Howard 2002

Endocrinopathy in pediatric ALL
(Table 1). Endocrine complications during therapy include

Endocrine complications in bone demineralization, disordered growth, adrenocortical
insufficiency, diabetes mellitus, the syndrome of inappropri-
pediatric patients with ate secretion of anti-diuretic hormone (SIADH), and changes
in thyroid hormone concentration. These endocrine sequelae
acute lymphoblastic can cause morbidity and mortality during therapy for ALL.
leukemiaq Because more than 80% of children with ALL now survive to
adulthood,2–4 the late complications of therapy must also be
considered. Late complications, defined here as those that
Scott C. Howard1,3, Ching-Hon Pui1,2,3 occur after completion of all radiation and chemotherapy,
include bone demineralization, short stature, growth hor-
1
Department of Hematology-Oncology, University of Tennessee Health Science mone deficiency, obesity, hypothyroidism, gonadal dysfunc-
Center, Memphis, TN, USA tion, and infertility. This review discusses the early and late
2
Department of Pathology, St. Jude Children’s Research Hospital, University of endocrine complications of childhood ALL and its treatment.
Tennessee Health Science Center, Memphis, TN, USA Gonadal function and fertility in survivors of childhood ALL
3
Department of Pediatrics, University of Tennessee Health Science Center, and endocrine dysfunction after bone marrow transplanta-
Memphis, TN, USA tion will not be reviewed here, but they have been discussed
and reviewed elsewhere.5–17 We describe the epidemiology,
Abstract Endocrine complications of therapy for acute symptoms and signs, diagnosis, treatment, prevention, and
lymphoblastic leukemia (ALL) are common and are potentially research questions for each endocrinopathy.
debilitating both during and after therapy. Growth velocity slows
during therapy for ALL, especially during the first year; however,
children who do not receive cranial irradiation usually reach DIMINISHED GROWTH, GROWTH HORMONE
normal adult height. While growth hormone deficiency generally DEFICIENCY, AND OBESITY
occurs in patients who have received 24 Gy of cranial irradiation,
it may also develop in those treated with lower doses (18 Gy) of Growth velocity during therapy for ALL
cranial radiation or with only high-dose methotrexate. Obesity Growth velocity is diminished during all phases of therapy
commonly occurs during therapy and persists after completion for childhood ALL.18–26 Patients who undergo cranial irradi-
of therapy. Osteopenia can occur early during therapy for ALL ation have diminished adult height,27–29 but patients who
and can persist for many years. Adrenal insufficiency should be receive only chemotherapy usually undergo accelerated
suspected in any child who has recently received glucocorticoid (‘‘catch-up’’) growth afterward and reach normal adult
therapy, and stress doses of steroid should be administered in height. Children who receive 18 or 24 Gy of cranial irradia-
the event of metabolic stress. Screening of urine is useful for tion have a greater reduction in growth velocity than do
early detection of hyperglycemia during therapy with children treated for ALL with chemotherapy alone.30 Argu-
glucocorticoids and L -asparaginase. The syndrome of elles et al.31 studied the growth of 26 children during therapy
inappropriate secretion of anti-diuretic hormone is usually on the BFM-90 protocol32 and found no difference in growth
associated with vincristine therapy and may be aggravated by velocity during the first three years after diagnosis between
concurrent use of azole antifungals. Finally, patients who have patients who received 12 Gy of cranial irradiation and those
received 18 or 24 Gy of cranial irradiation may have clinical or who received none. While the adverse effect of cranial irra-
subclinical deficiencies of thyroid hormones. c 2002 Elsevier diation on growth may occur only above a threshold dose,
Science Ltd. All rights reserved. longer follow-up is needed to determine if there is a delayed
deleterious effect of 12 Gy of irradiation.
KEY WORDS: acute lymphoblastic leukemia; glucocorticoids; Dexamethasone may contribute to reduced growth ve-
cranial irradiation; adrenal insufficiency; hyperglycemia; locity during therapy,33 but one study found that growth
inappropriate ADH syndrome; growth; osteopenia velocity was reduced even during continuation therapy that
did not include a glucocorticoid.23 Others have observed
some catch-up growth during the third year of therapy for
INTRODUCTION ALL, but only in patients who did not receive cranial irradi-
ation.34 In the UKALL XI-92 trial, a third block of intensive
ne fourth of all cases of childhood cancer are acute
O lymphoblastic leukemia (ALL), which is the most

common form of leukemia in children.1 Pediatric
patients with ALL can experience endocrine dysfunction
chemotherapy given at week 35 of continuation therapy di-
minished the velocity of lower leg growth in nine patients
evaluated for growth, but normal growth resumed after
completion of the two weeks of dexamethasone therapy
during therapy, after therapy, and even many years later
(weeks 35 and 36) despite six additional weeks of intensive
therapy without glucocorticoid.33
q
Supported in part by Cancer Center Support (CORE) grant
CA-21765 from the National Cancer Institute, by a Center of Final height and growth hormone deficiency in
Excellence grant from the state of Tennessee, and by the American survivors of ALL
Lebanese Syrian Associated Charities (ALSAC). C-H. Pui is an Patients who do not receive cranial irradiation usually expe-
American Cancer Society-F.M. Kirby Clinical Research Professor. rience adequate catch-up growth after completion of
225
c 2002 Elsevier Science Ltd. All rights reserved. Blood Reviews (2002) 16, 225–243
doi:10.1016/S0268-960X(02)00042-5
Howard and Pui
Table 1 Incidence and timing of endocrinopathy in children with acute lymphoblastic leukemia
Endocrinopathy At diagnosis During induction or During maintenance After completion of Comments

delayed intensification therapy therapy
Hypothyroidism Rare Rare Rare Rare

Hyperthyroidism Rare Rare Rare Rare
Diabetes mellitus Rare Common Uncommon Rare Incidence and timing depend on
the dosage and schedule of
glucocorticoid and L -asparaginase
therapy
Adrenal insufficiency Rare Common but rarely Rare Rare Incidence and timing depend on
of clinical consequence the dosage, schedule, and choice
of glucocorticoid
Syndrome of Rare Rare Rare Rare
inappropriate
secretion of
anti-diuretic hormone
Growth retardation Rare Very common Common Uncommon
Growth hormone Rare Rare Rare Uncommon to Growth hormone deficiency is
deficiency very common uncommon in patients treated
with chemotherapy only but
is common in those who
receive 18 Gy or more of cranial
irradiation. The effect of 12 Gy
of cranial irradiation on growth
hormone secretion is unknown.
Obesity Uncommon Very common Very common Very common
Osteopenia Common Common Common Common
Very common: >25% of patients are affected; common: 10–25% of patients are affected; uncommon 2–9% of patients are affected; rare: <2% of patients
are affected.
therapy.27–29 However, the growth of patients who have re- deficiency causes numerous complications, including dysli-
ceived cranial irradiation (especially at a dose of 24 Gy) often pidemia, decreased lean body mass, obesity, osteopenia,
remains slowed after the completion of therapy; this effect is and reduced quality of life.17;42–44 These sequelae can lead
more noticeable during the pubertal stage of develop- to early morbidity and mortality caused by cardiac disease
ment17;18;20;22;24;26;27;30;35–39 Sklar et al.30 reviewed the growth and osteoporotic fracture; therefore, detection of GH defi-
and final height of 127 patients treated for ALL, of whom 38 ciency remains important even in asymptomatic patients
received no cranial irradiation, 36 received 18 Gy, and 53 whose growth is complete. Although GH levels have been
received 24 Gy. Final height was diminished in patients who reported to be elevated at diagnosis of childhood ALL,45 GH
received 24 Gy but not in the other two groups; the effect secretion is decreased in patients receiving intensive glu-
was most pronounced in girls who were 6 4 years of age at cocorticoid therapy20 and in long-term survivors who were
the time of treatment, although other investigators have not treated with 18 or 24 Gy of cranial irradiation.20;37 In one
observed greater sensitivity among girls.18;27 In fact, Hokken- study, dexamethasone therapy completely suppressed GH
Koelega et al.22 found that patients who were near pubertal secretion,20 a finding consistent with the diminished
age at the time of cranial irradiation had normal final height. growth seen during the dexamethasone-containing portion
We have observed growth hormone deficiency in patients of a third block of intensification chemotherapy in the
whose CNS-directed therapy comprised only intrathecal UKALL XI-92 protocol.33 The effects of cranial irradiation on
chemotherapy and high-dose methotrexate.40 Hence, the GH secretion, unlike those of high-dose glucocorticoids or
growth of all children treated for ALL, even those who re- other intensive chemotherapy, are often permanent, and
ceive no cranial irradiation, should be closely monitored. the effect of 24 Gy is greater than that of 18 Gy.37 Blatt et
Furthermore, children who undergo intensive chemotherapy al.39 found that daily GH secretion was eightfold less in
or cranial irradiation can develop precocious puberty, which eight long-term survivors of childhood ALL who had re-
may be an additional cause of diminished final height.5;41 ceived 24 Gy than in control subjects,39 whereas GH se-
cretion was reduced (moderately) in only one of five ALL
Growth hormone deficiency and growth hormone survivors who had received 18 Gy.38 Similarly, Kirk et al.36
therapy found partial or complete GH deficiency in 30 of 46 long-
Growth hormone (GH) deficiency in children diminishes term survivors of ALL who had been treated with 24 Gy of
growth velocity and final height. In adults, growth hormone cranial irradiation.
226 Blood Reviews (2002) 16, 225–243 c 2002 Elsevier Science Ltd. All rights reserved.
There is limited information about the use of growth BONE DEMINERALIZATION
hormone replacement therapy in survivors of childhood ALL. Clinical significance of osteoporosis in pediatric ALL
There have been several reports of the development of leu- Osteoporosis is generally seen in children only when particular
kemia in otherwise healthy children who were treated with risk factors, such as a low calcium diet, glucocorticoid therapy,
growth hormone for primary growth hormone defi- or chronic inflammatory conditions, are present.65–68 Oste-
ciency.46–50 Although the relationship between GH therapy oporosis in children presents a particular problem, because
and the later development of ALL is unclear,51–54 these re- failure to achieve peak bone mass at the end of adolescence is
ports nevertheless have raised concerns about the safety of the main risk factor for subsequent osteoporotic fracture.69–71
GH therapy for patients with ALL. Growth hormone re- Peak bone mass is reached in the third decade of life and de-
placement therapy was efficacious in the group of 47 survi- clines progressively thereafter, with a precipitous drop at
vors of childhood ALL we recently reviewed, most of whom menopause.71–74 When bone mineral density (BMD) falls be-
reached normal adult height.40 Although we and others low the fracture threshold, the risk of osteoporotic fracture
found no evidence that growth hormone therapy was asso- rises exponentially with additional small decrements in BMD.
ciated with relapse or the development of second malig- Under normal circumstances, the risk of fracture begins to
nancy,40;55 a larger Childhood Cancer Survivor Study increase at around age 50 in women and age 65 in men.75
suggested a possible association between growth hormone However, if peak BMD is diminished, there is less reserve bone
replacement therapy and the development of osteogenic mineral, and the fracture threshold is reached earlier. Con-
sarcoma or meningioma within the irradiation field.56 ceivably, pediatric patients with ALL who fail to achieve opti-
mal peak BMD reach the fracture threshold prematurely and
Obesity during and after therapy for ALL are at risk of osteoporotic fracture at a much younger age. In
Obesity is common in survivors of childhood ALL, and cranial extreme cases, osteoporotic fractures can occur during ther-
irradiation is an important risk factor.17;28;31;57;58 In one study apy,76–78 which is not surprising since some children already
of 126 children with ALL, body mass index (BMI) increased have osteopenia at the time of ALL diagnosis.79;80
between diagnosis and the end of therapy only in patients
who received cranial irradiation, and the elevated BMI was
sustained at the time these children achieved final height, Epidemiology: survivors of ALL are at increased risk
with a 40% incidence of obesity (BMI > 85th percentile).57 of osteoporosis
Another study documented increased fat body mass in girls Adults who are treated with glucocorticoids are at dramati-
treated with cranial irradiation (18 or 24 Gy) compared to cally increased risk of osteoporosis,81–85 and the magnitude of
girls treated with chemotherapy alone and healthy controls, this effect in children has increasingly been investigated.
but no difference in fat body mass in boys between the three Several studies have documented decreased bone mineral
groups.59 Patients who received 24 Gy had larger increases in density in survivors of childhood cancer in general86–89 and in
BMI than those who received 18 Gy, whereas patients who survivors of leukemia in particular.90–94 In some patients,
received no cranial irradiation had no significant increase in BMD is reduced even at the time of cancer diagnosis,95;96
BMI and had no higher incidence of obesity than did popu- possibly due to the effect of inflammation and cytokine pro-
lation controls. However, other studies did not identify a duction on bone turnover and calcium excretion.97 Survivors
greater incidence of obesity in patients who received cranial of childhood ALL have decreased BMD even years after
irradiation than in those who did not.60;61 The mechanism therapy,98 but it is not known with certainty when osteope-
responsible for increased adiposity after cranial irradiation is nia develops, whether it worsens or improves after comple-
not known but may involve damage to CNS control of ap- tion of treatment, or what the long-term prognosis for bone
petite and eating behavior.62 Lustig et al.62 documented an mineralization may be. Possible contributors to osteopenia in
abnormal insulin response to an oral glucose challenge in children with ALL include diminished BMD at diagnosis, low
two obese patients who had been treated with 18 Gy of dietary calcium intake, decreased physical activity, abnor-
cranial irradiation for ALL at age three and four years. In both malities in vitamin D metabolism (which occur in a variety of
patients, the rate of weight gain dramatically decreased with inflammatory conditions), treatment with glucocortic-
octreotide therapy, a finding that if confirmed may provide a oids99–108 and other chemotherapeutic agents,109–114 and ra-
therapeutic option for patients with hypothalamic obesity. diation therapy.98
GH deficiency may also contribute;58;63 Halton et al.64 found Halton et al.78 measured lumbar (L2–L4) vertebral BMD at
that in children with ALL, the percentage of lean body mass diagnosis and every six months thereafter in 40 children with
was lower and that of fat was higher at the end of therapy ALL treated on the DFCI protocol 87-01. They used a Norland
than at diagnosis, as seen in GH deficiency. Furthermore, the 2600 dual-energy X-ray absorptiometry (DXA or DEXA)
body mass index of ALL survivors continues to increase in scanner and a pediatric control population from the same
relation to that of controls even after the completion of region of Canada. They found that BMD diminished in a linear
therapy, although similar increases are reported in patients fashion during the first two years of chemotherapy in pa-
with and without low GH levels.58 Therefore, efforts to tients more than 11-years old at the time of diagnosis but
prevent obesity should begin early in therapy for ALL and remained stable in those less than 11-years old. Several in-
continue after completion of therapy. Serum leptin concen- vestigators have reported decreased BMD after completion of
trations were significantly higher in patients who had un- therapy for childhood ALL in cross-sectional studies that in-
dergone cranial irradiation, an observation consistent with cluded 22–35 patients, but these small numbers of patients
the increased tendency toward obesity in such patients.62 prevent the meaningful assessment of risk factors for low
227
Howard and Pui
BMD.86;90;94;115 Nysom et al.91 performed lumbar spine DXA have been used to measure BMD, but their imprecision limits
measurements on 95 survivors of childhood ALL who re- their usefulness for screening and for longitudinal follow-
mained in first remission 3–23 years after diagnosis. They up.122–125 DXA or quantitative computed tomography (QCT)
found that cranial irradiation reduced bone size and mean are the current standard techniques for the diagnosis of os-
height for age, but when reduced bone size was taken into teopenia and for longitudinal assessment of BMD, and DXA is
account, bone mass was not significantly related to the use of currently the most commonly used method.68;113;126–133
cranial irradiation, age at diagnosis, age at follow-up, length Measurements of BMD that are obtained by different
of follow-up, the cumulative dose of methotrexate or corti- methods must be compared cautiously, and longitudinal fol-
costeroids, or endocrine status at follow-up.116 low-up of individual patients should be performed by a single
Kaste et al.98 avoided the problems of inadequate adjust- method. Further, BMD measurements can differ across
ment for bone size by using quantitative computed tomog- brands and models of DXA machines and software versions,
raphy (QCT) to measure lumbar spine BMD in 141 survivors especially in children. Ideally, the results of BMD measure-
of childhood ALL who had remained in first remission 8.9 to ment should be compared to those of controls from the same
14.6 years (median, 11.5 years) after diagnosis. They found population who are matched for age, race, and sex and
that the median BMD z score of participants was 0.78 stan- measured by the same instrument equipped with the same
dard deviations below the norm for the age and sex-matched version of software. For example, after Nysom et al.91 re-
population (p < 0:0001). Risk factors for low BMD included ported that whole-body bone mass was diminished 11 years
treatment with 24 Gy of cranial irradiation, male sex, and after diagnosis of childhood ALL, they found that the size-
Caucasian race. Patients who received 18 Gy of cranial irra- adjusted whole-body bone mass was neither reduced nor
diation had BMD values similar to those of patients who re- related to any of the predictive variables tested when reana-
ceived none. Similar results were obtained by Kadan-Lottick lyzed with more stringent controls.134 The site at which BMD
et al.117 in their study of 75 children with ALL in continuous is measured is also an important consideration. Because
complete remission 11–82 months after diagnosis. Only 9% of cortical and trabecular bone differ in their response to
their patients received cranial irradiation, and 31% were still glucocorticoids and other stimuli that promote demineral-
undergoing maintenance therapy. The overall mean BMD z ization, the BMD values of the femoral neck and vertebral
scores were no different from age- and sex-matched controls; bodies, which are rich in trabecular bone, may differ dra-
risk factors for low BMD included high risk ALL and post- matically from those of the mid-radius, which is rich in cor-
pubertal status at diagnosis. Longitudinal studies of a large tical bone. Finally, because BMD changes dramatically during
cohort of children with ALL who do not receive cranial ir- puberty, subjects should be matched by Tanner stage rather
radiation are needed to clarify the independent effect of than by age.135–139 Unfortunately, there are no available pe-
chemotherapy on both early and late osteoporosis. diatric reference ranges for BMD according to Tanner stage.
The risk of osteoporosis and fracture are increased Methodological issues in studies of bone
during therapy mineralization in children with ALL
Because osteoporotic fractures do not generally occur until Many studies of bone mineralization in pediatric oncology
age 50 or later, it is appealing to consider addressing this risk have suffered from small sample sizes, from inclusion of a
after a child has completed chemotherapy for ALL. Such a wide variety of ages or of both pre- and post-pubertal chil-
delay would also avoid increasing the risk of hypercalciuria dren, and from grouping patients who recently completed
and urolithiasis in children who are already at high risk of therapy with those who completed treatment many years
these complications. Unfortunately, however, children with earlier.78;101;115;140–145 Some studies also include patients with
ALL are at increased risk of fracture while on therapy, and various cancer diagnoses whose therapies differ. Especially
may even present with fracture at diagnosis of leukemia.79;118 difficult to interpret are studies in which some patients have
In patients treated for ALL on the Dana-Farber Consortium received glucocorticoids, some have undergone craniospinal
Protocol 91-01,2 the 5-year incidence of fracture was irradiation, others have received both treatments, and still
20% 4% for patients treated with prednisone and 36% 5% others have received neither. The use of different methods to
for those treated with dexamethasone.77 Because children assay BMD further confounds meaningful comparison of the
with ALL are at high risk of osteopenia and of both early and results of different studies. Nysom et al.91;116 found that when
late fractures, prevention of these complications early in the they improved the method used to control for patient height
course of their illness remains an important goal. and bone size, the conclusions of their previous study
changed significantly, a finding that highlights the impor-
Diagnosis of osteopenia tance of methodology in studies of BMD. They now use an
Osteopenia can be detected by plain radiography, quantita- elegant three-step approach based on sex-specific z scores
tive ultrasonography, single-photon X-ray absorptiometry, for height for age, bone area for height, and bone mineral
dual-photon X-ray absorptiometry, and quantitative com- content for bone area, to assure adequate control for patient
puted tomography.119–121 Plain radiography detects osteope- height and bone size.116;146;147
nia with low sensitivity but very high specificity, and all
patients who have osteopenia detected by plain films should Prevention and treatment of osteopenia in children
undergo measurement of BMD to establish a baseline for as- during therapy for ALL
sessing the effectiveness of therapy. Single-photon X-ray ab- Interventions to reduce osteoporosis and the risk of fracture
sorptiometry and quantitative ultrasound of the calcaneus in children with ALL include increased weight-bearing activ-
ity, bisphosphonate therapy, and calcium and/or vitamin D duration, and schedule of glucocorticoid therapy14;161–165 and
supplementation.148–153 Weight-bearing activity has no side possibly on genetic predisposition.166 There are few pub-
effects and may also improve muscle tone and general well lished data on the incidence of this complication, and
being. Unfortunately, because inactivity during therapy for screening studies have included small numbers of pa-
ALL is often the result of musculoskeletal complications of tients.167;168 However, clinically important adrenocortical in-
therapy, this alternative may not be feasible. Bisphosphonate sufficiency during therapy for ALL appears to be uncommon,
therapy is not approved for young children and may affect even during the four to six weeks of glucocorticoid therapy
the long-term quality of bone, but it should be considered for required for remission induction (Table 2). Kuperman et al.167
adolescent patients who have completed all growth and who evaluated 15 prepubertal children with ALL by using the
have severe osteopenia or a history of osteoporotic fracture. corticotrophin releasing hormone (CRH) stimulation test be-
Vitamin D supplementation is not recommended, because it fore and 7 and 14 days after the completion of remission in-
does not prevent glucocorticoid-induced bone demineraliza- duction therapy with daily glucocorticoid. All patients
tion and may increase the risk of hypercalcemia, increased received dexamethasone (6 mg/m2 per day divided into three
urine calcium excretion, and urolithiasis.85;154–157 Sambrook oral doses) during the first 42 days of chemotherapy. The
et al.85 noted hypercalcemia in 18 of 63 adults treated with patients’ baseline cortisol concentrations were elevated
glucocorticoids who received calcitriol (vitamin D) plus cal- (mean, 17.8 lg/dL [491 nmol/L]), and their response to CRH
cium but in only 1 of 29 who received calcium alone. stimulation was brisk. On days 7 and 14 after the completion
Therefore, calcium supplementation without vitamin D is the of remission induction, the cortisol levels were normal
preferred treatment for patients receiving glucocorticoids. (means, 10.8 lg/dL [298 nmol/L] and 11.5 lg/dL [317 nmol/
Magnesium depletion may exacerbate bone demineralization, L], respectively). The response to CRH stimulation was less
and magnesium supplementation should be added if patients marked than it had been at baseline before therapy but was
have low serum magnesium or risk factors for magnesium within the normal range in all patients but one on day 7 and in
depletion, such as treatment with amphotericin B or furo- all patients on day 14. No patient had symptoms or signs at-
semide. tributable to adrenal insufficiency and none required exoge-
Calcium supplementation improves bone mineralization nous cortisol. Felner et al.168 used the ACTH stimulation test
in healthy prepubertal children158 and, to a lesser extent, in to evaluate recovery of the hypothalamic-pituitary-adrenal
adults, even during glucocorticoid therapy.85;159 However, axis in 10 children with ALL after 28 days of remission in-
the effectiveness of calcium supplementation in preserving duction therapy with oral dexamethasone (6 mg/m2 divided
bone mineralization during therapy for ALL has not been into two daily doses). They found that adrenal function was
evaluated. Moreover, the safety of calcium supplements in normal at diagnosis, but adrenal response to ACTH was sup-
children with ALL has not been established; such therapy pressed in all 10 patients the day after the dexamethasone
may increase the incidence of hypercalciuria and urolithia- course was completed; adrenal function was found to have
sis,85 which is already elevated in children receiving gluco- recovered four weeks (7 patients) or eight weeks (3 patients)
corticoid therapy for ALL.160 Urolithiasis can pose special later. Again, symptomatic adrenal insufficiency was not ob-
problems for patients with ALL; not only does it cause pain served. Since four- to six-week courses of continuous gluco-
and unscheduled hospitalization, it may also necessitate de- corticoid rarely lead to symptomatic adrenal insufficiency, it is
lays in chemotherapy and compromise the renal clearance of not surprising that one to four weeks of prednisone therapy
chemotherapy agents (thereby increasing toxicity). Further, for malignancy or five-day pulses of prednisone for asthma did
in our experience, over a third of patients with ALL who have not produce symptoms of adrenal insufficiency.163;169 Recov-
had urolithiasis have experienced multiple episodes of stone ery of the hypothalamic-pituitary–adrenal axis occurred
formation (unpublished observation). within 7–10 days after these short courses of steroid therapy.
Screening studies of long-term survivors of ALL have
identified many young adults with diminished BMD, but the Symptoms and signs of adrenocortical insufficiency
optimal treatment for such patients is not known. We are Adrenal insufficiency in pediatric ALL is usually subclinical,
currently conducting a randomized, placebo-controlled trial becoming manifest only during times of metabolic stress.
that compares the efficacy of nutritional counseling, oral Common metabolic stresses during therapy for ALL include
calcium carbonate (1000 mg/24 h), and vitamin D (800 IU/ infection, fluid and electrolyte disturbances associated with
24 h) with that of nutritional counseling alone to determine chemotherapy-induced emesis or other side effects, and
whether intervention years after completion of therapy can surgery. It is under these circumstances that clinicians should
allow ALL survivors to achieve an adequate peak bone min- be especially vigilant for symptoms of adrenal insufficiency.
eral density that will prevent future osteoporotic fracture in Such symptoms include malaise, fatigue, weakness, anorexia,
these patients. nausea, vomiting, weight loss, abdominal pain, diarrhea, hy-
po- or hyperthermia, hypotension, altered mental status, and
coma. Hyponatremia is common, and hypoglycemia, hyper-
kalemia, metabolic acidosis, and prerenal azotemia may be
ADRENOCORTICAL INSUFFICIENCY
present.161;170–173
Epidemiology of adrenocortical insufficiency in
pediatric ALL Diagnosis of adrenocortical insufficiency
The incidence and timing of adrenal insufficiency in pediatric The diagnosis of adrenal insufficiency is often delayed, be-
patients undergoing therapy for ALL depend on the dose, cause the symptoms resemble those caused by chemother-
229
230
Howard and Pui

Blood Reviews (2002) 16, 225–243
Table 2 Effects of chemotherapy agents used in pediatric acute lymphoblastic leukemia on thyroid, adrenal, and pituitary function, glucose tolerance, and bone mineralization
Drug Endocrine effects Incidence Mechanism Treatment and prevention
L -Asparaginase Diabetes mellitus type I Uncommon Decreased insulin and insulin Adequate hydration, monitor urine glucose, give insulin in severe
receptor synthesis cases
Transiently abnormal thyroid test Common Decreased serum No treatment is needed
values thyroid-binding globulin
Glucocorticoids Diabetes mellitus type II Uncommon Insulin resistance Adequate hydration, monitor urine glucose, give insulin in severe
cases
Adrenocortical and pituitary Uncommon Suppression of ACTH Steroid replacement until pituitary and adrenal recovery;
c 2002 Elsevier Science Ltd. All rights reserved.
insufficiency production by the anterior stress-dose steroids in case of infection, trauma, surgery, or other
pituitary and atrophy of the metabolic stress
adrenal cortex
Growth retardation Common Multifactorial Catch-up growth usually occurs after completion of therapy
Obesity Common Polyphagia, insulin resistance, Diet and exercise
decreased activity
Osteopenia Common Activation of osteoclasts, Weight-bearing exercise, calcium and vitamin D supplementation
decreased activity are recommended, but calcium should be used cautiously and
vitamin D supplements avoided during steroid therapy because of
the increased risk of hypercalcemia and urolithiasis.
Vincristine Syndrome of inappropriate Uncommon to Diminished transport and Water restriction, liberal sodium in the diet, frequent monitoring of
secretion of anti-diuretic common release of anti-diuretic serum sodium and urine osmolality. Reduction of vincristine dosage
hormone hormone by the posterior may be necessary. Patients with symptomatic hyponatremia should
hypothalamus not receive further vincristine until symptoms have resolved and
serum sodium is normal. All medications should be carefully
reviewed, and the use of drugs that inhibit cytochrome P450
enzymes (e.g. azole antifungals) should be avoided during vincristine
treatment.
Doxorubicin and None – – –
Daunorubicin
Cytarabine None – – –
6-Mercaptopurine May affect the density and quality Unknown Unknown
of bone mineral
Methotrexate May affect the density and quality Unknown Unknown
of bone mineral
Transient oligospermia, Unknown Unknown No treatment is available. Pregnancy is contraindicated during
defective oogenesis, menstrual therapy for acute lymphoblastic leukemia
dysfunction, and gynecomastia
Cyclophosphamide Syndrome of inappropriate Rare Unknown
secretion of anti-diuretic hormone
Infertility Rare to Destruction of * The incidence of infertility depends on the cumulative dose of
common* germ cells cyclophosphamide.
Very common: >25% of patients are affected; common: 10–25% of patients are affected; uncommon 2–9% of patients are affected; rare: <2% of patients are affected.
apy, viral illnesses, bacteremia, and central nervous system Prevention of adrenocortical insufficiency and
disease, all of which may occur in patients with ALL. In research directions
healthy children and adults, plasma cortisol reaches a daily It may be possible to prevent adrenal insufficiency during
peak concentration before 09:00; therefore, an 09:00 serum continuation therapy by altering the schedule of steroid ad-
cortisol assay that shows extreme values is useful in the di- ministration, but virtually all modern ALL treatment protocols
agnosis of adrenal insufficiency. A cortisol concentration include daily steroid administration during remission induc-
< 100 nmol/L strongly suggests inadequate endogenous re- tion therapy. The optimal glucocorticoid agent, dose, and
serve, whereas one > 600 nmol/L strongly suggests normal schedule needed during remission induction, delayed inten-
adrenocortical reserves.174 Intermediate values require fur- sification, and continuation chemotherapy to maximize cure
ther testing when adrenal insufficiency is suspected, and rates for ALL and minimize adrenal suppression remains the
evaluation by an endocrinologist is warranted. Several tests of subject of investigation. In a study of 279 adults who had
hypothalamic-pituitary–adrenal axis function are commonly received 5–30 mg of prednisone daily for one week to 15
used, and these are discussed in detail elsewhere.175 Symp- years, there was a poor correlation between the degree of
tomatic adrenocortical insufficiency is uncommon, and adrenal suppression and the dose and duration of steroid
therefore a high index of suspicion is needed for early diag- therapy.162 Similarly, a daily dose of 5 mg or less of predni-
nosis and successful treatment. The diagnosis should be sone was not associated with adrenal suppression in adults,
considered whenever the degree of hemodynamic or neu- but doses above 5 mg caused hypothalamic-pituitary–adrenal
rologic compromise is out of proportion to the severity of the suppression to a markedly varying degree that was not cor-
illness.171 related with the dose or duration of therapy.181 Therefore,
host factors, rather than the dose and schedule of glucocor-
Treatment of adrenocortical insufficiency ticoid, may be the main determinants of hypothalamic-pitu-
Most patients require no therapy for adrenal insufficiency, itary–adrenal sensitivity to suppression by exogenous
which is usually both subclinical and self-limited and grad- steroids administered at conventional doses used to treat
ually resolves after cessation of glucocorticoid therapy. ALL.166
However, appropriate supportive care during metabolic
stress can be life saving, because untreated adrenal insuffi-
ciency in the setting of severe infection, surgery, or other DIABETES MELLITUS AND HYPOGLYCEMIA
physiologic stress can be fatal (Table 3). A healthy child with
no metabolic stress produces 6–8 mg/m2 =d of cortisol.176 Epidemiology of diabetes mellitus
However, because orally administered hydrocortisone is Diabetes mellitus, defined as glucose intolerance that leads to
only partially absorbed and is metabolized by passage hyperglycemia, occurs commonly in children treated for ALL
through the liver, the appropriate replacement dose for with a glucocorticoid and L -asparaginase. Glucocorticoids
patients who have no endogenous glucocorticoid produc- produce insulin resistance, and L -asparaginase reduces plas-
tion is 10–20 mg/m2 /d of hydrocortisone in three divided ma insulin levels, insulin secretion in response to hypergly-
doses, or two doses with two thirds of the total daily dose cemia, and possibly the number of insulin receptors.182;183
given in the morning and the remaining one third at din- Treatment with either glucocorticoids or L -asparaginase
nertime.161;171;174 Systemic inflammatory states can suppress causes hyperglycemia in about 1% of patients,182–187 but the
the hypothalamic-pituitary–adrenal axis even in previously combination synergistically increases glucose intolerance
healthy individuals, and the impairment of catecholamine (Table 2). We observed hyperglycemia during remission in-
synthesis by cortisol deficiency compounds the dangers of duction in 41 (9.7%) of 421 pediatric patients who received
insufficient cortisol production in patients undergoing met- prednisone and L -asparaginase for ALL.188 In 39 of the 41
abolic stress.177;178 In such cases, hydrocortisone should be patients, hyperglycemia developed within a week of the first
administered at a dose of 30 mg/m2 /d (moderate stress) or dose of L -asparaginase. Risk factors for hyperglycemia in-
100 mg/m2 /d (severe stress) divided into three or four doses, cluded age P 10 years, obesity, Down syndrome, and a
and the first dose should be given intravenously immedi- family history of diabetes mellitus. The frequency of hyper-
ately.179 Saline solution (0.9%) should be administered in- glycemia increased sharply when the patients had more than
travenously to restore intravascular volume and renal one risk factor. Iyer et al.186 observed hyperglycemia in 14
perfusion, and dextrose solution should be infused in the (4%) of 335 adults and children with ALL treated with
case of hypoglycemia. prednisolone and L -asparaginase after a median of five doses
Patients who receive long-term steroid therapy develop (range, 2–10 doses). Ten of the 14 patients were P 10 years
adrenal insufficiency because of prolonged pituitary and hy- old but none were obese. Hyperglycemia recurred during
pothalamic suppression and because of adrenal atrophy delayed intensification with the same drugs in only 10% of
caused by diminished endogenous ACTH production. The patients. The incidence of hyperglycemia differs with the
time-course of recovery depends primarily on the degree of type (and hence the potency) of L -asparaginase used189 and
adrenal atrophy, because the pituitary gland and hypothala- with the dose and schedule of administration.190
mus recover relatively quickly. In the absence of adrenal at-
rophy, full recovery often occurs within days of withdrawal Symptoms of hypothyroidism
of exogenous glucocorticoid, as seen in two studies of ad- Children with chemotherapy-induced hyperglycemia usually
renal function during therapy for ALL.167;168 When adrenal present with polyuria, polydipsia, polyphagia, and/or glu-
atrophy is present, full recovery requires months.180 cosuria found on routine urinalysis. If these early signs are
231
232
Howard and Pui

Blood Reviews (2002) 16, 225–243
Table 3 Guidelines for managing possible endocrine complications in pediatric patients with acute lymphoblastic leukemia
Clinical situation Suggested action Relevant endocrinopathy Comments

c 2002 Elsevier Science Ltd. All rights reserved.
Seizure Measure serum electrolytes Syndrome of inappropriate Hyponatremic seizures often do not respond to traditional anti- convulsants; thus,
secretion of anti-diuretic rapid measurement of serum sodium is essential in children with acute lymphoblastic
hormone leukemia and new seizures. Persistent seizures and hyponatremia require rapid
correction of serum sodium with 3% saline solution
Dehydration or altered Measure serum glucose Diabetes mellitus Initial treatment of hyperglycemia should include aggressive hydration with normal
mental status with polyuria saline. Insulin therapy should be added to correct hyperglycemia gradually since too
rapid correction of serum glucose can lead to cerebral edema
Infection, surgery, or Consider stress doses of corticosteroid, Adrenal insufficiency The risk of adrenocortical insufficiency is especially high during or just after induction
other metabolic stress especially if the patient has symptoms of or delayed intensification therapy with daily glucocorticoids. However, the possibility
Hypotension or any adrenocortical insufficiency, hyponatremia, of adrenocortical insufficiency should be considered even during maintenance
symptoms that are hyperkalemia, or hypoglycemia therapy with pulses of glucocorticoid
disproportionate to the
severity of the underlying
illness
Fracture Measure bone mineral density; measure Osteoporosis Dietary modification, weight-bearing exercise, and calcium supplementation may
serum electrolytes, including magnesium. prevent worsening of osteoporosis. If the patient has completed the majority of
expected growth, bisphosphonate therapy may be considered.
Growth failure during Evaluate sexual development Growth hormone Most children with slow growth during therapy for acute lymphoblastic leukemia
therapy deficiency have no specific endocrine defect, and catch-up growth often occurs during
continuation chemotherapy or after completion of therapy in patients who do not
receive cranial irradiation.
Low growth velocity after Measure growth hormone secretion, Growth hormone Growth hormone deficiency is common after treatment with 18 Gy or more of
therapy evaluate deficiency, cranial irradiation
Diminished final height sexual development, measure thyroid hypothyroidism
function and TSH response to TRH
Sidebar: essential points
not heeded, dehydration, hypotension, somnolence, and patient the 6-mercaptopurine was given in the morning to
coma can occur. Because this complication of therapy is well shorten the period of overnight fasting. The cause of the
recognized and is usually detected early, morbidity is un- sensitivity of young children with ALL to fasting is not clear.
common. Most patients who develop therapy-induced Collipp et al.194–196 have reported hepatic glucose-6-phos-
hyperglycemia recover when L -asparaginase and glucocor- phatase deficiency in childhood ALL, but this does not ex-
ticoids are discontinued, and they suffer no long-term adverse plain hypoglycemia during maintenance therapy when
effects. patients no longer have detectable leukemic cells. Parents of
young, thin patients should be educated about the symptoms
Diagnosis of diabetes mellitus of hypoglycemia and the period of fasting should be no
The diagnosis of secondary diabetes mellitus in pediatric longer than that required to assure adequate drug absorption.
patients with ALL is confirmed by laboratory evaluation.
A morning serum glucose concentration P 7:8 mmol/L Prevention of diabetes mellitus and research directions
(140 mg/dL) after an overnight fast confirms the diagnosis, Prevention of therapy-induced diabetes mellitus is not always
and most patients have a significantly higher glucose con- possible. Children who are not obese are at lower risk. Ex-
centration. A glucose tolerance test may be used to confirm ercise improves glucose tolerance, increases lean body mass,
the diagnosis of mild cases; however, glucose tolerance decreases fat mass, and may be a feasible way to reduce the
testing is not necessary for children with ALL, who do risk of diabetes in ambulatory patients. Although reduction of
not require treatment for mild therapy-induced diabetes dietary calorie and fat intake reduces the risk of diabetes in
mellitus. the general population, strict diets should be used with
caution in children receiving chemotherapy, whose protein
Treatment of diabetes mellitus and calorie intake may be inadequate because of the side
Treatment of diabetes mellitus during therapy for ALL in- effects of therapy and who are predisposed to loss of lean
cludes careful monitoring of serum and urine glucose, diet body mass.64
modification, and increased exercise (Table 3). Insulin ther- Further research is needed to determine the optimal
apy is added if these measures fail to adequately control hy- dosage and schedule of glucocorticoids and L -asparaginase
perglycemia. In our study, 10 of the 41 patients who needed to minimize the risk of diabetes while maintaining
developed hyperglycemia during remission induction ther- excellent cure rates. One way to reduce the risk of diabetes is
apy for ALL experienced spontaneous resolution of the hy- to give L -asparaginase during post-remission therapy, so that
perglycemia while receiving both prednisone and L - it is not given concurrently with steroids. The protocols of
asparaginase, whereas 29 required insulin therapy lasting an the Dana Farber Cancer Institute Consortium2;197 and the
average of 11.5 days.191 The goal of therapy is to avoid ex- German Cooperative Study Group for treatment of ALL
treme hyperglycemia. Strict glucose control is not necessary, (COALL)198 have successfully used this approach to reduce
because hyperglycemia resolves spontaneously in most cases. the risk of hyperglycemia and thrombotic complications and
Further, strict glucose control can be dangerous, because have maintained excellent treatment results. Clinical trials of
insulin requirements vary greatly, depending on the timing of dietary and lifestyle interventions may identify additional
steroid and L -asparaginase administration. If hypoglycemia strategies to prevent and control diabetes during therapy for
results from overly aggressive insulin therapy, it should be ALL.
corrected immediately and the patient monitored closely for
recurrence.
THE SYNDROME OF INAPPROPRIATE SECRETION OF
ANTI-DIURETIC HORMONE
Hypoglycemia
The most common cause of hypoglycemia in pediatric ALL is Epidemiology of SIADH
over-treatment of hyperglycemia with insulin, but two The syndrome of inappropriate secretion of anti-diuretic
groups have recently reported hypoglycemia in children re- hormone (SIADH) is characterized by sustained release of
ceiving maintenance chemotherapy that included 6-mercap- excessive antidiuretic hormone (ADH) from the posterior
topurine.192;193 Halonen et al.193 reported hypoglycemia in 16 pituitary gland. Excessive ADH causes water retention by the
of 35 children (54%) studied after a 16-h fast during contin- kidneys and leads to serum hypo-osmolarity. Although SIADH
uation therapy with oral methotrexate and 6-mercaptopur- is a well-known complication of vincristine therapy, there are
ine. Fasting blood glucose levels improved after completion limited data about its incidence and clinical consequences in
of therapy in all patients and normalized completely in 67%. pediatric patients with ALL,199–202 who are not systematically
Ziino et al.192 found that 6 of 86 children (6.9%) treated for screened for SIADH. Although many drugs can cause
intermediate-risk ALL with 6-mercaptopurine and 6-thiogua- SIADH,203–213 vincristine is usually the cause in children with
nine developed 18 episodes of symptomatic hypoglycemia ALL.200;201;214–219 The risk of SIADH peaks 7–10 days after
during consolidation (n ¼ 2), reinduction (n ¼ 7), or contin- administration of a dose of vincristine, and SIADH can occur
uation (n ¼ 9) therapy. Age was a significant risk factor: the even after the administration of multiple doses without
affected patients were 3–5-years old, the typical age group for problems. SIADH commonly occurs during remission induc-
ketotic hypoglycemia. Recurrence of symptomatic hypogly- tion therapy, which includes weekly doses of vincristine, and
cemia was prevented in five of the patients by encouraging it often recurs if no adjustment is made to the vincristine
large evening meals and early breakfast, and in the sixth dosage or schedule.
233
Howard and Pui
Concurrent administration of azole antifungal drugs, such for ALL. Patients who have documented hyponatremia and
as itraconazole and fluconazole, can potentiate the toxicity of persistent seizure or other significant neurologic dysfunction
vincristine.220–223 Azoles inhibit the cytochrome P450 en- should immediately be given 3% sodium chloride solution
zymes responsible for vincristine metabolism and cause intravenously (1–2 mL/kg of body weight per hour over 2–
prolonged exposure to high concentrations of active drug. If 3 h).230 If such aggressive therapy is necessary, the patient
azole antifungals must be given to treat life-threatening in- should be monitored in the intensive care unit and serum
fection, vincristine should be given at a reduced dosage or sodium measured every 1–2 h. Hyponatremia should be cor-
delayed. For patients who have oral thrush and are being rected no faster than 12 mEq/dL of sodium per 24 h to min-
treated with vincristine, we use clotrimazole, which has little imize the risk of central pontine myelinolysis, which
systemic effect. Finally, adrenocortical insufficiency can sometimes occurs even when the serum sodium is corrected
cause SIADH and should be considered in the differential at an appropriate rate.231–233
diagnosis.172;224;225
Prevention of SIADH and research directions
Symptoms and morbidity of SIADH SIADH often recurs when the causative medications are re-
Common symptoms of early or mild SIADH include lethargy, sumed. Vincristine is an important component of therapy for
weakness, headache, oliguria, and weight gain. Severe SIADH ALL; if SIADH occurs early in the treatment course and many
can cause confusion, seizures, coma, and death.226–229 Hyp- future doses are planned, the drug should be resumed with
onatremic seizures can cause neurologic damage if not careful monitoring. If SIADH recurs, the vincristine dose
promptly treated. If patients are receiving cyclophosphamide should be reduced, or aggressive prophylactic fluid restric-
or other chemotherapeutic drugs whose active metabolites tion should be initiated.200
are excreted in the urine, the oliguria and urinary stasis as-
sociated with SIADH can cause hemorrhagic cystitis.
THYROID DYSFUNCTION
Diagnosis of SIADH Epidemiology of thyroid dysfunction
Although the diagnosis is often made incidentally by detec- Thyroid dysfunction during therapy
tion of hyponatremia in a routine chemistry profile, patients Thyroid dysfunction has been reported during remission in-
may also present with oliguria or hyponatremic seizures. Mild duction therapy for childhood ALL234 and as a late compli-
hyponatremia occurs frequently during hyper-hydration gi- cation in patients who received cranial irradiation,235;236 but
ven with chemotherapy, and SIADH must be distinguished there are other reports that thyroid function is normal both
from dilutional hyponatremia by evaluation of urine output, during and after therapy.14;236;237 Ferster et al.234 evaluated
urine sodium, and urine osmolality. The diagnosis of SIADH is thyroid function in nine patients (ages 2–14 years) treated on
confirmed by elevated urine sodium concentration and os- the EORTC 58831 protocol that had ALL without CNS in-
molality concurrent with low serum sodium concentration volvement and had no early cranial irradiation. Remission
and osmolality. induction consisted of four weekly injections of vincristine
(1.5 mg/m2 Þ and daunorubicin (30 mg/m2 Þ, daily oral pred-
Treatment of SIADH nisolone (60 mg/m2 Þ for 28 days, and daily infusions of L -as-
SIADH is treated with fluid restriction, close monitoring of paraginase (5000 U/m2 Þ for 21 days. Serum thyroxine (T4 Þ,
urine output, serum sodium concentration, and neurologic free T4 , triiodothyronine (T3 Þ, thyroxine-binding globulin
status, and discontinuation of vincristine therapy until the (TBG), and thyroid-stimulating hormone (TSH) were mea-
acute episode has resolved.230 Furosemide should be given if sured on days 1, 10, 28, and 35 of remission induction ther-
symptoms or signs of fluid overload are present. All current apy. T4 , free T4 , T3 , and TBG had dropped significantly below
medications should be evaluated, with special attention to baseline values (p < 0:001 for all measurements) by day 28,
selective serotonin reuptake inhibitors, tricyclic anti-depres- but they returned to baseline by day 35. A similar pattern was
sants, anti-psychotics, anti-convulsants, thiazide diuretics, observed during delayed intensification therapy that included
and azithromycin, and any potential contributors to SIADH dexamethasone and L -asparaginase, both of which are known
should be discontinued until hyponatremia resolves. After to alter the concentration of thyroid hormone and TBG. Bossi
the serum sodium concentration returns to normal, patients et al.237 observed a transient reduction of T3 and free T3
may be rechallenged with the suspected offending agent if concentration after 1 week of induction chemotherapy with a
necessary, so long as neurologic status, serum sodium con- return to normal values by week 4 of treatment, but a thy-
centration, and urine output are closely monitored. Hospi- rotropin-releasing hormone (TRH) stimulation test induced a
talization is indicated for patients who have significant normal TSH response at both week 1 and week 4. Despite the
oliguria, hyponatremia, or any neurologic symptoms or who biochemical changes observed in these two studies, patients
cannot obtain prompt outpatient medical attention should showed no symptoms of hypothyroidism.234;237
such symptoms develop. Hyponatremic seizures require Thyroid dysfunction after completion of therapy that
emergent intervention. The response to traditional anticon- does not include cranial irradiation. Many modern ALL
vulsants is often suboptimal if the serum sodium concentra- treatment protocols do not include cranial irradiation, but all
tion is not corrected. Therefore, a high index of suspicion include multiple doses of intrathecal chemotherapy. The ef-
and expeditious serum sodium assays are warranted for fect of chemotherapy alone on thyroid function was examined
children who have new onset of seizures during treatment by Nygaard et al.236 in 61 children who had been off therapy
for a median of 25 months (range, 2 months to 10.3 years). very rare patient who has symptoms of hypothyroidism and a
None of the patients examined showed clinical signs of hy- low (< 0:8 ng/dL) free thyroxine level. Although the normal
pothyroidism or hyperthyroidism, and serum T4 , free T4 , TSH, range for free T4 is 0.8–2.0 ng/dL, the serum concentration
and T3 uptake values did not differ from those of controls. targeted during exogenous supplementation is 1.5–1.7 ng/dL
Similarly, 57 of the 95 patients evaluated by Lando et al. 1.2– in growing children and 1.0–1.7 ng/dL in patients who have
18.3 years after completion of ALL therapy had normal hor- completed their growth. Because central hypothyroidism is
mone levels and a normal TSH response to TRH stimulation.238 the form almost always seen in children with ALL, measure-
Thyroid dysfunction after completion of therapy ment of TSH is not useful for monitoring the efficacy of
that includes cranial irradiation. Chemotherapy used in thyroid hormone replacement; instead, therapy must be
ALL treatment regimens has little or no permanent impact on guided by symptoms and stage of growth. A wide range of
thyroid function, but irradiation of the thyroid gland can free thyroxine levels is acceptable in patients who have
cause hypothyroidism, hyperthyroidism, and thyroid cancer, completed their growth, if there are no symptoms of hypo-
and irradiation of the central nervous system can cause thyroidism. Symptoms may be subtle, and thus a careful re-
central hypothyroidism. Bessho et al.239 performed dosimetry view of systems is essential. Patients should be asked about
of radiation scattered to the thyroid gland in 17 children with heat and cold intolerance, constipation, energy level, mood,
ALL (ages 1–14 years) treated with 18–24 Gy of cranial irra- concentration, school or work performance, and regularity of
diation. The dose of radiation absorbed by the thyroid gland menses. Because thyroid hormone concentration may be al-
was 0.13–1.34 Gy, or 0.7–7.3% of the dose delivered to the tered by the regulatory actions of glucocorticoids, steroid
cranium. Doses in this range are associated with a modest therapy (or the cessation of such therapy, in the case of
increase in the risk of thyroid carcinoma but not with overt relative adrenocortical insufficiency) may affect the concen-
thyroid dysfunction, a finding consistent with reports of tration of T4 ; T3 , and TSH.243 Therefore, free thyroxine should
normal thyroid function in survivors of ALL whose therapy be measured frequently in patients who have suspected
included cranial irradiation.14 adrenocortical insufficiency or who are starting or discon-
Unlike the thyroid gland, the hypothalamus and pituitary tinuing glucocorticoid therapy.
gland receive the full dose of radiation delivered to the cra-
nium. When the dose received by the pituitary gland exceeds Prevention of hypothyroidism
20 Gy, the risk of overt TSH deficiency (central hypothy- Prevention of hypothyroidism in pediatric patients with ALL
roidism) is reportedly 9%.240 However, Birkebaek et al.58 depends primarily on avoidance of cranial irradiation. Many
observed normal TSH concentration in 18 survivors of ALL current ALL treatment protocols reduce the total dose of
who had been treated with 24 Gy, and Drinnan et al.241 found cranial irradiation to 12 Gy,3 reserve irradiation for patients
normal TSH, TRH, and thyroid hormone levels in 13 patients with high-risk disease, or, in some cases, eliminate irradiation
treated with 24 Gy. Although TSH levels are usually normal, altogether.244–246
sensitive assays of central thyroid function, such as mea-
surement of the maximal TSH response to TRH, demon-
strated that 50% of children who have received 24 Gy and
SUMMARY AND CONCLUSIONS
14% of those who have received 18 Gy of cranial irradiation
have an abnormally low TSH response to stimulation.235 In Endocrine complications of therapy for ALL are common and
contrast, Lando et al. found normal thyroid function in 95 potentially debilitating, both during and after therapy. Adre-
survivors of childhood ALL screened with TRH stimulation nal insufficiency should be suspected in any child who has
tests a median of 7.6 years after completion of therapy.238 No received glucocorticoid therapy in the preceding 12 months,
patients in either study had signs or symptoms of hypothy- and stress doses of steroid should be administered in the
roidism. Therefore, primary hypothyroidism is rare and sec- event of metabolic stress or clinical signs of adrenal insuffi-
ondary hypothyroidism uncommon in survivors of childhood ciency. Patients who have hypotension that does not readily
ALL. However, patients who receive 24 Gy of cranial irradi- respond to intravenous hydration should receive stress doses
ation may have subclinical abnormalities of TSH secretion of hydrocortisone until the possibility of adrenal insufficiency
that can be detected only by careful screening, especially in is excluded.
the first few years after therapy.238;242 Diabetes mellitus occurs during therapy with glucocor-
ticoids, L -asparaginase, or both. Screening of urine for glu-
Symptoms of hypothyroidism cose and questioning patients specifically about polyuria and
Symptoms of thyroid dysfunction include add-intolerance polydipsia allow prompt diagnosis. Treatment includes diet
anorexia, constipation, malaise, poor sleep quality, fatigue, modification, increased exercise, and insulin therapy if these
poor concentration, and depression. These symptoms are measures fail to achieve reasonable glucose control. The goal
common during therapy for ALL, but are rarely the result of of therapy is to avoid extreme hyperglycemia; strict glucose
thyroid dysfunction. Nevertheless, clinicians should remain control is not necessary and can be dangerous, because in-
aware of the possibility of hypothyroidism, especially in pa- sulin requirements vary greatly, depending on the timing of
tients who have been treated with cranial irradiation. steroid and L -asparaginase administration.
The syndrome of inappropriate secretion of ADH is not
Treatment of hypothyroidism uncommon during therapy for ALL and is usually associated
Changes in thyroid hormone concentration are rarely clini- with vincristine therapy, although many other medications
cally significant, and treatment should be reserved for the can cause the syndrome. Concurrent use of azole antifungals
235
Howard and Pui
Table 4
Endocrinopathy is a common cause of morbidity in pediatric patients both during and after therapy for acute lymphoblastic leukemia. Cranial
irradiation affects the pituitary gland and thus significantly increases the risk of endocrinopathy.
Endocrinopathy Highlights
Adrenocortical insufficiency Commonly occurs after remission induction therapy with daily glucocorticoids but is usually subclinical and requires
no therapy. Consider administration of stress-dose steroids to any patient undergoing metabolic stress who has
unexplained nausea, vomiting, hypotension, hyponatremia, hyperkalemia, or hypoglycemia.
Diabetes mellitus Commonly occurs during concurrent therapy with glucocorticoids and l-asparaginase; is usually successfully
managed with dietary modification, exercise, and exogenous insulin. Strict glucose control is discouraged during
therapy for acute lymphoblastic leukemia
Syndrome of inappropriate Symptomatic syndrome of inappropriate secretion of antidiuretic hormone is rare but potentially life-threatening.
secretion of anti-diuretic Serum electrolytes should be measured if a patient receiving therapy for acute lymphoblastic leukemia develops
hormone somnolence, altered mental status, or seizures. If the patient is hyponatremic, restrict fluids immediately and
discontinue all non-essential medications; administer 3% saline if neurologic symptoms are significant
Thyroid dysfunction Changes in thyroxine and free thyroxine levels during glucocorticoid and L -asparaginase therapy are common but
not clinically significant and do not require treatment. Patients who have received cranial irradiation are at
increased risk of central hypothyroidism and should be screened if symptoms arise
Bone mineralization Pediatric patients with acute lymphoblastic leukemia are at significant risk of early osteoporosis, which can lead to
fractures during and after therapy. Optimal prevention and treatment strategies await the results of clinical trials.
Calcium and vitamin D supplements should be used with caution during glucocorticoid therapy because of the risk
of hypercalcemia, hypercalciuria, and urolithiasis
and vincristine should be avoided to prevent adverse drug

interactions. Patients may have mild hyponatremia with no
symptoms or may have profound neurologic impairment and Correspondence to: Dr. Scott C. Howard, MD, MS, Department of Hematology
require emergent therapy for seizures. Serum sodium should and Oncology, St. Jude Children’s Research Hospital, 332 North Lauderdale,
be measured immediately in any patient with new neurologic Memphis, TN 38105-2794, USA. Tel.: 1+901-495-2972; Fax: 1+901-495-5319;
findings of any kind, especially if vincristine has been ad- E-mail: scott.howard@stjude.org (S.C. Howard).
ministered within the 2 weeks prior to the onset of symp-
toms.
Overt hypothyroidism is not common in survivors of
childhood ALL, and screening is warranted only in patients References
with symptoms and signs of thyroid dysfunction. Subtle pi- 1. Gurney JG, Severson RK, Davis S, Robison LL. Incidence of cancer
tuitary and thyroid deficiencies are present in many ALL in children in the United States. Sex-, race-, and 1-year age-specific
survivors who received 18–24 Gy of cranial radiation, and rates by histologic type. Cancer 1995; 75(8): 2186–2195.
such patients should be evaluated if they have symptoms of 2. Silverman LB, Gelber RD, Dalton VK, Asselin BL, Barr RD, Clavell
hypothyroidism. LA et al. Improved outcome for children with acute lymphoblastic
Growth velocity slows during therapy for ALL, especially leukemia: results of Dana-Farber Consortium Protocol 91-01.
during the first year, but final height is generally normal in Blood 2001; 97(5): 1211–1218.
children who do not receive cranial irradiation. Growth 3. Schrappe M, Reiter A, Ludwig WD, Harbott J, Zimmermann M,
hormone deficiency may occur in children who are treated Hiddemann W et al. Improved outcome in childhood acute
with 18 Gy or more of cranial irradiation or with intrathecal lymphoblastic leukemia despite reduced use of anthracyclines and
therapy and intensive chemotherapy that includes high-dose cranial radiotherapy: results of trial ALL-BFM 90. German–
methotrexate. Obesity commonly occurs during therapy and Austrian–Swiss ALL-BFM Study Group. Blood 2000; 95(11):
persists afterward. Treatment is the same for these children 3310–3322.
as for others: diet modification and increased exercise. 4. Pui C-H, Boyett JM, Rivera GK, Hancock ML, Sandlund JT, Ribeiro
Finally, osteopenia can occur early during therapy for ALL RC et al. Long-term results of total therapy studies 11, 12, and 13A
and persist for many years. Increased weight-bearing activity for childhood acute lymphoblastic leukemia at St. Jude children’s
is recommended, but further research is needed to deter- research hospital. Leukemia 2000; 14: 2286–2294.
mine optimal pharmacological prevention and treatment. 5. Muller J. Disturbance of pubertal development after cancer
(Table 4). treatment. Best Pract Res Clin Endocrinol Metab 2002; 16(1):
91–103.
6. Bozzola M, Locatelli F, Cisternino M, Gambarana D, Giorgiani G,
Acknowledgements Bonetti F et al. Growth in pubertal children after bone marrow
We thank Sharon Naron, MPA, ELS for editorial assistance. transplantation. Bone Marrow Transplant 1991; 8(Suppl 1): 60.
7. Cisternino M, Bozzola M, Locatelli F, Lahlou N, Gambarana D, 24. Groot-Loonen JJ, Otten BJ, van’t Hof MA, Lippens RJ, Stoelinga GB.
Manfredi P et al. Pubertal development after bone marrow Influence of treatment modalities on prepubertal growth in children
transplantation in adolescents. Bone Marrow Transplant 1991; with acute lymphoblastic leukemia. Pediatr Hematol Oncol 1995;
8(Suppl 1): 54–55. 12(4): 343–353.
8. Salooja N, Szydlo RM, Socie G, Rio B, Chatterjee R, Ljungman P 25. Arguelles B, Barrios V, Pozo J, Munoz MT, Argente J. Modifications
et al. Pregnancy outcomes after peripheral blood or bone marrow of growth velocity and the insulin-like growth factor system in
transplantation: a retrospective survey. Lancet 2001; 358(9278): children with acute lymphoblastic leukemia: a longitudinal study.
271–276. J Clin Endocrinol Metab 2000; 85(11): 4087–4092.
9. Howell SJ, Shalet SM. Testicular function following chemotherapy. 26. Logghe KA, Bourguignon JP, Craen M, Benoit Y. Factors
Hum Reprod Update 2001; 7(4): 363–369. contributing to the impairment of growth in children with acute
10. Meirow D. Reproduction post-chemotherapy in young cancer lymphoblastic leukemia. Horm Res 1988; 30(2–3): 62–67.
patients. Mol Cell Endocrinol 2000; 169(1–2): 123–131. 27. Katz JA, Pollock BH, Jacaruso D, Morad A. Final attained height in
11. Watson M, Wheatley K, Harrison GA, Zittoun R, Gray RG, patients successfully treated for childhood acute lymphoblastic
Goldstone AH et al. Severe adverse impact on sexual functioning leukemia. J Pediatr 1993; 123(4): 546–552.
and fertility of bone marrow transplantation, either allogeneic or 28. Moell C, Garwicz S, Marky I, Mellander L, Karlberg J. Growth in
autologous, compared with consolidation chemotherapy alone: children treated for acute lymphoblastic leukemia with and without
analysis of the MRC AML 10 trial. Cancer 1999; 86(7): 1231–1239. prophylactic cranial irradiation. Acta Paediatr Scand 1988; 77(5):
12. Legault L, Bonny Y. Endocrine complications of bone marrow 688–692.
transplantation in children. Pediatr Transplant 1999; 3(1): 60–66. 29. Schmiegelow M, Hertz H, Schmiegelow K, Holm K, Muller J. Insulin-
13. Mayer EI, Dopfer RE, Klingebiel T, Scheel-Walter H, Ranke MB, like growth factor-I and insulin-like growth factor binding protein-3
Niethammer D. Longitudinal gonadal function after bone marrow during maintenance chemotherapy of acute lymphoblastic leukemia
transplantation for acute lymphoblastic leukemia during childhood. in children. J Pediatr Hematol Oncol 1999; 21(4): 268–273.
Pediatr Transplant 1999; 3(1): 38–44. 30. Sklar C, Mertens A, Walter A, Mitchell D, Nesbit M, O’Leary M
14. Giona F, Annino L, Donato P, Ermini M. Gonadal, adrenal, androgen et al. Final height after treatment for childhood acute lymphoblastic
and thyroid functions in adults treated for acute lymphoblastic leukemia: comparison of no cranial irradiation with 1800 and 2400
leukemia. Haematologica 1994; 79(2): 141–147. centigrays of cranial irradiation. J Pediatr 1993; 123(1): 59–64.
15. Kreuser ED, Hetzel WD, Heit W, Hoelzer D, Kurrle E et al. 31. Arguelles B, Barrios V, Buno M, Madero L, Argente J.
Reproductive and endocrine gonadal functions in adults following Anthropometric parameters and their relationship to serum
multidrug chemotherapy for acute lymphoblastic or growth hormone-binding protein and leptin levels in children with
undifferentiated leukemia. J Clin Oncol 1988; 6(4): 588–595. acute lymphoblastic leukemia: a prospective study. Eur J Endocrinol
16. Nygaard R, Clausen N, Siimes MA, Marky I, Skjeldestad FE, 2000; 143(2): 243–250.
Kristinsson JR et al. Reproduction following treatment for 32. Schrappe M, Reiter A, Zimmermann M, Harbott J, Ludwig WD,
childhood leukemia: a population- based prospective cohort study Henze G et al. Long-term results of four consecutive trials in
of fertility and offspring. Med Pediatr Oncol 1991; 19(6): 459–466. childhood ALL performed by the ALL-BFM study group from
17. Gleeson HK, Shalet SM. Endocrine complications of neoplastic 1981 to 1995. Berlin–Frankfurt–Munster. Leukemia 2000; 14(12):
diseases in children and adolescents. Curr Opin Pediatr 2001; 13(4): 2205–2222.
346–351. 33. Crofton PM, Ahmed SF, Wade JC, Elmlinger MW, Ranke MB,
18. Schriock EA, Schell MJ, Carter M, Hustu O, Ochs JJ. Abnormal Kelnar CJ et al. Effects of a third intensification block of
growth patterns and adult short stature in 115 long-term survivors chemotherapy on bone and collagen turnover, insulin-like growth
of childhood leukemia. J Clin Oncol 1991; 9(3): 400–405. factor I, its binding proteins and short- term growth in children with
19. Moell C, Garwicz S. Influence of treatment modalities on acute lymphoblastic leukaemia. European Journal of Cancer 1999;
prepubertal growth in children with acute lymphoblastic leukemia. 35(6): 960–967.
Pediatr Hematol Oncol 1995; 12(5): 425–427. 34. Halton JM, Atkinson SA, Barr RD. Growth and body composition in
20. Marky I, Mellander L, Lannering B, Albertsson-Wikland K. A response to chemotherapy in children with acute lymphoblastic
longitudinal study of growth and growth hormone secretion in leukemia. Int J Cancer Suppl 1998; 11: 81–84.
children during treatment for acute lymphoblastic leukemia. Med 35. Sempoux P, Moell C, Cornu G, Malvaux P, Maes M. Subnormal
Pediatr Oncol 1991; 19(4): 258–264. growth during puberty in children treated for acute lymphoblastic
21. Marky I, Samuelsson BO, Mellander L, Karlberg J. Longitudinal leukemia. Pediatr Hematol Oncol 1992; 9(3): 217–222.
growth in children with non-Hodgkin’s lymphoma and children with 36. Kirk JA, Raghupathy P, Stevens MM, Cowell CT, Menser MA, Bergin
acute lymphoblastic leukemia: comparison between unirradiated M et al. Growth failure and growth-hormone deficiency after
and irradiated patients. Med Pediatr Oncol 1991; 19(2): 96–99. treatment for acute lymphoblastic leukaemia. Lancet 1987; 1(8526):
22. Hokken-Koelega AC, van Doorn JW, Hahlen K, Stijnen T, Muinck 190–193.
Keizer-Schrama SM, Drop SL. Long-term effects of treatment for 37. Stubberfield TG, Byrne GC, Jones TW. Growth and growth
acute lymphoblastic leukemia with and without cranial irradiation hormone secretion after treatment for acute lymphoblastic
on growth and puberty: a comparative study. Pediatr Res 1993; leukemia in childhood. 18-Gy versus 24-Gy cranial irradiation.
33(6): 577–582. J Pediatr Hematol Oncol 1995; 17(2): 167–171.
23. Groot-Loonen JJ, Otten BJ, t’ Hof MA, Lippens RJ, Steolinga GB. 38. Blatt J, Lee P, Suttner J, Finegold D. Pulsatile growth hormone
Chemotherapy plays a major role in the inhibition of catch-up secretion in children with acute lymphoblastic leukemia after
growth during maintenance therapy for childhood acute 1800 cGy cranial radiation. Int J Radiat Oncol Biol Phys 1988; 15(4):
lymphoblastic leukemia. Pediatrics 1995; 96(4 Pt 1): 693–695. 1001–1006.
237
Howard and Pui
39. Blatt J, Bercu BB, Gillin JC, Mendelson WB, Poplack DG. Reduced years after treatment for acute lymphoblastic leukemia in
pulsatile growth hormone secretion in children after therapy for childhood. Med Pediatr Oncol 1998; 30(6): 351–356.
acute lymphoblastic leukemia. J Pediatr 1984; 104(2): 182–186. 59. Warner JT, Evans WD, Webb DK, Gregory JW. Body composition
40. Leung W, Rose SR, Zhou Y, Hancock ML, Burstein S, Schriock EA of long- term survivors of acute lymphoblastic leukaemia. Med
et al. Outcomes of growth hormone replacement therapy in Pediatr Oncol 2002; 38(3): 165–172.
survivors of childhood acute lymphoblastic leukemia. J Clin Oncol 60. Dongen-Melman JE, Hokken-Koelega AC, Hahlen K, De Groot A,
2002; 20: 2959–2964. Tromp CG, Egeler RM. Obesity after successful treatment of acute
41. Bozzola M, Albanese A, Butler GE, Cherubini V, Cicognani A, lymphoblastic leukemia in childhood. Pediatr Res 1995; 38(1):
Caruso-Nicoletti M et al. Unresolved problems in optimal therapy 86–90.
of pubertal disorders in oncological and bone marrow transplanted 61. Birkebaek NH, Clausen N. Height and weight pattern up to 20
patients. J Pediatr Endocrinol Metab 2001; 14(Suppl 2): 997–1002. years after treatment for acute lymphoblastic leukaemia. Arch Dis
42. Birkebaek NH, Clausen N. Height and weight pattern up to 20 Child 1998; 79(2): 161–164.
years after treatment for acute lymphoblastic leukaemia. Arch Dis 62. Lustig RH, Rose SR, Burghen GA, Velasquez-Mieyer P, Broome DC,
Child 1998; 79(2): 161–164. Smith K et al. Hypothalamic obesity caused by cranial insult in
43. Brennan BM, Rahim A, Mackie EM, Eden OB, Shalet SM. Growth children: altered glucose and insulin dynamics and reversal by a
hormone status in adults treated for acute lymphoblastic leukaemia somatostatin agonist. J Pediatr 1999; 135(2 Pt 1): 162–168.
in childhood. Clin Endocrinol (Oxf) 1998; 48(6): 777–783. 63. Brennan BM, Rahim A, Blum WF, Adams JA, Eden OB, Shalet SM.
44. Vahl N, Juul A, Jorgensen JO, Orskov H, Skakkebaek NE, Hyperleptinaemia in young adults following cranial irradiation in
Christiansen JS. Continuation of growth hormone (GH) childhood: growth hormone deficiency or leptin insensitivity? Clin
replacement in GH-deficient patients during transition from Endocrinol (Oxf) 1999; 50(2): 163–169.
childhood to adulthood: a two-year placebo-controlled study. J Clin 64. Halton JM, Atkinson SA, Barr RD. Growth and body composition in
Endocrinol Metab 2000; 85(5): 1874–1881. response to chemotherapy in children with acute lymphoblastic
45. Rogers PC, Tze WJ, Chan KW, Teasdale JM. Human growth leukemia. Int J Cancer Suppl 1998; 11: 81–84.
hormone (HGH) levels at diagnosis of acute lymphoblastic leukemia 65. Garnero P, Delmas PD. Osteoporosis. Endocrinol Metab Clin
(ALL). Pediatr Hematol Oncol 1987; 4(4): 353–356. North Am 1997; 26(4): 913–936.
46. Growth hormone treatment and leukemia. CMAJ 1988; 139(9): 66. Sowers M. Clinical Epidemiology and Osteoporosis: Measures and
877. Their Interpretation. Endocrinol Metab Clin North Am 1997; 26(1):
47. Growth hormone treatment and leukemia. Canadian Growth 219–231.
Hormone Advisory Committee. Can Dis Wkly Rep 1988; 14(25): 67. Erikson EF, Langdahl BL. The pathogenesis of osteoporosis. Horm
109–110. Res 1997; 48(suppl 5): 78–82.
48. Leukaemia and growth hormone. Lancet 1988; 1(8598): 1335. 68. Cassidy JT. Osteopenia and osteoporosis in children. Clin Exp
49. Leukaemia in patients treated with growth hormone. Lancet 1988; Rheumatol 1999; 17(2): 245–250.
1(8595): 1159–1160. 69. Fassler A-LC, Bonjour J-P. Osteoporosis as a pediatric problem.
50. Aktan M, Tanakol R, Nalcaci M, Dincol G. Leukemia in a patient Pediatr Clin N Am 1995; 42: 811–824.
treated with growth hormone. Endocr J 2000; 47(4): 471–473. 70. Matkovic V. Calcium and peak bone mass. J Intern Med 1992;
51. Allen DB, Rundle AC, Graves DA, Blethen SL. Risk of leukemia in 231(2): 151–160.
children treated with human growth hormone: review and 71. Matkovic V, Fontana D, Tominac C, Goel P, Chesnut III CH. Factors
reanalysis. J Pediatr 1997; 131(1 Pt. 2): S32–S36. that influence peak bone mass formation: a study of calcium balance
52. Fradkin JE, Mills JL, Schonberger LB, Wysowski DK, Thomson R, and the inheritance of bone mass in adolescent females. Am J Clin
Durako SJ et al. Risk of leukemia after treatment with pituitary Nutr 1990; 52(5): 878–888.
growth hormone. JAMA 1993; 270(23): 2829–2832. 72. Rizzoli R, Bonjour JP. Determinants of peak bone mass and
53. Rapaport R, Oberfield SE, Robison L, Salisbury S, David R, Rao J mechanisms of bone loss. Osteoporos Int 1999; 9(Suppl 2):
et al. Relationship of growth hormone deficiency and leukemia. S17–S23.
J Pediatr 1995; 126(5 Pt 1): 759–761. 73. Bonjour JP, Theintz G, Law F, Slosman D, Rizzoli R. Peak bone
54. Stahnke N. Leukemia in growth-hormone-treated patients: an mass. Osteoporos Int 1994; 4(Suppl 1): 7–13.
update, 1992. Horm Res 1992; 38(Suppl 1): 56–62. 74. Matkovic V, Jelic T, Wardlaw GM, Ilich JZ, Goel PK, Wright JK et al.
55. Taha DR, Bastian W, Castells S. Growth hormone replacement Timing of peak bone mass in Caucasian females and its implication
therapy in children with leukemia in remission. Clin Pediatr (Phila) for the prevention of osteoporosis. Inference from a cross-
2001; 40(8): 441–445. sectional model. J Clin Invest 1994; 93(2): 799–808.
56. Sklar CA, Mertens AC, Mitby P, Occhiogrosso G, Qin J, Heller G, 75. Cooper C, Melton LJI. Magnitude and impact of osteoporosis and
et al. Risk of disease recurrence and second neoplasms (SN) in fractures. In: Marcus R, Feldman D, Kelsey J, eds. Osteoporosis. San
survivors of childhood cancer treated with growth hormone (GH): Diego: Academic Press; 1996: 419–434.
a report from the Childhood Cancer Survivor Study CCSS. J Clin 76. Blatt J, Martini S, Penchansky L. Characteristics of acute
Endocrinol Metab 2002 (in press). lymphoblastic leukemia in children with osteopenia and vertebral
57. Sklar CA, Mertens AC, Walter A, Mitchell D, Nesbit ME, O’Leary compression fractures. J Pediatr 1984; 105(2): 280–282.
M et al. Changes in body mass index and prevalence of overweight 77. Strauss AJ, Su JT, Dalton VM, Gelber RD, Sallan SE, Silverman LB.
in survivors of childhood acute lymphoblastic leukemia: role of Bony morbidity in children treated for acute lymphoblastic
cranial irradiation. Med Pediatr Oncol 2000; 35(2): 91–95. leukemia. J Clin Oncol 2001; 19(12): 3066–3072.
58. Birkebaek NH, Fisker S, Clausen N, Tuovinen V, Sindet-Pedersen S, 78. Halton JM, Atkinson SA, Fraher L, Webber CE, Gill GJ, Dawson S
Christiansen JS. Growth and endocrinological disorders up to 21 et al. Altered mineral metabolism and bone mass in children during
treatment for acute lymphoblastic leukemia. J Bone Miner Res 1996; 98. Kaste SC, Jones-Wallace D, Rose SR, Boyett JM, Lustig RH, Rivera
11(11): 1774–1783. GK et al. Bone mineral decrements in survivors of childhood acute
79. Soker M, Devecioglu C, Gurkan F, Haspolat K. Spontaneous lymphoblastic leukemia: frequency of occurrence and risk factors
humerus fracture and osteoporosis: an unusual initial presentation for their development. Leukemia 2001; 15(5): 728–734.
of acute lymphoblastic leukemia. J Pediatr Hematol Oncol 2000; 99. Lukert BP, Raisz LG. Glucocorticoid-induced osteoporosis. Rheum
22(4): 358–360. Dis Clin North Am 1994; 20(3): 629–651.
80. Bjerregaard LL, Rosthooj S. Vertebral compression and eosinophilia 100. Birkebaek NH. Prevention of glucocorticoid induced osteoporosis.
in a child with acute lymphatic leukemia. J Pediatr Hematol Oncol Ann Rheum Dis 1997; 56: 507–509.
2002; 24(4): 313–315. 101. Lukert BP, Raisz LG. Glucocorticoid-induced osteoporosis:
81. Sambrook PN. Corticosteroid induced osteoporosis. J Rheumatol pathogenesis and management. Ann Intern Med 1990; 112:
Suppl 1996; 45: 19–22. 352–364.
82. Sambrook PN. Corticosteroid osteoporosis: practical implications 102. Bockman RS, Weinerman SA. Steroid-induced osteoporosis. The
of recent trials. J Bone Miner Res 2000; 15(9): 1645–1649. Orthop Clin North Am 1990; 21(1): 97–107.
83. Sambrook PN. Corticosteroid osteoporosis. Z Rheumatol 2000; 103. Jutta JC. Corticosteroid-induced osteoporosis. Am J Hosp Pharm
59(Suppl 1): 45–47. 1994; 51: 188–197.
84. Spector TD, Sambrook PN. Steroid osteoporosis. BMJ 1993; 104. Reid IR, Grey AB. Corticosteroid osteoporosis. Bailliere’s Clin
307(6903): 519–520. Rheumatol 1993; 7(3): 573–587.
85. Sambrook P, Birmingham J, Kelly P, Kempler S, Nguyen T, Pocock 105. Sambrook PN, Jones G. Corticosteroid osteoporosis. Br J
N et al. Prevention of corticosteroid osteoporosis. A comparison Rheumatol 1995; 34: 8–12.
of calcium, calcitriol, and calcitonin. N Engl J Med 1993; 328(24): 106. Falcini F, Trapani S, Ermini M, Brandi ML. Intravenous administration
1747–1752. of alendronate counteracts the in vivo effects of glucocorticoids on
86. Hesseling PB, Hough SF, Nel ED, van Riet FA, Beneke T, Wessels G. bone remodeling. Calcif Tissue Int 1996; 58: 166–169.
Bone mineral density in long-term survivors of childhood cancer. 107. Nesbitt LT. Minimizing Complications from Systemic
Int J Cancer Suppl 1998; 11: 44–47. Glucocorticoid use. Dermatol. Clin. 995; 13(4): 925–939.
87. Nysom K, Molgaard C, Holm K, Hertz H, Michaelsen KF. Bone 108. Hahn TJ, Boisseau VC, Avioli LV. Effect of chronic corticosteroid
mass and body composition after cessation of therapy for childhood administration on diaphyseal and metaphyseal bone mass. J Clin
cancer. Int J Cancer Suppl 1998; 11: 40–43. Endocrinol Metab 1974; 39: 274–282.
88. Vassilopoulou-Sellin R, Brosnan P, Delpassand A, Zietz H, Klein MJ, 109. Mazanec DJ, Grisanti JM. Drug-induced osteoporosis. Cleve Clin J
Jaffe N. Osteopenia in young adult survivors of childhood cancer. Med 1989; 56: 297–303.
Med Pediatr Oncol 1999; 32(4): 272–278. 110. Cranney AB, McKendry RJ, Wells GA, Ooi DS, Kanigsberg ND,
89. Aisenberg J, Hsieh K, Kalaitzoglou G, Whittam E, Heller G, Kraag GR et al. The effect of low dose methotrexate on bone
Schneider R et al. Bone mineral density in young adult survivors of density. J Rheumatol 2001; 28(11): 2395–2399.
childhood cancer. J Pediatr Hematol Oncol 1998; 20(3): 241–245. 111. Gnudi S, Butturini L, Ripamonti C, Avella M, Bacci G. The effects of
90. Warner JT, Evans WD, Webb DK, Bell W, Gregory JW. Relative methotrexate (MTX) on bone. A densitometric study conducted on
osteopenia after treatment for acute lymphoblastic leukemia. 59 patients with MTX administered at different doses. Ital J Orthop
Pediatr Res 1999; 45(4 Pt 1): 544–551. Traumatol 1988; 14(2): 227–231.
91. Nysom K, Holm K, Michaelsen KF, Hertz H, Muller J, Molgaard C. 112. Ripamonti C, Avella M, Gnudi S, Figus E. Effect of high and low
Bone mass after treatment for acute lymphoblastic leukemia in doses of methotrexate MTX on bone mass in subjects treated for
childhood. J Clin Oncol 1998; 16(12): 3752–3760. osteosarcoma of the limbs. Minerva Med 1993; 84(3): 131–134.
92. Gilsanz V, Carlson ME, Roe TF, Ortega JA. Osteoporosis after 113. Buckley LM, Leib ES, Cartularo KS, Vacek PM, Cooper SM. Effects
cranial irradiation for acute lymphoblastic leukemia. J Pediatr 1990; of low dose methotrexate on the bone mineral density of patients
117(2 Pt 1): 238–244. with rheumatoid arthritis. J Rheumatol 1997; 24(8): 1489–1494.
93. Atkinson SA, Fraher L, Gundberg CM, Andrew M, Pai M, Barr RD. 114. Shane E, Epstein S. Immunosuppressive therapy and the skeleton.
Mineral homeostasis and bone mass in children treated for acute TEM 1994; 5(4): 169–175.
lymphoblastic leukemia. J Pediatr 1989; 114: 793–800. 115. Brennan BM, Rahim A, Adams JA, Eden OB, Shalet SM. Reduced
94. Arikoski P, Komulainen J, Voutilainen R, Riikonen P, Parviainen M, bone mineral density in young adults following cure of acute
Tapanainen P et al. Reduced bone mineral density in long-term lymphoblastic leukaemia in childhood. Br J Cancer 1999; 79(11–12):
survivors of childhood acute lymphoblastic leukemia. J Pediatr 1859–1863.
Hematol Oncol 1998; 20(3): 234–240. 116. Nysom K, Holm K, Hertz H, Muller J, Fleischer MK, Molgaard C.
95. Henderson RC, Madsen CD, Davis C, Gold SH. Longitudinal Bone mass after treatment for acute lymphoblastic leukemia in
evaluation of bone mineral density in children receiving childhood. J Clin Oncol 2001; 19(11): 2970–2971.
chemotherapy. J Pediatr Hematol Oncol 1998; 20(4): 322–326. 117. Kadan-Lottick N, Marshall JA, Baron AE, Krebs NF, Hambidge KM,
96. Halton JM, Atkinson SA, Fraher L, Webber CE, Cockshott WP, Albano E. Normal bone mineral density after treatment for
Tam C et al. Mineral homeostasis and bone mass at diagnosis in childhood acute lymphoblastic leukemia diagnosed between 1991
children with acute lymphoblastic leukemia. J Pediatr 1995; 126(4): and 1998. J Pediatr 2001; 138(6): 898–904.
557–564. 118. Ribeiro RC, Pui CH, Schell MJ. Vertebral compression fracture as a
97. Atkinson SA, Halton JM, Bradley C, Wu B, Barr RD. Bone and presenting feature of acute lymphoblastic leukemia in children.
mineral abnormalities in childhood acute lymphoblastic leukemia: Cancer 1988; 61(3): 589–592.
influence of disease, drugs and nutrition. Int J Cancer Suppl 1998; 119. Blake GM, Wahner HW, Fogelman I. Clinical interpretation of bone
11: 35–39. density scans. In: Blake GM, Wahner HW, Fogelman I, eds. The
239
Howard and Pui
Evaluation of Osteoporosis: Dual Energy X-ray Absorptiometry and 135. McKay HA, Bailey DA, Mirwald RL, Davison KS, Faulkner RA. Peak
Ultrasound in Clinical Practice. London, UK: Martin Dunitz; 1999: bone mineral accrual and age at menarche in adolescent girls: a
361–386. 6-year longitudinal study. J Pediatr 1998; 133(5): 682–687.
120. Miller CG. The use of bone densitometry in clinical trials. In: Blake 136. Moreira-Andres MN, Canizo FJ, de la Cruz FJ, Gomez-de LC,
GM, Wahner HW, Fogelman I, eds. The Evaluation of Hawkins FG. Bone mineral status in prepubertal children with
Osteoporosis: Dual Energy X-ray Absorptiometry and Ultrasound constitutional delay of growth and puberty. Eur J Endocrinol 1998;
in Clinical Practice. London, UK: Martin Dunitz; 1999: 388–394. 139(3): 271–275.
121. Blake GM, Wahner HW, Fogelman I. Bone densitometry in 137. Nordstrom P, Pettersson U, Lorentzon R. Type of physical activity,
secondary osteoporosis. In: Blake GM, Wahner HW, Fogelman I, muscle strength, and pubertal stage as determinants of bone
eds. The Evaluation of Osteoporosis: Dual Energy X-ray mineral density and bone area in adolescent boys. J Bone Miner Res
Absorptiometry and Ultrasound in Clinical Practice. London, UK: 1998; 13(7): 1141–1148.
Martin Dunitz; 1999: 395–414. 138. Molgaard C, Thomsen BL, Michaelsen KF. Influence of weight,
122. Laraque D, Arena L, Karp J, Gruskay D. Bone mineral content in age and puberty on bone size and bone mineral content in
black pre-schoolers: normative data using single photon healthy children and adolescents. Acta Paediatr 1998; 87(5):
absorptiometry. Pediatr Radiol 1990; 20(6): 461–463. 494–499.
123. Milinarsky A, Fischer S, Giadrosich V, Casanova D. Bone mineral 139. Boot AM, de Ridder MA, Pols HA, Krenning EP, de Muinck K. Bone
density by single photon X-ray absorptiometry in Chilean children mineral density in children and adolescents: relation to puberty,
and adolescents. J Rheumatol 1998; 25(10): 2003–2008. calcium intake, and physical activity. J Clin Endocrinol Metab 1997;
124. Mughal MZ, Langton CM, Utretch G, Morrison J, Specker BL. 82(1): 57–62.
Comparison between broad-band ultrasound attenuation of the 140. Atkinson SA, Halton JM, Bradley C, Wu B, Barr RD. Bone and
calcaneum and total body bone mineral density in children. Acta mineral abnormalities in childhood acute lymphoblastic leukemia:
Paediatr 1996; 85(6): 663–665. influence of disease, drugs, and nutrition. Int J Cancer 1998; 2(Suppl.
125. Sundberg M, Gardsell P, Johnell O, Ornstein E, Sernbo I. 11): 35–39.
Comparison of quantitative ultrasound measurements in calcaneus 141. Barr RD, Simpson T, Webber CE, Gill GJ, Hay J, Eves M et al.
with DXA and SXA at other skeletal sites: a population-based study Osteopenia in children surviving brain tumours. Eur J Cancer 1998;
on 280 children aged 11–16 years. Osteoporosis Int 1998; 8(5): 34(6): 873–877.
410–417. 142. Barr RD, Halton JM. Bone mineral density in survivors of cancer in
126. Glastre C, Braillon P, David I, Cochat P, Meunier PJ, Delmas PD. childhood. J Pediatr Hematol Oncol 1999; 21(3): 249–250.
Measurement of bone mineral content of the lumbar spine by 143. Cohn SL, Morgain ER, Mallette LE. The spectrum of metabolic bone
dual energy X-ray absorptiometry in normal children: correlations disease in lymphoblastic leukemia. Cancer 1987; 59: 346–350.
with growth parameters. J Clin Endocrinol Metab 1990; 70: 144. Crofton PM, Ahmed SF, Wade JC, Stephen R, Elmlinger MW, Ranke
1330–1333. MB et al. Effects of intensive chemotherapy on bone and collagen
127. Southard RN, Morris JD, Mahan JD, Hayes JR, Torch MA, Sommer turnover and the growth hormone axis in children with acute
A et al. Bone mass in healthy children: measurements with lymphoblastic leukemia. J Clin Endocrinol Metab 1998; 83(9): 3121–
qualitative DXA. Radiology 1991; 179: 735–738. 3129.
128. Faulkner RA, Bailey DA, Drinkwater DT, McKay HA, Arnold C, 145. De Schepper J, Hachimi-Idrissi S, Louis O, Maurus R, Otten J. Bone
Wilkinson AA. Bone densitometry in Canadian children 8–17 years metabolism and mineralisation after cytotoxic chemotherapy
of age. Calcif Tissue Int 1996; 59: 344–351. including ifosfamide. Arch Dis Child 1994; 71: 346–348.
129. Zanchetta JR, Plotkin H, Alvarez Filgueria ML. Bone mass in 146. Molgaard C, Thomsen BL, Prentice A, Cole TJ, Michaelsen KF.
children: normative values for the 2–20 year-old population. Bone Whole body bone mineral content in healthy children and
1995; 16: 393S–399S. adolescents. Arch Dis Child 1997; 76(1): 9–15.
130. Baroncelli GI, Bertelloni S, Ceccarelli C, Saggese G. Measurement 147. Molgaard C, Thomsen BL, Michaelsen KF. Influence of weight, age
of volumetric bone mineral density accurately determines degree of and puberty on bone size and bone mineral content in healthy
lumbar undermineralization in children with growth hormone children and adolescents. Acta Paediatr 1998; 87(5): 494–499.
deficiency. J Clin Endocrinol Metab 1998; 83(9): 3150–3154. 148. Bonjour JP, Rizzoli R. The property of calcium in the child and the
131. Leonard MB, Feldman HI, Zemel BS, Berlin JA, Barden EM, Stallings adolescent: importance in the acquisition of bone mineral density.
VA. Evaluation of low density spine software for the assessment of Arch Pediatr 1999; 6(Suppl 2): 155s–157s.
bone mineral density in children. J Bone Miner Res 1998; 13(11): 149. Ferrari S, Manen D, Bonjour JP, Slosman D, Rizzoli R. Bone mineral
1687–1690. mass and calcium and phosphate metabolism in young men:
132. Yeste D, del Rio L, Gussinye M, Carrascosa A. Bone mineral density relationships with vitamin D receptor allelic polymorphisms. J Clin
in nursing infants and young children (0–4 years old) at the level of Endocrinol Metab 1999; 84(6): 2043–2048.
the lumbar spine. The normal patterns. An Esp Pediatr 1998; 49(3): 150. Griffiths ID, Francis RM. Milk intake and bone mineral acquisition in
248–252. adolescent girls. Results in two groups are not so different. BMJ
133. Maynard LM, Guo SS, Chumlea WC, Roche AF, Wisemandle WA, 1998; 316(7146): 1747–1748.
Zeller CM et al. Total-body and regional bone mineral content and 151. Maggiolini M, Bonofiglio D, Giorno A, Catalano S, Marsico S, Aquila
areal bone mineral density in children aged 8–18 y: the Fels S et al. The effect of dietary calcium intake on bone mineral density
longitudinal study. Am J Clin Nutr 1998; 68(5): 1111–1117. in healthy adolescent girls and young women in southern Italy. Int J
134. Nysom K, Holm K, Hertz H, Muller J, Fleischer MK, Molgaard C. Epidemiol 1999; 28(3): 479–484.
Bone mass after treatment for acute lymphoblastic leukemia in 152. Teegarden D, Lyle RM, McCabe GP, McCabe LD, Proulx WR,
childhood. J Clin Oncol 2001; 19(11): 2970–2971. Michon K et al. Dietary calcium, protein, and phosphorus are
related to bone mineral density and content in young women. Am J 169. Spiegel RJ, Vigersky RA, Oliff AI, Echelberger CK, Bruton J, Poplack
Clin Nutr 1998; 68(3): 749–754. DG. Adrenal suppression after short-term corticosteroid therapy.
153. Weaver CM, Peacock M, Johnston CC. Adolescent nutrition in the Lancet 1979; 1(8117): 630–633.
prevention of postmenopausal osteoporosis. J Clin Endocrinol 170. Rongen-Westerlaken C, Drop SL, Van den Anker JN. Primary
Metab 1999; 84(6): 1839–1843. adrenocortical insufficiency in childhood. Acta Endocrinol Suppl
154. Rickers H, Deding A, Christiansen C, Rodbro P. Mineral loss in (Copenh) 1986; 279: 279–283.
cortical and trabecular bone during high-dose prednisone 171. August GP. Treatment of adrenocortical insufficiency. Pediatr Rev
treatment. Calcif Tissue Int 1984; 36(3): 269–273. 1997; 18(2): 59–62.
155. Bijlsma JW, Raymakers JA, Mosch C, Hoekstra A, Derksen RH, 172. Spital A. Hyponatremia in adrenal insufficiency: review of
Baart dlF et al. Effect of oral calcium and vitamin D on pathogenetic mechanisms. South Med J 1982; 75(5): 581–585.
glucocorticoid-induced osteopenia. Clin Exp Rheumatol 1988; 6(2): 173. Demiroglu H, Dundar S. Hyperkalaemia in acute leukaemia: a sign
113–119. of adrenocortical insufficiency. J Intern Med 1997; 242(2):
156. Braun JJ, Birkenhager-Frenkel DH, Rietveld AH, Juttmann JR, Visser 111–115.
TJ, Birkenhager JC. Influence of 1 alpha-(OH)D3 administration on 174. Jeffcoate W. Assessment of corticosteroid replacement therapy in
bone and bone mineral metabolism in patients on chronic adults with adrenal insufficiency. Ann Clin Biochem 1999; 36(Pt 2):
glucocorticoid treatment;a double blind controlled study. Clin 151–157.
Endocrinol (Oxf) 1983; 19(2): 265–273. 175. Agwu JC, Spoudeas H, Hindmarsh PC, Pringle PJ, Brook CG. Tests
157. Dykman TR, Haralson KM, Gluck OS, Murphy WA, Teitelbaum SL, of adrenal insufficiency. Arch Dis Child 1999; 80(4): 330–333.
Hahn TJ et al. Effect of oral 1,25-dihydroxyvitamin D and calcium on 176. Linder BL, Esteban NV, Yergey AL, Winterer JC, Loriaux DL,
glucocorticoid- induced osteopenia in patients with rheumatic Cassorla F. Cortisol production rate in childhood and adolescence.
diseases. Arthritis Rheum 1984; 27(12): 1336–1343. J Pediatr 1990; 117(6): 892–896.
158. Lee WT, Leung SS, Wang SH, Xu YC, Zeng WP, Lau J et al. 177. Zaloga GP. Sepsis-induced adrenal deficiency syndrome. Crit Care
Double-blind, controlled calcium supplementation and bone Med 2001; 29(3): 688–690.
mineral accretion in children accustomed to a low-calcium diet. 178. Zaloga GP, Marik P. Hypothalamic-pituitary-adrenal insufficiency.
Am J Clin Nutr 1994; 60(5): 744–750. Crit Care Clin 2001; 17(1): 25–41.
159. Reid IR, Ibbertson HK. Calcium supplements in the prevention 179. Leman P. Addison’s disease. Hydrocortisone should be started
of steroid-induced osteoporosis. Am J Clin Nutr 1986; 44(2): immediately adrenal insufficiency is considered. BMJ 1996;
287–290. 313(7054): 427.
160. Pui CH, Roy III S, Noe HN. Urolithiasis in childhood acute leukemia 180. Graber AL, Ney RL, Nicholson WE, Island DP, Liddle GW. Natural
and non-Hodgkin’s lymphoma. J Urol 1986; 136(5): 1052–1054. history of pituitary–adrenal recovery following long-term
161. Krasner AS. Glucocorticoid-induced adrenal insufficiency. JAMA suppression with corticosteroids. J Clin Endocrinol Metab 1965; 25:
1999; 282(7): 671–676. 11–16.
162. Schlaghecke R, Kornely E, Santen RT, Ridderskamp P. The effect of 181. LaRochelle Jr. GE, LaRochelle AG, Ratner RE, Borenstein DG.
long-term glucocorticoid therapy on pituitary-adrenal responses to Recovery of the hypothalamic-pituitary–adrenal (HPA) axis in
exogenous corticotropin-releasing hormone. N Engl J Med 1992; patients with rheumatic diseases receiving low-dose prednisone.
326(4): 226–230. Am J Med 1993; 95(3): 258–264.
163. Zora JA, Zimmerman D, Carey TL, O’Connell EJ, Yunginger JW. 182. Carpentieri U, Balch MT. Hyperglycemia associated with the
Hypothalamic-pituitary-adrenal axis suppression after short-term, therapeutic use of L -asparaginase: possible role of insulin receptors.
high- dose glucocorticoid therapy in children with asthma. J Allergy J Pediatr 1978; 93(5): 775–778.
Clin Immunol 1986; 77(1 Pt 1): 9–13. 183. Gailani S, Nussbaum A, Onuma T, Freeman A. Diabetes in patients
164. Wajchenberg BL, Cesar FP, Luthold WW, Okada H, Borghi VC. treated with asparaginase. Clin Pharmacol Ther 1971; 12(3):
Comparison of the subacute effects of a new glucocorticoid, 487–490.
deflazacort, and prednisone on the hypothalamic-pituitary–adrenal 184. Cetin M, Yetgin S, Kara A, Tuncer AM, Gunay M, Gumruk F et al.
axis of normal subjects. Braz J Med Biol Res 1986; 19(1): 39–47. Hyperglycemia, ketoacidosis and other complications of
165. Schurmeyer TH, Tsokos GC, Avgerinos PC, Balow JE, D’Agata R, L -asparaginase in children with acute lymphoblastic leukemia. J Med
Loriaux DL et al. Pituitary–adrenal responsiveness to corticotropin- 1994; 25(3–4): 219–229.
releasing hormone in patients receiving chronic, alternate day 185. Charan VD, Desai N, Singh AP, Choudhry VP. Diabetes mellitus and
glucocorticoid therapy. J Clin Endocrinol Metab 1985; 61(1): 22–27. pancreatitis as a complication of L -asparaginase therapy. Indian
166. Rosmond R, Chagnon YC, Holm G, Chagnon M, Perusse L, Lindell Pediatr 1993; 30(6): 809–810.
K et al. A glucocorticoid receptor gene marker is associated with 186. Iyer RS, Rao SR, Pai S, Advani SH, Magrath IT. L -asparaginase
abdominal obesity, leptin, and dysregulation of the hypothalamic- related hyperglycemia. Indian J Cancer 1993; 30(2): 72–76.
pituitary–adrenal axis. Obes Res 2000; 8(3): 211–218. 187. Wang YJ, Chu HY, Shu SG, Chi CS. Hyperglycemia induced by
167. Kuperman H, Damiani D, Chrousos GP, Dichtchekenian V, Manna chemotherapeutic agents used in acute lymphoblastic leukemia:
TD, Filho VO et al. Evaluation of the hypothalamic-pituitary–adrenal report of three cases. Chung Hua I Hsueh Tsa Chih (Taipei) 1993;
axis in children with leukemia before and after 6 weeks of high-dose 51(6): 457–461.
glucocorticoid therapy. J Clin Endocrinol Metab 2001; 86(7): 188. Pui CH, Burghen GA, Bowman WP, Aur RJ. Risk factors for
2993–2996. hyperglycemia in children with leukemia receiving sc l-asparaginase
168. Felner EI, Thompson MT, Ratliff AF, White PC, Dickson BA. Time and prednisone. J Pediatr 1981; 99(1): 46–50.
course of recovery of adrenal function in children treated for 189. Ridgway D, Neerhout RC, Bleyer A. Attenuation of asparaginase-
leukemia. J Pediatr 2000; 137(1): 21–24. induced hyperglycemia after substitution of the Erwinia carotovora
241
Howard and Pui
for the Escherichia coli enzyme preparation. Cancer 1989; 63(3): 208. Lei KI, Wickham NW, Johnson PJ. Severe hyponatremia due to
561–563. syndrome of inappropriate secretion of antidiuretic hormone in a
190. Lavine RL, DiCinto DM. L -Asparaginase diabetes mellitus in rabbits: patient receiving interferon-alpha for chronic myeloid leukemia. Am
differing effects of two different schedules of L -asparaginase J Hematol 1995; 49(1): 100.
administration. Horm Metab Res 1984; 16(Suppl 1): 92–96. 209. Spigset O, Hedenmalm K. Hyponatraemia and the syndrome of
191. Pui CH, Burghen GA, Bowman WP, Aur RJ. Risk factors for inappropriate antidiuretic hormone secretion (SIADH) induced by
hyperglycemia in children with leukemia receiving L -asparaginase psychotropic drugs. Drug Saf 1995; 12(3): 209–225.
and prednisone. J Pediatr 1981; 99(1): 46–50. 210. Otto C, Richter WO. Syndrome of inappropriate antidiuretic
192. Ziino O, Russo D, Orlando MA, Benigno V, Locatelli F, Arico M. hormone secretion induced by different drugs. Ann Pharmacother
Symptomatic hypoglycemia in children receiving oral purine 1994; 28(10): 1199–1200.
analogues for treatment of childhood acute lymphoblastic leukemia. 211. Baliga RR, McHardy KC. Syndrome of inappropriate antidiuretic
Med Pediatr Oncol 2002; 39: 32–34. hormone secretion due to fluvoxamine therapy. Br J Clin Pract
193. Halonen P, Salo MK, Makipernaa A. Fasting hypoglycemia is 1993; 47(2): 62–63.
common during maintenance therapy for childhood acute 212. Castrillon JL, Mediavilla A, Mendez MA, Cavada E, Carrascosa M,
lymphoblastic leukemia. J Pediatr 2001; 138(3): 428–431. Valle R. Syndrome of inappropriate antidiuretic hormone secretion
194. Collipp PJ. Hypoglycemia and leukemia. Pediatrics 1972; 49(5): (SIADH) and enalapril. J Intern Med 1993; 233(1): 89–91.
788–789. 213. Adlakha A, Manocha AP, Bechard DL. Imipramine-induced
195. Collipp PJ, Kaplan SA, Patrick JR. Reduced liver glucose-6- syndrome of inappropriate antidiuretic hormone secretion. South
phosphatase in human leukemia. Proc Soc Exp Biol Med 1965; Med J 1991; 84(12): 1507–1509.
118: 42. 214. Slater LM, Wainer RA, Serpick AA. Vincristine neurotoxicity with
196. Collipp PJ, Patrick JR, Gilchrist GS, Donnell GN, Brubaker C. Liver hyponatremia. Cancer 1969; 23(1): 122–125.
glucose-6-phosphatase and carbohydrate metabolism in childhood 215. Fine RN, Clarke RR, Shore NA. Hyponatremia and vincristine
leukemia. Pediatr Res 1967; 1(116): 121. therapy. Syndrome possibly resulting from inappropriate
197. Silverman LB, Declerck L, Gelber RD, Dalton VK, Asselin BL, antidiuretic hormone secretion. Am J Dis Child 1966; 112(3):
Barr RD et al. Results of Dana-Farber Cancer Institute 256–259.
Consortium protocols for children with newly diagnosed acute 216. Tomiwa K, Mikawa H, Hazama F, Yazawa K, Hosoya R, Ohya T
lymphoblastic leukemia (1981–1995). Leukemia 2000; 14(12): et al. Syndrome of inappropriate secretion of antidiuretic hormone
2247–2256. caused by vincristine therapy: a case report of the neuropathology.
198. Harms DO, Janka-Schaub GE. Co-operative study group for J Neurol 1983; 229(4): 267–272.
childhood acute lymphoblastic leukemia (COALL): long-term 217. Oldham RK, Pomeroy TC. Vincristine-induced syndrome of
follow-up of trials 82, 85, 89 and 92. Leukemia 2000; 14(12): inappropriate secretion of antidiuretic hormone. South Med J 1972;
2234–2239. 65(8): 1010–1012.
199. Nicholson RG, Feldman W. Hyponatremia in association with 218. Suskind RM, Brusilow SW, Zehr J. Syndrome of inappropriate
vincristine therapy. Can Med Assoc J 1972; 106(4): 356–357. secretion of antidiuretic hormone produced by vincristine toxicity
200. Stuart MJ, Cuaso C, Miller M, Oski FA. Syndrome of recurrent (with bioassay of ADH level). J Pediatr 1972; 81(1): 90–92.
increased secretion of antidiuretic hormone following multiple 219. Cutting HO. Inappropriate secretion of antidiuretic hormone
doses of vincristine. Blood 1975; 45(3): 315–320. secondary to vincristine therapy. Am J Med 1971; 51(2): 269–271.
201. Robertson GL, Bhoopalam N, Zelkowitz LJ. Vincristine 220. Kamaluddin M, McNally P, Breatnach F, O’Marcaigh A, Webb D,
neurotoxicity and abnormal secretion of antidiuretic hormone. O’Dell E et al. Potentiation of vincristine toxicity by itraconazole in
Arch Intern Med 1973; 132(5): 717–720. children with lymphoid malignancies. Acta Paediatr 2001; 90(10):
202. Kebaili K, Bertrand Y, Foray P, Taylor P, Combet S, Berthier JC 1204–1207.
et al. A rare cause of hyponatremia during introductory treatment 221. Jeng MR, Feusner J. Itraconazole-enhanced vincristine neurotoxicity
of acute lymphoblastic leukemia in an infant: inappropriate secretion in a child with acute lymphoblastic leukemia. Pediatr Hematol
of atrial natriuretic factor? Arch Pediatr 1994; 1(10): 898–902. Oncol 2001; 18(2): 137–142.
203. Monmany J, Vazquez G, Rodriguez J, Domingo P. Syndrome of 222. Gillies J, Hung KA, Fitzsimons E, Soutar R. Severe vincristine
inappropriate secretion of antidiuretic hormone induced by toxicity in combination with itraconazole. Clin Lab Haematol 1998;
paroxetine. Arch Intern Med 1999; 159(17): 2089–2090. 20(2): 123–124.
204. Kintzel PE. Symptomatic syndrome of inappropriate antidiuretic 223. Bohme A, Ganser A, Hoelzer D. Aggravation of vincristine-induced
hormone secretion associated with azithromycin. Ann neurotoxicity by itraconazole in the treatment of adult ALL. Ann
Pharmacother 1998; 32(3): 388. Hematol 1995; 71(6): 311–312.
205. Bouman WP, Pinner G, Johnson H. Incidence of selective serotonin 224. Demura R. The role of antidiuretic hormone in hyponatremia in
reuptake inhibitor (SSRI) induced hyponatraemia due to the adrenal insufficiency–is the guideline for the diagnosis of syndrome
syndrome of inappropriate antidiuretic hormone (SIADH) of inappropriate secretion of the antidiuretic hormone appropriate?
secretion in the elderly. Int J Geriatr Psychiatry 1998; 13(1): 12–15. Intern Med 1999; 38(5): 382–383.
206. Cadle RM, Darouiche RO, Ashton CM. Symptomatic syndrome of 225. Kamoi K, Tamura T, Tanaka K, Ishibashi M, Yamaji T. Hyponatremia
inappropriate antidiuretic hormone secretion associated with and osmoregulation of thirst and vasopressin secretion in patients
azithromycin. Ann Pharmacother 1997; 31(11): 1308–1310. with adrenal insufficiency. J Clin Endocrinol Metab 1993; 77(6):
207. Chan TY. Drug-induced syndrome of inappropriate antidiuretic 1584–1588.
hormone secretion. Causes, diagnosis and management. Drugs 226. Lorini R, Larizza D, Garibaldi E, Polito E. [Paralytic ileus, convulsions
Aging 1997; 11(1): 27–44. and hyponatremia during vincristine treatment. Observations on a
case in a young girl with acute lymphocytic leukemia. Minerva 238. Lando A, Holm K, Nysom K, Rasmussen AK, Feldt-Rasmussen U,
Pediatr 1977; 29(28): 1733–1738. Petersen JH et al. Thyroid function in survivors of childhood acute
227. van der Klooster JM, Peters R, Ashruf RZ, Grootendorst AF. lymphoblastic leukaemia: the significance of prophylactic cranial
Hyponatraemia and the syndrome of inappropriate antidiuretic irradiation. Clin Endocrinol (Oxf) 2001; 55(1): 21–25.
hormone secretion with convulsions, coma and pulmonary 239. Bessho F, Ohta K, Akanuma A, Sakata K. Dosimetry of radiation
oedema in a patient using paroxetine. Neth J Med 1997; 51(6): scattered to thyroid gland from prophylactic cranial irradiation for
237–239. childhood leukemia. Pediatr Hematol Oncol 1994; 11(1): 47–53.
228. Krutisch G, Valentin A. Comatose state due to severe 240. Littley MD, Shalet SM, Beardwell CG, Robinson EL, Sutton ML.
hyponatremia in a patient with the syndrome of inappropriate Radiation-induced hypopituitarism is dose-dependent. Clin
antidiuretic hormone secretion. Intensive Care Med 2001; 27(5): Endocrinol (Oxf) 1989; 31(3): 363–373.
944. 241. Drinnan CR, Miller JD, Guyda HJ, Esseltine DW, Chevalier LM,
229. Kloster R, Borresen HC, Hoff-Olsen P. Sudden death in two Freeman CR. Growth and development of long-term survivors of
patients with epilepsy and the syndrome of inappropriate childhood acute lymphoblastic leukemia treated with and without
antidiuretic hormone secretion (SIADH). Seizure 1998; 7(5): prophylactic radiation of the central nervous system. Clin Invest
419–420. Med 1985; 8(4): 307–314.
230. Haycock GB. The syndrome of inappropriate secretion of 242. Rose SR, Lustig RH, Pitukcheewanont P, Broome DC, Burghen GA,
antidiuretic hormone. Pediatr Nephrol 1995; 9(3): 375–381. Li H et al. Diagnosis of hidden central hypothyroidism in survivors
231. Omari A, Kormas N, Field M. Delayed onset of central pontine of childhood cancer. J Clin Endocrinol Metab 1999; 84(12):
myelinolysis despite appropriate correction of hyponatraemia. 4472–4479.
Intern Med J 2002; 32(5–6): 273–274. 243. Grubeck-Loebenstein B, Vierhapper H, Waldhausl W, Nowotny P.
232. Lampl C, Yazdi K. Central pontine myelinolysis. Eur Neurol 2002; Thyroid function in adrenocortical insufficiency during withdrawal
47(1): 3–10. and re-administration of glucocorticoid substitution. Acta
233. Pirzada NA, Ali II. Central pontine myelinolysis. Mayo Clin Proc Endocrinol (Copenh) 1983; 103(2): 254–258.
2001; 76(5): 559–562. 244. Manera R, Ramirez I, Mullins J, Pinkel D. Pilot studies of species-
234. Ferster A, Glinoer D, Van Vliet G, Otten J. Thyroid function during specific chemotherapy of childhood acute lymphoblastic leukemia
L -asparaginase therapy in children with acute lymphoblastic using genotype and immunophenotype. Leukemia 2000; 14(8):
leukemia: difference between induction and late intensification. Am 1354–1361.
J Pediatr Hematol Oncol 1992; 14(3): 192–196. 245. Vilmer E, Suciu S, Ferster A, Bertrand Y, Cave H, Thyss A et al.
235. Mohn A, Chiarelli F, Di Marzio A, Impicciatore P, Marsico S, Angrilli Long- term results of three randomized trials (58831, 58832,
F. Thyroid function in children treated for acute lymphoblastic 58881) in childhood acute lymphoblastic leukemia: a CLCG-
leukemia. J Endocrinol Invest 1997; 20(4): 215–219. EORTC report. Children Leukemia Cooperative Group. Leukemia
236. Nygaard R, Bjerve KS, Kolmannskog S, Moe PJ, Wesenberg F. 2000; 14(12): 2257–2266.
Thyroid function in children after cytostatic treatment for acute 246. Kamps WA, Bokkerink JP, Hakvoort-Cammel FGAJ et al. BFM
leukemia. Pediatr Hematol Oncol 1988; 5(1): 35–38. oriented treatment for children with acute lymphoblastic leukemia
237. Bossi G, Larizza D, Conter V. Thyroid function is not affected by without cranial irradiation and treatment reduction for standard
second exposure to erwinia asparaginase for childhood acute risk patients;results of DCLSG protocol ALL-8 (1991–1996).
lymphoblastic leukemia. Haematologica 1997; 82(4): 507–508. Leukemia 2002; 16(6): 1099–1111.
243

Howard 2002

Uploaded by

Copyright:

Available Formats

Howard 2002

Uploaded by

Document Information

Original Description:

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Howard 2002

Uploaded by

Copyright:

Available Formats

Endocrinopathy in pediatric ALL

(Table 1). Endocrine complications during therapy include

O lymphoblastic leukemia (ALL), which is the most

Endocrinopathy At diagnosis During induction or During maintenance After completion of Comments

Hypothyroidism Rare Rare Rare Rare

Howard and Pui

Drug Endocrine effects Incidence Mechanism Treatment and prevention

Howard and Pui

Clinical situation Suggested action Relevant endocrinopathy Comments

and vincristine should be avoided to prevent adverse drug

You might also like