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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 7 3279-3283
Copyright © 2001 by The Endocrine Society

Original Articles

Growth Hormone-Releasing Peptide-2 Stimulates GH Secretion in GH-Deficient Patients with Mutated GH-Releasing Hormone Receptor1

Rogério G. Gondo, Manuel H. Aguiar-Oliveira, César Y. Hayashida, Sergio P. A. Toledo2, Neusa Abelin, Michael A. Levine, Cyril Y. Bowers, Anita H. O. Souza, Rossana M. C. Pereira, Norma L. Santos and Roberto Salvatori

Endocrine-Genetics Unit/LIM 25, Department of Medicine, University of Sao Paulo School of Medicine (R.G.G., C.Y.H., N.A., S.P.A.T.), 01246–903 Sao Paulo, Brazil; Division of Endocrinology, Federal University of Sergipe (M.H.A.-O., A.H.O.S., R.M.C.P., N.L.S.), 49060-100 Aracajo Sergipe, Brazil; Division of Endocrinology, Departments of Medicine (M.A.L., R.S.) and Pediatrics (M.A.L.), and the Ilyssa Center for Molecular Endocrinology (M.A.L., R.S.), The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; and Department of Medicine, Division of Endocrinology, Tulane University, School of Medicine, Endocrine Section (C.Y.B.), New Orleans, Louisiana 70112

Address all correspondence and requests for reprints to: Dr. Rogério G. Gondo, Endocrine-Genetics Unit/LIM 25, Sao Paulo University School of Medicine, Avenue Dr. Arnaldo, 455/5th Floor, 01246–903 Sao Paulo, Brazil. E-mail: gondo_rog{at}hotmail.com

Abstract

GH-releasing peptides (GHRPs) are synthetic peptides that bind to specific receptors and thereby stimulate the secretion of pituitary GH. In vivo it is uncertain whether these peptides act directly on somatotroph cells or indirectly via release of GHRH from the hypothalamus. In this study we compared the pituitary hormone response to GHRP-2 in 11 individuals with isolated GH deficiency (GHD) due to a homozygous mutation of the GHRH receptor (GHRH-R) gene and in 8 normal unrelated controls.

Basal serum GH levels were lower in the GHD group compared with controls [0.11 ± 0.11 (range, <0.04 to 0.38) vs. 0.59 ± 0.76 µg/L (range, 0.04–2.12 µg/L); P = 0.052]. After GHRP-2 administration there was a 4.5-fold increase in serum GH relative to baseline values in the GHD group (0.49 ± 0.41 vs. 0.11 ± 0.11 µg/L; P = 0.002), which was significantly less than the 79-fold increase in the control group (46.8 ± 17.6 vs. 0.59 ± 0.76 µg/L; P = 0.008). Basal and post-GHRP-2 serum levels of ACTH, cortisol, and PRL were similar in both groups. Basal levels of serum TSH were significantly higher in the GHD group than in the control group (3.23 ± 2.21 vs. 1.37 ± 0.34 µIU/mL; P = 0.003). TSH levels in both groups did not change after GHRP-2 administration.

These results suggest that an intact GHRH signaling system is not an absolute requirement for GHRP-2 action on GH secretion and that GHRP-2 has a GHRH-independent effect on pituitary somatotroph cells.

GH SECRETAGOGUES (GHSs) are synthetic compounds that stimulate GH secretion in vitro and in vivo (1). They include peptide molecules [GH-releasing peptide (GHRP)], such as ipamorelin (2); ep51 16; GHRP-1, -2, and -6 (hexarelin) (3); and Tyr-Ala-hexarelin (4), as well as nonpeptide compounds, such as MK0677 and L-692,585 (5). GHSs also stimulate ACTH/cortisol and PRL release (6, 7, 8) and have been shown to modulate food intake, sleep, and cardiac tone (9, 10, 11).

Despite the broad range of substances, all GHSs seem to act through a specific cell membrane receptor, identified, among other tissues, in both the pituitary and the arcuate nucleus of the hypothalamus (12). Recently, an endogenous ligand to GHS receptor, termed Ghrelin, has been isolated from rat stomach and hypothalamus as well as human stomach, indicating that GHSs may exist naturally (13).

In vitro, GHSs directly stimulate GH secretion from the pituitary somatotroph cells, as well as indirectly, by acting upon the arcuate nucleus of the hypothalamus to release GHRH into the portal hypophyseal circulation (14, 15). It is not clear which of these two mechanisms is more important in vivo as the basis of the stimulatory effect of GHS on GH secretion. There is some indirect evidence that GHSs act mainly on the hypothalamus, with a marginal direct effect on the pituitary (16).

To test whether GH release by GHSs requires the presence of an intact GHRH pathway, we studied the acute GH response to GHRP-2, a potent GHS, in individuals with GH deficiency (GHD) caused by a homozygous inactivating mutation of the GHRH receptor (GHRH-R) gene (17, 18, 19).

Subjects and Methods

Peptide

GHRP-2, KP-10-2, was synthesized by Kaken Pharmaceutical, Inc. (Tokyo, Japan), and prepared for human usage under the supervision of one of the authors (C.Y.B).

Study design

Eleven individuals with isolated GHD from Itabaianinha, Brazil, who are homozygous for a splicing mutation in the GHRH-R gene (17, 18, 19, 20), and eight healthy volunteers (controls) from Aracaju (118 km from Itabaianinha) were studied. Four of the GHD group (subjects 1, 2, 3, and 6) had received GH therapy for 1 yr until 2 yr before this study. None of the study subjects was taking any drug at the time of the study. Sex, age, and anthropometric measurements are presented in Table 1Go. SD scores of height were calculated based on growth charts published by WHO (21). The body mass index (was calculated as weight (kilograms)/height (meters) squared. The body mass index percentile for height age was derived from published charts (22, 23).


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  		Table 1. Clinical and biochemical data of 11 individuals with isolated GH deficiency due to mutated GHRH receptor gene and 8 normal controls

 
Informed consent was obtained from each individual or parent before participation in this study. The study protocol was approved by local institutional review boards.

GHRP-2 stimulation tests were started between 0800–0900 h after an overnight fast. An indwelling catheter was introduced into an antecubital vein and was kept patent by heparinized saline solution. GHRP-2 (2 µg/kg BW) was administered iv as a bolus. Blood samples were collected 15 min before, immediately before (time zero), and 15, 30, 45, 60, 90, and 120 min after the injection. Serum and plasma were separated immediately and stored at -20 C until hormone assays were performed.

Assays

Each hormone assay was performed in duplicate using kits from the same lot. GH, TSH, and ACTH were measured by an immunoradiometric assay (Cis-Biointernational, Saclay, France). The detection limit for GH was 0.04 µg/L, with an intraassay variation of 2.3–2.8%; the detection limit for TSH was 0.02 µIU/mL, with an intraassay variation of 2.9–3.5%; and that for ACTH was 0.44 pg/mL, with an intraassay variation of 10.4–14.8%. PRL and cortisol were determined by RIA (CIS-Bio International), with detection limits of 0.004 and 4.6 nmol/L, respectively.

Statistical analysis

Basal hormone concentrations were calculated as the mean of the -15 and 0 min concentrations. The Mann-Whitney rank-sum test was used to compare the hormone levels obtained from control and GHD groups. The Wilcoxon test was used to compare basal and GHRP-2-stimulated hormone levels. All data are expressed as the mean ± SD. Statistical significance was assumed at P < 0.05.

Results

As shown in Table 1Go, subjects with GHD had detectable basal serum GH levels, which were lower (although statistically not significant, with P = 0.052) than GH levels of normal control subjects. The peak serum GH after GHRP-2 in the GHD group was significantly lower than that in the control group. There was, however, a significant GH increase in both groups after GHRP-2: a 4.5-fold increase over the basal values in the GHD group, and a 79-fold increase in the control group (Fig. 1Go).



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  		Figure 1. Serum GH (mean ± SD) response to GHRP-2 (2 µg/kg BW). Zero time is the mean of -15 and basal GH values. There was a significant difference in all points, except at time zero (P = 0.052), between GHD and control groups.

 
Mean basal cortisol was not significantly different between the two groups (445.8 ± 205.9 nmol/L for GHD vs. 330.7 ± 134.0 nmol/L for controls; P = 0.23). There was a nearly 2-fold increase in serum cortisol levels after GHRP-2, in both groups (Table 1Go). The magnitudes of absolute and relative cortisol increments were similar for the two groups.

Basal ACTH serum levels were not significantly different between the two groups (3.82 ± 4.06 pg/mL for GHD vs. 1.60 ± 0.88 pg/mL for controls; P = 0.17). ACTH increased after GHRP-2 treatment in both groups, with no statistically significant difference between the peak responses.

GHRP-2 elicited significant and similar increases in PRL levels in both groups (Table 1Go).

Finally, in the GHD group, basal TSH (3.23 ± 2.21 µIU/mL) was higher than that in the control group (1.37 ± 0.34 µIU/mL; P = 0.003) (Fig. 2Go). The two GHD subjects with TSH levels out of the normal range (no. 3 and 6) had negative thyroid peroxidase and thyroglobulin autoantibodies, as tested by an immunofluorometric assay. These subjects were considered to have subclinical hypothyroidism based on normal free T4 levels. No thyroid hormone replacement therapy was instituted. The difference in serum TSH between the two groups remained significant even when these two subjects were removed from the statistical calculations. There was no increase in serum TSH levels after GHRP-2 treatment.



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  		Figure 2. Serum TSH (mean ± SD) of GHD (3.23 ± 2.21 µIU/mL) and control groups (1.37 ± 0.34 µIU/mL). The difference remained statistically significant even when the two highest values of TSH from GHD group (subjects 3 and 6) were excluded from the analysis (2.33 ± 0.69 vs. 1.37 ± 0.34 µIU/mL; P = 0.004).

 
Discussion

The predominant site of action of GHSs on GH secretion has not been established. As receptors for GHSs have been identified in both pituitary and hypothalamus (24, 25, 26), it is possible that GHSs act at either or both sites. GH synthesis and secretion are primarily regulated by the hypothalamic hormones, GHRH and somatostatin, as well as by the negative feedback of insulin-like growth factor I (27). GHRH is necessary for normal somatotroph cell proliferation and for the synthesis and secretion of GH (28). GHRH acts on somatotroph cells via a specific seven-transmembrane domain, G protein-coupled receptor, the activation of which causes an increase in intracellular cAMP and activation of the protein kinase A pathway (28). By contrast, GHSs act on a receptor that is coupled via members of the Gq/i family to activation of phospholipase C (1). Inactivating mutations of the GHRH-R gene have been recently described by us and others (17, 29, 30, 31, 32, 33) and represent an interesting model to test whether GHSs require an intact GHRH pathway for their action on GH secretion. For this reason, we tested the response of pituitary hormones to acute administration of GHR-2 in a genetically homogeneous group of individuals with GHD secondary to a homozygous inactivating mutation of the GHRH-R gene. This mutation affects the splice donor site at the beginning of intron 1 of the GHRH-R gene and predicts the production of a severely truncated GHRH-R protein or no protein at all (17). The complete absence of functional GHRH-R in these patients is confirmed by the absolute lack of increase in serum GH after both acute (1 µg/kg BW GHRH, iv bolus) and chronic GHRH (acute GHRH test after 6 nights of 5 µg/kg BW GHRH, sc) stimulation (17).

The presence of a small, but significant (4.5-fold), GH rise after GHRP-2 administration in these patients supports the hypothesis that an intact GHRH signaling system may not be an absolute requirement for GH secretion. The finding of a relatively low GH response to GHRP-2 is probably due to pituitary somatotroph hypoplasia, which is well documented in the little mouse, a naturally occurring murine model of GHRH-R mutation (34, 35, 36) that also has a low content of GH secretory granules per cell (34). Somatotroph cell hypoplasia to date has not been documented histologically in human subjects homozygous for GHRH-R mutations; however, small pituitary dimensions were observed by magnetic resonance imaging in our patients with the IVS1 + 1 G->A mutation of the GHRH-R gene (unpublished data) as well in patients with the Glu72Stop mutation (30, 37).

Our findings conflict with the previous work of Maheshwari et al. (38), who showed a complete lack of GH response to GHRP-6 (2 µg/kg) in individuals with a different inactivating GHRH-R gene mutation (Glu72Stop; peak GH, <1 µg/L). The GH assay method used in that study, however, had limited sensitivity (0.35 vs. 0.04 µg/L in our assay), possibly explaining such a difference. The higher biological potency of GHRP-2 compared with that of GHRP-6 (39) and the different kinds of mutation could also explain the different findings of these studies.

Potential diagnostic and therapeutic uses of GHRP-2 have been recently discussed (40). It is conceivable that in our GHRH-R-deficient patients chronic exogenous administration of GHRP-2 or another GHS would lead to a more robust stimulation of GH release. ACTH, cortisol, and PRL responses to GHRP-2 stimuli in our cases were similar to those seen in our control volunteers, supporting the idea that an intact GHRH signaling system is not necessary for the GHS releasing effect on these hormones. Similar results were observed with GHRP-6 in individuals with the Glu72Stop mutation (38).

Our finding of normal, but higher than control, TSH has not been noticed in other similar GHRH-R-deficient cases (29, 30, 31, 32, 33). The reason for our finding is unknown, but the lack of difference in the hormonal response to GHRP-2 between subjects with increased TSH and the others indicates that if hypothyroidism is present, it is subclinical and of little consequence.

In conclusion, we found a small, but significant, GH response to acute GHRP-2 administration in GHD individuals with inactive GHRH-R. This observation and the current availability of orally absorbable nonpeptide GHS (41) present the possibility for a long-term trial with GHS in GHD patients with a mutated GHRH-R gene.

Acknowledgments

We thank Susimeire Gomes and Valéria Samuel Lando for technical assistance.

Footnotes

1 This work was supported in part by NIH-NCRR General Clinical Research Center CAP Award 3-M01-RR-000052–38S1 (to R.S.), a grant from the Genentech Foundation for Growth and Development (R.S.), Grants DK-34281 (to M.A.L.) and NCCR General Clinical Research Center Grant 5–01-RR-00052 from the NIH, and CPDIA/NEC of Brazil. Back

2 CNPQ researcher (300.346/82–4). Back

Received November 15, 2000.

Revised February 27, 2001.

Accepted March 5, 2001.

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E. V. Dimaraki, C. A. Jaffe, C. Y. Bowers, P. Marbach, and A. L. Barkan
Pulsatile and nocturnal growth hormone secretions in men do not require periodic declines of somatostatin
Am J Physiol Endocrinol Metab, July 1, 2003; 285(1): E163 - E170.
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T. L. Horvath, S. Diano, P. Sotonyi, M. Heiman, and M. Tschop
Minireview: Ghrelin and the Regulation of Energy Balance--A Hypothalamic Perspective
Endocrinology, October 1, 2001; 142(10): 4163 - 4169.
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H. G. Maheshwari, S. S. Pezzoli, A. Rahim, S. M. Shalet, M. O. Thorner, and G. Baumann
Pulsatile growth hormone secretion persists in genetic growth hormone-releasing hormone resistance
Am J Physiol Endocrinol Metab, April 1, 2002; 282(4): E943 - E951.
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