Effects of synthetic ACTH on corticosteroid-induced growth suppression

ALLERGY ROUNDS

Effects of synthetic ACTH on corticosteroid-induced growth suppression William Barbara

PRESENTATION

C. Wright, M. Lippe,

M.D., Sheldon C. Siegel, M.D., M.D., and S. Raymond Wong, M.D. Los rl?zyeks,

C&f.

OF CASE (Dr. Wright)

lt. W. is a 14%-year-old boy with severe asthma and growth retardation secondary to chronic use of corticosteroids. At birth he weighed 7 pounds, 2 ounces and was 21 inches long. There was no family history of growth, endocrine, allergic, or other disorders, except that a great aunt had asthma and his mother has urticaria pigmentosa. He was ~~11 until 18 months of age, when hc developed wheezing associated with an uppei respiratory infection. From that time until the age of 4, he was hospitalized II times in status asthmaticus. Skin tests done at the age of 2 years showed reactions to molds, house dust, grasses, ragweeds, and many foods. Elimination of milk and other foods and a one-year trial of hyposensitization resulted in no improvement. Corticosteroid therapy was started at the age of 3, and was continued with a few brief interruptions until 1962, when he moved from Minnesota to Northern California. While there, he continued to wheeze perenially and required hospitalization approximately 3 times per year. Skin testing was repeated in 1963 and showed similar responses. Hyposensitization was again attempted using an e~~~ironmental-mold mix and a mixed respiratory vaccine. Steroids were continued because it was felt that he could not survive without them. In ,July, 1965, at the age of 7 years, his family moved to Los Angeles. At that time he was taking prednisone, 20 mg. q.o.tl., but was having severe difficulty on the day off prednisonc. His growth was markedly retarded, as shown in Fig. 1. Thrre admissions to I’CllA for status asthmaticus were required during his first year in INS Angeles. I)aily administration of prcdnisone became necessary and suhscqucnt attempts to r&urn to an alternate-day schedule were unsuccessful. BW~LIW of the difficulty in controlling his asthma and because of the secondary effects of long-term corticosteroid therapy, he was admitted at. the From the meekly pediatric allergy-immunology Angeles, UCLA School of Medicine. Received for publication Xay 4, 1973. Reprint requests to: Dr. S. C. Siegel, Childrens Calif. 90043. Vol. 53, No. 1, pp. 58-63

rounds held at the University

Medical

Group, 5830 Overhill

Hospital

at LOS

Dr., Los Angeles,

Effects of synthetic

VOLUME 53 NUMBER 1

80-

G-

70-

3

s

53

3rd percentile

97 th percentde

-a

ACTH

6050403097

th percentile

7065c 60;

55-

4

504540-

dally

n--1

!&!!I!&

CARIH

PREDNISONE mg/day

ANAVAR ,,,,TAc

I,” IO

I

I

!

7

8

9 3

FIG. 1. Height and weight curve plotted by Iowa Welfare Research Station.

I

,

0

I

1

Al/emote 1

10 11 12 13 14 15 4 4 4$ 59 6; 9 on growth

standards

da,v f

16 Chronologic age, yr Bone age,yr taken

from

data

compiled

age of Sl/, to Children’s Asthma Research Institute and Hospital (C.A.R.I.H.) in Denver, Colorado, where he remained for 2 years. Attempts to change to an alternate-day or single daily dose schedule were again unsuccessful, and he was discharged on a divided daily dose of prednisone. In an attempt to increase his linear growth an anabolic androgen, oxandrolone (Anavar), 2.5 mg. daily, was administered from December, 1968, to March, 1969, at the age of 10 years. Although a gain in weight was observed there was no significant increase in height or advancement of bone age. Regular attempts to change his prednisone schedule continued to result in severe exacerbations of symptoms, and he continued to require prednisone each morning and evening. Cromolyn sodium became available in 1970 and it was also tried, but was discontinued after 2 months because of lack of apparent beneficial effects. Numerous laboratory studies have been done over the course of this illness. Increased numbers of eosinophils have been noted in his peripheral blood, sputum, and nasal secretions. Immunoglobulins have been normal except for an

54

Wright

et al.

J. ALLERGY CLIN. IMMUNOL. JANUARY 1976

TABLE I. Growth hormone and arginine (December 20, 1970) G!ucors

total

hg.

corticoids

%)

Growth

65

53 75 61 58

0

SE

response

hormone*

15 16 42 29 11

to insulin-hypoglycemia

(ng./ml.)

and

Total coriicoiddrt

to

(~9 % 1

9.6

8.5

62 68

105 120 135 150

30 17 15

%chalch and Parker.8 tMurphy.4 $Crystalline insulin, 0.125 U. per kilogram intravenously. QArginine hydrochloride (Cutter Laboratories, Inc.), 5y0 solution in 0.97, saline administered over a 45 minute period in a total dose of 0.5 Gm. per kilogram intravenously.

elevated IgE of 1,630 1.1’. Sweat. chloride, T4, and other chemist.ries were normal. so prccipitins have been detected to Aspergillus, Candida, or milk. Bone age, determined by comparing serial hand and wrist films to the standards of Gruelich and Pyle,’ has been ret.arded and is commensurate with his height age. Pulmonary function studies have shown reversib1.e bronchospasm, and arterial blood gases have revealed no evidence of a right-to-left shunt. Brcmehial challcngc was positive with mixed ragweed extract and negative with Alternaria. In l&ember, 1970, at the age of 1234 years, he was admitted to UCLA for evaluation of pituitary and adrenal function prior to institution of ACTH therapy. At the time of admission he was taking 5 mg. of prednisone two times daily. Physical examination revealed a well-appearing, short, muscular boy. His height was 48 inches (4 S.D. below the mean), and his weight was 52 pounds i 3 ST). below the mean). There were no features of Cushing’s syndrome except a full, ruddy face. The anteroposterior diameter of his chest was slightly inrreased, and scatt.ered inspiratory and expiratory rhonchi and wheezes were heard. His testes were prepubertal, 1.5 C.P. in volume, and pubic, facial, and axillary hair was absent. Prior to evaluation hc was pretreated with diethylstilbest.rol, 5 mg. two times dai1.v for 3 days.’ His plasma total corticoids (TC) and growth hormone (GH) responses to insulin and to arginine infusion are seen in Table I. Plasma growth hormone responses to both stimuli were normal. The level of plasma total eorticoids showed no elevation above base line 60 minutes after insulin. On the following morning an injection of synthetic ACTH (Cortrosyn I)epot) ,* 1 cc. (0.5 mg.) intramuscularly elicited a total corticoid response of only 6.3 ,ug per 100 ml. at 5 hours. Kormal response is a TC level of at least 35 big per 100 ml. The fa.ilure to respond t.o insulin stress with an increase in corticoid *Supplies of Cortrosyn Depot as well as a grant hy Henry A. Strade, M.D., of Organon, Inc.

to support

these studies were kindly

supplied

VOLUME 53 NUMBER 1

Effects

of

synthetic

ACTH

55

60

CORTROSYN

FIG.

2.

Total

plasma

corticoids

response

to

daily

(ACTHICC

and

q.o.d.

synthetic

ACTH

(Cortrosyn

Depot).

‘t5915 ACTH

24 HOURS AFTER

FIG. trosyn)

3. Total

plasma

in December,

corticoids 1971,

response and

January,

72

48

to 0.5

INJECTION

C.C. (0.25

mg.)

synthetic

depot

ACTH

(Cor-

1973.

secretion, and the poor response to exogenous Cortrosyn confirmed suppression of his adrenal function. Daily injections of one milliliter of Cortrosyn Depot (0.5 mg.) were begun on January 18, 1971, and TC levels were measured 5 hours after each injection (Fig. 2). Adequate adrenal response to synthetic ACTH was reached after 7 days, and prednisone was then tapered over a 3 week period and discontinued. Alternate-day administration of ACTH was begun on March 4, 1971, and the dose was decreased gradually to 0.5 cc. over the next 3 weeks. He then experienced increased wheezing on the morning of his injection, and the TC level on the day off Cortrosyn fell to 4.7 pg per cent at 2 P.M., indicating that both exogenous and endogenous ACTH stimulation were deficient on the off day. Signs of glucocorticoid excess, such as facial redness and obesity, which had increased during the transition to ACTH, returned to former levels. Attempts to decrease the dose of ACTH below 0.5 cc. (0.25 mg.) were unsuccessful.

56

Wright

J. ALLERGY CLIN. IMMUNOL. JANUARY 1974

et al.

II. Growth hormone (December 23, 1971)

TABLE

Time

(min.)

“Insulirl-c!ryYt,?lline

and total

Glucose

insulin,

hag.

corticoids

% I

]

response

Growth

0.125 17. per kilogram

to insulin-induced

hormone

lng./ml.)

) Total

hypoglycemiu

corticoidr

lpg

% i

intravenously.

ln December, 1971, one year after converting to ACTH, he was again pretreated wit,h estrogen and was admitted to TitXA for re-evaluation. Physical examination was essentially unchanged except for a 1.5 inch increase in height and a 12.3 pound gain in weight. Fig. 3 shows TC levels obt.ained following an ACTH injection. The peak response was now normal, but 24 and 48 hours later levels were very low, indicating failure of endogenous ACTH stimulation on the altematc day. The responses of (III and TC to intravenous insulin are recorded in Table II. Results were similar to those of 1970 (Table I), with a normal GH response and a TC response less than normal. A (:N level determined one hour after sleep on bhe day of an ACTH injection was 17 ng. per milliliter, indicat.ing normal nocturnal GH secretion even after exogenous ACTH. After his discharge, attempts were first made t,o decrease the amount of A(:TH administered, and when this failed, to space the injections farther apart. For the past 8 months it has been possible t.o reduce the frequency of injections to 0.5 e.c. (0.25 mg.) every third day. He has felt best 24 to 48 hours following an ACTH injection and has regularly wheezed on the night before receiving ACTH. Attacks of severe wheezing have also occurred unpredictably several times a week. He has continued to require round-the-clock bronchodilators and use of racemic cpinephrinc by IPPR at bedtime. Psychological problems as a result of his small stature arc becoming more overt. His present height is 53 inches, an increase of 2.6 inches in the past year, and his weight is 65 pounds, unchanged from a year ago. He does not have any features of (Yushing’s syndrome, as shown in the recent photograph (Fig. 4). Testicular size has not increased in the past year, and there are no other signs of advancing puberty. Plasma follicle st.imulating hormone (< 1 mIu per milliliter), luteinizing hormone ( 1 mIu per milliliter), and testosterone (11 ng. per cent,) levels are low. Bone age is 9 years (chronological age, 143/4). Current TC levels following ACTH arc recorded on Fig. 3. The TC levels are higher at 24 and 4X hours than were the corresponding levels in 1971, and return of endogenous ACTH stimulation is suggested by the rise of TC levels at 72 hours, just before the next dose of ACTH is administered. I)R. %EGEt: It has been known for many years that most. chronic diseases, including severe persistent asthma, may impair linear growth in children. Falhers and associates” and, more recently, Snyder, Collipp, and Greene6 have presented data suggesting that the more severe the asthma, the greater the suppressive effect on linear growth. The discovery of the additional marked

Effects of synthetic

VOLUME 53 NUMBER 1

FIG. 4. Photograph

of R. W. taken

in January,

ACTH

57

1973.

suppressive effects on growth of the corticosteroids served to focus our attention on this complication, which in our experience is one of the more common and serious side effects of long-term continuous corticosteroid therapy in children. The case presented this morning is a typical example of the effect of continuous corticosteroid therapy on growth and also illustrates some of the techniques that have been proposed to avoid growth impairment resulting from corticosteroid therapy. I would first like to review for you some of the literature concerning the suppressive effects of the corticosteroids on linear growth. Second, I would like to discuss the reasons for transferring his hormone treatment from oral corticosteroids to synthetic corticotropin and the results of this change. Finally, I would like to call upon our endocrinology colleagues, Drs. Lippe and Wong, to comment on the possible mechanisms involved in growth suppression and to get their views on the use of the synthetic androgenie or anabolic steroids in children. Although it had long been recognized that Gushing’s syndrome interfered with growth when it occurred in children, the first report clearly showing that corticosteroid therapy had an adverse effect on statural growth was provided by Blodgett and his co-workers.7 These authors showed that shortly after instituting

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cortisone therapy in doses exceeding 45 mg. per square mctcr of body SW~~W slowing of statural growth and skeletal maturation ocourrcd. Subsequently, thesv results wcrc confirmed by others (‘CTan Mctre, PCicrmann, and Iiosci~.” l+llicrs anti associatcs,5 and Kcrrebijn and associates”), who also showed that, t,hc tIcgrt(; of growth inhibition was related to the duration and dosage of the corticostcroi!i administ~crcd as well as t.o the type of corticosteroid used. Cortisone caused t hc lrast rctartlation of growth whereas cquivaIent, pharmacologic doses of the n(~?*1’ synthetic analogues inhibited linear growth to a greater degree. Our stuclics I Siegrl ant1 associates*“) and t.hosc of other investigators (Soyka and Saxelm” : Hatleghi-Nrjad and Xc~nior’2) have tlamonstratd t,hat growth suppression is alsO relatccI to the method of administration of the hormones. Xi) intcrmittcrlt rcginmu of hormone administration minimized growth inhibition. Our findings iit 5 I children on alternate-day pretlnisonc therapy who were under observation for prriods ranging from one year to 12 years showed that linear pro~th was not, significantly retardetf either 1~L variations in the dosage of prednisoncL or in the length of treatment. IYnfortnnatrly, as the cast presented this morning clearly illustrates, not alI c*hildrcn I\-it,h scverc asthma who arc steroid-dependent can be controlled with an altt:rnat.e-day regimen. Despite intensive allergic management by several tliffercnt allergists in several locales over a span of 13 years, this bo)- continued to require daily doses of prednisone to keep his disease under reasonable control. Even whtn rcmovecl from his home and placed in the environment of C.A.R.I.I~., he remained steroid-dependent, and attempts to convert him to alternate-day therapy were unsuccessful. Following the report by Friedman and Strang 13 that statural growth may be rcsumcd and may even undergo a spurt if corticosteroid therapy is replaced by corticotropin therapy, wc de&cd to try this therapeutic approach as a potcrnial method of stimulating this boy’s linear growth. To minimize hypersensitivity reactions and the number of parentera injections required, a synthetic zinc depot corticotropin (Cortrosyn Ilepot ) was selectotl. Prior to initiating the ccJrticOtrOpil1 therapy he was admitbed to I:CILA for base line assessment of his hypothalamic-pituitary-adrenal axis and to determint: his plasma growth hormone rcsponscs to insulin-hypoglycemia and argininc. The results of these initial studies arc shown in Table 1. Although the patient did ilot exhibit a profountl drop in his blood glucose levels, clinically hc did manifcst lethargy, tliaphorcsis, and tachyeardia. Sorrnal growth hormone (,GH ) responses to both insulin and arginine wcrc noted. Those findings are in keeping with the results of Morris, ,Jorgensen, and JenkinsI and also of Root, Bongiovanni, anfl E:herlcirr,l~ who found that children with corticosteroid-intllxcetl growth retardation have a normal response of GH to these stimuli. On the other hand, adrenal function was impaired, as shown by the failure of the plasma, eort.ic:oids to rise in response to either insulin or exogenous ACTH. E’ollowing discharge from the hospital, he was given daily injections of on8 cubic centimeter of Cortrosyn. The levels of total corticoids measured periodically during this period arc shown in Fig. 2. Despite this intensive stimulation of his adrenal. glands. it was not until his seventh day of therapy that a significant

VOLUME 53 NUMBER 1

Effects

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59

increase in secretion of cortisol was noted as shown by the rise in TC levels. This delayed adrenal response is one of the main reasons why an abrupt change to treatment with corticotropin alone is potentially dangerous for the management of asthmatic patients who have previously received prolonged corticosteroid therapy. After it was established that his adrenal glands were adequately responding to the exogenous ACTH (which required approximately a week of daily injections), his daily prednisone dosage was reduced 21/z mg. each week over a 3 week span and discontinued a month after instituting ACTH therapy. One and one-half months after initiating the ACTH therapy an alternate-day regimen of administering Cortrosyn was started, and he continued on this type of regimen for approximately a year, the dose of the ACTH varying from 0.25 Gm. (0.5 cc.) to 0.5 Gm. (1.0 cc.). In Fig. 1 his growth pattern is plotted on a standard anthropometric grid that was derived from data compiled by the Department of Maternal and Child Health, Harvard School of Public Health. As can be seen from his growth curve, he is markedly retarded in statural growth, falling considerably below the third percentile for age. The marked suppressive effect on skeletal maturation is also shown in Fig. 1. His skeletal maturation lagged considerably behind his chronologic age and at the time of instituting ACTH therapy was still delayed about 7 years. Although it is hazardous to draw conclusions from a single case, it is apparent from his growth curve that there was not any appreciable spurt in growth after initiating the ACTH therapy. However, when his height was plotted on height velocity standards, there did appear to be a tendency over the past six months for him to exhibit some increase in height velocity.16 In view of his low follicle stimulating hormone, luteinizing hormone, and testosterone levels, and his failure to develop findings characteristic of puberty, it is unlikely that this slight growth spurt is related to the onset of puberty. It would seem more likely that the increase in height velocity could have been due to the intermittent administration of ACTH (every 3 days). Zutshi, Friedman, and Ansell” have shown that an increase in linear growth in patients with juvenile rheumatoid arthritis occurred only when plasma cortisol returned to normal prior to the next injection of ACTH, suggesting either that return of endogenous ACTH production is necessary for growth or that growth occurs when the dose of exogenous therapy is insufficient to produce suppression of the adrenal axis. Fig. 3 shows the patient’s response to a single ACTH injection at 8 A.M. In December, 1971, after approximately 9 months of alternate-day ACTH therapy, his total corticoid level rose normally following the injection, and then rapidly fell. There was no suggestion of return of endogenous pituitary-adrenal function 48 hours later, when the next dose of ACTH was administered. However, in January, 1973, after approximately 8 months of a schedule of ACTH administration every three days, total cortieoid levels did return to normal by the time of the next ACTH administration (72 hours), indicating that return of endogenous production of ACTH was occurring. His bone age is now 9 years, and his present height is that of a normal g-year-

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.I. ALLERGY CtIN. IMMUNOL. JANUARY 1974

old boy, suggesting that it may be possible to attain normal adult height. HOWever, despite more t.han 2 years of ACTH therapy, he has failed to approach the normal percentile height curve for his age and has not shown any major acceleration in linear growth. Consequently, I have some reservations as to whether ACTH, especially if administered on a daily basis, does indeed avoid the complications of linear growth inhibition. With that. negative note, I would like to ask Dr. Lippe if she would comment on the possible mechanisms by which the corticost.eroids induce growth retardation. I)R. LIPPE : As summarized by Dr. Siegel, the suppressive effect of pharmacologic doses of corticosteroids on linear growth has been well documented. The exact mechanism of the growth retardation, however, is unknown. The studies of Morris and associatesl*g I0 in 1968 indicated that. although plasma growth hormone responses to insulin-induced hypoglycemia mere similar in normal and corticosteroid-treated children, the acute metabolic responses to exogenous human growth hormone were absent in the corticosteroid-treated group. Similarly, they showed that large doses of exogenous GH administered to these children over several mont,hs failed to increase their linear growth rate. They concluded, therefore, that. cort.icosteroids antagonized the effects of BH at the peripheral tissue level. This hypothesis is the most widely accepted concept of the mechanism of growth retardation, but in vitro and experimental in vivo models of this mechanism have not been clearly established. While there is no question that steroids impair growth, as previously ment,ioned by Dr. Siegel, Friedman and Strang13 reported that, exogenous A4CTH treatment in lieu of ora steroids appeared to result in less growth retardation in the 70 patients they studied. This finding stimulated renewed interest in the problem, and in 1969 Zahnd, Sadeau, and Van hiIuhlendahl’g suggested that the mechanism might be a direct effect of ACTH on the release of GH. However, other workers have not generally confirmed the findings by Friedman and Strang that ACTH is indeed more beneficial, and our initial trial wit,h this pat.ient was similarly unsuccessful. Most recently, studies on the fluctuation of GH during a 24 hour cycle have suggested that consistent peaks, notably several hours following meals and, particularly, a peak 1 to 11,$ hours following onset of sleep, might have a regulatory effect on growth.“” Their findings stimulated the interest of other investigators to study these fluct,uations in corticosteroid-treated children. Pantelakis and associates” measured the night and day GH secretion in 5 children before corticosteroid treatment and after both oral steroids and exogenous ACTH. They showed that while normal peaks of GH were present in the blood of untreated children, there was almost complete abolit.ion of these peaks aft.er either form of therapy. They postulated, therefore, that part of the growth retardation effected by corticosteroids or ACTH might be secondary to the failure of these naturally occurring peaks, representing surges of GH release. This hypothesis is most attractive since it takes into account the failure of spontaneous GH secretion in these children and the known ability of these children to secrete GH following a

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provocative stimulus such as insulin-induced hypoglycemia or arginine infusion. It does not, however, explain the poor response to exogenously administered GH as demonstrated by Morris and associates1s and as seen in hypopituitary subjects who receive both GH and cortisone, One might postulate that if, indeed, GH and cortisone are peripheral antagonists, then the spontaneous peak of GH during early sleep, occurring at a time when endogenous corticosteroid production is at its lowest, might be more effective than a similar release or administration of GH would be at another time of day. If this diurnal relationship could be established as necessary for maximum growth promotion, an approach to exogenous therapy could be devised to mimic this timing, DR. SIEGEL: As Dr. Wright indicated, this patient was also given a brief trial of oxandrolone, and I have asked Dr. Wong to discuss the relative merits of testosterone and its derivatives as growth-promoting agents. DR. WONG: Testosterone and its derivatives have been suggested for use in short children as growth-promoting agents. However, they have potent skeletalmaturation effects and may have the potential to cause accelerated epiphyseal fusion. These anabolic steroids are also androgenic and consequently may induce development of secondary sexual characteristics and virilization. Only a few reports are available describing the combined use of anabolic and corticosteroids in children with severe asthma. Evans** used methandrostenolone (Dianabol) in 12 children with this problem and claimed to have promoted growth both in weight and height. Laron23 reported the use of fluoxymesterone (Halotestin) in a 12&year-old steroid-treated asthmatic boy with growth retardation. Although increments in height were observed, neither of these reports included evaluation of skeletal maturation or data concerning final stature. On the other hand, Falliers and his co-workersz4 did evaluate the effects on skeletal maturation of an anabolic agent, Stanozolol, in 15 children with asthma. Although their patients exhibited an acceleration of linear growth, advancement of skeletal age beyond the mean expected height increase was evident in over half of their subjects, These authors appropriately cautioned against the indiscriminate use of these drugs and pointed out that further long-term observations of patients on these drugs were necessary to appropriately assess their value. Somewhat more data is available pertaining to the use of anabolic steroids on children with “constitutional delay of growth and development.” Various preparations such as testosterone, methyltestosterone, fluoxymesterone, methandrostenolone, and oxandrolone have been tried. Although anabolic effects such as increases in growth rate were uniformly observed, conflicting results were seen with regard to the jeopardy of the patients’ ultimate height. A recent retrospective study with matched controls employing fluoxymesterone, methyltestosterone, and testosterone enanthate (Delatestryl) by Kaplan and associatesz5 showed that these agents did not affect ultimate height adversely while an accelerat,ed gain in height and sexual maturation were observed. The latter corresponded to the induced skeletal maturation. Oxandrolone was used in a study of 27 short children by Bettmann and associates. 26 Post-treatment follow-up was

62

Wright et al.

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CLIN. IMMUNOL. JANUARY 1974

only 6 to 12 months and unfortunately not to final stature. The authors fou~ltl that oxandrolone had no adverse effect on predicted adult height based on studies at the time of the last follow-up if treatment was started after bone age halI reached at least 9 years. I-ntil more data becomes available on the ultimate adult heights, it is difficult to ascertain the safe@ of oxandrolonc therapy in these children. Furthermore, although oxandrolone appeared to be somewhat promising in these constitution ally short children, it wouhl be hazardous to extrapolate the results of these studies to the steroid-treated child whose growing osseous tissue is under the influence of the growth-inhibiting effects of corticosteroids. In the case of our patient, oxandrolonc (0.1 mg. per kilogram per day,!: administered at the age of 10 for 3 months, did not produce any increase iu growth rate nor did it advance his bone age although weight gain was observed. This may be explained on the basis of the possible hyporesponsiveness of the epiphyscs to oxandrolone in the presence of excessive corticosteroids. 1)~. SIEGEI, : 1.would like to add that these anabolie agents are also potentially hepatotoxic and should, for this reason, and the reasons already mentioned by Dr. IVong? be used with a great deal of traution and probably best only under experimental conditions in children. Before adjourning, I would like to take this opportunity of thanking IIrs. WTright, Lippe, and Wonp for participating in today’s allergy-immunology rounds. REFERENCES 1 Gruelich, IIT. W., and Pyle, S. I.: Radiographic atlas of skeletal development of the hand a,nd wrist, ed. 2, Stanford, Calif., 1959, Stanford University Press. S. A.: Simultaneous assessment of growth 2 I,ippe, H. M., Wang, S-L. R, and Kaplan, hormone and ACTH reserve in children pretreated with diethylstilbestrol, .J. Clin. Endocrinol. Metab. 53: 949, 1971. double antibody immunoassay for 3 Hchalch, D. S., and Parker, M. I,.: A sensitive human growth hormone in plasma, Nature 203: 1141, 1964. 4 Murphy, 13. E:. P.: Some studies of the protein-binding of’ steroids and their application to the routine micro and ultramicro measurement of various steroids in hod? fluids by competitive protein-binding radioassay, J. Clin. Endocrinol. Metab. 27: 973, 1967. 5 E”alliers, C. J., Tan, I,. S., Szentivanyi, J., Jorgensen, J. II.., and Rukentz, 8. C.: Childhood asthma and steroid therapy as influences ou growth, Am. .T. His. Child. 105: 127, 1963. 6 Snyder, 1~. I)., Collipp, 1’. .I., and Greene, J. S.: Growth and ultimate height of children with asthma, Clin. Pediatr. 6: 389, 1967. 7 Hlodgott, F. M., Burgin, L., lezzoni, I)., Gribetz, l)., and Talbot, S. B.: Effects of prolonged cortisone therapy on the statural growth, skeletal maturation and metabolic status of children, N. Engl. J. Med. 254: 636, 1956. 8 Van Metre, T. E., Niermann, 51’. 8., and Rosen, 1,. ,I.: A comparison of the growth suppressive effect of cortisone, prednisone, and other adrenal cortical hormones, .J. RI,I,ERC,Y 31: 531, 1960. 9 Rerrebijn, K. F., De Kroon, J. I’. X., Post, Ii. ,J., and Ituijser, K. L.: Effect, on height of eorticosteroid therapy in asthmatic children, Arch. His. Child. 43: 556, 196X. 10 Siegel, S. (‘., Goldberg, M.: Richards, W., and Busser, R. J.: Effects of alternate-da? c*ortiscosteroid therapy on linear growth in children with intractable asthma, Tsr. .r. MetI. Sci. 6: 7.13, 1970. 11 Royka, I,. F., anti Saxena, K. M.: Alternate-day steroid therapy for nephrotic children, 5. A. M. A. 192: 225, 1965. 12 Sadeghi-Nejad, A., and Senior, R.: The treatment of ulcerative colitis in children with alternate-day corticosteroids, Pediatrics 43: 840, 1969.

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