ENDOCRINOLOGY

A.E. Melin á L. Adan á G. Leverger á J.C. Souberbielle á G. Schaison á R. Brauner

Growth hormone secretion, puberty and adult heightafter cranial irradiation with 18 Gy for leukaemia

Received: 17 November 1997 /Accepted: 9 February 1998

Abstract The dose of prophylactic cranial irradiation given to patients for acutelymphoblastic leukaemia has been decreased from 24 to 18 Gy, but the bene®cial e�ect ofthis decrease on growth is controversial.This study compares the growth hormone (GH) secretion and growth of 35 patients (20

boys) given 18 Gy at 3.7 � 0.3 (SE) years, and routinely evaluated 5.4 � 0.4 years afterirradiation to de®ne the indications for GH treatment in these patients. Of these, 63%had a low GH peak (<10 lg/l) after one (22 cases) or two (17 cases) stimulation tests.The plasma concentrations of insulin-like growth factor I and its GH-dependent bindingprotein were normal for age in all but two cases. The height changes between irradiationand evaluation were correlated with the GH peaks (P < 0.03) and were concordant,except in patients with early puberty. This occurred in 16 patients including all 12 girlsirradiated before 4 years of age. A signi®cant (P < 0.03) reduction in height (SD) be-tween irradiation and adult height occurred in untreated GH-de®cient patients()1 � 0.3, n � 6), but not in GH-de®cient patients given GH ()0.6 � 0.3, n � 8) or inthose with normal GH peak ()0.4 � 0.3, n � 7).

Conclusion In children irradiated for acute lymphoblastic leukaemia, GH de®ciency isfrequent after 18 Gy but its impact on adult height is smaller than after higher doses. Wesuggest that the indications for gonadotropin releasing hormone analogue therapyshould be broad in patients with early or rapidly progressing puberty and those for GHtherapy in those patients with a below average constitutional height before irradiation.

Key words Cranial irradiation á Growth factors á Growth hormone á Growthhormone de®ciency á Leukaemia

Abbreviations BMI body mass index á CI cranial irradiation á GH growthhormone á GnRH gonadotropin releasing hormone á IGF-I insulin-like growth factor I áIGFBP-3: IGF binding protein 3

Eur J Pediatr (1998) 157: 703±707 Ó Springer-Verlag 1998

This work was supported by a grant from the Association pour laRecherche sur le Cancer (ARC, N° 6543). It was presented in partat the 35th Meeting of the European Society for Pediatric Endo-crinology, Montpellier, France, 1996.

R. Brauner (&)Pediatric Endocrinology Unit,Hoà pital Necker-Enfants Malades,149 rue de SeÁ vres,F-75743 Paris Cedex 15, France,Tel.: +33 1 44 49 48 03,Fax: +33 1 48 95 55 54

A. E. Melin á L. Adan á R. BraunerPediatric Endocrinology Unit, Universite Paris V and Hoà pitalNecker-Enfants Malades, Hoà pital Saint-Louis,Assistance Publique-Hoà pitaux de Paris, France

J. C. SouberbiellePhysiology Laboratory, Universite Paris V and Hoà pitalNecker-Enfants Malades, Hoà pital Saint-Louis,Assistance Publique-Hoà pitaux de Paris, France

G. Leverger á G. Schaisoà nHematology Unit, Hoà pital Saint-Louis,Assistance Publique-Hopitaux de Paris, France

Introduction

The dose of prophylactic cranial irradiation (CI) given topatients for acute lymphoblastic leukaemia has been de-creased from 24 to 18 Gy. This decrease results in a lesssevere reduction in growth hormone (GH) secretion [17]and in adult height [16]. Butwhile the e�ects are less severethan those produced by 24 Gy, patients treated with18 Gy still have GH secretion and adult height belowthose of the normal population [16, 17]. This is particu-larly true for the adult height of girls given CI at veryyoung age (�4 years) [16]. In addition, girls given 18 GyCI enter puberty signi®cantly earlier than controls orthose given 24 Gy [18]. This early puberty may maintainnormal growth in spite of GH de®ciency, but it shortensthe growing period and hence reduces the adult height.Treating patients with GH de®ciency and early pubertywith a combination of GH and gonadotropin releasinghormone (GnRH) analogue leads to normal adult height[2]. However, there is no consensus about the indicationsfor GH evaluation and therapy in those given 18 Gy be-cause there is a question as to whether the reduced GHsecretion alters the adult height and if it is does so, howGH de®ciency and early puberty in¯uence this reduction.

This study was therefore carried out to compare GHsecretion and growth, taking into account the patient'spubertal status, and to evaluate the e�ect of GH therapyon the adult height in patients routinely evaluated after18 Gy CI.

Patients and methods

Patients

A total of 52 patients were treated at the Hopital Saint Louis, Paris.They were given 18 Gy (9 ´ 200 cGy, 5 fractions/week) CI for acutelymphoblastic leukaemia before they were 10 years old. Of these,GH secretion had been evaluated in 35 (20 boys). There was nodi�erence between them and the 17 patients (8 boys) not evaluatedin terms of sex ratio, age at CI, duration of chemotherapy, age atonset of puberty and at ®rst menstruation in girls, height changeafter CI and follow up time. CI was performed at 3.7 � 0.3 years(limits 0.6±9.1 years). No patient had any CNS involvement at di-agnosis or CNS relapse. The chemotherapy (protocol Fralle 83)consisted of induction with vincristine, daunorubicine, cyclophos-phamide, prednisone, L-asparaginase, and maintenance with vin-cristine, methotrexate, 6-mercaptopurine, and prednisone. Threepatients underwent bilateral testicular irradiation (12 ´ 200 cGy)for testicular involvement, and were given testosterone heptylate(25 mg im every 15 days) for Leydig cell de®ciency at 13.4, 14 and14.2 years, respectively, until the end of their growth. As the pu-bertal growth on this treatment is similar to spontaneous pubertalgrowth [1], they were not excluded from the study.

Protocol

Informed consent for the evaluations and for GH and/or GnRHanalogue therapies was obtained from the parents. GH secretionwas assessed ®rst by the sequential arginine-insulin test at5.4 � 0.4 years (2±10 years, >4 years in 75%) after CI and then by

the ornithine test (at 8.4 � 0.5 years after CI) in the 20 patientstested twice (17 with low and 3 with normal GH peak at the ®rstevaluation). GH was given to 13 patients as a daily sc injection, 6days a week, at 0.53 � 0.01 U/kg per week (limits 0.4±0.6). TheGnRH analogue (Decapeptyl, D-Trp6-GnRH, 3.75 mg, im, every24±26 days) was given to eight patients to treat early puberty (onset�10 years in girls and �11 years in one boy). Each GH and GnRHanalogue treatment was given for at least 2 years. They were giventogether to seven patients, four of them previously reported (cases2, 3, 5 and 8, Table 1) [2].

Methods

Height was measured twice at each visit using a Harpendenstadiometer. Bone age was assessed by one of us (RB), [9] in 27patients (14 boys). Plasma insulin-like growth factor I (IGF-I) andits GH-dependent binding protein (IGFBP-3) were measured at thesame time as GH on 48 (IGF-I) and 36 (IGFBP-3) occasions. Thecontrol group was comprised of 125 children with idiopathic shortstature and a normal GH peak response to a stimulation test. Thehormones were measured by radio-immunoassay with commercial(SB-hGH, CIS Bio-International, Gif/Yvette, France, and IGFBP-3 with a kit from the Nichols Institute, San Juan Capristiano, CA)or non-commercial reagents (IGF-I without extraction by the non-equilibrium method of Furlanetto et al [8]).

Data are means �SE, except for height, which is given as SDfor chronological age [15] and body mass index (BMI), weight inkilograms/height in meters squared, as Z-score [14]. They wereanalysed by the non-parametric Mann-Whitney U test. The heightchanges were analysed by a Wilcoxon ranked sign test. Correla-tions between variables were analysed by Spearman's test.

Results

GH secretion

The GH peak was low (<10 lg/L) at the ®rst evaluationin 21/35 cases. The GH-de®cient and GH-su�cient pa-tients had similar characteristics (ages at CI and atevaluation, duration of chemotherapy, percentage ofpubertal patients 29% vs 36%) and BMI. The 20 pa-tients tested twice had similar GH peaks at the ®rst(11.1 � 1.7 lg/L) and second evaluation (8.8 � 1.8 lg/L), and the peaks were correlated (r � 0.45, P < 0.05).The GH peaks were not correlated with the age at CI orwith the BMI.

The plasma concentrations of IGF-I and IGFBP-3were normal for age in all but two cases (Fig 1). Theywere similar in the GH-de®cient (IGF-I 1.3 � 0.2 U/mL; IGFBP-3 2.2 � 0.1 mg/L) and GH-su�cient(1.3 � 0.1 U/mL; 2.5 � 0.1 mg/L) patients, but sig-ni®cantly lower (P � 0.0001 and 0.002) in prepubertal(0.9 � 0.1 U/mL; 2.0 � 0.2 mg/L) than in pubertal(1.9 � 0.2 U/mL; 2.7 � 0.1 mg/L) patients. They werecorrelated with each other (r � 0.77, P < 0.001) andwith the BMI, but not with the GH peak or with theheight change.

Height and puberty

The height changes between CI and evaluation werecorrelated with the GH peaks (Fig 2). The mean di�er-

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ences between the chronological and bone ages weresimilar in patients with low GH (0.7 � 0.2 years,n � 17 ) and in those with normal GH peaks (0.1 � 0.5years, n � 10). Among the 28 patients of the pubertalage, excluding the three boys with Leydig cell de®ciency,

the mean age at onset of puberty was at 9.2 � 0.3 years(8±11) in girls and 11.7 � 0.4 years (9.5±14) in boys.Among the 15 girls, 12 had been given CI before 4 yearsof age and had early puberty and 3 after this age andunderwent puberty at a normal age (2 cases) or was

Table 1 Characteristics of the patients who had reached their adult height

Patient/Sex GH peak, lg/L Ages attreatment

GH,years

Age atonset ofpuberty,

Age attreatment

GnRH,years

Adultheight,SD

Height changefromirradiation, SD

1st 2nd Onset End years Onset End

1 M 9.9 9.8 6.7 13.5 9.5 )2.0 )1.62 F 8.6 8.8 11.7 13.7 9.5 10.3 12.3 )1.0 )0.93 F 4.6 2.5 10.8 15.3 10.0 10.4 12.9 0.1 )1.54 M 7.8 4.2 14.4 17.0 10.5 11.6 13.6 )0.5 0.55 F 6.3 4.6 12.3 14.3 8.5 9.3 12.3 )0.9 )0.46 F 9.8 9.9 12.0 14.0 9.5 )1.7 07 F 9.4 6.0 12.3 15.1 11.0 )1.1 )0.38 F 7.2 7.2 13.0 15.0 8.0 9.0 11.8 )0.9 )0.39 F 7.5 6.0 9.0 )1.1 )1.410 M 6.0 12.5 )2.5 )2.311 M 8.5 8.0 10.5 0.4 )0.612 M 6.9 12.5 )0.5 )0.413 M 17.8 5.2 11.2 0.3 )0.314 F 6.8 14.0 0.4 )0.815 F 25.0 8.0 9.6 11.6 )0.9 )1.716 F 21.7 33.8 10.0 )1.8 0.217 M 11.1 10.0 12.0 )1.0 )0.218 M 18.4 12.5 )0.8 )1.219 M 15.0 11.5 1.0 )0.820 M 30.6 12.0 )0.4 0.421 F 16.4 10.5 )0.3 0.7

Fig. 1 Plasma insulin-likegrowth factor I (IGF-I) and itsGH-dependent binding protein(IGFBP-3) in patients given18 Gy CI, according to age (thedotted lines show the upper andlower limits in children withidiopathic short stature, thesolid lines are average values)and compared to the body massindex (BMI). P1±P5 indicatepubertal stages

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prepubertal (1 case aged 8.1 years). Among the 20 boys,14 were in pubertal age, 4 of them had early puberty,including one given CI before 4 years of age.

Thirteen patients having two GH peaks of <10 lg/Land a total height loss from CI � 1SD or no increase ingrowth rate despite puberty (Fig 2) were given GH. Nineother patients with low GH peaks were not treated withGH because of uterine relapse (one case) or normalprepubertal growth. Because of the frequency of earlypuberty and its interference with the growth rate beforeand during GH therapy, only the growth of the 21 pa-tients who had reached their adult height (growth duringthe preceding year <1 cm, and bone age >15 years ingirls and >17 years in boys) was analysed (Table 1). Asigni®cant (P < 0.03) reduction in height (SD) betweenirradiation and adult height occurred in untreated GH-de®cient patients()1 � 0.3, cases 9±14) but not in GH-de®cient patients given GH ()0.6 � 0.3, cases 1±8) or inthose with normal GH peak ()0.4 � 0.3, cases 15±21).Their mean target height was similar (0.3 � 0.4 SD inthe two GH-de®cient groups and )0.2 � 0.2 SD in thegroup with normal GH peak).

Discussion

This study shows that 63% (21 at the ®rst and 1 addi-tional at the second evaluation) of the patients whoseGH secretion was routinely evaluated after 18 Gy CIhad a GH peak <10 lg/L, without any decrease in theconcomitant plasma IGF-I and IGFBP-3 values. Thelack of a link between the GH peak and BMI suggeststhat the low GH peak is not due to increased BMI. It hasbeen suggested that the threshold dose for risk of GHde®ciency-induced CI is about 18 Gy [3]. Decreased GHsecretion after 18 Gy CI has been reported, with spon-taneous GH secretion with an abnormal periodicity andquantitatively low GH secretion restricted to puberty [6].

In another study, the total amount of GH secretion wasreduced both before and during puberty [10]. The fre-quency of low GH peaks in this study, the decreasedpituitary height with a signi®cant correlation betweenpituitary height and GH peak and area in the argininetest, and mean GH concentration at night [4] all suggestthat 18 Gy CI decreases GH secretion. This reduced GHsecretion is probably not su�cient to reduce the plasmaIGF-I or IGFBP-3 values, but the normal values for ageof these in spite of GH de®ciency may re¯ect the earlysecretion of sex steroids, as suggested by the signi®cantlylower values in the prepubertal compared to the pubertalpatients. This raises the question of whether the reducedGH secretion alters growth and the adult height. Thisstudy shows that the GH peaks are concordant withheight changes, except in patients with early puberty,who showed no height change despite a low GH peak.Various data have been reported concerning the meanheight loss between irradiation and adult height. Forpatients with spontaneous growth, it was 0.65 SD (16),0.93 SD [18], 0.69 in boys and 1.04 SD in girls withheight losses of >1 SD in 30% and 49% of cases [7]. Inour study, it was 0.6 � 0.3 SD (12 cases), signi®cantlylower (P < 0.01) than that after 24 Gy CI (1.3 � 0.1SD, 26 cases) [1].

The indications for GH therapy in this population aredi�cult to de®ne. The normal plasma IGF-I andIGFBP-3 values and the less severe reduction in adultheight than after 24 Gy, except in girls with early pu-berty, are against GH therapy. Costin [5] reported anincrease in growth rate after GH therapy, but the con-comitant puberty may have contributed to this increase.This study shows that there is a signi®cant reduction in®nal height (SD) only in untreated GH-de®cient pa-tients. The absence of height loss in our patients withnormal GH peak, except in one patient with early pu-berty, and in those with a low GH peak treated withGH, suggest that GH therapy is indicated in patientswith a low GH peak.

Fig. 2 Individual spontaneousheight changes between the timeof 18 Gy cranial irradiation andthe ®rst (5.4 � 0.4 years) andsecond (8.4 � 0.5 years) evalu-ation compared to the GHpeaks. Numbered cases hadreached their adult height.Cases 1±8 had been given GHtherapy and cases 1±4, 8 and 15GnRH analogue therapy afterthis evaluation (Table 1)

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Over half the patients of pubertal age (57%) hadearly puberty, as did all the girls given CI before 4 years.The high incidence of early puberty in these girls prob-ably explains the data reported by Sklar et al [16], whofound that the mean height loss between 18 Gy CI andadult height was 1.38 SD in girls irradiated before 4years of age, signi®cantly (P � 0.03) greater than thatof the others (0.50 SD). It has been shown [11] that theages at irradiation and at onset of puberty are corre-lated, but the greater frequency of early puberty of girlsin this study than reported may be due to the lower CIdoses. The interval between the thelarche and the men-arche in girls was shorter than in normal puberty [13],which probably contributed to this height loss. Thesedata suggest that the indications for GnRH analoguetherapy after 18 Gy CI should be broad, even if pubertyis frequently early (onset at 8±10 years in girls and 9±11years in boys) rather than precocious (onset before 8years in girls and 9 years in boys).

Our current policy for patients given 18 Gy CI is towarn parents about the frequent occurrence of earlypuberty, particularly in girls given CI before 4 years ofage, and to ask them to bring their children to us ifbreast development begins before 10 years of age in girlsor pubic hair before 11 years in boys, or if these changesbegin just after these ages and progress quickly. Testic-ular volume is monitored. Patients with early pubertyare evaluated for their bone age, gonadotropin responseto GnRH stimulation test, and plasma oestradiol ingirls, or testosterone in boys. They are then treated withGnRH analogue, if indicated [2]. GH secretion is eval-uated if they have a decreased growth rate before pu-berty and after the end of chemotherapy, or routinely atthe onset of puberty. In those with low GH peaks aftertwo stimulation tests, the indication for GH therapyshould take into account the height before CI and thegrowth rate. The indications for GH therapy should bebroader for those patients with a below average consti-tutional height before CI. Currently, CI is reserved forpatients who have features indicating CNS involvementor suggesting a high risk of CNS relapse and CI is re-placed by chemotherapy administered intrathecally [12].

Acknowledgements We thank Dr F. Veber (Immuno-HaematologyUnit, Hoà pital Necker-Enfants Malades) for sending us four pa-tients, MC. Perret for technical assistance, the nurses of the pae-diatric endocrinology unit for carrying out the tests, the NIDDK(Baltimore, MD) for donating anti-IGF-I immunoserum, and DrO. Parkes for editorial help. GH treatment was given by FranceHypophyse.

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