0021-972X/78/4703-0686$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1978 by The Endocrine Society
Vol. 47, No. 3 Printed in U.S.A.
Collaborative Study of the Effects of Human Growth Hormone in Growth Hormone Deficiency. V. Treatment with Growth Hormone Administered Once a Week* S. DOUGLAS FRASIER, THOMAS ACETO, JR., AND ALVIN B. HAYLES Department of Pediatrics, University of Southern California School of Medicine, Los Angeles, California; University of South Dakota School of Medicine, Sioux Falls, South Dakota; The Mayo Clinic, Rochester, Minnesota; and the State University of New York, Buffalo, New York ABSTRACT. Twenty-two GH-deficient patients received 6 IU GH weekly for 6 months. They increased their growth rate from 1.0 ± 0.2 to 2.9 ± 0.3 (SE) cm/6 months (P < 0.01). However, their rate of growth was significantly less (P < 0.05) than the rate [4.1 ± 0.5 (SE) cm/6 months] observed earlier when they had received 2 IU GH three times a week. Seven patients received
weekly GH for 18 months and they also grew significantly less (P < 0.01) than when they had received GH divided over the week. These results suggest that once a week GH does not provide the most effective therapy for GH deficiency. (J Clin Endocrinol Metab 47: 686, 1978)
T
HE OPTIMAL treatment for patients with GH deficiency has not yet been defined. An early report (1) and a recent abstract (2) by Rosenbloom suggest that a single weekly injection of human GH leads to "optimal growth" in GH-deficient children. We investigated the growth-promoting effect of a single weekly injection of GH in an attempt to corroborate Rosenbloom's earlier results.
6 months were termed "good responders." Twentyeight good responders were randomly assigned to this phase II protocol. All patients received a single weekly injection of GH in a dose of 6 IU regardless of body weight or surface area. Biological potency data were supplied by the National Pituitary Agency. The response to treatment was evaluated by the patient's pediatric endocrinologist after 6 months. Those patients who had grown at least 2.5 cm continued to receive GH for an additional 12 months. As required by the Materials and Methods National Pituitary Agency when this protocol was approved, GH treatment was discontinued in paThe basic criteria for patient selection have been tients who grew less than 2.5 cm during the initial previously reported (3). At the conclusion of phase 6 months of weekly GH administration. I of the collaborative study (4), all patients had Data were submitted for analysis from 22 pareceived GH for 18 months and were then followed tients who completed 6 months of therapy. Sixteen for a variable period of time without therapy. For were male and 6 were female. The interval between the purpose of planning additional treatment prothe first and second course of GH therapy in the 22 tocols, phase I patients were divided into two patients averaged 13.6 ± 5.5 (SD) months and varied groups depending on their rate of growth during from 6-24 months. One patient had a craniopharthe last 6 months of their initial therapy. Fortyyngioma and the remaining patients had idiopathic eight patients who grew at a rate >2.5 cm in those GH deficiency. Four patients received cortisone acetate (20 mg/m2/day) in three divided doses and Received August 29, 1977. sodium-L-T4 (0.2 mg/m2/day) as a single daily dose Address requests for reprints to: S. Douglas Frasier, during the 6 months they were given a weekly LAC-USC Medical Center, 1129 N. State Street, Room injection of GH. 4E8, Los Angeles, California 90033. * This work was supported by grants from the Niagara At the end of the first 6 months of phase II Frontier Chapter of the Human Growth Foundation, The treatment, GH was continued in 15 patients. ThirVariety Club of Buffalo and Trans-World Airlines Clipped teen completed the full 18 months of a weekly Wings International and by USPHS General Research Grant through The Professional Staff Association of the injection of GH. These patients included the subLos Angeles County-University of Southern California ject with a craniopharyngioma and 12 children with Medical Center (Project 8-142). idiopathic GH deficiency. Two patients who had 686
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687
COMMENTS received GH for 18 months were also treated with cortisone acetate and sodium-L-T4. Height age (HA) was determined from standards published in Nelson's Textbook of Pediatrics (5), as modified by the Pediatric Endocrine Service of the Johns Hopkins Hospital, and the ratio of change in HA to change in chronological age (AHA:ACA) was calculated. Statistical analysis was performed with the standard methods (6).
Results The phase I treatment group to which a patient had been assigned did not influence the response to either 6 or 18 months of weekly .. GH administration. Therefore, the results from all patients were combined in the following analysis. As shown in Table 1A, the growth rate of > the 22 patients treated for 6 months increased significantly when compared to their rate of growth during the intertreatment period between the completion of phase I and entering this protocol. In 15 patients (68%), the growth rate exceeded 2.5 cm/6 months and the AHA:ACA was >1.0 while receiving weekly GH. As shown in Table IB, the rate of growth of the 13 patients who received 6 IU GH once a week for 18 months was significantly greater than during iLe intertreatment period of observation. The rate of growth was >7.5 cm/18 " months in 8 (62%) of these patients. However, the AHA:ACA was >1.0 over the full 18 months in only 4 patients (31%). The growth rate decreased from 3.8 ±0.1 (SE) cm during the first 6 months of treatment to 2.4 ± 0.4 (SE) during the second 6 months of therapy '* (P < 0.02 by paired t test). There was no v
TABLE 1. Response to GH (6 IU once a week) Intertreatment growth rate"
Treatment growth rate6
22), cm/6
1.0 ± 0.2
2.9 ± 0.3
B (n = 13), cm/18 months
4.0 ± 0.7
8.5 ± 0.6
A (n = months
Values given are means ± SE. " Extrapolated from intertreatment data. b P < 0.001 when compared to intertreatment growth by paired t test.
TABLE 2. Comparison of growth rates while receiving 6 IU GH once a week and 2 IU GH three times a week
A (n = 22)
Phase I 4.1 ± 0.5"
Phase II 2.9 ± 0.36c
8.5 ± 0.9rfe 14.9 ± 1.5" Values given are mean ± SE cm; number of subjects is in parentheses. " Twelve to 18 months. h Zero to 6 months. 0 P < 0.05 when compared to phase I by paired t test. '' Zero to 18 months. e P < 0.01 when compared to phase I by paired t test. B (n = 7)
further decrease during the last 6 months of GH administration. As shown in Table 2A, the growth rate of the 22 patients who received 6 IU GH once a week for 6 months was significantly less than that observed during the last 6 months of phase I when the same patients had received 2 IU GH three times a week. A comparison between 18 months of therapy with weekly GH and 18 months of therapy with GH administered three times a week could be made in 7 patients. As shown in Table 2B, their response to weekly GH was significantly less than when they had received the same amount of GH given in three doses over the week. Three of these 7 patients (43%) grew at a rate in excess of 7.5 cm when receiving weekly GH for 18 months. In 2 (29%), the AHA:ACA was
Discussion A complete comparison between our results and those of Rosenbloom (1) is not possible. His report gives neither the biological potency of the GH preparation (s) used nor the growth rate of his patients. His results can be expressed in terms of AHA:ACA. Rosenbloom treated six patients with 2.5 mg GH weekly for between 4-24 months. In three patients (50%), the AHA:ACA was >1.0. Four of these same patients were subsequently treated with 5 mg GH once a week for between 3-17 months. The AHA:ACA was >1.0 in three (75%). Assuming a GH potency of 1 U/mg, this higher dose is comparable to that which we used in this study. When our results are
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688
COMMENTS
also expressed in terms of AHA:ACA, they are comparable to those of Rosenbloom. However, our conclusion is not the same. We would interpret both Rosenbloom's and our results as indicating that GH administered once a week does not stimulate optimal growth in GH-deficient patients. Sufficient data is not given in Rosenbloom's recent abstract (2) to allow a comparison with our results. Our results indicate that while GH in a dose of 6 IU once a week will stimulate the growth of patients with GH deficiency, weekly treatment is less effective than treatment divided over the week. This interpretation is consistent with our previous conclusion drawn from an analysis of the pertinent literature (7) that GH administered three times a week is more effective than twice a week therapy. However, an alternative interpretation is also possible. As weekly GH administration followed therapy with GH given three times a week, the decreased response to 6 IU once a week may represent the expected waning effect of GH therapy with time (4, 7-9). A study designed to control for this phenomenon, e.g. two comparable groups of patients receiving 2 IU GH three times a week and 6 IU weekly as their initial therapy (preferably employing a crossover design), would provide a more definitive answer to the question of whether once a week GH administration will provide effective therapy for GH deficiency. This study remains to be done.
JCE&M • 1978 Vol47 • No 3
Acknowledgments Human GH was provided by The National Pituitary Agency, NIAMDD. The following physicians provided patient data: C. Anast. M. D. Cloutier, P. J. Collipp, S. S. Dunkelman, O. C. Green, W. H. Hoffman, D. C. Leach, M. MacGillivray, J. F. Marks, I. Rosenthal, H. Sauls, J. F. Sotos, and J. S. Spaulding. Invaluable clerical and secretarial assistance was given by Mr. R. Oliver, Ms. J. Krebs, and Ms. S. Dills.
References 1. ROSENBLOOM, A. L., Growth hormone replacement therapy, JAMA 198: 364, 1966. 2. ROSENBLOOM, A. L., M. L. NETZLOFK, A. D. GARNICA, AND F.
T. WEBER, Replacement therapy with human growth hormone (hGH); conservation via low dosage and routine thyroid (T) replacement, Pediatr Res 11: 431, 1977 (Abstract 359). 3. ACETO, T., JR., S. D. FRASIER, A. B. HAYLES, H. F. L. MEYERBAHLBURG, M. L. PARKER, R. MUNSCHAUER, AND G. DI-
CHIRO, Collaborative study of the effects of human growth hormone in growth hormone deficiency. I. First year of therapy, J Clin Endocrinol Metab 35: 483, 1972. 4. ACETO, T., JR., S. D. FRASIER, A. B. HAYLES, H. F. L. MEYERBAHLBURG, M. L. PARKER, R. MUNSCHAUER, AND G. DI-
CHIRO, Collaborative study of the effects of growth hormone in growth hormone deficiency. III. First eighteen months of therapy, In Raiti, S. (ed.), Advances in Human Growth Hormone Research, A Symposium, Baltimore, October 9-12,1973, DHEW Publication (NIH) 74-612, pp. 695-714. 5. VAUGHN, V. D , R. J. MCKAY, AND W. E. NELSON, Textbook
of Pediatrics, ed. 10, Philadelphia, W. B. Saunders Co., 1975. 6. BATSON, H. C, An Introduction to Statistics in the Medical Sciences, Minneapolis, Burgess Publishing Co., 1956. 7. FRASIER, S. D., T. ACETO, JR., A. B. HAYLES, AND V. G.
MIKITY, Collaborative study of the effects of human growth hormone in growth hormone deficiency. IV. Treatment with low doses of human growth hormone based on body weight, J Clin Endocrinol Metab 44: 22, 1977. 8. SOYKA, L. F., H. H. BODE, J. D. CRAWKROD, AND F. J. FLYNN,
JR., Effectiveness of long-term human growth hormone therapy for short stature in children with growth hormone deficiency, J Clin Endocrinol Metab 30: 1, 1970. 9. RUDMAN, D., J. H. PATTERSON, AND D. L. GIBBAS, Respon-
siveness of growth hormone deficient children to human growth hormone, J Clin Invest 52: 1108, 1973.
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Vol. 47, No. 3 Printed in U.S.A.
Collaborative Study of the Effects of Human Growth Hormone in Growth Hormone Deficiency. V. Treatment with Growth Hormone Administered Once a Week* S. DOUGLAS FRASIER, THOMAS ACETO, JR., AND ALVIN B. HAYLES Department of Pediatrics, University of Southern California School of Medicine, Los Angeles, California; University of South Dakota School of Medicine, Sioux Falls, South Dakota; The Mayo Clinic, Rochester, Minnesota; and the State University of New York, Buffalo, New York ABSTRACT. Twenty-two GH-deficient patients received 6 IU GH weekly for 6 months. They increased their growth rate from 1.0 ± 0.2 to 2.9 ± 0.3 (SE) cm/6 months (P < 0.01). However, their rate of growth was significantly less (P < 0.05) than the rate [4.1 ± 0.5 (SE) cm/6 months] observed earlier when they had received 2 IU GH three times a week. Seven patients received
weekly GH for 18 months and they also grew significantly less (P < 0.01) than when they had received GH divided over the week. These results suggest that once a week GH does not provide the most effective therapy for GH deficiency. (J Clin Endocrinol Metab 47: 686, 1978)
T
HE OPTIMAL treatment for patients with GH deficiency has not yet been defined. An early report (1) and a recent abstract (2) by Rosenbloom suggest that a single weekly injection of human GH leads to "optimal growth" in GH-deficient children. We investigated the growth-promoting effect of a single weekly injection of GH in an attempt to corroborate Rosenbloom's earlier results.
6 months were termed "good responders." Twentyeight good responders were randomly assigned to this phase II protocol. All patients received a single weekly injection of GH in a dose of 6 IU regardless of body weight or surface area. Biological potency data were supplied by the National Pituitary Agency. The response to treatment was evaluated by the patient's pediatric endocrinologist after 6 months. Those patients who had grown at least 2.5 cm continued to receive GH for an additional 12 months. As required by the Materials and Methods National Pituitary Agency when this protocol was approved, GH treatment was discontinued in paThe basic criteria for patient selection have been tients who grew less than 2.5 cm during the initial previously reported (3). At the conclusion of phase 6 months of weekly GH administration. I of the collaborative study (4), all patients had Data were submitted for analysis from 22 pareceived GH for 18 months and were then followed tients who completed 6 months of therapy. Sixteen for a variable period of time without therapy. For were male and 6 were female. The interval between the purpose of planning additional treatment prothe first and second course of GH therapy in the 22 tocols, phase I patients were divided into two patients averaged 13.6 ± 5.5 (SD) months and varied groups depending on their rate of growth during from 6-24 months. One patient had a craniopharthe last 6 months of their initial therapy. Fortyyngioma and the remaining patients had idiopathic eight patients who grew at a rate >2.5 cm in those GH deficiency. Four patients received cortisone acetate (20 mg/m2/day) in three divided doses and Received August 29, 1977. sodium-L-T4 (0.2 mg/m2/day) as a single daily dose Address requests for reprints to: S. Douglas Frasier, during the 6 months they were given a weekly LAC-USC Medical Center, 1129 N. State Street, Room injection of GH. 4E8, Los Angeles, California 90033. * This work was supported by grants from the Niagara At the end of the first 6 months of phase II Frontier Chapter of the Human Growth Foundation, The treatment, GH was continued in 15 patients. ThirVariety Club of Buffalo and Trans-World Airlines Clipped teen completed the full 18 months of a weekly Wings International and by USPHS General Research Grant through The Professional Staff Association of the injection of GH. These patients included the subLos Angeles County-University of Southern California ject with a craniopharyngioma and 12 children with Medical Center (Project 8-142). idiopathic GH deficiency. Two patients who had 686
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 29 November 2015. at 17:51 For personal use only. No other uses without permission. . All rights reserved.
687
COMMENTS received GH for 18 months were also treated with cortisone acetate and sodium-L-T4. Height age (HA) was determined from standards published in Nelson's Textbook of Pediatrics (5), as modified by the Pediatric Endocrine Service of the Johns Hopkins Hospital, and the ratio of change in HA to change in chronological age (AHA:ACA) was calculated. Statistical analysis was performed with the standard methods (6).
Results The phase I treatment group to which a patient had been assigned did not influence the response to either 6 or 18 months of weekly .. GH administration. Therefore, the results from all patients were combined in the following analysis. As shown in Table 1A, the growth rate of > the 22 patients treated for 6 months increased significantly when compared to their rate of growth during the intertreatment period between the completion of phase I and entering this protocol. In 15 patients (68%), the growth rate exceeded 2.5 cm/6 months and the AHA:ACA was >1.0 while receiving weekly GH. As shown in Table IB, the rate of growth of the 13 patients who received 6 IU GH once a week for 18 months was significantly greater than during iLe intertreatment period of observation. The rate of growth was >7.5 cm/18 " months in 8 (62%) of these patients. However, the AHA:ACA was >1.0 over the full 18 months in only 4 patients (31%). The growth rate decreased from 3.8 ±0.1 (SE) cm during the first 6 months of treatment to 2.4 ± 0.4 (SE) during the second 6 months of therapy '* (P < 0.02 by paired t test). There was no v
TABLE 1. Response to GH (6 IU once a week) Intertreatment growth rate"
Treatment growth rate6
22), cm/6
1.0 ± 0.2
2.9 ± 0.3
B (n = 13), cm/18 months
4.0 ± 0.7
8.5 ± 0.6
A (n = months
Values given are means ± SE. " Extrapolated from intertreatment data. b P < 0.001 when compared to intertreatment growth by paired t test.
TABLE 2. Comparison of growth rates while receiving 6 IU GH once a week and 2 IU GH three times a week
A (n = 22)
Phase I 4.1 ± 0.5"
Phase II 2.9 ± 0.36c
8.5 ± 0.9rfe 14.9 ± 1.5" Values given are mean ± SE cm; number of subjects is in parentheses. " Twelve to 18 months. h Zero to 6 months. 0 P < 0.05 when compared to phase I by paired t test. '' Zero to 18 months. e P < 0.01 when compared to phase I by paired t test. B (n = 7)
further decrease during the last 6 months of GH administration. As shown in Table 2A, the growth rate of the 22 patients who received 6 IU GH once a week for 6 months was significantly less than that observed during the last 6 months of phase I when the same patients had received 2 IU GH three times a week. A comparison between 18 months of therapy with weekly GH and 18 months of therapy with GH administered three times a week could be made in 7 patients. As shown in Table 2B, their response to weekly GH was significantly less than when they had received the same amount of GH given in three doses over the week. Three of these 7 patients (43%) grew at a rate in excess of 7.5 cm when receiving weekly GH for 18 months. In 2 (29%), the AHA:ACA was
Discussion A complete comparison between our results and those of Rosenbloom (1) is not possible. His report gives neither the biological potency of the GH preparation (s) used nor the growth rate of his patients. His results can be expressed in terms of AHA:ACA. Rosenbloom treated six patients with 2.5 mg GH weekly for between 4-24 months. In three patients (50%), the AHA:ACA was >1.0. Four of these same patients were subsequently treated with 5 mg GH once a week for between 3-17 months. The AHA:ACA was >1.0 in three (75%). Assuming a GH potency of 1 U/mg, this higher dose is comparable to that which we used in this study. When our results are
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 29 November 2015. at 17:51 For personal use only. No other uses without permission. . All rights reserved.
688
COMMENTS
also expressed in terms of AHA:ACA, they are comparable to those of Rosenbloom. However, our conclusion is not the same. We would interpret both Rosenbloom's and our results as indicating that GH administered once a week does not stimulate optimal growth in GH-deficient patients. Sufficient data is not given in Rosenbloom's recent abstract (2) to allow a comparison with our results. Our results indicate that while GH in a dose of 6 IU once a week will stimulate the growth of patients with GH deficiency, weekly treatment is less effective than treatment divided over the week. This interpretation is consistent with our previous conclusion drawn from an analysis of the pertinent literature (7) that GH administered three times a week is more effective than twice a week therapy. However, an alternative interpretation is also possible. As weekly GH administration followed therapy with GH given three times a week, the decreased response to 6 IU once a week may represent the expected waning effect of GH therapy with time (4, 7-9). A study designed to control for this phenomenon, e.g. two comparable groups of patients receiving 2 IU GH three times a week and 6 IU weekly as their initial therapy (preferably employing a crossover design), would provide a more definitive answer to the question of whether once a week GH administration will provide effective therapy for GH deficiency. This study remains to be done.
JCE&M • 1978 Vol47 • No 3
Acknowledgments Human GH was provided by The National Pituitary Agency, NIAMDD. The following physicians provided patient data: C. Anast. M. D. Cloutier, P. J. Collipp, S. S. Dunkelman, O. C. Green, W. H. Hoffman, D. C. Leach, M. MacGillivray, J. F. Marks, I. Rosenthal, H. Sauls, J. F. Sotos, and J. S. Spaulding. Invaluable clerical and secretarial assistance was given by Mr. R. Oliver, Ms. J. Krebs, and Ms. S. Dills.
References 1. ROSENBLOOM, A. L., Growth hormone replacement therapy, JAMA 198: 364, 1966. 2. ROSENBLOOM, A. L., M. L. NETZLOFK, A. D. GARNICA, AND F.
T. WEBER, Replacement therapy with human growth hormone (hGH); conservation via low dosage and routine thyroid (T) replacement, Pediatr Res 11: 431, 1977 (Abstract 359). 3. ACETO, T., JR., S. D. FRASIER, A. B. HAYLES, H. F. L. MEYERBAHLBURG, M. L. PARKER, R. MUNSCHAUER, AND G. DI-
CHIRO, Collaborative study of the effects of human growth hormone in growth hormone deficiency. I. First year of therapy, J Clin Endocrinol Metab 35: 483, 1972. 4. ACETO, T., JR., S. D. FRASIER, A. B. HAYLES, H. F. L. MEYERBAHLBURG, M. L. PARKER, R. MUNSCHAUER, AND G. DI-
CHIRO, Collaborative study of the effects of growth hormone in growth hormone deficiency. III. First eighteen months of therapy, In Raiti, S. (ed.), Advances in Human Growth Hormone Research, A Symposium, Baltimore, October 9-12,1973, DHEW Publication (NIH) 74-612, pp. 695-714. 5. VAUGHN, V. D , R. J. MCKAY, AND W. E. NELSON, Textbook
of Pediatrics, ed. 10, Philadelphia, W. B. Saunders Co., 1975. 6. BATSON, H. C, An Introduction to Statistics in the Medical Sciences, Minneapolis, Burgess Publishing Co., 1956. 7. FRASIER, S. D., T. ACETO, JR., A. B. HAYLES, AND V. G.
MIKITY, Collaborative study of the effects of human growth hormone in growth hormone deficiency. IV. Treatment with low doses of human growth hormone based on body weight, J Clin Endocrinol Metab 44: 22, 1977. 8. SOYKA, L. F., H. H. BODE, J. D. CRAWKROD, AND F. J. FLYNN,
JR., Effectiveness of long-term human growth hormone therapy for short stature in children with growth hormone deficiency, J Clin Endocrinol Metab 30: 1, 1970. 9. RUDMAN, D., J. H. PATTERSON, AND D. L. GIBBAS, Respon-
siveness of growth hormone deficient children to human growth hormone, J Clin Invest 52: 1108, 1973.
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