0021-972X/91/7306-1191$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright (p) 1991 by The Endocrine Society
Vol. 73, No. 6 Printed in U.S.A.
Dexamethasone Treatment in Man Induces Changes in 24-Hour Growth Hormone (GH) Secretion Profile without Altering Total GH Released* F. P. PRALONG, J. P. MIELLf, R. CORDER, AND R. C. GAILLARD Neuroendocrine Unit, Division of Endocrinology, Department of Medicine, University Hospital, 1211 Geneva 4, Switzerland
ABSTRACT. Glucocorticoids inhibit growth in man and laboratory animals and reduce the GH response to the majority of exogenously administered stimuli. Recently, however, glucocorticoids have been shown to have varying effects on GH secretion depending on the time of administration and, furthermore, to be potent secretagogues in their own right. To investigate this further, we have carried out sampling over two 24-h periods in six normal male volunteers both before and directly after treatment with dexamethasone (DEX; 2 mg twice daily) for 96 h. After DEX administration, all volunteers showed an increase in mean GH secretion during the first 9 h of sampling (0900-1800 h) compared with pre-DEX control profiles (5.1 ± 1.2 vs. 1.7 ± 0.5 Mg/L; P < 0.001). DEX treatment also had the effect of delaying and attenuating the nocturnal peak; mean GH secretion between 0000-0200 h was significantly greater before DEX (13.6 ± 2.7 ng/L) than after DEX (3.6 ± 0.7 ^g/L; P < 0.001), whereas that between 0300-0800 h was greater after DEX (5.5 ± 0.8 vs. 0.7 ± 0.2 /xg/L; P < 0.001). Individual nocturnal peaks ranged from 7.0-56.8 /ig/L, occurring between 0030-0200 h before DEX, and 2.6-21.2 jig/L, occurring between 0300-0400 h after DEX. Overall mean GH secretion was not significantly altered by DEX treatment (3.8 ± 0.6 vs. 4.2 ± 0.5 Mg/L; P = NS).
T
HE INHIBITORY effects of pharmacological doses of glucocorticoids on normal growth have been recognized for many years in both animals (1) and humans (2). Patients with hypercortisolemia due to either Cushing's disease or long term glucocorticoid therapy demonstrate reduced GH secretion (3, 4), and short term steroid treatment generally has a suppressive effect on the GH response to known secretagogues (5-10). In contrast, recent reports suggest that glucocorticoids can have permissive effects on stimulated GH release depending on the duration of pituitary exposure (11,12) and, in some cases, the secretagogue employed (13). Received November 26,1990. Address all correspondence and requests for reprints to: Dr. F. P. Pralong, Clinique Medicale, University Hospital, 1211 Geneva 4, Switzerland. * This work was supported by the Swiss National Science Fundation (Grant 3.091.087). t Present address: Department of Medicine, King's College School of Medicine, Bessemer Road, London, SE5 9PJ England.
Total insulin-like growth factor-I (IGF-I) levels, measured after acid-ethanol extraction, were significantly increased by DEX treatment, with mean IGF-I over the 24-h sampling period rising from 292.2 ± 31.8 to 425.9 ± 37 ng/h (P < 0.005). All individuals showed an increase in mean 24-h IGF-I of between 10-75%. In a second study, 12 male volunteers were treated with DEX in an identical manner, and blood was taken at 0800 h daily. Total IGF-I levels rose steadily from 307.9 ± 13.3 fig/L, reached a plateau at 72 h and remained elevated at 96 h (424.9 ± 16.5 Mg/L; P < 0.001). These results suggest that glucocorticoids alter the normal pattern of GH secretion with an increase in daytime levels, but a delaying and attenuating effect on the nocturnal pulse. Previous studies have suggested that IGF-I concentrations are decreased by steroid treatment, but these have been based on bioassay systems. Total IGF-I, measured by RIA, would appear to be consistently elevated; the apparent decrease seen in bioassay systems may be due to glucocorticoid-induced changes in binding protein concentrations. (J Clin Endocrinol Metab 73: 1191-1196,1991)
Furthermore, physiological levels of glucocorticoids seem to be mandatory for a normal GH response to stimulatory tests (14). In vitro studies have demonstrated a glucocorticoiddependent enhancement of both basal (15) and GHreleasing hormone (GHRH)-stimulated (16) GH secretion. These discrepancies may indicate that the pituitary effects of glucocorticoids are outweighed in vivo by an inhibitory hypothalamic action. The exact role of glucocorticoids in the regulation of GH secretion is, therefore, still unclear. Contrasting with the generally accepted idea that glucocorticoids inhibit GH secretion in man, Casanueva and colleagues (17) have recently been able to demonstrate that dexamethasone (DEX) alone administered acutely can result in a stimulation of GH release, hence complicating further the understanding of the effects of glucocorticoids on GH secretion. To assess whether this acute stimulatory effect is maintained after longer term treat1191
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PRALONG ET AL.
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merit with glucocorticoids, and whether there is any effect on overall 24-h GH secretion, we have assessed 24h GH profiles before and after DEX treatment. As growth and other anabolic actions of GH are mediated by the somatomedins (18, 19), we have also assessed the effects of glucocorticoids on insulin like growth factor-I (IGF-I) concentrations. Materials and Methods Six male volunteers (age range, 22-28 yr; mean weight, 66.2 kg; range, 58-71.4 kg, within the limits of the New-York Life Insurance tables of ideal body weight for height) were studied. Subjects were admitted at 0700 h on the morning of the first study day after an overnight fast and iv cannulae were placed in the antecubital fossa of the nondominant arm. An initial blood sample was taken at 0900 h; successive samples were taken at appropriate intervals thereafter over a 24-h period. Blood was collected into EDTA-coated tubes and immediately separated, and the plasma was stored at -20 C. During the sampling periods, subjects remained recumbent, apart from meal times (1200 and 1800 h) when they were allowed to sit up. At the end of the first 24-h period, DEX treatment was commenced; tablets were taken at 0900 and 2000 h daily. After 96 h of DEX treatment, the 24-h profiles were repeated in a manner identical to the first sampling day, with identical meals and meal times. Because the two 24-h sampling periods were separated by a period of only 96 h, it was decided to minimize the amount of samples taken as much as possible. Consequently, samples were generally taken at hourly intervals, with half-hourly sampling at times corresponding to postprandial rises in GH secretion and the expected peak after dexamethasone administration (17) (1400-1700 h) and the major nocturnal pulse (0000-0400 h). This gave a total of 32 samples over each 24-h period. To assess the time course of changes in total insulin-like growth factor (IGF-I) concentration, a second study was carried out. Twelve male volunteers (age range 21-26 yr; mean weight 68.2 kg; range, 61-79kg) were treated with oral DEX (2 mg twice daily for 96 h). Before the first dose and thereafter daily at 0800 h, blood was taken for estimation of cortisol and IGFI concentrations. The protocols were approved by the Ethical Committee, and all volunteers gave informed written consent and underwent full biochemical and physical screening before inclusion in the study. Assays and statistical analyses Human GH was measured using an immunoradiometric assay (Allegro), employing reagents purchased from Nichols Institute (San Juan Capistrano, CA). This assay has a sensitivity of 0.02 Mg/L- Intra- and interassay coefficients of variation were 1.8% and 6.2%, respectively. Total IGF-I was measured after acid-ethanol extraction (20), using kits purchased from the same company. Intra- and interassay coefficients of variation were 2.3% and 5.7%, respectively. Cortisol was measured by a competitive protein binding assay, as previously described (21), with intra- and interassay coefficients of variation of 5%
JCE & M • 1991 Vol 73 • No 6
and 10%, respectively, at 470 nmol/L. All samples from the same subjects were assayed simultaneously. Statistics GH demonstrates a nonparametric distribution, and therefore, all values were logarithmically transformed before data analysis. Mean GH secretion over a given time period was calculated by averaging the logarithmically transformed GH values for all subjects at all time points within that period; data were compared by Student's t test. For clarity, raw data are illustrated. Because nocturnal and daytime peaks did not necessarily occur simultaneously in all subjects, the maximum GH values attained for all subjects during the day (0900-2200 h) and at night (2200-0800 h) were identified. For both the pretreatment profiles and post-DEX profiles, these values are expressed as medians with 25th and 75th percentiles and were compared by Wilcoxon signed rank tests. Significance was
assumed when P < 0.05.
Results Expl A representative GH profile of one of the six subjects before and after DEX treatment is shown in Fig. 1 and illustrates a delayed and attenuated nocturnal peak in addition to an acute rise in GH levels after DEX treatment. Mean GH concentrations from 0900-1900 h are shown in Fig. 2a and illustrate a rise that was maximal some 6 h after the final DEX tablet was administered (1400 h). Mean GH secretion over the period 1300-1900 h was significantly increased by DEX (6.1 ± 1 . 6 us. 1.8 ± 0.6 M g / L ; P < 0.001). GH secretion between 2300-0900 h is shown in Fig. 2b. The nocturnal pulse was attenuated and delayed by DEX. Mean GH secretion between 0000-0200 h was significantly greater during the pre-DEX profile (13.6 ± 2.7 vs. 3.7 ± 0.7 /ig/L; P < 0.001), whereas that between 60 50 40 •
GH
30 20
10 0
0900
1300 1700 2100 0100 0500
0900
Time FIG. 1. A representative 24-h GH profile for one of six male volunteers before (O) and after (•) DEX treatment.
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DEX AND 24-h GH SECRETION
DEX (9.3 fig/L; 2.9-16.6; P = 0.046). In contrast, the median peak GH secretion occurring during the day (1.9 ixg/L; 0.5-6) 1.9 /ug/L; 0.5-6) was significantly increased by DEX treatment (13.0 Mg/L; 10-19.6; P = 0.026). Mean IGF-I concentrations over the 24-h sampling period before and after DEX for each of the six individual subjects are shown in Fig. 3. All subjects showed an increase in mean IGF-I after DEX; overall increases were from 292.2 ± 31.9 Mg/L pre-DEX to 425.9 ± 37.4 Mg/L post-DEX (P < 0.001). All subjects demonstrated adequate suppression of cortisol after DEX (432 ± 43 nmol/ L pre-DEX; 41.8 ± 4.1 post-DEX).
20 IS '
GH (Hg/L)
10 • 5 0 0900
1100 1300 1500
1700 1900
Time
25
Exp2
20 "
GH
1193
Figure 4 illustrates the rise in total IGF-I measured at 0800 h daily in 12 subjects. Basal values (307.9 ± 13.3 Mg/L) rose over the initial 72 h and remained elevated at 96 h (424.9 ± 16.5 »g/U P < 0.001 compared with basal levels). Within this group, all subjects showed adequate suppression of cortisol from basal 0800 h values of 417.2 ± 30.7 to 39 ± 2.6 nmol/L after the full course of DEX.
1S
10 " 5 '
2300 0100 0300
0500 0700 0900
Discussion
Time FIG. 2. GH secretion over the period 0900-1900 h and 2300-0900. The shaded area represents the mean ± SEM of six observations before DEX therapy. D, The mean of six observations after DEX. Bars indicate the SEM. *,P< 0.05; **, P < 0.01; ***, P < 0.001.
Growth retardation is a well described feature of both endogenous and exogenous glucocorticoid excess (3, 4), and in vivo glucocorticoids generally suppress the GH response to the majority of physiological and pharmacological stimuli (5-10). In vitro, glucocorticoids appear to have the opposite effect, with an enhancement of basal (15) and GHRH-stimulated GH release (16) and an increase in GH gene transcription (22) and GHRH receptor density (23). These apparently conflicting reports would suggest that in vivo regulation of the somatotroph axis by glucocorticoids is mediated at the hypothalamus, presumably through alteration in somatostatinergic tone (24, 25).
0300-0800 h was greater after DEX (5.5 ± 0.8 vs. 0.7 ±
0.2 ng/h;P< 0.001). The individual nocturnal or post-DEX GH peaks were not necessarily simultaneous; therefore, individual peak values with their times of occurrence were identified for each subject and are shown in Table 1 along with median values and quartiles. Median peak nocturnal GH secretion before DEX (20.6 /ug/L; 25th to 75th percentiles: 8.9-35.9 /ig/L) was significantly greater than that after
TABLE 1. Peak GH levels attained by each volunteer during day and nighttime sampling, with their times of occurrence, as well as the median values and 25th and 75th percentiles Nocturnal peaks Volunteer no.
1 2 3 4 5 6 Median (25th, 75th percentiles) 0
Pre-DEX
Daytime peaks Post-DEX
Pre-DEX
Post-DEX
Max GH
Time (h)
MaxGH
Time (h)
Max GH
Time (h)
MaxGH
Time (h)
7.0 20.8 8.9 56.8 20.4 35.9
0200 0200 0130 0100 0100 0030
11.0 11.2 2.6 7.6 2.9 17.2
0330 0330 0400 0500 0400 0400
0.3 0.5 0.5 11.6 5.9 3.3
1500 1530 1500 1500 1500 1500
10.1 15.7 5.4 19.6 55.2 10.3
1630 1500 1530 1500 1630 1700
on eo
(8.9, 35.9)
Q
o
(2.9,16.6)
1 Q°
(0.5, 6.0)
13.0 (10,19.6)
P < 0.05.
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PRALONG ET AL.
1194
IGF-1
600
n
500
-
400
-
300
-
I
200 r
post
pre
Treatment FIG. 3. Mean IGF-I concentrations over the 24-h sampling period in six volunteers. Symbols represent the mean of all observations over the 24-h period for each individual. • , Pre-DEX; D, post-DEX. ***, P < 0.001.
450
1 1 M l•i— I 1
400
IGF1 (ug/L)
350
300
250
24
48
72
96
Time (h) FIG. 4. Mean IGF-I concentrations at 0800 h daily in 12 volunteers over the 96-h DEX treatment period. Each symbol (•) represents the mean of 12 observations. Bars indicate the SEM; arrows represent each dose of DEX (2 mg).
Casanueva and colleagues (17) have recently demonstrated that DEX itself is a potent stimulator of GH secretion when administered acutely, and we have assessed the patterns of GH secretion before and after DEX to assess whether there is an overall change in 24h GH secretion and whether the apparent acute stimulus of DEX is maintained after more prolonged treatment. DEX treatment did not result in a significant alteration of the total amount of GH secreted over the entire period, confirming the report by Vazquez and colleagues (26) in a 14-yr-old child. However, significant changes in the secretion profile were noticed, with a marked increase in the amount of hormone released in the afternoon, and a delay and attenuation of the nocturnal peak. In animals, the pattern of GH pulsatility is an important determinant of body weight gain and organ growth (2730), and it is possible that alterations induced by glucocorticoids may play a role in growth inhibition in man.
JCE & M • 1991 Vol 73 • No 6
The increase in GH secretion observed in the afternoon, although not resulting in a very well synchronized peak among the various subjects, occurred approximately 5 h after the last DEX administration, corresponding approximately to the time course of stimulation recently described (17). Although the mechanism of this stimulation remains to be elucidated, its time course is different from that of other known secretagogues (31), with a quite markedly delayed onset of action, followed by a protracted period of GH elevation. It has been suggested that glucocorticoids may have an initial stimulating effect on GH release, due to either somatostatin inhibition or direct pituitary stimulation, followed by and indeed superceded by a protracted inhibitory effect, presumably mediated by increased somatostatin release. This in vivo observation is again in direct contrast to that seen in in vitro models, where an initial inhibitory effect of glucocorticoids is followed by stimulatory effects (32). The acute stimulation of GH induced by DEX in vivo mirrors the permissive effects of short term DEX treatment (3 h) on GHRH-dependent GH secretagogues (12), an effect that could be explained by either increased pituitary GHRH sensitivity or acute inhibition of hypothalamic somatostatin release. The observation by Giustina and colleagues (33) of a dosedependent suppression of GHRH-induced GH stimulation by cortisone acetate, which was given just 1 h before the stimulation tests, would appear to contradict this hypothesis. Despite the differing kinetics between DEX and cortisone acetate and the problems in comparing the effects of these steroids, it is difficult to reconcile the differences in observed results. Nevertheless, it would appear that in the majority of cases, DEX does have an initial stimulatory capacity. The delay and attenuation of the nocturnal peak of GH secretion after DEX treatment may be due to an increase in somatostatin release or to classical negative feedback as a result of either the initial increase in GH levels or by induction of IGF-I, which has been shown to participate in a long loop inhibitory feedback on GH both in vivo and in vitro (34, 35). Interestingly, a pattern of GH secretion similar to that described here is seen in patients suffering from depression (36, 37), with an increase in daytime GH secretion and a loss of the postsleep-onset nocturnal pulse. These patients also exhibit alterations in cortisol secretion, with hypercortisolism and impaired DEX suppression (38). Furthermore, Lesch and colleagues (38) have demonstrated a significant increase in plasma IGF-I levels in depressed patients, the levels correlating positively with maximum post-DEX cortisol levels. In this study we have demonstrated a consistent and significant increase in plasma IGF-I levels after DEX treatment. The rise in IGF-I was gradual, reaching a plateau after 72 h of treatment. Other studies
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DEX AND 24-h GH SECRETION
have shown either an increase, no net change, or a decrease in IGF-I levels in patients with exogenous or endogenous hypercortisolism (39-42). The differences in the observed results may reflect the various assay procedures used: RIA, bioassay, or receptor assay. Early studies showed a glucocorticoid-induced inhibition of sulfate incorporation into cartilage both in vivo and in vitro, which could explain the apparent low levels of somatomedin activity in bioassay systems. Unterman and Phillips (43) have demonstrated an increase in somatomedin inhibitors after glucocorticoid therapy and have suggested that this may be an important part of the mechanism of steroid-induced growth failure. In the rat, Luo and Murphy (44) have shown that DEX has a suppressive effect on IGF-I mRNA levels in the tibia, liver, lung, and kidney, despite causing an acute increase in serum IGF-I levels. They have explained this apparent discrepancy by postulating either a glucocorticoid-induced alteration of translation, synthesis, and secretion of IGF-I or glucocorticoid modulation of binding protein synthesis, with concomitant alteration in the MCR of IGF-I. IGF-binding proteins, however, have a more complex role than merely carrier proteins (for review, see Ref. 45). Indeed, Taylor and colleagues (46) have recently demonstrated that the small mol wt binding protein (BP28) is possibly an inhibitor of IGF-I activity in diabetic serum, as measured in bioassay systems, and that despite relatively steady state concentrations of total IGF-I measured by RIA over a 24-h period, there is a marked fluctuation in IGF-I bioactivity. It is possible that glucocorticoids may have similar effects, with alterations in concentrations of binding proteins with inhibitor activity despite an overall increase in total IGF-I levels. In summary, we have shown that 4 days of moderate glucocorticoid excess do not alter the 24-h integrated GH secretion in man, but markedly affect its profile. These changes are similar to the alterations of GH secretion seen in depressed patients. We have also demonstrated that DEX treatment increases total IGF-I, measured by RIA after acid-ethanol extraction. It is likely that glucocorticoid-induced inhibition of somatic growth is multifactorial, and before the mechanisms involved are fully understood, further studies are necessary to assess the effects of glucocorticoids on IGF-binding proteins and IGF mRNA translation in man. Acknowledgments We thank Mrs. D. Turnill, Mrs. Pat Miell, and Mrs. C. ChauffatRabere for their expert technical assistance.
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1981;212:1279-81. 35. Ceda GP, Davis RG, Rosenfeld RG, Hoffman AR. The growth hormone (GH)-releasing hormone (GHRH)-GH-somatomedin axis: evidence for rapid inhibition of GHRH-elicited GH release by insulin-like growth factors I and II. Endocrinology. 1987;120:1658-62. 36. Mendlewicz J, Linkowski P, Kerkhofs M, et al. Diurnal hypersecretion of growth hormone in depression. J Clin Endocrinol Metab. 1985;60:505-12. 37. Linkowski P, Mendlewicz J, Kerkhofs M, et al. 24-hour profiles of adrenocorticotropin, cortisol, and growth hormone in major depressive illness: effect of antidepressant treatment. J Clin Endocrinol Metab. l987;65:141-52. 38. Lesch KP, Rupprecht R, Erb A, Niehaus A, Muller U. Hypothalamic-pituitary-adrenal (HPA) activity and growth hormone (GH) secretion in depression. Neuroendocrinol Lett. 1988;10:253. 39. Elders MJ, Wingfield BS, McNatt ML, Clarke JS, Hughes ER. Glucocorticoid therapy in children. Am J Dis Child. 1975;129:13936. 40. Gourmelen M, Girard F, Binoux M. Serum somatomedin/insulinlike growth factor (IGF) and IGF carrier levels in patients with Cushing's syndrome or receiving glucocorticoid therapy. J Clin Endocrinol Metab. 1982;54:885-92. 41. Furlanetto RW, Underwood LE, Van Wyk JJ, D'Ercole AJ. Estimation of somatomedin-C levels in normals and patients with pituitary disease by radioimmunoassay. J Clin Invest. 1977;60:64857. 42. Thoren M, Hall K, Rahn T. Somatomedin A levels in patients with Cushing's disease. Acta Endocrinol (Copenh). 1981;97:12-7. 43. Unterman TG, Phillips LS. Glucocorticoid effects on somatomedins and somatomedin inhibitors. J Clin Endocrinol Metab. 1985;61:618-26. 44. Luo J, Murphy LJ. Dexamethasone inhibits growth hormone induction of insulin-like growth factor-1 (IGF-1) messenger ribonucleic acid (mRNA) in hypophysectomized rats and reduces IGF-1 mRNA abundance in the intact rat. Endocrinology. 1989; 125:16571. 45. Ooi GT. Insulin like growth factor binding-proteins: more than just 1,2,3. Mol Cell Endocrinol. 1990;71:39-43. 46. Taylor AM, Dunger DB, Preece MA, et al. The growth hormone independent insulin-like growth factor-I binding protein BP-28 is associated with serum insulin-like growth factor-I inhibitory bioactivity in adolescent insulin-dependent diabetics. Clin Endocrinol (Oxf). 1990;32:229-39.
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Vol. 73, No. 6 Printed in U.S.A.
Dexamethasone Treatment in Man Induces Changes in 24-Hour Growth Hormone (GH) Secretion Profile without Altering Total GH Released* F. P. PRALONG, J. P. MIELLf, R. CORDER, AND R. C. GAILLARD Neuroendocrine Unit, Division of Endocrinology, Department of Medicine, University Hospital, 1211 Geneva 4, Switzerland
ABSTRACT. Glucocorticoids inhibit growth in man and laboratory animals and reduce the GH response to the majority of exogenously administered stimuli. Recently, however, glucocorticoids have been shown to have varying effects on GH secretion depending on the time of administration and, furthermore, to be potent secretagogues in their own right. To investigate this further, we have carried out sampling over two 24-h periods in six normal male volunteers both before and directly after treatment with dexamethasone (DEX; 2 mg twice daily) for 96 h. After DEX administration, all volunteers showed an increase in mean GH secretion during the first 9 h of sampling (0900-1800 h) compared with pre-DEX control profiles (5.1 ± 1.2 vs. 1.7 ± 0.5 Mg/L; P < 0.001). DEX treatment also had the effect of delaying and attenuating the nocturnal peak; mean GH secretion between 0000-0200 h was significantly greater before DEX (13.6 ± 2.7 ng/L) than after DEX (3.6 ± 0.7 ^g/L; P < 0.001), whereas that between 0300-0800 h was greater after DEX (5.5 ± 0.8 vs. 0.7 ± 0.2 /xg/L; P < 0.001). Individual nocturnal peaks ranged from 7.0-56.8 /ig/L, occurring between 0030-0200 h before DEX, and 2.6-21.2 jig/L, occurring between 0300-0400 h after DEX. Overall mean GH secretion was not significantly altered by DEX treatment (3.8 ± 0.6 vs. 4.2 ± 0.5 Mg/L; P = NS).
T
HE INHIBITORY effects of pharmacological doses of glucocorticoids on normal growth have been recognized for many years in both animals (1) and humans (2). Patients with hypercortisolemia due to either Cushing's disease or long term glucocorticoid therapy demonstrate reduced GH secretion (3, 4), and short term steroid treatment generally has a suppressive effect on the GH response to known secretagogues (5-10). In contrast, recent reports suggest that glucocorticoids can have permissive effects on stimulated GH release depending on the duration of pituitary exposure (11,12) and, in some cases, the secretagogue employed (13). Received November 26,1990. Address all correspondence and requests for reprints to: Dr. F. P. Pralong, Clinique Medicale, University Hospital, 1211 Geneva 4, Switzerland. * This work was supported by the Swiss National Science Fundation (Grant 3.091.087). t Present address: Department of Medicine, King's College School of Medicine, Bessemer Road, London, SE5 9PJ England.
Total insulin-like growth factor-I (IGF-I) levels, measured after acid-ethanol extraction, were significantly increased by DEX treatment, with mean IGF-I over the 24-h sampling period rising from 292.2 ± 31.8 to 425.9 ± 37 ng/h (P < 0.005). All individuals showed an increase in mean 24-h IGF-I of between 10-75%. In a second study, 12 male volunteers were treated with DEX in an identical manner, and blood was taken at 0800 h daily. Total IGF-I levels rose steadily from 307.9 ± 13.3 fig/L, reached a plateau at 72 h and remained elevated at 96 h (424.9 ± 16.5 Mg/L; P < 0.001). These results suggest that glucocorticoids alter the normal pattern of GH secretion with an increase in daytime levels, but a delaying and attenuating effect on the nocturnal pulse. Previous studies have suggested that IGF-I concentrations are decreased by steroid treatment, but these have been based on bioassay systems. Total IGF-I, measured by RIA, would appear to be consistently elevated; the apparent decrease seen in bioassay systems may be due to glucocorticoid-induced changes in binding protein concentrations. (J Clin Endocrinol Metab 73: 1191-1196,1991)
Furthermore, physiological levels of glucocorticoids seem to be mandatory for a normal GH response to stimulatory tests (14). In vitro studies have demonstrated a glucocorticoiddependent enhancement of both basal (15) and GHreleasing hormone (GHRH)-stimulated (16) GH secretion. These discrepancies may indicate that the pituitary effects of glucocorticoids are outweighed in vivo by an inhibitory hypothalamic action. The exact role of glucocorticoids in the regulation of GH secretion is, therefore, still unclear. Contrasting with the generally accepted idea that glucocorticoids inhibit GH secretion in man, Casanueva and colleagues (17) have recently been able to demonstrate that dexamethasone (DEX) alone administered acutely can result in a stimulation of GH release, hence complicating further the understanding of the effects of glucocorticoids on GH secretion. To assess whether this acute stimulatory effect is maintained after longer term treat1191
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PRALONG ET AL.
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merit with glucocorticoids, and whether there is any effect on overall 24-h GH secretion, we have assessed 24h GH profiles before and after DEX treatment. As growth and other anabolic actions of GH are mediated by the somatomedins (18, 19), we have also assessed the effects of glucocorticoids on insulin like growth factor-I (IGF-I) concentrations. Materials and Methods Six male volunteers (age range, 22-28 yr; mean weight, 66.2 kg; range, 58-71.4 kg, within the limits of the New-York Life Insurance tables of ideal body weight for height) were studied. Subjects were admitted at 0700 h on the morning of the first study day after an overnight fast and iv cannulae were placed in the antecubital fossa of the nondominant arm. An initial blood sample was taken at 0900 h; successive samples were taken at appropriate intervals thereafter over a 24-h period. Blood was collected into EDTA-coated tubes and immediately separated, and the plasma was stored at -20 C. During the sampling periods, subjects remained recumbent, apart from meal times (1200 and 1800 h) when they were allowed to sit up. At the end of the first 24-h period, DEX treatment was commenced; tablets were taken at 0900 and 2000 h daily. After 96 h of DEX treatment, the 24-h profiles were repeated in a manner identical to the first sampling day, with identical meals and meal times. Because the two 24-h sampling periods were separated by a period of only 96 h, it was decided to minimize the amount of samples taken as much as possible. Consequently, samples were generally taken at hourly intervals, with half-hourly sampling at times corresponding to postprandial rises in GH secretion and the expected peak after dexamethasone administration (17) (1400-1700 h) and the major nocturnal pulse (0000-0400 h). This gave a total of 32 samples over each 24-h period. To assess the time course of changes in total insulin-like growth factor (IGF-I) concentration, a second study was carried out. Twelve male volunteers (age range 21-26 yr; mean weight 68.2 kg; range, 61-79kg) were treated with oral DEX (2 mg twice daily for 96 h). Before the first dose and thereafter daily at 0800 h, blood was taken for estimation of cortisol and IGFI concentrations. The protocols were approved by the Ethical Committee, and all volunteers gave informed written consent and underwent full biochemical and physical screening before inclusion in the study. Assays and statistical analyses Human GH was measured using an immunoradiometric assay (Allegro), employing reagents purchased from Nichols Institute (San Juan Capistrano, CA). This assay has a sensitivity of 0.02 Mg/L- Intra- and interassay coefficients of variation were 1.8% and 6.2%, respectively. Total IGF-I was measured after acid-ethanol extraction (20), using kits purchased from the same company. Intra- and interassay coefficients of variation were 2.3% and 5.7%, respectively. Cortisol was measured by a competitive protein binding assay, as previously described (21), with intra- and interassay coefficients of variation of 5%
JCE & M • 1991 Vol 73 • No 6
and 10%, respectively, at 470 nmol/L. All samples from the same subjects were assayed simultaneously. Statistics GH demonstrates a nonparametric distribution, and therefore, all values were logarithmically transformed before data analysis. Mean GH secretion over a given time period was calculated by averaging the logarithmically transformed GH values for all subjects at all time points within that period; data were compared by Student's t test. For clarity, raw data are illustrated. Because nocturnal and daytime peaks did not necessarily occur simultaneously in all subjects, the maximum GH values attained for all subjects during the day (0900-2200 h) and at night (2200-0800 h) were identified. For both the pretreatment profiles and post-DEX profiles, these values are expressed as medians with 25th and 75th percentiles and were compared by Wilcoxon signed rank tests. Significance was
assumed when P < 0.05.
Results Expl A representative GH profile of one of the six subjects before and after DEX treatment is shown in Fig. 1 and illustrates a delayed and attenuated nocturnal peak in addition to an acute rise in GH levels after DEX treatment. Mean GH concentrations from 0900-1900 h are shown in Fig. 2a and illustrate a rise that was maximal some 6 h after the final DEX tablet was administered (1400 h). Mean GH secretion over the period 1300-1900 h was significantly increased by DEX (6.1 ± 1 . 6 us. 1.8 ± 0.6 M g / L ; P < 0.001). GH secretion between 2300-0900 h is shown in Fig. 2b. The nocturnal pulse was attenuated and delayed by DEX. Mean GH secretion between 0000-0200 h was significantly greater during the pre-DEX profile (13.6 ± 2.7 vs. 3.7 ± 0.7 /ig/L; P < 0.001), whereas that between 60 50 40 •
GH
30 20
10 0
0900
1300 1700 2100 0100 0500
0900
Time FIG. 1. A representative 24-h GH profile for one of six male volunteers before (O) and after (•) DEX treatment.
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DEX AND 24-h GH SECRETION
DEX (9.3 fig/L; 2.9-16.6; P = 0.046). In contrast, the median peak GH secretion occurring during the day (1.9 ixg/L; 0.5-6) 1.9 /ug/L; 0.5-6) was significantly increased by DEX treatment (13.0 Mg/L; 10-19.6; P = 0.026). Mean IGF-I concentrations over the 24-h sampling period before and after DEX for each of the six individual subjects are shown in Fig. 3. All subjects showed an increase in mean IGF-I after DEX; overall increases were from 292.2 ± 31.9 Mg/L pre-DEX to 425.9 ± 37.4 Mg/L post-DEX (P < 0.001). All subjects demonstrated adequate suppression of cortisol after DEX (432 ± 43 nmol/ L pre-DEX; 41.8 ± 4.1 post-DEX).
20 IS '
GH (Hg/L)
10 • 5 0 0900
1100 1300 1500
1700 1900
Time
25
Exp2
20 "
GH
1193
Figure 4 illustrates the rise in total IGF-I measured at 0800 h daily in 12 subjects. Basal values (307.9 ± 13.3 Mg/L) rose over the initial 72 h and remained elevated at 96 h (424.9 ± 16.5 »g/U P < 0.001 compared with basal levels). Within this group, all subjects showed adequate suppression of cortisol from basal 0800 h values of 417.2 ± 30.7 to 39 ± 2.6 nmol/L after the full course of DEX.
1S
10 " 5 '
2300 0100 0300
0500 0700 0900
Discussion
Time FIG. 2. GH secretion over the period 0900-1900 h and 2300-0900. The shaded area represents the mean ± SEM of six observations before DEX therapy. D, The mean of six observations after DEX. Bars indicate the SEM. *,P< 0.05; **, P < 0.01; ***, P < 0.001.
Growth retardation is a well described feature of both endogenous and exogenous glucocorticoid excess (3, 4), and in vivo glucocorticoids generally suppress the GH response to the majority of physiological and pharmacological stimuli (5-10). In vitro, glucocorticoids appear to have the opposite effect, with an enhancement of basal (15) and GHRH-stimulated GH release (16) and an increase in GH gene transcription (22) and GHRH receptor density (23). These apparently conflicting reports would suggest that in vivo regulation of the somatotroph axis by glucocorticoids is mediated at the hypothalamus, presumably through alteration in somatostatinergic tone (24, 25).
0300-0800 h was greater after DEX (5.5 ± 0.8 vs. 0.7 ±
0.2 ng/h;P< 0.001). The individual nocturnal or post-DEX GH peaks were not necessarily simultaneous; therefore, individual peak values with their times of occurrence were identified for each subject and are shown in Table 1 along with median values and quartiles. Median peak nocturnal GH secretion before DEX (20.6 /ug/L; 25th to 75th percentiles: 8.9-35.9 /ig/L) was significantly greater than that after
TABLE 1. Peak GH levels attained by each volunteer during day and nighttime sampling, with their times of occurrence, as well as the median values and 25th and 75th percentiles Nocturnal peaks Volunteer no.
1 2 3 4 5 6 Median (25th, 75th percentiles) 0
Pre-DEX
Daytime peaks Post-DEX
Pre-DEX
Post-DEX
Max GH
Time (h)
MaxGH
Time (h)
Max GH
Time (h)
MaxGH
Time (h)
7.0 20.8 8.9 56.8 20.4 35.9
0200 0200 0130 0100 0100 0030
11.0 11.2 2.6 7.6 2.9 17.2
0330 0330 0400 0500 0400 0400
0.3 0.5 0.5 11.6 5.9 3.3
1500 1530 1500 1500 1500 1500
10.1 15.7 5.4 19.6 55.2 10.3
1630 1500 1530 1500 1630 1700
on eo
(8.9, 35.9)
Q
o
(2.9,16.6)
1 Q°
(0.5, 6.0)
13.0 (10,19.6)
P < 0.05.
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PRALONG ET AL.
1194
IGF-1
600
n
500
-
400
-
300
-
I
200 r
post
pre
Treatment FIG. 3. Mean IGF-I concentrations over the 24-h sampling period in six volunteers. Symbols represent the mean of all observations over the 24-h period for each individual. • , Pre-DEX; D, post-DEX. ***, P < 0.001.
450
1 1 M l•i— I 1
400
IGF1 (ug/L)
350
300
250
24
48
72
96
Time (h) FIG. 4. Mean IGF-I concentrations at 0800 h daily in 12 volunteers over the 96-h DEX treatment period. Each symbol (•) represents the mean of 12 observations. Bars indicate the SEM; arrows represent each dose of DEX (2 mg).
Casanueva and colleagues (17) have recently demonstrated that DEX itself is a potent stimulator of GH secretion when administered acutely, and we have assessed the patterns of GH secretion before and after DEX to assess whether there is an overall change in 24h GH secretion and whether the apparent acute stimulus of DEX is maintained after more prolonged treatment. DEX treatment did not result in a significant alteration of the total amount of GH secreted over the entire period, confirming the report by Vazquez and colleagues (26) in a 14-yr-old child. However, significant changes in the secretion profile were noticed, with a marked increase in the amount of hormone released in the afternoon, and a delay and attenuation of the nocturnal peak. In animals, the pattern of GH pulsatility is an important determinant of body weight gain and organ growth (2730), and it is possible that alterations induced by glucocorticoids may play a role in growth inhibition in man.
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The increase in GH secretion observed in the afternoon, although not resulting in a very well synchronized peak among the various subjects, occurred approximately 5 h after the last DEX administration, corresponding approximately to the time course of stimulation recently described (17). Although the mechanism of this stimulation remains to be elucidated, its time course is different from that of other known secretagogues (31), with a quite markedly delayed onset of action, followed by a protracted period of GH elevation. It has been suggested that glucocorticoids may have an initial stimulating effect on GH release, due to either somatostatin inhibition or direct pituitary stimulation, followed by and indeed superceded by a protracted inhibitory effect, presumably mediated by increased somatostatin release. This in vivo observation is again in direct contrast to that seen in in vitro models, where an initial inhibitory effect of glucocorticoids is followed by stimulatory effects (32). The acute stimulation of GH induced by DEX in vivo mirrors the permissive effects of short term DEX treatment (3 h) on GHRH-dependent GH secretagogues (12), an effect that could be explained by either increased pituitary GHRH sensitivity or acute inhibition of hypothalamic somatostatin release. The observation by Giustina and colleagues (33) of a dosedependent suppression of GHRH-induced GH stimulation by cortisone acetate, which was given just 1 h before the stimulation tests, would appear to contradict this hypothesis. Despite the differing kinetics between DEX and cortisone acetate and the problems in comparing the effects of these steroids, it is difficult to reconcile the differences in observed results. Nevertheless, it would appear that in the majority of cases, DEX does have an initial stimulatory capacity. The delay and attenuation of the nocturnal peak of GH secretion after DEX treatment may be due to an increase in somatostatin release or to classical negative feedback as a result of either the initial increase in GH levels or by induction of IGF-I, which has been shown to participate in a long loop inhibitory feedback on GH both in vivo and in vitro (34, 35). Interestingly, a pattern of GH secretion similar to that described here is seen in patients suffering from depression (36, 37), with an increase in daytime GH secretion and a loss of the postsleep-onset nocturnal pulse. These patients also exhibit alterations in cortisol secretion, with hypercortisolism and impaired DEX suppression (38). Furthermore, Lesch and colleagues (38) have demonstrated a significant increase in plasma IGF-I levels in depressed patients, the levels correlating positively with maximum post-DEX cortisol levels. In this study we have demonstrated a consistent and significant increase in plasma IGF-I levels after DEX treatment. The rise in IGF-I was gradual, reaching a plateau after 72 h of treatment. Other studies
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DEX AND 24-h GH SECRETION
have shown either an increase, no net change, or a decrease in IGF-I levels in patients with exogenous or endogenous hypercortisolism (39-42). The differences in the observed results may reflect the various assay procedures used: RIA, bioassay, or receptor assay. Early studies showed a glucocorticoid-induced inhibition of sulfate incorporation into cartilage both in vivo and in vitro, which could explain the apparent low levels of somatomedin activity in bioassay systems. Unterman and Phillips (43) have demonstrated an increase in somatomedin inhibitors after glucocorticoid therapy and have suggested that this may be an important part of the mechanism of steroid-induced growth failure. In the rat, Luo and Murphy (44) have shown that DEX has a suppressive effect on IGF-I mRNA levels in the tibia, liver, lung, and kidney, despite causing an acute increase in serum IGF-I levels. They have explained this apparent discrepancy by postulating either a glucocorticoid-induced alteration of translation, synthesis, and secretion of IGF-I or glucocorticoid modulation of binding protein synthesis, with concomitant alteration in the MCR of IGF-I. IGF-binding proteins, however, have a more complex role than merely carrier proteins (for review, see Ref. 45). Indeed, Taylor and colleagues (46) have recently demonstrated that the small mol wt binding protein (BP28) is possibly an inhibitor of IGF-I activity in diabetic serum, as measured in bioassay systems, and that despite relatively steady state concentrations of total IGF-I measured by RIA over a 24-h period, there is a marked fluctuation in IGF-I bioactivity. It is possible that glucocorticoids may have similar effects, with alterations in concentrations of binding proteins with inhibitor activity despite an overall increase in total IGF-I levels. In summary, we have shown that 4 days of moderate glucocorticoid excess do not alter the 24-h integrated GH secretion in man, but markedly affect its profile. These changes are similar to the alterations of GH secretion seen in depressed patients. We have also demonstrated that DEX treatment increases total IGF-I, measured by RIA after acid-ethanol extraction. It is likely that glucocorticoid-induced inhibition of somatic growth is multifactorial, and before the mechanisms involved are fully understood, further studies are necessary to assess the effects of glucocorticoids on IGF-binding proteins and IGF mRNA translation in man. Acknowledgments We thank Mrs. D. Turnill, Mrs. Pat Miell, and Mrs. C. ChauffatRabere for their expert technical assistance.
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