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Estradiol Supplementation Enhances Submaximal Feed-Forward Drive of Growth Hormone (GH) Secretion by Recombinant Human GH-Releasing Hormone-1,44-Amide in a Putatively Somatostatin-Withdrawn Milieu

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; Department of Internal Medicine (W.S.E.), General Clinical Research Center, University of Virginia School of Medicine, Charlottesville, Virginia 22908; and Department of Internal Medicine (C.Y.B.), Division of Endocrinology and Metabolism, Tulane Medical School, 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, 200 First Street Southwest, Mayo Clinic, Rochester, Minnesota 55905. E-mail: veldhuis.johannes{at}mayo.edu.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
To test the clinical hypothesis that an estrogen-enriched milieu enhances GHRH action, we administered placebo (Pl) and estradiol-17ß (E₂) orally for 23 d to six postmenopausal women in a prospectively randomized, double-masked, within-subject crossover design with 6 wk intervening. The GHRH stimulation protocol entailed consecutive iv infusion of L-arginine and a single iv pulse of saline or one of five randomly ordered doses of recombinant human GHRH-1,44-amide (0.03, 0.1, 0.3, 1.0, or 3.0 µg/kg) in a total of 12 separate morning, fasting sessions. GH secretion was monitored by sampling blood every 10 min for 6 h; chemiluminescence assay of GH concentrations; deconvolution analysis of stimulated GH release; and nonlinear dose-response reconstruction. Supplementation with E₂, compared with Pl: 1) increased (mean ± SEM) E₂ concentrations from 18 ± 3 (Pl) to 164 ± 12 pg/ml (to convert to picomoles per liter, multiply by 3.57) (P < 0.001); 2) decreased IGF-I concentrations from 181 ± 14 to 120 ± 11 µg/liter (P < 0.01); 3) elevated mean GH concentrations from 0.27 ± 0.06 to 0.59 ± 0.08 µg/liter (P = 0.014); 4) potentiated GH secretion stimulated by L-arginine alone by 1.43-fold (P = 0.012); 5) reduced the ED₅₀ of GHRH from 0.27 ± 0.02 to 0.13 ± 0.01 µg/kg (P < 0.01), denoting enhanced GHRH potency; and 6) heightened the maximal slope of the dose-response function from 1.1 ± 0.1 to 1.4 ± 0.05 [(µg/liter) (µg/kg)^-1] (P < 0.05), signifying augmented pituitary sensitivity. The foregoing facilitative mechanisms were specific because E₂ replacement did alter maximal L-arginine/GHRH-induced GH secretion, indicating unchanged secretagogue efficacy. In conclusion, inasmuch as E₂ also attenuates inhibition of GH secretion by infused somatostatin and potentiates stimulation of GH secretion by GH-releasing peptide-2, we postulate that estrogenic steroids drive pulsatile GH production in part via mechanisms that include all three of GHRH, somatostatin, and putatively GH-releasing peptide/ghrelin signaling.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
IN CROSS-SECTIONAL analyses, estradiol (E₂) concentrations predict the amplitude of GH pulses in pubertal girls, young women, and aging adults (1, 2, 3, 4). Estrogen administration in girls with Turner syndrome, postmenopausal women, male-to-female transsexual patients, and men with prostatic cancer stimulates GH secretion (5, 6, 7, 8, 9). However, the precise mechanisms that mediate estrogenic drive of GH production are unknown (10).

The present investigation tests the hypothesis that E₂ facilitates the stimulatory actions of GHRH, a dominant GH secretagogue (11). To this end, we applied a 4-fold experimental strategy comprising: 1) infusion of a 100-fold dose range of single pulses of recombinant human (rh)GHRH-1,44-amide or saline on separate days, fasting and under presumptive somatostatin withdrawal induced by prior infusion of L-arginine (10, 12); 2) multiparameter deconvolution analysis to quantitate the mass of GH secreted (micrograms) per unit distribution volume (liters) corrected for baseline GH concentrations (13, 14); 3) nonlinear regression analysis to estimate GHRH potency and efficacy and pituitary sensitivity (15); and 4) a prospectively randomized, placeboe (Pl)-controlled, double-masked, within-subject crossover design to enhance statistical power.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

Six healthy, unmedicated clinically postmenopausal women (aged 55–70 yr) participated. Weight was within 25% of New York Metropolitan Life normative data. Medical history, physical examination, and screening biochemical tests of hepatic, renal, hematologic, metabolic, and endocrine function were normal. Exclusion criteria included spontaneous menses within the preceding 2 yr; use of psychoactive medications; endocrinopathy; acute or chronic organ-system disease; recent weight change (2 kg gain or loss in 6 wk) or transmeridian travel (more than three time zones traversed within the preceding 10 d); hypertension uncontrolled by diet, exercise, a diuretic, or an angiotensin-converting enzyme inhibitor; triglyceride-predominant hyperlipidemia; ischemic cardiovascular disease; arterial thrombosis; venous thrombophlebitis; undiagnosed vaginal bleeding; and/or any personal history of an estrogen-responsive neoplasm.

Women were recruited by advertisements in churches, newspapers, bulletin boards, and other community venues. Written informed consent, approved by the Human Investigation Committee, was provided by each subject before enrollment. Individuals were reimbursed for the time committed to participate.

Clinical protocol

Participants were admitted to the General Clinical Research Center (GCRC) on the evening before study to allow overnight adaptation to the unit. To minimize artifacts introduced by variable caloric intake, subjects received a standardized meal at 1800 h the evening before study (8 kcal/kg distributed as 55% carbohydrate, 15% protein, and 30% fat). Volunteers remained fasting and abstained from caffeinated beverages overnight until 1400 h the next day. In the morning at 0700 h, iv catheters were placed bilaterally in the forearms. Beginning at 0800 h, blood samples (1.2 ml) were withdrawn every 10 min for a total of 6 h. The first 2.5-h (0800–1030 h) interval served as a preinjection baseline; the next 30 min permitted continuous iv infusion of 30 g L-arginine (1030–1100 h), followed immediately by bolus iv injection of saline or GHRH (below); and the last 3.0 h allowed monitoring of stimulated GH release (Fig. 1). Each participant undertook 12 separate infusion sessions (six while receiving Pl and six E₂ supplementation at least 6 wk apart). Secretagogues included saline or rhGHRH-1,44-amide administered iv at a weight-adjusted dose of 0.03, 0.1, 0.3, 1.0, 3.0 µg/kg [obtained under an investigator-initiated Food and Drug Administration-approved investigational new drug from BioNebraska Inc. (Restoragen), Lincoln, NE]. GCRC admissions occurred on alternate days (48 h between infusions) within the inclusive time window of 7–23 d after beginning Pl or E₂ (see below). The latter interval was chosen because oral estrogen administration stimulates GH secretion within 2–5 d and throughout at least 5 wk of continuing exposure (7).

View larger version (22K): [in this window] [in a new window]   FIG. 1. Experimental design to test the impact of E2 vs. Pl supplementation on GHRH’s dose-dependent stimulation of GH secretion in postmenopausal women. Saline or one of five randomly ordered doses of rhGHRH-1,44-amide (µg/kg) was injected by iv bolus on each of six separate mornings immediately after a 30-min infusion of L-arginine in the fasting state. Each volunteer undertook six studies during the administration of Pl and six others during replacement with E2 (1 mg orally twice daily for 23 d). Interventions were separated by a 6-wk washout interval. The design was prospectively randomized, within-subject crossover, and double masked. GH release was monitored by sampling blood every 10 min for 6 h beginning 2.5 h before the onset of L-arginine infusion (see Subjects and Methods).

Pl or 1 mg micronized (crystalline) E₂ (Estrace, Ciba Geigy Corp., Ardsley, NY) was administered twice daily orally for 23 d in a prospectively randomized, double-masked, within-subject crossover design. Compliance was corroborated by measuring serum E₂ concentrations at 0800 h in each of the 12 sampling sessions. A washout interval of 6 wk or more separated the Pl and E₂ intervention. Based on clinical standards of practice, micronized progesterone was administered orally for 12 d (or a single im injection of 100 mg progesterone in oil was given) at the end of study in uterus-intact individuals.

GH assay

Serum GH concentrations were quantitated in duplicate by a robotics-assisted chemiluminescence assay (Nichols Diagnostics Institute, San Juan Capistrano, CA) (16). Recombinant human GH (22,000 Da) served as standard. Sample values were interpolated from replicated standards via four-parameter logistic regression analysis (see below). Assay sensitivity was 0.005 µg/liter at 3 SDs above blank. Intraassay and interassay coefficients of variation were 4.3–6.5% (absolute range) and 5.8–8.6%, respectively. Within-sample variance (square of SD) was computed as an algebraic power function of GH concentration and applied in deconvolution analysis (see below).

Other hormone assays

Serum concentrations of total IGF-I were measured by RIA after acid-ethanol extraction (Nichols Diagnostics Institute), E₂ by coated-tube RIA, and LH and FSH by immunoradiometric assay (8).

Deconvolution analysis

Multiparameter deconvolution analysis was applied to quantitate saline and GHRH-stimulated GH secretion (13, 14). This methodology computes pulsatile and basal GH release corrected for the biexponential rate of disappearance of GH from plasma; viz., a 3.5-min rapid-phase and 20.9-min slow-component half-life, wherein the latter contributes 63% to the total decay amplitude (14). The end point is the (summed) mass of GH (micrograms) secreted per unit distribution volume (liters) over the preinjection basal GH secretion rate.

Outcomes

The primary end point was the mass of GH secreted above baseline after GHRH injection. Secondary end points were (GHRH-stimulated) absolute GH peak height (maximal GH concentration), incremental peak height (maximum value minus preinjection nadir), and incremental mean GH release (mean 3-h post-GHRH minus mean 2-h preinjection serum GH concentration).

Dose-response analysis

A sigmoidal (four-parameter logistic) function was used to regress stimulated GH release (micrograms per liter) on injected GHRH dose (micrograms per kilogram) (15). Dose-response curves from all six subjects [separately defined during Pl and E₂ supplementation] were analyzed simultaneously, as described initially by DeLean et al. (17). Simultaneous regression allows valid estimation of cohort parameter mean and 95% statistical confidence intervals (CIs). Determinable dose-response parameters (end points) are the baseline (zero dose), maximal positive slope (sensitivity), ED₅₀ (potency), and maximal response (efficacy).

Statistical analyses

Parameters of the dose-response function (above) were compared via 95% CI testing in the Pl vs. E₂ setting. Two-way ANOVA in a (nested) repeated-measures design (two interventions x six repeated measures) was applied to compare baseline (0800 h) serum hormone concentrations (mean ± SEM) between the Pl and E₂ interventions.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Estrogen replacement elevated the mean (0800 h) serum concentration of E₂ (0800 h) from 18 ± 3 (Pl) to 164 ± 12 pg/ml (P < 0.001) (multiply by 3.57 to convert to picomoles/liter); increased the mean (saline infusion, 6-h) GH concentration from 0.27 ± 0.06 to 0.59 ± 0.09 µg/liter (P = 0.014); and suppressed LH by 35 ± 5% (P < 0.01), FSH by 58 ± 9.7% (P < 0.01), and IGF-I by 34% (viz., from 181 ± 14 to 120 ± 11 µg/liter) (P < 0.01).

Figure 2 presents mean (±SEM) GH concentration time series in each of the 12 separate 10-min sampling sessions for the group of six volunteers.

View larger version (38K): [in this window] [in a new window]   FIG. 2. Serum GH concentration time series in six postmenopausal women each studied 12 times, as described in Fig. 1. Time zero corresponds to 0800 h. L-Arginine was infused over 30 min (beginning at the arrow), followed immediately by a bolus iv injection of saline or a randomly ordered dose of rhGHRH-1,44-amide (µg/kg). Data are the cohort mean ± SEM (n = 6).

View larger version (23K): [in this window] [in a new window]   FIG. 3. Four-parameter logistic-regression analysis of the relationship between rhGHRH-1,44-amide dose (µg/kg) or saline (NONE) (x-axis) and stimulated GH release (y-axis). Data points are the (deconvolution-computed) mass of GH secreted per unit distribution volume (µg/liter per 3 h) (mean ± SEM, n = 6 subjects) as assessed during administration Pl (continuous lines) and E2 (interrupted lines). Numerical values denote the ED50 of GHRH and the maximal GH response (MAX). Parentheses enclose the corresponding 95% statistical CIs.

View larger version (21K): [in this window] [in a new window]   FIG. 4. Impact of E2 vs. Pl repletion on saline and rhGHRH-1,44-amide-stimulated GH release. Compared with Pl, E2 supplementation reduced the ED50 of GHRH significantly, demonstrating heightened GHRH potency (A); did not alter maximal GHRH-stimulated GH release, indicating fixed efficacy (B); elevated the maximal slope of the GHRH dose-GH secretory-response function, signifying greater pituitary sensitivity (C); and amplified the stimulatory effect of L-arginine alone (D). Horizontal or vertical bars flanking the mean estimate define 95% statistical CIs for the cohort of six subjects.

E₂ supplementation accentuated pituitary sensitivity to GHRH, i.e. increased the slope of the GHRH dose-GH secretory-response relationship for all four outcomes; viz., GH secretory burst mass, absolute GH peak height, incremental peak height, and mean GH concentration (Fig. 4C). E₂ also amplified the effect of L-arginine alone by a mean of 1.43-fold (P = 0.012 over L-arginine plus Pl) (Fig. 4D).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The present study shows that E₂ supplementation facilitates GHRH-stimulated GH secretion in postmenopausal women. Stated in dose-response terms, E₂ replacement specifically doubles GHRH potency, doubles somatotrope sensitivity, and does not alter GHRH efficacy. The capability of E₂ to enhance submaximal GHRH drive was demonstrable by both model-specific (deconvolution analysis) and model-free (simple algebraic) measures of stimulated GH release.

For experimental reasons, we infused L-arginine immediately before injection of saline or the GHRH stimulus in the fasting state. Whereas other (unknown) mechanisms of action cannot be excluded definitively, both L-arginine and the fasting state appear to suppress hypothalamic somatostatin outflow (10, 12, 18, 19). E₂ supplementation enhanced the stimulatory effect of L-arginine alone. Thus, if a primary action of L-arginine is to reduce somatostatin release, then the present data signify that E₂ can stimulate GH secretion under low somatostatinergic restraint; i.e. via presumptively partially somatostatin-independent mechanism(s). We show that one such mechanism is potentiation of dose-responsive feed-forward by GHRH. In other studies, E₂ administration also augmented the stimulatory effect of a synthetic GH-releasing peptide (GHRP), GHRP-2 (20, 21). Whether estrogen facilitates the action of either cognate endogenous secretagogue is not known. However, transgenic neuronally targeted silencing of the murine GHRP/ghrelin receptor significantly lowers GH and IGF-I concentrations in the affected female adult animal (22).

The majority of earlier clinical studies of estrogen action used a single maximal dose of GHRH, and none employed prior L-arginine infusion in an estrogen-withdrawn vs. E₂-replete crossover design. As reviewed elsewhere (9, 10), the response to a single dose of GHRH has been reported variously as: 1) unchanged or accentuated in the late, compared with early, follicular phase of the menstrual cycle; 2) equivalent, increased, or decreased in women, compared with men; and 3) positively, negatively, or not correlated with E₂ concentrations in adults. These marked discrepancies could reflect differences in study design, cohort composition, blood-sampling protocol, GH assay, and/or data analysis. The present findings suggest two additional explanations. First, E₂ supplementation enhances the potency of and pituitary sensitivity to GHRH but does not influence efficacy (maximal responsiveness). These distinctive outcomes predict largely estrogen-independent actions of a single maximal dose of GHRH, as reported in some studies (9, 10). In fact, one other GHRH dose-response study reported 2-fold greater GHRH potency (but not efficacy) in young women than men (23); i.e. ED₅₀ values were 0.2 and 0.4 µg/kg in female and male volunteers, respectively. The present ED₅₀ estimates are numerically comparable, viz., 0.13 µg/kg (E₂) and 0.27 µg/kg (Pl) in postmenopausal women. Second, marked nonuniformity of GHRH effects among and within earlier investigations would be consistent with the notion that endogenous somatostatin release varies significantly over time within individuals (19). An appropriate means of muting somatostatin outflow would thus seem relevant to assess GHRH action per se.

Delivery of estrogen(s) by oral, iv, im, intranasal, intravaginal, and (at higher doses) transdermal routes stimulates GH secretion and reduces (or does not affect) systemic IGF-I concentrations in girls, women, and men (8, 9, 10). Blood-borne IGF-I can exert negative feedback on the hypothalamo- pituitary unit because constant infusion of rhIGF-I suppresses GH concentrations markedly, and, conversely, pharmacological reduction of IGF-I concentrations by blocking GH-receptor activation with pegvisomant stimulates pulsatile GH secretion by 1.8-fold (24, 25). Thus, one plausible hypothesis is that exogenous E₂ enhances the stimulatory effect of GHRH in part by depleting systemic IGF-I concentrations, thereby attenuating expected autoinhibition (26, 27). In counterpoint, elevated E₂ production in the preovulatory phase of the menstrual cycle is associated with concomitant increases in GH and IGF-I concentrations (3). In addition, E₂ replacement in postmenopausal individuals accentuates the inhibitory effect of infused rh IGF-I on pulsatile and GHRH-stimulated GH secretion (28). Thus, further studies are needed to clarify the precise nature of interactive feedback control of pulsatile GH secretion by E₂ and IGF-I.

In summary, E₂ supplementation enhances the potency of and pituitary sensitivity to GHRH but does not alter GHRH efficacy in fasting postmenopausal women pretreated with L-arginine. In other studies, E₂ replacement potentiates stimulation by GHRP-2 and attenuates inhibition by infused somatostatin. Accordingly, we hypothesize that estrogen modulates the activity of an ensemble of primary peptidyl signals, which together amplify pulsatile GH secretion.

	Acknowledgments

 
We thank Professors Daniel M. Keenan and Peter O’Brien (Department of Statistics), Robert Abbott (Department of Health Evaluation Sciences, Division of Biostatistics), and Michael L. Johnson (Department of Pharmacology) for contributing to the statistical procedures; Jean Plote for expert assistance in preparing the manuscript; and the GCRC nursing staff for implementing the research protocol.

	Footnotes

 
This work was supported in part by Grants MO1 RR00847 and MO1 RR00585 to the General Clinical Research Centers of the University of Virginia and Mayo Clinic from the National Center for Research Resources and RO1 AG19596 and AG14779 from the National Institutes of Health (Bethesda, MD).

Abbreviations: CI, Confidence interval; E₂, estradiol; GHRP, GH-releasing peptide; Pl, placebo; rh, recombinant human.

Received March 10, 2003.

Accepted August 7, 2003.

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Top Abstract Introduction Subjects and Methods Results Discussion References

 

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				R. C. Paulo, M. Cosma, C. Soares-Welch, J. N. Bailey, K. L. Mielke, J. M. Miles, C. Y. Bowers, and J. D. Veldhuis Gonadal Status and Body Mass Index Jointly Determine Growth Hormone (GH)-Releasing Hormone/GH-Releasing Peptide Synergy in Healthy Men J. Clin. Endocrinol. Metab., March 1, 2008; 93(3): 944 - 950. [Abstract] [Full Text] [PDF]

				M. Cosma, J. Bailey, J. M. Miles, C. Y. Bowers, and J. D. Veldhuis Pituitary and/or Peripheral Estrogen-Receptor {alpha} Regulates Follicle-Stimulating Hormone Secretion, Whereas Central Estrogenic Pathways Direct Growth Hormone and Prolactin Secretion in Postmenopausal Women J. Clin. Endocrinol. Metab., March 1, 2008; 93(3): 951 - 958. [Abstract] [Full Text] [PDF]

				A. A van der Klaauw, N. R Biermasz, P. M J Zelissen, A. M Pereira, E. G W M Lentjes, J. W A Smit, S. W van Thiel, J. A Romijn, and F. Roelfsema Administration route-dependent effects of estrogens on IGF-I levels during fixed GH replacement in women with hypopituitarism Eur. J. Endocrinol., December 1, 2007; 157(6): 709 - 716. [Abstract] [Full Text] [PDF]

				J. D. Veldhuis, D. M. Keenan, and C. Y. Bowers Peripheral estrogen receptor-{alpha} selectively modulates the waveform of GH secretory bursts in healthy women Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2007; 293(4): R1514 - R1521. [Abstract] [Full Text] [PDF]

				J. D. Veldhuis, M. Cosma, D. Erickson, R. Paulo, K. Mielke, L. S. Farhy, and C. Y. Bowers Tripartite Control of Growth Hormone Secretion in Women during Controlled Estradiol Repletion J. Clin. Endocrinol. Metab., June 1, 2007; 92(6): 2336 - 2345. [Abstract] [Full Text] [PDF]

				L. S. Farhy, C. Y. Bowers, and J. D. Veldhuis Model-projected mechanistic bases for sex differences in growth hormone regulation in humans Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2007; 292(4): R1577 - R1593. [Abstract] [Full Text] [PDF]

				J. D. Veldhuis, D. M. Keenan, A. Iranmanesh, K. Mielke, J. M. Miles, and C. Y. Bowers Estradiol Potentiates Ghrelin-Stimulated Pulsatile Growth Hormone Secretion in Postmenopausal Women J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3559 - 3565. [Abstract] [Full Text] [PDF]

				J. D. Veldhuis, A. Iranmanesh, K. Mielke, J. M. Miles, P. C. Carpenter, and C. Y. Bowers Ghrelin Potentiates Growth Hormone Secretion Driven by Putative Somatostatin Withdrawal and Resists Inhibition by Human Corticotropin-Releasing Hormone J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2441 - 2446. [Abstract] [Full Text] [PDF]

				J. D. Veldhuis, J. N. Roemmich, E. J. Richmond, and C. Y. Bowers Somatotropic and Gonadotropic Axes Linkages in Infancy, Childhood, and the Puberty-Adult Transition Endocr. Rev., April 1, 2006; 27(2): 101 - 140. [Abstract] [Full Text] [PDF]

				J. D. Veldhuis, D. Erickson, K. Mielke, L. S. Farhy, D. M. Keenan, and C. Y. Bowers Distinctive Inhibitory Mechanisms of Age and Relative Visceral Adiposity on Growth Hormone Secretion in Pre- and Postmenopausal Women Studied under a Hypogonadal Clamp J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 6006 - 6013. [Abstract] [Full Text] [PDF]

				J A Kanaley, I Giannopoulou, S Collier, R Ploutz-Snyder, and R Carhart Jr Hormone-replacement therapy use, but not race, impacts the resting and exercise-induced GH response in postmenopausal women Eur. J. Endocrinol., October 1, 2005; 153(4): 527 - 533. [Abstract] [Full Text] [PDF]

				J. D Veldhuis, D. M Keenan, K. Mielke, J. M Miles, and C. Y Bowers Testosterone supplementation in healthy older men drives GH and IGF-I secretion without potentiating peptidyl secretagogue efficacy Eur. J. Endocrinol., October 1, 2005; 153(4): 577 - 586. [Abstract] [Full Text] [PDF]

				J. D. Veldhuis, L. Farhy, A. L. Weltman, J. Kuipers, J. Weltman, and L. Wideman Gender Modulates Sequential Suppression and Recovery of Pulsatile Growth Hormone Secretion by Physiological Feedback Signals in Young Adults J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2874 - 2881. [Abstract] [Full Text] [PDF]

				C. Soares-Welch, L. Farhy, K. L. Mielke, F. H. Mahmud, J. M. Miles, C. Y. Bowers, and J. D. Veldhuis Complementary Secretagogue Pairs Unmask Prominent Gender-Related Contrasts in Mechanisms of Growth Hormone Pulse Renewal in Young Adults J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2225 - 2232. [Abstract] [Full Text] [PDF]

				J. D. Veldhuis, S. M. Anderson, A. Iranmanesh, and C. Y. Bowers Testosterone Blunts Feedback Inhibition of Growth Hormone Secretion by Experimentally Elevated Insulin-Like Growth Factor-I Concentrations J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1613 - 1617. [Abstract] [Full Text] [PDF]

				D. Erickson, D. M. Keenan, L. Farhy, K. Mielke, C. Y. Bowers, and J. D. Veldhuis Determinants of Dual Secretagogue Drive of Burst-Like Growth Hormone Secretion in Premenopausal Women Studied under a Selective Estradiol Clamp J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1741 - 1751. [Abstract] [Full Text] [PDF]

				J. D. Veldhuis, J. T. Patrie, K. T. Brill, J. Y. Weltman, E. E. Mueller, C. Y. Bowers, and A. Weltman Contributions of Gender and Systemic Estradiol and Testosterone Concentrations to Maximal Secretagogue Drive of Burst-Like Growth Hormone Secretion in Healthy Middle-Aged and Older Adults J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6291 - 6296. [Abstract] [Full Text] [PDF]

				J. D. Veldhuis, J. Y. Weltman, A. L. Weltman, A. Iranmanesh, E. E. Muller, and C. Y. Bowers Age and Secretagogue Type Jointly Determine Dynamic Growth Hormone Responses to Exogenous Insulin-Like Growth Factor-Negative Feedback in Healthy Men J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5542 - 5548. [Abstract] [Full Text] [PDF]

				D. Erickson, D. M. Keenan, K. Mielke, K. Bradford, C. Y. Bowers, J. M. Miles, and J. D. Veldhuis Dual Secretagogue Drive of Burst-Like Growth Hormone Secretion in Postmenopausal Compared with Premenopausal Women Studied under an Experimental Estradiol Clamp J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4746 - 4754. [Abstract] [Full Text] [PDF]

				S. Grinspoon, K. K. Miller, D. B. Herzog, K. A. Grieco, and A. Klibanski Effects of Estrogen and Recombinant Human Insulin-Like Growth Factor-I on Ghrelin Secretion in Severe Undernutrition J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3988 - 3993. [Abstract] [Full Text] [PDF]

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