/or other CNS sleep/wake centers. These three principal mechanistic responses to GHRP-2 infusions in estrogen-deprived women also are displayed spontaneously in midpuberty and during sex hormone treatment (4, 35, 36, 37). Such similitude suggests, but does not prove, that GHRP-related pathways might participate in one or more of the physiological neuroregulatory responses triggered by sex hormones in human puberty.

A novel action of GHRP-2 documented here, but not yet identified during pubertal activation of the GH axis, is marked stimulation (by 4.5-fold) of basal/nonpulsatile GH secretion. Basal GH release has become detectable only recently in adults via ultrasensitive (e.g. enzyme-linked, immunofluorometric, and chemiluminescence-based) GH assays (26, 27, 30, 38). In contrast, studies in puberty have not yet used a chemiluminescence assay to quantitate low rates of basal daytime GH secretion, which often fall below the limits of detection of conventional RIA, IRMA, and, in lesser measure, immunofluorometric GH assays (27, 30, 36). Indeed, the physiological mechanisms that regulate putatively basal GH release in the human are not well delineated and may or may not be sex hormone dependent or of hypothalamo-pituitary origin. However, a gender difference consisting of higher basal (interpulse) serum GH concentrations of 1.5- to 8-fold in women than men was unveiled by immunofluorometric (30) and chemiluminescence assays (26, 39). Assuming that functionally significant endogenous ligands exist for the GHRP receptor, then the present data affirming exogenous GHRP-2’s ability to stimulate (by 4.5-fold) basal GH release would allow the novel speculation that a putative endogenous GHRP-like ligand family may be responsible for maintaining higher basal GH secretion in women than in men (26, 30, 39).

Somatostatin can oppose in part the actions of both GHRH and GHRP at the hypothalamic and pituitary levels (see introduction). Thus, we speculate that women may maintain lower somatostatin (GHRH- and GHRP-antagonizing) tone than men, thereby allowing for relatively greater basal GH release. Alternatively, given that a 3-day pulsatile GHRH infusion can augment basal GH secretion [at least in men (40)], we speculate that women (compared with men) maintain relatively greater GHRH release, thus evoking higher basal (interpulse) serum GH concentrations. Higher effective GHRH stimulation in women could arise not only by way of enhanced GHRH secretion but also via heightened putative GHRP activity, as GHRP can release and interact synergistically with GHRH (4).

GHRP-2 infusion elicited a marked (7-fold) amplification of GH secretory burst mass (due to a 10-fold rise in amplitude) in estrogen-withdrawn women. This specific amplitude dependence of GHRP-2 action is consistent with earlier inferences by discrete peak detection applied to 20-min blood sampling, in which other GHRP receptor agonists elevated serum GH concentration peak heights (41, 42, 43). Here, by 10-min blood sampling and via multiparameter deconvolution analysis, we could establish further that GHRP-2 specifically magnifies the calculated mass of and maximal rate of GH secretion (amplitude) attained within each discrete GH secretory pulse. This occurs without altering GH burst duration, frequency, or half-life in ovariprival women. We believe that such preferentially increased GH secretory burst mass and amplitude are compatible with (but not definitive proof of) facilitation by GHRP-2 of endogenous GHRH action. Indeed, recent clinical studies using a GHRH receptor antagonist reveal that blockade of GHRH receptors can substantially (by ~85%) impair GHRP-6’s stimulation of GH secretion (44). Moreover, GHRH and GHRP administered together in the intact animal or human typically act synergistically (4, 15, 20). This important supraadditive interaction between GHRH and GHRP could arise via one or more plausible mechanisms, such as 1) joint amplification of intracellular second messenger signaling in pituitary cells, 2) recruitment of GHRH-responsive somatotroph cells by GHRP stimulation (8), 3) evolution of GHRH release (18), 4) antagonism by GHRP of somatostatin’s (central) inhibitory linkages to GHRH neurons (12), and/or 5) opposition by GHRP of somatostatin’s inhibition of GH secretion (4). Any one or more of these postulated mechanisms could account for GHRP’s augmentation of the mass of GH secreted per burst, as quantitated here during continuous iv GHRP-2 stimulation.

The estimated frequency of GH secretory bursts was not altered by uninterrupted iv GHRP-2 infusion over 24 h. This probably does not reflect a type II statistical error, as power analysis indicated a power of 85% or greater for detecting a 30% change in GH frequency at an {alpha} (P) value of 0.05 in the cohort of seven women studied here. Mechanistically, the apparent frequency independence of GHRP-2’s actions could suggest that somatostatin release, which is a presumptive inhibitor of GH pulse frequency (38), is relatively fixed and/or already maximally reduced in estrogen-unreplaced women. An earlier study using 20-min blood sampling analogously found higher serum GH peak heights but unchanged frequency during oral treatment with MK0677, a nonpeptidyl agonist of the GHRP receptor (41). Infusion of GHRP-6 also did not accelerate serum GH concentration peak frequency in young men (42, 43). In extension of these findings, our use of deconvolution analysis independently corroborates the frequency invariance of GHRP actions and establishes that higher serum GH concentration peaks are due mechanistically to greater GH secretory burst mass rather than a prolonged GH half-life, an extended GH pulse duration, and/or a rise in basal (interpulse) GH levels (29).

If the frequency of GH pulses is controlled to a significant extent by somatostatin (4, 38), then our findings of unchanged GH pulse frequency point to a limited ability of GHRP-2 at the dose schedule used (and in the population studied) to fully antagonize somatostatin release and/or its actions. In contrast, sleep, fasting, and type I diabetes mellitus, each of which putatively reduces hypothalamic somatostatin release, all exhibit increased GH pulse frequency (4); conversely, iv somatostatin infusion suppresses detectable GH pulse frequency in young men (38). Nonetheless, GHRP agonists can partially overcome the inhibitory impact of several agents and/or conditions believed to enhance somatostatin release, e.g. GH autofeedback; the muscarinic cholinergic antagonist, pirenzepine; the ß2-agonist, salbutamol; glucose administration; infused somatostatin or octreotide; glucocorticoid excess; and hypothyroidism (4, 21, 22, 45). Thus, available clinical studies point to significant, but incomplete, antagonism of somatostatin’s actions by GHRPs. Such antagonism would also tend to enlarge GH secretory burst mass, as observed here during constant GHRP-2 infusion.

Continuous infusion of either GHRH and/or GHRP in critically ill patients analogously amplifies GH pulse mass/amplitude without changing GH pulse frequency (46, 47). Thus, factors other than intermittent release of GHRH (e.g. episodic withdrawal of somatostatin and/or intermittent release of other effectors) probably modulate GH pulse frequency (4). Because constant combined GHRH/GHRP infusions also elicit pulsatile GH secretion (46, 47), we infer that endogenous (non-GHRP, non-GHRH) neuromodulators (e.g. somatostatin and/or other effectors) probably supervise GH secretory burst frequency (4). The nature of such effectors in the human remains speculative.

Cosinor analysis of GH pulse-frequency variations over 24 h of saline vs. GHRP-2 infusions revealed that whereas GHRP-2 did not greatly influence the mean 24-h frequency of GH episodes, this potent peptidyl secretagogue abolished the expected daytime slowing of GH pulse frequency. This observation may be relevant, because daytime somatostatin release is probably elevated compared to that during sleep (4). Thus, our new findings provide indirect evidence that, at least in the daytime, GHRP-2 may partially oppose inferred CNS actions of somatostatin on GH pulse generation.

In the human, most GH secretagogues, including GHRPs, appear to require GHRH receptor/mediation to evoke or maintain the release of pituitary GH stores (4). According to this axiom and given that estrogen-withdrawn women evince remarkable (7- to 10-fold) augmentation of pulsatile GH release during GHRP-2 infusion, we hypothesize that significant GHRH secretion continues in the adult female gonadoprival state. We further infer that the amount of and/or the degree of pituitary responsiveness to endogenously secreted GHRH may be magnified by GHRP-2 stimulation in older women in view of the heightened GH pulse mass elicited by GHRP-2.

The present clinical studies also demonstrate for the first time that GHRP-2 increases the quantifiable disorderliness of the 24-h GH release process. The consistency or reproducibility of GH release patterns can be monitored quantitatively by ApEn. This statistic is largely scale invariant, thus allowing valid comparisons even when mean hormone concentrations differ very significantly, e.g. as in acromegaly (32). ApEn distinguishes degrees of regularity (or subpattern reproducibility) in time series. Application of ApEn previously documented significantly more disorderly GH release in mid- to late puberty in normal boys as well as during treatment with estrogen or aromatizable androgen (but not 5{alpha}-dihydrotestosterone) (4, 35). Moreover, ApEn captures a vivid sex distinction between the regularity of GH release patterns in men and women (33, 48). Thus, the loss of orderly patterns of GH release under exogenous GHRP-2 drive, as observed here in estrogen-withdrawn older women, is analogous to the neuroregulatory changes of normal puberty, in healthy young women compared to men, and in response to GH axis stimulation by estrogen or (aromatizable) androgen.

An earlier study in men revealed that fixed 90-min pulsatile iv GHRH infusions for 72 h heightens the disorderliness of GH release patterns (40). In conjunction with this action of GHRH itself, the present continuous GHRP-2 infusion data are consistent with an overall unifying hypothesis that GHRP amplifies endogenous GHRH action and thereby augments the irregularity of GH release. As a corollary, we speculate that the increased irregularity of GH release induced by estrogen, aromatizable androgens, puberty, and the more estrogenized milieu of young women (compared to men) may reflect increased endogenous GHRH and/or (putative) GHRP activities. These hypotheses might be investigated when safe, potent, and selective antagonists of GHRH vs. GHRP receptors become available for clinical studies.

Cosinor analysis disclosed that GHRP-2 infusion amplifies the amplitude and mesor (cosine mean) of the 24-h rhythmicity of serum GH concentrations by 5- to 6-fold. A higher mesor of nyctohemeral GH rhythms also emerges during pubertal activation of the male GH axis (36). Whether similar augmentation of diurnal GH rhythms occurs during sex steroid treatment is not so well established to our knowledge, but is evident during 72-h pulsatile GHRH infusions in men (40). Clinical studies suggest that 24-h rhythms of GH release comprise both true circadian and sleep/wake regulation (4). Our study did not evaluate whether GHRP-2 infusions preferentially facilitate circadian vs. sleep stage-specific GH release. Although both GHRH and GHRP infusions can facilitate slow wave sleep, here GHRP-2 infusion shifted the acrophase (time of maximal GH release) to the daytime. This reflected strong stimulation of GH secretion at the start of the GHRP-2 infusion at 0800 h. Increased GH release continued over the full 24 h, including during the hours of sleep, thus providing no evidence of down-regulation of GHRP-2 actions in these estrogen-withdrawn women. Indeed, GHRP-2 further enhanced the overall day-night contrast in GH secretory burst mass. Consequently, we infer that GHRP-2 can strongly potentiate the underlying physiological nyctohemeral variation in GH secretory pulse mass.

No adverse clinical sequelae occurred during the 24-h GHRP-2 infusions, and pooled serum TSH, LH, FSH, and estradiol concentrations did not change. Although bolus GHRP injections often stimulate an acute rise in serum cortisol and/or PRL concentrations (5, 17, 49), longer term treatment (over 2–4 weeks) with an orally active GHRP mimetic (MK-0677) did not alter daily cortisol concentrations in older adults (41). In the present studies, we observed only small increases in serum cortisol and PRL concentrations (24 h pooled). Concomitantly, incremental (0800 h at the end vs. 0800 h at the start of the 24-h GHRP-2 infusions) serum IGF-I concentrations rose significantly in GHRP-2-infused volunteers. Longer term treatment with GHRP receptor agonists similarly can elevate serum IGF-I as well as IGF-binding protein-3 concentrations, alter body composition, and promote linear growth (4, 41, 50). The combined elevation in circulating GH and IGF-I concentrations in response to GHRP-2 stimulation observed here in the female gonadoprival state is mechanistically similar to the concerted changes in the GH-IGF-I axis in puberty (4). This analogy suggests, but does not establish, a possible mediatory role for an endogenous (putative) GHRP receptor pathway in normal puberty or in response to sex steroid hormone activation of the GH-IGF-I axis.


   Acknowledgments
 
We thank Patsy Craig for her skillful preparation of the manuscript; Paula P. Azimi for the data analysis, management, and graphics; Ginger Bauler for performance of the RIA, IRMA, and chemiluminescence assays; and Sandra Jackson and the expert nursing staff at the University of Virginia General Clinical Research Center for conduct of the clinical research protocols.


   Footnotes
 
1 This work was supported in part by NIH Grant MO1-RR-00847 (to the General Clinical Research Center of the University of Virginia Health Sciences Center), the NSF Center for Biological Timing (Grant DIR89–20162), NIH Grant RO1-AG-14799–01 (to J.D.V.), and NIH Clinical Research Scholar’s Award (to N.S.). Back

2 Current address: Omni Healthcare, 95 Bulldog Boulevard, Sheridan Building, Suite 101, Melbourne, Florida 32903. Back

Received October 20, 1998.

Revised February 1, 1999.

Accepted February 8, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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