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Short-Term Estradiol Supplementation Augments Growth Hormone (GH) Secretory Responsiveness to Dose-Varying GH-Releasing Peptide Infusions in Healthy Postmenopausal Women¹

Division of Endocrinology, Department of Internal Medicine, General Clinical Research Center, Center for Biomathematical Technology, University of Virginia Health Sciences Center (S.M.A., N.S., W.S.E., J.T.P., J.D.V.), Charlottesville, Virginia 22908; and Division of Endocrinology and Metabolism, Department of Internal Medicine, Tulane University Medical Center (C.Y.B.), New Orleans, Louisiana 70112-2699

Address all correspondence and requests for reprints to: Dr. S. M. Anderson, Division of Endocrinology, Department of Internal Medicine, Box 800-202, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908-0746. E-mail: sg4c{at}virginia.edu

	Abstract

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Estrogen is a prominent stimulus to GH secretion throughout the human life span, albeit via neuroendocrine mechanisms that are incompletely defined. Here, we test the hypothesis that estradiol replacement in postmenopausal women enhances the responsiveness of the hypothalamo-pituitary unit to the GH-releasing effect of GH-releasing peptide-2 (GHRP-2). GHRP-2 is a potent and selective synthetic hexapeptide capable of activating an endogenous GHRP receptor/effector pathway, for which a ³Ser-octanoylated 28-amino acid ligand was cloned recently. To examine this postulate, we studied 10 healthy estrogen-withdrawn postmenopausal women, who were given oral placebo or estrogen supplementation [1 mg micronized 17ß-estradiol (E₂) twice daily for 7–15 days] in a patient-blinded, prospective, randomized, and within-subject cross-over design. The GH-releasing actions of five semilogarithmically increasing doses of GHRP-2 (absolute range, 0.03–3 µg/kg by bolus iv infusion) vs. saline were evaluated by frequent blood sampling on separate days in the morning while fasting. Serum GH concentrations were determined in blood sampled every 10 min using an ultrasensitive chemiluminescence assay and analyzed by multiparameter deconvolution to calculate the summed mass of GH secreted during the 2-h interval after bolus GHRP-2 infusion. Logarithmically transformed secretory responses were compared across the different dosages of infused GHRP-2 by two-way repeated measures ANOVA. Estradiol replacement increased the global mean (±SEM) serum E₂ concentration from 15 ± 0.8 to 470 ± 17 pg/mL (55 ± 2.9 to 1725 ± 62 pmol/L; P = 0.004) and lowered insulin-like growth factor I levels by approximately 27% (P = 0.087). Administration of E₂ elevated the geometric mean basal (saline-infused) GH secretory burst mass by 2.1-fold (95% confidence interval, 1.4- to 3.1-fold) compared with placebo ingestion (geometric mean ratios; P < 0.001). E₂ exposure enhanced the efficacy of the highest GHRP-2 dose tested (3 µg/kg) by 2.1-fold (1.3- to 3.3-fold; P = 0.010). Compared with the effect of placebo and saline, E₂ combined with the highest dose of GHRP-2 stimulated GH secretory burst mass by a total of 31-fold (24- to 41-fold; P < 0.001). Random coefficient regression analysis of the relationship between the logarithm of GHRP-2 dose and GH secretory burst mass revealed that E₂ significantly augmented the amount of GH secreted per unit GHRP-2 dose (E₂, 16.6 ± 1.8 slope units; placebo, 10.1 ± 1.4 slope units; P = 0.03). Although the global mean endogenous GH half-life did not differ between the E₂ and placebo sessions (E₂, 18 ± 0.6 min; placebo, 17 ± 0.5 min), GH half-life varied directly with dose of GHRP-2 (and, hence, the mean serum GH concentration) in both the E₂ and placebo sessions (test of zero slope hypothesis, P = 0.0018). The deconvolved GH secretory burst peaked within 8–13 min of the bolus iv injection of GHRP-2, and this latency was not altered by E₂. Based on a mixed effects analysis of covariance model, GHRP-2 dose and E₂, but not the plasma insulin-like growth factor I concentration, determined the magnitude of the GH secretory response (P < 0.001).

We conclude that short-term oral E₂ repletion in postmenopausal women selectively augments GH secretory pulse mass, enhances the steepness of the GHRP-2 dose-GH secretory response relationship (greater sensitivity), and heightens the maximal GH secretory response to the highest dose of GHRP-2 tested (greater efficacy). These data point to a facilitative interaction between E₂ and the GHRP receptor/effector pathway in driving the mass of GH secreted per burst.

	Introduction

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GH PRODUCTION declines exponentially in normal aging (1). Given the important role of GH in anabolic processes governing muscle strength, bone mass, body composition, lipoprotein metabolism, the cardiovascular system, and the central nervous system, the diminution in GH secretion may account for some of the functional deficits that accompany aging (2, 3, 4, 5, 6).

Estrogen deficiency probably mediates certain of the repressive effects of advancing age on GH secretion, especially in the postmenopausal setting. For example, in cross-sectional statistical analyses, the serum estradiol (E₂) concentration accounts for significant variability in daily GH production among adults of different ages and between women and men (7, 8). Indeed, prepubertal girls and boys with low sex steroid hormone levels maintain indistinguishable overnight GH secretory profiles (9). During puberty, children exhibit a 2- to 3-fold increase in pulsatile GH secretion commensurate with their concurrent rise in E₂ and aromatizable androgen availability (10, 11, 12). In menstruating women, the periovulatory elevation in estrogen is marked by a concomitant amplification of 24-h pulsatile GH production and an increase in the plasma insulin-like growth factor I (IGF-I) concentration (13). Likewise, hyperestrogenism achieved in ovulation induction regimens is accompanied by a significant (4-fold) augmentation of GH output (14). Supplementation with oral or higher dose transdermal E₂ also stimulates a 1.5- to 2.2-fold increase in 24-h integrated serum GH concentrations in hypogonadal girls or postmenopausal women (15, 16, 17, 18). Conversely, muting of endogenous estrogen actions by ovariectomy, antiestrogen administration, or GnRH agonist-induced gonadal down-regulation in young women lowers fasting serum GH and IGF-I concentrations (1, 19, 20, 21). Therefore, the estrogenic milieu strongly and positively impacts GH secretion throughout the adult lifetime. However, the precise neuroregulatory mechanisms by which estrogen governs the activity of the hypothalamo-pituitary GH-IGF-I feedforward and feedback axes are not fully understood.

The GH-releasing peptides (GHRPs) or GH secretagogues comprise a family of molecules capable of dose-dependent and reproducible stimulation of GH secretion in many species, including humans (1, 22, 23, 24, 25). GHRPs were discovered 2 decades ago as synthetic, met-enkephalin-derived oligopeptides that preferentially release GH in vitro and in vivo (26, 27). Using conformational energy calculations, progressively more active analogs were synthesized (28), including more recently the hexapeptide GHRP-2 (DAlaDßNalAlaTrpDPheLysNH₂) (29, 30, 31). The incorporation of three D-amino acid residues protects GHRP-2 from peptidase degradation, making it the most active GHRP compound available for human investigative use. Most recently, a ³Ser-octanoylated 28-amino acid natural ligand for the GHRP receptor/effector pathway was cloned in the rat and human and found to circulate in human blood (25).

Given the putatively sexually dimorphic regulation of GHRP activity in the experimental animal and human (see Discussion), here we examine the postulate that E₂ can amplify the secretagogue activity of a potent synthetic GHRP agonist. To this end, we implemented a prospective, randomly ordered, patient-blinded, and separate day analysis of the dose-dependent actions of GHRP-2 in postmenopausal women studied in the estrogen-replete vs. the estrogen-withdrawn milieu.

	Subjects and Methods

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Subjects

The study was approved by the Human Investigation Committee and the General Clinical Research Advisory Committee of the University of Virginia. Ten healthy postmenopausal women, aged 47–73 yr (mean ± SD, 60 ± 3), were studied after providing written informed consent. All subjects were nonsmokers and were taking no chronic medications, with the exception of multivitamins, ferrous sulfate, or stable thyroid hormone replacement (one woman). Acetaminophen, salicylates, and nonsteroidal anti-inflammatory drugs were allowed. Each woman had an unremarkable history and physical examination and normal screening laboratory tests of liver, kidney, thyroid, and hematological function. Each volunteer had been clinically postmenopausal for at least 2 yr. Postmenopausal status was confirmed by an elevated serum FSH level (mean ± SD, 71 ± 9 IU/L) and a low serum E₂ level (15 ± 0.8 pg/mL or 55 ± 2.9 pmol/L). Women previously taking estrogen were withdrawn from the hormone for at least 3 weeks before entry into the study. There was no transmeridian travel (within 2 weeks), nightshift work, significant weight change (within 3 kg in 2 weeks), acute illness, chronic disease, psychiatric illness, or substance abuse in the study subjects.

Study design

A prospective, patient-blinded, randomized, cross-over design was used to assess the GH secretory response initially to saline or 4 doses of GHRP-2 [0 (saline), 0.03, 0.10, 0.30, and 1.0 µg/kg, iv, in randomly assigned order] in the estrogen-deficient vs. the estrogen-replaced state. Each woman underwent a total of at least 10 admissions, 5 during estrogen and 5 during placebo treatment (below). Estrogen supplementation consisted of 1 mg oral micronized 17ß-estradiol (Estrace; Bristol-Myers Squibb, Princeton, NJ) administered twice daily for 7–15 days. The estrogen and placebo treatment arms were followed by a wash-out period of at least 3 weeks to allow for physiological recovery. Admissions began on day 7 of placebo or estrogen treatment and were separated by a minimum of 48 h. Volunteers were admitted to the General Clinical Research Center the evening before the study to allow overnight adaptation. Studies were performed in the fasting state (except for water and ice) from 0000–1400 h to eliminate food-related confounds. An iv catheter was inserted into the forearm at 0600 h for blood sampling and for later saline or GHRP-2 infusions. Blood was sampled (1 cc) every 10 min from 0800–1400 h. GHRP-2 was infused by iv bolus at 1000 h. Activity was limited to bedrest with lavatory use during the blood sampling.

Ten women received saline and the foregoing range of GHRP-2 doses (0.03–1 µg/kg). In view of preliminary data indicating failure of 1 µg/kg GHRP-2 to achieve maximal GH release, eight volunteers were restudied after additional institutional review board-approved informed consent. These women were given a single dose of 3 µg/kg GHRP-2 during placebo vs. E₂ replacement for a minimum of 7 days, with an intervening wash-out period of at least 3 weeks.

Percent body fat

Hydrodensitometry was used to estimate the percentage of total body fat as described previously (32).

Assays

Serum GH concentrations were measured in each sample in duplicate by an automated ultrasensitive GH chemiluminescence assay (modified Nichols Luma Tag hGH assay, Nichols Institute Diagnostics, San Juan Capistrano, CA) using 22-kDa human recombinant GH as the assay standard. The sensitivity of the assay was 0.005 µg/L. The median dose-dependent inter- and intraassay coefficients of variation were also reported previously (33, 34). All 37 serum samples from each admission were assayed together. Serum E₂ was measured by an automated E₂ chemiluminescence assay (ACS 180 Bayer Corp., Norwood, MA), and serum IGF-I (after acid-ethanol extraction) was measured by RIA (Nichols Institute Diagnostics) from a single morning blood sample collected before the infusion.

Data reduction and multiparameter deconvolution analysis of pulsatile GH release

The GH secretory response and endogenous half-life were determined by multiparameter deconvolution analysis (35, 36). Summed GH secretory burst mass and the peak serum GH concentration attained during the 2-h sampling period after GHRP-2 infusion were evaluated as stimulated responses.

Statistical analysis

Assessment of mean serum E₂ and IGF-I concentrations, GH half-lives, and GH burst mass at GHRP-2 doses of 0 (saline), 0.03, 0.10, 0.30, 1.0, and 3.0 µg/kg was made using a two-way repeated measures ANOVA. ANOVA model specification included terms to estimate the treatment and GHRP-2 effects, as well as treatment by GHRP-2 dose interaction (37). All data were transformed to the natural logarithmic scale as a variance-stabilizing transformation before analysis. Comparisons are reported in terms of the fold change in the geometric mean (37).

GHRP-2 dose-response profiles of stimulated GH burst mass (micrograms per L), half-life (minutes), and stimulated peak GH (micrograms per L) were analyzed by random coefficient regression analysis (38). Model specification allowed for the intercept and the slope parameters to vary within the E₂ and placebo treatment arms. A mixed effects regression model was used to examine the impact of plasma IGF-I and/or E₂ concentrations on the maximal GH response to GHRP-2 infusions (38).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Figure 1 depicts individual illustrative GHRP-2 dose-response profiles in two of eight women, each of whom received a bolus injection of 0, 0.03, 0.1, 0.3, 1.0, and 3.0 µg/kg of the GHRP-2 agonist with or without concurrent E₂ replacement. ANOVA showed that the morning E₂ concentration was invariant on study days 7–12 within either the placebo or E₂ supplementation arm, as was the mean plasma IGF-I concentration. The grand mean (±SEM) serum E₂ level rose from 55 ± 2.9 to 1725 ± 62 pmol/L (P = 0.004). The serum IGF-I concentration declined by 0.78-fold [95% confidence limits (CL), 0.53–1.2; P = 0.087] during E₂ treatment.

View larger version (67K): [in this window] [in a new window]   Figure 1. Illustrative individual profiles of serum GH concentration responses to placebo or E2 supplementation followed by the bolus iv infusion of saline (zero dose) or 0.03, 0.1, 0.3, 1.0, or 3.0 µg/kg GHRP-2 in two postmenopausal women. Continuous curves through the observed data were predicted by deconvolution analysis.

View larger version (19K): [in this window] [in a new window]   Figure 2. Log-linear regression of GH secretory pulse mass vs. GHRP-2 dose in postmenopausal women pretreated with placebo or E2 for 7–12 days. Interrupted lines project the 95% statistical confidence intervals of the mean random effects regression plot (solid line). Each regression line exhibits a significantly positive nonzero slope at P < 0.001.

View larger version (17K): [in this window] [in a new window]   Figure 3. Relationship between infused GHRP-2 dose (log x-axis) and peak serum GH concentrations (y-axis) in 8 women (3 µg/kg GHRP-2 dose) or 10 women (all doses except 3 µg/kg). Data are plotted otherwise as given in Fig. 2.

View larger version (19K): [in this window] [in a new window]   Figure 4. Regression plot of the relationship between GHRP-2 dose (log x-axis) and estimated endogenous GH half-life (y-axis). The latter is an indirect measure of the GH metabolic clearance at any given distribution volume. Data are presented as defined in Fig. 2.

View larger version (19K): [in this window] [in a new window]   Figure 5. Impact of percent total body fat (top panel) or age (bottom panel) on placebo vs. E2-enhanced maximal GHRP-2 (3 µg/kg)-stimulated GH secretory burst mass in eight postmenopausal women who received both placebo and estradiol supplementation. The vertical bar connects the placebo () and estradiol () responses in each volunteer.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

The physiological relevance of the GHRP-related secretagogue pathway has been highlighted by the recent cloning in the rat, pig, and human of the gene encoding a specific GHRP receptor expressed in the hypothalamus, pituitary gland, and various nonendocrine tissues and a natural ligand, ghrelin, for this agonist pathway (24, 25, 40). The GH-stimulating actions and central nervous system binding of synthetic GHRPs decline with aging in the human (1). Whereas GHRPs exert some direct pituitary effects in vitro (23), their considerably higher in vivo efficacy probably reflects stimulation of GHRH release, synergy with GHRH’s actions, and partial relief of somatostatinergic restraint (41, 42, 43, 44, 45, 46, 47, 48). In the last regard, GHRPs can antagonize somatostatin’s inhibitory impact in the central nervous system and on somatotropes (23, 45), but these peptides do not directly block the hypothalamic secretion of somatostatin (1, 41, 44). Thus, in principle, E₂’s synergistic amplification of GHRP-2’s near-maximal stimulatory effect, as observed here, might result from one or more plausible mechanisms of estrogen action: 1) up-regulation of the GHRP receptor/effector pathway, 2) facilitation of GHRP’s enhancement of GHRH release or action, and/or 3) muting of endogenous somatostatin’s inhibitory control. With respect to the first consideration, the promoter of the human GHRP receptor gene exhibits a hemiestrogen-responsive element, which could allow estrogen-dependent up-regulation of this secretagogue pathway (49). In relation to the second postulate, estrogen itself may increase endogenous GHRH release, but does not appear to amplify its pituitary efficacy (1). In pilot studies, E₂ pretreatment appears to blunt exogenous somatostatin’s potency, but not efficacy, in inhibiting fasting GH secretion (50).

In the mouse and rat, GHRPs can exert sexually dimorphic effects on the GH-IGF-I axis (1, 19). Data in children further indicate that estrogen and aromatizable androgen may enhance GHRP-stimulated GH secretion. For example, in prepubertal girls and boys, a single injection of testosterone enanthate or oral administration of ethinyl estradiol for 3 days augmented the GH secretory response to a bolus injection of hexarelin (51). In contrast, oxandrolone, a nonaromatizable androgen, did not influence the GHRP effect. This distinction is consistent with the inference that testosterone stimulates GH release conditional on its aromatization (1, 52, 53). Another investigation across the human life span documented maximal hexarelin effects in pubertal girls (54), in whom GH secretory responsiveness correlated positively with concomitant serum E₂ concentrations. However, stage of the menstrual cycle in young women and low dose transdermal E₂ (0.05 mg daily) replacement in postmenopausal women did not influence GH secretion stimulated by a single iv bolus injection of the same GHRP (55, 56). Although the basis for the foregoing disparities is not known, the present paradigm is unique in its separate day, randomly ordered, within-subject, cross-over design, short-term supplementation with oral 17ß-estradiol, 10-min sampling of plasma GH concentrations, deconvolution analysis of baseline-corrected GH secretion, choice of GHRP receptor agonist, and appraisal of an extended (100-fold) GHRP dose range. In this experimental context, E₂ repletion enhanced both the potency and efficacy of acute GHRP-2-driven GH secretion. The most vivid facilitative effect of E₂ occurred in response to the highest dose of GHRP-2 investigated and was independent of variations in body composition (assessed by percent body fat) and postmenopausal age.

Higher GHRP-2 doses slightly, but consistently, increased the estimated half-life of secreted GH. This finding may mirror the small decline in the MCR of GH observed at higher circulating GH concentrations (57). Concentration-dependent GH kinetics are, in turn, controlled by the high affinity and finite capacity GH-binding protein in plasma, a limited tissue capacity to remove GH irreversibly and the relative amounts of 20- and 22-kDa GH isoforms released, detected, and/or retained in the circulation (1, 58).

In summary, the accompanying clinical investigation establishes a prominent facilitative effect of short-term oral E₂ replacement on the potency and efficacy of GHRP-2’s acute stimulation of GH secretion in postmenopausal women. Estrogen’s enhancement entailed specific amplification of GH secretory burst mass and amplitude and was apparently independent of body composition or postmenopausal age within the ranges studied here. Thus, the present data indicate that E₂ might act mechanistically to up-regulate the responsiveness of the human GHRP receptor/effector pathway. The extent, if any, to which the concomitant trend toward lower plasma IGF-I concentrations induced by estrogen supplementation enhanced GHRP-2’s efficacy or potency is unknown, as the serum E₂ concentration and the infused dose of GHRP-2, rather than concomitant IGF-I levels, determined the magnitude of stimulated GH secretion in this cohort of women.

	Acknowledgments

 
We thank Patsy Craig for her skillful preparation of the manuscript, Ginger Bauler for performance of the immunoassays, 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.

	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 (to S.M.A.), and NIH Grant RO1-AG-14799 (to J.D.V.).

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

Received June 21, 2000.

Revised October 6, 2000.

Accepted October 28, 2000.

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