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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 5 1644-1649
Copyright © 1998 by The Endocrine Society

Original Studies

Growth Hormone Status during Long-Term Hexarelin Therapy

A. Rahim, P. A. O’Neill and S. M. Shalet

Department of Endocrinology (A.R., S.M.S.), Christie Hospital, Withington, Manchester, M20 4BX; and University Department of Geriatric Medicine (P.A.O.), South Manchester University Hospital Trust, Manchester, M20 8LR, United Kingdom

Address all correspondence and requests for reprints to: Professor S. M. Shalet, Department of Endocrinology, Christie Hospital National Health Service Trust, Wilmslow Road, Manchester M20 4BX, United Kingdom.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Hexarelin, a powerful GH-releasing peptide, is capable of causing profound GH release in normal subjects after oral, intranasal, iv, and sc administration. The effect of long-term administration on GH levels in adults is unknown. We have, therefore, assessed the effects of 16 weeks of twice-daily sc hexarelin therapy (1.5 µg/kg BW) on the GH response to a single injection of hexarelin, and also the GH response to hexarelin 4 weeks after cessation of hexarelin therapy. We have also assessed the effects of chronic hexarelin therapy on serum insulin-like growth factor (IGF)-I, IGF binding protein-3, markers of bone formation (osteocalcin, procollagen-type-III-N-terminal-peptide, and C-terminal propeptide of type I collagen), and resorption (urinary deoxypyridinoline and pyridinoline), body composition, and bone mineral density.

The mean (±SEM) area under the GH curve (AUCGH) at weeks 0, 1, 4, 16, and 20 were 19.1 ± 2.4 µg/L·h, 13.1 ± 2.3 µg/L·h, 12.3 ± 2.4 µg/L·h, 10.5 ± 1.8 µg/L·h, and 19.4 ± 3.7 µg/L·h, respectively. There was a significant change in AUCGH over the study period (P = 0.0003). Further analysis showed that, compared with baseline, the decrease in AUCGH at week 4 and week 16 were significant (P < 0.05 and P < 0.01, respectively). Four weeks after completion of hexarelin therapy, the AUCGH increased significantly, compared with AUCGH at week 16 (P < 0.05), and was not significantly different from that at week 0.

Serum IGF-I and IGF binding protein-3 did not change significantly over the 20-week period (P = 0.24 and P = 0.74, respectively). Of the bone markers measured, only serum C-terminal propeptide of type I collagen changed significantly and was higher at week 16, compared with baseline (P = 0.019). Total body fat, lean body mass, and bone mineral density had not changed significantly at week 16, compared with baseline (P = 0.6, P = 0.3, and P = 0.3, respectively).

In summary, we have demonstrated that chronic hexarelin therapy results in a partial and reversible attenuation of the GH response to hexarelin. In the present study, the biological impact of this hexarelin schedule on the GH-IGF-I axis seems to be minimal. The therapeutic potential of chronic hexarelin requires further investigation.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
HEXARELIN, a powerful GH-releasing peptide (GHRP), is capable of causing profound GH release in normal subjects after oral, intranasal, iv, and sc administration (1). The availability of an orally active compound and the added potential attraction of being able to cause pulsatile GH release may make hexarelin a useful therapeutic GH secretagogue.

To date, the longest study of the effects of hexarelin on GH release in adults has been for 15 days (2). Ghigo et al. (2) administered either oral or intranasal hexarelin to normal elderly subjects and demonstrated no significant decrease in hexarelin-stimulated GH release after either 15 days of oral or 8 days of intranasal administration. Ghigo et al. (2) were also able to demonstrate a small, but significant, rise in serum insulin-like growth factor (IGF)-I and IGF binding protein (IGFBP)-3 levels in those treated with the oral preparation. After intranasal hexarelin, however, no significant change was seen in serum IGF-I, although serum IGFBP-3 did increase.

In animals, hexarelin has been administered for longer periods. In six old beagle dogs, Cella and colleagues (3) demonstrated a decrease in hexarelin-stimulated GH release during twice-daily sc hexarelin therapy given for periods of 7 weeks, 4 weeks, and 1 week, with no change in serum IGF-I. If the GH response to hexarelin in humans becomes appreciably attenuated after long-term administration, then this will seriously limit the potential therapeutic use of hexarelin and similar agents. There are no data available on the GH releasing capacity of hexarelin after long-term administration or on the effect of hexarelin-stimulated GH release on serum IGF-I and IGFBP-3 levels in normal adult subjects. Furthermore, there are few data on the GH response to hexarelin after a period off treatment. We have, therefore, assessed the effect of 16 weeks of twice-daily sc hexarelin therapy on the GH response to a single injection of hexarelin and also the GH response 4 weeks after cessation of hexarelin therapy. We also have assessed the effect of hexarelin-stimulated GH release on serum IGF-I, IGFBP-3, markers of bone formation [osteocalcin, procollagen-type-III-N-terminal-peptide (PIIINP), and C-terminal propeptide of type I collagen (CICP)], and resorption (urinary deoxypyridinoline and pyridinoline), body composition, and bone mineral density (BMD).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Twelve (four female) healthy elderly subjects, with a median age of 68 (range, 66–81) yr and median BMI of 26 (range, 19.6–30.1) kg/m2 at the time of recruitment, were entered into the study. Three subjects were on regular medication, none of which interfered with GH release. All were nonsmokers and had no significant medical problems, as determined by medical history, physical examination, and screening laboratory analyses.

The study was approved by the South Manchester Medical Research Ethics Committee, and written informed consent was obtained from each subject. Each subject underwent a screening visit, at which inclusion and exclusion criteria were checked. At the prestudy screening visit, a test dose of hexarelin was given, and only those subjects with a peak response greater than 6 µg/L were entered into the study. A peak GH response of at least 6 µg/L was considered mandatory, because it was believed that any potential reduction in GH response could only be demonstrated in those with a definite GH response to hexarelin initially.

The procedure at the prestudy screen visit was as follows; at 0730–0800 h, after an overnight fast, an iv cannula was inserted into a vein in the antecubital fossa. Blood samples were taken for serum IGF-I and IGFBP-3 estimations. A stimulation test, using sc hexarelin at a dose of 1.5 µg/kg BW, was carried out, with blood samples being taken at -10, 0, 10, 20, 30, 40, 50, 60, 90, 120, 170, and 180 min. Hexarelin was administered at 0 min. Only water was allowed during the sampling period. Serum was separated from each sample and stored at -70 C and later analyzed for GH concentration. Subjects entered into the study then, attended on five further occasions (as shown in Fig. 1Go). The procedure at each visit was identical to that at the prescreen study visit. At the baseline and week 16 visits, serum was also collected for osteocalcin, PIIINP, and CICP estimations. Urine was collected at baseline and at week 16 for urinary deoxypyridinoline and pyridinoline estimations. Body composition and BMD measurements were performed no more than 7 days before the baseline visit and within 7 days of the week 16 visit.



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  		Figure 1. Study design.

 
After the baseline study visit, each subject was given twice-daily sc injections of hexarelin at a dose of 1.5 µg/kg BW, for a total of 16 weeks. Compliance was 100%, with injections being given by nurses who visited the subjects twice daily at their homes. The dose of hexarelin was adjusted according to weight at each study visit.

Hexarelin

Hexarelin (His/D-2-Methyl-Trp/Ala/Trp/D-Phe/Lys-NH2) (Pharmacia and Upjohn, Stockholm, Sweden) was given twice daily at a dose of 1.5 µg/kg BW. Hexarelin was supplied in a vial, as a sterile lyophilized powder, for sc injection. Each vial contained 100 µg hexarelin and 20 mg mannitol. Each vial was reconstituted in 1 mL physiological sodium chloride solution. The study product was reconstituted immediately before administration, and the unconstituted vials were stored between 2–8 C at all times. The composition per milliliter, after reconstitution, was 100 µg hexarelin, 20 mg mannitol, and 9 mg sodium chloride.

Assays

Human GH (hGH) was assayed using a DELFIA-hGH assay commercial kit (Wallac Oy, Turku, Finland). The assay is a solid-phase (micro-titerplate), two-site fluouroimmunometric assay based on the direct sandwich technique, in which two monoclonal antibodies are directed against two separate antigenic determinants on the hGH molecule.

The minimum detectable concentration was 0.01 µg/L. At 22.6 µg/L and 0.36 µg/L, the intraassay coefficients of variation (CVs) were 1% and 1.6%, and interassay CVs were 2.9% and 1.6%, respectively. The assay has negligible cross-reactivity against human PRL, TSH, FSH, LH (<0.1%), and 20-kDa GH (<0.001%). In the present study, 1 µg/L is equivalent to 3 mU/L.

PIIINP. Serum PIIINP was assayed using a commercial RIA kit (Orion Diagnostica, Sin, Finland). The sensitivity of the assay is 0.2 µg/L. At concentrations of 2.6, 5.1, and 27.4 µg/L, the intraassay CVs are 4.3, 2.5, and 3.7%, respectively. At concentrations of 2.5, 4.7, and 26.8 µg/L, the interassay CVs are 4.0, 3.2, and 5.3%.

CICP. Serum CICP was assayed using a nonisotopic sandwich immunoassay commercial kit (Metra Biosystems, Mountain View, CA). At concentrations of 80.8, 98.1, and 296.7 ng/mL, the intraassay CVs are 6.8, 5.5, and 6.6%, respectively, and the interassay CVs are 7.0, 7.2, and 5.0%.

Osteocalcin. Serum osteocalcin was measured using a two-site immunoradiometric assay (DSL, Webster, TX). All the samples were assayed in a single batch. The sensitivity of this assay was 0.27 ng/mL. The intraassay variability was 4.6%, 2.9%, and 1.4% at 2.88 ng/mL, 9.84 ng/mL, and 28.2 ng/mL, respectively.

Urinary deoxypyridinoline and pyridinoline. An isocratic ion-pairing reverse-phase high-performance liquid chromatography method was used. The intraassay and interassay precisions were 5–7% and 12–14%, respectively (4).

IGF-I. Serum IGF-I concentration was measured by Pharmacia and Upjohn using an in-house RIA. The minimum detectable concentration was 20 µg/L. Because IGFBPs interfere with the assay, all serum samples were treated with acid-ethanol and a truncated IGF-I analogue before assay, to precipitate and reduce IGFBPs. At an IGF-I concentration of 202 µg/L, the intraassay and interassay CVs were 3.1 and 10.0%, respectively. Cross-reactivity of the assay with IGF-II is 1%, and for insulin and proinsulin, it is negligible (0.01%).

IGFBP-3. Serum IGFBP-3 was measured using a modified commercial kit (Diagnostic Systems Laboratories, Webster, TX). At 4.32 µg/L, the intraassay and interassay CVs were 4.9% and 7.2%, respectively. The assay has negligible cross-reactivity (<0.3%) against IGFBP-1, BP-2, and BP-4.

Body composition and BMD. Body composition and BMD were determined using dual-energy x-ray absorptiometry. All the scans were performed using the Hologic QDR-4500A scanner (Hologic Inc, Waltham, MA). The scanner employs a fan beam dual-x-ray absorptiometry method. The CVs for the determination of fat mass and fat-free mass and BMD all were 1.0%.

Statistical analysis

The average of the baseline and prestudy screen visits was used for statistical analysis of peak GH response and area under the GH curve (AUCGH). This new baseline will be referred to as week 0.

Statistical analyses were performed using parametric tests. ANOVA with repeated measures was used to analyze peak GH response, AUCGH, serum IGF-I, and serum IGFBP-3, over the study period. If a significant difference had occurred over the study period, then Tukey test was performed to determine between which time points significant changes had occurred. Paired t tests were used to analyze the remaining data. P < 0.05 was considered statistically significant. Results are presented as the mean and SEM.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The mean (±SEM) AUCGH, at weeks 0, 1, 4, 16, and 20, were 19.1 ± 2.4 µg/L·h, 13.1 ± 2.3 µg/L·h, 12.3 ± 2.4 µg/L·h, 10.5 ± 1.8 µg/L·h, and 19.4 ± 3.7 µg/L·h, respectively (Fig. 2Go). There was a significant change (P = 0.0003) in AUCGH, over the study period. Further analysis showed that, compared with baseline, the decreases in AUCGH at weeks 4 and 16 were significant (P < 0.05 and P < 0.01, respectively). Four weeks after completion of hexarelin therapy, the AUCGH increased significantly, compared with AUCGH at week 16 (P < 0.05) and was not significantly different from that at week 0.



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  		Figure 2. Changes in AUCGH (above) and peak GH response (below), in response to a single sc injection of hexarelin, over the study period (mean shown).

 
The mean (±SEM) peak GH responses at weeks 0, 1, 4, 16, and 20 were 15.9 ± 2.0 µg/L, 12.8 ± 2.1 µg/L, 11 ± 2.0 µg/L, 10.1 ± 1.8 µg/L, and 15.3 ± 2.9 µg/L, respectively (Fig. 2Go). There was a significant change in peak GH response over the study period (P = 0.006). Further analysis showed that, compared with baseline, the decrease in peak GH response was significant (P < 0.05) only at week 16. Four weeks after completion of hexarelin therapy, peak GH response increased significantly, compared with peak GH response at week 16 (P < 0.05) and was not significantly different from that at week 0.

The mean (± SEM) serum IGF-I levels at the prestudy screen visit and at weeks 1, 4, 16, and 20 were 115 ± 12 µg/L, 121 ± 10 µg/L, 113 ± 12 µg/L, 130 ± 10 µg/L, and 124 ± 12 µg/L, respectively (Fig. 3Go). Serum IGF-I did not change significantly, over the 20-week period (P = 0.24).



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  		Figure 3. Changes in serum IGF-I (above) and IGFBP-3 (below), after 16 weeks of hexarelin-stimulated GH release and 4 weeks after stopping hexarelin (mean shown).

 
The mean (± SEM) serum IGFBP-3 levels at the prestudy screen visit and at weeks 1, 4, 16, and 20 were 3.7 ± 0.2 µg/L, 3.7 ± 0.3 µg/L, 3.9 ± 0.3 µg/L, 3.7 ± 0.2 µg/L, and 3.5 ± 0.2 µg/L, respectively (Fig. 3Go). There was no significant change in serum IGFBP-3, over the whole study period (P = 0.74).

Only one subject demonstrated an almost absent GH response to hexarelin after chronic therapy (Fig. 4Go). After 16 weeks of continuous therapy in this individual, the peak GH response and AUCGH had decreased by 94.5% and 94.7%, respectively. In this individual, the largest single decrease occurred after 1 week (peak GH response and AUCGH, by 56.3% and 67.9%, respectively). Four weeks after cessation of hexarelin therapy, however, the peak GH response and AUCGH both increased.



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  		Figure 4. Changes in GH response to hexarelin, at each visit. Each visit is plotted horizontally, starting with the prestudy screen visit through to week 20 visit. Subjects are plotted vertically with subject 1 at the bottom to subject 12 at the top. Note subject 3, the only subject who failed to respond to hexarelin at week 16.

 
Of the bone markers measured (Table 1Go), only serum CICP changed significantly and was higher at week 16, compared with baseline (P = 0.019). Total body fat, lean body mass, and BMD had not changed significantly at week 16, compared with baseline (P = 0.6, P = 0.3, and P = 0.3, respectively).


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  		Table 1. The effect of long-term hexarelin therapy on body composition and markers of bone formation and resorption

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The therapeutic use of GHRH has been limited by desensitization occurring after long-term administration and resulting in a progressively reduced GH response. This has been clearly demonstrated in rats (5) and man (6). The mode of administration and poor bioavailability of GHRH further hinders its use. The recent use of a GHRH analogue, administered sc to normal elderly subjects, however, suggested more favorable results with no attenuation of the GH response to the GHRH analogue after 16 weeks of administration (7). Khorram et al. (7) also demonstrated an increase in serum IGF-I, IGFBP-3, and GH binding protein over the 16-week study. Furthermore, this group went on to demonstrate significant changes in biological endpoints, with an increase in skin-fold thickness in both male and female subjects, and an increase in lean body mass, insulin sensitivity, general well-being, and libido in the male subjects. The increase in endogenous GH, as a result of GHRH analogue administration in elderly subjects, may therefore be beneficial. The route of administration of the GHRH analogue, however, remains a disadvantage and may affect com-pliance.

Hexarelin is capable of causing GH release in normal subjects after oral administration (1, 8). The availability of a powerful orally active GH secretagogue with an ability to cause pulsatile GH release, has obvious advantages over administration of sc GH and GHRH analogues. The potential therapeutic use of hexarelin and similar agents, however, will be determined, in part, by their GH releasing capacity after chronic administration. In the present study, we have demonstrated that 16 weeks of twice-daily sc hexarelin therapy results in an attenuated GH response to hexarelin, as evidenced by a decrease in both peak GH response and AUCGH. Importantly, however, this reduction in hexarelin-stimulated GH release was partial, with all but one subject still releasing GH after 16 weeks of therapy.

Four weeks after completion of therapy, both hexarelin-stimulated AUCGH and peak GH response had recovered completely, suggesting that the mechanism responsible for the attenuated GH response is not only partial, but also reversible. A similar partial and reversible attenuated GH response to hexarelin has been demonstrated by Klinger and colleagues (9) in seven prepubertal constitutionally short children, after 6–10 months of thrice-daily intranasal hexarelin administration. At completion of hexarelin therapy, the mean peak GH response had decreased by about 75%, compared with baseline. Three months after completion of hexarelin therapy, the mean peak GH response to iv hexarelin had increased to 50% of pretreatment levels. Despite the attenuated GH response to hexarelin, serum IGF-I increased during the study period; and furthermore, growth rate was increased during therapy with hexarelin, compared with that before commencing therapy.

In seven normal elderly subjects, Ghigo and colleagues (2) were unable to demonstrate a change in AUCGH after 8 days of intranasal hexarelin administration. In seven elderly female subjects, 15 days of oral hexarelin administration also failed to reduce hexarelin-stimulated GH release. This is in accord with the findings of our study, in which we demonstrated a statistically nonsignificant decrease in the GH response after 1 week of therapy.

Klinger et al. (9) observed an attenuated GH response after intranasal hexarelin was administered. The difference in dose (three times higher in the pediatric study) and duration of administration (6–10 months, compared with 8 days) may account, in part, for the difference between the results obtained by Klinger et al. (9) and those of Ghigo and colleagues (2), because the route of administration was the same in both studies.

The mechanism of decreased GH release, in response to chronic hexarelin therapy, remains unclear. It is likely that this occurs via a number of mechanisms, including negative feedback from increased circulating GH. GH feedback affects the GH axis at several levels. Pretreatment with GH dampens the GH response to provocative stimuli (including insulin, clonidine, and GHRH) (10, 11). GH seems to have a direct effect on the reduction in GH release, because short-term administration of GH results in negative feedback before IGF-I levels have increased (12). Furthermore, SRIH neurones possess GH receptor mRNA (13), and in vitro GH studies have shown that GH stimulates SRIH secretion (14). GH may also influence GHRH expression, either directly or via IGF-I (15).

Administration of exogenous GH (16, 17) has been shown to attenuate the GH response to hexarelin, suggesting that hexarelin-stimulated GH release is subject to partial feedback inhibition by the action of GH on SRIH and/or GHRH. Cella and colleagues (3) demonstrated increased pulse frequency and amplitude of GH release, with chronic sc hexarelin administration, suggesting an overall increase in GH levels, which (through a negative feedback effect at the hypothalamic-pituitary level) may, in part, be responsible for the attenuated GH response in our subjects after a bolus administration of hexarelin.

IGF-I acts directly at the pituitary level, to inhibit basal and GHRH-induced GH secretion and also to suppress GH gene expression (18, 19, 20, 21). IGF-I acts at the hypothalamus, where it increases SRIH secretion (22). In the present study, it is unlikely that IGF-I played a major role in the reduced GH response after chronic hexarelin therapy, because attenuation of the GH response occurred without any significant alteration in circulating IGF-I.

It is more probable that down-regulation of receptor and post-receptor mechanisms, as seen after prolonged stimulation with GHRH (23) and GHRP-6 (24) in humans, is responsible for the decrease in hexarelin-stimulated GH release.

Compared with normal young adults, GH production is reduced by 30–50% and serum IGF-I levels tend to be lower in normal elderly subjects (25, 26, 27, 28). This state of hyposomatotropism is associated with biological changes (29, 30), e.g. increased body fat, reduced lean tissue, and reduced BMD. These changes also occur in individuals with GH deficiency, and GH replacement in these individuals will reverse some of these changes (31, 32). It has been proposed that the bodily changes associated with aging may be amenable to correction by exposure to an increase in GH (33, 34, 35, 36, 37).

The biological impact of hexarelin-stimulated GH release, without a significant concomitant rise in serum IGF-I, in humans, has not been established. In old dogs, Cella et al. (3) were able to increase endogenous GH levels using hexarelin. Serum IGF-I, however, did not change. Hexarelin was administered twice daily by sc injection for 7 weeks, 4 weeks, and 1 week, with treatment periods separated by 2 weeks. Urinary lysylpyridinoline, a marker of bone resorption, was shown to decrease significantly with chronic hexarelin therapy, although hydroxylysylpyridinoline (also a marker of bone resorption) was not altered significantly. In addition, serum alkaline phosphatase, a marker of bone formation, was not modified by treatment. Cella and colleagues (3) concluded that inhibition of bone resorption seemed uncoupled from bone formation, suggesting that chronic hexarelin therapy may have a beneficial effect on bone mass.

In the present study, however, we have been unable to demonstrate significant changes in body composition or BMD. Two of the three markers of bone formation did not change significantly over the study period, but CICP was higher at week 16, compared with baseline. Markers of bone degradation remained unaltered over the study period. Serum IGF-I levels did not change significantly over the study period; and, because many of the biological actions of GH are mediated via IGF-I, it is not surprising that there was little impact on the biological endpoints assessed. The reason for the unimpressive change in serum IGF-I may be caused by the frequency of administration and dose of hexarelin given. Klinger et al. (9) and Ghigo et al. (2) observed increases in serum IGF-I with thrice-daily administration, whereas we and Cella et al. (3) were unable to show an increase in IGF-I after twice-daily therapy.

In summary, we have demonstrated that the attenuation of the GH response, after long-term hexarelin therapy, is partial and reversible. Furthermore, serum IGF-I and several biological endpoints of GH action do not seem to be affected by long-term hexarelin administered twice daily sc in a dose of 1.5 µg/kg BW.


   Acknowledgments
 
The authors would like to thank Kate Roberts for her help during the study and David Ryder for his statistical advice. We would also like to thank Christina Herder (Pharmacia and Upjohn) for her help throughout the study and Pharmacia and Upjohn for their support of this study.

Received November 14, 1997.

Revised January 21, 1998.

Accepted January 29, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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