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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 2 700-712
Copyright © 2001 by The Endocrine Society

Original Studies

Continuous 24-Hour Intravenous Infusion of Recombinant Human Growth Hormone (GH)-Releasing Hormone-(1–44)-Amide Augments Pulsatile, Entropic, and Daily Rhythmic GH Secretion in Postmenopausal Women Equally in the Estrogen-Withdrawn and Estrogen-Supplemented States1

W. S. Evans, S. M. Anderson, L. T. Hull, P. P. Azimi, C. Y. Bowers and J. D. Veldhuis

Division of Endocrinology, Department of Internal Medicine, General Clinical Research Center, Center for Biomathematical Technology, University of Virginia School of Medicine (W.S.E., S.M.A., L.T.H., P.P.A., J.D.V.), Charlottesville, Virginia 22908-0202; and Endocrinology and Metabolism Section, 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, P.O. Box 800202, University of Virginia School of Medicine, Charlottesville, Virginia 22908-0202. E-mail: jdv{at}virginia.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
How estrogen amplifies GH secretion in the human is not known. The present study tests the clinical hypothesis that estradiol modulates the stimulatory actions of a primary GH feedforward signal, GHRH. To this end, we investigated the ability of short-term (7- to 12-day) supplementation with oral estradiol vs. placebo to modulate basal, pulsatile, entropic, and 24-h rhythmic GH secretion driven by a continuous iv infusion of recombinant human GHRH-(1–44)-amide vs. saline in nine healthy postmenopausal women. Volunteers underwent concurrent blood sampling every 10 min for 24 h on four occasions in a prospectively randomized, single blind, within-subject cross-over design (placebo/saline, placebo/GHRH, estradiol/saline, estradiol/GHRH). Intensively sampled serum GH concentrations were quantitated by ultrasensitive chemiluminescence assay. Basal, pulsatile, entropic (feedback-sensitive), and 24-h rhythmic modes of GH secretion were appraised by deconvolution analysis, the approximate entropy (ApEn) statistic, and cosine regression, respectively. ANOVA revealed that continuous iv infusion of GHRH in the estrogen-withdrawn (control) milieu 1) amplified individual basal (P = 0.00011) and pulsatile (P < 10-13) GH secretion rates by 12- and 11-fold, respectively; 2) augmented GH secretory burst mass and amplitude each by 10-fold (P < 10-11), without altering GH secretory burst frequency, duration, or half-life; 3) increased the disorderliness (ApEn) of GH release patterns (P = 0.0000002); 4) elevated the mesor (cosine mean) and amplitude of the 24-h rhythm in serum GH concentrations by nearly 30-fold (both P < 10-12); 5) induced a phase advance in the clocktime of the GH zenith (P = 0.021); and 6) evoked a new 24-h rhythm in GH secretory burst mass with a maximum at 0018 h GH (P < 10-3), while damping the mesor of the 24-h rhythm in GH interpulse intervals (P < 0.025). Estradiol supplementation alone 1) increased the 24-h mean and integrated serum GH concentration (P = 0.047); 2) augmented GH secretory burst mass (P = 0.025) without influencing pulse frequency, duration, half-life, or basal secretion; 2) stimulated more irregular patterns of GH release (higher ApEn; P = 0.012); and 3) elevated the 24-h rhythmic GH mesor (P = 0.0005), but not amplitude. Notably, combined stimulation of the GH axis with GHRH-(1–44)-amide and estradiol exerted no further effect beyond that evoked by GHRH alone, except for normalizing the acrophase of 24-h GH rhythmic release and elevating the postinfusion plasma insulin-like growth factor I concentration (P = 0.016). Unexpectedly, the two GHRH-infused serum GH concentration profiles monitored after placebo and estradiol pretreatment showed strongly nonrandom synchrony with a 20- to 30-min lag (P < 0.001).

In summary, the present clinical investigations unmask a 3-fold (pulsatile, entropic, and daily rhythmic) similitude between the neuroregulatory actions of estradiol and GHRH in healthy postmenopausal women. However, GHRH infusion was multifold more effectual than estradiol, and only GHRH elevated nonpulsatile (basal) GH secretion, shifted the GH acrophase, and synchronized GH profiles. Given the nonadditive nature of the joint effects of estradiol and GHRH on pulsatile and entropic GH release, we hypothesize that estrogen amplifies GH secretion in part by enhancing endogenous GHRH release or actions. In addition, the distinctive ability of GHRH (but not estradiol) to increase basal (nonpulsatile) GH secretion, shift the GH acrophase and synchronize GH output patterns identifies certain divergent hypothalamo-pituitary actions of these two major GH secretagogues.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
FROM A MECHANISTIC perspective, GH output is controlled by hypothalamic GHRH and somatostatin se- cretion, as well as GH and/or insulin-like growth factor (IGF-I)-mediated autonegative feedback (1, 2, 3). Thus, in principle, deficient hypothalamic GHRH feedforward or excessive somatostatin feedback could subserve the hyposomatotropism associated with aging and/or the estrogen-deficient state (2). Indeed, partial GHRH deficiency is inferable in the elderly human based on blunted rebound GH secretion after somatostatin infusion (4), accentuated inhibition of GH release by a selective GHRH receptor antagonist (5), and attenuated GH responsiveness to exogenous GHRH stimulation (6). How estrogen deprivation or replacement in postmenopausal individuals influences the GHRHergic pathway remains unknown. This is a pivotal mechanistic issue, because estradiol is a dominant positive determinant of GH secretion over the human lifetime (1, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17).

In the rodent, estradiol tends to repress or not alter hypothalamic GHRH secretion, pituitary GHRH receptor expression, and acute somatotrope responsiveness to GHRH (18, 18, 19, 20). In the human, the stimulatory actions of GHRH are affected minimally by pubertal status, menstrual cycle stage, ovariectomy, antiestrogen administration, gonadal axis down-regulation, oral contraceptive use, and sex steroid hormone replacement (15, 21, 22, 23, 24). However, short-term gonadal axis down-regulation in young women increases the likelihood of nonresponsiveness to a single GHRH injection (15). Such relative refractoriness to GHRH would be consistent with heightened cyclical release of somatostatin and/or impaired somatotrope responsiveness to GHRH in the estrogen-deprived milieu. The former seems less likely, as L-arginine infusion to withdraw somatostatin stimulates greater GH release in an estrogen-enriched milieu, suggesting that estrogen may augment endogenous somatostatinergic activity (1, 2, 8, 10, 25, 26).

The present study applies a new clinical investigative strategy to appraise estrogen’s impact on pituitary responsiveness to GHRH. To this end, we infused human recombinant GHRH-(1–44)-amide (GHRH) continuously iv for 24 h in estradiol-supplemented vs. estrogen-withdrawn healthy postmenopausal women. To capture dynamic GH neuroregulation, we quantitated all four primary modes of daily GH secretion: 1) basal, 2) pulsatile, 3) 24-h rhythmic, and 4) entropic (feedback-dependent) GH release (see Materials and Methods). These analyses unveil marked stimulation by GHRH of basal (12-fold), pulsatile (11-fold), nyctohemeral (30-fold), and entropic GH secretion and establish that certain actions of GHRH occur independently of estrogen repletion.


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

Nine healthy postmenopausal women (mean age ± SEM, 64 ± 3; absolute range, 50–75 yr) with onset of clinical menopause at least 2 yr previously provided informed and voluntary written consent approved by the human investigation committee of the University of Virginia Health System. The body mass index averaged 29 ± 1.1 (median, 28) kg/m2. Volunteers had received no estrogen replacement therapy for 4–6 weeks before the study. Each woman provided an unremarkable medical history and physical examination and had normal screening biochemical tests of hematological, renal, hepatic, endocrine, and metabolic function. There was no acute illness, chronic disease, psychiatric disorder, recent use of systemic medications (within five biological half-lives), transmeridian travel (more than three times zones within 1 week), or significant weight change (2 kg or more within 10 days).

17ß-Estradiol (1 mg micronized steroid) or placebo was administered twice daily orally in a prospective, randomly assigned, single blind, within-subject, cross-over manner for 7–12 days. Volunteers were admitted to the General Clinical Research Center on the evening before the study to allow overnight adaptation to the unit. The next day subjects received a weight-maintaining diet consisting of three isocaloric meals provided at 0800, 1200, and 1700 h (clocktimes). Each meal contained 55% carbohydrate, 30% fat, and 15% protein. Blood samples (1.5 mL) were withdrawn at 10-min intervals for 24 h beginning at 0800 h via an indwelling contralateral forearm venous catheter placed at least 1 h earlier. Concomitantly, subjects received a continuous 24-h iv infusion of saline or recombinant human GHRH-(1–44)-amide [1 µg/kg·h; obtained from BioNebraska, Inc. (Lincoln, NE), under an investigator-initiated FDA Investigational New Drug]. Infusions were randomly ordered and separated by at least 72 h.

Assays

Serum GH concentrations were measured in each sample in duplicate (145 samples/24-h infusion session) by an automated ultrasensitive GH chemiluminescence assay (modified Luma Tag hGH assay, Nichols Institute, Inc., San Juan Capistrano, CA; sensitivity 0.005 µg/L) as previously described (27, 28). Human recombinant GH (22 kDa) was used as the assay standard. The median intra- and interassay coefficients of variation were, respectively, less than 6.5% and less than 8.5%. Serum estradiol, LH, FSH, and PRL concentrations were assayed in duplicate by RIA or immunoradiometric assay in 24-h serum pools (6, 27, 28, 29). IGF-I concentrations were measured in samples collected at 0800 h at the beginning and end of each infusion session (30).

Deconvolution analysis

Multiparameter deconvolution analysis was applied to quantitate basal and pulsatile GH secretion and estimate the apparent half-life of endogenous GH (31). Daily pulsatile GH secretion is the product of secretory burst frequency and the mean mass of GH released per pulse. Basal GH secretion represents the calculated time-invariant interpulse (nonpulsatile) component (28). Total GH secretion is the sum of the pulsatile and basal components. Secretory pulse identification required that the estimated mass of each GH secretory burst exceed 95% statistical confidence intervals (31, 32). The analyst was blinded to the randomization scheme.

Cosine regression

The 24-h rhythmicity of serum GH concentrations was evaluated by cosinor analysis to quantitate the amplitude (50% of the nadir-zenith difference), mesor (cosine mean), and acrophase (clocktime of maximum value). In addition, 24-h cosine regression was applied to deconvolution-calculated GH secretory burst mass and interpulse interval (33, 34).

Approximate entropy (ApEn)

ApEn was used as a scale-invariant and model-independent regularity statistic, which is complementary to deconvolution analysis and cosine fitting (35). ApEn quantifies the relative orderliness or subpattern reproducibility of successive hormone measurements (36, 37). Normalized ApEn parameters of m = 1 (series length) and r = 20% (threshold) of each intraseries SD were used here, as previously validated (37, 38, 39, 40). This statistic, designated ApEn (1, 20%), has good statistical replicability, with a SD of approximately 0.06–0.08 within series (37, 39, 41). Increased ApEn (at equal series lengths and similar m and r parameter values, as used here) indicates greater irregularity of secretory patterns, as reported for GH release in the adult female compared with that in the male (12, 14, 40, 41).

Cross-correlation analysis

Cross-correlation analysis with variable lag was applied to test the null hypothesis that serum GH concentrations in each of the six paired sets of the four randomized study sessions were uncorrelated. A protected P <= 0.001 was used for significance testing (42).

Statistical analyses

Because of nonnormality (1), analytically derived measures of GH secretion and half-life were logarithmically transformed and then compared across interventions by one-way repeated measures ANOVA. Duncan’s new multiple range test was applied post-hoc to contrast means. Data are presented as the mean ± SEM. P < 0.05 was construed as statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Figure 1AGo illustrates 24-h serum GH concentration profiles obtained by sampling blood every 10 min during a constant iv infusion of saline or GHRH-(1–44)-amide after randomly ordered oral placebo or estradiol ingestion for 7–12 days. Matching deconvolution-calculated GH secretory profiles are shown in Fig. 1BGo.



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  		Figure 1. Illustrative 24-h serum GH concentration profiles (A) and corresponding deconvolution-calculated GH secretory rates (B) in three postmenopausal women administered placebo (control) or 17ß-estradiol (1 mg, orally, twice daily) for 7–12 days, and then infused continuously iv with saline (control) or human recombinant GHRH-(1–44)-amide (GHRH, 1 µg/kg·h) beginning at 0800 h on separate occasions 72 h apart in randomly assigned order. Blood was sampled at 10-min intervals during the 24-h infusions for later chemiluminescence-based assay of GH (sensitivity, 0.005 µg/L; see Materials and Methods). Zero time on the x-axis is 0800 h clocktime.

 
Mean and integrated serum GH concentrations rose by 1.8-fold after estradiol supplementation alone (P = 0.047) and by 11.5-fold during continuous iv GHRH infusion (P < 10-16; Fig. 2Go). Combined stimulation elicited no further increase compared with GHRH infusion alone.



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  		Figure 2. Dispersion of the mean (upper panel) and integrated (lower panel) serum GH concentrations in nine postmenopausal women sampled every 10 min for 24 h (see Fig. 1Go). Numerical values are the mean ± SEM. The stated P value denotes the statistical significance of the overall interventional effect as determined by repeated measures ANOVA (see Materials and Methods). The individual P value above the arrows defines the statistical significance of the a priori postulate of no difference between placebo and estradiol replacement, as assessed via a two-tailed, unequal variance paired Student’s t test.

 
Deconvolution analysis of GH concentration profiles revealed the following effects of estradiol or GHRH: 1) GHRH elevated basal (nonpulsatile) GH secretion by 12-fold (P = 0.00011); 2) no intervention altered the duration of GH secretory bursts, their frequency, interpulse interval, or the half-life of GH; 3) estradiol augmented GH pulse mass by 1.8-fold (P = 0.025), and GHRH infusion did so by 10-fold (P < 10-11) due to stimulation of GH secretory pulse amplitude (P < 10-12); 4) estradiol and GHRH amplified daily pulsatile GH secretion by 2- and 11-fold, respectively (P < 10-13); and 5) estradiol and GHRH increased the total daily production rate of GH by 1.7- and 12-fold, respectively (P = 0.045 and P < 10-13; Table 1Go and Figs. 3Go and 4Go). The percentage of total daily GH secretion that was pulsatile was invariant of intervention [88 ± 1.5 (control), 88 ± 2.0 (estradiol), 87 ± 2.8 (GHRH), and 85 ± 2.9% (both agonists)]. Coadministration of estradiol and GHRH exerted no additive or supraadditive effects on any of the foregoing specific measures.


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  		Table 1. Selected deconvolution measures of pulsatile GH secretion or half-life in postmenopausal women administered placebo or estradiol for 7–12 days and infused iv with saline or GHRH-(1–44)-amide continuously for 24 h

 


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  		Figure 3. Deconvolution-estimated values of GH secretory burst mass (upper panel) and interburst interval (lower panel) in nine postmenopausal women who were studied as defined in Figs. 1Go and 2Go.

 


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  		Figure 4. Calculated 24-h basal (top), pulsatile (middle), and total (basal plus pulsatile; bottom) GH secretory rates in nine postmenopausal women who were studied as defined in Fig. 2Go.

 
Estradiol (P = 0.012) and GHRH (P < 10-5) each elevated the ApEn of GH profiles (Fig. 5Go). These changes denote more irregular or disorderly GH release. Combining the two agonists exerted no further effect. GH ApEn diverged prominently from the maximal random value [determined from the null set of 1000 randomly shuffled GH series; by 21 ± 0.62 (placebo, control), 21 ± 1.1 (estradiol), 17 ± 0.92 (GHRH), and 18 ± 1.4 (estradiol plus GHRH) SD].



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  		Figure 5. ApEn (1, 20%) values of 24-h serum GH concentration profiles. Data are presented as described in Fig. 2Go.

 
Cosinor analysis of 24-h serum GH concentration profiles disclosed that both estradiol (P = 0.0005) and GHRH (P < 10-17) elevated the GH mesor significantly, but only GHRH augmented the daily GH rhythmic amplitude (P < 10-12; Fig. 6Go). GHRH also advanced the acrophase significantly; this effect was normalized by coadministration of estradiol (P = 0.021).



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  		Figure 6. Twenty-four-hour cosine rhythmicity of serum GH concentrations. The amplitude (upper panel), mesor (middle panel), and acrophase (bottom panel) values are shown in the manner described in Fig. 2Go.

 
Cosinor analysis of the 24-h variations in deconvolution-calculated GH pulse mass are summarized in Fig. 7Go. GHRH infusion induced a new 24-h rhythm in GH secretory burst mass, which was undetectable at baseline. The acrophase was at 0018 h (95% confidence interval, 2134–0301 h), and the mesor and amplitude were 3.3 (95% confidence interval, 2.9–3.7) and 0.75 (95% confidence interval, 0.21–1.3) µg/L, respectively (P < 10-3). Estrogen induced an analogous rhythm, but of only one half the amplitude and one sixth the mesor (P < 10-2 vs. GHRH effect). Combining the two stimuli evoked no significant further changes.



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  		Figure 7. Cosine regression of 24-h rhythmicity of deconvolution-calculated GH secretory burst mass in a group of nine postmenopausal women. Numerical values are given for the amplitude, acrophase (time of zenith), and mesor (cosine mean) along with their 95% statistical confidence intervals in parentheses (see Materials and Methods). Under control (placebo) conditions, there was no detectable daily rhythm in GH secretory pulse mass (P = NS). Thus, only the mesor (linear fit) of these values is shown (upper left panel).

 
The daily rhythm in GH intersecretory burst intervals exhibited a nadir (maximal GH secretory burst frequency) at 0359 h, which was not influenced by estradiol or GHRH administration (Table 2Go). GHRH decreased the mesor slightly (P < 0.025), but showed no interaction with estradiol.


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  		Table 2. Twenty-four-hour rhythmicity of deconvolution-calculated GH interburst intervals in postmenopausal women

 
Plasma IGF-I concentrations obtained at 0800 h before each infusion depended only on prior estradiol vs. placebo supplementation (placebo, 204 ± 24 µg/L; estradiol, 140 ± 16 µg/L; P = 0.028). Postinfusion IGF-I levels did not change (244 ± 33 µg/L after GHRH vs. 217 ± 49 µg/L after saline) after placebo, but rose (278 ± 45 µg/L after GHRH vs. 153 ± 30 µg/L after saline; P = 0.016) after estradiol pretreatment. Estradiol concentrations during replacement rose to 358 ± 31 from 18 ± 3 pg/mL (placebo; P < 10-3; to convert to picomoles per L, multiply picograms per mL by 3.67).

Figure 8Go summarizes the results of cross-correlation analysis of the six paired sets of 24-h serum GH concentration profiles for the four different study sessions. Only the two profiles driven by exogenous GHRH exhibited significant synchrony (P < 0.001) at a consistent (20- to 30 min) lag time.



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  		Figure 8. Cross-correlation analyses of six sets of paired 24-h serum GH concentration profiles obtained during placebo, estradiol, saline, and/or GHRH infusion sessions in nine postmenopausal women. The y-axis gives between-session cross-correlation r (rho) values, depicted as the median ± absolute range (n = 9 volunteers). The x-axis defines the various time lags examined (intervals between successively paired comparisons of serum GH concentrations). A positive time lag (right side) signifies that changes in the first-named series precede those in the second (and vice versa). A positive r indicates that the paired serum GH concentrations vary in the same direction. ***, P <= 0.001 at intersession lag times of 20 and 30 min, wherein correlated changes in serum GH concentrations during the GHRH sessions precede those in the matching combined GHRH and estradiol sessions by this time interval.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present clinical study establishes multifold stimulatory actions of continuous iv GHRH stimulation on basal, pulsatile, entropic (pattern-dependent), and 24-h rhythmic GH secretion in estrogen-withdrawn postmenopausal women and documents that certain actions of estradiol are comparable, whereas others are distinct from those of GHRH. Unvarying GHRH feedforward amplified total daily (pulsatile plus basal) GH secretion by 12-fold. The latter value approximates a GH production rate of 800-1000 µg/day (43), akin to GH output achieved in normal puberty (14, 44). Thus, the aging human pituitary gland retains a remarkable capacity to secrete GH under exogenous GHRH drive. Notably, coadministration of estradiol did not further enhance GHRH-stimulated pulsatile or total daily GH secretion. Assuming adequate statistical power (see Results), this finding could indicate that 1) estrogen does not alter pituitary responsiveness to sustained GHRH signaling; 2) estrogen acts by releasing endogenous GHRH; thus, its effects cannot surmount those of a near-maximal exogenous GHRH stimulus; and/or 3) GH secretion under an external GHRH clamp is already maximal. The first inference would be consistent with earlier clinical experiments using a single bolus GHRH injection and with most in vitro studies showing unaltered or slightly repressed GHRH actions after estrogen exposure (1, 20, 22, 24, 45). The second consideration that estrogen releases GHRH in the human has not been established directly, albeit it is inferable from the present data. The third hypothesis seems unlikely, because combining L-arginine with a GHRH or GH-releasing peptide (GHRP) stimulus nearly doubles GH release acutely in older individuals (1, 26, 46, 47).

GHRH, but not estradiol, increased the estimated rate of basal (nonpulsatile) GH secretion by 12-fold. Analytically calculated basal GH secretion should be distinguished from measured interpulse serum GH concentrations, which are determined by the composite of true basal GH secretion, GH half-life, and GH secretory burst amplitude, duration, and frequency (48). Indeed, estradiol elevates interpeak serum GH levels indirectly by only one of these mechanisms, viz. by augmenting GH pulse mass (29). Akin to the present data in older women, pulsatile iv infusion of GHRH for 72 h in men of varying ages and continuous iv stimulation with GHRP-2 for 24 h in postmenopausal women also amplify basal GH secretion by severalfold (6, 30). Conversely, administration of somatostatin and octreotide will suppress basal (as well as pulsatile) GH production in men and women (49, 50, 51). Thus, the lack of a significant action of estrogen on calculated basal GH secretion is distinguishable mechanistically from the effects of GHRH, GHRP, or somatostatin. Although the basal/nonpulsatile mode of GH secretion accounts for only a minority (8–15%) of the total daily GH output in healthy adults, sustained low serum GH concentrations can exert important metabolic effects on certain target tissues (1, 45, 52).

GHRH can stimulate somatostatin secretion putatively via intrahypothalamic neuronal connections in the rat and/or by delayed GH-induced autonegative feedback (1, 53, 54). If the latter mechanism operated during continuous iv GHRH infusion, then the present data would indicate that estradiol does not significantly relieve such secondary somatostatinergic outflow. In contrast, estradiol replacement in postmenopausal women does reduce the inhibitory potency, but not the efficacy, of exogenously infused somatostatin-14 (51). Moreover, estrogen supplementation significantly enhances hypothalamo-pituitary sensitivity and maximal responsiveness to the dose-dependent effects of a selective synthetic GHRP receptor agonist, GHRP-2 (55, 56). Accordingly, available clinical data allow us to postulate that estrogen exerts tripartite neuroregulatory effects on the human hypothalamo-pituitary axis: 1) augments release of endogenous GHRH and influences its near-maximal efficacy (present data); 2) enhances hypothalamo-pituitary responsiveness to GHRP stimulation (above); and 3) mutes the potency of somatostatin’s submaximal repression of GH secretion (above).

GH secretion remained vividly pulsatile during an unvarying iv GHRH stimulus, as recognized previously in younger individuals (57). Thus, we reason that GHRH might magnify spontaneous oscillations in somatotrope GH secretion (58) or, more likely, amplify pulsatile GH output, as governed by the cyclical release of somatostatin and/or a non-GHRH secretagogue(s), such as that of GHRP (3, 59, 60, 61). However, GHRP alone may not serve as the GH pacemaker, as continuous 24-h iv infusion of GHRP-2 also evokes recurrent high amplitude GH pulses of unchanged frequency (30, 55).

ApEn analysis documented more disorderly patterns of GH release during constant GHRH stimulation, as observed previously in response to fixed 90-min pulsatile GHRH infusions or continuous GHRP-2 infusion in adults (6, 30, 55). GH secretion also becomes irregular transpubertally and after the administration of estradiol or an aromatizable androgen (12, 14, 29, 62, 63, 64) and remains more irregular in women than in men at all ages (14, 40, 41). Greater disorderliness of GH release (increased ApEn) is believed to denote altered feedback signaling within the interactive GH/IGF-I axis (37, 39). Although GHRH alone did not evoke maximally random patterns of GH release (see Results), adding estradiol failed to heighten the irregularity of GHRH-induced GH secretion. Thus, we infer that GHRH and estradiol may control GH ApEn via a common and noninteractive mechanism.

In the estrogen-deficient state, postmenopausal women did not generate any 24-h rhythmicity in GH secretory burst mass and produced only a minimal diurnal variation in serum GH concentrations. However, continuous GHRH infusion evoked the former rhythm and amplified the latter by 30-fold. Estradiol supplementation exerted an analogous (albeit lesser) effect without altering the degree of stimulation achieved by GHRH. Accordingly, we speculate that estrogen and GHRH may regulate the amplitude of nyctohemeral GH release via a common or noninteractive neuroendocrine mechanism. However, only GHRH advanced the GH acrophase, and coadministration of estradiol reversed this effect. The former action of GHRH could reflect its prompt stimulation of GH secretion at the outset of the infusion. Nonetheless, as GHRH, like estrogen, can influence sleep, short-term memory, and appetite (1, 65, 66), this peptidyl agonist might also act on central nervous system sites to control the timing of the diurnal GH rhythm and thereby elicit the foregoing interaction.

Estradiol supplementation suppressed fasting morning plasma IGF-I concentrations, consistent with earlier studies of oral, iv, transvaginal, intranasal, im, and higher dose transdermal estrogen replacement (reviewed in Ref. 67). A fall in circulating IGF-I levels most likely reflects down-regulation of GH-stimulated hepatic IGF-I production (68, 69). The reduced availability of IGF-I might contribute to enhanced GH secretion by muting IGF-I-dependent negative feedback. However, the decline in IGF-I availability did not further augment GHRH’s stimulation of basal, pulsatile, entropic, or 24-h rhythmic GH secretion.

Cross-correlation analysis revealed that 24-h serum GH concentration profiles in the paired (placebo vs. estrogen pretreatment) GHRH infusion sessions fluctuated in significant synchrony within a 20- to 30-min time lag (P < 10-3). Analogous interdiem GH synchrony was recognized recently during constant GHRP-2 stimulation (55). Whether GHRH or GHRP-2 unmasks or simply accentuates an endogenous ultradian rhythmicity in the neuroregulation of GH secretion is not known.

In summary, continuous iv infusion of recombinant human GHRH-(1–44)-amide for 24 h in healthy postmenopausal women markedly augments basal/nonpulsatile (12-fold), pulsatile (11-fold), and nyctohemeral rhythmic (30-fold) GH secretion and induces irregular GH release patterns (elevated ApEn). Oral estradiol replacement also stimulates the foregoing pulsatile, 24-h rhythmic, and entropic modes of GH secretion and does not modify GHRH’s stimulation of these particular neuroendocrine end points. Thus, we hypothesize that one action of estradiol is to release endogenous GHRH without altering GHRH’s efficacy at the pituitary level, thereby mimicking, but not adding to, these actions of exogenous GHRH. As GHRH, but not estradiol, was able to elevate basal GH secretion, advance the timing of the GH acrophase, and synchronize daily GH release profiles, we infer that estradiol and GHRH also exert certain mechanistically distinct effects on the female somatotropic axis.


   Acknowledgments
 
We thank Patsy Craig for her skillful preparation of the manuscript, Ginger Bauler for performance of the assays, and Sandra Jackson and the expert nursing staff at the University of Virginia General Clinical Research Center for conduct of the research protocols. This focused report necessarily omits many primary references because of editorial constraints. We, therefore, acknowledge numerous colleagues who have made earlier foundational observations in this arena.


   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), a Clinical Associate Physician Award from the National Center for Research Resources (to S.M.A.), and NIH Grant RO1-AG-14799–01 (to J.D.V. and W.S.E.). Back

Received June 14, 2000.

Revised October 6, 2000.

Accepted October 18, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Giustina A, Veldhuis JD. 1998 Pathophysiology of the neuroregulation of GH secretion in experimental animals and the human. Endocr Rev. 19:717–797.[Abstract/Free Full Text]
  2. Mueller EE, Locatelli V, Cocchi D. 1999 Neuroendocrine control of growth hormone secretion. Physiol Rev. 79:511–607.[Abstract/Free Full Text]
  3. Bowers CY, Granda-Ayala R. 1996 GHRP-2, GHRH and SRIF interrelationships during chronic administration of GHRP-2 to humans. J Pediatr Endocrinol Metab. 9:261–270.
  4. degli Uberti EC, Ambrosio MR, Cella SG, et al. 1997 Defective hypothalamic growth hormone (GH)-releasing hormone activity may contribute to declining GH secretion with age in man. J Clin Endocrinol Metab. 82:2885–2888.[Abstract/Free Full Text]
  5. Russell-Aulet M, Jaffe CA, DeMott-Friberg R, Barkan AL. 1999 In vivo semiquantification of hypothalamic growth hormone-releasing hormone (GHRH) output in humans: evidence for relative GHRH deficiency in aging. J Clin Endocrinol Metab. 84:3490–3497.[Abstract/Free Full Text]
  6. Iranmanesh A, South S, Liem AY, Clemmons D, Thorner MO, Weltman A, Veldhuis JD. 1998 Unequal impact of age, percentage body fat, and serum testosterone concentrations on the somatotropic, IGF-I, and IGF-binding protein responses to a three-day intravenous growth-hormone-releasing-hormone (GHRH) pulsatile infusion. Eur J Endocrinol. 139:59–71.[Abstract]
  7. Unger R, Eisentraut A, Madison LSM. 1965 Fasting levels of growth hormone in men and women. Nature. 205:804–805.[CrossRef]
  8. Frantz AG, Rabkin MT. 1965 Effects of estrogen and sex difference on secretion of human growth hormone. J Clin Endocrinol Metab. 25:1470–1480.[Medline]
  9. Yen SSC, Vela P, Rankin J, Littell AS. 1970 Hormonal relationships during the menstrual cycle. JAMA. 211:1513–1517.[CrossRef][Medline]
  10. Merimee TJ, Fineberg SE. 1971 Studies of the sex-based variation of human growth hormone secretion. J Clin Endocrinol Metab. 33:896–902.[Medline]
  11. Mauras N, Rogol AD, Veldhuis JD. 1990 Increased hGH production rate after low-dose estrogen therapy in prepubertal girls with Turner’s syndrome. Pediatr Res. 28:626–630.[Medline]
  12. Veldhuis JD, Metzger DL, Martha Jr PM, et al. 1997 Estrogen and testosterone, but not a non-aromatizable androgen, direct network integration of the hypothalamo-somatotrope (growth hormone)-insulin-like growth factor I axis in the human: evidence from pubertal pathophysiology and sex-steroid hormone replacement. J Clin Endocrinol Metab. 82:3414–3420.[Abstract/Free Full Text]
  13. Wennink JMB, Delemarre-van de Waal HA, Schoemaker R, Blaauw G, van den Braken C, Schoemaker J. 1991 Growth hormone secetion patterns in relation to LH and estradiol secretion throughout normal female puberty. Acta Endocrinol (Copenh). 124:129–135.[Medline]
  14. Veldhuis JD, Roemmich JN, Rogol AD. 2000 Gender and sexual maturation-dependent contrasts in the neuroregulation of growth-hormone (GH) secretion in prepubertal and late adolescent males and females. J Clin Endocrinol Metab. 85:2385–2394.[Abstract/Free Full Text]
  15. Devesa J, Lois N, Arce V, Diaz MJ, Lima L, Tresguerres JA. 1991 The role of sexual steroids in the modulation of growth hormone (GH) secretion in humans. J Steroid Biochem Mol Biol. 40:165–173.[CrossRef][Medline]
  16. van den Berg G, Veldhuis JD, Frolich M, Roelfsema F. 1996 An amplitude-specific divergence in the pulsatile mode of GH secretion underlies the gender difference in mean GH concentrations in men and premenopausal women. J Clin Endocrinol Metab. 81:2460–2466.[Abstract]
  17. Metzger DL, Kerrigan JR. 1994 Estrogen receptor blockade with tamoxifen diminishes growth hormone secretion in boys: evidence for a stimulatory role of endogenous estrogens during male adolescence. J Clin Endocrinol Metab. 79:513–518.[Abstract]
  18. Lam KS, Lee MF, Tam SP, Srivastava G. 1996 Gene expression of the receptor for growth-hormone-releasing hormone is physiologically regulated by glucocorticoids and estrogen. Neuroendocrinology. 63:475–480.[Medline]
  19. Argente J, Chowen JA, Zeitler P, Clifton DK, Steiner RA. 1991 Sexual dimorphism of growth hormone-releasing hormone and somatostatin gene expression in the hypothalamus of the rat during development. Endocrinology. 128:2369–2375.[Abstract]
  20. Evans WS, Krieg Jr RJ, Limber ER, Kaiser DL, Thorner MO. 1985 Effects of in vivo gonadal hormone environment on in vitro hGRF-40-stimulated GH release. Am J Physiol. 249:E276–E280.
  21. De Leo V, Lanzetta D, D’Antona D, Danero S. 1993 Growth hormone secretion in premenopausal women before and after ovariectomy: effect of hormone replacement therapy. Fertil Steril. 60:268–271.[Medline]
  22. Evans WS, Borges JL, Vance ML, Kaiser DL, Rogol AD, Thorner MO. 1984 Effects of human pancreatic growth hormone-releasing factor-40 on serum growth hormone, prolactin, luteinizing hormone, follicle-stimulating hormone, and somatomedin-C concentrations in normal women throughout the menstrual cycle. J Clin Endocrinol Metab. 59:1006–1010.[Abstract]
  23. Gelato MC, Pescovitz OH, Cassorla F, Loriaux DL, Merriam GR. 1984 Dose-response relationships for the effects of growth hormone releasing factor-(1–44)-NH2 in young adult men and women. J Clin Endocrinol Metab. 59:197–201.[Abstract]
  24. Gelato MC, Malozowski S, Caruso-Nicoletti M, et al. 1986 Growth hormone (GH) responses to GH-releasing hormone during pubertal development in normal boys and girls: comparison to idiopathic short stature and GH deficiency. J Clin Endocrinol Metab. 63:174–179.[Abstract]
  25. Wideman L, Weltman JY, Patrie JT, et al. 2000 Synergy of L-arginine and growth hormone (GH)-releasing peptide-2 (GHRP-2) on GH release: influence of gender. Am J Physiol. 279:RR1455–RR1466.
  26. Ghigo E, Arvat E, Goffi S, et al. 1991 Repetitive GHRH and arginine administration to explore the maximal secretory capacity of somatotrope cells during lifespan. Clin Exp Endocrinol. 10:191–198.
  27. Iranmanesh A, Grisso B, Veldhuis JD. 1994 Low basal and persistent pulsatile growth hormone secretion are revealed in normal and hyposomatotropic men studied with a new ultrasensitive chemiluminescence assay. J Clin Endocrinol Metab. 78:526–535.[Abstract]
  28. Veldhuis JD, Liem AY, South S, et al. 1995 Differential impact of age, sex-steroid hormones, and obesity on basal versus pulsatile growth hormone secretion in men as assessed in an ultrasensitive chemiluminescence assay. J Clin Endocrinol Metab. 80:3209–3222.[Abstract]
  29. Shah N, Evans WS, Veldhuis JD. 1999 Actions of estrogen on the pulsatile, nyctohemeral, and entropic modes of growth hormone secretion. Am J Physiol. 276:R1351–R1358.
  30. Shah N, Evans WS, Bowers CY, Veldhuis JD. 1999 Tripartite neuroendocrine activation of the human growth-hormone (GH) axis in women by continuous 24-hour GH-releasing peptide (GHRP-2) infusion: pulsatile, entropic, and nyctohemeral mechanisms. J Clin Endocrinol Metab. 84:2140–2150.[Abstract/Free Full Text]
  31. Veldhuis JD, Carlson ML, Johnson ML. 1987 The pituitary gland secretes in bursts: appraising the nature of glandular secretory impulses by simultaneous multiple-parameter deconvolution of plasma hormone concentrations. Proc Natl Acad Sci USA. 84:7686–7690.[Abstract/Free Full Text]
  32. Veldhuis JD, Moorman J, Johnson ML. 1994 Deconvolution analysis of neuroendocrine data: waveform-specific and waveform-independent methods and applications. Methods Neurosci. 20:279–325.
  33. Veldhuis JD, Iranmanesh A, Lizarralde G, Johnson ML. 1989 Amplitude modulation of a burst-like mode of cortisol secretion subserves the circadian glucocorticoid rhythm in man. Am J Physiol. 257:E6–E14.
  34. Veldhuis JD, Iranmanesh A, Johnson ML, Lizarralde G. 1990 Twenty-four hour rhythms in plasma concentrations of adenohypophyseal hormones are generated by distinct amplitude and/or frequency modulation of underlying pituitary secretory bursts. J Clin Endocrinol Metab. 71:1616–1623.[Abstract]
  35. Pincus SM, Singer BH. 1996 Randomness and degrees of irregularity. Proc Natl Acad Sci USA. 93:2083–2088.[Abstract/Free Full Text]
  36. Pincus SM, Mulligan T, Iranmanesh A, Gheorghiu S, Godschalk M, Veldhuis JD. 1996 Older males secrete luteinizing hormone and testosterone more irregularly, and jointly more asynchronously, than younger males. Proc Natl Acad Sci USA. 93:14100–14105.[Abstract/Free Full Text]
  37. Pincus SM, Hartman ML, Roelfsema F, Thorner MO, Veldhuis JD. 1999 Hormone pulsatility discrimination via coarse and short time sampling. Am J Physiol. 277:E948–E957.
  38. Friend K, Iranmanesh A, Veldhuis JD. 1996 The orderliness of the growth hormone (GH) release process and the mean mass of GH secreted per burst are highly conserved in individual men on successive days. J Clin Endocrinol Metab. 81:3746–3753.[Abstract]
  39. Hartman ML, Pincus SM, Johnson ML, et al. 1994 Enhanced basal and disorderly growth hormone secretion distinguish acromegalic from normal pulsatile growth hormone release. J Clin Invest. 94:1277–1288.
  40. Hindmarsh PC, Dennison E, Pincus SM, et al. 1999 Sexually dimorphic pattern of growth hormone secretion in the elderly. J Clin Endocrinol Metab. 84:2679–2685.[Abstract/Free Full Text]
  41. Pincus SM, Gevers E, Robinson ICAF, van den Berg G, Roelfsema F, Hartman ML, Veldhuis JD. 1996 Females secrete growth hormone with more process irregularity than males in both human and rat. Am J Physiol. 270:E107–E115.
  42. Veldhuis JD, Johnson ML, Faunt LM, Seneta E. 1994 Assessing temporal coupling between two, or among three or more, neuroendocrine pulse trains: cross-correlation analysis, simulation methods, and conditional probability testing. Methods Neurosci. 20:336–376.
  43. Shah N, Aloi J, Evans WS, Veldhuis JD. 1999 Time-mode of growth hormone (GH) entry into the bloodstream and steady-state plasma GH concentrations rather than sex, estradiol, or menstrual-cycle stage primarily determine the GH elimination rate in healthy young women and men. J Clin Endocrinol Metab. 84:2862–2869.[Abstract/Free Full Text]
  44. Martha Jr. PM, Goorman KM, Blizzard RM, Rogol AD, Veldhuis JD. 1992 Endogenous growth hormone secretion and clearance rates in normal boys as determined by deconvolution analysis: relationship to age, pubertal status and body mass. J Clin Endocrinol Metab. 74:336–344.[Abstract]
  45. Jansson J-O, Eden S, Isaksson OGP. 1985 Sexual dimorphism in the control of growth hormone secretion. Endocr Rev. 6:128–150.[Abstract]
  46. Arvat E, Gianotti L, Grottoli S, et al. 1994 Arginine and growth hormone-releasing hormone restore the blunted growth hormone-releasing activity of hexarelin in elderly subjects. J Clin Endocrinol Metab. 79:1440–1443.[Abstract]
  47. Arvat E, Gianotti L, Divito L, et al. 1995 Modulation of growth hormone-releasing activity of hexarelin in man. Neuroendocrinology. 61:51–56.[Medline]
  48. Veldhuis JD, Lassiter AB, Johnson ML. 1990 Operating behavior of dual or multiple endocrine pulse generators. Am J Physiol. 259:E351–E361.
  49. Calabresi E, Ishikawa E, Bartolini L, et al. 1996 Somatostatin infusion suppresses GH secretory burst number and mass in normal men: a dual mechanism of inhibition. Am J Physiol. 270:E975–E979.
  50. Mulligan T, Jaen-Vinuales A, Godschalk M, Iranmanesh A, Veldhuis JD. 1999 Synthetic somatostatin analog (octreotide) suppresses daytime growth hormone secretion equivalently in young and older men: preserved pituitary responsiveness to somatostatin’s inhibition in aging. J Am Geriatr Soc. 47:1422–1424.[Medline]
  51. Bray M, Shah N, Veldhuis JD. Impact of estrogen on the dose-dependent inhibition by somatostatin of GH secretion in postmenopausal women. Proc of the 81st Annual Meet of The Endocrine Soc. 1999.
  52. Jorgensen JO, Moller J, George K. 1993 Marked effects of sustained low growth hormone (GH) levels on day-to-day fuel metabolism. Studies in GH-deficient patients and healthy untreated subjects. J Clin Endocrinol Metab. 77:1589–1596.[Abstract]
  53. Katakami H, Arimura A, Frohman LA. 1986 Growth hormone (GH)-releasing factor stimulates hypothalamic somatostatin release: an inhibitory feedback effect on GH secretion. Endocrinology. 118:1872–1877.[Abstract]
  54. Tannenbaum GS. 1994 Multiple levels of cross-talk between somatostatin (SRIF) and growth hormone (GH)-releasing factor in genesis of pulsatile GH secretion. Clin Pediatr Endocrinol. 3:97–110.
  55. Shah N, Evans WS, Bowers CY, Veldhuis JD. 2000 Oral estradiol administration modulates continuous intravenous growth hormone (GH)-releasing peptide-2 driven GH secretion in postmenopausal women. J Clin Endocrinol Metab. 85:2649–2659.[Abstract/Free Full Text]
  56. Anderson SM, Shah N, Patrie JT, Evans WS, Bowers CY, Veldhuis JD. Short-term estradiol supplementation augments growth hormone (GH)-secretory responsiveness to dose-varying growth hormone-releasing peptide (GHRP-2) infusions in postmenopausal women. J Clin Endocrinol Metab. In press.
  57. Vance ML, Kaiser DL, Evans WS, Furlanetto R, Vale WW, Rivier J, Thorner MO. 1985 Pulsatile growth hormone secretion in normal man during a continuous 24-hour infusion of human growth hormone releasing factor (1–40). J Clin Invest. 75:1584–1590.
  58. Holl RW, Thorner MO, Mandell GL, Sullivan JA, Sinha YN, Leong DA. 1988 Spontaneous oscillations of intracellular calcium and growth hormone secretion. J Biol Chem. 263:9682–9685.[Abstract/Free Full Text]
  59. Martha Jr. PM, Blizzard RM, McDonald JA, Thorner MO, Rogol AD. 1988 A persistent pattern of varying pituitary responsivity to exogenous growth hormone (GH) releasing hormone in GH deficient children: evidence supporting periodic somatostatin secretion. J Clin Endocrinol Metab. 67:449–454.[Abstract]
  60. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. 1999 Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 402:656–660.[CrossRef][Medline]
  61. Leong DA, Pomes A, Gaylinn BD, Thorner MO, Hellmann PH, Veldhuis JD. A novel hypothalamic hormone measured in hypophyseal portal plasma drives rapid bursts of GH secretion. Proc of the 80th Annual Meet of The Endocrine Soc. 1998.
  62. Pincus SM, Veldhuis JD, Rogol AD. 2000 Longitudinal changes in growth hormone secretory process irregularity assessed transpubertally in healthy boys. Am J Physiol. 279:E417–E424.
  63. Fryburg DA, Weltman A, Jahn LA, Weltman JY, Samolijik E, Veldhuis JD. 1997 Short-term modulation of the androgen milieu alters pulsatile but not exercise or GHRH-stimulated GH secretion in healthy men. J Clin Endocrinol Metab. 82:3710–3719.[Abstract/Free Full Text]
  64. Giustina A, Scalvini T, Tassi C, et al. 1997 Maturation of the regulation of growth hormone secretion in young males with hypogonadotropic hypogonadism pharmacologically exposed to progressive increments in serum testosterone. J Clin Endocrinol Metab. 82:1210–1219.[Abstract/Free Full Text]
  65. Alvarez XA, Cacabelos R. 1990 Effects of GRF (1–29) on short-term memory: neuroendocrine and neuropsychological assessment in healthy young subjects. Methods Findings Exp Clin Pharmacol. 12:493–499.[Medline]
  66. Kerkhofs M, Van Cauter E, Van Onderbergen A, Caufriez A, Thorner MO, Copinschi G. 1993 Sleep-promoting effects of growth hormone-releasing hormone in normal men. Am J Physiol. 264:E594–E598.
  67. Veldhuis JD, Evans WS, Shah N, Story S, Bray MJ, Anderson SM. 1999 Proposed mechanisms of sex-steroid hormone neuromodulation of the human GH-IGF-I axis. In: Veldhuis JD, Giustina A, eds. Sex-steroid interactions with growth hormone. New York: Springer-Verlag; 93–121.
  68. Gabrielsson BG, Carmignac DF, Flavell DM, Robinson ICAF. 1995 Steroid regulation of growth hormone (GH) receptor and GH-binding protein messenger ribonucleic acid in the rat. Endocrinology. 136:209–217.[Abstract]
  69. Janssen YJH, Helmerhorst F, Frolich M, Roelfsema F. 2000 A switch from oral (2 mg/day) to transdermal (50 µg/day) 17ß-estradiol therapy increases serum insulin-like growth factor-I levels in recombinant human growth hromone (GH)-substituted women with GH deficiency. J Clin Endocrinol Metab. 85:464–467.[Abstract/Free Full Text]



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