0021-972X/90/7006-01612$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1990 by The Endocrine Society
Vol. 70, No. 6 Printed in U.S.A.
Preservation of Physiological Growth Hormone (GH) Secretion in Idiopathic Short Stature after Recombinant GH Therapy* RICHARD H. K. WU, YOLAINE ST. LOUIS, JOAN DiMARTINO-NARDI, SUSAN WESOLY, EDNA H. SOBEL, BARRY SHERMAN, AND PAUL SAENGER Department of Pediatrics, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York 10467; and Genentech, Inc., South San Francisco, California 94080
ABSTRACT. This study was undertaken to assess the recovery of spontaneous GH secretion 48 h after the cessation of GH therapy in children with idiopathic short stature treated with recombinant DNA-generated human GH (rhGH-M). Eleven prepubertal children with GH responses of 10.0 ng/mL or more after provocation were divided into therapeutic (n = 7) and control (n = 4) groups. GH was sampled every 20 min for 24 h in six treated and three control patients. One treated and one control patient had 12-h overnight studies because of their weight. The sampling studies were carried out before GH therapy was initiated and 48 h after rhGH was discontinued after 12 months of therapy. Three patients in the treated group also underwent a 24-h study at the 6 month time point. The treated group started treatment with rhGH (0.1 mg/kg), given three times a week. The results showed that pre- and posttreatment GH secretory profiles were comparable with respect to the
S
EVERAL short term studies recently demonstrated that human GH treatment in short children without GH deficiency will increase their growth velocity (1-3). The long term efficacy of GH therapy, using GH synthesized by recombinant DNA, technology is currently being investigated in children with idiopathic short stature (ISS). One large study has met with initial success, demonstrating significant increases in growth velocity (4). In most cases, GH will be given for many years until the patient is close to or at final height. The effect of recombinant GH (rhGH) therapy for 1 yr on spontaneous exogenous GH secretion when the subject is awake or asleep is unknown. Administration of GH for 2-3 days results in blunted GH responses to provocative stimuli and GH-releasing hormone (GHRH) infusion. Chronic administration may also cause a blunted
number of peaks, mean concentrations, peak amplitude, and secretory rate. At the 6 month point, the mean GH and peak GH amplitude (n = 3) were greater than the means of the treatment group (n = 7) at the 0 and 12 month points, but the difference was not statistically significant. Somatomedin-C rose in the treated group from 0.42 ± 0.1 to 1.25 ± 0.3 U/mL (mean ± SD; P < 0.01). In the control group it rose from 0.56 ± 0.1 to 1.16 ± 0.8 U/mL (mean ± SD; P > 0.05) because one patient entered puberty in the 12-month period of observation; his somatomedin-C level rose from 0.72 to 2.5 U/mL. We conclude that exogenous GH therapy does not interfere with the maintenance of endogenous pulsatile secretion of GH. These data show that exogenous GH therapy does not interfere with the maintenance of endogenous pulsatile secretion of GH and provide evidence for the resilience of the GH secretory system in the growing child. (J Clin Endocrinol Metab 70: 1612-1615,1990)
response to testing (5-9). In this study we investigated the effect of prolonged exogenous rhGH administration on endogenous GH secretion over a 24-h period in children with ISS.
Materials and Methods Subjects
Received July 5, 1989. Address all correspondence and reprints for reprints to: Paul Saenger, M.D. Department of Pediatrics, Montefiore Medical Center, 111 East 210th Street, Bronx, New York 10467. * Presented in part at the 68th Annual Meeting of The Endocrine Society, New Orleans, LA, 1988. This work was supported by Investigative Endocrinology Grant NIH-2T32-AM-007004-12.
Eleven children with ISS chosen for the study met the following criteria: height more than 2 SD below the mean; bone age retarded at least 1 yr relative to chronological age, growth velocity less than the 50th percentile for age, and GH responses greater than 10.0 ng/mL on provocative testing. These children were assigned to treatment and control groups in a manner such as to maintain the balance between the treated and control groups with respect to the pretreatment variables: height, age, maternal height, and body mass index (4). Seven children (six males and one female, aged 6 10/12 to 12 5/12 yr) were randomly chosen for treatment using 0.1 mg/kg rhGH, given three times weekly. Four (three males and one female) served as controls and received no treatment. One of the control subjects entered puberty after the baseline studies. All other children remained prepubertal during the 12-month study period. This study was approved by the Institutional Review
1612
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GH SECRETION IN ISS AFTER GH THERAPY Board at Montefiore Medical Center. Informed consent was obtained from parents, and assents were obtained from minors. Study design Physiological GH secretion was assessed by measuring GH in blood sampled every 20 min for 24 h. Two subjects, one in each group, had 12-h nocturnal studies rather than 24-h studies because their body weight was less than 20 kg. Their data were included in the nocturnal phase of the analysis (see figures). The same procedures and facilities were used for each subject in order to minimize variations in the study conditions. Catheters for blood sampling were inserted at 0800 h, and the electroenceophalogram electrodes were placed on the subjects at 0900 h. The catheter and the electrode wires exited the study room via a portal in the wall so as not to disturb the subjects during sleep. Each subject had 24-h studies (or 12-h nocturnal studies) at 0 and 12 months. Three children in the treated group underwent studies at 6 and 12 months. The 24-h studies were performed after GH administration was discontinued for 48 h. GH therapy resumed immediately after the blood sampling study was completed. Data analysis In analyzing the data, we calculated the mean GH concentrations, the number of GH secretory peaks, and the maximum peak GH concentration in the 24-h period as well as in the wake and sleep periods. The mean GH concentration is the arithmetic mean of the GH values from samples collected during the 24-h study. Any blood sample with a GH level below the limit of sensitivity of the assay (0.5 ng/mL) was assigned a value of 0.5 ng/mL. We also examined the concentration and secretory patterns of GH during sleeping and waking periods, paying special attention to the question of whether prior GH administration disturbed the physiological nocturnal increase in GH secretion. A secretory episode of GH was defined as follows: a peak GH concentration of 2.5 ng/mL or more, preceded or followed by a GH level of 1.5 ng/mL or more (3 times the sensitivity of the assay). These criteria insure that any single sample with a GH concentration of 2.5 ng/mL not preceded or followed by significant GH levels will not be considered a secretory episode. The results of our method of peak analysis were verified using the Cluster program supplied by Veldhuis and Johnson (10). Peak GH amplitude is the maximum GH concentration detected during a secretory episode. The GH secretory rate was calculated using a method developed for cortisol secretion and adapted for GH (11). Laboratory data GH was measured using the Hybritech (San Diego, CA) Tandem immunoradiometric assay kit. The sensitivity of the assay was 0.5 ng/mL, and the intra- and interassay coefficients of variation were 5.2% and 3.8%, respectively (12). Sleep stage was determined by scoring the electroencephalograms according to the method of Rechtschaffen and Kales (13).
1613
Results The 24-h secretory profiles of GH (mean, peak amplitude, and number of peaks) were similar at 0 and 12 months in the treated and control patients (Fig. 1). There were no significant differences in GH secretion when the sleep and wake periods at 0 and 12 months were compared (Figs. 2 and 3). GH secretory rates for the waking, sleeping, and 24-h periods are shown in Fig. 4. There
FIGURE 1 GH:ng/ml,# Peaks
TREATED CONTROL TREATED CONTROL TREATED CONTROL MEAN PEAKS SPEAKS • i O
MONTHS
n=4 CONTROL
H ! i 2 MONTHS AND
n=6 TREATED
FlG. 1. The 24-h mean GH concentrations, peak GH amplitudes, and number of GH secretory peaks in treated (n = 6) and control groups (n = 3) are shown here. Studies were conducted at 0 and 12 months. In the treated group, no rhGH was given for 48 h before the study at 12 months (Figs. 1-4). There were no statistically significant differences between the 0 and 12 month values or between the treated and control groups. Lines above the vertical bars indicate the SE.
FIGURE 2 GH:ng/ml,# Peaks
TREATED CONTROL TREATED CONTROL TREATED CONTROL MEAN PEAK AMPLITUDE #PEAKS 10 MONTHS
12 MONTHS
n=3 CONTROL and n-6 TREATED
FlG. 2. The GH profiles (mean, peak amplitude, and number of peaks) for the treated (n = 6) and control (n = 3) groups during waking hours are shown here. There were no differences between the treated and control groups. Lines above vertical bars indicate the SE.
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WU ET AL.
1614
FIGURE 3 GH:ng/ml, # Peaks
5 -
TREATED CONTROL TREATED CONTROL TREATED CONTROL MEAN PEAK AMPLITUDE #PEAKS
• H O MONTHS n=4 CONTROL
H ! i 2 MONTHS and
n=7 TREATED
FIG. 3. The GH profiles (mean, peak amplitude, and number of peaks) for the treated (n = 7) and control groups (n = 4) during sleep are shown here. There were no significant differences between the groups. Lines above the vertical bars indicate the SE.
FIGURE 4 500
400
400
300
300
200
200
100
100 I
^^^^fS-o-Qj
^^^^K--S^>C-i
^^^^•T i i I
differences in the patterns of GH secretion or the mean GH concentrations (3.1 vs. 3.6 ng/mL, pre- and posttreatment, respectively). Somatomedin-C levels rose from 0.42 ± 0.1 to 1.42 ± 0.3 U/mL (mean ± SD) at 0 and 12 months, respectively in the treated group and from 0.55 ± 0.1 to 1.15 ± 0.8 U/mL (mean ± SD) at 0 and 12 months, respectively, in the control group. The rise in somatomedin-C was expected in the treated group. In the control group the rise was attributable to one patient who entered puberty during the year of observation (somatomedin-C rose from 0.7 to 2.5 U/mL). Three of the treated patients had studies at 6 months. They had slightly higher mean concentrations and peak amplitudes compared to baseline and 12 month data. The difference was in no instance statistically significant (data not shown). The number of peaks, too, remained similar. Total sleep time, verified by sleep stage scoring, was nearly identical at the 0 and 12 month points in the treated group [453 ± 27 and 460 ± 25 min (mean ± SE), respectively] and in the control group (431 ± 16 and 444 ± 2 1 min, respectively).
Discussion
GH Secretion, ug/period 500
f\
JCE & M • 1990 Vol70«No6
^^^W|*^^*"^
^^^^M->^Ov*>t
I r\
TREATED CONTROL TREATED CONTROL TREATED CONTROL 24 Hr GH GH AWAKE GH ASLEEP • I 0 MONTHS ^ H 12 MONTHS n=6 TREATED n=3 CONTROL(Awake) n=7 TREATED n=4 CONTROL(24hr GH, Asleep)
FIG. 4. GH secretory rates (SR) for the treated (n = 7) and control (n = 4; sleep, n = 3; 24-h and awake) at 0 and 12 months are shown here. No statistically significant differences are found between the groups at 0 or 12 months, although it appeared that the control group had increased mean SR at 12 months (see Results). Vertical lines indicate the SE.
were no significant differences (P > 0.05) in the treated and control groups at 0 and 12 month. The mean secretory rate in the control group rose slightly at 12 months because of a single patient who entered puberty. In analyzing the GH secretory rate separately for awake and sleep periods, no statistically significant difference was found in either group. Figure 5 shows the GH secretory profiles in a representative subject from the treated group. There were no
Facilitated by the availability of recombinant DNAgenerated GH, several studies have begun to assess whether GH therapy is efficacious in the treatment of ISS. One year treatment data show that one such large study has met with initial success (4). Continuing improved growth rates may allow several growth-retarded children some measure of relief from the stigma of short stature (14,15). Our study attempted to assess the effect of GH therapy on physiological GH secretion in view of the reports of blunted GH responses to provocative stimuli in ISS children after treatment with GH (5-9). The study was undertaken to assess the resumption of physiological endogenous GH secretion after a protracted period of GH therapy in children who are not defined as GH deficient according to currently accepted criteria. Previously, one study had demonstrated reduced sleepentrained GH secretion in normal adult subjects after the acute administration of GH. However, GH secretion after protracted GH administration was not assessed in that study (8). The present study does not support the notion that long-term GH treatment may lead to an attenuation of endogenous GH secretion and possible growth deceleration after GH therapy has been discontinued. The data presented here demonstrate that physiological GH secretion, as defined by the mean GH concentration, maximum peak GH concentration, GH secretory rate, and number of secretory pulses over a 24h period of wake/sleep periods, was virtually unchanged by GH treatment.
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GH SECRETION IN ISS AFTER GH THERAPY
FIGURE 5a
1615
FIGURE 5b GH ng/ml
GH ng/ml
10 -
6a oo
6:00
12:00
MEAN CONCENTRATION 3.1 NO/ML
6; 00
6:00
MEAN CONCENTRATION 3.0 NO/ML
FlG. 5. Representative 24-h profiles of one study subject at 0 and 12 months are illustrated here. Serum GH was determined every 20 min for 24 h (0800-0800 h). Mean concentrations were 3.1 and 3.6 ng/mL, respectively.
Recently, Vance et al. (16) reported the preservation of pulsatile GH secretion after 14 days of continuous GHRH infusion in normal men. These researchers concluded that GHRH desensitization does not occur after chronic GHRH infusion. This conclusion, in turn, supports our premise that long-term exposure to high exogenous or endogenous GH levels does not interfere with physiological GH secretory dynamics. Furthermore, our control subjects displayed similar GH secretion and secretory patterns, on two separate tests, providing evidence that GH secretory patterns and GH secretory rates are generally similar on any given day. Minor variations in GH secretion may exist, but they were not significant for individual subjects or the group as a whole (P > 0.05). While it may be reassuring to note that in our study GH treatment does not delay the resumption of nor dampen the endogenous GH secretion once GH therapy is discontinued, further controlled studies are needed to confirm these findings afer more protracted, long term use of GH in the treatment of children with ISS.
Acknowledgments We wish to acknowledge the assistance of Lorraine Miller and Linda Kinsey for manuscript preparation, and Ken Fishman and Jonathan Smith for technical assistance.
References 1. Van Vliet G, Styne DM, Kaplan SL, Grumbach MM. Growth hormone treatment for short stature. N Engl J Med. 1983;309:1016-22. 2. Gertner JM, Genel M, Gianfredi SP, et al. Prospective clinical trial of human growth hormone in short children without growth hormone deficiency. J Pediatr. l984;104:172-6. 3. Raiti S, Kaplan SL, Van Vliet G, Moore WV. The National Hormone and Pituitary Program Growth Hormone Committee. Short term treatment of short stature and subnormal growth rate
with human growth hormone. J Pediatr. 1987;110:357-61. 4. Sherman B, Genentech Collaborative Group. Idiopathic short stature: results of a one-year controlled study of human growth hormone treatment. J Pediatr. 1989;115:713-9. 5. Abrams RL, Grumbach MM, Kaplan SL. The effect of administration of human growth hormone on the plasma growth hormone, cortisol, glucose and free fatty acid response to insulin: evidence for growth hormone autoregulation in man. J Clin Invest. 1971;50:940-50. 6. Hanew K, Goh M, Sato S, et al. The effects of acute and chronic growth hormone (GH) administration on GH secretion in patients with idiopathic GH deficiency. J Clin Endocrinol Metab. 1988;66:715-21. 7. Nakamoto JM, Gertner JM, Press CM, et al. Suppression of the growth hormone (GH) responses to clonidine and GH-releasing hormone by exogenous GH. J Clin Endocrinol Metab. 1986;62:82276. 8. Mendelson, WB, Jacobs LS, Gillin JC. Negative feedback suppression of sleep-related growth hormone secretion. J Clin Endocrinol Metab. 1983;56:486-8. 9. Ross RJM, Borges F, Grossman A, et al. Growth hormone pretreatment in man blocks the response to growth hormone releasing hormones: evidence for a direct effect of growth hormone. Clin Endocrinol (Oxf). 1987;26:117-23. 10. Veldhuis JD, Johnson ML. Cluster analysis: a simple, versatile and robust algorithm for endocrine pulse detection. Am J Physiol. 1986;250:E486-93. 11. Finkelstein JW, Roffwarg HP, Boyer RM, Kream J, Hellman L. Age-related change in the twenty-four hour spontaneous secretion of growth hormone. J Clin Endocrinol Metab. 1972;35:665-70. 12. Celniker AC, Chen AB, Wert Jr RM, Sherman BM. Variability in the quantitation of circulating growth hormone using commercial immunoassays. J Clin Endocrinol Metab. 1989;68:467-76. 13. Rechtschaffen A, Kales A. A manual of standardized terminology, techniques and scoring systems for sleep stages in human subjects. Washington DC: US Government Printing Office; 1968. 14. Steinhausen HC, Stahnke N. Negative impact of growth hormone deficiency on psychological functioning in dwarfed children and adolescents. Eur J Pediatr. 1977;126:263-370. 15. Albertsson-Wikland K. Growth hormone treatment in short children-short-term and long-term effects on growth. Acta Pediatr Scand. 1988;(Suppl)343:78-84. 16. Vance MI, Kaiser DL, Martha Jr PM, et al. Lack of in vivo somatotroph desensitization or depletion after 14 days of continuous growth hormone (GH)-releasing hormone administration in normal and a GH deficient boy. J Clin Endocrinol Metab. 1989;68:22-8.
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Vol. 70, No. 6 Printed in U.S.A.
Preservation of Physiological Growth Hormone (GH) Secretion in Idiopathic Short Stature after Recombinant GH Therapy* RICHARD H. K. WU, YOLAINE ST. LOUIS, JOAN DiMARTINO-NARDI, SUSAN WESOLY, EDNA H. SOBEL, BARRY SHERMAN, AND PAUL SAENGER Department of Pediatrics, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York 10467; and Genentech, Inc., South San Francisco, California 94080
ABSTRACT. This study was undertaken to assess the recovery of spontaneous GH secretion 48 h after the cessation of GH therapy in children with idiopathic short stature treated with recombinant DNA-generated human GH (rhGH-M). Eleven prepubertal children with GH responses of 10.0 ng/mL or more after provocation were divided into therapeutic (n = 7) and control (n = 4) groups. GH was sampled every 20 min for 24 h in six treated and three control patients. One treated and one control patient had 12-h overnight studies because of their weight. The sampling studies were carried out before GH therapy was initiated and 48 h after rhGH was discontinued after 12 months of therapy. Three patients in the treated group also underwent a 24-h study at the 6 month time point. The treated group started treatment with rhGH (0.1 mg/kg), given three times a week. The results showed that pre- and posttreatment GH secretory profiles were comparable with respect to the
S
EVERAL short term studies recently demonstrated that human GH treatment in short children without GH deficiency will increase their growth velocity (1-3). The long term efficacy of GH therapy, using GH synthesized by recombinant DNA, technology is currently being investigated in children with idiopathic short stature (ISS). One large study has met with initial success, demonstrating significant increases in growth velocity (4). In most cases, GH will be given for many years until the patient is close to or at final height. The effect of recombinant GH (rhGH) therapy for 1 yr on spontaneous exogenous GH secretion when the subject is awake or asleep is unknown. Administration of GH for 2-3 days results in blunted GH responses to provocative stimuli and GH-releasing hormone (GHRH) infusion. Chronic administration may also cause a blunted
number of peaks, mean concentrations, peak amplitude, and secretory rate. At the 6 month point, the mean GH and peak GH amplitude (n = 3) were greater than the means of the treatment group (n = 7) at the 0 and 12 month points, but the difference was not statistically significant. Somatomedin-C rose in the treated group from 0.42 ± 0.1 to 1.25 ± 0.3 U/mL (mean ± SD; P < 0.01). In the control group it rose from 0.56 ± 0.1 to 1.16 ± 0.8 U/mL (mean ± SD; P > 0.05) because one patient entered puberty in the 12-month period of observation; his somatomedin-C level rose from 0.72 to 2.5 U/mL. We conclude that exogenous GH therapy does not interfere with the maintenance of endogenous pulsatile secretion of GH. These data show that exogenous GH therapy does not interfere with the maintenance of endogenous pulsatile secretion of GH and provide evidence for the resilience of the GH secretory system in the growing child. (J Clin Endocrinol Metab 70: 1612-1615,1990)
response to testing (5-9). In this study we investigated the effect of prolonged exogenous rhGH administration on endogenous GH secretion over a 24-h period in children with ISS.
Materials and Methods Subjects
Received July 5, 1989. Address all correspondence and reprints for reprints to: Paul Saenger, M.D. Department of Pediatrics, Montefiore Medical Center, 111 East 210th Street, Bronx, New York 10467. * Presented in part at the 68th Annual Meeting of The Endocrine Society, New Orleans, LA, 1988. This work was supported by Investigative Endocrinology Grant NIH-2T32-AM-007004-12.
Eleven children with ISS chosen for the study met the following criteria: height more than 2 SD below the mean; bone age retarded at least 1 yr relative to chronological age, growth velocity less than the 50th percentile for age, and GH responses greater than 10.0 ng/mL on provocative testing. These children were assigned to treatment and control groups in a manner such as to maintain the balance between the treated and control groups with respect to the pretreatment variables: height, age, maternal height, and body mass index (4). Seven children (six males and one female, aged 6 10/12 to 12 5/12 yr) were randomly chosen for treatment using 0.1 mg/kg rhGH, given three times weekly. Four (three males and one female) served as controls and received no treatment. One of the control subjects entered puberty after the baseline studies. All other children remained prepubertal during the 12-month study period. This study was approved by the Institutional Review
1612
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GH SECRETION IN ISS AFTER GH THERAPY Board at Montefiore Medical Center. Informed consent was obtained from parents, and assents were obtained from minors. Study design Physiological GH secretion was assessed by measuring GH in blood sampled every 20 min for 24 h. Two subjects, one in each group, had 12-h nocturnal studies rather than 24-h studies because their body weight was less than 20 kg. Their data were included in the nocturnal phase of the analysis (see figures). The same procedures and facilities were used for each subject in order to minimize variations in the study conditions. Catheters for blood sampling were inserted at 0800 h, and the electroenceophalogram electrodes were placed on the subjects at 0900 h. The catheter and the electrode wires exited the study room via a portal in the wall so as not to disturb the subjects during sleep. Each subject had 24-h studies (or 12-h nocturnal studies) at 0 and 12 months. Three children in the treated group underwent studies at 6 and 12 months. The 24-h studies were performed after GH administration was discontinued for 48 h. GH therapy resumed immediately after the blood sampling study was completed. Data analysis In analyzing the data, we calculated the mean GH concentrations, the number of GH secretory peaks, and the maximum peak GH concentration in the 24-h period as well as in the wake and sleep periods. The mean GH concentration is the arithmetic mean of the GH values from samples collected during the 24-h study. Any blood sample with a GH level below the limit of sensitivity of the assay (0.5 ng/mL) was assigned a value of 0.5 ng/mL. We also examined the concentration and secretory patterns of GH during sleeping and waking periods, paying special attention to the question of whether prior GH administration disturbed the physiological nocturnal increase in GH secretion. A secretory episode of GH was defined as follows: a peak GH concentration of 2.5 ng/mL or more, preceded or followed by a GH level of 1.5 ng/mL or more (3 times the sensitivity of the assay). These criteria insure that any single sample with a GH concentration of 2.5 ng/mL not preceded or followed by significant GH levels will not be considered a secretory episode. The results of our method of peak analysis were verified using the Cluster program supplied by Veldhuis and Johnson (10). Peak GH amplitude is the maximum GH concentration detected during a secretory episode. The GH secretory rate was calculated using a method developed for cortisol secretion and adapted for GH (11). Laboratory data GH was measured using the Hybritech (San Diego, CA) Tandem immunoradiometric assay kit. The sensitivity of the assay was 0.5 ng/mL, and the intra- and interassay coefficients of variation were 5.2% and 3.8%, respectively (12). Sleep stage was determined by scoring the electroencephalograms according to the method of Rechtschaffen and Kales (13).
1613
Results The 24-h secretory profiles of GH (mean, peak amplitude, and number of peaks) were similar at 0 and 12 months in the treated and control patients (Fig. 1). There were no significant differences in GH secretion when the sleep and wake periods at 0 and 12 months were compared (Figs. 2 and 3). GH secretory rates for the waking, sleeping, and 24-h periods are shown in Fig. 4. There
FIGURE 1 GH:ng/ml,# Peaks
TREATED CONTROL TREATED CONTROL TREATED CONTROL MEAN PEAKS SPEAKS • i O
MONTHS
n=4 CONTROL
H ! i 2 MONTHS AND
n=6 TREATED
FlG. 1. The 24-h mean GH concentrations, peak GH amplitudes, and number of GH secretory peaks in treated (n = 6) and control groups (n = 3) are shown here. Studies were conducted at 0 and 12 months. In the treated group, no rhGH was given for 48 h before the study at 12 months (Figs. 1-4). There were no statistically significant differences between the 0 and 12 month values or between the treated and control groups. Lines above the vertical bars indicate the SE.
FIGURE 2 GH:ng/ml,# Peaks
TREATED CONTROL TREATED CONTROL TREATED CONTROL MEAN PEAK AMPLITUDE #PEAKS 10 MONTHS
12 MONTHS
n=3 CONTROL and n-6 TREATED
FlG. 2. The GH profiles (mean, peak amplitude, and number of peaks) for the treated (n = 6) and control (n = 3) groups during waking hours are shown here. There were no differences between the treated and control groups. Lines above vertical bars indicate the SE.
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WU ET AL.
1614
FIGURE 3 GH:ng/ml, # Peaks
5 -
TREATED CONTROL TREATED CONTROL TREATED CONTROL MEAN PEAK AMPLITUDE #PEAKS
• H O MONTHS n=4 CONTROL
H ! i 2 MONTHS and
n=7 TREATED
FIG. 3. The GH profiles (mean, peak amplitude, and number of peaks) for the treated (n = 7) and control groups (n = 4) during sleep are shown here. There were no significant differences between the groups. Lines above the vertical bars indicate the SE.
FIGURE 4 500
400
400
300
300
200
200
100
100 I
^^^^fS-o-Qj
^^^^K--S^>C-i
^^^^•T i i I
differences in the patterns of GH secretion or the mean GH concentrations (3.1 vs. 3.6 ng/mL, pre- and posttreatment, respectively). Somatomedin-C levels rose from 0.42 ± 0.1 to 1.42 ± 0.3 U/mL (mean ± SD) at 0 and 12 months, respectively in the treated group and from 0.55 ± 0.1 to 1.15 ± 0.8 U/mL (mean ± SD) at 0 and 12 months, respectively, in the control group. The rise in somatomedin-C was expected in the treated group. In the control group the rise was attributable to one patient who entered puberty during the year of observation (somatomedin-C rose from 0.7 to 2.5 U/mL). Three of the treated patients had studies at 6 months. They had slightly higher mean concentrations and peak amplitudes compared to baseline and 12 month data. The difference was in no instance statistically significant (data not shown). The number of peaks, too, remained similar. Total sleep time, verified by sleep stage scoring, was nearly identical at the 0 and 12 month points in the treated group [453 ± 27 and 460 ± 25 min (mean ± SE), respectively] and in the control group (431 ± 16 and 444 ± 2 1 min, respectively).
Discussion
GH Secretion, ug/period 500
f\
JCE & M • 1990 Vol70«No6
^^^W|*^^*"^
^^^^M->^Ov*>t
I r\
TREATED CONTROL TREATED CONTROL TREATED CONTROL 24 Hr GH GH AWAKE GH ASLEEP • I 0 MONTHS ^ H 12 MONTHS n=6 TREATED n=3 CONTROL(Awake) n=7 TREATED n=4 CONTROL(24hr GH, Asleep)
FIG. 4. GH secretory rates (SR) for the treated (n = 7) and control (n = 4; sleep, n = 3; 24-h and awake) at 0 and 12 months are shown here. No statistically significant differences are found between the groups at 0 or 12 months, although it appeared that the control group had increased mean SR at 12 months (see Results). Vertical lines indicate the SE.
were no significant differences (P > 0.05) in the treated and control groups at 0 and 12 month. The mean secretory rate in the control group rose slightly at 12 months because of a single patient who entered puberty. In analyzing the GH secretory rate separately for awake and sleep periods, no statistically significant difference was found in either group. Figure 5 shows the GH secretory profiles in a representative subject from the treated group. There were no
Facilitated by the availability of recombinant DNAgenerated GH, several studies have begun to assess whether GH therapy is efficacious in the treatment of ISS. One year treatment data show that one such large study has met with initial success (4). Continuing improved growth rates may allow several growth-retarded children some measure of relief from the stigma of short stature (14,15). Our study attempted to assess the effect of GH therapy on physiological GH secretion in view of the reports of blunted GH responses to provocative stimuli in ISS children after treatment with GH (5-9). The study was undertaken to assess the resumption of physiological endogenous GH secretion after a protracted period of GH therapy in children who are not defined as GH deficient according to currently accepted criteria. Previously, one study had demonstrated reduced sleepentrained GH secretion in normal adult subjects after the acute administration of GH. However, GH secretion after protracted GH administration was not assessed in that study (8). The present study does not support the notion that long-term GH treatment may lead to an attenuation of endogenous GH secretion and possible growth deceleration after GH therapy has been discontinued. The data presented here demonstrate that physiological GH secretion, as defined by the mean GH concentration, maximum peak GH concentration, GH secretory rate, and number of secretory pulses over a 24h period of wake/sleep periods, was virtually unchanged by GH treatment.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 12 November 2015. at 14:35 For personal use only. No other uses without permission. . All rights reserved.
GH SECRETION IN ISS AFTER GH THERAPY
FIGURE 5a
1615
FIGURE 5b GH ng/ml
GH ng/ml
10 -
6a oo
6:00
12:00
MEAN CONCENTRATION 3.1 NO/ML
6; 00
6:00
MEAN CONCENTRATION 3.0 NO/ML
FlG. 5. Representative 24-h profiles of one study subject at 0 and 12 months are illustrated here. Serum GH was determined every 20 min for 24 h (0800-0800 h). Mean concentrations were 3.1 and 3.6 ng/mL, respectively.
Recently, Vance et al. (16) reported the preservation of pulsatile GH secretion after 14 days of continuous GHRH infusion in normal men. These researchers concluded that GHRH desensitization does not occur after chronic GHRH infusion. This conclusion, in turn, supports our premise that long-term exposure to high exogenous or endogenous GH levels does not interfere with physiological GH secretory dynamics. Furthermore, our control subjects displayed similar GH secretion and secretory patterns, on two separate tests, providing evidence that GH secretory patterns and GH secretory rates are generally similar on any given day. Minor variations in GH secretion may exist, but they were not significant for individual subjects or the group as a whole (P > 0.05). While it may be reassuring to note that in our study GH treatment does not delay the resumption of nor dampen the endogenous GH secretion once GH therapy is discontinued, further controlled studies are needed to confirm these findings afer more protracted, long term use of GH in the treatment of children with ISS.
Acknowledgments We wish to acknowledge the assistance of Lorraine Miller and Linda Kinsey for manuscript preparation, and Ken Fishman and Jonathan Smith for technical assistance.
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