endocrine consequences of treatment disease

Archives of Disease in Childhood, 1989, 64, 1635-1641

Current topic

Endocrine consequences of treatment of malignantdiseaseS M SHALET

Christie Hospital and Holt Radium Institute, Manchester

Cancer is a major cause of morbidity and mortalityin childhood and affects about one in 650 children bythe age of 15 years. When survival during the threedecades 1954-63, 1964-73, and 1974-83 was com-pared striking improvements were observed.' Forall childhood cancers, five year survival increasedfrom 21% in the first decade to 49% in the thirddecade. During the first and third decades five yearsurvival rates for acute lymphoblastic leukaemiaincreased from 2% to 47%, for Hodgkin's diseasefrom 44% to 91%, for Wilms' tumour from 31% to85%, and for medulloblastoma from 25% to 41%.The improved chances of survival have stimulated

great interest in the effects on the endocrine systemand the impairment of growth after radiotherapyand cytotoxic chemotherapy for childhood cancer.

Radiation may directly impair hypothalamic,pituitary, thyroid, and gonadal function, or alterna-tively it may induce the development of hyperpara-thyroidism, thyroid adenomas, or carcinomas.Cytotoxic chemotherapy may damage the gonad andboth irradiation and cytotoxic chemotherapy mayinterfere with the normal growth of bone. Thesecomplications of treatment may lead to variousclinical presentations including short stature, failureto undergo normal pubertal development,precocious puberty, hypothyroidism, thyroidtumours, hyperparathyroidism, gynaecomastia, andvarying degrees of hypopituitarism.

Brain tumours

GROWTHShort stature is a common complication after thetreatment of brain tumours in childhood. Thesebrain tumours include gliomas, ependymomas, andmedulloblastomas-all lesions that do not directlyaffect the hypothalamic-pituitary axis. The treat-ment of these tumours may include operation,cranial or craniospinal irradiation, and chemo-

therapy. The final height achieved by the patientsmay be adversely influenced by a number of factorsincluding growth hormone deficiency, impairedspinal growth, precocious puberty, chemotherapy,malnutrition, and occult tumour.The impact of malnutrition and residual tumour

on growth has not been studied in these children andthere are few studies of cytotoxic chemotherapy andgrowth retardation.

GROWTH HORMONE DEFICIENCYIrradiation of the hypothalamic-pituitary axis mayproduce a range of pituitary hormone deficienciesranging from isolated growth hormone deficiency topanhypopituitarism.2 Of the six anterior pituitaryhormones, the first to be affected by radiationdamage is always growth hormone, followed bygonadotrophin and adrenocorticotrophic hormonesecretion. The extent of hypothalamic-pituitarydysfunction is dose dependent, growth hormonedeficiency occurring at lower doses of irradiation,and panhypopituitarism after higher doses. Thespeed with which individual pituitary hormonedeficiencies occur is also dose dependent. Thehigher the radiation dose, the earlier growthhormone deficiency will develop after treatment. Inchildren irradiated for a brain tumour, a radiationdose to the hypothalamic-pituitary axis of between2700 and 3500 cGy over three weeks is sufficient toproduce subnormal growth hormone responses tostandard provocation tests in most patients withintwo years of radiotherapy. In an occasional patient,however, growth hormone deficiency may not occurfor three to six years after irradiation.Both the hypothalamus and the pituitary may be

directly damaged by irradiation. There are a numberof studies, however, which indicate that thehypothalamus is more vulnerable to such damagethan the pituitary. Therefore the primary patho-physiological defect in such children is likely to be

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subnormal endogenous production of growthhormone releasing hormone rather than inadequategrowth hormone secretion by pituitary somato-trophs. Thus if an intranasal or depot preparation ofa suitable growth hormone releasing hormoneanalogue becomes available, it may prove ideal forthe treatment of children with radiation inducedgrowth hormone deficiency.

SPINAL IRRADIATION AND GROWTHChildren treated for medulloblastomas, ependymo-mas, and certain other brain tumours receive spinalas well as cranial irradiation. After a dose of spinalirradiation of 2700 to 3500 cGy over 22 to 27 daysspinal growth may be appreciably impaired.3 Theyounger the child at the time of irradiation, thegreater the loss in growth potential-from 9 cm ifirradiated at 1 year of age, to 5-5 cm at 10 years ofage. It is likely that these estimates of eventual lossin height are conservative figures and furthermore,in centres where the spinal irradiation dose isgreater than that used in the above study, even morepotential growth may be lost. Much of the impair-ment in spinal growth occurs during puberty,irrespective of the age at irradiation. Consequently,the prognosis for spinal growth in an irradiated childwho is still prepubertal should not be too optimistic.

PRECOCIOUS PUBERTYEarly4 or precocious5 puberty has been reported insome children who have received cranial irradiation.The onset of puberty at a very young age is, how-ever, rarely seen. Puberty starts at appreciablyearlier chronological and bone ages in children withradiation induced growth hormone deficiency com-pared with children who have idiopathic growthhormone deficiency.2 The radiation induced shift inthe onset of puberty may affect both sexes. Theclinical implication for the treatment of childrenwith radiation induced growth hormone deficiencyand early puberty is to foreshorten the time avail-able for treatment with growth hormone.

TREATMENT WITH GROWTH HORMONEData about final height in children with radiationinduced growth hormone deficiency after the treat-ment of brain tumours indicate that their growth inresponse to treatment is less impressive than thatseen in children with idiopathic growth hormonedeficiency. I have already discussed some of thefactors such as spinal irradiation and early pubertywhich prevent a better growth response. None theless, in the group with cranial irradiation alone,treatment with growth hormone prevented furtherloss in height SD scores,6 while in the children whoreceived craniospinal irradiation growth hormone

restricted the amount of further loss in height SDscores.7A further important adverse factor in the height

prognosis of these children was the time intervalbetween irradiation and initiation of treatment withgrowth hormone, which averaged between 5-5 and6-7 years.6 7 There is little doubt that better resultswould have been achieved if treatment with growthhormone had been started earlier. This leads on tothe fundamental question of when should treatmentwith growth hormone be started?There has been a tendency to wait until the child

exhibits a poor growth rate. Adverse factors,however, such as impaired spinal growth andcytotoxic chemotherapy, may lead to poor growthand-alternatively-early puberty may beassociated with an 'apparently normal' growth ratethat may give rise to false optimism about the child'sheight prognosis.What, if any, tests of growth hormone secretion

should be carried out? Lannering and Albertsson-Wiklund suggested that 24 hour spontaneous growthhormone profiles provide the most usefulinformation.8 For pragmatic reasons, however, Ibelieve that the 24 hour growth hormone profile islikely to remain a research investigation, as thedemands on the laboratory and clinical team make itunacceptable as a routine method of investigation inpaediatric endocrinology. Furthermore, discordancybetween physiological growth hormone secretionand growth hormone responses to pharmacologicalstimuli is uncommon after the higher doses ofcranial irradiation used in the treatment of braintumours. The majority of such children willtherefore show a subnormal growth hormoneresponse to an insulin tolerance test as well asblunted physiological growth hormone secretion. Iftests of growth hormone secretion are carried out,the insulin tolerance test remains a particularlyuseful investigation in the child who has receivedcranial irradiation.The chances of recurrence of a brain tumour are

greatest within two years of the primary treatmentof the tumour.2 There is no evidence that treatmentwith growth hormone, increases the risk ofrecurrence of a brain tumour in children withradiation induced growth hormone deficiency.9 Onereasonable approach therefore would be to treat allthe children with brain tumours treated by standardradiation schedules (including a dose to thehypothalamic-pituitary axis in excess of 2700 cGy)with growth hormone two years after their primarytreatment. At this time they would no longer bereceiving cytotoxic chemotherapy, the chance ofrecurrence of a tumour is low, and it is establishedthat most will be growth hormone deficient by this

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Endocrine consequences of treatment of malignant disease 1637

time. This policy would not require routine tests ofgrowth hormone secretion. One drawback,however, is that a minority of the children wouldreceive growth hormone at a time when they had notyet developed growth hormone deficiency.

In practice, I submit the children at our owncentre to routine annual insulin tolerance test andarginine stimulation test from two years afterirradiation until the decision is taken to start themon treatment with growth hormone. Other centresmay choose different provocation tests and at leastone centre does not carry out any tests at all, buttreats all children irradiated for brain tumours withgrowth hormone two years after irradiation.Whatever policy an individual centre practices, theprinciple of administering treatment with growthhormone earlier in this group of children is centralto the prognosis of their ultimate height;

THYROID DYSFUNCTIONDirect irradiation to the thyroid gland is a consequ-ence of the spinal component of craniospinal irradia-tion. The two serious complications of radiationinduced thyroid damage are hypothyroidism andthyroid tumours.'0

Hyperparathyroidism may develop many yearsafter neck irradiation in adults and, despite the factthat this specific complication has not beendescribed after irradiation in children, it is clearly apossibility.

Radiation induced thyroid tumours may bebenign or malignant. Typically there is a long latencyperiod between irradiation and the clinical presenta-tion with a thyroid swelling. In clinical practice anychildren who have received neck irradiation shouldhave their thyroid glands palpated at least once ayear. Routine use of isotope scanning is not recom-mended.The degree of thyroid dysfunction after thyroid

irradiation may range from frank hypothyroidismwith increased concentration of thyroid stimulatinghormone and low thyroxine concentration, tosubtle disturbance with increased thyroid stimulat-ing hormone, and normal thyroxine concentra-tions. A thyrotrophin releasing hormone test isunnecessary. An annual assessment of the basalthyroid stimulating hormone and thyroxine concen-trations will suffice in children who have beenirradiated.

In children with obvious biochemical hypothy-roidism, thyroxine replacement is indicated. If theonly abnormality in the thyroid function tests is anincrease in the concentration of thyroid stimulatinghormone, then interpretations in reports about adultpatients vary between mild hypothyroidism and'compensated thyroid dysfunction'. In the context of

children who have been irradiated, this is anacademic discussion as treatment with thyroxine isindicated for a number of reasons. Firstly, there isstrong circumstantial evidence that an increasedconcentration of thyroid stimulating hormone mayincrease the risk of thyroid tumours developing in anirradiated thyroid gland. Secondly, in a child whomay be short for a number of reasons it is importantto be certain that the child is euthyroid. Thesearguments weigh strongly in favour of early thyrox-ine replacement with a dose of thyroxine sufficientto restore the circulating concentration of thyroidstimulating hormone to within the normal range.There is one report that suggests that the inci-

dence of thyroid dysfunction is significantly greaterin children who receive cytotoxic chemotherapy andcraniospinal irradiation compared with craniospinalirradiation alone.11 I know of no conclusiveevidence, however, that cytotoxic chemotherapyalone may modify thyroid function.

GONADAL DYSFUNCTIONBoth the adjuvant cytotoxic chemotherapy and thespinal fields of irradiation may damage the gonads inchildren treated for brain tumours. Long termfollow up in 21 girls and 29 boys who had receiveda nitrosourea-carmustine (BCNU) or lomustine(CCNU)-with or without procarbazine has shownthat there is a high incidence of primary gonadaldysfunction.12 13 Both sexes progressed throughpuberty normally with consistently raised basalconcentrations of follicle stimulating hormone andoccasionally increased concentrations of luteinisinghormone. The girls achieved menarche at anappropriate age. As adults most of the boys hadinappropriately small testicular volumes, which arelikely to be associated with severe oligospermia orazoospermia, and infertility. In these children, as inthose treated for other malignant diseases, gonadaldamage in prepubertal life may not be associatedwith abnormal gonadotrophin concentrations eitherbasally or after gondatrophin releasing hormonestimulation; these develop during the peripubertalyears.A sex difference in the reversibility of damage was

observed. The boys showed no evidence of recoveryof germinal epithelial function and no deteriorationin Leydig cell function in a follow up extended to 11years. In contrast, several girls who had previouslybeen shown to have ovarian damage have continuedwith regular menses and normal follicle stimulatinghormone and oestradiol concentrations. Although itwas not known whether these cycles were ovulatory,it is likely that these girls had recovered from theovarian damage. The prospects for fertility amongsuch girls are good in the early child bearing years.

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As with other cytotoxic combinations, however,premature menopause remains a possibility.Many of these children have also received cranio-

spinal irradiation, which results in scattered doses tothe gonad. In the boys, this results in a small totaldose to the testis (estimated at 46-120 cGy after afractionated course of total spinal dose 3500 cGy inthe Manchester centre). This is likely to contributeto testicular damage, as seen in individual boystreated with craniospinal irradiation but nochemotherapy who have developed testiculardysfunction. 14 In girls, however, the dose of irradia-tion to the ovary may show greater variation. In theManchester centre a total dose in the range 90-1000cGy has been estimated to reach the ovary; this maycontribute appreciably to ovarian dysfunction,which may be irreversible. The scattered dose to theovary will differ among treatment centres dependingon the method of giving the radiotherapy. Hence theindividual contributions of spinal irradiation andcytotoxic chemotherapy to ovarian damage willvary. 15

Acute lymphoblastic leukaemia

GROWTHMuch confusion and controversy have been gener-ated over the growth patterns and growth hormonerequirements of the child with acute lymphoblasticleukaemia treated with prophylactic cranial irradia-tion and combination cytotoxic chemotherapy forseveral years. Some groups have found no adverseeffect on final height, while other groups (includingour own) have noted a modest adverse effect ongrowth,'6 but as final height is unknown in most ofthe children, the possibility of impaired pubertalgrowth may mean that final height loss is substantialin a pro)Jortion of children. Finally, there is a thirdgroup, who have studied children with acutelymphoblastic leukaemia and found a much greaterretardation of growth. An analysis of the radiationschedules and chemotherapy protocols used in thedifferent centres has led to some understanding ofthe explanation for the differences in height lossobserved between groups.There is in vitro evidence that cytotoxic chemo-

therapy may effect growth mechanisms and in vivoevidence of an effect on growth.'6 17 In the childwith acute lymphoblastic leukaemia the durationand nature of the combination cytotoxic chemo-therapy will influence the growth prognosis. Aftertreatment with regimens used in the UnitedKingdom the effects of cytotoxic chemotherapy arelikely to be minor, but more intense cytotoxicchemotherapy regimens have had a profound impacton growth.

Children irradiated prophylactically for acutelymphoblastic leukaemia rather than for a braintumour tend to receive a lower radiation dose to thehypothalamic-pituitary axis. Most of the growthstudies have been carried out in children whoreceived a total cranial radiation dose of 2400-2500cGy. The incidence of growth hormone deficiency insuch children will depend on the number of frac-tions, fraction size, and duration of the radiationschedule.For a number of reasons the demand for treat-

ment with growth hormone is more difficult topredict after treatment for acute lymphoblasticleukaemia than after a brain tumour. I have alreadydiscussed the dissimilar growth patterns in childrenwith acute lymphoblastic leukaemia studied bydifferent groups. In the children with severe growthretardation, even though cytotoxic chemotherapy isa serious adverse factor, radiation induced growthhormone deficiency is common.17 It is appropriatetherefore that most of these children are offeredtreatment with growth hormone whereas I have onlytreated a minority of the children with acute lym-phoblastic leukaemia in Manchester.'6 The clinicaldilemma is how to identify the few who shouldreceive treatment. We have suggested that thosechildren who are below the tenth centile or whosegrowth rate is persistently poor after completion ofcytotoxic chemotherapy, and who have growthhormone deficiency, should receive a therapeutictrial of growth hormone. 16 It should be understood,however, that this is an arbitrary definition ofgrowth hormone requirement.Moell et al have studied the growth patterns of

children with acute lymphoblastic leukaemia duringdifferent phases of childhood.'8 Their girls treatedfor acute lymphoblastic leukaemia lost very littlestanding height SD score during prepubertal life, asin other studies, but had an attenuated pubertalgrowth spurt. The contribution of growth hormonedeficiency to the disturbed pubertal growth and theeffect of treatment with growth hormone to improveit, with or without the addition of a gonadotrophinreleasing hormone analogue to delay the ratherearly pubertal onset in some of the girls, are underinvestigation.

Since 1980 the total dose of cranial irradiation foracute lymphoblastic leukaemia has been reduced to1800 cGy. There are, however, few detailed studiesof growth hormone secretion after this dose and thegrowth data available cover only the first four to five

2years after irradiation.

THYROID DYSFUNCTIONIn the past the prophylactic irradiation of the centralnervous system for acute lymphoblastic leukaemia

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included spinal as well as cranial fields. The possibil-ity of radiation induced thyroid tumours or thyroiddysfunction, therefore, exists as previously discus-sed. In recent years children with acute lymphoblas-tic leukaemia have not received spinal irradiation,and so thyroid damage should not occur.

GONADAL DYSFUNCTIONThe impact, both transient and permanent, ofcombination cytotoxic chemotherapy on gonadalfunction is totally dependent on the nature anddosage of the drugs received by the child.

In boys who received cyclophosphamide or

cytosine arabinoside, or both, as part of theircombination cytotoxic chemotherapy for acutelymphoblastic leukaemia, the germinal epithelialmorphology was profoundly disturbed.2' In otherswho did not receive alkylating drugs or methyl-hydrazines, the gonadotrophin and testosteroneconcentrations, and semen analysis, were normal.Lendon et al had indicated that the damage to thetesticular germinal epithelium was likely to be rever-sible and therefore fertility a realistic prospect.2"

In girls the outlook is even brighter, in thatcytotoxic chemotherapy induced ovarian damagehas been reported only rarely. Morphologicalstudies have shown that the main abnormality isinhibition of follicular maturation rather than severe

depletion of primordial follicles, an observationmore consistent with reversible rather than withpermanent functional changes.2' Both boys and girlsprogress through puberty spontaneously indicatingthat gonadal steroidogenesis is adequate.Most boys with leukaemic relapse of the testes

receive direct testicular irradiation with a total dosebetween 2000 and 2400 cGy. The effects of thetesticular irradiation are dependent on the age andpubertal stage of the boy.22-24 The young pre-

pubertal boy seems most vulnerable to the develop-ment of severe and persistent testicular dysfunction.The germinal epithelium is completely ablated in all,and Leydig cell function seriously affected in most.Increased basal concentrations of follicle stimulatinghormone and luteinsing hormone will often firstoccur around the ages of 9 to 10 years. The serum

testosterone concentration is usually low, which is ofcourse normal for a prepubertal boy, but there is aninadequate or absent testosterone response to an

acute bolus of human chorionic gonadotrophin.Most boys require androgen replacement to enablenormal pubertal development to occur. Initiation ofandrogen replacement should be considered around12 to 13 years of age, and the requirement will bepermanent.

Girls are also susceptible to radiation inducedgonadal damage during treatment of acute lympho-

blastic leukaemia.25 In 97 girls treated for acutelymphoblastic leukaemia with identical regimens ofcytotoxic chemotherapy but different modalities ofirradiation, abnormalities of follicle stimulating hor-mone or luteinising hormone secretion, or both,were more commonly seen after craniospinalcombined with abdominal irradiation, than aftercraniospinal irradiation alone. Not surprisingly,abnormalities of gonadotrophin secretion were rarein the group that received cranial irradiation alone.After craniospinal and abdominal irradiation,arrested puberty and delayed menarche occurredbecause of the ovarian damage.

Bone marrow transplantation

Marrow transplantation has become a life savingprocedure for an increasing number of children andyoung adults with either non-malignant or malignanthaematological disorders, in particular leukaemia.Follow up studies evaluating growth and develop-ment have shown that the delayed effects are relatedto the regimen used for preparation for marrowtransplantation. Few endocrine abnormalities havebeen observed after regimens containing only highdoses of cyclophosphamide, but growth disturbanceand multiple endocrine abnormalities have beenseen after regimens that include total bodyirradiation.26

Total body irradiation has been given in singledose exposures of 750 to 1000 cGy, and morerecently in fractionated exposures of total dosesranging from 1200 to 1575 cGy given over three toseven days. In a series of 116 children who receivedtransplants for malignancy after preparation withcyclophosphamide and total body irradiation, 18%developed compensated thyroid dysfunction, 11%developed hypothyroidism and two children de-veloped thyroid tumours four and eight yearslater.26As might be expected, there is a high incidence of

gonadal dysfunction after total body irradiation withablation of the germinal epithelium in the boys andirreversible ovarian failure in most of the girls. Thedegree of Leydig cell failure is dependent on thepubertal stage of the boy, and whether or not he hasreceived previous testicular irradiation.

Severe growth disturbance is common and may becaused by various aetiological factors includinggrowth hormone deficiency, thyroid dysfunction,radiation induced impairment of bone growth, orgraft versus host disease and its treatment. Growthhormone deficiency may occur even if the child hasnot previously received prophylactic cranialirradiation .27 It is, however, too early to drawconclusions about the beneficial effects of treatment

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with growth hormone in growth hormone deficientchildren after total body irradiation, but there isroom for optimism.

Abdominal tumours

In the past it was more common to find that childrenwith malignancies such as Wilms' tumour receivedwhole abdomen irradiation. Gonadal dysfunctionwas common, with azoospermia and infertilityresulting from the scatter dose of irradiation to thetestes, and ovarian failure caused by direct radiationdamage to the ovaries. In the girls in whom ovarianfunction was preserved the reproductive outcomewas still poor, presumably as a result of the effects ofirradiation on the uterus or its blood supply.28

Fortunately irradiation of the whole abdomen forWilms' tumour is used much less often now. Ifradiotherapy is given then only the relevant flank istreated. Consequently the incidence of ovarianfailure and azoospermia have been dramaticallyreduced.

Irradiation, both of the whole abdomen and of theflank, will include part of the vertebral column inthe radiation field. Some degree of skeletal dispro-portion and height loss will therefore occur, but thisis less than that seen after irradiation of the wholespine for brain tumours.

Lymphomas

Hypothyroidism, compensated thyroid dysfunc-tion, and thyroid tumours may occur in children whohave received neck or mediastinal irradiation forlymphoma.

In those boys treated with six or more courses ofMVPP (mustine, vinblastine, procarbazine, andprednisolone) or MOPP (mustine, vincristine, pro-carbazine, and prednisolone) testicular dysfunctionis inevitable.29 The damage to the germinalepithelium is severe and seems irreversible, whereasLeydig cell dysfunction-if it occurs-is subtle anddoes not prevent the boys from progressing throughpuberty spontaneously.Gonadal dysfunction is less common in girls than

in boys but it may occur and, if so, then sex steroidreplacement may be necessary for pubertal develop-ment. It is likely but not proved that ovarianfunction is less vulnerable to cytotoxic chemo-therapy induced damaged in young girls than inadult women in whom the incidence of ovarianfailure is between 15 and 60%.

Conclusions

In this review I have concentrated on the growth and

endocrine results of the treatment of the morecommon childhood malignancies. Irrespective of theprimary malignancy, however, the damage is causedif the radiation field includes an endocrine gland,or if a cytotoxic chemotherapy regimen containsgonadotoxic drugs. For instance, if a child is growingpoorly after irradiation for a rhabdomyosarcoma ofthe orbit, consider the possibility that an appreciableamount of irradiation reached the hypothalamic-pituitary axis and caused growth hormonedeficiency. Alternatively, if a boy has receivedcombination cytotoxic chemotherapy for a bonetumour and has pathologically small testes, considerthe possibility that the alkylating agent or cis-platinum used in the cytotoxic chemotherapyregimen has caused severe damage to the germinalepithelium. The first boy may require treatmentwith growth hormone, while the second will needsome advice and counselling about his potentialinfertility at the appropriate time.

All children attending an oncology centre shouldhave their standing height, weight, and pubertalstage noted at each visit. The measurements shouldbe recorded on standard Tanner growth charts. If allor part of the child's spine has been irradiated thenthe sitting height should be measured regularly.There are standard charts available for recordinggrowth in leg length and sitting height.The oncologist can screen for abnormalities of

thyroid function and morphology, and manyoncologists will feel competent to titrate the replace-ment dose of thyroxine against the clinical state, andthyroid stimulating hormone and thyroxine concen-trations of the child.Growth disturbance and the hormonal manage-

ment of pubertal development are much morecomplicated and require expertise in endocrinology.The equipment required consists of standing andsitting height stadiometers and an orchidometer.The personnel must include an endocrinologist andan oncologist.The numbers of patients recovering from cancer

in childhood are growing, and for optimum manage-ment every major paediatric oncology serviceshould offer a combined clinic at which both thepaediatric oncologist and the endocrinologistcontribute.

References

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2 Shalet SM. Clayton PE. Price DA. Growth and pituitaryfunction in children treated for brain tumours or acute lympho-blastic leukaemia. Hor,n Res 1988;30:53-61.

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8 Moell C, Garwicz S, Westgren U, Wiebe T. Disturbed pubertalgrowth in girls treated for acute lymphoblastic leukaemia.Pediatric Hemnatology anid Onicology, 1987;4:1-5.

9 Leiper AD, Stanhope R, Preece MA, Grant DB, Chessells JM.Precocious or early puberty and growth failure in girls treatedfor acute lymphoblastic leukaemia. Hormn Res 1988;30:72-6.

2() Lendon M, Hann IM, Palmer MK, Shalet SM, Morris-JonesPH. Testicular histology after combination chemotherapy inchildhood for acute lymphoblastic leukaemia. Lanicet1978;ii:439-41.

2 Himmelstein-Braw R, Peters H, Faber M. Morphological studyof the ovaries of leukaemic children. Br J Canticer 1978;38:82-7.

22 Shalet SM, Horner A, Ahmed SR, Morris-Jones PH. Leydig celldamage after testicular irraidiation for lymphoblastic leukaeinia.Med Pediatr Onicol 1985;13:65-8.

23 Leiper AD, Grant DB. Chessells JM. Gonadal function aftertesticular radiation for acute lymphoblaistic leukaemina. Arc-I DisChild 1986;61:53-6.

24 Brauner R, Caltabiano P, Rappaport R. Leverger G. SchaisonG. Leydig cell insufficiency aifter testicular irradiation for acutelymphoblastic leukaemia. Hormn Res 1988;30:111-4.

25 Hamre MR, Robison LL. Nesbit ME, et al. Effects of radiationon ovarian function in long-term survivors of childhood acutelymphoblastic leukaemia: a report from the children's cancerstudy group. J Cliti Oticol 1987;5:1759-65.

26 Sanders JE, Buckner CD, Sullivan KM, et al. Growth anddevelopment in children after bone marrow transplantation.Hormn Res 1988;30:92-7.

27 Borgstrom B, Bolme P. Growth and growth hormone inchildren after bone marrow transplantation. Hormn Res1988;30:98-100.

2_ Li FP. Gimbrere K, Gelber RD, et al. Outconme of pregnancy insurvivors of Wilms' tumour. JAMA 1987;257:216-9.

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Correspondence to Dr SM Shalet, Christie Hospital and HoltRadium Institute, Wilmslow Road. Withington, ManchesterM2(0 9BX.

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endocrine consequences of treatment disease

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