metabolic effects of human growth hormone in · the relationship of human growth hormone (hgh) to...

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Metabolic effects of human growth hormone in corticosteroid-treated children Helen G. Morris, … , Harold Elrick, Richard E. Goldsmith J Clin Invest. 1968; 47(3):436-451. https://doi.org/10.1172/JCI105740. The effects of administered human growth hormone (HGH) were evaluated in dwarfed, prepubertal children who were receiving long-term corticosteroid therapy for a chronic disease. During 11 complete metabolic balance studies, the eight corticosteroid-treated children demonstrated impaired response to large doses of HGH with minimal nitrogen and no phosphorus retention. In contrast, two hypopituitary subjects and two asthmatic children not receiving corticosteroid responded to the same preparations of HGH with nitrogen, potassium, and phosphorus retention. Six corticosteroid-treated children were given large doses of HGH (40-120 mg/wk for 4 to 8 months and showed no improvement in their retarded rate of growth, whereas the hypopituitary subjects showed accelerated growth during administration of 10-15 mg of HGH/wk. It is concluded that dwarfism in steroid- treated children results from corticosteroid-induced antagonism of the effects of HGH at the peripheral tissue level. Research Article Find the latest version: http://jci.me/105740-pdf

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Page 1: Metabolic effects of human growth hormone in · the relationship of human growth hormone (HGH) to this form of dwarfism. Response to HGH was evaluated during complete metabolic balance

Metabolic effects of human growth hormone incorticosteroid-treated children

Helen G. Morris, … , Harold Elrick, Richard E. Goldsmith

J Clin Invest. 1968;47(3):436-451. https://doi.org/10.1172/JCI105740.

The effects of administered human growth hormone (HGH) were evaluated in dwarfed,prepubertal children who were receiving long-term corticosteroid therapy for a chronicdisease. During 11 complete metabolic balance studies, the eight corticosteroid-treatedchildren demonstrated impaired response to large doses of HGH with minimal nitrogen andno phosphorus retention. In contrast, two hypopituitary subjects and two asthmatic childrennot receiving corticosteroid responded to the same preparations of HGH with nitrogen,potassium, and phosphorus retention. Six corticosteroid-treated children were given largedoses of HGH (40-120 mg/wk for 4 to 8 months and showed no improvement in theirretarded rate of growth, whereas the hypopituitary subjects showed accelerated growthduring administration of 10-15 mg of HGH/wk. It is concluded that dwarfism in steroid-treated children results from corticosteroid-induced antagonism of the effects of HGH at theperipheral tissue level.

Research Article

Find the latest version:

http://jci.me/105740-pdf

Page 2: Metabolic effects of human growth hormone in · the relationship of human growth hormone (HGH) to this form of dwarfism. Response to HGH was evaluated during complete metabolic balance

Metabolic Effects of Human Growth Hormone

in Corticosteroid-Treated Children

HELENG. MoRms, JACQUELINER. JORGENSEN,HAROLDELRICK, and

RICHARDE. GOLDSMITH, with the technical assistance of VIBART L. SUBRYAN

From the Department of Medicine, Veterans Administration Hospital,University of Colorado School of Medicine, and Children's AsthmaResearch Institute and Hospital, Denver, Colorado; MetabolicLaboratories, Cincinnati General Hospital, Cincinnati, Ohio.

A B S T R A C T The effects of administered humangrowth hormone (HGH) were evaluated indwarfed, prepubertal children who were receivinglong-term corticosteroid therapy for a chronic dis-ease. During 11 complete metabolic balance stud-ies, the eight corticosteroid-treated children dem-onstrated impaired response to large doses ofHGHwith minimal nitrogen and no phosphorusretention. In contrast, two hypopituitary subjectsand two asthmatic children not receiving corti-costeroid responded to the same preparations ofHGHwith nitrogen, potassium, and phosphorusretention. Six corticosteroid-treated children weregiven large doses of HGH (40-120 mg/wk for4 to 8 months and showed no improvement intheir retarded rate of growth, whereas the hypo-pituitary subjects showed accelerated growth dur-ing administration of 10-15 mg of HGH/wk. Itis concluded that dwarfism in steroid-treated chil-dren results from corticosteroid-induced antago-nism of the effects of HGH at the peripheraltissue level.

INTRODUCTION

One of the more distressing features of long-termcorticosteroid therapy of children is the resultant

A preliminary report was presented in part in the Pro-ceedings of the Endocrine Society, 47th meeting, 1965.(Abstr. No. 183)

Address requests for reprints to Dr. Helen G. Morris,1055 Clermont Street, Denver, Colo. 80220.

Received for publication 7 November 1966 and in re-vised form 21 September 1967.

inhibition of growth (1). The present study wasundertaken to obtain further information aboutthe relationship of human growth hormone(HGH) to this form of dwarfism. Response toHGHwas evaluated during complete metabolicbalance study and during prolonged administra-tion to children who were receiving corticosteroidsfor a chronic disease and who exhibited growthretardation as a result of corticosteroid therapy(2-4).

METHODSPatients. The corticosteroid-treated group consisted of

eight children who were 2 or more standard deviationsbelow normal in height. Most of the children showedminimal evidence of Cushing's syndrome other thangrowth retardation. Prepubertal subjects were selected sothat any response to HGHwould not be confused withan adolescent growth spurt. Six children were receivingcorticosteroids for intractable asthma, one for rheuma-toid arthritis, and one for the nephrotic syndrome. Theasthmatic subjects were drawn from the patient popula-tion of the Children's Asthma Research Institute andHospital where previous studies have shown that growthretardation is directly attributable to corticosteroid ther-apy, since steroid-treated children show more severegrowth inhibition, despite better control of asthma, thanthe nonsteroid-treated children (3, 4). The metaboliceffects of HGHduring 11 studies of the corticosteroid-treated patients were compared with those of two childrenwith panhypopituitarism and two asthmatic children not

receiving corticosteroid. The pertinent clinical featuresare summarized in Table I.

Metabolic balance studies. During a prolonged pre-study observation period, and during both the acute bal-ance and the long-term phases of the study, corticosteroid(prednisone) dosage was maintained at a constant level

436 The Journal of Clinical Investigation Volume 47 1968

Page 3: Metabolic effects of human growth hormone in · the relationship of human growth hormone (HGH) to this form of dwarfism. Response to HGH was evaluated during complete metabolic balance

TABLE I

Clinical Data on Subjects for Metabolic Balance Study

Height, deviationPatient Sex Age Diagnosis from mean Steroid dose Fasting HGH

m~.g/mlP. L. M 12 Asthma -2.2 SD Prednisone, 5 mg b.i.d. 8.5J. O'N. M 12 Asthma -2.6 sD Prednisone, 5 mg q.i.d. 14C. B. F 12 Asthma -4.4 SD Study 1, no steroid

Study 2, prednisone2.5 mg t.i.d. 6

J. S. M 12 Asthma -3.7 SD Prenisone, 2.5 mg t.i.d. 1.5M. K. F 12 Asthma -3.4 SD Prednisone, 5 mg b.i.d. 4.2K. K. M 13.5 Asthma -4.0 SD Prednisone, 5 mg t.i.d. <1M. P. F 12 Rheumatoid arthritis -5.5 SD Prednisone, 5 mg t.i.d.C. W. F 8 Nephrosis -4.0 SD Prednisone, 5 mg q.i.d. 10E. LJ. M 12 Asthma -2.2 SD None 5.0D. H. M 18 Panhypopituitarism None <1J. M. F 16 Panhypopituitarism None <1

and was the minimum required by each child at thebeginning of the study for control of symptoms. Childrenwere hospitalized in the Clinical Research Center of theUniversity of Colorado Medical School for completemetabolic balance studies which were carried out bystandard balance techniques. Each study consisted of an8 day stabilization period, an 8 day pre-HGH controlperiod, 8-12 days of HGHadministration, and an 8 daypost-HGH period. Throughout the study, urine wascollected in 24-hr pools and stools in 96-hr pools. Childrenreceived a constant diet of their choice. Food was eatenunder observation of the dietitian, and there were noreturns or refusals (except by patient J. M. whose re-turns were analyzed and during study I by patient C. B.who managed to hide some food). Most of the balancestudies were performed on two children simultaneouslyto provide an additional check on the technical aspects ofthe study.

HGH (Elrick) had an activity of 1.0 USP unit/mg(5, 6), as demonstrated by rat tibia bioassay. The hor-mone was dissolved with several drops of 0.1 N NaOHand diluted with normal saline; fresh solutions wereprepared every 48 hr. HGHwas administered daily byintramuscular injection in a volume of 1 ml preceded by0.4 ml of 1%o procaine hydrochloride given through thesame needle (7). During the pre-HGH control period,children were given placebo inj ections of procaine fol-lowed by normal saline. HGHdosage for the childrenwith hypopituitarism was 5 mg/day. Preliminary observa-tions suggested that steroid-treated children were un-responsive to HGH doses of 10 mg/day. Therefore,steroid-treated children received several consecutive 4-dayperiods of HGHadministration during which the dosewas progressively increased from 10 to 30 mg/day in anattempt to achieve a dose of HGH which would bemetabolically effective.

Methods of analysis. Specimens were analyzed fornitrogen by the micro-Kjeldahl method (8), calcium by

atomic absorption (9), phosphate by the method of Chen,Toribara, and Warner (10), sodium and potassium bythe flame photometer, and chloride and creatinine by theAutoAnalyzer (11, 12). For some of the studies (M. P.,E. LJ., D. H., J. M.) intake was determined by analysis.In the remaining studies intake was determined by calcu-lation from standard food composition charts (13, 14).Studies in our laboratory have indicated excellent agree-ment between analyzed and calculated diet compositionwith the exception of phosphorus content where analysisconsistently yields slightly higher values than thosedetermined by calculation.1

Metabolic balance was calculated for each substance andwas compared with theoretic balance (15). The resultsof the balance studies are charted according to the methodof Reifenstein, Albright, and Wells (16), with intakeplotted down from the zero line and excretion plotted upfrom the intake line. Positive metabolic balance is indi-cated by a clear zone below the zero line and negativebalance by excretion above the zero line. Nitrogen, phos-phorus, and calcium balances are plotted on scale, accord-ing to their ratios in normal body composition; potassiumbalance is not on this scale.

Long-term effects of HGH. After completion of themetabolic balance studies, six steroid-treated children weregiven prolonged courses of HGH. Steroid dosage wasmaintained at a constant level, and HGHwas adminis-tered intramuscularly 2 or 3 times a wk for 4-8 monthsat a total dose of 40-120 mg/wk. In contrast, the hypo-pituitary subjects received 10-15 mg of HGH/wk (in1-2 injections). Initially, a week's supply of HGHwasprepared at one time. Later each dose was dissolvedimmediately before injection. Children were seen weeklyfor measurement of height and weight and for observationof any untoward effects of the HGHor change in thepattern of their disease.

1 Unpublished observations.

Effects of HGHin Steroid-Treated Children 437

Page 4: Metabolic effects of human growth hormone in · the relationship of human growth hormone (HGH) to this form of dwarfism. Response to HGH was evaluated during complete metabolic balance

Assay of endogenous HGH concentration. Fastingplasma samples obtained during the control phase of thebalance studies were stored in the freezer and later ana-lyzed for endogenous HGHconcentration by the Glick,Roth, Yalow, and Berson radioimmunoassay (17).

RESULTSMetabolic balance studies. Fig. 1 illustrates

the results of a metabolic balance study duringwhich HGH (preparation E-54) was adminis-tered to a child with hypopituitarism at a doseof 5 mg/day. It can be seen that HGHresultedin nitrogen and potassium retention in associationwith marked phosphorus retention. The responsescontinued throughout the 12 day period of HGHadministration and are similar to those reportedin hypopituitary patients with other preparationsof HGH (18-22). This study, published previ-ously (7), is included here for comparison withthe effects observed in steroid-treated children.

Fig. 2 illustrates the response observed whenthe same preparation of HGH(E-54) was admin-istered in doses of 10 and 20 mg/day to an

J.M. s Age 16

asthmatic child (P. L.) who was receiving 10 mgof prednisone daily. Despite administration ofHGHat 2 and 4 times the dose found to be meta-bolically effective in the child with hypopituitarism,the steroid-treated child showed minimal nitrogenor phosphate retention and rapid rebound excre-tion after termination of HGH. Detailed balancedata are given in Table II A.

Fig. 3 demonstrates even less response whenthe same preparation of HGH (E-54) was ad-ministered simultaneously to another asthmaticchild (J. O'N.) who was receiving 20 mg/dayof. prednisone. In this study (see Table II B)there was minimal response to HGHwith returnto control excretion during the short period ofhormone administration. Despite a 1700 caloriediet containing 80- g of protein, the child was innegative metabolic balance. During a previousstudy, he received a higher calorie diet and main-tained positive metabolic balance, but he showeda similar poor response to HGH.

Fig. 4 illustrates the response to a different

Hypopituitarism

g/24 hrP can~

mm_PHOSPHORUS

0.2 i$/«/<

( -5H mg/dal

a I a 2 . 3 . 4 . 5 . 6 . 7 ,

4 Day PeriodsFIGURE 1 Metabolic effects of HGH (E-54) in a hypopituitary subject. In this study, as inall balance studies to be shown, results are plotted according to the method of Reifenstein,Albright, and Wells (15).

438 Morris, Jorgensen, Elrick, and Goldsmith

2 . 3 . 4 5 . 6 . 7II

Page 5: Metabolic effects of human growth hormone in · the relationship of human growth hormone (HGH) to this form of dwarfism. Response to HGH was evaluated during complete metabolic balance

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0.8.

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FIGURE 2 Metabolic effects of HGH(E-54) in an asthmatic child receiving 10 mg ofprednisone daily. Note that because of the larger dietary intake, the scale used forplotting the balance results is different from that of Fig. 1. Analyzed phosphorusretention is slightly less than theoretic balance during the control period and equalto theoretic balance during first HGHperiod.

preparation of HGH(E2P2) when administeredin doses of 10, 20, and 30 mg/day to a child(M. K.) receiving 10 mg of prednisone daily.The child was in positive metabolic balance duringthe control period. HGHproduced an increasein nitrogen and potassium retention and in urinarycalcium excretion. It can be seen, however, that thenitrogen and potassium retention were associatedwith paradoxical decrease in phosphorus retention,because of increase in both stool and urinary phos-phorus. The negative calcium balance duringHGHadministration also resulted in part fromparadoxical increase in stool excretion. The bal-ance study carried out simultaneously in patientK. K. was similar to that shown in Fig. 4 andlisted in Table II C.

The effect of steroid on calcium and phosphorusbalance during HGH administration is furtherdemonstrated by the responses of C. B. (Fig. 5).In the first study, shown on the left, the child was

not receiving steroid and had severe asthma. This

study was not entirely satisfactory because ofdifficulties with food intake. The second study,shown on the right, was performed several monthslater while the child was receiving 7.5 mg ofprednisone daily, and her asthma was well-con-trolled. In both studies, HGHcaused retention ofnitrogen and potassium but there was less reten-tion during steroid administration. When the childwas not receiving steroid, HGHadministration re-

sulted in phosphorus retention and growth duringthe course of the balance study. When she was

receiving steroid, HGH administration resultedin decreased phosphorus retention, and growth didnot occur. It can be seen from the figure thatphosphorus intake was comparable during the twostudies and that steroid therapy alone was asso-

ciated with increased stool phosphorus. When thechild was under the influence of HGHand steroid,there was a further marked increase in stool phos-phorus and negative phosphorus balance. Duringsteroid therapy, a similar paradoxical increase in

Effects of HGHin Steroid-Treated Children 439

MITROGEN

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Page 6: Metabolic effects of human growth hormone in · the relationship of human growth hormone (HGH) to this form of dwarfism. Response to HGH was evaluated during complete metabolic balance

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Page 7: Metabolic effects of human growth hormone in · the relationship of human growth hormone (HGH) to this form of dwarfism. Response to HGH was evaluated during complete metabolic balance

Asthma (Prednisone 20 mg /day)

g/24 hr

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FIGURE 3 Metabolic effects of HGH (E-54) in an asthmatic child receiving 20 mg ofprednisone daily. Analyzed phosphorus balance equals theoretic balance during thecontrol period and the HGHperiod.

stool calcium resulted in negative calcium balanceduring the HGHperiod.

The data shown in Table II and illustrated inFigs. 2-5 are representative of the results ob-served during each of the balance studies in thesteroid-treated children. Several children showedminimal response to HGHby every parametertested. Three of these subjects (P. L., J. O'N.,and J. S.) were studied during two balance periodsseparated by an interval of several months, andthey showed minimal responses on both occa-

sions. In some of the children, (M. K., K. K.,and M. P.), HGHadministration was associatedwith significant nitrogen retention, but even inthese patients corresponding retention of phos-phorus did not occur.

Table III lists the metabolic data obtained dur-ing HGHadministration to two asthmatic childrenwho were not receiving corticosteroid therapy.The markedly positive metabolic balance seen

throughout study 1 of C. B. (Table III A) may

be partly related to defective intake; however,excretion of nitrogen, phosphorus, and potassiumshowed definite decrease during HGHadminis-tration and reverted toward control after termi-nation of HGH. When the child was restudiedafter institution of prednisone therapy, (TableII D), HGHproduced minimal change in nitrogenand potassium excretion and a marked increase incalcium and phosphorus excretion.

The responses of another nonsteroid-treatedasthmatic child (E. LJ.) are shown in Fig. 6 andTable III B. In contrast to patient C. B., this pa-

tient had been symptom-free for a number ofmonths and, except for small stature (as a resultof previous corticosteroid therapy), he was essen-

tially a normal child at the time of study. Reten-tion of nitrogen observed during administrationof 5 mg/day of HGHincreased further whenHGH was increased to 10 mg/day. Nitrogenretention was associated with slight retention ofpotassium and phosphorus (greatest at the 10 mg

Effects of HGHin Steroid-Treated Children 441

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Page 8: Metabolic effects of human growth hormone in · the relationship of human growth hormone (HGH) to this form of dwarfism. Response to HGH was evaluated during complete metabolic balance

dose of HGH). There was no significant changein calcium balance during HGHadministrationbut after withdrawal calcium balance becamemarkedly positive.

Long-term effects of HGH. Despite the poor

responses to HGHwhich were observed duringthe metabolic balance periods, six of the steroid-treated children were given large doses of HGHfor periods of 4-8 months. Table IV lists theheights and weights of each of the children before,during, and after the period of HGHadministra-tion and for comparison also shows the growthrecord of a patient with panhypopituitarism whoreceived the same preparations of HGH. In con-

trast to the hypopituitary patient, none of thesteroid-treated children showed any change intheir retarded rate of growth during prolongedadministration of HGH. While the childrenshowed no change in height or bone age, severalshowed significant increase in weight during HGHadministration. This weight increase may be partly

related to maintenance of corticosteroid at a con-

stant level.Fig. 7 graphically compares the growth re-

sponse of one steroid-treated child (K. K.) withthat of the hypopituitary patient (D. H.). Thehypopituitary patient received 10-20 mg ofHGH/wk and showed an increase in growth.The steroid-treated child received HGH for 8months with doses of 120 mg/wk during the last3 months and showed minimal growth. The figurefurther demonstrates that the growth retardationassociated with corticosteroid therapy may be even

more severe than that of hypopituitarism. Thus,D. H., who had panhypopituitarism secondary to

craniopharyngioma (partially resected at age 5),grew 15 inches over a period of 13 yr with no

endocrine replacement therapy. In contrast, K. K.,the steroid-treated subject, grew normally untilshortly after institution of high dose corticosteroids(15 mg of prednisone daily), after which heshowed essentially no growth.

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FIGURE 4 Metabolic effects of a different HGHpreparation in an asthmatic child receiving10 mg of prednisone daily. Analyzed nitrogen and phosphorus balance equals theoretic balanceduring the control period.

442 Morris, Jorgensen, Elrick, and Goldsmith

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Page 9: Metabolic effects of human growth hormone in · the relationship of human growth hormone (HGH) to this form of dwarfism. Response to HGH was evaluated during complete metabolic balance

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FIGURE 5 Comparison of the effects of HGHon phosphorus and calcium balancein an asthmatic child before and during treatment with 7.5 mg of prednisone daily.

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FIGURE 6 Metabolic effects of HGH in an asthmatic childcorticosteroid therapy.

4, 5, 6 7

not receiving

Effects of HGHin Steroid-Treated Children 443

Page 10: Metabolic effects of human growth hormone in · the relationship of human growth hormone (HGH) to this form of dwarfism. Response to HGH was evaluated during complete metabolic balance

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Page 11: Metabolic effects of human growth hormone in · the relationship of human growth hormone (HGH) to this form of dwarfism. Response to HGH was evaluated during complete metabolic balance

TABLE IVEffect of Human Growth Hormone on Longitudinal Growth

Patient Date Age Height Weight HGH

K.K. Masthmaprednisone,5 mg t.i.d.

M.K. Fasthmaprednisone,5 mg b.i.d.

intermittentsteroid

J. O'N. Masthmaprednisone,5 mg q.i.d.

P.L. Masthmaprednisone,S mg b.i.d.

M.P. Frheumatoidarthritisprednisone,S mg t.i.d.

C.W. Fnephrosisprednisone,5 mg q.i.d.

D.H. Mhypopituitarismno steroid

2/6312/633/645/647/648/64

12/642/65

11/633/645/647/648/64

12/642/654/656/658/65

7/648/64

10/6412/642/654/658/65

2/647/649/64

10/6412/64

2/654/657/65

10/6411/64

1/653/65

10/658/66

2/638/63

10/6311/63

1/642/64

10/621/635/63

11/637/64

12/645/65

In.12.5 5113 5213.5 52.25

52.2552.50

14 52.7552.75

14.5 53

11.5 51.512 51.5

51.55252

12.5 5252

13 52.553

13.5 54

52.512 52.5

52.552.5

12.5 52.552.5

13 53

11.5 53.512 53.75

53.7553.7553.75

12.5 54.2554.50

13 55

14 52.552.552.552.5

15 52.516 52.25

7 417.5 42

4242.2542

8 42.25

19 54.554.5

19.5 55.220 57.520.5 5921 6022 61

Lb.7581878889919597

72757787858283828584

79879399

102103106

6065717275767781

747981818178

565956586463

747476758989.598

Metabolic study (HGH 240 mg)HGH, 25 mg b.i.w.HGH, 40 mg b.i.w.HGH, 40 mg t.i.w.HGHdiscontinued

Metabolic study (HGH 240 mg)HGH, 15 mg b.i.w.HGH, 25 mg b.i.w.HGH, 25 mg t.i.w.HGHdiscontinued

Metabolic study 1 (HGH 240 mg)

Metabolic study 2 (HGH 160 mg)HGH, 20 mg t.i.w.HGH, 20 mg t.i.w.HGHdiscontinued

Metabolic study 1 (HGH 240 mg)

Metabolic study 2 (HGH 160 mg)HGH20 mg t.i.w.HGH20 mg t.i.w.HGHdiscontinued

Metabolic studyHGH, 35 mg b.i.w.HGH, 35 mg b.i.w.HGHdiscontinued

Metabolic study (HGH 60 mg)HGH20 mg b.i.w.HGH20 mg b.i.w.HGHdiscontinued

Metabolic study (HGH 30 mg)HGH5 mg b.i.w.HGH5 mg b.i.w.HGH15 mgq wkHGH15 mg q wkHGH15 mg q wkHGH20 mg q wk

Effects of HGHin Steroid-Treated Children 445

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Hypopituitarism

HGH(Elrick)./ 15 mg/ week

14 16 Is 20

K.K. dAsthma

Prednisone 15mg/day

HGH(Etrick)120 mg / week

I I I . I .I8 10 12 14

AgeFIGURE 7 Growth response to human growth hormone. The hypopituitary subject showedacceleration of growth rate with small doses of HGH. The asthmatic child showed no improve-ment in his markedly retarded growth rate during treatment with large doses of HGH.

Most of the children tolerated the HGHwell.C. B. whose asthma was poorly controlled whenshe was not receiving corticosteroid became more

symptomatic during a period of marked fluid re-

tention while receiving HGH. Local skin reactionscharacterized by redness, tenderness, and swellingoccurred in K. K. after each injection of HGH.A minute amount of the same HGH prepara-

tion injected intracutaneously produced localizedblanching for 15-20 min and suggested that thelocal reactions were an irritant rather than an

allergic phenomenon. HGHadministration causedno other change in the pattern or severity of thebasic disease.

Endogenous GH concentrations. The concen-

trations of endogenous growth hormone in fastingplasma samples obtained during control periodsof the balance study are shown in the last columnof Table I. It can be seen that the steroid-treatedchildren had fasting levels of GH which are

similar to those reported in normal preadolescentchildren (23, 24). The hypopituitary subject hadunmeasurable levels of growth hormone both dur-ing fasting and after induced hypoglycemia.

DISCUSSION

The metabolic effects of HGH have been de-scribed by a number of investigators. Subjectshave included children with hypopituitarism (22),

gonadal dysgenesis (25, 26), constitutional dwarf-ism (27, 28), primordial dwarfism (22, 29), mal-nutrition (30), and infants (31, 32) and adultswith a wide variety of diseases (18-21, 33), in-cluding Cushing's syndrome (21). In virtually allreports, the effects of small doses of HGHhavebeen similar to those effects observed during theinitial metabolic balance studies in 1958-60(18-21), which demonstrated the effectiveness ofHGHin man and showed that the response toacute administration of HGHis characterized bynitrogen, potassium, and phosphorus retention andincreased urinary calcium excretion. The onlyexceptions to this response to HGHhave beenobserved in children with primordial dwarfism(29). The acute metabolic responses to HGHare

seen with such regularity that Wright, Brasel,Aceto, Finklestein, Kenny, Spaulding, and Bliz-zard (22), in reporting an extensive experiencewith HGHadministration to children with variousforms of dwarfism, indicated that the acute effectsof administered HGHrepresent a pharmacologicresponse which is to be expected whenever an

active preparation of HGH is administered; butacute metabolic effects, as judged by urinary ex-

cretion, are not necessarily indicative of improvedgrowth rate during prolonged HGHadministra-tion.

In this study the effects of HGHwere observed

446 Morris, Jorgensen, Elrick, and Goldsmith

62-1 D.H. d'

60-

58-

Height 56-

(Inches) 54-

52-

50

48

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during 11 complete metabolic balance studies ofeight children who had significant growth retarda-tion as a result of prolonged corticosteroid therapy.Results were compared with those observed intwo children with hypopituitarism and in twochildren with asthma who were not receiving corti-costeroids. The hypopituitary patients exhibitedthe greatest sensitivity to HGHin terms of magni-tude and duration of response, a finding which isin agreement with other reports. The two chil-dren who were not receiving corticosteroid demon-strated less response than the hypopituitary pa-tients, but both showed nitrogen retention inassociation with phosphorus and potassium reten-tion, and one child (C. B.) grew during the periodof HGHadministration. In contrast, the steroid-treated children had impaired response to admin-istered growth hormone. Although large doses ofHGH were given, most of the steroid-treatedchildren showed only minimal nitrogen retention.Phosphorus balance appeared to be an even moresensitive index of anabolic response since evenwhen nitrogen was retained, none of the steroid-treated children retained phosphorus.

Some of the abnormalities demonstrated in thesteroid-treated children would have been com-pletely overlooked had stool analysis not beenperformed in addition to urinary excretion studies.The paradoxical decrease in net intestinal absorp-tion of calcium and phosphorus during HGHad-ministration to the steroid-treated children em-phasizes the influence of the gastrointestinal tracton metabolic balance. In contrast to previous re-ports which have shown that HGHadministrationincreases absorption of phosphorus (18, 25) andcalcium (18, 34) from the gastrointestinal tract,in several steroid-treated children increased stoolexcretion was largely responsible for the negativephosphorus balance and contributed to the nega-tive calcium balance during HGHadministration(Figs. 4 and 5).

The repeated observation of absence of phos-phorus retention during administration of HGHto the corticosteroid-treated children is of particu-lar interest. Corticosteroids alone are known tocause profound effects on phosphorus balance withdecreased phosphorus content of muscle (35-37)and increased phosphorus excretion in urine (38-41) and stool (37, 41). HGHalone also producessignificant changes in phosphorus metabolism.

While the usual effect of administered HGHdur-ing balance study has been increased retention ofphosphorus in parallel with the improved nitrogenretention (18, 20, 25) HGHis known to affectphosphorus balance in the opposite direction aswell. In patients with acromegaly, the bone dis-ease presumably due to excessive GH has beenshown to be the result of marked increase in bothbone accretion and resorption rates (42). More-over, a number of patients with active acromegalyhave shown negative phosphorus balance in con-junction with the negative calcium balance (42,43). It thus appears that the over-all effect ofHGH-on external phosphorus balance is the resultof two opposing forces, deposition and resorption.In our study there was increased excretion of phos-phorus under the influence of corticosteroidsalone. The further increase in excretion under theinfluence of HGHmay be the result of increasedmobilization of phosphorus which is not utilizablein the presence of excess corticosteroid. The con-sistent finding of diminished phosphorus retentionduring administration of HGHseems significant,because it is difficult to conceive of new tissue for-mation occurring without phosphorus retention.

Similarly, it is impossible to conceive of newtissue formation in the absence of nitrogen reten-tion. In many studies nitrogen has been used asthe major parameter of GH response. However,the magnitude of the nitrogen retention often ob-served during administration of HGHis difficultto explain because it is seen in adults as well asin children (18-21) and is far in excess of theamount of nitrogen retained by normal, activelygrowing children (44). Furthermore, it has beenshown that the nitrogen retention may not be fol-lowed by growth during long-term HGHadminis-tration (22). Recently the concept that nitrogen"retention" is adequately reflected by the differ-ence between dietary intake and urine and stoolexcretion has been challenged (45, 46). There isevidence that urine and stool excretion may not bethe only sources of nitrogen loss from the body,since excess nitrogen or ammonia is also presentin expired air (46-48).

While HGH is of proven effectiveness in thetherapy of children with growth retardation sec-ondary to hypopituitarism (22), prolonged ad-ministration of HGHto children with other forms

Effects of HGHin Steroid-Treated Children 447

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of dwarfism has yielded variable results. Someobservers have reported significant improvementin growth rate during administration of HGHtochildren with gonadal dysgenesis (49) and con-stitutionally short stature (28), while others havereported minimal or no improvement in growthrate in children with dwarfism unrelated to pitui-tary disease (27, 50). In the present study, noneof the corticosteroid-treated children demonstratedany improvement in their retarded rate of growthduring prolonged therapy with large doses ofHGH.

In contrast to our studies, some investigatorshave reported that even small doses of HGHcanovercome effects of excessive corticosteroid. Ber-genstal and Lipsett described reversal of the nega-tive nitrogen balance with 5 mg/day of Rabengrowth hormone in a patient with Cushing's syn-drome (21). Matiasevic and Gershberg (51) de-scribed marked improvement in growth rate dur-ing administration of 9 mg/wk of Wilhelmi HGHto two children who were receiving corticosteroidin doses similar to our patients. We have noexplanation for these differences from our results.

It seems very unlikely that the responses ob-served in the present study are related to thespecific preparations- of HGHused (Elrick HGH).Each of the preparations was demonstrated bythe rat tibia bioassay to have potent biologic ac-tivity (5, 6), and the hypopituitary subjectsshowed typical responses to HGH during bothacute and long-term administration. It seems ap-parent that the altered effects observed in thesteroid-treated children were related to alteredability to respond to the hormone.

Antagonism between growth hormone and cor-ticosteroids has been suggested by reports ofothers. In 1952, Selye (52) demonstrated in in-tact rats that inhibition of linear growth duringcorticosteroid administration could be overcomeby simultaneous administration of a crude beefgrowth hormone preparation and that largeramounts of growth hormone were required assteroid dosage was increased. Similar results werereported earlier with ACTH in intact (53) andhypophysectomized (54) rats and more recentlywith cortisone by Soyka and Crawford (55).Small doses of cortisone have also been shownto inhibit growth in children with hypopituitarism.Blodgett, Burgin, Iezzoni, Gribetz, and Talbot re-

ported cortisone-inhibition of the retarded growthrate in untreated patients (1), while Soyka andCrawford (55) showed that the improved growthrate during HGHadministration was inhibitedby steroids but could be restored by increasingthe dose of HGH. In both studies, the dosage ofcortisone was lower than that which permits nor-mal growth in children with Addison's disease(1). These observations suggest that the antago-nistic effects of growth hormone and corticoster-oids are dose-related. In the present study, wewere unable to demonstrate any difference in re-sponse to HGHduring steroid therapy at dosesranging between 7.5 and 30 mg/day of prednisone.The deleterious effects of the steroid were notovercome by 30 mg/day of HGHduring the acutebalance study or by dosages up to 120 mg ofHGH/wk during long-term studies. It is possiblethat during steroid therapy in the dose rangeencountered in this study, still larger doses ofHGHwould be required to overcome the effectof the steroid.

It has recently been reported that in adults cor-ticosteroids inhibit pituitary release of growthhormone after hypoglycemia (56, 57), and it hasbeen postulated that relative deficiency of en-dogenous growth hormone might in part explainthe growth retardation of steroid-treated children(56). The results of the present study demonstratethat doses of HGHin the range of 8 times theamount shown to be growth promoting in a hy-popituitary patient are ineffective in the steroid-treated children. Moreover, as indicated in TableI and as will be described further in a separatecommunication from this laboratory, plasma levelsof endogenous HGH, both during the fasting stateand after hypoglycemia, are similar in steroid-treated and nonsteroid-treated asthmatic children(58). Our results are in agreement with thethesis that the growth retardation is related tothe "anti-anabolic effect" of corticosteroids (59)and may be associated with peripheral tissue in-ability to respond normally to available HGH.

Several lines of evidence indicate that deficiencyof growth hormone is not the responsible mecha-nism for most forms of dwarfism. Most childrenwith growth retardation have normal plasmalevels of GHand show normal responsiveness toinduced hypoglycemia (24, 60, 61). Furthermore,such children show little or no improvement in

448 Morris, Jorgensen, Elrick, and Goldsmith

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growth rate during therapy with HGH (27, 50).These data suggest that the growth retardationmay result from limited capacity of peripheraltissue to respond to available GH.

In certain forms of dwarfism such as gonadaldysgenesis and primordial dwarfism, the abnor-mality in responsiveness to HGHmay be a geneticdefect. In steroid-induced dwarfism, the abnor-mality results from the medication (3, 4) and isreversible if steroids can be discontinued (1).Other evidence which demonstrates the role oftissue responsiveness has been obtained in thislaboratory where it has been observed that starv-ing but otherwise normal individuals demonstratea paradoxical response to HGH, with increasedexcretion of nitrogen, phosphorus, and sodiuminstead of the opposite effect seen during HGHadministration to fed subjects (62). The require-ments necessary for tissue responsiveness to HGHare unknown. However, if the mechanisms respon-sible for corticosteroid-induced dwarfism can bedetermined, these may point the way to mecha-nisms responsible for other forms of dwarfism.

ACKNOWLEDGMENTThe authors gratefully acknowledge the expert dietarymanagement provided by Miss Therese Beaudette, HeadDietitian, University of Colorado Clinical Research Cen-ter; we are also indebted to Dr. Dalton Jenkins foradvice and encouragement throughout the course of thiswork.

This work was supported by a V.A. Clinical Investi-gatorship and Clinical Research Grants FR00051 andFR00068 from the U. S. Public Health Service. Dr.Morris is a V.A. Clinical Investigator.

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Effects of HGHin Steroid-Treated Children 451