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The Effects of Dose, Nutrition, and Age on Hexarelin-Induced Anterior Pituitary Hormone Secretion in Adult Patients on Maintenance Hemodialysis¹

Department of Medicine, University of Sheffield, Clinical Sciences Center (R.C.J., R.J.M.R.), and Sheffield Kidney Institute (A.M.E.N., M.E.W., C.B.B.), Northern General Hospital, Sheffield, United Kingdom S5 7AU; the Department of Medicine, King’s College School of Medicine and Dentistry (J.J.), Denmark Hill, London, United Kingdom SE 9PJ; and the Division of Endocrinology, Department of Internal Medicine, University of Turin, Ospedale Molinette (E.G.), 10126 Torino, Italy

Address all correspondence and requests for reprints to: Dr. R. J. M. Ross, Department of Medicine, University of Sheffield, Clinical Sciences Center, Northern General Hospital, Herries Road, Sheffield, United Kingdom S5 7AU. E-mail: r.j.ross{at}sheffield.ac.uk

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Malnutrition is common in chronic renal failure (CRF) and adversely affects prognosis. In view of the anabolic action of GH in CRF, we have studied the effects of hexarelin, a GH secretagogue, on CRF. An iv dose-response study in six 20- to 40-yr-old well nourished hemodialysis (HD) patients was followed by administration of the maximally effective dose to six 20- to 40-yr-old healthy controls, six 20- to 40-yr-old poorly nourished HD patients, and six 50- to 70-yr-old poorly nourished HD patients.

GH secretion (area under the curve over 180 min, mean ± SE) after 2 and 1 µg/kg doses (10.7 ± 4.2 and 8.2 ± 5.2 min/U·L, respectively) was greater than after placebo (0.60 ± 0.11 min/U·L; P < 0.001 and P < 0.05, respectively). The most effective dose (2 µg/kg) produced similar GH secretion (11.4 ± 3.3 min/U·L) in controls. GH secretion in the younger poorly nourished HD group (19.0 ± 4.4 min/U·L) was not significantly different from that in the well nourished 20- to 40-yr-old HD patients (P = 0.06). GH secretion in the older, poorly nourished HD patients (9.4 ± 2.2 min/U·L) was similar to that in the young, poorly nourished group (P = 0.18). ACTH and cortisol concentrations increased in all groups, whereas PRL concentrations were not affected in CRF.

The profound action of hexarelin on GH secretion has been shown to extend to CRF. Trends were evident toward increasing efficacy in malnourished subjects and decreasing efficacy with age. Further studies are required to determine whether the acute actions of hexarelin can be translated into long term anabolic changes.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Protein-calorie malnutrition is common in patients with end-stage renal failure and is a major factor predicting long term outcome (1). In chronic renal failure (CRF), there are complex changes at all levels of the GH/insulin-like growth factor I (GH/IGF-I) axis, resulting in a GH-resistant state. GH secretion is increased in CRF (2), and patients have abnormal GH dynamics (3) with an increased GH response to GHRH (4). Despite raised GH levels, patients with CRF have decreased IGF secretion rates (5), and IGF-I is a marker of nutritional state in hemodialysis (HD) (6). GH treatment in CRF promotes growth in children and has beneficial metabolic effects in adults (7). The demonstration that exogenous GH has an anabolic action in patients with CRF suggests that agents that increase endogenous GH secretion may also be of benefit.

Hexarelin is a member of a new class of potent GH secretagogues (GHS) that act through their own specific receptor, independent from GHRH and somatostatin, at the hypothalamus and pituitary (8). Hexarelin is active in humans when given iv, sc, or orally (9). The availability of an oral GH secretagogue could be a major advance in the treatment of conditions where chronic GH administration is required, such as in renal failure. The effects of hexarelin are dose related in healthy subjects (9, 10), but are not specific for GH secretion. Slight, but significant, stimulatory effects on PRL, ACTH, and cortisol secretion have been demonstrated (9, 10, 11, 12). The stimulatory effect of hexarelin on GH secretion decreases in middle age, but persists in the elderly (13). Prolonged intermittent treatment with hexarelin has been shown to increase IGF-I and IGF-binding protein-3 (IGFBP-3) levels in short children and in normal elderly subjects (14, 15). Critically ill patients have preserved GH responses to single iv doses (16, 17) or prolonged iv infusion of GHS (18), and GHS have also been shown to reverse diet-induced catabolism over a 2-week period (19).

As high serum GH levels may reduce the efficacy of GHS (20) and in view of the known perturbations of the GH/IGF-I axis in CRF (21, 22), studies of the effects of hexarelin in health cannot be extrapolated to CRF. This study has examined the GH, ACTH, and PRL dose responses to iv hexarelin in adult patients treated with maintenance HD. The effects of renal failure, nutrition, and age on the response to the maximally effective dose was determined using appropriate control groups.

	Subjects and Methods

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Subjects (Table 1)

The study was approved by the ethics committee of the Northern General Hospital (Sheffield, UK), and informed written consent was obtained from each subject before participation in the study. Four groups of six Caucasian subjects were studied: 20- to 40-yr-old well nourished HD patients; 20- to 40-yr-old healthy controls with normal renal function who were age, sex, and nutritionally matched to the preceding group; 20- to 40-yr-old poorly nourished HD patients; and 50- to 70-yr-old poorly nourished HD patients. Patients with diabetes mellitus, active malignancy, active hepatitis, active vasculitis, or systemic bacterial infection were excluded. Hospitalization within the preceding month, participation in other clinical trials, use of anabolic or catabolic hormones including high dose glucocorticoid therapy, a positive pregnancy test, or treatment with intradialytic parenteral nutrition also excluded patients.

All subjects had their nutritional status assessed within a 3-month period before inclusion in the study. This consisted of measurement of triceps skinfold thickness (TSF), midarm circumference, height, and weight by a dietician. Midarm muscle circumference (MAMC) was calculated from the following formula: MAMC (cm) = MAC (cm) - TSF (mm) x /10. Subjects were also assessed using a subjective nutritional scale, Subjective Global Assessment (23). Measurements were converted to age and sex percentile ranges using standard tables (24). Each subject was assessed by the following criteria: TSF less than the 25th percentile, MAMC less than the 25th percentile, and Subjective Global Assessment score B (mild to moderately malnourished) or C (severely malnourished). Subjects were classified as well nourished if none of these criteria was satisfied or as malnourished if two or more criteria were satisfied.

Hexarelin tests

The young, well nourished HD patients received three iv injections of hexarelin at doses of 1 µg/kg hexarelin, 2 µg/kg hexarelin, and placebo. Hexarelin tests were separated by at least 7 days, and the order of dosing was determined by a Latin square design to minimize the possibility of an order effect. The other study groups had one hexarelin test with a dose of 2 µg/kg. The tests were performed in the morning after the patient had fasted. An iv cannula was inserted into a forearm vein, and an iv injection of hexarelin was given, followed by a flush of 0.9% saline at time zero. Blood samples were taken at -15, 0, 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 165, and 180 min. After each sampling a flush of 1 mL 0.9% saline was used to maintain cannula patency. Samples were taken into siliconized glass tubes with ethylenediamine tetraacetate and immediately centrifuged at 3000 rpm for 5 min at 4 C. Plasma was separated, frozen with dry ice, and stored at -20 C before assay. At all time points, GH, PRL, ACTH, and cortisol were assayed. At time zero, IGF-I, IGFBP-1, and IGFBP-3 were also assayed.

Assays

GH was measured by a solid phase immunoradiometric assay [IRMA; NETRIA; sensitivity, 0.2 mU/L; intraassay coefficient of variation (CV), 2.4% at 4.5 mU/L; interassay CV, 3.3% at 7.7 mU/L]. PRL was measured by a solid phase IRMA (NETRIA; sensitivity, 10 mU/L; intraassay CV, 1.4% at 562 mU/L; interassay CV, 5.1% at 506 mU/L). ACTH was measured by RIA (Diagnostic Systems Laboratories, Inc., Webster, TX; sensitivity, 3.5 pg/mL; intraassay CV, 5.9% at 324 pg/mL; interassay CV, 4.0% at 328 pg/mL). Cortisol was measured by solid phase RIA (Diagnostic Products, Los Angeles, CA; sensitivity, 6 nmol/L; intraassay CV, 3.0% at 551 nmol/L; interassay CV, 4.0% at 579 nmol/L). IGF-I was assayed by RIA after acid-ethanol extraction (sensitivity, 13 ng/mL; intraassay CV, 6.5% at 243 ng/mL; interassay CV, 10.1% at 196 ng/mL). IGFBP-I was assayed by IRMA (Diagnostic Systems Laboratories, Inc.; sensitivity, 0.33 ng/mL; intraassay CV, 4.6% at 50.2 ng/mL; interassay CV, 6.0% at 47 ng/mL). IGFBP-3 was assayed by IRMA (Diagnostic Systems Laboratories, Inc.; sensitivity, 0.5 mg/L; intraassay CV, 4.1% at 2.2 mg/L; interassay CV, 4.6% at 3.5 mg/L).

Statistics

Area under the curve (AUC) calculations were made using the trapezoidal method. GH AUC were log transformed before statistical tests. One-sided ANOVA tests with a Bonferroni adjustment for multiple analyses were performed to determine whether there were statistically significant differences between the groups. Paired t tests were used to quantify the P values of comparisons deemed significant. Comparison of indexes of nutritional status between groups was performed using the Mann-Whitney U test. Significance was accepted if P < 0.05. Calculations were made using SPSS software (SPSS, Inc., Evanston, IL).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Results are given as the mean and SE. P values are given where appropriate.

Nutritional status and basal hormone concentrations (Table 1)

Table 1 summarizes the nutritional assessment of subjects. The well nourished groups had similar TSF, MAMC, and body mass index (BMI) values. The poorly nourished groups had similar TSF and BMI values; the older poorly nourished group had significantly lower MAMC than the younger poorly nourished group (P < 0.05). Within the 20- to 40-yr-old HD groups, the well nourished group had significantly higher TSF thickness (P < 0.01) and BMI (P < 0.05) than the poorly nourished group. Mean fasting IGFBP-1 and IGFBP-3 were significantly higher and the IGF-I/IGFBP-1 ratio was significantly lower in the well nourished HD patients than in healthy controls. No significant differences in IGF-I, IGFBP-1, IGFBP-3, or IGF-I/IGFBP-1 ratio were seen among the renal failure groups.

GH secretion after hexarelin

Effect of dose in well nourished 20- to 40-yr-old HD patients (Fig. 1). In well nourished, young HD patients, the 1 and 2 µg/kg hexarelin doses augmented peak GH levels (P = 0.01 and P < 0.05, respectively) and the AUC between 0–180 min (AUC_0–180) for GH (P = 0.02 and P < 0.001) compared with values in the placebo group. The responses to the 1 and 2 µg/kg doses were not significantly different (peak, P = 0.12; AUC, P = 0.09).

View larger version (22K): [in this window] [in a new window]   Figure 1. GH concentration after iv hexarelin (placebo, 1 and 2 µg/kg) in well nourished 20- to 40-yr-old HD patients.

Effect of CRF (Fig. 2).

View larger version (29K): [in this window] [in a new window]   Figure 2. GH concentration after iv hexarelin (2 µg/kg) in HD patients and healthy controls.

Effect of nutritional status and age (Fig. 2).

Peak GH and AUC_0–180 GH were nonsignificantly (P = 0.17 and P = 0.18, respectively) lower in older, poorly nourished HD patients than in young, poorly nourished HD patients (Table 2). There was a trend toward higher GH secretion in young, poorly nourished HD patients than in the healthy controls (AUC_0–180 19.0 ± 3.3 vs. 11.4 ± 4.4 min/U·L; P = 0.06).

ACTH, cortisol, and PRL secretion after hexarelin (Table 3 and Figs. 3–5)

ACTH levels were nonsignificantly higher at baseline in HD patients than in normal controls. After hexarelin, ACTH rose in all groups, other than the placebo group in which it fell, to peak at 15 min before returning to baseline by 30 min. ACTH AUC_0–30 was significantly higher in patients after the 2 µg/kg dose than after the placebo (P < 0.05). There were no significant differences in peak ACTH or AUC_0–30 ACTH between the groups. The AUC_0–30 of the percent change in ACTH from baseline was significantly greater in healthy controls than in well nourished HD patients (3715 ± 195 vs. 3180 ± 172; P < 0.05).

View larger version (23K): [in this window] [in a new window]   Figure 3. ACTH (percent change from baseline concentration) after iv hexarelin (placebo, 1 and 2 µg/kg) in well nourished 20- to 40-yr-old HD patients.

View larger version (21K): [in this window] [in a new window]   Figure 4. Cortisol concentration (percent change from the baseline concentration) after iv hexarelin (placebo, 1 and 2 µg/kg) in well nourished 20- to 40-yr-old HD patients.

View larger version (30K): [in this window] [in a new window]   Figure 5. PRL concentration after iv hexarelin (2 µg/kg) in HD patients and in healthy controls.

After hexarelin, the PRL concentration rose significantly (P < 0.05) in normal controls to peak at 15 min before returning to baseline over 90 min. In contrast, PRL levels in HD patients were raised at baseline and then did not significantly change after hexarelin treatment. The PRL AUC_0–90 was similar in all groups, although there was wide interindividual variation.

Predictors of response to hexarelin

Analysis of the patients with renal failure found that the GH response to hexarelin (AUC, AUC log GH, or peak concentration) could not be predicted from age, height, weight, BMI, MAMC, TSF, IGF-I, IGFBP-1, IGFBP-3, or IGF-I/IGFBP-1 ratio. Stratification of the patients into those with a low or high IGF-I/IGFBP-1 ratio produced two groups with indistinguishable GH responses to hexarelin.

Side-effects

Side-effects were minor and lasted less than 5 min. Flushing affected one of six HD patients after placebo, four of six after 1 µg/kg, three of six after 2 µg/kg, and two of six normal subjects after 2 µg/kg. Nausea was reported by one HD patient after the 1 µg/kg dose and by one normal control. Hunger was reported by one normal control.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We have found that hexarelin produces significant GH secretion in well nourished, young adult patients receiving maintenance HD. The greatest GH secretion followed a 2 µg/kg dose, but the overall response was statistically similar to the response to 1 µg/kg dose. Well nourished HD patients and age-, sex-, and nutritionally matched healthy controls produced indistinguishable GH responses to 2 µg/kg hexarelin, indicating that the efficacy of hexarelin on GH secretion is normal in HD-treated renal failure patients. A trend toward increased GH secretion after hexarelin was seen in malnourished young HD patients, but this trend was not maintained in an older malnourished group. Most GH secretagogues are less potent in elderly subjects, as has previously been shown for hexarelin in healthy volunteers (13), and our data suggest that this general principle may extend to malnourished elderly HD patients. We were unable to predict the GH response to hexarelin from the baseline characteristics of the renal failure subjects.

The potential anabolic benefits of hexarelin-stimulated GH secretion could be offset if accompanied by significant elevations of ACTH and cortisol as has been found to occur in other patient groups. We found that hexarelin administration led to a short, rapid pulse of ACTH secretion in HD patients and controls, which was followed by a slightly delayed increase in cortisol levels. The proportional rise in cortisol was markedly less than that seen in GH, and it is possible that lower hexarelin doses could produce useful elevations in GH levels without having marked effects on cortisol levels; this is supported by a recent study in elderly subjects (25), which did not find increased cortisol production after long term recurrent hexarelin administration. We found raised fasting ACTH concentrations and similar cortisol levels in CRF patients compared to healthy controls as has been recognized for some time (26). This raises the question of whether there is resistance to ACTH action in renal failure, although adrenal responsiveness to Synacthen testing has been reported to be normal (27).

The PRL-releasing action of hexarelin in normal controls has been reported previously (9), but although basal PRL levels were higher in HD patients, no further rise was produced by hexarelin. This is similar to the finding in patients with hyperprolactinemia (12) and raises the possibility that preceding hyperprolactinemia abolishes the PRL-stimulating effect of hexarelin.

CRF is associated with abnormally high concentrations of IGFBPs that may modulate the level and function of free IGF-I (28). Recently, the ratio of IGF-I/IGFBP-1 has been shown to be a predictor of the anabolic response to GH in malnourished HD patients (29) with low ratios being associated with reduced anabolism. It is of note that in this study, the IGF-I/IGFBP-1 ratios were lower in CRF patients than in healthy controls, with the lowest values being seen in the poorly nourished groups (Table 1). Hexarelin efficacy was not affected by the IGF-I/IGFBP-1 ratio.

A recent, well designed, controlled clinical trial of a 4-week course of recombinant human GH in end-stage renal failure demonstrated a significant action of GH to increase the serum IGF-I concentration and to improve other markers of nutritional status in adults (30), which is consistent with the known anabolic actions of GH in childhood renal failure (31, 32). The patients studied were of an age comparable to that of our 50- to 70-yr-old group and had similar MAMC but much higher TSF thickness than our poorly nourished patients. Taking these results together with our findings in a similarly aged group suggests that if the efficacy of GHS is maintained with chronic treatment, then this is likely to produce a potentially beneficial metabolic effect. Few studies have examined whether the acute actions of GHS are maintained with longer term treatment, but it appears that this is the case during a 21-h GHS infusion that led to a rise in GH concentration and consequently in the serum IGF-I level even in critically ill patients, who, in common with patients with renal failure, will have resistance to the action of GH (18). A 16-week duration study of hexarelin in healthy elderly subjects (median age, 68 yr) found that the action of hexarelin persisted, but was partially attenuated during chronic treatment (33); no change was seen in the IGF-I concentration, but there was some evidence for increased bone formation. Our preliminary results of GHS efficacy in renal failure pave the way for further studies that will need to establish the safety and efficacy, in clinical as well as metabolic terms, of repeated, prolonged GHS treatment.

In conclusion, we have found that the GH-secreting action of hexarelin is unaffected by renal failure, although there are trends toward increased efficacy in malnourished subjects and decreased efficacy in older patients. ACTH and cortisol secretion are also stimulated to a similar degree in CRF patients and normal subjects, although the former group do not have increased PRL secretion after hexarelin treatment. These results demonstrate the acute efficacy of GH secretagogues in CRF and indicate the need for further work to determine whether long term treatment will produce anabolic effects.

	Acknowledgments

 
We are grateful to Val Jacobs for help in patient assessments, to Vicky Ibbotson, and to Pharmacia & Upjohn, Inc. for supplies of hexarelin.

	Footnotes

 
¹ This work was supported by Pharmacia & Upjohn, Inc., the University of Sheffield, and the Northern General Hospital NHS Trust.

Received October 1, 1998.

Revised January 13, 1998.

Accepted January 19, 1998.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Jenkins, R. C. Articles by Ross, R. J. M. Search for Related Content PubMed PubMed Citation Articles by Jenkins, R. C. Articles by Ross, R. J. M.