help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Van den Berghe, G.
Right arrow Articles by Bowers, C. Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Van den Berghe, G.
Right arrow Articles by Bowers, C. Y.
The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 2 309-319
Copyright © 1998 by The Endocrine Society

Original Studies

Neuroendocrinology of Prolonged Critical Illness: Effects of Exogenous Thyrotropin-Releasing Hormone and Its Combination with Growth Hormone Secretagogues1

Greet Van den Berghe2, Francis de Zegher, Robert C. Baxter, Johannes D. Veldhuis, Pieter Wouters, Miet Schetz, Charles Verwaest, Erik Van der Vorst, Peter Lauwers, Roger Bouillon and Cyril Y. Bowers

Departments of Intensive Care Medicine (G.VdB., P.W., M.S., C.V., E.VdV., P.L.), Pediatrics (F.dZ.), and Endocrinology (R.B.), University Hospital Gasthuisberg, University of Leuven, B-3000 Leuven, Belgium; Kolling Institute of Medical Research, Royal Shore Hospital (R.C.B.), St. Leonards New South Wales 2065, Australia; Department of Medicine, Division of Endocrinology, University of Virginia Health Sciences Center (J.D.V.), Charlottesville, Virginia 29908; and Department of Medicine, Division of Endocrinology, Tulane University Medical Center (C.Y.B.), New Orleans, Louisiana 70112-2699

Address all correspondence and requests for reprints to: Greet Van den Berghe, Department of Intensive Care Medicine, University Hospital Gasthuisberg, University of Leuven, B-3000 Leuven, Belgium. E-mail: greta.vandenberghe{at}uz.kuleuven.ac.be


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
The catabolic state of prolonged critical illness is associated with a low activity of the thyrotropic and the somatotropic axes. The neuroendocrine component in the pathogenesis of these low activity states was assessed by investigating the effects of continuous intravenous infusions of TRH, GH-releasing peptide-2 (GHRP-2), and GHRH. Twenty adult patients, critically ill for several weeks, were studied during two consecutive nights. They had been randomly allocated to one of three combinations of peptide infusions, each administered in random order: TRH (one night) and placebo (other night), TRH + GHRP-2 (one night) and GHRP-2 (other night), or TRH + GHRH + GHRP-2 (one night) and GHRH + GHRP-2 (other night). The peptide infusions were started after a 1-µg/kg bolus and infused (1 µg/kg per h) until 0600 h. Blood sampling was performed every 20 min, and pituitary hormone secretion was quantified by deconvolution analysis. Reduced pulsatile fraction of TSH, GH, and PRL secretion and low serum concentrations of T4, T3, in-sulin growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), and the acid-labile subunit (ALS) were documented in the untreated state.

Infusion of TRH alone or in combination with GH secretagogues augmented nonpulsatile TSH release 2- to 5-fold; only TRH + GHRP-2 increased pulsatile TSH secretion (4-fold). Average rises in T4 (40–54%) and in T3 (52–116%) were obtained with all three combinations, whereas reverse T3 levels did not increase, except when TRH was infused alone. Pulsatile GH secretion was amplified >6- and >10-fold, respectively, by GHRP-2 and GHRH + GHRP-2 infusions, generating mean increases of serum IGF-I (66% and 106%), IGFBP-3 (50% and 56%), and ALS (65% and 97%) within 45 h. The addition of TRH did not alter the GH secretory patterns. TRH infusion increased PRL release only when combined with GH secretagogues. No effects on serum cortisol were detected.

In conclusion, the pathogenesis of the low activity state of the thyrotropic and somatotropic axes in prolonged critical illness appears to have a neuroendocrine component, because these axes are both readily activated by coinfusion of TRH and GH secretagogues.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
PROLONGED critical illness is the phase following resuscitation of an acute life-threatening disease or trauma during which vital organ functions remain dependent on intensive care support for several weeks. In this condition, feeding is unable to reverse ongoing wasting of protein, whereas fat, in contrast, is preserved or stored (1). The protein wasting results from both activated degradation and suppressed synthesis of protein. The latter determines the residual protein content, the decrease of which correlates with the duration of illness (2). Protein loss from vital organs and tissues aggravates dysfunction of the involved systems and, consequently, prolongs dependency on intensive care support, such as mechanical ventilation and artificial feeding.

In prolonged critical illness, suppression of pulsatile TSH, GH, and PRL release has been documented and related to, respectively, low serum levels of thyroid hormone and insulin growth factor-I (IGF-I), and this takes place in the presence of hypercortisolism (3, 4, 5, 6). Circulating IGF-I has been shown to reflect protein wasting in this condition; in nonsurvivors, the tissue thyroid hormone levels are also reduced (7, 8, 9). Consequently, there is reason to believe that the above-described wasting syndrome could, at least in part, be brought about by the changes in the somatotropic and thyrotropic axes and in cortisol secretion, a hypothesis that already prompted the investigation of the anabolic properties of exogenous GH and IGF-I (10, 11).

TRH and GHRH of hypothalamic origin are currently considered to be the major endogenous and specific secretagogues for TSH and GH, respectively (12, 13). Recently, a series of synthetic peptides (GH-releasing peptides or GHRPs) and nonpeptide agents have been shown to potently and specifically release GH (14, 15, 16) through a specific G protein-coupled receptor located in the hypothalamus and the pituitary (17). It now appears plausible that the still unknown endogenous ligand of the GHRP-receptor is one of the key factors in the physiological regulation of GH secretion.

Studying the responses to the administration of hypothalamic releasing factors in prolonged critical illness may, to a certain extent, localize the origin of the endocrine changes. In previous studies, it appeared that the GH response to a GHRH bolus is blunted, the GH response to GHRP-2 exaggerated, and the GH response to TRH paradoxical (18, 19). Similarly, the TSH response to TRH is blunted, and the TSH response to GHRH is paradoxical (18, 19). The continuous infusion of GH secretagogues is able to amplify pulsatile GH release and to generate a rise of IGF-I within 21 h (3).

To further delineate the relative importance of central (hypothalamic-pituitary) vs. peripheral components in the low-activity status of the thyrotropic and somatotropic axes, we investigated whether these axes could be jointly reactivated by infusing combinations of TRH, GHRP-2, and GHRH in patients with prolonged critical illness.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Patients and concomitant treatment

Because loss of protein content has been related to the time course of critical illness rather than to the underlying disease (2), only patients depending on intensive care (including mechanical ventilatory support) for at least 1 week were eligible for participation in this study. Further inclusion criteria were a stable condition without dopamine treatment for at least 48 h, because dopamine infusion has been shown to profoundly affect pituitary function in this condition (5, 20), and an expected stay in the intensive care unit (ICU) for at least another 48 h. This study was conducted between April and November 1996.

Exclusion criteria were age <18 yr; preexisting neurological, psychiatric, metabolic or endocrine disease; intracranial lesions; important liver failure (prothrombin time <20%); renal failure requiring dialysis or hemofiltration; or concomitant treatment with glucocorticoids, estrogens, somatostatin, thyroid hormones, Ca2+-reentry blockers, clonidine, amiodarone, or dopamine agonists or antagonists.

A total of 20 patients (7 women, 13 men) were included (Table 1Go). The mean ± SEM age was 68 ± 3 yr (range, 32–87 yr). Body mass index (BMI) on ICU admission was 25 ± 1 kg/m2 (range, 17.8–40.4 kg/m2). Apache II score on the ICU admission day, an indicator of severity of illness with higher values reflecting a more critical condition (21), was 14 ± 1 (range 5–28).


View this table:
[in this window]
[in a new window]
  		Table 1. Clinical patient data

 
Patients were critically ill for 25 ± 3 days (range, 12–59) at the time of inclusion. Concomitant treatment included continuous total (n = 14) or partial (n = 4) parenteral nutrition or full enteral feeding (n = 2), with normal caloric intake (a mean of 24 nonprotein Cal/kg per day, range, 12–35 Cal/kg per day) and standard composition (0.8–1.6 g/kg amino acids per day, 2.8–4.3 g/kg glucose per day, and 1–1.5 g/kg fat per day covering 25–40% of nonprotein calories) (22); inotropic support with exogenous nondopaminergic catecholamines (n = 7); antibiotics (n = 16); and analgesia and sedation with continuously infused opioids (n = 17) and/or benzodiazepines (n = 13). Plasma glucose levels were monitored; insulin was infused when plasma glucose was >=12 mmol/L (n = 11) (23). Plasma glucose levels were elevated at the time of study start: 8.3 ± 0.5 mmol/L (range 5.7–14 mmol/L). Human albumin was continuously infused when serum levels were low (mean serum albumin concentration at inclusion was 2.8 ± 0.1 g/dL). The mean serum level of triglycerides was 188 ± 26 mg/dL (range, 66–557 mg/dL) and C-reactive protein concentration was elevated (12.5 ± 1.4 mg/dL). Continuous hemodynamic monitoring included electrocardiogram (n = 20), intra-arterial blood pressure (n = 20), central venous pressure (n = 20), and core and peripheral temperature (n = 20). During the study period of 45 h, the concomitant ICU therapy remained virtually unaltered in all patients.

The mean total ICU stay of the studied patients was 54 ± 9 days (range, 24–181). Eleven patients died on the ICU (55%), a mean 31 ± 6 days after the study. Seven patients were discharged to the ward and subsequently left the hospital (35%). One patient still remains in the ICU (5%) 5 months after study inclusion, and one patients still resides on a hospital ward (5%) 4 months after study inclusion.

The study was approved by the Institutional Review Board of the University of Leuven School of Medicine. Informed consent from a first degree relative was obtained before patient inclusion.

Study design and peptide administration

Patients were studied during a total time span of 45 h, including sampling every 20 min during two consecutive nights from 2100–0600 h and were given one study compound per night. They were randomly allocated to one of three study groups (Fig. 1Go, upper. Group 1 (n = 8) received TRH infusion (1 µg/kg bolus at 0900 h, followed by a 1 µg/kg per h continuous infusion until 0600 h) vs. placebo (24). Group 2 (n = 6) received TRH + GHRP-2 (1 + 1 µg/kg bolus at 0900 h, followed by a 1 + 1 µg/kg per h continuous infusion until 0600 h) vs. GHRP-2 infusion (1 µg/kg bolus at 0900 h, followed by a 1 µg/kg/h continuous infusion until 0600 h) (25). Group 3 (n = 6) received TRH + GHRH + GHRP-2 infusion (1 + 1 + 1 µg/kg bolus at 0900 h, followed by a 1 + 1 + 1 µg/kg per h continuous infusion until 0600 h vs. GHRH + GHRP-2 infusion (1 + 1 µg/kg bolus at 0900 h, followed by a 1 + 1 µg/kg per h continuous infusion until 0600 h) (26).



View larger version (27K):
[in this window]
[in a new window]
  		Figure 1. Upper, Twenty patients were randomly allocated to one of three groups: group 1, placebo vs. TRH infusion (n = 8); group 2, GHRP-2 vs. TRH + GHRP-2 infusion (n = 6); group 3, GHRH + GHRP-2 vs. TRH + GHRH + GHRP-2 infusion (n = 6). Lower, Within these three groups, patients were randomly assigned for order of peptide infusion into two cross-over subgroups. Duration of each infusion was 21 h. Patients were studied during a total time span of 45 h, with sampling every 20 min during two consecutive nights from 2100–0600 h.

 
Within these three groups (Fig. 1Go, lower), patients were randomly assigned for the order of peptide infusion. Duration of each infusion was 21 h. This randomized, cross-over design was applied to minimize possible interference by order of peptide administration or by spontaneous recovery.

Placebo (NaCl 0.9%), TRH (200 µg/mL NaCl 0.9%; UCB, Pharma, Brussels, Belgium), GHRP-2 (Kaken Pharmaceutical Co., Ltd., Tokyo, Japan) (50 µg/mL NaCl 0.9%), and human GHRH (50 µg/mL NaCl 0.9%; Ferring, Kiel, Germany) infusions were given through a separate lumen of a central venous catheter, inserted for clinical purposes. A PERFUSOR secura FT pump with a 50-mL PERFUSOR syringe (B. Braun, Melsungen, Germany) permitted precise infusions of small volumes at a constant rate. Inadvertent interruption of the infusion or unanticipated bolus injections of the peptides were thereby avoided.

Serum concentrations of TSH, PRL, and GH were measured in each sample, serum cortisol levels were measured every hour, and serum T4, T3, reverse T3 (rT3), IGF-I, IGFBP-3, and the acid-labile subunit (ALS) concentrations were determined before start of the infusions and in the first and the last sample of each night profile.

Blood sampling

All blood samples were collected through an arterial line inserted for clinical purposes independently of this study. The Edwards VAMP system (Baxter Healthcare Corp., Irvine, CA) was used, permitting withdrawal of undiluted blood samples from an indwelling catheter, without undue blood loss. The total amount of blood sampled per patient was 140 mL. Blood was collected into glass tubes; after clotting and centrifugation, the serum was kept frozen at -20 C until assay.

Assays

All samples of each individual patient were processed in the same assay run. Serum concentrations of TSH were measured by immunoradiometric assay using the TSH Riabead II (Abbott Labs., North Chicago, IL). The intraassay coefficient of variation was 4.3% at 1.2 mIU/L and 2.2% at 7.0 mIU/L. The detection limit was less than 0.02 mIU/L. Normal values range from 0.15–4.6 mIU/L.

Serum concentrations of T4 were measured by RIA using the Tetrabead-125 Diagnostic Kit (Abbott Labs.). The intraassay coefficient of variation was 4.6% at 59 nmol/L and 4.4% at 102 nmol/L. Normal values range from 71–154 nmol/L. The serum concentrations of T3 were measured by RIA using the T3 Riabead Kit (Abbott Labs.). The intra-assay coefficient of variation was 5.9% at 1.1 nmol/L and 4.4% at 2.8 nmol/L. Normal values range from 1.2–2.9 nmol/L. Serum concentrations of rT3 were measured by RIA using the rT3 Kit (Techland SA, Liege, Belgium). The intraassay coefficient of variation was 10.5% at 0.8 nmol/L and 10.3% at 4 nmol/L. Normal values range from 0.3–0.8 nmol/L.

Serum concentrations of PRL were measured by immunoradiometric assay using the PRL-IRMA Kit (Medgenix, Fleurus, Belgium). The intraassay coefficient of variation was 6.2% at 6.6 µg/L and 4.7% at 46.4 µg/L. The detection limit was 2.9 µg/L. Daytime normal levels for men are <=9.9 µg/L, for females in the reproductive period <=19.7 µg/L, elderly women <=8 µg/L, and older men <=4.9 µg/L. Sleep-associated nocturnal PRL concentrations range between 9–25 µg/L. Serum concentrations of GH in all profiles were measured by RIA using a polyclonal antibody (27). The intraassay coefficient of variation was 7.3% at 6.7 µg/L and 4.6% at 14.4 µg/L. The detection limit was 0.5 µg/L.

Plasma concentrations of total IGF-I were measured by RIA, after acid-ethanol extraction. The intraassay coefficient of variation was 10.1% at 95 µg/L and 5.5% at 474 µg/L. The between-assay coefficient of variation was 14.8% at 109 µg/L and 10.1% at 389 µg/L. The detection limit was 10 µg/L. Normal range in healthy adults is 100–300 µg/L. Serum IGFBP-3 concentrations were measured by RIA as previously described (28), using antiserum R-100. The intraassay coefficient of variation was 6.2% at 2.5 mg/L and 5.5% at 5.7 mg/L, and the between-assay coefficient of variation was 11.9% at 2.9 mg/L and 14.5% at 6.3 mg/L. Normal ranges are 2.2 to 4.6 mg/L.

Serum ALS concentrations were assessed by RIA, as described elsewhere (29). The intraassay coefficient of variation was 3.4%, and the between-assay coefficient of variation was 10.5% at 5.3 mg/L and 5.4% at 24 mg/L. Normal ranges are 17–34 mg/L. Serum concentrations of cortisol were measured by RIA after extraction with dichloromethane. The intraassay coefficient of variation was 3.1% at 417 nmol/L. Normal ranges are 276–607 nmol/L at 0800 h, 0–276 nmol/L at 2000 h, and <50 nmol/L at 2400 h if asleep.

Data analysis

The sequential serum concentrations of TSH, PRL, and GH measured in each night profile were transformed into pituitary secretion profiles by eliminating the effect of metabolic clearance, using multiple parameter deconvolution analysis (30). This method is designed to compute hormonal half-life and the number, amplitude, and mass of underlying pituitary secretory bursts and to estimate tonic (basal or nonpulsatile) secretion (30).

Individual GH and PRL half-lives were determined in each study night and applied to the data series. For TSH, we determined a mean half-life in critical care conditions by deconvolving the distinct TRH-induced TSH peak (sampling at time 0, 20, 40, 60, and 120 min) measured in a group of subjects with similar study inclusion and exclusion criteria and using the same TSH assay (n = 10) (19). This mean TSH half-life (87 min) was applied to the data series for deconvolution analysis of the sequential serum TSH concentrations measured in each profile.

Besides mean serum concentrations, the following parameters were calculated for each hormonal profile in each subject: basal secretion rate [estimated as the amount of hormone that should be continuously released from the pituitary to achieve serum concentrations approximating the mean of the lowest 5% of all values observed, which is micrograms or milli-international units per liter of distribution volume (Lv) and per minute], amplitudes [maximal secretory rate (micrograms or milli-international units per Lv and per minute] and temporal positions of all secretory bursts, the mass of hormone secreted per burst [estimated as the area of the resolved secretion burst (micrograms or milli-international units per Lv)], and the mean pulsatile production [calculated as the product of the number of secretory bursts and the mean secretory burst mass over the time interval considered (micrograms or milli-international units per Lv over 9 h). The proportion of pulsatile secretion (percent) was calculated as the pulsatile production divided by the sum of the pulsatile and basal production, each expressed as micrograms or milli-international units per Lv over 9 h, multiplied by 100. The total GH production (µg/Lv per 9 h) was calculated as the sum of pulsatile GH production (µg/Lv over 9 h) and basal GH secretion (µg/Lv·min x 560 min).

Approximate entropy statistic (ApEn)

ApEn is a model-independent statistic for assessing regularity of time series (31, 32). ApEn measures a logarithmic likelihood that runs of patterns that are similar remain similar on next incremental comparisons. It assigns a single nonnegative number to a time series, with larger values corresponding to greater apparent process randomness. ApEn has been demonstrated to be stable to small changes in noise characteristics and to infrequent and significant artefacts. It detects variations in episodic behavior that are not reflected in changes in peak occurrences or amplitudes. Additionally, ApEn provides a direct barometer of feedback system change in many coupled systems. The calculation of ApEn was performed as previously reported (33). Because ApEn will generally increase with increasing process noise (and increasing intraassay variation), it is important to compare data sets with similar assay coefficients of variation, as performed in this study. To this end, we used a tolerance/threshold for ApEn of 0.2 times the series between sample SD, and a window/range of m = 1 consecutive samples over which to test for pattern reproducibility, as is appropriate for time series of <150 samples.

Data were analyzed using paired and unpaired Student’s t test, and by multiple comparisons ANOVA, as appropriate. Nonnormally distributed data were logarithmically transformed before analysis. Comparison with the literature reference values for pulsatile fraction of pituitary hormone release was performed using the two-tailed, one sample t test. Results are expressed as mean ± SEM unless indicated otherwise.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Within each of the three study groups, the GH, TSH, PRL, and cortisol results of the cross-over subgroups were similar (Fig. 1Go, lower); accordingly, cross-over results within each group were pooled.

The releasing peptides were well tolerated. No side effects were noted during either of the peptide infusions, apart from an increased glucose intolerance during GHRP-2 and during GHRH + GHRP-2 infusions in those patients already receiving exogenous insulin infusion (Table 1Go); this was overcome by increasing the dose of infused insulin.

Thyroid axis

At study start, the patient population (n = 20) had a low serum T4 (63 ± 5.2 nmol/L), a low T3 (0.72 ± 0.08 nmol/L), and a mean rT3 concentration just below the upper normal limit (0.78 ± 0.13 nmol/L). These variables were not different among the three groups.

TRH vs. placebo. The placebo profiles confirmed (4) that mean nightly serum concentrations of TSH were normal (0.92 ± 0.28 mIU/L), but that the fraction of TSH released in a pulsatile manner was reduced: 37 ± 6% vs. normal 65% (P = 0.002) (34, 35) (Fig. 2Go, upper and Fig. 3Go, left).



View larger version (55K):
[in this window]
[in a new window]
  		Figure 2. Representative serum TSH concentration profiles from three critically ill men, age 69, 80, and 60 yr, respectively (two consecutive nights with sampling every 20 min between 2100–0600 h) are shown: Infusions containing TRH (1 µg/kg per h) increased nonpulsatile (basal) TSH secretion. Only when TRH was infused together with GHRP-2 (1 µg/kg per h) was pulsatile TSH secretion increased (middle two panels).

 


View larger version (35K):
[in this window]
[in a new window]
  		Figure 3. Upper, Effects of TRH infusion (1 µg/kg per h) compared with placebo (n = 8), of addition of TRH (1 µg/kg per h) to GHRP-2 (1 µg/kg per h) infusion (n = 6), and of addition of TRH (1 µg/kg per h) to GHRH + GHRP-2 (1 + 1 µg/kg per h) infusion on mean serum TSH concentrations and basal and pulsatile TSH secretion are shown. Lower, Twenty four-hour changes in peripheral thryoid hormone levels in three study groups.

 
TRH infusion increased mean nightly TSH serum concentrations 4-fold: 3.84 ± 0.44 mIU/L vs. 0.92 ± 0.28 mIU/L, P < 0.0001 (Fig. 2Go, upper and Fig. 3Go, left). This was mainly because of a 4-fold increase in TSH basal secretion: 0.022 ± 0.002 mIU/Lv·min vs. 0.005 ± 0.001 mIU/Lv·min, P < 0.0001. Although mean pulsatile TSH production was not significantly different, secretory burst amplitude (0.046 ± 0.015 mIU/Lv·min vs. 0.019 ± 0.009 mIU/Lv·min, P = 0.006) and secretory burst mass (0.746 ± 0.099 mIU/Lv vs. 0.348 ± 0.123 mIU/Lv, P = 0.05) were higher during TRH infusion. The number of TSH bursts over 9 h was not significantly altered (3.9 ± 0.7 vs. 5.2 ± 0.4, P = 0.1).

When TRH was infused for 21 h after a placebo infusion, circulating T4 increased by 44 ± 7% over 24 h, whereas it decreased by 14 ± 2% when placebo was infused after TRH, P = 0.0003 (Fig. 3Go, left). Similar changes were observed for circulating T3: +116 ± 22% vs. -35 ± 5%, P = 0.0005. Circulating rT3 increased more during TRH infusion than during placebo: +39 ± 13% vs. +10 ± 4%, P = 0.05.

During TRH infusion, the overnight decrease of serum TSH (-1.63 ± 0.34 mIU/L) was more pronounced (P = 0.002) than during placebo (-0.04 ± 0.07 mIU/L) (Fig. 4Go). Significant TSH decreases (a decrease in TSH that was at least twice the intraassay coefficient of variation) correlated (R2 = 0.86, P = 0.003) with the circulating T3 levels measured at the end of the TRH infusion (0600 h) (mean 1.86 ± 0.17 nmol/L) (Fig. 4Go).



View larger version (20K):
[in this window]
[in a new window]
  		Figure 4. Mean ± SEM serum TSH concentrations between 2100–0600 h during a TRH infusion (1 µg/kg per h) that was started at 0900 h (n = 8). In all but one patient, TSH concentration at 0600 h was significantly (at least twice variation coefficient of TSH assay) lower than at 2100 h. Overnight TSH decrease (difference between 0600 and 2100 h serum TSH concentration) correlated with serum T3 concentration measured at end of TRH infusion (at 0600 h) (R2 = 0.86 and P = 0.003), suggesting feedback inhibition.

 
The infusion of TRH did not alter the regularity in the TSH secretory pattern, as indicated by similar ApEn scores during TRH and placebo infusions (0.766 ± 0.061 and 0.887 ± 0.053, respectively, P = 0.2).

TRH + GHRP-2 vs. GHRP-2. The addition of TRH to the infusion of GHRP-2 increased mean nightly serum TSH concentrations 4-fold: 4.65 ± 1.56 mIU/L vs. 1.32 ± 0.78 mIU/L, P < 0.0001 (Figs. 2Go and 3Go, middle). This was because of a 5-fold increase in basal TSH secretion (0.029 ± 0.011 mIU/Lv·min vs. 0.005 ± 0.0004 mIU/Lv-min, P = 0.002) as well as to a 4-fold increase in nightly pulsatile TSH production (4.023 ± 1.213 mIU/Lv vs. 1.112 ± 0.78 mIU/Lv, P = 0.02). The latter was because of a higher secretory burst amplitude (0.024 ± 0.005 mIU/Lv-min vs. 0.008 ± 0.003 mIU/Lv-min, P = 0.002), and secretory burst mass (1.003 ± 0.3 mIU/Lv vs. 0.324 ± 0.198 mIU/Lv, P = 0.02) during TRH + GHRP-2 infusion, whereas the number of TSH bursts remained unaltered (number of bursts per 9 h: 4.3 ± 0.4 vs. 4.8 ± 0.4, P = 0.4).

When TRH and GHRP-2 were infused after GHRP-2 alone, circulating T4 increased by 40 ± 7% over 24 h, whereas it decreased by -10 ± 6% when GHRP-2 was infused after TRH + GHRP-2, P = 0.006 (Figs. 2Go and 3Go, middle). Similar observations were made for circulating T3: +73 ± 3% vs. -52 ± 24%, P = 0.007. The infusion of TRH together with GHRP-2 after a GHRP-2 infusion did not alter rT3: -3 ± 6% over 24 h vs. +10 ± 4% for GHRP-2 infusion alone, P = 0.2.

The serum T3 concentrations, measured at the end of the TRH + GHRP-2 infusion (1.11 ± 0.092 nmol/L) were lower (P = 0.02) compared with those obtained after TRH infusion alone (1.86 ± 0.17 nmol/L). There was no difference in overnight changes in serum TSH during TRH + GHRP-2 as compared with GHRP-2 infusion (-0.66 ± 0.34 mIU/L vs. -0.27 ± 0.15 mIU/L, P = 0.4). The addition of TRH did not alter the regularity of TSH secretion obtained during GHRP-2 infusion, as indicated by a constant ApEn score (0.867 ± 0.071 and 0.914 ± 0.049, respectively, P = 0.5).

TRH + GHRH + GHRP-2 vs. GHRH + GHRP-2. The addition of TRH to GHRH + GHRP-2 infusion increased mean nightly serum TSH concentrations 4-fold: 5.2 ± 3.4 mIU/L vs. 1.76 ± 1.01 mIU/L (median TSH 2.8-fold: 1.85 mIU/L vs. 0.66 mIU/L), P = 0.01 (Figs. 2Go and 3Go, right). This was essentially because of a 2.6-fold increase in basal TSH secretion: 0.026 ± 0.017 mIU/Lv-min vs. 0.01 ± 0.006 mIU/Lv-min, P = 0.006. The number of TSH bursts over 9 h remained constant (4.3 ± 0.4 vs. 4.3 ± 0.6).

When TRH was infused together with GHRH + GHRP-2 for 21 h after a GHRH + GHRP-2 infusion, circulating T4 increased by 54 ± 21%, whereas it decreased by -± 9% when GHRH + GHRP-2 was infused after TRH + GHRH + GHRP-2, P = 0.04 (Fig. 4Go). Similar observations were made for circulating T3: +52 ± 38% vs. -31 ± 10%, P = 0.008. The infusion of TRH together with GHRH + GHRP-2 after a GHRH + GHRP-2 infusion did not raise rT3 (+35 ± 29% vs. +0.7 ± 10%, P = 0.3).

The T3 concentrations measured at the end of the TRH + GHRH + GHRP-2 infusion (0.88 ± 0.023 nmol/L), were lower (P = 0.004) than those measured during TRH + GHRP-2 (1.11 ± 0.092 nmol/L), and those obtained during the infusion of TRH alone (1.86 ± 0.17 nmol/L). There was no difference in overnight changes in serum TSH during TRH + GHRH + GHRP-2 as compared with GHRH + GHRP-2 infusion (-08 ± 1.80 mIU/L vs. -0.61 ± 0.44 mIU/L, P = 0.4). The addition of TRH did not alter the regularity of TSH secretion obtained during GHRH + GHRP-2 infusion, as indicated by similar ApEn scores (0.903 ± 0.059 and 0.792 ± 0.042, respectively, P = 0.3).

PRL

TRH vs. placebo. The placebo profiles confirmed (4) that mean nightly serum PRL levels were normal (19.5 ± 5.9 µg/L; median 11.4 µg/L and interquartile range 28 µg/L), and that PRL half-life was normal (63 ± 11 min), but that the fraction of PRL released in a pulsatile fashion ws reduced (P = 0.03): 31 ± 6% vs. normal 48% (36).

Surprisingly, TRH infusion did not increase serum PRL concentrations. In contrast, it suppressed pulsatile PRL production over 9 h (18.5 ± 6.8 µg/Lv vs. 36.2 ± 11.6 µg/Lv, P = 0.05), whereas basal PRL secretion was maintained. TRH infusion did not alter the number of PRL secretory bursts over 9 h (TRH 5.0 ± 0.4 vs. placebo 5.7 ± 0.4, P = 0.3), the PRL half-life (71.8 ± 11 min vs. 63 ± 11 min, P = 0.6), or the regularity of the PRL secretory pattern, as indicated by the ApEn score (1.012 ± 0.057 vs. 0.911 ± 0.039, P = 0.1).

TRH + GHRP-2 vs. GHRP-2. The addition of TRH to the infusion of GHRP-2 induced a minute but consistent increase of mean nightly PRL serum concentrations: 17.3 ± 5.6 vs. 14.9 ± 5 µg/L, P = 0.02. This was exclusively because of an increase in basal PRL secretion: 0.210 ± 0.081 µg/Lv·min vs. 0.166 ± 0.072 µg/Lv·min, P = 0.03.

Again, the number of PRL secretory bursts over 9 h (5.5 ± 0.2 vs. 5.8 ± 0.3, P = 0.4) as well as PRL half-life (60 ± 10 min vs. 58 ± 12 min, P = 0.6) remained unaltered. Moreover, the addition of TRH to GHRP-2 infusion significantly increased irregularity of the PRL secretory pattern, as indicated by a higher ApEn score (P = 0.01) during TRH + GHRP-2 infusion (0.97 ± 0.028) compared with that obtained during the infusion of GHRP-2 alone (0.856 ± 0.041).

TRH + GHRH + GHRP-2 vs. GHRH + GHRP-2. The addition of TRH to the infusion of GHRH + GHRP-2 also induced minute but consistent increase in mean nightly PRL serum concentrations: 23.5 ± 5.1 µg/L vs. 21.1 ± 5.6 µg/L, P = 0.04. This occurred without significant alterations of the different deconvolution-derived parameters including PRL half-life (67.9 ± 14.3 min vs. 68.1 ± 8.3 min, P = 0.99), and ApEn score (0.969 ± 0.021 vs. 0.892 ± 0.033, P = 0.2).

Somatotropic axis

At inclusion, the study population (n = 20) had low serum concentrations of IGF-I (86 ± 6 µg/L), IGFBP-3 (1.88 ± 0.12 mg/L), and ALS (7.21 ± 0.61 mg/L). These variables were not different among the three groups.

The placebo profiles (n = 8) confirmed that mean nightly GH concentrations were normal (2.3 ± 0.4 µg/L), and that GH half-life was normal (17.3 ± 1.6 min), but that the fraction of GH released in a pulsatile fashion was reduced (P < 0.0001): 48.1 ± 5.2% vs. normal 99% (3, 36). Moreover, the GH secretory pattern appeared to be relatively irregular, as indicated by a high ApEn score (0.868 ± 0.076) (37).

The addition of TRH to the infusions of either placebo, GHRP-2, or GHRH + GHRP-2 did not alter within 24 h any of the deconvolution-derived parameters of the GH secretory patterns (Fig. 5Go); the ApEn score; or serum IGF-I, IGFBP-3, or ALS (data not shown).



View larger version (71K):
[in this window]
[in a new window]
  		Figure 5. Representative overnight serum GH concentration profiles obtained in three patients (one man age 69 yr and two women age 85 and 63 yr, respectively) during two consecutive nights, with sampling every 20 min between 2100–0600h. Infusion of TRH alone or in combination with GHRP-2 or GHRH + GHRP-2 did not detectably alter GH secretory patterns.

 
Consequently, GH secretion is reported over two study nights, and the generation of IGF-I, IGFBP-3, and ALS are described over 45 h during either placebo, GHRP-2, or GHRH + GHRP-2 infusion (Figs. 5Go and 6Go). Nightly mean serum GH concentration was different in the three groups (P = 0.005): 2.8 ± 0.5 µg/L during placebo (±TRH), 17.3 ± 6.8 µg/L during GHRP-2 (±TRH), and 24 ± 4.1 µg/L during GHRH + GHRP-2 (±TRH).



View larger version (29K):
[in this window]
[in a new window]
  		Figure 6. Effect on mean serum GH concentration, pulsatile GH production, basal GH secretion, and increments over 45 h in IGF-I, IGFBP-3, and ALS, obtained with a 45-h infusion of placebo ± TRH (n = 8), a 45-h infusion of GHRP-2 ± TRH (n = 6), and a 45-h infusion of GHRH + GHRP-2 ± TRH (n = 6) were distinct as calculated with ANOVA. Bars, Represent means + 95% confidence interval.

 
Nightly pulsatile GH production was different in the three groups (P = 0.008): 29 ± 7 µg/Lv over 9 h during placebo (±TRH), >6-fold higher during GHRP-2 (±TRH) infusion (180 ± 66 µg/Lv over 9 h), and >10-fold higher during GHRH + GHRP-2 (±TRH) infusion (307 ± 85 µg/Lv over 9 h).

Nightly basal GH secretion was different in the three groups (P = 0.009): 0.052 ± 0.007 µg/Lv·min during placebo (±TRH), >5-fold higher during GHRP-2 (±TRH) infusion (0.309 ± 0.131 µg/Lv·min), and >7-fold higher during GHRH + GHRP-2 (±TRH) infusion (0.328 ± 0.074 µg/Lv·min).

IGF-I change was different in the three groups (P = 0.0004): placebo (±TRH) infusion did not significantly alter the low serum IGF-I levels over 45 h: 91 ± 14 µg/L at study start and 98 ± 17 at the end of the second study night (P = 0.6).

Infusion of GHRP-2 (±TRH) increased serum IGF-I by 66% from 86 ± 8.1 µg/L to 143 ± 20 µg/L (P = 0.01). Infusion of GHRH + GHRP-2 (±TRH) increased serum IGF-I by 106% from 78 ± 6.7 µg/L to 161 ± 17 µg/L (P = 0.001).

IGFBP-3 change was different in the three groups (P = 0.002): placebo (±TRH) infusion did not alter the low IGFBP-3 levels over 45 h: 2.11 ± 0.22 mg/L at study start and 2.32 ± 0.27 mg/L at the end of the second study night (P = 0.1). Infusion of GHRP-2 (±TRH) increased IGFBP-3 levels by 50% from 1.73 ± 0.08 mg/L to 2.61 ± 0.22 mg/L (P = 0.004). Infusion of GHRH + GHRP-2 (±TRH) increased IGFBP-3 levels by 65% from 1.73 ± 0.27 to 2.66 ± 0.20 mg/L (P = 0.0003).

ALS change was different in the three groups (P = 0.0003): placebo (±TRH) infusion did not alter the low ALS levels over 45 h: 8.53 ± 0.97 mg/L at study start and 9.61 ± 1.21 mg/L at the end of the second study night (P = 0.12). Infusion of GHRP-2 (±TRH) increased ALS levels by 56% from 6.97 ± 0.87 mg/L to 10.63 ± 1.33 mg/L (P = 0.01). Infusion of GHRH + GHRP-2 (±TRH) increased ALS levels by 96% from 5.68 ± 1.08 to 10.77 ± 1.83 mg/L (P = 0.003).

Increments over 45 h of IGFBP-3 and ALS correlated positively with serum IGF-I rise (R2 = 0.49, P = 0.0006 and R2 = 0.42, respectively, P = 0.002), as well as with each other (R2 = 0.64, P < 0.0001).

An exponential regression line universally fitted the relationship between GH secretion and the 45-h increments in IGF-I, IGFBP-3, or ALS, as shown in Fig. 7Go.



View larger version (26K):
[in this window]
[in a new window]
  		Figure 7. Exponential regression of relationship between GH secretion and 45-h increments in IGF-I, IGFBP-3, or ALS. {Delta} IGF-I (percent) correlated with total (basal + pulsatile) GH production (R2 = 0.71) and with pulsatile GH production (R2 = 0.67). {Delta} IGFBP-3 (percent) correlated with total (basal + pulsatile) GH production (R2 = 0.58) and with pulsatile GH production (R2 = 0.57). {Delta} ALS (percent) correlated with total (basal + pulsatile) GH production (R2 = 0.70) and with pulsatile GH production (R2 = 0.76). Combined average {Delta} (percent) of IGF-I, IGFBP-3, and ALS (an index of responsiveness to GH) correlated with total (basal + pulsatile) GH production (R2 = 0.82) and with pulsatile GH production (R2 = 0.81). The regression lines indicate that severely impaired (pulsatile) GH secretion during prolonged critical illness allows circulating IGF-I to decrease progressively, whereas amplifying GH secretion with GH secretagogues substantially increases IGF-I levels, up to a certain level, above which further increase in GH secretion has little or no additional effect.

 
Cortisol

The addition of TRH did not change mean nightly cortisol concentrations obtained during placebo (449 ± 27 nmol/L and 407 ± 23 nmol/L, respectively, P = 0.1), GHRP-2 (417 ± 76 nmol/L and 407 ± 74 nmol/L, respectively, P = 0.4), or GHRH + GHRP-2 infusion (484 ± 22 nmol/L and 477 ± 30 nmol/L, respectively, P = 0.8).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The finding of a uniformly reduced pulsatile GH, TSH, and PRL secretion in a context of low IGF-I and thyroid hormone levels, and the observation of a spontaneous rise of serum TSH preceding recovery led to the hypothesis of the presence of a neuroendocrine component in the pathogenesis of the low activity status of the somatotropic and thyrotropic axes in the chronic, catabolic phase of critical illness (3, 4, 38). Continuous infusion of GHRP-2 or GHRH + GHRP-2 has previously been shown to amplify pulsatile GH secretion and to raise serum IGF-I in this condition (3). The present study reveals that adding TRH to the continuous infusion of GH secretagogues concomitantly activates the thyrotropic axis and PRL secretion, without attenuating the GH-releasing properties of the GH secretagogues. The substantial peripheral responsiveness to amplified GH and TSH secretion points towards a predominantly central, rather than peripheral, origin of the low circulating IGF-I and thyroid hormone levels in the chronic phase of intensive care dependency.

In healthy subjects, TRH infusion increases both basal and pulsatile TSH secretion (24). In prolonged critical illness, TRH infusion alone increased only basal TSH release. The mechanisms underlying the lack of effect on the pulsatile component are unclear, but may include an illness-induced TRH resistance (39), or an increased suppressive tone on the thyrotropes, e.g. exerted by endogenous dopamine (5, 18, 40), somatostatin (41), or cortisol (42), all of which are known to suppress TSH pulse amplitude.

When TRH was infused together with GHRP-2, it also increased pulsatile TSH secretion, thereby normalizing the TSH response (24). This finding is consistent with the previously formulated hypothesis of a deficiency of the putative endogenous GHRP-like ligand in the catabolic condition of prolonged critical illness (3, 19). Further support for this hypothesis is provided by the PRL response to TRH infusion. When TRH is administered alone, PRL secretion is paradoxically suppressed, whereas coinfusion of GHRP-2 tends to normalize the PRL response to TRH. None of the peptide infusions altered TSH or PRL pulse frequency, indicating that neither TRH, GHRH, nor GHRP-2 are involved in the pacing of pulsatile TSH or PRL secretion.

Continuous TRH infusion results in a striking increase of serum T4 and T3. When TRH was infused alone, there was also a rise in circulating rT3, indicating incomplete peripheral conversion of increased T4 into T3. When TRH was infused together with GHRP-2 or with GHRH + GHRP-2, the increase of serum T3 concentrations was less pronounced but circulating rT3 was not altered. This finding is in line with in vitro data indicating that GHRPs in large doses have a direct inhibitory effect on T3 synthesis in human thyroid follicles (43). The observation that circulating rT3 did not rise when TRH was infused together with GH secretagogues, suggests that the concomitant increase of GH secretion amplifies the efficacy of the peripheral conversion of increased T4 into T3, as has been defined in earlier independent studies of GH action (44).

The effect of TRH infusion in critically ill patients appears to be self-limiting; once serum T3 approaches the upper-normal range, the TSH response to TRH decreases (Fig. 4Go). Thus, TRH infusion does not appear to overcome the negative feedback exerted by thyroid hormones at the pituitary level, which serves as a safety mechanism preventing overstimulation of the thyroid gland (45). Consequently, the continuous infusion of TRH, as compared with T4 or T3 administration, appears to be a theoretically safer strategy to drive the thyrotropic axis in prolonged critical illness. Continuous TRH infusion did not detectably alter any of GHs secretory characteristics during placebo, GHRP-2, or GHRH + GHRP-2 infusion, suggesting that the paradoxical GH response, previously observed after a bolus injection of TRH in critically ill patients, is a transient phenomenon (18).

GHRP-2 and GHRH + GHRP-2 infusions were found to elicit >6-fold and >10-fold increases of GH secretion, respectively, and to be associated with striking rises of serum IGF-I, IGFBP-3, and ALS, thus confirming previous findings over 21 h (3) and extending them over 45 h. Hence, the somatotropes of critically ill patients appear to maintain responsiveness to GH secretagogues over at least 45 h, despite increasing serum IGF-I, which has been shown to suppress GH release in the fasting human (46).

Close correlations were observed between total or pulsatile GH secretion on one hand and separate or combined serum markers (IGF-I, IGFBP-3 and ALS) of GH responsiveness on the other hand (47, 48). In addition to their regulation by GH, both IGF-I and ALS are regulated by nutritional status (49), although nutritional factors do not appear to have compromised the GH responsiveness in this study. The correlation between GH secretion and serum IGFBP-3 was somewhat weaker, suggesting that IGFBP-3 may be less directly GH dependent than IGF-I or ALS. Nutritional factors and IGF-I itself may also affect IGFBP-3 (49, 50). Furthermore, IGFBP-3 may be subject to limited proteolysis in critically ill patients, which may affect its ability to complex with ALS and thus its stability in the circulation (51).

The aforementioned correlations between variables of GH secretion and indices of responsiveness to GH were obtained along exponential regression lines (Fig. 7Go). This relationship indicates that circulating IGF-I, IGFBP-3, and particularly ALS further increase in proportion to GH secretion up to a certain point, beyond which further increase of GH secretion has apparently little or no additional effect. It is noteworthy that the latter point corresponds to a pulsatile GH secretion of approximately 200 µg/Lv over 9 h or less, a value that can be evoked by the infusion of GHRP-2 alone.

Together, these findings corroborate the retention of considerable responsiveness to GH, thus further delineating the distinct pathophysiological paradigm of the chronic, nonthriving phase of critical illness, as opposed to that of the acute phase, which is thought to be primarily a condition of GH resistance (52). In conclusion, the present investigations indicate that low serum T4, T3, IGF-I, IGFBP-3, and ALS levels in the chronic phase of critical illness may have at least in part a hypothalamic origin. The alterations occurring in the thyroid and somatotropic axes are reversed to a significant degree by the combined infusion of TRH and GH secretagogues. The extent to which this finding should be considered a pharmacological effect is at present unclear. It also remains to be determined whether this endocrine reactivation by intervening at the hypothalamic-pituitary level can be maintained over a longer interval, and whether it will enhance clinical indices of recovery from critical illness.


   Acknowledgments
 
We thank the medical and nursing staff of the Intensive Care Unit for their cooperation. Prof. Norbert Blanckaert and Dr. Jaak Billen are acknowledged for the TSH and thyroid hormone determinations. We thank Ms. Sri Meka, Ms. Viviane Celis, Ms. Martine Ade, Ms. Tina Schreurs, Ms. Myriam Smets, Ms. Christiane Eyletten, Ms. Marianne Aerts, and Mr. Mathieu Gerits for expert technical assistance. Mr. Jean Hellings (Baxter, Belgium) is acknowledged for generously providing the Vamp-systems. Professor Seymour Reichlin and Professor Robert Utiger are acknowledged for critical manuscript review.


   Footnotes
 
1 This work was supported by research grants from the National Science Foundation Center for Biological Timing USA (to J.D.V.); The National Health and Research Council, Australia (to R.C.B.); the Fund for Scientific Research Flanders, Belgium (G.0162.96), the Research Council of the University of Leuven (OT 95/24), and the Belgian Study Group for Pediatric Endocrinology (to G.VdB. and F.dZ.). Back

2 Clinical Research Investigator of the Fund for Scientific Research Flanders, Belgium (G.3c05.95N). Back

Received July 21, 1997.

Revised September 9, 1997.

Revised October 17, 1997.

Accepted October 22, 1997.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Streat SJ, Beddoe AH, Hill GL. 1987 Aggressive nutritional support does not prevent protein loss despite fat gain in septic intensive care patients. J Trauma. 27:262–266.[Medline]
  2. Gamrin L, Essén P, Forsberg AM, Hultman E, Wernerman J. 1996 A descriptive study of skeletal muscle metabolism in critically ill patients: free amino acids, energy-rich phosphates, protein, nucleic acids, fat, water, and electrolytes. Crit Care Med. 24:575–583.[CrossRef][Medline]
  3. Van den Berghe G, de Zegher F, Veldhuis JD, et al. 1997 The somatotropic axis in critical illness: effect of continuous GHRH and GHRP-2 infusion. J Clin Endocrinol Metab. 82:590–599.[Abstract/Free Full Text]
  4. Van den Berghe G, de Zegher F, Veldhuis JD, et al. 1997 Thyrotropin and prolactin release in prolonged critical illness: dynamics of spontaneous secretion and effects of growth hormone secretagogues. Clin Endocrinol. 47:599–612.[CrossRef][Medline]
  5. Van den Berghe G, de Zegher F. 1996 Anterior pituitary function during critical illness and dopamine treatment. Crit Care Med. 24:1580–1590.[CrossRef][Medline]
  6. Fliers E, Guldenaar SEF, Wiersinga WM, Swaab DF. 1997 Thyrotropin-releasing hormone gene expression in the human hypothalamus in relation to non-thyroidal illness. 79th Annual Meeting of The Endocrine Society, June 11–14, 1997, Minneapolis MN. Abstract OR44–3, P129,
  7. Hawker FH, Steward PM, Baxter RC, Borkman M, Tan K, Caterson ID, McWilliam DB. 1997 Relationship of somatomedin-C/insulin-like growth factor-I levels to conventional nutritional indices in critically il patients. Crit Care Med. 15:732–736.
  8. Arem R, Wiener GJ, Kaplan SG, Kim HS, Reichlin S, Kaplan MM. 1993 Reduced tissue thyroid hormone levels in fatal illness. Metabolism. 42:1102–1108.[CrossRef][Medline]
  9. Chopra IJ. 1997 Euthyroid sick syndrome: is it a misnomer? J Clin Endocrinol Metab. 82:329–334.[Free Full Text]
  10. Wilmore DW. 1991 Catabolic illness: strategies for enhancing recovery. N Engl J Med. 325:695–702.[Abstract]
  11. Kupfer SR, Underwood, Baxter RC, Clemmons DR. 1993 Enhancement of the anabolic effects of growth hormone and insulin-like growth factor-1 by use of both agents simultaneously. J Clin Invest. 91:391–396.
  12. Frohman LA, Jansson JO. 1986 Growth hormone-releasing hormone. Endocr Rev. 7:223–253.[Abstract]
  13. Jackson IMD. 1982 Thyrotropin releasing hormone. N Engl J Med. 306:145–155.[Medline]
  14. Bowers CY, Momany FA, Reynolds GA, Hong A. 1984 On the in vitro and in vivo activity of a new synthetic hexapeptide that acts on the pituitary to specifically release growth hormone. Endocrinology. 114:1537–1545.[Abstract]
  15. Korbonitz M, Grossman AB. 1995 Growth hormone-releasing peptide and its analogues. Novel stimuli to growth hormone release. Trends Endocrinol Metab. 6:43–49.
  16. Chapman IM, Bach MA, Van Cauter E, et al. 1996 Stimulation of the growth hormone (GH)-insulin-like growth factor I axis by daily oral administration of a GH-secretagogue (MK-677) in healthy elderly subjects. J Clin Endocrinol Metab. 81:4249–4257.[Abstract]
  17. Howard AD, Feighner SD, Cully DF, et al. 1996 A receptor in pituitary and hypothalamus that functions in growth hormone release. Science. 273:974–977.[Abstract]
  18. Van den Berghe G, de Zegher F, Vlasselaers D, et al. 1996 Thyrotropin releasing hormone in critical illness: from a dopamine-dependent test to a strategy for increasing low serum triiodothyronine, prolactin and growth hormone. Crit Care Med. 24:590–595.[CrossRef][Medline]
  19. Van den Berghe G, de Zegher F, Bowers CY, et al. 1996 Pituitary responsiveness to growth hormone (GH) releasing hormone, GH-releasing peptide-2 and thyrotropin releasing hormone in critical illness. Clin Endocrinol (Oxf). 45:341–351.[CrossRef][Medline]
  20. Van den Berghe G, de Zegher F, Lauwers P, Veldhuis JD. 1994 Growth hormone secretion in critical illness: effect of dopamine. J Clin Endocrinol Metab. 79:1141–1146.[Abstract]
  21. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. 1985 APACHE II: a severity of disease classification system. Crit Care Med. 13:818–829.[Medline]
  22. Souba WW. 1997 Nutritional support. N Engl J Med. 336:41–48.[Free Full Text]
  23. Mizock BA. 1995 Alterations in carbohydrate metabolism during stress: a review of the literature. Am J Med. 98:75–84.[CrossRef][Medline]
  24. Samuels MH, Henry P, Luther M, Ridgway EC. 1993 Pulsatile TSH secretion during 48-hour continuous TRH infusion. Thyroid. 3:201–206.[Medline]
  25. Imbimbo BP, Mant T, Edwards M, et al. 1994 Growth hormone-releasing activity of hexarelin in humans; a dose-response study. Eur J Clin Pharmacol. 46:421–425.[Medline]
  26. Spoudeas HA, Winrow AP, Hindmarsh PC, Brook CGD. 1994 Low-dose growth hormone-releasing hormone test: a dose-response study. Eur J Endocrinol. 131:238–245.[Abstract]
  27. Bouillon R, De Moor P. 1974 Heterogeneity of human growth hormone in serum. Ann d’Endocrinol. 35:606–613.[Medline]
  28. Baxter RC, Martin JL. 1986 Radioimmunoassay of growth hormone-dependent insulin-like growth factor binding protein in human plasma. J Clin Invest. 78:1504–1512.
  29. Baxter RC. 1990 Circulating levels and molecular distribution of the acid-labile ({alpha}) subunit of the high molecular weight insulin-like growth factor-binding protein complex in normal subjects. J Clin Endocrinol Metab. 70:1347–1353.[Abstract]
  30. Veldhuis JD, Johnson ML. 1992 Deconvolution analysis of pulsatile hormone data. Methods Enzymol. 210:539–575.[Medline]
  31. Pincus SM. 1991 Approximate entropy as a measure of system complexity. Proc Natl Acad Sci USA. 88:2297–2301.[Abstract/Free Full Text]
  32. Pincus SM, Gladstone IM, Ehrenkranz RA. 1991 A regularity statistic for medical data analysis. J Clin Monit. 7:335–345.[CrossRef][Medline]
  33. Pincus SM, Gevers EF, Robinson ICAF, et al. 1996 Females secrete growth hormone with more process irregularity than males in both humans and rats. Am J Physiol. 270:E107–E115.
  34. Veldhuis JD, Iranmanesh A, Johnson ML, Lizarralde G. 1990 Twenty-four-hour rhythms in plasma concentrations of adenohypophyseal hormones are generated by distinct amplitude and/or frequency modulation of underlying pituitary secretory bursts. J Clin Endocrinol Metab. 71:1616–1623.[Abstract]
  35. Sarapura VD, Samuels MH, Ridgway CE. 1995 Thyroid stimulating hormone. In: Melmed S, ed. The pituitary. Cambridge, MA: Blackwell Science; 187–229.
  36. Veldhuis JD, Iranmanesh A, Wilkowski MJ, Samojlik E. 1994 Neuroendocrine alterations in the somatotropic and lactotropic axes in uremic men. Eur J Endocrinol. 131:489–498.[Abstract]
  37. Hartman ML, Pincus SM, Johnson ML, et al. 1994 Enhanced basal and disorderly growth hormone secretion distinguish acromegaly from normal pulsatile growth hormone release. J Clin Invest. 94:1277–1288.
  38. Bacci V, Schussler GC, Kaplan TC. 1982 The relationship between serum triiodothyronine and thyrotropin during systemic illness. J Clin Endocrinol Metab. 54:1229–1235.[Abstract]
  39. Beck-Peccoz P, Persani L. 1994 Variable biological activity of thyroid stimulating hormone. Eur J Endocrinol. 131:331–340.[Abstract]
  40. Van den Berghe G, de Zegher F, Lauwers P. 1994 Dopamine and the sick euthyroid syndrome in critical illness. Clin Endocrinol (Oxf). 41:731–737.[Medline]
  41. Samuels MH, Henry P, Ridgeway EC. 1992 Effects of dopamine and somatostatin on pulsatile pituitary glycoprotein secretion. J Clin Endocrinol Metab. 74:217–222.[Abstract]
  42. Samuels MH, Luther M, Henry P, Ridgeway EC. 1994 Effects of hydrocortisone on pulsatile pituitary glycoprotein secretion. J Clin Endocrinol Metab. 78:211–215.[Abstract]
  43. Kraiem Z, Bowers CY, Sobel E, Laron Z. 1995 Growth hormone (GH)-releasing heptapeptide, but not GH-releasing hormone, inhibits thyrotropin-stimulated thyroid hormone secretion and cAMP formation in cultured human thyroid follicles. Eur J Endocrinol. 133:117–120.[Abstract]
  44. Jorgensen JO, Pedersen SA, Laurberg P, Weeke J, Skakkebaek NE, Christiansen JS. 1989 Effects of growth hormone therapy on thyroid function of growth hormone deficient adults with and without thyroxine substituted central hypothyroidism. J Clin Endocrinol Metab. 69:1127–1132.[Abstract]
  45. Perrone MH, Hinkle PM. 1977 Regulation of pituitary receptors for thyrotropin-releasing hormone by thyroid hormones. J Biol Chem. 253:5168–5173.[Free Full Text]
  46. Hartman ML, Clayton PE, Johnson ML, et al. 1993 A low dose euglycemic infusion of recombinant human insulin-like growth factor I rapidly suppresses fasting-enhanced pulsatile growth hormone secretion in humans. J Clin Invest. 91:2453–2462.
  47. Baxter RC. 1994 Insulin-like growth factor binding proteins in the human circulation: a review. Horm Res. 42:140–144.[Medline]
  48. Thalange NKS, Price DA, Gill MS, Whatmore AJ, Addison GM, Clayton PE. 1996 Insulin-like growth factor binding protein-3 generation: an index of growth hormone sensitivity. Pediatr Res. 39:849–855.[Medline]
  49. Thissen JP, Ketelslegers J-M, Underwood LE. 1994 Nutritional regulation of insulin-like growth factors. Endocr Rev. 15:80–101.[Abstract]
  50. Jorgensen JOL, Blum WF, Moller N, Ranke MB, Christiansen JS. 1991 Short-term changes in serum insulin-like growth factors (IGF) and IGF binding protein 3 after different modes of intravenous growth hormone (GH) exposure to GH-deficient patients.
  51. Baxter RC. 1997 Acquired growth hormone insensitivity and insulin-like growth factor I bioavailability. Endocrinol Metab. 4[Suppl B]):65–69.
  52. Bentham J, Rodriguez-Arnao J, Ross RJ. 1993 Acquired growth hormone resistance in patients with hypercatabolism. Horm Res. 40:87–91.[Medline]



This article has been cited by other articles:


Home page
 EndocrinologyHome page
Y. Debaveye, B. Ellger, L. Mebis, T. J. Visser, V. M. Darras, and G. Van den Berghe
Effects of Substitution and High-Dose Thyroid Hormone Therapy on Deiodination, Sulfoconjugation, and Tissue Thyroid Hormone Levels in Prolonged Critically Ill Rabbits
Endocrinology, August 1, 2008; 149(8): 4218 - 4228.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
M. Granado, A. I. Martin, M. Lopez-Menduina, A. Lopez-Calderon, and M. A. Villanua
GH-releasing peptide-2 administration prevents liver inflammatory response in endotoxemia
Am J Physiol Endocrinol Metab, January 1, 2008; 294(1): E131 - E141.
[Abstract] [Full Text] [PDF]

Home page
 Eur J EndocrinolHome page
J. Svensson, G. Johannsson, A. Iranmanesh, K. Albertsson-Wikland, J. D Veldhuis, and B.-A. Bengtsson
GH secretory pattern in young adults who discontinued GH treatment for GH deficiency and decreased longitudinal growth in childhood.
Eur. J. Endocrinol., July 1, 2006; 155(1): 91 - 99.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
Y. Debaveye, B. Ellger, L. Mebis, E. Van Herck, W. Coopmans, V. Darras, and G. Van den Berghe
Tissue Deiodinase Activity during Prolonged Critical Illness: Effects of Exogenous Thyrotropin-Releasing Hormone and Its Combination with Growth Hormone-Releasing Peptide-2
Endocrinology, December 1, 2005; 146(12): 5604 - 5611.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
G. Marchesini, G. Bianchi, P. Lucidi, N. Villanova, M. Zoli, and P. De Feo
Plasma Ghrelin Concentrations, Food Intake, and Anorexia in Liver Failure
J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2136 - 2141.
[Abstract] [Full Text] [PDF]

Home page
 J Intensive Care MedHome page
E. S. Nylen and B. Muller
Endocrine Changes in Critical Illness
J Intensive Care Med, March 1, 2004; 19(2): 67 - 82.
[Abstract] [PDF]

Home page
 FASEB J.Home page
A. INUI, A. ASAKAWA, C. Y. BOWERS, G. MANTOVANI, A. LAVIANO, M. M. MEGUID, and M. FUJIMIYA
Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ
FASEB J, March 1, 2004; 18(3): 439 - 456.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
S. K. Andersen, J. Gjedsted, C. Christiansen, and E. Tonnesen
The roles of insulin and hyperglycemia in sepsis pathogenesis
J. Leukoc. Biol., March 1, 2004; 75(3): 413 - 421.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
F. Weekers, M. Michalaki, W. Coopmans, E. Van Herck, J. D. Veldhuis, V. M. Darras, and G. Van den Berghe
Endocrine and Metabolic Effects of Growth Hormone (GH) Compared with GH-Releasing Peptide, Thyrotropin-Releas