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Division of Endocrinology, Department of Internal Medicine, General Clinical Research Center, Center for Biomathematical Technology, University of Virginia School of Medicine (J.D.V., W.S.E.), Charlottesville, Virginia 22908-0202; and Endocrinology and Metabolism Section, Department of Medicine, 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, University of Virginia School of Medicine, P.O. Box 800202, Charlottesville, Virginia 22908-0202. E-mail: jdv{at}virginia.edu
Abstract
As an indirect probe of estrogen-regulated hypothalamic somatostatin restraint, the present study monitors the ability of short-term oral E2 supplementation to modulate GH secretion during combined continuous stimulation by recombinant human GHRH [GHRH-(1–44)-amide] and the potent and selective synthetic GH-releasing peptide, GHRP-2. According to a simplified tripeptidyl model of GH neuroregulation, the effects of estrogen in this dual secretagogue paradigm should mirror alterations in endogenous somatostatinergic signaling. To this end, seven healthy postmenopausal women underwent frequent (10-min) blood sampling for 24 h during simultaneous iv infusion of GHRH and GHRP-2 each at a rate of 1 µg/kg·h on d 10 of randomly ordered placebo or 17ß-estradiol (E2) (1 mg orally twice daily) replacement. Serum GH concentrations (n = 280/subject) were assayed by chemiluminescence. The resultant GH time series was evaluated by deconvolution analysis, the approximate entropy statistic, and cosine regression to quantitate pulsatile, entropic (feedback-sensitive), and 24-h rhythmic GH release, respectively. Statistical comparisons revealed that E2 repletion increased the mean (±SEM) serum E2 concentration to 222 ± 26 pg/ml from 16 ± 1.7 pg/ml during placebo (P < 0.001) and suppressed the serum LH by 48% (P = 0.0033), serum FSH by 64% (P < 0.001), and serum IGF-I by 44% (P = 0.021). Double peptidyl secretagogue stimulation elevated mean 24-h serum GH concentrations to 8.1 ± 1.0 µg/liter (placebo) and 7.7 ± 0.89 µg/liter (E2; P = NS) and evoked prominently pulsatile patterns of GH secretion. No primary measure of pulsatile or basal GH release was altered by the disparate sex steroid milieu, i.e. GH secretory burst amplitudes of 0.62 ± 0.93 (placebo) and 0.72 ± 0.16 (E2) µg/liter·min, GH pulse frequencies of 27 ± 1.8 (placebo) and 23 ± 1.9 (E2) events/24 h, GH half-lives of 12 ± 0.74 (placebo) and 15 ± 4.5 (E2) min, and basal (nonpulsatile) GH secretion 70 ± 22 (placebo) and 57 ± 18 (E2) ng/liter·min. The approximate entropy (ApEn) of serial GH release [1.297 ± 0.061 (placebo) and 1.323 ± 0.06 (E2)] and the mesor (cosine mean), amplitude, and acrophase (time of the maximum) of 24-h rhythmic GH secretion were likewise invariant of estrogen supplementation. Estimated statistical power exceeded 90% for detecting significant (P < 0.05) within-subject changes exceeding 30–50% in the mean serum GH concentration, GH ApEn, or GH mesor. In contrast, ApEn analysis of the evolution of successive GH secretory burst-mass values over 24 h disclosed that E2 replacement disrupts the serial regularity of pulsatile GH output (elevates the ApEn ratio) during combined GHRH/GHRP-2 stimulation (P = 0.004).
In summary, short-term elevation of serum E2 concentrations in postmenopausal individuals into the midfollicular phase range observed in young women does not significantly alter 24-h basal, pulsatile, entropic, or nyctohemeral GH secretion monitored under continuous combined drive by GHRH and GHRP-2. As E2 repletion without enforced GHRH/GHRP-2 stimulation augments each of the foregoing regulated facets of GH release, we infer that one or both of the infused peptidyl secretagogues may itself participate in E2’s short-term amplification of GH secretion in postmenopausal individuals. Estrogen’s disruption of the orderliness of sequential GH pulse-mass values during fixed GHRH/GHRP-2 feedforward would be consistent with a subtle reduction in the release and/or actions of hypothalamic somatostatin or an (unexpected) direct pituitary action of the sex steroid. Whether comparable dynamics mediate the effects of endogenous estrogen on the GH axis in premenopausal women or pubertal girls is not known.
SEX STEROIDS AMPLIFY GH secretion in men and women (1, 2, 3, 4). In cross-sectional studies, serum estradiol (E2) concentrations predict daily serum GH concentrations in pubertal girls, in young women at various stages of the menstrual cycle, and in aging adults (5, 6, 7, 8). Exogenous and endogenous estrogens (e.g. before the preovulatory LH surge) consistently augment GH secretion, whereas GnRH agonist- induced down-regulation of the gonadal axis in precocious puberty, ovariectomy in premenopausal women, and antiestrogen exposure in young men suppress GH production (9, 10, 11, 12, 13, 14, 15, 16, 17). However, the precise neuroendocrine mechanisms by which estrogenic hormones promote GH secretion in the human are not known.
Experimental analyses document feedforward control of GH secretion by hypothalamic GHRH, inferred stimulatory input by an endogenous GH-releasing peptide (GHRP) pathway, and evident feedback restraint by somatostatin (4, 18). Other peptides (e.g. opioids, galanin, NPY, CRH, leptin, substance P, bombesin, neurotensin, and cytokines) can also impact GH release, but their in vivo roles are not established. Thus, a minimal construct of hypothalamic peptidyl regulation of somatotrope secretion would include the principal effectors, GHRH, a GHRP, and somatostatin (19, 20, 21, 22, 23, 24, 25).
The present investigation implements a novel two-peptide (GHRH and GHRP-2) stimulation paradigm to examine the mechanism(s) by which estrogen amplifies pulsatile, entropic (feedback-sensitive) and 24-h rhythmic (nyctohemeral) GH secretion. To this end, we administered GHRP-2, a selective and potent synthetic hexapeptide agonist of the GHRP/ghrelin receptor (24, 25), and recombinant human GHRH-(1–44)-amide (GHRH) simultaneously by continuous iv infusion for 24 h in estrogen-withdrawn vs. E2-replaced postmenopausal women in a prospectively randomized, cross-over design. We postulated that modulation of GH secretion by short-term E2 supplementation during dual secretagogue drive should reflect altered somatostatin release and/or action.
Materials and Methods
Clinical protocol
The study was approved by the human investigation committee of the University of Virginia Health Sciences System. Each volunteer provided prior written informed consent. Seven healthy postmenopausal women (body mass index range, 23–28 kg/m2; age range, 51–68 yr) participated. Infusions consisted of GHRH and GHRP-2 (each 1 µg/kg·h) delivered simultaneously and continuously iv for 24 h beginning at 0800 h. Blood samples were withdrawn concomitantly every 10 min via a contralateral forearm venous catheter for later GH assay (below). Medical history, physical examination, and screening measurements of hepatic, renal, metabolic, endocrine, and hematological function were normal. No subject was taking systemic medications, hormones, or illicit drugs or ingesting excessive alcohol. Recent transmeridian travel (more than three time zones within 1 wk) or weight changes (gain or loss of >3 kg in 2 wk) were exclusion criteria. Volunteers were withdrawn from any prior estrogen use for 6 wk before receiving randomly ordered placebo or oral 17ß-E2 (1 mg micronized twice daily) for 10 d including the day of sampling. There was an intervening 6-wk washout period between study sessions.
Hormone assays
Serum GH concentrations were measured in each sample in duplicate by an ultrasensitive chemiluminescence robotics-based assay (Nichols Institute Diagnostics, San Juan Capistrano, CA) using 22-kDa recombinant human GH as standard (26). All 290 samples from a subject’s two admissions were analyzed in one run. The sensitivity of the assay (defined as 3 SD above the zero dose tube) was 0.005 µg/liter. The median intra- and interassay coefficients of variation (CV) were 6.5% and 8.7%, respectively, at the serum GH concentrations measured here. E2 was quantitated by RIA with a sensitivity of 12 pg/ml and a within-assay CV of 5.2% (Coat-A-Count, Diagnostic Products, Los Angeles, CA) (27). Serum LH and FSH concentrations were measured by immunoradiometric assay (Nichols Institute Diagnostics), using the First and Second International Reference Preparations, respectively, as standards (14). The corresponding sensitivities and intraassay CVs were 0.2 and 2.0 IU/liter, and 6.3% and 7.4%. Interassay CVs were less than 10%. IGF-I was assayed by RIA after acid-ethanol extraction (Nichols Institute Diagnostics) with an intraassay CV of 10.3% and a normal range in this age group of 65–200 µg/liter (14, 15, 16). Glucose was measured by an automated glucose oxidase technique.
Deconvolution analysis
Multiparameter deconvolution analysis was applied to quantitate pulsatile GH secretion and estimate its endogenous half-life (28). Daily pulsatile GH secretion is the product of secretory burst frequency and the mean mass of GH released per pulse (integral of the secretory burst) (26, 28, 29). Basal GH secretion represents the time-invariant interpulse component of the release profile. Secretory pulse identification required that calculated burst mass exceed zero by 95% statistical confidence intervals.
Approximate entropy (ApEn)
ApEn was used as a scale- and model-independent statistic, which is complementary to deconvolution and cosine analyses (9, 29, 30, 31). ApEn quantifies the serial orderliness of hormone measurements. Normalized ApEn parameters of m = 1 (series length) and r = 20% (threshold) of the intraseries SD were used, as previously validated for 24-h serum GH concentration time series (32). This statistic is thus designated ApEn (1,20%). Increased ApEn (at equal series lengths and similar parameter values, as used here) indicates greater irregularity of data patterns, as reported for GH profiles in acromegaly (32) as well as for GH release in the female compared with the male (9, 29, 30). ApEn was also applied to the succession of GH pulse-mass values calculated by deconvolution analysis of each serum GH concentration-time series.
Cosinor analysis
The 24-h rhythmicity of plasma GH concentrations was quantitated by cosinor analysis as described previously (33). This procedure entails unweighted regression of a cosine function of 1440 min periodicity on the observed hormone time series. Ninety-five percent statistical confidence intervals were determined for the fitted amplitude (50% of the nadir-zenith difference), mesor (cosine mean), and acrophase (clocktime of calculated maximum value).
Statistical analysis
A paired two-tailed t test was applied to compare mean hormone concentrations and log-transformed measures of GH secretion. Data are presented as the mean ± SEM.
Results
Figure 1
illustrates four of seven serum GH concentration profiles (A) and corresponding deconvolution-calculated GH secretory rates (B). Time series reflect blood sampling at 10-min intervals for 24 h beginning at 0800 h on d 10 of randomly ordered oral placebo vs. E2 administration. Combined GHRH and GHRP-2 infusions (1 µg/kg·h each) maintained comparable mean daily serum GH concentrations of 8.1 ± 1.0 µg/liter during placebo and 7.7 ± 0.89 µg/liter during estrogen repletion (P = NS). Integrated serum GH concentrations were likewise similar in the two study sessions. Further analyses revealed approximately 95% statistical power (ß or type II statistical error <0.05) for identifying a 50% within-subject increase in mean serum GH concentrations at P < 0.05 for this cohort size.
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). Conversely, serum concentrations of FSH, LH, and IGF-I fell by 46%, 64%, and 44% (P < 0.0001, P = 0.0033, and P = 0.021), respectively. Such data identify unequivocal estrogen-dependent effects on several neuroendocrine axes in this setting.
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). Daily pulsatile and total (pulsatile plus basal) GH production rates, GH interpulse intervals, secretory burst half-duration, and percent pulsatile GH secretion also were unaffected by estrogen repletion. Corresponding power estimates for pulsatile and total daily GH secretion rates exceeded 90% (above). Thus, under the joint stimulus of GHRH and GHRP-2, the principal parameters of daily GH secretion remained stable despite marked estrogen enrichment.
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). GH profiles were significantly organized (nonrandom), inasmuch as observed ApEn values averaged 11.7 ± 0.98 (placebo) and 11.1 ± 1.3 (E2) SD removed from predicted mean random (P < 10-6 based on shuffling each data series randomly 1000 times). As the coefficient of variation of the ApEn ratio is approximately 4%, the statistical power for detecting a 30% rise in ApEn [as observed consistently for the effect of estrogen alone (14)] exceeds 99%. In contrast, ApEn analysis of sequential GH burst-mass values (obtained by deconvolution analysis) disclosed a significant loss of regularity under 3-fold stimulation by E2, GHRH, and GHRP-2 (P = 0.004 vs. placebo/GHRH/GHRP-2; Fig. 5).
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, the mesor (rhythmic mean), amplitude (one-half of the nadir to zenith difference), and acrophase (clock time of the daily maximum) of nyctohemeral GH variations during joint GHRH/GHRP-2 infusion were uninfluenced by estrogen administration. Statistical analysis revealed a power of more than 90% for identifying a 35% or greater within-subject increase in the GH mesor by paired parametric testing at P < 0.05.
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The present study probes the neuroendocrine mechanisms that mediate estrogen’s stimulation of pulsatile, entropic (feedback-sensitive), and daily rhythmic GH secretion in healthy postmenopausal women. Based on a tripeptidyl model of GH neurosecretory control (see introduction), alterations of GH production induced by E2 repletion in the present unique experimental context of continuous 24-h iv infusion of combined GHRH and GHRP-2 stimuli should denote modulation of somatostatinergic outflow and/or reflect direct pituitary actions of E2. Little, if any, evidence exists for the latter mechanism (4, 17, 18, 34, 35, 36, 37). Accordingly, the current investigational paradigm allows an indirect appraisal of possible estrogenic control of hypothalamic somatostatinergic restraint. To enhance statistical power (here, 90–99%), dual secretagogue infusions were carried out in the same postmenopausal subject after randomly ordered administration of placebo or E2. Accordingly, the inability of E2 replacement to alter 24-h basal, pulsatile, entropic (feedback-sensitive), or diurnally rhythmic GH release significant during simultaneous stimulation by GHRH and GHRP-2 argues against prominent estrogen-dependent regulation of somatostatin production in this setting (see below).
This is the first investigation to our knowledge to evaluate the effect of a sex steroid on the combined continuous actions of GHRP and GHRH over 24 h in the human. Indeed, GH responses to dual secretagogue stimulation in the estrogen-withdrawn individual are remarkable (ApEn and pulsatile, basal, and circadian GH release) and remarkable in magnitude. Mean serum GH concentrations over 24 h exceeded 8 µg/liter in this stimulatory context. Whether absolutely higher daily GH output is achievable in this unique setting is not known. However, the human pituitary content of immunoreactive GH is reported as 5–10 mg, whereas presently estimated daily GH secretion rates were 2–3 mg. In addition, L-arginine infusion in older subjects augments the acute stimulatory effects of GHRH and/or GHRP (4), although not necessarily the sustained effects of GHRH/GHRP-2 delivered over a full 24 h. Accordingly, further investigations will be required to establish the absolute maximal daily GH secretory capacity of the human pituitary gland in various age groups. In any case, the ApEn statistic remains a valid quantitative marker of altered somatostatinergic signaling to somatotropes (9, 29, 30, 31, 32). The concentration independence of ApEn is indicated by greater quantifiable GH secretory irregularity in patients with acromegaly, on the one hand, and those with a GHRH receptor mutation, on the other, hand (across a 300- to 1000-fold range of mean serum GH concentrations) (32). Unlike the unchanging orderliness of 24-h serum GH concentration profiles, the quantifiable regularity of successive GH pulse-mass values was degraded by E2 replacement under joint GHRH/GHRP-2 drive. Such data are consistent with quantifiable actions of estrogen on somatostatinergic (or other) signaling inputs to somatotropes, viz. decreased release and/or blunted actions of endogenous somatostatin. The latter sensitivity change was inferred earlier for exogenous infusion of this tetradecapeptide (38).
Oral E2 supplementation alone augments daily pulsatile GH secretion by approximately 1.6- to 2.4-fold and elevates the ApEn and 24-h rhythmicity of GH output (9, 11, 14, 15, 16, 17, 34, 36, 37). We corroborated the bioavailability of estrogen in the present study by documenting an elevation of serum E2 concentrations into the midfollicular phase range expected in young women and reciprocal suppression of serum concentrations of LH, FSH, and IGF-I by 35–50% each. In relation to the fall in plasma IGF-I concentrations, experiments in the rat, rabbit, and human indicate that E2 can antagonize GH-stimulated hepatic IGF-I production (4, 17). The decline in serum IGF-I concentrations may contribute to enhanced GH secretion by withdrawing presumptive negative feedback by this insulinomimetic peptide.
The ability of simultaneous continuous iv infusion of GHRH and GHRP-2 to sustain the pulsatile and nyctohemeral dynamics of GH production is striking. Indeed, GH secretion remained predominantly pulsatile (Table 1) and measurably 24-h rhythmic (Table 2
). Albeit observed earlier for single secretagogue infusions (15, 16, 27, 36, 37, 39, 40), the persistence of pulsatile and circadian-like GH release during fixed dual peptidyl secretagogue drive could indicate 1) amplification of an inherent rhythmicity in somatotrope cell GH secretion and/or 2) comodulation by other (non-GHRH and non-GHRP) secretagogues or antagonists of GH release (4, 18, 41, 42, 43, 44, 45). Pituitary tissue imperifusion and hypothalamo-pituitary-disconnected sheep maintain low amplitude, high frequency, and irregular GH pulses in vitro and in vivo, respectively (4, 18). Whether GHRH and/or GHRP-2 can enhance such putative oscillations in the somatotrope is not known. If such oscillations should prevail, the present data show that short-term estrogen supplementation does not modify their frequency. Cyclical somatostatin release or possibly intermittent secretion of an (unidentified) cosecretagogue would more likely contribute to the genesis of GH pulses in the human, as inferred previously in the rodent (4, 18, 44, 45, 46, 47, 48, 49), and could explain the continuing pulsatile secretion of GH during joint stimulation with GHRH and GHRP-2. A role for episodic somatostatin release was also suggested based on retention of GH pulsatility, albeit at very low absolute amplitudes, in two patients with a rare loss of function (truncational) mutation of the GHRH receptor (50). The mechanistic basis of putative hypothalamic somatostatin pulse generation is not known, but could arise by way of an intrinsic automaticity of periventricular somatostatinergic neurons and/or by time-delayed negative feedback by GH/IGF-I on the central nervous system (4, 18, 44, 45, 46, 47, 48, 49, 51). If cyclical somatostatin release were relevant to GH pulse generation in postmenopausal women, our observations indicate that estrogen administration does not accelerate the frequency of this activity. In humans, GH pulse frequency is also unaffected by antiestrogen or antiandrogen administration, stage of the menstrual cycle, androgenic stimulation, GHRH or GHRP-2 infusions, pubertal development in the male, or age in the male or female (7, 9, 13, 15, 16, 17, 29, 37).
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Quantitation of the serial orderliness of GH secretion by the ApEn statistic revealed significantly organized (nonrandom) patterns of GH release during 2-fold stimulation by GHRH and GHRP-2. The ApEn of 24-h serum GH concentration profiles was not affected further by estrogen exposure in this setting. In contrast, administration of estrogen alone consistently alters the quantifiable regularity of GH release (9, 14, 15, 16, 30, 38, 55). However, more subtle analysis of the regularity of consecutive GH pulse-mass values disclosed that addition of estrogen markedly degraded the serial orderliness of GH pulse-mass values during the continuing dual GHRH/GHRP-2 stimulus. This finding could denote antagonism of somatostatin’s coordination of somatotrope cell GH secretion (55, 56, 57, 58) and/or reduced hypothalamic release of this inhibitory peptide (above). Interestingly, GHRP itself can oppose central somatostatinergic effects (4, 18, 20, 23). Thus, we reason that the foregoing ability of estrogen to limit presumptive somatostatinergic actions might be more evident in (other) contexts devoid of an exogenous GHRP input that potentially already reduce central somatostatin restraint.
Twenty-four-hour rhythmic GH release persisted during combined continuous iv infusion of GHRH and GHRP-2 at an average nyctohemeral amplitude of 15% of the daily mean (mesor). The zenith occurred at approximately 0600–0700 h, which is later than the nominally expected acrophase of 0100–0300 h (4). The delayed timing of maximal GH output during joint GHRH/GHRP-2 stimulation probably reflects sustained augmentation of GH secretion by the foregoing two secretagogues. E2 supplementation did not alter any of the primary measures of 24-h rhythmic GH secretion. These observations would speak against major estrogen-induced changes in 24-h rhythmic somatostatin release during fixed dual peptidyl drive (see introduction).
In summary, combined continuous iv infusion of GHRH and GHRP-2 amplifies daily GH secretion equivalently in estrogen-deficient and E2-replete postmenopausal women. Moreover, short-term supplementation with E2 does not alter daily basal, pulsatile, entropic (feedback-sensitive), or 24-h rhythmic GH release under dual secretagogue stimulation. Such collective outcomes would argue against major E2-induced relief of hypothalamic somatostatinergic outflow while inferentially pointing to estrogen-dependent facilitation of the release or actions of endogenous GHRH and/or GHRP. On the other hand, the ability of E2 supplementation to unequivocally alter the regularity of successive GH pulse-mass values during joint GHRH/GHRP-2 feedforward allows for more subtle estrogenic modulation of somatostatinergic activity, unanticipated direct pituitary actions of this sex steroid, and/or modulation of other (non-GHRH and non-GHRP) coregulators of pulsatile GH secretion. Whether the foregoing mechanisms of estrogen action also prevail in young women and pubertal girls under endogenous sex steroid drive is not known.
Footnotes
Abbreviations: ApEn, Approximate entropy; CV, coefficient of variation; GHRP, GH-releasing peptide.
Received May 25, 2001.
Accepted November 3, 2001.
References
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