A STUDY OF GROWTH PROMOTION IN CHILDRENBY

DOUGLAS HUBBLE and DUNCAN R. MACMILLANDepartment ofPaediatrics and Child Health, University of Birmingham

(RECEIVED FOR PUBLICATION MAY 29, 1962)

Androgens have been used for many years topromote growth in children. Many therapists haveeither discarded them or have used them only onselected patients who have been carefully observedduring the period of treatment. The well-justifieddislike of paediatricians and endocrinologists forthese drugs has depended, not only on the produc-tion of virilism, but more particularly on the advance-ment of skeletal maturation which they produce.If the acceleration of epiphyseal developmentadvances coincidentally with the acceleration ofheight no certain good has been achieved as a resultof therapy. Although such treatment may havejustified itself in individual patients by improvedconfidence, nutrition or musculature, yet all thathas been done, in a biological sense, is to anticipatethe pubertal growth spurt. If skeletal maturationhas been advanced to a greater degree than heightthen harm will result because of the earlier fusionof the epiphyses. The therapist has purchased animmediate credit at the price of future insolvency.

Physicians who have the care of these shortchildren have naturally been interested in the newtestosterone derivatives that are claimed to havea heightened effect on protein anabolism and areduced androgenic effect. Bongiovanni (1961) hasrecently reviewed the indications for the use of thesenew protein anabolic agents in accelerating growthin children, and he states a conservative opinionof their value with which we cordially agree. Hewrites, 'the earliest clinical studies must be regardedwith caution; it may be several years before the firstoptimistic reports can be accepted with assurance'.The need for this warning has been quickly demon-strated. One group of workers (Reilly and Gordan,1961) reported that fluoxymesterone produced anaverage growth in 16 short children of 3-2 in. (8 1cm.) a year [average growth 1 9 in. (5 -8 cm.) a yearbefore treatmentl while the average advancementin skeletal maturation was 0-83 years: the drug,therefore, showed a clear profit in the promotion ofgrowth as against the development of the skeleton.Other investigators (Mellman, Bongiovanni andHope, 1959) subsequently reported a small double

blind study of 17 children of average height, dividedinto three groups: the first group was treated withfluoxymesterone (2 mg. daily); the second withmethyl testosterone (10 mg. daily) and the thirdwith a placebo. They concluded that whilefluoxymesterone may be more effective than methyltestosterone in promoting growth, it has an effecton skeletal maturation equal to that of methyltestosterone. It is now generally recognized that inmaking the final assessment of the effect of a drugon skeletal advancement it is necessary to examineradiographs taken not less than six months afterthe period of treatment is complete. While thisperiod of precaution was observed in the secondinvestigation, there is no clear indication in thefirst report that attention was paid to it.

In this investigation we have used methandienone(l-dehydro-17-methyltestosterone; 'dianabol') whichdiffers from methyl testosterone only in having adouble bond between carbon 1 and 2 in the A ringof the steroid nucleus. Liddle and Burke (1960)state that methandienone has 10 times the nitrogen-retaining effect ofmethyl testosterone, and Wynn andLandon (1961) have shown that it produces markednitrogen retention in doses of 0-2-0*4 mg./kg. bodyweight per day, i.e. 15-30 mg. for the average-sizedwoman. Although Wynn and Landon report thatthe virilizing effects of the drug were 'slight' or'absent' in their 30 male and female patients theydo in fact record a considerable endocrine effect.In the four pre-menopausal women who had regularmenses before the drug was taken amenorrhoeadeveloped in all, and in the four older women whohad menopausal symptoms when the drug wasstarted, these symptoms were relieved. Schiirer,Habich and Prader (1960) used 1-dehydromethyl-testosterone to promote growth in children, andsome of their conclusions are similar to thosereported by us below. The relevant animal experi-ments were made by Desaulles, Kriihenbuhl,Schuler and Bein (1959) who reported that in therat methyltestosterone was 30 times more activethan methandienone in the inhibition of the oestrouscycle. It is apparent that the anterior pituitary

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GROWTH, PROMOTION IN CHILDRENTABLE

ANALYSIS OF EFFECTS OF METHANDIENONE THERAPY ON HEIGHTAND SKELETAL MATURATION IN 23 CHILDREN

3 4 5 6 7 8 9

MethandienoneTherapy Total

Height Bone PeriodAge Age HA/ HA/ Dura- Average of(HA) (BA) CA BA tion Dose Obser-(yrs) (yrs) (mths) (mg./kg. vation

/day) (mths)

Organic Hypopituitary Dwarfism10i 13 0-65 0-8 12 0 15 129k 12k 0-75 0 75 19 0 31 19

101, 12 0 7 0 9 6 0 12 16

Congenital Hypopituitary Dwarfism2 1 2 0 5 1*2 8 0 73 141-'§ 1k 0 3 0-7 6 0-73 166 10 0-5 0-6 7 0 11 1231 3k 04 1*1 10 0-28 20

Turner's Syndrome610 11 0-55 0-6 4 0 17 11t152 2 0-6 0 7 12 0 09 185' 10 0 55 0 55 5 0 28 16

Familial Short Stature62 6 0 75 1*0 3 0-22 129 11 0-65 0-8 6 0-08 119i 11 075 085 4 0-15 121i 3 0.4 0-4 3 073 8

Primordial Dwarfism2k 3 04 0-85 9 0-26 1621g 3 0-65 0 95 7 0-37 12I 1i 05 09 14 045 20f, 1 0-2 0-4 4 0-73 18

410 4k 0 7 1l1 9 0-25 14

Dwarfism and Obesity, Mental and Sexual Retardation3- 4 0-7 0-95 7 0-11 12611 13 05 055 7 0-1 219i 12 0-55 0-75 9 0-11 1210} 13 0.75 0-8 11 0-15 11

10 11

Height HeightGain Age(in.) Increase

(mths)

1 624- 162k 10

2 1 124 123 172 1 11

l5 96 215i 17

5i353is2k

52f5k5k6k4k

31333I

5,1s

2822226

2326161124

9191031

12

BoneAge

Increase(mths)

123024

18182436

244512

24302412

36482121242

24241818

hormones of man, through which it must be assumedthe endocrine effects are mediated, are more sus-ceptible to the depressive effect of methandienonethan is the pituitary of the rat.

It becomes apparent, too, that these proteinanabolic drugs have complicated actions (nitrogenretaining, virilizing and endocrine) and interactions.We know little of the mechanisms involved and theseconsiderations also encourage a conservative attitudein their use.

The PatientsWe report here the use of methandienone to

promote growth in 23 children who were below thethird percentile for height. They were diagnosedas suffering from organic hypopituitarism (Cases 1,2 and 3), from congenital hypopituitarism (Cases4, 5, 6 and 7), from Turner's syndrome (Cases8, 9 and 10), from familial short stature (Cases 11,

12, 13 and 14), from primordial dwarfism (Cases15, 16, 17, 18 and 19), and from dwarfism, obesity,mental and sexual retardation (Cases 20, 21, 22and 23). Although the data in regard to height

and skeletal development are given in the Table we

give here a brief statement of our diagnostic criteriain the various groups.

Organic Hypopituitarism. These three childrenall showed dwarfism, sexual retardation, and some

degree of adrenocortical and thyroid deficiency.Cases I and 2 showed calcification in the sellaturcica, and Case 3 had an operation at 8 years forremoval of a chromophobe adenoma.

Congenital Hypopituitarism. These four children-three boys and one girl-had the necessaryclinical criteria for this presumptive diagnosis,i.e. normal length and weight at birth, growthfailure noticed first during the second or third yearof life, immaturity of bony facies, hypercholes-terolaemia (except Case 6) despite the lack of anyevidence of hypothyroidism.

Turner's Syndrome. Cases 8 and 9 had a sexchromosomal complement of XO, Case 10 ofXO, XX, XXX. Case 10 is now pubertal.

6

Column No.

519

1413

AHA/ AIHA/JICA zIBA

CaseNo.

23

4567

8910

11121314

1516171819

202122

Sex

FMF

MMF

FFF

MIMMM

MM

F

F

'i

IM

2

Height(in.)

54152k55

35k3014539

4613144

45151k52k301

3573729k24k42k

39k47251k55M

Age(yrs)

15,'`13151,-'

4k3 fl;2

12C} 4

12

2*10k

814 14*21243

514k22k6 141

5 ri2134l 3 i12

164124

0-50 850-6

0-850 91 *40-55

0-81 *21*1

2-32 01 *80-75

1 *42-20-80-61 *7

0 750 90-852-8

0* 50 5504

0-650-65070 3

040451-4

1 *20 75090 5

0-650 550 750 90 55

0 40-80 551 7

~~

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ARCHIVES OF DISEASE IN CHILDHOODFamilial Short Stature. All of these children

came of families of whom one or more memberswere well below the third percentile for height.Case 14 was atypical, his father is 59 in. (149-8 cm.)in height and has a disproportionately large skullas does his son, our patient. In the other threechildren the bone age was retarded-these childrenmay well be 'late maturers'.

Primordial Dwarfism. These five children allweighed less than 41 lb. (2-04 kg.) at birth despitefull gestation and the birth lengths were 18 in.(45*72 cm.) or less in the three children in whichthis measurement was recorded (intrauterine growthretardation). They do not comprise a singleclinical group, however, since one has hypo-glycaemia, three have minor skeletal abnormalitiesand two are mentally retarded.

Obesity, Mental and Sexual Retardation andShort Stature. This clinical description definesa group which is probably of multiple patho-genesis.

MethodsDosage. The doses of methandienone used are

detailed in the Table. They varied from 0-08 mg./kg./day to 0 73 mg./kg./day.

Course of Treatment. All patients were given aninitial course of treatment of three months' dura-tion. Therapy was continued if there was no evi-dence of virilization and no appreciable advance inbone age at the end of this time. Patients con-tinuing on methandienone were examined atintervals of one to three months, and skeletalmaturation was determined every three months.Virilization other than slight hypertrophy of thephallus, and skeletal maturation proceeding at arate obviously faster than the rate of growth, wereregarded as indications for stopping treatment.After cessation of therapy the height and skeletalmaturation were determined at three-monthlyintervals. Two patients (Cases 3 and 18) receivedshort second courses of methandienone followingregression of the signs of virilization that hadrequired the termination of the first course oftreatment.

Records. The charts for height and weight inboth sexes prepared by J. M. Tanner and R. H.Whitehouse (University of London, Institute ofChild Health, for The Hospital for Sick Children,Great Ormond Street, London) were used to recordthe serial measurements in these children. Theywere also used to estimate 'height age', referring

the measured height of the patient to the 50 percen-tile measurement on the chart, and reading therelevant age (e.g. a height of 40 in. (101 *6 cm.) is onthe 50 percentile for 4 years and the height age ofthe patient is therefore 4 years). This useful con-vention has been criticized and has obvious limita-tions.

Skeletal Maturation. There are many pitfallsawaiting investigators who use radiographs toassess skeletal maturation and its response to treat-ment, and much attention has been paid to them inthe literature. We have already commented on theneed to make a final assessment at least six monthsafter treatment has been completed. The observererror has been well documented (Mainland, 1953).There are wide variations in the rate of skeletaldevelopment in normal children, and occasionallybetween different sites in the same child (Melimanet al., 1959). We refer below to the difficulty causedby the carpal bones appearing in an irregular order.We have limited our assessment to the bones of thehand and wrist, and matched them with the Greulichand Pyle Atlas (1959). We have assessed thesefilms independently, and in the few assessments inwhich we differed we have arrived at an agreedopinion. The fact that our conclusions havedepended on repeated serial examinations will havereduced to some extent the inherent uncertaintiesof such findings. We have employed the usualdescription of 'bone-age', although this conventioncannot, for example, distinguish the normal 'latematurer' from the abnormally retarded child. Wehave not reported our results in terms of the altera-tion in predictable height (Bayer and Bayley, 1959).These tables do not apply to children with skeletalmaturation below the six-year level, and the predic-tion of height in children whose growth is abnormalmust give these calculations an additional fallibility(Table).The period of treatment and the follow-up period

are included together in the total period of obser-vation (column 9). The period of follow-up wassix months (±1I month) unless there was evidenceof accelerated growth or skeletal maturationcontinuing beyond this period (Cases 5, 10 and 11).Treatment was continued in the follow-up periodin Cases 1 and 2. The final examination was at8 and 10 months after stopping treatment in Cases7 and 13. Case 23 has not been available for afollow-up examination to date. The age (column1), and height (column 2), the height age (column 3)and the bone age (column 4) are as recorded at thebeginning of treatment. Although there wereavailable in many cases records of height and

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skeletal maturation going back some time we havenot used them to compare our results with pre-

treatment rates, since they were not available in allpatients. Column 5 gives the ratio of height age tochronological (actual) age; all of these values are

below unity indicating varying degrees of dwarfism.Column 6 gives the ratio of height age to bone age;

in all but four of our patients (Cases 4, 7, 11 and 19)this ratio was below unity indicating that in 19patients the height was more retarded than skeletalmaturation. Column 13 gives the ratio of theadvance in height age to the advance in chrono-logical age, and column 14 gives the ratio of theadvance in height age to the advance in bone age

during the period of treatment and follow-up.The responses to methandienone of the 23 patientsare plotted in Fig. 1 according to JHA: JCAand HA: BA ratios. Values for JIHA/JICA aregrouped into three categories: (i) less than theoriginal value for HA/CA; (ii) less than unity butgreater than original HA/CA; (iii) unity and above.A similar grouping is made for IHA/ZIBA.

Analysis of ResultsComparison of the increments in height age in

months (column 11) to the corresponding advancesin chronological age (column 9) and bone age

(column 12) indicates the response to therapy ineach patient. These relations are expressed asratios in columns 13 and 14. Where the increasein height age is equal to or greater than the increasein chronological age (ZIHA/zICA > 1) growthhas occurred at a rate at least as rapid as that ofnormal children of the same height. Similarly,where the increase in height age is equal to or greaterthan the increase in bone age (LIHA/LJBA = > 1)the height gain for each year of skeletal maturationhas been comparable to that of normal children on

the 50th percentile.Where values for ZIHA/ziBA are below unity,

a comparison with the pre-treatment values forHA/CA and HA/BA is useful, as these ratios reflectthe child's previous rate of growth and previousheight increment per year of skeletal maturation.As summarized in the Figure, three cases (Cases 10,

11 and 23) showed an increase in height age greaterthan both the increase in chronological age and theincrease in bone age (zJHA/ZJCA and ZHA/LIBAboth greater than unity). Unquestionably, thesecases have had a good response to therapy for theyhave grown faster than do comparable children andtheir potential ultimate height may have beenincreased. Three more (Cases 6, 12 and 13) hadan equally good growth response but the advancein skeletal maturation, though no greater than

A

0

4

4cu

14

.4

'a

.C

I..

C-

V0

< initial HA/CA < I but> InitialHA/CA >I

AHA: ABA RATIOFIGURE.-Distribution of therapeutic responses of 23 short children

treated with methandienone.A organic hypopituitary dwarfism; A congenital hypopituitarydwarfism; * Turner's syndrome; 0 familial short stature;* primordial dwarfism; dwarfism with obesity, mental and sexual

retardation.

before treatment, makes an increase in ultimateheight improbable. In four (Cases 9, 15, 16 and 19)satisfactory acceleration of growth was offset by a

degree of skeletal maturation which suggested thatultimate height had been compromised (A HA/zIBAless than pre-treatment HA/BA).

In three cases (Cases 14, 18 and 21) the changesin height age relative to both chronological ageand bone age, though more favourable than beforetreatment, were not sufficient to claim any thera-peutic advantage though certainly no harm had beendone.

In the remaining 10 (Cases 1, 2, 3, 4, 5, 7, 8,17, 20 and 22) growth stimulation was slight or

absent and skeletal maturation was accelerated so

that potential ultimate height was presumablydecreased. Theoretically it must be consideredthat harm has been done to these children but itshould be noted that six of them are hypopituitarydwarfs. In these children the prognosis for futuregrowth without treatment is poor, so a sacrifice ofapparent growth potential may be justifiable if thegrowth rate can be increased (see below).For the whole group of 23 children the average

growth rate during treatment was 1 -2 (AIHA/AJCA).This compares with the overall rate before treat-ment (as inferred from the initial value for HA/CA)of 0 6. The average ratio of advance in heightage to advance in bone age (ZIHA/AIBA) was 0 7and the average initial ratio for HA/BA was 0-85.

a 0* 00 0mo.

0

A

* 0* U00 0

AA

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This suggests that in these children, considered asa group, there was some reduction of their growthpotential.

Responses of Various Groups

When we started this inquiry we hoped that itmight indicate in which groups of children withretarded growth the use of a protein anabolic drugwould be useful. We also hoped that its use mightfacilitate diagnosis in a field in which the criteriafor an aetiological classification are woefullyinadequate. For example, do children sufferingfrom hypopituitarism in whom a defective outputof growth hormone may be assumed obtain theexpected response to a protein anabolic drug?And do children in whom there is genetic resistanceto growth respond to the drug? And do the childrenwhose growth was defective in intrauterine liferespond to the action of a protein anabolic agent?The answers given to these questions are at best

tentative and we certainly cannot conclude that theuse of the drug will facilitate diagnosis. But thereare differences in the growth response to methan-dienone between the various groups, and occa-sionally the response in an individual patient isatypical for the group so that some doubt is thrownon the accuracy of the original diagnosis.The growth response in patients suffering from

hypopituitarism, whether organic or congenital, wasthe least satisfactory. Generally in this grouptreatment accomplishes no more than the main-tenance of growth parallel to the third percentile(but at a distance below it varying from 5 to 10 in.)(12 7-25-4 cm.). This has been the experience ofone of us in treating such children with varyingdoses of these weak androgens over many years.These drugs are clearly no substitute for the growthhormone. However, if these children are nottreated the gap between their growth curve and thethird percentile for height steadily deepens.

If Case 6 maintains his high IHA/ICA ratiounder continued treatment he is clearly atypicalfor this group. In all but one other respect he is acharacteristic example ofcongenital hypopituitarism.His birth weight was 7 lb. (3- 17 kg.) and he grewnormally until the third year of life since when hisgrowth has averaged little more than 1 in. (2 54 cm.)a year. As is shown on the Table his height at theage of 12 years was 45 in. (I14 3 cm.) (height age6 years) and his bone age was 10 years. He hada characteristically immature facies; his intelligencewas good; the genitalia were within average limitsfor his height; the right testis was retracted, the leftwas in the scrotum. The sella turcica was notenlarged and all other tests of endocrine function

gave normal values. There was no elevation of theserum cholesterol such as one of us (Hubble, 1957)has described in hypopituitarism, whether or notthere is an associated hypothyroidism. This wasthe only other finding which casts doubt on theoriginal diagnosis.

In the two patients with classical Turner's syndrome(Cases 8 and 9) the effect of the drug was markedlyvirilizing despite the small doses employed. Markedskeletal maturation accompanied growth stimula-tion in both cases. We speculate that the tendencyto virilization in these patients may depend on thelack of oestrogen or the absence ofanX chromosome.Although the three children (Cases 11, 12 and 13)

are classified as familial short stature, for whichthere was adequate family history, they also showedskeletal retardation and might equally be regardedas 'late maturers'. The history of Case 11 is asfollows. His father was 5 ft. 6 in. (167-6 cm.) inheight and his mother 5 ft. 1 in. (154-9 cm.). Hisheight and bone age were synchronous at 6 years,while his actual age was 8 years. He was giventreatment for three months only, but the responsewas dramatic. He grew 5 25 in. (I3 3 cm.) in theyear's period of observation. His bone age advancedtwo years in this period; one year's advance occurredduring the period of from four to nine months aftertherapy was stopped. Such an experience empha-sizes the need for a long period of observation beforethe final assessment of skeletal maturation is made.The drug has obviously given this boy a pubertalgrowth spurt. His muscles have thickened, hisfacial development has matured, and his confidencemarkedly increased-a response to therapy gratifyingto the boy, his parents and his doctors.The fourth patient in this group (Case 14),

although undoubtedly suffering from familial shortstature has inherited an undefined osseous disorderfrom his father.The patients with primordial dwarfism (Cases

15-19) show a well-differentiated response insidetheir group. Cases 15, 16 and 19 show a good growthresponse to treatment and Cases 17 and 18 a poorresponse. In all these patients the HA/BA ratioworsened as a result of therapy, but the initialassessment of the bone age may have been too lowin Cases 15 and 19, owing to absence of ossificationof the lunate and triquetrum which rapidly appearedafter treatment was begun. It is now our impressionthat the bones of the hand give a better indicationof skeletal maturation than does the carpus, and thatdiscordant carpal centres should be ignored in theassessment of bone age.Treatment may well be justified in children such

as Cases 15, 16 and 19 who have a retarded skeletal

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maturation. Cases 15 and 19 are now approxi-mately on the 25 percentile for height and theirbone age is little, if at all, advanced for their chrono-logical age.The group of children with dwarfism, obesity,

mental and sexual retardation also display a differingpattern of response, possibly implying a differentaetiology within the group. In all of them thedosage of the drug was small yet in three of themthere was a considerable advance in skeletal matura-tion. In three (Cases 20, 21 and 22) the growthresponse was fair and in the fourth (Case 23)exceptionally good, the result equalling that inCase 11, although his period of observation is notyet complete.

Discussion of ResultsIn the dosage in which the drug was used in this

trial a satisfactory growth response was obtainedin 10 out of the 23 children treated. We haveemployed the drug in the smaller dosage recom-mended by Liddle and Burke (1960) (0 05 mg./kg./day) in a group of children not reported here and theeffect on growth has not been striking and viriliza-tion has occasionally been observed. Whetherwhen the androgenic quality of the drug is soreduced any useful effect on growth remains (dueto the nitrogen-retaining properties of the drug) isa matter not yet decided, but worth decision, andwe propose to continue its use in this small dosage.It must be remembered that 13 of our children whengiven* larger doses than those now recommendedhad a disappointing growth response. Six of themwere, however, patients with hypopituitarism anda seventh was a dwarfed girl with hypoglycaemia(Case 18). We have already made the commentthat these protein anabolic agents are no substitutefor the growth hormone, and we may speculate asto whether some circulating growth hormone isnecessary for their effective action.We may consider, too, in what circumstances a

nitrogen-retaining drug-with a much reducedandrogenic component- is likely to be effective inpromoting growth. We believe that there may betwo such situations, one in which the totalcaloric intake is inadequate and the other wherethere is a deficiency of protein substrate. Anorexia,

* Subsequent to the completion of this survey 14 children withvarying types of short stature have been treated with methandienonein doses of 0 05 mg./kg. body weight for periods varying from fiveto 10 months. With these small doses the height increments were50%0 or more above the expected rate in only four children. Threeof these four show some virilization, while no virilization occurredin the remaining II children. The reduction of the dose diminishesthe rate of acceleration of growth, but the risk of virilization, and withit the hazard of advanced skeletal maturation, is not altogethereliminated by the use of such small doses (0 05 mg./kg.).

the malabsorption syndrome, and prolonged corti-sone therapy are examples of such conditions.Methandienone stimulated the appetite in eight ofour children (Cases 5, 8, 12, 13, 15, 17, 19 and 23)and three of these were in the group of primordialdwarfs who seem to have appetites that are smalleven in relation to their size. We have, therefore,a third possible factor in growth promotion to addto the two (protein-anabolic and endocrine) alreadylisted-that of an appetite stimulant. An increasedcaloric intake as occurs in obesity undoubtedlyresults in an increased rate of growth both inchildren (Wolff, 1955) and animals (Widdowson andMcCance, 1960), but whether the addition of proteinto a diet already adequate does so in normalchildren remains to be shown.

Virilization, in greater or lesser degree, occurredin all our patients, whether taking small or largedoses of methandienone, and this finding confirmedthe opinion that the effect of the drug in promotinggrowth was in part due to its androgenic action,concomitant with an equal or greater effect onskeletal maturation. As with other testosteronederivatives the virilizing effect is predominantlyshown by enlargement of the phallus.Our conclusions with regard to the use of these

protein anabolic drugs such as methandienone arethat they should be used in hypopituitarism, despitetheir disappointing effect on growth promotion;that it is safe to use them, with due precaution,where the skeletal maturation is retarded and theiruse is to be considered especially in 'late maturing'boys and in 'primordial dwarfs' with a retardedbone age; that sensitivity to their action varies indifferent individuals and in different syndromes;that they should be used for short courses and in thesmallest doses shown to be effective; that the drugshould be withheld in from three to six monthsafter the start of treatment and that radiographs ofepiphyseal development should be taken in a furthersix months before treatment is resumed.

SummaryIn this study 23 children with short stature of

differing aetiology were treated by methandienonein doses of 0-08 to 0 73 mg./kg./day.

In 10 of these 23 children growth rates greaterthan those of normal children were produced.

All 23 children showed some degree of virilismand all but three an advance in skeletal maturationwhich correlated with or exceeded their gain instature.The effects of such drugs in growth promotion are

complicated and difficult to define. The action ofmethandienone on growth promotion in the doses

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524 ARC!IVPSI OF DfSFASF [ATHlDused was predominantly androgenic. In eightchildren the drug stimulated appetite. The proteinanabolic effects of the drug could not be separatedfrom its androgenic action.

Indications are stated for the use of such drugsin children of short stature, together with the pre-cautions to be observed in their use.

We are grateful to Dr. A. V. Campbell, Dr. J. G.Dathan, Dr. M. E. Disney, Dr. H. Fisher, Dr. J. G. H.Frew, Dr. M. R. Green, Dr. A. C. Kendall, Dr. P. R.Kemp, Dr. R. S. MacArthur, Dr. J. C. Macaulay,Dr. M. E. MacGregor, Dr. J. C. Mole, Dr. C. Parsons,Dr. S. H. Sangster, Sir Wilfrid Sheldon, Dr. D. C.Thursby Pelham, and Dr. B. S. B. Wood, for referringsome of these patients to us for investigation and treat-ment. Dr. R. Astley kindly assisted us with the radio-logical investigations.

REFERENCESBayer, L. M. and Bayley, N. (1959). growth Diagnosis. University

of Chicago Press, Chicago, Illinois.

Bongiovanni, A. M. (1961). Anabolic drugs to promote growth.Pediatrics, 27, 519.

Desaulles, P. A., Krahenbuhl, C., Schuler, W. and Bein, H. J. (1959).Etude experimentale du Dianabol, un nouvel anabolisant.Schweiz. med. Wschr., 89, 1313.

Greulich, W. W. and Pyle, S. I. (1959). Radiographic Atlas ofSkeletal Development of the Hand and Wrist, 2nd ed. StanfordUniversity Press, California.

Hubble, D. (1957). Hormonal influence on growth. Brit. med. J.,1, 601.

Liddle, G. W. and Burke, H. A., Jr. (1960). Anabolic steroids inclinical medicine. Helv. med. Acta, 27, 504.

Mainland, D. (1953). Evaluation of the skeletal age method ofestimating children's development. Pediatrics, 12, 114.

Mellman, W. J., Bongiovanni, A. M. and Hope, J. W. (1959). Thediagnostic usefulness of skeletal maturation in an endocrine clinic.ibid., 23, 530.

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