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The Growth Hormone Response to Hexarelin in Children: Reproducibility and Effect of Sex Steroids¹

Servizio di Endocrinologia Pediatrica, Ospedale Regionale per le Microcitemie (S.L., A.F.), Cagliari; Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Università Federico II (A.C., G.L.), Naples; Divisione di Endocrinologia, Ospedale Bambino Gesù IRCCS (M.C.), Palidoro, Rome; Divisione di Endocrinologia, Dipartimento di Fisiopatologia Clinica, Università di Torino (J.B., G.A., E.G.), Torino; and Clinica Pediatrica, Università di L’Aquila (G.F.), L’Aquila, Italy; and Europeptides (R.D.), Argenteuil, France

Address all correspondence and requests for reprints to: Sandro Loche, M.D., Servizio di Endocrinologia Pediatrica, Ospedale Regionale per le Microcitemie, via Jenner, 09121 Cagliari, Italy.

	Abstract

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We studied the variability of the GH response to the synthetic hexapeptide hexarelin (Hex) and the effect of sex steroids on the GH-releasing effect of Hex in a group of prepubertal short normal children. Twenty-five children were tested on two occasions 3–7 days apart with 2 µg/kg, iv, Hex. The GH response to Hex was reevaluated after testosterone (T) administration in 10 boys, after ethinyl estradiol (EE) administration in 15 children (5 boys and 10 girls), and after oxandrolone (Ox) administration in 8 boys. In the 25 children tested twice, the mean GH peak and mean area under the curve after the first and second tests were similar. The mean (±SD) coefficients of variation of the GH peak and area under the curve responses to Hex was 22.7 ± 21.0% and 24.0 ± 20.7%, respectively. Priming with T and EE resulted in an increased GH response to Hex [41.8 ± 21.0 before vs. 71.1 ± 28.3 after T (P < 0.001); 43.0 ± 14.5 before vs. 60.0 ± 20.0 after EE (P < 0.005)], whereas Ox administration had no effect on the Hex-induced GH release. These data confirm that Hex is a potent stimulus for GH secretion in children with a limited intraindividual variability. In addition, we have shown that both T and EE, but not Ox, significantly augment the GH-releasing effect of Hex. Our data suggest that the sex steroid-induced increase in the GH response to Hex is mediated by estrogens.

	Introduction

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SEX STEROIDS have profound effects on GH/insulin-like growth factor I physiology. Spontaneous GH secretion (1) as well as the response of GH to several stimuli (2) are increased in puberty and after the administration of testosterone (T) (3) or estrogens (2). Sex steroid priming is widely used to test pituitary function before the onset of the growth spurt, when, without priming, pharmacological and physiological tests may yield subnormal responses (4). The GH increase in puberty is due to an increase in GH pulse amplitude rather than frequency (1), occurs earlier in girls than in boys, and is seen in children with precocious puberty (1). A similar pulse amplitude-dependent increase in GH secretion is also seen after the pharmacological induction of puberty with estrogens, androgens, hCG, or GnRH (1) as well as after androgen treatment in hypogonadal men (5, 6). Conversely, suppression of ovarian function by GnRH analogs in girls with central precocious puberty results in decreased GH secretion (1).

Comparison of the effects of T and the nonaromatizable androgens oxandrolone (Ox) (7, 8) and dihydrotestosterone (9, 10) as well as studies on the effects of the antiestrogen tamoxifen (6, 11) on the somatotropic axis have provided convincing evidence that the androgen-dependent increase in GH secretion is due to the conversion of T to estradiol after aromatization.

Hexarelin (Hex) is a synthetic hexapeptide analog to GH-releasing peptide-6 (GHRP-6) (12) with potent GH-releasing activity in both adults (13, 14) and children (15, 16). The GH response to a maximal dose of Hex is consistently higher than that elicited by a maximal dose of GHRH (13, 15), shows a limited intrasubject variability in both adults (13) and children (16), and increases at puberty (16) as well as after T administration in boys (15).

In this study, we wanted to extend the previous observation on the reproducibility of the GH response to Hex in children (16) and to further characterize the effects of sex steroids on the Hex-induced GH secretion. To this end we have investigated the effects of T, Ox, and ethinyl estradiol (EE) on the GH response to Hex in a group of short normal children.

	Subjects and Methods

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A total of 44 subjects were studied. They were referred to our institutions for evaluation of short stature and were found to have familial short stature and/or constitutional delay of growth. All children had normal insulin-like growth factor I levels and thyroid function tests, and none of them had taken long term medications. The studies were carried out under institutionally approved protocols, and informed consent was obtained from the patients and their legal guardians.

Twenty-five subjects (17 boys and 8 girls, aged 9.5–13.5 yr, all prepubertal) were tested on two occasions with Hex (2 µg/kg, iv; prepared and supplied by Europeptides, Argenteuil, France), with an interval of 3–7 days. Blood samples were drawn from an indwelling catheter inserted in an antecubital vein 15 min and immediately before the injection of Hex and then every 15 min for 2 h.

The GH response to Hex was reevaluated in 10 boys (aged 10.0–13.7 yr; data for 5 of these boys have been previously reported in Ref.15) 1 week after the administration of T (T enanthate; 100 mg, iv), in 8 boys (aged 9.5–13 y) 1 week after the administration of Ox (2.5 mg/day, orally), and in 15 subjects (5 boys and 10 girls, aged 8.1–12.4 yr) after 3 days of EE administration (0.1 mg/day, orally).

All experiments started between 0800–0900 h after the children fasted overnight.

GH was measured by an immunoradiometric assay (HGH-CTK-IRMA, Sorin, Italy). The sensitivity of the assay was 0.2 µg/L, with intra- and interassay coefficients of variation of 1.9–4.5% and 4.9–7.9%, respectively.

All values are expressed as peak GH levels or the area under the curve (AUC) calculated by trapezoidal integration. Statistical analysis of the results was carried out using the Wilcoxon test for paired data and the Mann-Whitney U test to compare groups. Correlations were performed by regression analysis. Variability was expressed as the coefficient of variation (CV). All values are given as the mean ± SD.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
None of the subjects experienced serious side-effects after Hex administration. In eight of them, Hex administration induced transient facial flushing.

Reproducibility of the GH response to Hex

The individual GH responses to Hex in the 25 children studied on 2 different occasions are shown in Table 1. The GH peaks and the AUCs after the first and second test sessions were significantly correlated (peak: r = 0.858; P < 0.0001; AUC: r = 0.910; P < 0.0001). The mean CVs of the peak and AUC GH responses to Hex were 22.7 ± 21.0% and 24.0 ± 20.7%, respectively, indicating a limited intraindividual variability.

Mean GH peak and mean AUC in the 10 boys before T administration were 41.8 ± 21.0 µg/L and 1967 ± 799 µg/min·L, respectively. After priming with T, the GH response to Hex was significantly increased [peak, 71.1 ± 28.3 µg/L (P < 0.001); AUC, 3753 ± 1344 µg/min·L (P < 0.005); Fig. 1]. The mean GH peak (45.1 ± 14.1 µg/L) and mean AUC (2107 ± 637 µg/min·L) in the 8 children after Ox administration were not significantly different from those before treatment (peak, 49.0 ± 25.7 µg/L; AUC, 2424 ± 1079 µg/min·L; Fig. 1).

View larger version (33K): [in this window] [in a new window]   Figure 1. Mean (±sem) GH peak and AUC responses to iv bolus injection of Hex before (closed bars) and after (shaded bars) pretreatment with T (10 boys), EE (5 boys and 10 girls), and Ox (8 boys).

Mean GH peak (60.0 ± 20.0 µg/L) and mean AUC (3010 ± 1428 µg/min·L) in the 15 children after EE administration were significantly higher than those before treatment [peak, 43.0 ± 14.5 µg/L (P < 0.005); AUC, 2176 ± 951 µg/min·L (P < 0.02); Fig. 1]. The GH response to Hex before EE was slightly higher in girls (peak, 46.8 ± 15.6 µg/L; AUC, 2512 ± 957 µg/min·L) than in boys [peak, 35.2 ± 8.8 (P > 0.1); AUC, 1486 ± 459 µg/min·L (P < 0.05)]. After EE treatment, the GH response to Hex was similar between girls (peak, 58.7 ± 22.7 µg/L; AUC, 3328 ± 1584 µg/min·L) and boys (peak, 62.3 ± 14.9 µg/L; AUC, 2960 ± 1401 µg/min·L).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
This study confirms that Hex is a potent GH-releasing stimulus in children (15, 16). Furthermore, we have confirmed that the GH response to Hex has a limited intraindividual variability. In two previous reports in which the issue of the reproducibility of the GH stimulation tests in children was addressed, the CV of the arginine and L-DOPA tests averaged 86.5% and 77.6%, respectively (17), whereas the CV for the GHRH test averaged 73.4%, a value that was slightly improved to 47.5% when the children were pretreated with pyridostigmine (18). Thus, the intrasubject CV of the GH response to Hex found in this study (22.7%) is much lower than that previously reported for other pharmacological stimuli. The availability of a GH stimulation test that is potent and reproducible could be of value in the clinical setting. In children with short stature and poor growth, the diagnosis of GH deficiency is classically established when GH concentrations do not reach an arbitrary cut-off value after two pharmacological stimuli. One of the major problems of the provocative tests lies in their poor reproducibility and in the great number of false negative responses frequently observed in normal children (17, 18, 19). The reason for this variability has been attributed to the periodic secretion of somatostatin, which may influence the somatotroph response to the stimulus (20). Furthermore, the GH responses to stimulation may also be influenced by the pattern of GH secretion preceding the stimulus, i.e. whether the latter is administered during a spontaneous trough or peak of GH secretion (20). However, recent observations indicate that the GH response to Hex is partially refractory to variations in the hypothalamic somatostatin tone (21, 22) or to the feedback action of GH (23). These findings might explain the limited variability of the GH response to Hex observed in adults (13) as well as in the children of this study.

It has been previously shown that Hex-induced GH release increases at puberty (16) as well as after T administration (15). In this study we have shown that both T and EE pretreatments increase the GH response to Hex. Interestingly, Ox had no effect on the Hex-induced GH release. Our findings are in agreement with those of other investigators, who showed that the effects of T on the somatotropic axis are dependent on its aromatization to estradiol. In fact, Ox (7, 8) and dihydrotestosterone (9, 10), both nonaromatizable androgens, fail to increase spontaneous GH secretion in boys. Furthermore, estrogen receptor blockade with tamoxifen reduces GH secretion in late pubertal boys (11) and in normal adult men (6), and inhibits GH secretion induced by T treatment in hypogonadal men (6). Thus, our data indicate that the enhancing effect of T on the GH response to Hex is mediated by estradiol. Indirect support for this conclusion comes from the observations that the GH response to Hex is greater in pubertal girls than in pubertal boys, and that it correlates with circulating estradiol in girls, but not with T concentrations in boys (16). Furthermore, studies in animals have shown that the GH response to GHRP-6 is greater in the female than in the male rat (24).

A number of findings indicate that the principal site of action of GHRPs is the hypothalamus (25, 26, 27, 28). In addition, GHRPs act synergistically with GHRH to release GH both in vitro (25, 29) and in vivo (13, 30). A specific receptor for GHRP-6, the parent compound of Hex (13), has been recently cloned (31), suggesting that Hex may represent a synthetic analog of an endogenous ligand.

The stimulatory effects of sex steroids on the somatotropic axis cannot be explained with an increased pituitary responsiveness to GHRH, because the GH response to GHRH does not change with puberty (16) or after sex steroid administration (10). Furthermore, the GH response to GHRH after reduction of the hypothalamic somatostatin tone by pyridostigmine also does not change with puberty (32) or after T administration (10), suggesting that a decreased somatostatin tone does not mediate the T-induced GH increase. Eakman et al. suggested that the mechanism involves an increase in hypothalamic GHRH release (10).

Based on the foregoing, our findings that both T and EE enhance the GH response to Hex fit with the latter hypothesis. As Hex and GHRH are synergistic in vivo (13), it is possible that the augmentation of the GH-releasing effect of Hex induced by sex steroid priming is due to the ability of the latter to increase the release of endogenous GHRH. Alternatively, it could be speculated that sex steroids increase the number/activity of the hypothalamic and/or pituitary GHRP receptors.

In conclusion, we have confirmed that Hex is a potent and reproducible stimulus for GH secretion in children. In addition, we have shown that sex steroids markedly augment the GH-releasing effect of Hex. Our data suggest that the sex steroid-induced increase in the GH response to Hex is mediated by estrogens.

	Footnotes

 
¹ This work was supported in part by a grant from the Ministero della Università e della Ricerca Scientifica e Tecnologica.

Received September 16, 1996.

Revised November 1, 1996.

Accepted November 11, 1997.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

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