| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Original Articles |
Division of Endocrinology, Department of Internal Medicine, General Clinical Research Center, Center for Biomathematical Technology, University of Virginia School of Medicine (J.D.V., S.M.A.), Charlottesville, Virginia 22908-0202; and Medizinische Klinik, Klinikum der LMU-Innenstadt (M.B., Z.W., C.J.S.), 80336 Munich, Germany
Address all correspondence and requests for reprints to: Dr. J. D. Veldhuis, Division of Endocrinology, Department of Internal Medicine, P.O. Box 800202, University of Virginia School of Medicine, Charlottesville, Virginia 22908-0202. E-mail: jdv{at}virginia.edu
Abstract
The present clinical study implements a novel interventional strategy of short-term profound and selective blockade of GH receptors to reduce plasma insulin-like growth factor I (IGF-I) concentrations reversibly in healthy eumetabolic adults. Thereby, we examine the feedback role of systemic IGF-I on GH secretion without introducing the complex metabolic disarray that can otherwise accompany secondary IGF-I deprivation. To this end, we sampled blood at 10-min intervals for 10 h overnight in 8 men (aged 19–46 yr) and 4 women (aged 19–39 yr) to quantitate endogenous GH secretion and half-life 72 h after the prospective, randomly ordered, double blind, and within-subject cross-over administration of pegvisomant (1 mg/kg) or saline (0.5 mL) sc. Pegvisomant is an oligopegylated recombinant human GH peptide mutated to antagonize GH receptor-dependent signaling. Statistical analyses of paired plasma IGF-I concentrations and deconvolution-based quantitation of pulsatile GH secretion revealed that GH receptor blockade 1) suppressed fasting total IGF-I concentrations by 31%, viz. from (mean ± SEM) 276 ± 42 (placebo) to 190 ± 20 µg/L (pegvisomant; P = 0.006) 84 h after drug injection; 2) increased the 10-h mean serum GH concentration by 71% from 1.4 ± 0.33 (placebo) to 2.4 ± 0.58 (pegvisomant; P = 0.024); 3) augmented the amplitude of underlying GH secretory bursts by 2.1-fold (i.e. from 0.13 ± 0.032 to 0.27 ± 0.076 µg/L·min; P = 0.0088); and 4) elevated the basal/nonpulsatile rate of GH secretion by 2.5-fold (from 2.3 ± 0.77 to 5.07 ± 1.8 µg/L·10 h; P = 0.022). The rise in the amplitude of GH secretory bursts correlated with the fall in plasma IGF-I concentrations (r = 0.603; P = 0.038). In contrast, IGF-I depletion did not alter GH secretory pulse frequency, half-duration, interpulse interval, percentage of pulsatile GH release, or half-life of endogenous GH.
In summary, selective short-term reduction of systemic IGF-I concentrations in healthy eumetabolic adults drives GH secretion via the specific bipartite neuroregulatory mechanism of amplified GH secretory burst amplitude and elevated basal/nonpulsatile GH release. Endogenous GH half-life and frequency-related features of pulsatile GH secretion are not measurably affected, thus identifying a highly distinctive mode of IGF-I feedback-dependent control of GH output. As the increment in GH secretory burst amplitude correlated with the decrement in plasma IGF-I concentrations, we infer that variations in circulating IGF-I availability within the adult midphysiological range can influence pulsatile and basal GH production by way of negative feedback. Based on data in experimental animals, we speculate that the negative feedback actions of systemic IGF-I on GH secretion are mediated via increased hypothalamic somatostatin release, decreased GHRH (or GH-releasing peptide) secretion, and/or suppressed pituitary GH biosynthesis.
A SIMPLIFIED CONCEPT of hypothalamic control of GH secretion would encompass tripeptidyl regulatory inputs, e.g. by GHRH and GH-releasing peptide(s) (GHRP) as feedforward effectors and somatostatin as a repressive signal (1, 2, 3). Like other dynamic neuroendocrine systems, the somatotropic axis is regulated further by negative feedback exerted by the secreted hormone or its target tissue products (4, 5). In the rodent GH acts via time-limited autonegative feedback to stimulate somatostatin gene expression in the hypothalamic periventricular nucleus, evoke somatostatin release into hypothalamo-pituitary portal venous blood, and reciprocally inhibit arcuate nucleus GHRH gene expression. Infusions of somatomedin C/insulin-like growth factor I (IGF-I) also suppress the hypothalamo-pituitary drive of GH secretion in vivo, directly inhibit pituitary GH secretion and gene expression in vitro, and (along with IGF-II) reduce somatostatin production in vivo and in vitro (1, 2, 4, 6, 7, 8).
Clinical investigations have demonstrated that peripheral infusions of GH or IGF-I can suppress daily pulsatile, short-term fasting, and acute secretagogue-stimulated GH secretion in men and women (9, 10). However, most such studies have used parenteral doses of IGF-I (e.g. 10 µg/kg·h, iv), which would probably achieve supraphysiological elevations in plasma free IGF-I concentrations. Conversely, available analyses of secondary IGF-I-deficient states are confounded by the primary underlying metabolic disorder triggering relative tissue resistance to GH’s action, e.g. hepatorenal failure, chronic malnutrition, fasting, type I diabetes mellitus, strenuous physical training, neonatal prematurity, anorexia nervosa, oral estrogen administration, etc. (1, 2, 11). Consequently, the nature and magnitude of the physiological feedback actions of systemic IGF-I on GH secretion under eumetabolic conditions remains uncertain. Indeed, recent experiments in transgenic mice with developmentally activated, liver-specific IGF-I gene disruption and in young men administered a GH receptor antagonist to deplete peripheral IGF-I levels revealed only minimal elevations in serum GH concentrations (12, 13). Such data could argue against a major role for circulating IGF-I availability in the normal feedback control of GH secretion (see Discussion). Alternatively, the foregoing investigations may have overlooked an impact of IGF-I feedback withdrawal by assaying single blood samples for GH content (12) and/or by monitoring GH levels during relatively minimal systemic IGF-I depletion (13). Accordingly, the present study reexplores the feedback role of peripheral IGF-I signaling in eumetabolic men and women under conditions where plasma total IGF-I concentrations are reduced by one third after the administration of a potent and highly selective GH receptor antagonist peptide (14, 15).
Subjects and Methods
Subjects
The study was conducted under an investigator-initiated IND and approved by the human investigation committee of the University of Virginia Health Sciences System. All volunteers provided written informed consent. Medical history, physical examination, and screening measurements of hepatic, renal, metabolic, endocrine, and hematological function were normal.
Volunteers comprised eight men (mean age, 29 yr; absolute range, 19–46 yr) and four women (mean age, 22 yr; range, 19–39 yr) with respective body weight ranges of 58–77 and 71–88 kg. Women had normal menstrual cycles and were studied in the early follicular phase within 3–8 days of the onset of monthly bleeding. None was receiving any contraceptive hormones.
Subjects were given a single injection of placebo (0.5 mL saline) or pegvisomant (1 mg/kg) sc 72 h before the onset of blood sampling to maximize drug effects. The design was prospectively randomized and double blind, with within-subject cross-over least 4 weeks apart. Pegvisomant is a recombinant engineered peptide that blocks activation of the human GH receptor profoundly and specifically (13, 14, 15). To monitor pulsatile and basal GH secretion, blood was sampled every 10 min for 10 h from 2000–0600 h overnight. To minimize nutritional confounds, volunteers received a standardized snack (70 Cal/kg; 55% carbohydrate, 15% protein, and 30% fat) at 1800 h the evening before the study and remained fasting thereafter during the sampling procedure.
Hormone assays
Serum GH concentrations were determined in each sample in duplicate by a two-site immunoradiometric assay described in detail previously and shown not to cross-react with pegvisomant up to 50 mg/mL (13, 16). The standard was 22-kDa recombinant human GH International Reference Preparation 88/624. All serum samples from any given subject’s two admissions were analyzed in one run. GH was detectable in all sera in the present data series, and the median intra- and interassay coefficients of variation were less than 6.5% and less than 8.7%, respectively, at the serum GH concentrations measured. Serum IGF-I concentrations were assayed by RIA after acid-ethanol extraction (Nichols Institute Diagnostics, San Juan Capistrano, CA), with intra- and interassay coefficients of variation of 8.8% and 10.3%, respectively, and a normal range in this group of 85–350 µg/L (17, 18).
GH deconvolution analysis
Multiparameter deconvolution analysis was applied to the 10-min serum GH concentration time series to quantitate pulsatile and basal GH secretion and estimate the endogenous GH half-life (19). Pulsatile GH secretion is the product of secretory burst frequency and the mean mass of GH released per pulse. Burst mass is determined jointly by the secretory pulse amplitude (maximal rate of GH secretion attained within a release episode, micrograms per L/min) and half-duration (duration of the calculated secretory burst at half-maximal amplitude, minutes). Basal GH secretion represents the time-invariant interpulse component of the release profile. Secretory pulse identification required that estimated GH secretory burst mass values exceed zero by 95% joint statistical confidence intervals.
Statistics
Because of nonnormality, analytically derived parameters of GH secretion and half-life were logarithmically transformed and then compared via paired two-tailed Student’s t test assuming unknown variance. Plasma IGF-I and serum GH concentrations were contrasted analogously without logarithmic transformation. Linear regression analysis was used to test for proportionate changes in plasma IGF-I concentrations and GH secretory pulse amplitude. Data are presented as the mean ± SEM. P < 0.05 was construed as statistically significant.
Results
Figure 1A
illustrates serum GH
concentration profiles obtained by sampling blood every 10 min for
10 h in two men and two women beginning 72 h after the
injection of placebo or pegvisomant (1 mg/kg, sc) assigned in
randomized order. The corresponding deconvolution-calculated GH
secretory profiles are shown in Fig. 1B. Mean and integrated (10-h) serum GH
concentrations rose by 71% (P = 0.024 and
P = 0.020; Fig. 2).
Plasma IGF-I concentrations were measured while fasting at 0800 h,
84 h after pegvisomant injection, declined by a mean of 31%
compared with values in the placebo group (P = 0.006;
Fig. 3).
|
|
|
shows that the GH receptor
antagonist amplified GH secretory burst amplitude by 2.1-fold (maximal
rate of GH secretion attained within each release episode;
P = 0.0088; Fig. 4A), and elevated the
basal/nonpulsatile rate of GH release by 2.5-fold (P =
0.022; Fig. 4B). In contrast, as summarized in Table 1, pegvisomant administration did not
alter the calculated half-life of endogenous GH, GH secretory burst
frequency, interpulse interval or half-duration, or percentage of total
GH secretion that was pulsatile.
|
|
). BMI and gender did not influence
incremental GH responses. Momentary mild burning at the injection site
was noted after either saline or pegvisomant injection by three
subjects. No clinical adverse events were observed.
|
Whether physiological variations in systemic IGF-I concentrations in the human govern pulsatile or basal GH secretion by negative feedback has not been established (1, 2). Although metabolic disarray is associated with reduced plasma IGF-I concentrations and reciprocally elevated GH output (see introduction), such GH-deficient states are complicated by multiple concurrent alterations. Conversely, parenteral infusions of recombinant human IGF-I can lower GH output, but only one study used nearly physiological amounts of iv IGF-I. Primary GH receptor defects deplete IGF-I and stimulate overproduction of GH (20, 21), the increase in which could jointly reflect the loss of central nervous system (CNS) GH receptor-dependent autofeedback and withdrawal of systemic IGF-I feedback (22). Analogously, rare partial IGF-I gene deletion elevates GH secretion, possibly due to reductions in the availability of both CNS and blood-borne IGF-I (4, 6, 8, 23, 24, 25). Moreover, the lack of uniform elevation in about one third of the single measurements of serum GH concentrations in transgenic mice with liver-specific disruption of the IGF-I gene resulting in a 65–70% fall in plasma total IGF-I concentrations could denote either sampling bias and/or preservation of CNS autonegative feedback by GH (12). The present clinical investigation applies instead intensive (10-min) and extended (10-h) blood sampling, which was timed 72 h after pegvisomant administration so as to capture its maximal single dose effect on IGF-I levels (13, 14, 15). Thereby, we show that a 31% fall in the total plasma IGF-I concentration induced by this highly specific GH receptor antagonist elevates the mean serum GH concentration by 71% via augmenting both GH secretory burst amplitude (2.1-fold) and basal/nonpulsatile GH release (2.5-fold). The observed increment in GH secretory pulse amplitude correlated significantly with the pegvisomant-induced decrement in plasma IGF-I concentrations.
Continuous infusions of GHRH or GHRP-2 also jointly amplify GH secretory burst amplitude and the basal/nonpulsatile rate of GH secretion, whereas injections of somatostatin or octreotide achieve precisely the opposite bipartite effects (18, 26, 27). This mechanistic similarity to IGF-Idependent GH secretory responses could suggest, but does not prove, that IGF-I feedback withdrawal stimulates endogenous GHRH or GHRP feedforward and/or mutes somatostatinergic inhibition, as inferred for central IGF-I/IGF-II actions in the experimental animal (1, 2). Available clinical data cannot distinguish among these nonexclusive mechanisms.
IGF-I can directly inhibit the pituitary production of GH in vitro in the rat (7) and in vivo in the sheep (28). Whereas this mechanism cannot be excluded entirely in the human, clinical studies in young adults indicate that infusion of recombinant human IGF-I impedes GHRH-driven (but not L-arginine-stimulated) GH- and TRH-stimulated TSH secretion; these responses are consistent with IGF-I-induced hypothalamic somatostatin release (24, 29). Thus, an emergent postulate is that variations in systemic IGF-I availability within the midphysiological range can govern GH secretion by modulating the input of endogenous somatostatin and/or GHRH/GHRP and, less likely, by inhibiting somatotropes directly.
The ability of systemic IGF-I depletion to amplify GH pulse amplitude and basal/nonpulsatile GH secretion without influencing GH half-life, secretory burst frequency, interpulse interval, secretory burst half-duration, or percentage of pulsatile GH production in healthy eumetabolic individuals defines a highly specific mechanism of IGF-I feedback. Supplementation with testosterone analogously stimulates GH secretory burst amplitude and basal/nonpulsatile GH secretion quite selectively (30). In contrast, oral estradiol replacement evokes a greater mass of GH released within each underlying burst without elevating the calculated basal/nonpulsatile GH secretory rate (17). Although the physiological basis for this apparent distinction is not known, the phenotypic similarity between the actions of pegvisomant and testosterone could indicate that testosterone acts in part to functionally oppose endogenous IGF-I or GH autonegative feedback. However, the present analyses do not exclude the postulate that oral estrogen replacement augments GH secretory pulse amplitude in part via the systemic IGF-I deprivation it induces. The latter mechanism is apparently nonexclusive, as transdermal estradiol at higher doses can elevate GH production without (or while only minimally) lowering plasma IGF-I concentrations (31, 32), oral estradiol does not increase calculated basal/nonpulsatile GH secretion (above), and GH and IGF-I rise simultaneously in pubertal girls and preovulatory phase young women. Accordingly, estrogen also appears to drive GH secretion independently of IGF-I feedback withdrawal in the female (33, 34).
The absence of any measurable prolongation of the half-life of GH in the face of pharmacologically effective GH receptor blockade (as attested to by the significant fall in plasma IGF-I concentrations) was unexpected. This finding may indicate that peripheral GH receptors play a minimal (if any) role in the irreversible removal of GH in humans. However, as the distribution volume of GH was not estimated here, we cannot exclude the possibility that GH receptors influence GH distribution (20, 35).
The rise in GH secretion observed here in response to GH receptor blockade could in principle reflect inhibition of CNS GH receptor-dependent signaling. However, the oligopegylation of (addition of four or five bulky polyethylene glycol moieties to) the recombinant mutant GH protein to stabilize in vivo residence time and reduce immunogenicity should substantially limit its CNS access, as observed in the rat. If pegvisomant did block CNS GH receptors in the humans, the same inferential feedback principles would apply in explicating increased GH secretion (36).
In summary, selective short-term depletion of systemic total IGF-I concentrations induced by acute administration of a novel recombinant human GH receptor antagonist peptide stimulates GH secretion in eumetabolic men and women. IGF-I deprivation unleashes GH secretion via the distinctive bipartite neuroregulatory mechanism of amplified GH secretory burst amplitude and elevated basal/nonpulsatile GH secretion. The increment in GH secretory activity is proportionate to the fall in plasma IGF-I concentrations, consistent with the idea of IGF-I autoregulation of GH output.
Acknowledgments
We thank Patsy Craig for her skillful preparation of the manuscript; Paula P. Azimi for the deconvolution analysis, data management, and graphics; and Sandra Jackson and the expert nursing staff at the University of Virginia General Clinical Research Center for conduct of the research protocols. We also thank Drs. Robert Davis and Rolf Gunnarsson at Sensus Drug Development Corp. (Austin, TX) for donating pegvisomant for use in these studies. This focused report necessarily omits many primary references because of editorial constraints. The authors, therefore, acknowledge numerous colleagues who have made earlier foundational observations.
Footnotes
1 This work was supported in part by NIH Grants RO1-AG14799 and
MO1-RR-0084 (General Clinical Research Center of the University of
Virginia Health Sciences Center) and the Center for Biomathematical
Technology. 
Received December 11, 2000.
Revised February 7, 2001.
Accepted March 5, 2001.
References
This article has been cited by other articles:
 |
|
 |
|
  J. Gibney, M.-L. Healy, and P. H. Sonksen The Growth Hormone/Insulin-Like Growth Factor-I Axis in Exercise and Sport Endocr. Rev., October 1, 2007; 28(6): 603 - 624. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. L. Asa, R. DiGiovanni, J. Jiang, M. L. Ward, K. Loesch, S. Yamada, T. Sano, K. Yoshimoto, S. J. Frank, and S. Ezzat A Growth Hormone Receptor Mutation Impairs Growth Hormone Autofeedback Signaling in Pituitary Tumors Cancer Res., August 1, 2007; 67(15): 7505 - 7511. [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]
|
|
|
|
 |
|
 A N Paisley, K Hayden, A Ellis, J Anderson, G Wieringa, and P J Trainer Pegvisomant interference in GH assays results in underestimation of GH levels Eur. J. Endocrinol., March 1, 2007; 156(3): 315 - 319. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Yin, F. Vreeland, L. J. Schaaf, R. Millham, B. A. Duncan, and A. Sharma Clinical Pharmacodynamic Effects of the Growth Hormone Receptor Antagonist Pegvisomant: Implications for Cancer Therapy Clin. Cancer Res., February 1, 2007; 13(3): 1000 - 1009. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Sachdev and D. Yee Disrupting insulin-like growth factor signaling as a potential cancer therapy Mol. Cancer Ther., January 1, 2007; 6(1): 1 - 12. [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. D. Veldhuis, A. Iranmanesh, and C. Y. Bowers Joint Mechanisms of Impaired Growth-Hormone Pulse Renewal in Aging Men J. Clin. Endocrinol. Metab., July 1, 2005; 90(7): 4177 - 4183. [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]
|
|
|
|
|
|
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. N. Roemmich, E. J. Richmond, A. D. Rogol, J. C. Lovejoy, M. Sheffield-Moore, N. Mauras, and C. Y. Bowers Endocrine Control of Body Composition in Infancy, Childhood, and Puberty Endocr. Rev., February 1, 2005; 26(1): 114 - 146. [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]
|
|
|
|
|
|
K. Yuen, J. Frystyk, M. Umpleby, L. Fryklund, and D. Dunger Changes in Free Rather Than Total Insulin-Like Growth Factor-I Enhance Insulin Sensitivity and Suppress Endogenous Peak Growth Hormone (GH) Release following Short-Term Low-Dose GH Administration in Young Healthy Adults J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3956 - 3964. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Veldhuis, S. M. Anderson, P. Kok, A. Iranmanesh, J. Frystyk, H. Orskov, and D. M. Keenan Estradiol Supplementation Modulates Growth Hormone (GH) Secretory-Burst Waveform and Recombinant Human Insulin-Like Growth Factor-I-Enforced Suppression of Endogenously Driven GH Release in Postmenopausal Women J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1312 - 1318. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Veldhuis, S. M. Anderson, J. T. Patrie, and C. Y. Bowers 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 J. Clin. Endocrinol. Metab., January 1, 2004; 89(1): 121 - 127. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. R. Biermasz, A. M. Pereira, M. Frolich, J. A. Romijn, J. D. Veldhuis, and F. Roelfsema Octreotide represses secretory-burst mass and nonpulsatile secretion but does not restore event frequency or orderly GH secretion in acromegaly Am J Physiol Endocrinol Metab, January 1, 2004; 286(1): E25 - E30. [Abstract] [Full Text]
|
|
|
|
|
|
J. D. Veldhuis, W. S. Evans, and C. Y. Bowers 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 J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5484 - 5489. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Veldhuis, M. Bidlingmaier, S. M. Anderson, W. S. Evans, Z. Wu, and C. J. Strasburger Impact of Experimental Blockade of Peripheral Growth Hormone (GH) Receptors on the Kinetics of Endogenous and Exogenous GH Removal in Healthy Women and Men J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5737 - 5745. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Richmond, A. D. Rogol, D. Basdemir, O. L. Veldhuis, W. Clarke, C. Y. Bowers, and J. D. Veldhuis Accelerated Escape from GH Autonegative Feedback in Midpuberty in Males: Evidence for Time-Delimited GH-Induced Somatostatinergic Outflow in Adolescent Boys J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3837 - 3844. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Weekers, E. Van Herck, W. Coopmans, M. Michalaki, C. Y. Bowers, J. D. Veldhuis, and G. Van den Berghe A Novel in Vivo Rabbit Model of Hypercatabolic Critical Illness Reveals a Biphasic Neuroendocrine Stress Response Endocrinology, March 1, 2002; 143(3): 764 - 774. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
) and four women (•) who were
studied as described in Fig. 1
