Postgraduate Medical Journal (October 1976) 52, 625-630.

The effect of administered corticosteroids on the growth of children

M. A. PREECEM.B.B.S., M.R.C.P., D.C.H.

Department of Growth and Development, Institute of Child Health, University of London

SummaryThe growth-inhibiting effect of exogenous corti-costeroids has been reported in many papers. Most ofthem have concerned the clinical problems of asthmaand rheumatoid arthritis but it is probable that theunderlying disease is relatively unimportant in deter-mining the effect on growth. Steroid therapy on alter-nate days seems to produce less undesirable effectsthan steroid treatment every day and corticotrophinmay be preferable.

Although the mechanisms are uncertain it seemslikely that the action is peripheral and certainlyexogenous growth hormone does not prevent thesteroid effect. A minimal dosage of corticosteroidsshould always be used in replacement therapy forhypopituitarism.

THE harmful effects of glucocorticoids on growthare well known to all clinicians who treat children.In general, this is recognized in the management ofbronchial asthma, rheumatoid arthritis and thenephrotic syndrome, as these are the most commonchildhood disorders that are treated with long-termcorticosteroids. This poor growth may also be associ-ated with a degree of maturational delay, which isusually observed as delayed skeletal age. The mech-anism of this effect on growth and how to prevent itis not known. Investigation of the various con-ditions in which it occurs can, however, give usvaluable insight into the pathogenesis of the poorgrowth and perhaps suggest ways of avoiding it.Growth retardation has long been recognized as a

feature of childhood Cushing's syndrome where thesource of excessive glucocorticoids is endogenous.Prader, Tanner and von Harnack (1963) described agirl who had suffered with Cushing's syndrome from4 months to 4 years of age, at which time an adrenaladenoma was removed. By the time of the operationshe was 5 2 s.d. below the mean of stature for agealthough her weight was well above the mean. Thegrowth velocity over the 2 years before the operationwas 3 -2 cm/year but following the surgery it increasedrapidly so that it was 17-8 cm/year during the sub-sequent year. Growth velocity remained above the

Correspondence: M. A. Preece, Institute of Child Health,30 Guilford Street, London WC1N 1EH.

mean until after 11 years of age by which time herstature was well inside the normal range. Skeletalmaturation was delayed by 2-7 'years' at the time ofsurgery but advanced very rapidly after the removalof the tumour so that at 11 years of age the bone agewas some 1P5 'years' advanced.

Similar reports of the growth retarding effect andpostoperative growth of Cushing's syndrome havebeen reported by Strickland et al. (1972) in fourcases due to bilateral adrenal hyperplasia. Theircases were all older than that of Prader et al. (1963)at the time of surgery (9-8-15-8 years) but all showedsimilar 'catch-up' growth. In three of these cases theserum growth hormone concentration in response toinsulin hypoglycaemia and arginine infusion wasmeasured before surgery and in all four patientsafterwards. In one of the cases tested before surgery,an abnormally low growth hormone response wasobserved. In the other two cases the response was inthe normal range and in all four cases the post-operative tests gave quite normal responses.

Growth in children receiving systemic steroids forchronic asthma

In a condition such as perennial and intractableasthma, a multiplicity of factors of varying impor-tance may influence growth. The illness itself mayhave important effects, but certainly nutritional andpharmacological influences may overlay and aggra-vate this basic problem. In recent years the role ofprolonged therapy with corticosteroids in suppressinggrowth has attracted great interest, and ways havebeen sought to minimize the harmful effects orto avoid them completely. Falliers et al. (1963)reviewed the growth status in two groups of asth-matic children; one group included many who werereceiving systemic steroids and were in-patients, theother group received conservative treatment only asout-patients.There were 302 children in the first group who

were considered to have intractable asthma and whowere admitted to the Children's Asthma ResearchInstitute and Hospital in Denver, U.S.A., between1958 and 1960. The age group of the patients rangedfrom 5 to 16 years and they were in residence for anaverage of 18 months. Heights and weights were

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TABLE 1. The distribution of height in the groups of asthmatic patients admittedto the Children's Asthma Research Institute and Hospital in Denver, U.S.A., and

a further 103 children seen as out-patients.

Theoretical No steroidsnormal Intermittent Continuous

s.d. mean population 1940-1950 1958-1960 steroids steroids

> +2-0 2-3 1-9 00 19 0+2-0-+1l0 13-6 4 9 2-0 10 1 3-2+1 0- 0.0 34-1 20-4 14-3 9-5 9-50 0--1-0 34-1 33 0 46-9 32-3 25-3

-10--2-0 13-6 31-1 28-6 31-0 29-5> -2-0 2-3 8-7 8-2 15-2 32-6

Total no. 103 49 158 95

determined on admission and at regular intervalsthereafter, and these measurements were comparedwith standards for an equivalent normal population.Initially, 20% of the children were 2 or more s.d.below the mean for height, which is about tentimes as many as would be expected in the generalpopulation.Bone age was also determined on admission and

at yearly intervals during their stay, using themethod of Greulich and Pyle (1959), and in generalthere was an equivalent degree of maturational delay;that is, the children on average had a normal heightfor bone age, although a low height for chrono-logical age. Thus, at least part of the short staturewas due to growth retardation.

Retrospective histories of the patients' intake ofsteroids were recorded as far as possible and allowedthe division of these 302 children into three sub-groups as shown in Table 1. The three sub-groupswere: (a) children who had never received steroids(16-2%); (b) children who had received interruptedcourses of steroids (52-3 %); (c) children who hadreceived steroids continuously or with only shortinterruptions for at least 1 year before admission(31'5%).

In the majority of children in the category (c)there was a long history of steroid administrationwhich had usually started intermittently and gradu-ally become continuous. Also shown is the heightdistribution for a second major group, consisting of103 children seen on a purely out-patient basisbetween 1940 and 1950. None had received steroidsand their asthma was probably milder.Comparison of the children's stature with their

history of steroid dosage indicated that the childrenwith more normal growth had on the whole receivedless steroids. For example, only about 8% of thechildren who had received no steroids in the pastwere more than 2 s.d. below the mean for staturewhereas 33%/ of the children on continuous steroidswere below this same limit. Recalculations from thepublished data show that the proportion of children

with heights more than 2 s.d. below the mean dif-fered very significantly between the groups, beinglower in those with low or absent dosage (P< 0 005).The more steroids, the shorter the child.A major problem with this type of datum is the

interaction between the severity of the disease, thesteroid therapy and the effects on growth. It is almostimpossible to dissociate these factors, as the moreseverely asthmatic patients are more likely to receivesteroids, and are also the smallest. When the staturesof the 302 children with severe asthma were com-pared with those of the 103 children treated in thepre-steroid era it was seen that the second groupassumed an intermediate position between normalchildren and the severely affected children, many ofwhom had received steroids.

In the same paper the relative stunting effects ofprednisone, betamethasone and cortisone were com-pared. The authors came to the conclusion that adosage of prednisone of 6 mg/m2/day and beta-methasone at 0'6 mg/M2 would produce significantgrowth retarding effects but that cortisone at a dosagebetween 50 and 70 mg/m2/day did not usually pro-duce poor growth. This result is surprisingly high anddoes not relate well to other estimates (see below).In a more recent paper Kerrbijn and De Kroon (1968)studied seventeen children between 5 6 and 10 5 yearsof age (bone ages between 6-3 and 10-0 'years').These children were all treated with prednisone orprednisolone in varying doses; each child receivedseveral different dosages of the drug for a period ofat least 6 months each. Growth rates and skeletalmaturation rates were related to the dosage ofsteroids for each child so that each acted as his owncontrol. The authors concluded that when the dosageof prednisone was less than 2X9 mg/m2/day therewas no significant growth retardation, but when itwas > 4 mg/m2/day then significant growth retarda-tion resulted. This is of particular interest, as theformer dosage level is equivalent to less than 12 mg ofcortisol/m2/day and therefore less than the normaldaily hydrocortisone production by the adrenal gland

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Steroids and growth 627

whereas the higher dosage range is clearly above thenormal secretion rate (Weitzman et al., 1971). Theseauthors also showed that the higher doses of steroidswere associated with a reduced rate of skeletalmaturation.The importance of the frequency of administration

of exogenous steroids has been particularly investi-gated by Morris (1975) in a study of 189 childrenwith severe asthma who were admitted to a resi-dential treatment centre in Denver, U.S.A. Thesechildren were divided into two groups; ninety-oneadmitted in 1965 and ninety-eight in 1970. Morrisconcluded that significant growth and maturationaldelay were related to the more continuous higherdose steroid regimes whereas low frequency inter-mittent regimes seemed to be associated with rela-tively little effect. A sub-group of seventy-six childrenwas studied while under treatment in the centre. Inthose where the regime was unchanged from thatwhich the child experienced before admission, therewas little effect on growth or maturational pattern.In contrast, when relatively intermittent treatmentbefore admission was changed to a steroid-freeregime, there was an increase in growth rate in allof ten such patients. The reverse was seen in twofurther groups of patients where steroids were in-creased from rare or intermittent dosage regimes tomore frequent therapy. In these two situations therewas a worsening in the growth retardation in eightof ten and nine of eleven cases respectively. Changesin the rate of bone age maturation paralleled theeffects on linear growth.Two major approaches have been made towards

circumventing this undesirable effect of steroids. Atrial of corticotrophin (ACTH) suggested that it maynot only prevent the growth retardation, if usedinstead of corticosteroids, but that it may also reversepre-existent growth retardation (Friedman andStrang, 1966). However, when a similar study wascarried out by Norman and Sanders (1969) theyfailed to confirm this effect. Comparison betweenthe two studies is not really possible, however,because the dosages of steroids and corticotrophinwere different and, as Norman and Sanders (1969)state, the severity of the asthma in the two groupsmay have been quite different. Further, the latterpaper only covered a growth period of 6 monthsfollowing the first administration of the cortico-trophin and this may have been an inadequate time.Zutshi, Friedman and Ansell (1971), discussingchildren and rheumatoid arthritis, commented thatan increase in height was only observed when endo-genous ACTH production had recovered, a processwhich may take up to 1 year.Another regime for avoiding growth retardation

has been the use of alternate-day steroid therapy.This was introduced following observations that a

30

CP

- 200E0

1020E

30

E

20

010

E

0

Steroid- free day Steroid doy

FIG. 1. Growth and hormone cortisol, fasting (E) andpeak during an insulin tolerance test (C]); mean con-centration ± s.e. mean (n=14). Data from Sadeghi-Nejad and Senior (1969).

single dose of steroids may exert its therapeuticeffect longer than its adrenal suppression effect(Reichling and Kligman, 1961). The more physio-logical nature of episodic doses of cortisol has alsobeen suggested by the data of Weitzman et al. (1971)which demonstrated the pulsatile nature of cortisolsecretion by the normal adrenal. Sadeghi-Nejad andSenior (1969) reported a study in fourteen childrenof whom seven were suffering with nephrotic syn-drome, six with ulcerative colitis and one withasthma. All received alternate-day prednisonetherapy for periods between 6 and 50 months. Noneofthem showed a Cushingoid appearance and growthwas normal or accelerated in twelve of the fourteenchildren. Insulin tolerance tests were performed onall the children on days when they were takingsteroids and on days when they were not; theseresults are summarized in Fig. 1. On the day ofprednisone ingestion the initial concentration ofplasma cortisol was initially very low and failed toincrease with the stress of hypoglycaemia, whereason the steroid-free day the inital concentration ofcortisol was higher and there was a marked increasein response to hypoglycaemia. The basal concen-tration of growth hormone was the same on the twodays and on both occasions increased significantlyfollowing hypoglycaemia. However, the maximalincrease of growth hormone on the steroid day was

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significantly less than that on the steroid-free day.In a rather different group of children who had renaltransplantation, alternate-day steroid therapy wassimilarly shown to be more compatible with normalgrowth than daily therapy (McEnery et al., 1973).There is thus evidence that an alternate-day regimemay well be preferable to continuous steroids inavoiding the harmful effects of growth, but stillallow the full therapeutic benefit.

Juvenile rheumatoid arthritisBefore turning to discussion of the cause of the

growth retardation in steroid treatment we shouldconsider briefly one other cause for children toreceive long-term steroids. In juvenile rheumatoidarthritis, when more conservative methods havefailed, steroids or ACTH remain the only usefultherapy. Here again, like asthma, growth retardationcan be a problem but unlike asthma there is anotherproblem of interpretation, namely, the destructionof many of the ossification centres by the primarydisease, making assessment of skeletal maturityimpossible. Retardation of growth may occur in thisdisease as a result of the disease process itself, par-ticularly when the inflammatory process remainsactive for many years but this retardation may beintensified by maintained, long-term, daily corti-costeroid therapy (Bywaters, 1965). In 1971, Zutshiet al. reported the use of ACTH therapy and con-cluded that if the ACTH was substituted for pre-existing steroid therapy then there was some benefitin terms of growth rate in three of five patients butthat there might be a flare-up of the rheumatoidprocess during the change-over. In contrast, ifACTHwas used as the primary therapy then normal growthwas usually maintained and the symptoms could, ingeneral, be adequately controlled. Sometimes, extratherapy was needed intermittently to control acuteexacerbations. These authors felt that the ACTHdosage should aim to allow endogenous ACTH pro-duction to occur, as gauged by measuring the 9 a.m.plasma cortisol levels 48 hr after ACTH administra-tion.

Sturge et al. (1970) studied cortisol and growthhormone secretion together with growth in anothergroup of twenty children suffering with rheumatoidarthritis who were on four different treatmentregimes. Five were receiving no steroids and theygrew normally. Six were on daily steroids, threereceived alternate day steroids and six were receivingalternate day ACTH injections. The growth ratewas least in group 2 but essentially normal in thosemembers of groups 3 and 4 who had started on

alternate steroids rather than being converted froma daily regime.The responses of growth hormone concentration

in an insulin tolerance test were inconsistent but it

was concluded that they were probably normal. Morerecently, Daly et al. (1974) measured growth hor-mone, ACTH and corticosteroid concentrationsduring insulin tolerance tests in three different groupsof patients with rheumatoid arthritis (twelve in eachgroup); these patients were all adults. One group wasreceiving corticosteroids, one ACTH and the thirdgroup neither drug. It was shown that cortisol pro-duction was essentially normal in the ACTH groupbut very low in the steroid group; the ACTH peakwas low in the ACTH group but the total amountsecreted during the test (integrated response) wasnormal. In contrast the peak and integrated secre-tions were low in the steroid-treated group. Thegrowth hormone peaks were low in both treatmentgroups but lower in the steroid group. They con-cluded that the timing of the dosage may be impor-tant; it seemed that if the steroids were given in asingle large dose, there was less interference with theendogenous mechanisms. This observation accordswell with the other observations which have beenmade about relative benefits of alternate-day steroidsover the daily dosages.

Mechanism of growth retardationThe manner in which corticosteroids reduce

growth is unknown. There are, however, some indi-cators worth reviewing. As described above, theevidence as to the effect of steroids on growth hor-mone secretion, is contradictory. It seems that themajor effect is to block growth hormone action; adirect effect to inhibit its production by the pituitaryis slight or non-existent. The use of exogenousgrowth hormone to counteract the steroid effect hasbeen uniformly disappointing as long as the steroidshave continued to be taken. Tanner et al. (1971)reported the use of human growth hormone in twochildren with rheumatoid arthritis who were receivingcorticosteroids. In the first case there was noresponse, even to 60 i.u./week, while on a steroiddosage equivalent to 50 mg of cortisone daily. In thesecond case, a growth spurt occurred while thepatient was still receiving prednisone 3 mg/day, butas she entered puberty at the same time the signifi-cance is obscured.

Morris et al. (1968) in short term metabolic studiesand longer term growth studies showed markedimpairment of the action of growth hormone ineight steroid-treated children as compared to non-steroid-treated children.

In patients with multiple pituitary hormone de-ficiencies who are receiving both steroids and growthhormone replacement therapy the growth benefit ofthe latter is severely impaired by steroids, even indoses of 25 mg cortisone acetate daily, and moremarkedly with larger doses. Fig. 2 shows an exampleof such a patient (S.J.). Clearly the full growth effect

628

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Steroids and growth 629

UmGn growth hrm.on (20 Ju J/Wk) -

6

-5

4 -'

,>%, etZ,lL~~~~~~~~~~~.D.c.............................. t..

X~~~~~I . ii;Z.'t.)..iiillF

.. !:- IS.-l

'' '' '' '' I.... ^.1.- ....... p .-g.-ug--i

Age (yawrs)FIG. 2. Growth velocity response of patient S.J. to humangrowth hormone replacement while receiving differentdoses of cortisone acetate.

of the growth hormone was not seen until the cor-tisone acetate was reduced to 17-5 mg/day andpossibly further benefit would have been achievedif the dose of the steroids could have been furtherreduced. In a patient not receiving steroids, themaximum growth velocity on receiving growth hor-mone replacement is always seen in the first 3 or 6months and the gradual build up of the growthvelocity as seen in this boy is distinctly unusual. Itis likely that he had been positively held back by thecorticosteroids until the dosage was adequatelyreduced. In this context it is particularly interestingthat his growth velocity was closely correlated withthe dose of cortisone (r=0-93, P<0 001) over sixobservations. Hall and Olin (1972), in hypopituitarypatients receiving growth hormone and cortisolacetate found no significant growth inhibition by thelatter at doses of 10-15 mg/day. These results arein good agreement with our own experience in theGrowth Clinic at the Hospital for Sick Children,Great Ormond Street, London.

It appears, then, that the site of action of thesteroids is at the periphery. It is now well knownthat growth hormone induces the synthesis of afamily of smaller peptides by the liver. These areusually referred to as the 'somatomedins' or 'sul-phation factor' and appear to mediate the growthpromoting action of growth hormone. It is thereforepossible that one site of action of cortisol is ininhibiting the production of the somatomedin by theliver. In a small series of seven growth-hormone-deficient patients, Hall (1971) measured serumsomatomedin concentrations following intravenoushuman growth injection (4 or 8 i.u.). All the patientswere receiving maintenance growth hormone replace-ment and three were also receiving cortisone acetate12-5-25 mg/day. Maximum somatomedin responsewas seen at 3 hr, but no later values were reported.

In two of the three patients receiving cortisoneacetate there was no somatomedin response and asimilar lack of response was seen in one of the fourpatients not taking steroids. These data may lendsome support to the supposition that the steroidsinhibit the action of growth hormone on the liver.There is also evidence of interference at one of thetarget cells of the somatomedins, namely, thechondrocytes. The primary action of somatomedinon the chondrocyte is to stimulate the incorporationof sulphate into the cartilage molecule; Mosier andJansons (1975) have demonstrated reduced sul-phate uptake by the cartilage when exposed to cor-ticosteroids. Similarly Van den Brande (1975) hasobserved a sulphate uptake inhibiting effect of highconcentrations of corticosteroids in serum samples,in which somatomedin activity is being assayed bythe porcine rib cartilage assay. Thus, corticosteroidsin the blood samples may lower the sulphate uptakeand give a falsely low value for circulating somato-medin concentrations. Clearly, much work remainsto be done in this area to elucidate the actual pro-cesses involved.

ConclusionThe action of corticosteroids in inhibiting growth

cannot be disputed. The mechanisms are, for thepresent, obscure but it appears that the action isperipheral and is reduced by alternate-day regimes.If steroids need to be used for anti-inflammatorypurposes, in relatively high non-physiological dosesthen it seems that alternate day (or even less frequent)regimes are worthwhile. Here the dosage is dic-tated by the clinical response of the patients butobviously should be the minimum that will controlthe patient's primary symptoms.When steroids, usually as cortisone acetate or

cortisol, are being used for replacement therapy, therequired dosage is much lower. In congenital adrenalhyperplasia a dosage of cortisol of 25 mg/M2 ofbody surface area has been advocated for replace-ment (Brook et al., 1974) but it should be remem-bered that this is a quite different clinical situation.In our experience of patients receiving growthhormone and cortisone acetate for hypopituitarism,doses of 7 5-10 mg of the latter have usually beenadequate, provided the patient is aware of the needfor increasing this at times of concurrent illnesses.The time relationships between the administration ofcortisol and growth hormone has been studied byRudman et al. (1973) studying short-term anaboliceffects. It appears that if these two hormones must begiven then they should be separated in time as muchas possible, although no direct study has yet beenmade in terms of long-term growth. It would seemmost physiological if the cortisol was given in themorning and growth hormone at night.

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Finally, the need for keeping the use of corti-costeroids to a minimum makes especially importantclear confirmation that steroid therapy is necessary,by unequivocal demonstration that ACTH secretionis impaired in hypopituitary patients.

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(1974) Experience with long-term therapy in congenitaladrenal hyperplasia. Journal of Pediatrics, 85, 12.

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DALY, J.R., FLETCHER, M.R., GLASS, D., CHAMBERS, D.J.,BITENSKY, L. & CHAYEN, J. (1974) Comparison of effects oflong-term corticotrophin and corticosteroid treatment onresponses of plasma growth hormone, ACTH, and corti-costeroid to hypoglycaemia. British Medical Journal, 3,521.

FALLIERS, C.J., TAN, L.S., SZENTIVANYI, J., JORGENSEN, J.R.& BUKANTZ, S.C. (1963) Childhood asthma and steroidtherapy as influences on growth. American Journal ofDiseases of Children, 105, 127.

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PRADER, A., TANNER, J.M. & VON HARNACK, G.A. (1963)Catch-up growth following illness or starvation. Journal ofPediatrics, 62, 646.

REICHLING, G.H. & KLIGMAN, A.M. (1961) Alternate-daycorticosteroid therapy. Archives of Dermatology, 83, 980.

RUDMAN, D., FREIDES, D., PATTERSON, J.H. & GIBBAS, D.L.(1973) Diurnal variation in the responsiveness of humanisubjects to human growth hormone. Jouirnal of ClinicalInvestigation, 52, 912.

SADEGHI-NEJAD, A. & SENIOR, B. (1969) Adrenal function,growth, and insulin in patients treated with corticoids onalternate days. Pediatrics, 43, 277.

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ZUTSHI, D.M., FRIEDMAN, M. & ANSELL, B.M. (1971) Corti-cotrophin therapy in juvenile chronic polyarthritis (Still'sdisease) and effect on growth. Archives of Disease inChildhood, 46, 584.

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