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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 4 1540-1544
Copyright © 2000 by The Endocrine Society

Original Studies

Effects of Short-Term Glucocorticoid Deprivation on Growth Hormone (GH) Response to GH-Releasing Peptide-6: Studies in Normal Men and in Patients with Adrenal Insufficiency1

Ana-Cláudia A. R. Pinto, Magnus R. D. Silva, Manoel R. Martins, Elisa Brunner and Ana-Maria J. Lengyel2

Division of Endocrinology, Department of Medicine, Universidade Federal de São Paulo, Universidade Federal de Sao Paulo/Escola Paulista de Medicina, Sao Paulo 04034-970, Brazil

Address all correspondence and requests for reprints to: Dr. Ana-Cláudia de Assis Rocha Pinto, Division of Endocrinology, Escola Paulista de Medicina, Universidade Federal de Sao Paulo, Sao Paulo S.P. 04034-970, C.P. 20266, Brazil. E-mail: ana0292{at}zaz.com.br


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
There are no data in the literature about the effects of glucocorticoid deprivation on GH-releasing peptide-6 (GHRP-6)-induced GH release. The aims of this study were to evaluate GH responsiveness to GHRP-6 1) after metyrapone administration in normal men, and 2) in patients with chronic hypocortisolism after glucocorticoid withdrawal for 72 h. In normal subjects, metyrapone ingestion did not alter significantly GH responsiveness to GHRP-6 [n = 8; peak, 39.3 ± 7.1 µg/L; area under the curve (AUC), 1958.8 ± 445.7 µg/min·L; mean ± SE] compared to placebo (n = 8; peak, 21.9 ± 4.5; AUC, 1131.0 ± 229.6). In patients with chronic hypocortisolism (n = 8), GH responses to GHRP-6 were similar both during replacement therapy (peak, 11.8 ± 3.9; AUC, 563.2 ± 208.7) and after withdrawal of prednisone (peak, 14.4 ± 4.5; AUC, 695.6 ± 272.9) and did not differ from those in controls. Interestingly, after glucocorticoid withdrawal, GH responsiveness to GHRP-6 in patients with chronic hypocortisolism was significantly lower than that in normal subjects pretreated with metyrapone. Our data suggest that short term glucocorticoid deprivation does not have a major impact on GHRP-6-dependent GH-releasing mechanisms. However, in long standing hypocortisolism, subtle changes in GHRP-6 secretory pathways may be present.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GLUCOCORTICOIDS play an important role in the hypothalamic-pituitary GH secretory axis. Physiological amounts of these steroids are necessary for normal GH synthesis and secretion (1, 2, 3). However, chronic exposure to supraphysiological quantities of these hormones causes growth retardation and a decrease in GH release (4). There are glucocorticoid receptors in the arcuate and periventricular nuclei of the hypothalamus, suggesting that these steroids could modulate GHRH and/or somatostatin synthesis and release (5, 6). At the pituitary level, glucocorticoids increase GH gene transcription and GH messenger ribonucleic acid levels, and an effect on GHRH receptor messenger ribonucleic acid has also been described (1, 7, 8). In humans, several reports have shown that glucocorticoid excess decreases GH responsiveness to GHRH (9, 10, 11). However, hypercortisolism seems to have a different effect on the GH-releasing mechanisms stimulated by GHRH and GH-releasing peptide-6 (GHRP-6) (12). Data in humans suggest that GHRPs are able to counteract the inhibitory effects of glucocorticoid excess on GH secretion (12, 13, 14). The effect of hypocortisolism on GH release has been less studied in both animals and man. In rats, adrenalectomy decreases GH responsiveness to submaximal doses of GHRH, which is restored after glucocorticoid administration (15, 16). This could be due to changes in pituitary sensitivity to GHRH consequent to a decrease in GHRH receptor number (16). In patients with ACTH deficiency, prolonged glucocorticoid deprivation also reduces GH responsiveness to several stimuli, including GHRH (17, 18, 19). The effects of short term hypocortisolism on GH secretion in man are controversial (20, 21, 22, 23). In patients with Addison’s disease, acute glucocorticoid withdrawal does not impair GH responsiveness to GHRH (21). In normal subjects pretreated with metyrapone, which causes a decrease in circulating cortisol, either a lack of effect or an increase in GHRH-induced GH release has been reported (20, 23).

GHRP-6 is a synthetic hexapeptide with potent GH-releasing activity in both man and animals (24, 25, 26, 27, 28, 29). GHRP-6-induced GH release is dose dependent and similar in men and women (26, 29, 30). The effect of this peptide is exerted through specific G protein-coupled receptors, which are different from those of GHRH (31, 32, 33, 34, 35). These receptors are mainly localized in the hypothalamus and pituitary gland (35, 36). This finding suggests the existence of an unknown natural GHRP receptor ligand. The mechanisms by which GHRP-6 stimulates GH release are not yet fully known (37). This peptide apparently acts at both pituitary and hypothalamic levels (26, 27, 38, 39). It may increase hypothalamic GHRH release and/or stimulate the secretion of an unknown hypothalamic factor (U factor) that interacts with GHRH to enhance GH secretion (26, 28, 40). GHRP-6 probably does not decrease hypothalamic somatostatin secretion (41, 42, 43), but it may act as a functional somatostatin antagonist at the pituitary and hypothalamic levels (37, 42, 44).

There are no data in the literature about the effects of glucocorticoid deprivation on GH responsiveness to GHRP-6 in man. Therefore, the aims of this study were 1) to evaluate the effects of metyrapone administration, which blocks the conversion of 11-deoxycortisol to cortisol, on GH responsiveness to GHRP-6 in normal men; and 2) to investigate whether the GH response to GHRP-6 is affected by glucocorticoid withdrawal in patients with chronic hypocortisolism.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Sixteen normal subjects (10 men and 6 women) with a mean age of 28.6 ± 3.0 yr (range, 26–37) and with a mean body mass index (BMI) of 22.2 ± 2.0 kg/m2 were studied. They were free of any medication at the time of the study protocol. The women were tested in the early follicular phase of their menstrual cycles. Seven patients with Addison’s disease (3 men and 4 women) and a woman with idiopathic ACTH deficiency were also studied (Table 1Go). Their mean age was 39.5 ± 8.4 yr (range, 22–48), and their mean BMI was 26.1 ± 5.6 kg/m2. All patients had long standing hypocortisolism and had been receiving glucocorticoid replacement therapy with prednisone for more than 6 months. The corticoid was administered at a dose of 5 or 7.5 mg/day, divided into 1 or 2 daily doses (at 0800 and 1600 h). Five patients also had mineralocorticoid deficiency and were receiving replacement therapy with fludrocortisone at a dose of 0.1 mg/day (patients 1, 2, 3, 6, and 8). Two patients with Addison’s disease (patients 3 and 6) also had associated hypothyroidism and were receiving adequate replacement therapy with T4 at doses of 100 and 125 µg/day, respectively, for at least 6 months before the study.


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  		Table 1. Clinical and laboratory data of patients with chronic hypocortisolism

 
Study protocol

The experimental protocol was approved by the ethics committee of Universidade Federal de São Paulo, Escola Paulista de Medicina, and all subjects gave prior informed consent.

Metyrapone administration. The normal subjects were divided into two groups, matched for age and sex. Eight subjects received metyrapone (Metopirone, Ciba, Nürnberg, Germany) at a dose of 1.5 g, orally, at midnight, followed by 750 mg at 0800 h, as previously described (23), and the other eight were pretreated with placebo. The acute administration of this drug causes a slight decrease in cortisol levels and stimulation of ACTH release. All tests were performed after an overnight fast, and the subjects remained recumbent throughout. One hour before starting the tests (0800 h), an indwelling catheter was inserted into an antecubital vein and was kept patent by a slow saline infusion. After the first blood sample (0900 h), all subjects received GHRP-6 (Peninsula Laboratories, Inc., Merseyside, UK) at a dose of 1 µg/kg, iv, and blood samples were obtained every 15 min until 120 min. GH levels were measured in all samples, whereas blood glucose was only determined every 30 min. In both groups, cortisol and 11-deoxycortisol were measured in the first blood sample. Pulse and blood pressure were monitored during the tests.

Adrenal insufficiency. These patients were studied on two occasions in random order, with an interval of at least 30 days between the tests. On one occasion, they received GHRP-6 during their regular prednisone replacement therapy on an out-patient basis. To avoid a possible stimulating effect of acute glucocorticoid administration on GHRP-6-induced GH release (20), on the morning of the test the patients only received their normal dose of prednisone after the end of the sampling period. The second GHRP-6 test was performed after 72 h of withdrawal of prednisone replacement therapy, with the patients inside the hospital. The tests were performed as described above (for metyrapone administration). In these patients ACTH was also measured in the first blood sample, and GH, glucose, and cortisol levels were determined as reported above.

Methods

Serum GH was measured in duplicate by a two-site monoclonal antibody immunofluorometric assay (45). Monoclonal antibodies were developed as previously described (45). The sensitivity of the method was 0.05 µg/L, with mean intra- and interassay coefficients of variation of 7% and 9%, respectively. Plasma ACTH levels were measured in duplicate by an immunochemiluminometric assay, using commercial kits (Nichols Institute Diagnostics, San Juan Capistrano, CA). The sensitivity of the assay was 0.2 pmol/L (normal ACTH, 2.2–13.2 pmol/L). Serum cortisol and 11-deoxycortisol were measured in duplicate by RIA, with sensitivities of 11.0 and 0.4 nmol/L, respectively. Glucose was determined by the glucose oxidase method, using a glucose analyzer (Beckman Coulter, Inc., Palo Alto, CA). All samples from each subject were measured in the same assay.

Statistical analysis

Friedman’s ANOVA was performed to analyze GH levels after each treatment. The Wilcoxon signed rank test was used for comparisons within the same group, and the Mann-Whitney rank sum test was performed for comparisons between two different groups. The area under the curve (AUC) was calculated by trapezoidal integration. The Spearman correlation coefficient was calculated when appropriate. Undetectable GH, ACTH, and cortisol levels were considered to be equal to 0.05 µg/L, 0.2 pmol/L, and 11.0 nmol/L, respectively, for statistical purposes. P < 0.05 was considered statistically significant. Results are reported as the mean ± SE.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
In normal subjects pretreated with placebo, the mean peak GH (micrograms per L; mean ± SE) and AUC (micrograms per min/L) values after GHRP-6 injection were 21.9 ± 4.5 and 1131.0 ± 229.6, respectively. With metyrapone administration, the mean peak GH level after GHRP-6 treatment was 39.3 ± 7.1, and the AUC was 1958.8 ± 445.7 (Fig. 1Go). When the two groups were compared, no statistical differences were observed, although there was a trend to an increased response in terms of peak GH values (P = 0.08) in metyrapone-pretreated subjects.



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  		Figure 1. Mean plasma GH levels after GHRP-6 administration in normal subjects pretreated with placebo (NS) or metyrapone (METYR) and in patients with chronic hypocortisolism before (ON) and after (OFF) glucocorticoid withdrawal (mean ± SE; a, P < 0.05 vs. off).

 
In patients with chronic hypocortisolism, a significant increase in mean GH values after GHRP-6 administration was seen both during replacement therapy (peak, 11.8 ± 3.9; AUC, 563.2 ± 208.7) and after short term glucocorticoid withdrawal (peak, 14.4 ± 4.5; AUC, 695.6 ± 272.9; Fig. 1Go). No significant differences in GH levels were observed in these two situations. Moreover, as a group, patients with chronic hypocortisolism both on and off replacement therapy did not show significant changes in GH release compared to normal subjects (Fig. 1Go). A great variability in individual GH responsiveness to GHRP-6 was observed in these patients (Table 1Go). Three patients with Addison’s disease had peak GH values below 7 µg/L during replacement therapy, which were associated with high ACTH levels. However, after 72 h of glucocorticoid withdrawal, this pattern was not maintained. In patients with Addison’s disease no significant correlations were found between peak GH values and ACTH levels, age, BMI, duration of disease, and prednisone replacement dose. Interestingly, after glucocorticoid withdrawal, GH responsiveness to GHRP-6 in patients with chronic hypocortisolism was significantly lower than that observed in normal subjects pretreated with metyrapone in terms of both peak GH (14.4 ± 4.5 vs. 39.3 ± 7.1) and AUC values (695.6 ± 272.9 vs. 1958.8 ± 445.7; Fig. 1Go). No differences in BMI were seen between the two groups, but patients with chronic hypoadrenalism were significantly older than controls. As expected, metyrapone ingestion induced a significant rise in 11-deoxycortisol levels (193.0 ± 42.0 nmol/L) compared to placebo (0.7 ± 0.1), which was associated with a decrease in circulating cortisol (314.5 ± 24.8 vs. 146.2 ± 24.8 nmol/L; cortisol range after metyrapone, 11.0–237.2). In patients with Addison’s disease, ACTH levels were significantly higher after glucocorticoid withdrawal (218.2 ± 86.6 pmol/L) than during replacement therapy (38.1 ± 17.1). In most patients cortisol values were under the detection limit of the assay in both situations. No significant changes in glucose levels were observed throughout or between the tests in both study groups.

Transient nausea was seen in four subjects after GHRP-6 administration. Metyrapone ingestion caused variable degrees of drowsiness and fatigue in four volunteers and gastric discomfort in the other two subjects. In patients with hypoadrenalism, glucocorticoid withdrawal for 72 h did not cause significant symptoms, and all manifestations were well tolerated. None of the patients had to interrupt the study protocol.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In our study an acute decrease in circulating cortisol levels caused by metyrapone administration did not significantly modify the GH response to GHRP-6 in normal subjects. To our knowledge there are no previous data on the effect of metyrapone on GHRP-6-induced GH release in man. Earlier studies using this compound together with GHRH have yielded conflicting results, showing either a lack of effect or an increase in GH responsiveness to GHRH in normal subjects (20, 23). It has been suggested that this latter finding could be due to an attenuation of the inhibitory effect of somatostatin on GH release caused by a reduction in cortisol levels (46). Substances that decrease hypothalamic somatostatin release may have a slight enhancing effect on GHRP-6-induced GH release (47, 48). Although there was a trend to an increase in GH responses to GHRP-6, we could not find any major effect of an acute decrease in cortisol levels on GH responsiveness to GHRP-6 in normal subjects.

Patients with chronic hypoadrenalism on replacement therapy had significant increases in GH values after GHRP-6 injection, although a great variability of responses was observed, as previously described after GHRH administration to these patients (21). Because of the small number of patients with Addison’s disease, it was not possible to conclusively establish different patterns of response; however, we did observe that three poor GH responders during replacement therapy had quite high ACTH values compared to the other patients. This could eventually indicate that subtle changes in somatotroph function may be present in a subgroup of patients with chronic hypocortisolism. After glucocorticoid interruption for 72 h, significant increases in ACTH values were seen, which suggests that this period of withdrawal was adequate considering the biological half-life of prednisone (12–36 h). However, no significant changes in GH responsiveness were noticed. Moreover, GHRP-6-induced GH release both on and off replacement therapy was similar to that observed in control subjects. Most earlier reports have shown decreased GH release in patients with ACTH deficiency, which is an easier subset of patients to study than patients with Addison’s disease (17, 18, 19). In patients with ACTH deficiency, a 9-day period of glucocorticoid withdrawal decreases GH responsiveness to GHRH by approximately 50%, but these responses remain within the normal range (49). In these patients glucocorticoid replacement therapy restores GH release after GHRH injection (17, 18, 19). It has also been shown that in patients with Addison’s disease, acute glucocorticoid withdrawal does not impair GH responsiveness to GHRH (21). These results suggest that somatotrophs and corticotrophs have different pituitary sensitivities to glucocorticoid withdrawal and that somatotroph function is preserved in states of glucocorticoid deprivation.

Interestingly, a significantly higher GH release after GHRP-6 was seen in normal subjects pretreated with metyrapone than in patients with chronic hypoadrenalism after withdrawal of replacement therapy. Patients with hypocortisolism were older and had slightly, although not significantly, higher BMI than controls. However, age apparently does not decrease GHRP-6-induced GH release (50) and GH values less than 7 µg/L after GHRP-6 administration are not seen even in massive obesity (51). Acute administration of GHRPs stimulates ACTH and cortisol release (37). However, Arvat et al. showed that suppression of ACTH levels after dexamethasone administration does not alter the GH response to hexarelin, a GHRP analog (52). Therefore, it is unlikely that this effect could interfere with the GH response to GHRP-6 in our study.

Although controversial, it has been previously shown that glucocorticoids modulate pituitary and hypothalamic GHRP receptor gene expression in the rat (53, 54, 55). Adrenalectomy markedly decreases GHRP gene expression (53), whereas glucocorticoid treatment has the opposite effect (53, 54). Therefore, if these mechanisms are also operating in humans, it is possible that glucocorticoid replacement therapy is not able to adequately restore GHRP-6 receptor gene expression, with consequent attenuation of GH release after GHRP-6 administration. Moreover, our results suggest that hypoadrenal patients, even those receiving regular replacement therapy, may have chronically inadequate circulating glucocorticoid levels to maintain a completely normal somatotroph function.

In summary, acute glucocorticoid deprivation apparently does not alter GH responsiveness to GHRP-6 in normal subjects. As a group, patients with chronic hypoadrenalism release normal amounts of GH after GHRP-6 treatment. However, after glucocorticoid withdrawal, GHRP-6-induced GH release in these patients is lower than that observed in normal subjects pretreated with metyrapone. In conclusion, our data suggest that short term glucocorticoid deprivation does not have a major impact on GHRP-6-dependent GH-releasing mechanisms. However, in long standing hypocortisolism, subtle changes in GHRP-6 secretory pathways may be present.


   Acknowledgments
 
We are grateful to Prof. Ashley Grossman for the gift of metyrapone. We thank Ms. Aparecida F. P. F. Machado and Ms. Walkiria L. Miranda for technical assistance.


   Footnotes
 
1 This work was supported by Fundação de Amparo à Pesquisa do Estado de Sao Paulo and Conselho Nacional de Desenvolvimento Científico e Tecnológico. Back

2 Senior Scientist of Conselho Nacional de Desenvolvimento Científico e Tecnológico. Back

Received August 9, 1999.

Revised December 15, 1999.

Accepted December 23, 1999.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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