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Estradiol Supplementation in Postmenopausal Women Doubles Rebound-Like Release of Growth Hormone (GH) Triggered by Sequential Infusion and Withdrawal of Somatostatin: Evidence that Estrogen Facilitates Endogenous GH-Releasing Hormone Drive

Division of Endocrinology and Metabolism (J.D.V.), Department of Internal Medicine, Mayo Medical and Graduate Schools of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905; Division of Endocrinology (S.M.A.), Department of Internal Medicine, Department of Health Evaluation Sciences (J.T.P.), General Clinical Research Center, University of Virginia Health System, Charlottesville, Virginia 22908; and Division of Endocrinology and Metabolism (C.Y.B.), Department of Internal Medicine, Tulane University Medical Center, New Orleans, Louisiana 70112

Address all correspondence and requests for reprints to: Johannes D. Veldhuis, Division of Endocrinology and Metabolism, Department of Internal Medicine, Mayo Medical and Graduate Schools of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905. E-mail: veldhuis.johannes{at}mayo.edu.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We postulated that short-term estradiol replacement in postmenopausal women may act, in part, by facilitating endogenous GHRH release or action. A prediction of this hypothesis is that estradiol repletion should enhance postsomatostatin rebound GH secretion, which appears to be driven by hypothalamic outflow of GHRH. To this end, we administered placebo and estradiol to eight healthy estrogen-withdrawn postmenopausal volunteers in a prospectively randomized, patient-blinded, within-subject crossover design for a total of 36 d. Rebound release of GH was assessed between d 7 and 36 of intervention on separate randomly ordered mornings after continuous iv infusion of saline or somatostatin (9 µg/kg·h for 3 h). Secretion was quantitated by frequent (10-min) blood sampling for 7 h, GH chemiluminescence assay, and deconvolution analysis. Compared with placebo, estradiol replacement: 1) stimulated spontaneous pulsatile GH secretion by 3.5-fold (95% confidence interval, 2.1- to 5.6-fold) (P < 0.001); and 2) amplified the mass of GH secreted in response to abrupt somatostatin withdrawal by 2.1-fold (95% confidence interval, 1.3- to 3.4-fold) (P = 0.003). Estrogenic augmentation of rebound-like GH secretion was specific, because the pharmacological effects of exogenous GHRH (1 µg/kg) and GH-releasing peptide-2 (1 µg/kg, a synthetic ghrelin analog) were not affected.

In summary, short-term supplementation with estradiol in postmenopausal individuals doubles the mass of rebound-like GH secretion induced by abrupt somatostatin withdrawal without modifying stimulation by a pharmacological dose of GHRH or GH-releasing peptide-2. Accordingly, we hypothesize that estradiol stimulates pulsatile GH secretion, at least in part, by enhancing the release and/or action of hypothalamic GHRH.

	Introduction

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THE SYSTEMIC AVAILABILITY of GH falls significantly in the aging human and animal (1, 2, 3, 4, 5). Plausible but unproven reasons for the decline are diminished pituitary stimulation (feedforward) by endogenous secretagogues, such as GHRH; and/or heightened somatotrope suppression (feedback) by hypothalamic inhibitors, such as somatostatin (6, 7, 8). An inferentially important contributory factor to the decrement in GH secretion in older individuals is relative depletion of gonadal sex-steroid hormones (9, 10). In this regard, cross-sectional analyses indicate that concentrations of total (and free) estradiol correlate positively with GH secretion in puberty, across the menstrual cycle and in healthy young and older adults (11, 12, 13, 14, 15, 16). In addition, interventional studies demonstrate that administration of estradiol stimulates pulsatile GH production in girls and women with primary or secondary ovarian failure, men with prostatic cancer, and genotypic male patients undergoing gender reassignment (9, 17, 18, 19, 20, 21). From a mechanistic perspective, estradiol supplementation specifically amplifies GH secretory-burst mass (17, 19) and enhances the potency of low (but not pharmacological) doses of recombinant human (rh)GHRH-1,44-amide (22). Assuming that hypothalamic GHRH drive is a major determinant of GH pulse amplitude (23), such collective observations are consistent with a postulate that estrogen augments GH pulse amplitude and, thereby, GH production in part by facilitating stimulation by endogenous GHRH and/or by increasing the synthesis and pituitary accumulation of releasable GH stores.

Clinical and laboratory investigations indicate that, whereas peripheral infusion of somatostatin suppresses GH secretion, abrupt cessation of the infusion induces rebound-like burst of GH secretion (24, 25, 26, 27, 28, 29). Mechanistic studies in the laboratory animal have documented that postsomatostatin rebound GH secretion is dependent on the outflow of hypothalamic GHRH (1, 2). The key role of GHRH in this context is inferable from: 1) successive inhibition and stimulation of GHRH release into hypothalamo-pituitary portal blood by single peripheral injection of octreotide in the unanesthetized ram (30); 2) significant (50–83%) attenuation of postsomatostatin rebound GH secretion by passive immunoneutralization of GHRH in the adult male and female rat (24, 31, 32, 33); 3) in vitro potentiation of GH release by exposing pituitary cells to somatostatin and GHRH in sequence (25); and 4) integrative model-based predictions that cycles of autofeedback-mediated somatostatin release and withdrawal are both necessary and sufficient to sustain recurrent high-amplitude bursts of GHRH and GH secretion (34, 35, 36).

According to the foregoing experimental foundation, changes in the magnitude of postsomatostatin rebound GH secretion should mirror corresponding changes in effectual hypothalamic GHRH stimulation. The present study applies this investigative strategy to test the postulate that estradiol enhances endogenous GHRH drive, as reflected in augmentation of the amplitude of the somatostatin rebound phase of GH secretion. Control interventions to test the specificity of the putatively estrogen-responsive GH rebound process comprised exogenous secretagogue stimulation.

	Subjects and Methods

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Subjects

Eight healthy postmenopausal women enrolled in and completed all 12 sessions of the study. Participants provided written informed consent approved by the Institutional Review Board. The protocol was approved by the National Institutes of Health and United States Food and Drug Administration under investigator-initiated investigational new drug for the use of somatostatin and GHRP-2. Volunteers were nonsmokers and free of known or suspected cardiac, peripheral arterial, or venous thromboembolic disease. None were receiving neuroactive medications. Some enrollees continued to take multivitamins, ferrous sulfate, calcium carbonate, alendronate (one individual), latanoprost eye drops (one woman), salicylic acid, and ibuprofen on nonstudy days. Each subject had an unremarkable medical history and physical examination and normal screening laboratory tests of hepatic, renal, endocrine, metabolic, and hematologic function. The mean (±SEM) age was 65 ± 3 yr and body mass index 25 ± 1.5 kg/m². Individuals had been clinically postmenopausal for at least 1 yr, and ovariprival status was confirmed by elevated FSH (77 ± 14 IU/liter) and LH (35 ± 3.9 IU/liter) and reduced estradiol (14 ± 4 pg/ml, 51 ± 15 pmol/liter) concentrations measured at 0800 h during outpatient screening. Women discontinued any hormone replacement at least 6 wk before study. There was no recent transmeridian travel (within 2 wk), night-shift work, significant weight change (3 kg in 2 wk), acute illness, chronic disease, recent psychiatric treatment, or substance abuse. Postmenopausal bleeding, type 2 diabetes mellitus, and herbal polypharmacy excluded three candidates during the screening process. Two other volunteers were withdrawn from the study, one after a vasovagal episode precipitated by somatostatin-induced abdominal cramps, and the other in the face of scheduling difficulties.

Protocol design

The design was a prospectively randomized, placebo-controlled, patient-blinded, within-subject crossover intervention. The schema is defined statistically as a double split-plot randomization comparable with a 2 x 2 x 3 factorial Latin-squares design. Infusion sessions were begun on d 7 and completed on or before d 36 of placebo or estradiol administration (below) and were separated by a minimum of 48 h. Each woman underwent 12 admissions (six during placebo and six during estrogen supplementation). Estrogen administration comprised 1 mg micronized 17ß-estradiol (Estrace, Bristol-Myers Squibb, Princeton, NJ) orally twice daily for up to 36 d. Placebo and estradiol interventions were separated by a washout interval of at least 4 wk.

Volunteers were admitted to the General Clinical Research Center (GCRC) the evening before study, to allow overnight adaptation to the Unit. To obviate food-related confounds, subjects were given a constant snack (turkey sandwich or vegetarian alternative) of 500 kcal, containing 55% carbohydrate, 15% protein, and 30% fat, at 2000 h. Participants then remained fasting overnight until lunch the next day (1400 h). Vigorous exercise was restricted, and sleep was deferred until 2100 h. Lunch was provided, at 1400 h, before discharge from the GCRC.

On the day of sampling and infusion(s), two iv catheters were inserted in contralateral forearm veins at 0600 h (Fig. 1). Serum was withdrawn at 0700 h for later assay of estradiol, FSH, LH, and IGF-I concentrations. Thereafter, blood was sampled (2 ml) every 10 min, from 0700 h to 1400 h. Saline (10 ml/h) or somatostatin-14 (9 µg/kg·h) was infused continuously iv during the interval 0800 to 1100 h (27). To stimulate GH secretion in the rebound (postsomatostatin) interval, a single iv bolus of saline, GHRH (1.0 µg/kg), or GHRP-2 (1.0 µg/kg) was injected at 1110 h. The 10-min time delay after ceasing the constant somatostatin infusion was chosen to allow approximately 3 half-lives of systemic somatostatin decay before secretagogue delivery. Somatostatin was used under an investigator-initiated Food and Drug Administration-approved investigational new drug and (in this study) purchased from Bachem Bioscience, Torrance, CA.

View larger version (22K): [in this window] [in a new window]   FIG. 1. Schematic outline of clinical protocol to quantitate the impact of estradiol repletion on postsomatostatin rebound GH secretion. Saline, GHRH (1 µg/kg), or GHRP-2 (1 µg/kg) was injected by iv bolus at 1110 h (10 min after stopping the somatostatin infusion).

GH concentrations were measured in each serum sample in duplicate by automated ultrasensitive chemiluminescence assay (modified Nichols Chemiluminescent human GH assay, Nichols Institute Diagnostics, San Clemente, CA) using 22-kDa recombinant human GH as assay standard (37). Samples from any given subject’s six admissions were analyzed together. Sensitivity of the GH assay is 0.005 µg/liter (defined as 3 SDs above the zero-dose tube), and median intra- and interassay coefficients of variation (CVs) are 5.2 and 6.3%, respectively, at the GH concentrations measured here (6). No values less than 0.020 µg/liter were observed in the present study. LH and FSH concentrations were quantitated by automated chemiluminescence assay (ACS 180, Bayer, Norwood, MA), using as standards the First and Second International Reference Preparations, respectively (19). Corresponding procedural sensitivities are 0.5 and 2.0 IU/liter; intraassay CVs are 6.3 and 7.4% and interassay CVs 6.5 and 8.5% for LH and FSH. Estradiol was quantitated by RIA with a sensitivity of 10 pg/ml (36 pmol/liter) and within-assay CV of 7.0% (Coat-A-Count, Diagnostic Products, Los Angeles, CA) (19). Measures less than assay sensitivity were assigned the threshold value. Total IGF-I concentrations were measured by RIA after extraction in acid-ethanol (Nichols Institute Diagnostics), with resultant intra- and interassay CVs of 5.3 and 6.2%, respectively (6).

Analysis of pulsatile GH secretion

Pulsatile GH secretion was quantitated by multiparameter deconvolution analysis (38, 39). Biexponential decay was defined by a rapid-phase half-life of 3.5 min; a slow-phase, half-life determined analytically in each subject; and a fractional (slow/total) decay amplitude of 0.63 (37). The outcome measure is the summed mass of GH secreted per unit distribution volume (µg/liter) above the basal rate: 1) during saline infusion (0700–1400 h); and 2) after sequential saline, somatostatin/saline, and secretagogue/saline injections (1100–1400 h).

Statistical analysis

Summed GH secretory-burst mass (µg/liter·7 h or µg/liter·3 h) and IGF-I (µg/liter) and estradiol (pg/ml) concentrations were analyzed on the natural logarithmic scale. Logarithmic transformation was performed as a variance-stabilizing procedure. Transformed data were analyzed by way of mixed-effects ANOVA. Model specification was in accordance with a double split-plot design (40), wherein subjects were treated as the blocking factor and model classification factors included specific intervention (two levels; placebo or estrogen), type of constant infusion (two levels; saline or somatostatin), and choice of secretagogue (three levels; saline, GHRH, or GHRP). Model-parameter estimation was by restricted maximum likelihood, and the within-subject variance-covariance matrix structure was modeled in the compound symmetry form. Between-group comparisons were made of the fold change (and 95% statistical confidence intervals) in the geometric mean over placebo. Multiple-comparison adjustment was based on a restricted Fisher’s least-significantly different criterion with an overall (experiment-wise) type I error rate of 0.05.

Absolute measures are presented in the text and tables as the arithmetic mean ± SEM (median).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Administration of estradiol was well tolerated. Complaints attributable to the infusion of somatostatin included mild nausea (common), emesis, generalized dysesthesia or faintness (rare), flushing, epigastric cramping, vasovagal reaction (once), and dizziness, fatigue, headache, or muscle twitching (uncommon). GHRH injection was associated with a brief flush or facial warmth on three occasions; and GHRP-2 with transient facial flushing, headache, or borborygmi in five sessions.

Preinfusion fasting (0800 h) serum hormone concentrations were averaged across the six sessions within subject and within intervention, after corroborating the absence of significant time trends by ANOVA. Estradiol replacement increased estradiol concentrations from 14 ± 1.7 pg/ml (51 ± 6.2 pmol/liter) to 318 ± 13 pg/ml (1170 ± 48 pmol/liter) (P < 0.001); and, reduced FSH (IU/liter) concentrations from 64 ± 4.6 to 32 ± 2.7 (P < 0.001), LH (IU/liter) from 30 ± 1.4 to 22 ± 1.3 (P < 0.001), and IGF-I (µg/liter) from 110 ± 6.3 (14.3 ± 0.8 nmol/liter) to 68 ± 5.5 (8.8 ± 0.1 nmol/liter) (P < 0.001).

Figure 2A depicts fasting GH concentrations monitored serially every 10 min, for 7 h, in an individual postmenopausal volunteer during placebo and estradiol supplementation. Panel B summarizes mean (±SEM) profiles for the group of eight women, in relation to each of the 12 infusion sessions. Expanded y-axes in the insets allow visualization of control (saline/saline) and somatostatin-induced (somatostatin/saline) rebound-like release of GH.

View larger version (35K): [in this window] [in a new window]   FIG. 2. Group GH concentration profiles in postmenopausal women, administered placebo (left) and estradiol (E2, right). Each study session comprised repetitive blood sampling, continuous iv infusion of saline or somatostatin-14, and delayed bolus iv injection of saline, GHRH, or GHRP-2 (large arrow at 1110 h) (see schema, Fig. 1). The two insets (top) give expanded y-axes to visualize rebound-like release of GH in the absence of secretagogue injection. Data are the mean ± SEM (n = 8 volunteers).

View larger version (20K): [in this window] [in a new window]   FIG. 3. Impact of estradiol vs. placebo administration on the summed mass of GH secreted in pulses (µg/liter) after abrupt cessation of an iv infusion of somatostatin-14 (SS), compared with saline (Sal) and bolus iv injection of saline, GHRH, or GHRP-2. Rebound-like GH secretion was quantitated by biexponential deconvolution analysis (Subjects and Methods). Data are the arithmetic mean (±SEM, n = 8 volunteers). Asterisks, P < 0.001 for the contrast between the effect of somatostatin and saline in the indicated pair.

View larger version (18K): [in this window] [in a new window]   FIG. 4. Effect of administration of estradiol, compared with placebo, on the amount of GH secreted in response to constant infusion and withdrawal of Sal or SS followed by bolus injection of saline, GHRH, or GHRP-2. The y-axis gives the geometric mean ratio of the within-subject estrogen/placebo (fold) effect. The null hypothesis predicts an equivalent effect of estradiol and placebo, and thus a ratio of unity (interrupted line). Error bars encompass 95% (asymmetric) statistical confidence intervals for each ratio (n = 8 volunteers).

View larger version (18K): [in this window] [in a new window]   FIG. 5. Stimulation with GHRP-2 (but not saline or GHRH) overcomes the SS-imposed time delay to attain maximal rebound-like GH concentrations (Fig. 2). The y-axis gives the time delay (min) between bolus iv injection of saline or secretagogue and the subsequent peak GH concentration. Asterisks, P 0.012 for the contrast in time delay after somatostatin withdrawal and stimulation with GHRP-2, compared with saline or GHRH. Data are the arithmetic mean (±SEM, n = 8 subjects).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Precisely how estradiol amplifies postsomatostatin rebound GH secretion is not known. In principle, GHRH-dependent (as well as GHRH independent) mechanisms could be involved. Figure 6 highlights experimentally predicted GHRH-dependent mechanisms of postsomatostatin rebound GH secretion (see Introduction). GHRH-independent actions of estradiol on somatotrope cells are evident in animal models. For example, whereas not observed acutely, longer exposure to estradiol (for 12 h to 6 d) induces GH synthesis and enhances GHRH-stimulated GH secretion by primate, bovine and rodent pituitary cells in vitro and by the ectopically autotransplanted pituitary gland in vivo (41, 42, 43). If an analogous direct stimulatory mechanism operates in the human in response to short-term estradiol administration, then potentiation of rebound GH secretion could, in part, reflect direct estrogenic stimulation of somatotrope synthesis, accumulation and GHRH-dependent release of GH. The current data argue against this postulate, given that estradiol supplementation does not augment GH secretion induced by a maximally effective dose of GHRH or a potent GHRP-receptor agonist.

View larger version (25K): [in this window] [in a new window]   FIG. 6. Schema of experimentally inferred GHRH-dependent mechanisms of postsomatostatin burst-like GH secretion. Each site is a potential locus of estradiol’s potentiation of rebound-like GH secretion, as observed here (Results). Non-GHRH-dependent mechanisms are not excluded by these data (Discussion).

Available clinical data do not exclude a corollary mechanism, wherein estradiol also stimulates hypothalamic GHRH secretion directly. For example, estradiol evokes GHRH secretion by bovine hypothalamic tissue under in vitro perifusion conditions (48). And, the intact adult rat female exhibits 2- to 7-fold greater resistance to GH-dependent feedback inhibition of GH secretion and GHRH gene expression, compared with the male animal (49, 50, 51, 52, 53). Whether analogous mechanisms operate in the human is not known.

Estrogen has the capability to potentiate the effects of synthetic GHRP. For example, administration of estradiol amplifies GH secretion stimulated by: 1) a high (3 µg/kg, but not 1 µg/kg) dose of GHRP-2 in postmenopausal women (54); and 2) a near-maximally effective dose of hexarelin in prepubertal children (55). Estradiol administration and female gender also accentuate the stimulatory action of GHRP-6 in the rodent (56, 57). Conversely, transgenic knockdown of catecholaminergic neuronal GHRP-receptor expression reduces GH and IGF-I concentrations and GH peak amplitude in the adult female but not male mouse (8). A plausible mechanistic basis for the foregoing observations is the capability of estradiol to up-regulate in vitro transcriptional activity of the (human) GHRP-receptor gene promoter (58). In the last regard, the adult female rat maintains at least 5-fold greater pituitary concentrations of GHRP-receptor transcripts than the male under GH-deficient (feedback-withdrawn) conditions (59). Enhanced responsiveness to endogenous GHRP could be relevant to estradiol’s potentiation of postsomatostatin rebound GH release, because both synthetic GHRP and natural ghrelin synergize with even minimal doses of GHRH (60). According to such reasoning, estrogen-induced sensitization to endogenous GHRP receptor-effector signaling would further amplify the stimulatory effect of any given amount of hypothalamic GHRH released after acute somatostatin withdrawal.

The central actions of GHRP include partial antagonism of somatostatinergic restraint in the mediobasal hypothalamus and anterior pituitary gland (60, 61, 62, 63). One or both of the foregoing mechanisms may account for the novel finding that GHRP-2 (but not GHRH) shortens the time delay to reach maximal GH concentrations after somatostatin withdrawal (Fig. 5). Estradiol replacement does not alter this unique facet of GHRP stimulation.

In summary, short-term estradiol supplementation in healthy postmenopausal women doubles postsomatostatin rebound GH secretion without affecting the response to a pharmacological dose of GHRH or GHRP-2. Based on present concepts of the mechanistic basis of the rebound phase of GH secretion, we postulate that estrogen repletion promotes the hypothalamic release and/or potentiates the pituitary action of submaximally stimulating amounts of endogenous GHRH.

	Acknowledgments

 
We thank Jean Plote and Kandace Bradford for excellent support of manuscript preparation, Ginger Bauler and Brenda Grisso for performance of the immunoassays, and Sandra Jackson and associated nursing staff for conduct of the research protocol.

	Footnotes

 
This work was supported, in part, by General Clinical Research Center Grants MO1 RR00847 and RR00585 to the University of Virginia and Mayo Clinic and Foundation from the National Center for Research Resources (Rockville, MD); and Clinical Associate Physician Award (to S.M.A.) and Grant R01 NIA AG 14799-06 (to J.D.V.) from the National Institutes of Health (Bethesda, MD).

Abbreviations: CI, Confidence interval; CV, coefficient of variation; GHRP, GH-releasing peptide; rh, recombinant human.

Received July 24, 2003.

Accepted September 22, 2003.

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