October 1976

TheJournalofPEDIATRICS 553

Delayed onset of hypopituitarism: Sequelae of

therapeutic irradiation of central nervous system,
eye, and middle ear tumors

Four children with short stature who received irradiation to the head in conventional doses had clinical
and laboratory evidence of hypothalamie-pituitary hormone deficiencies several years later. Growth
hormone was deficient in all. One patient also had evidence of TSH, A CTH, and gonadotropin
deficiency. Basal prolaetin levels and prolactin response to synthetic TRF were normal in all patients
tested. Treatment with human growth hormone significantly increased growth rate. We suggest that
children should have the hypothalamic-pituitary area shielded from irradiation. Periodic measurements
of hypothalamic-pituitary funetion should be performed in children who have had irradiation to the head,
in order to detect and treat hormonal deficiencies before growth and development are seriously
compromised.

Gail E. Riehards, M.D.,* William M. Wara, M.D., Melvin M. Grumbach, M.D.,**

Selna L. Kaplan, M.D., Glenn E. Sheline, M.D., and Felix A. Conte, M.D.,
S a n F r a n c i s c o , Calif.

THE PROGNOSIS of many neoplastic diseases of child-
hood has improved with the introduction of more aggres-
sive radio- and chemotherapeutic regimens. The
improved survival exposes more children to the risks and
long-term effects of ionizing radiation to normal tissues.
Pituitary hormone deficiencies have been reported in
several children 1-3 and two adults 4 after irradiation to the
From the Departments of Pediatrics and Radiology,
University o f California San Francisco.
Supported in part by grants from the National
Institutes o f Child Health and Human Development
and the National Institute of Arthritis, Metabolism,
and Digestive Diseases, National Institutes of Health,
United States Public Health Service.
Studies conducted in the Pediatric Clinical Research
Center were supported by the Division of Research
Resources, National Institutes of Health, United
States Public Health Service.
*Recipient of a Research Fellowship in Pediatric
Endocrinology from the National Institute of Arthritis,
Metabolism, and Digestive Diseases, National Institutes of
Health, United States Public Health Service.
**Reprint address: Department of Pediatrics. University of
California San Francisco, San Francisco, Calif. 94143.
head for tumors that did not involve the hypothalamic or
pituitary area. Shalet and colleagues 3 reported "inade-
quate response" of plasma growth hormone to insulin
hypoglycemia in 11 of 16 children who had been treated
one to 12 years previously for intracranial tumors that did
not involve the hypothalamus or pituitary. All of these
patients had both surgery and chemotherapy, in addition
to irradiation. Four of the 11 patients with inadequate
growth hormone responses were at or below the third
percentile for height.
Abbreviations used
TSH: plasma thyrotropin
TRF: thyrotropin-releasing factor
LH: luteinizing hormone
FSH: follicle-stimulatinghormone
LRF: luteinizing hormone releasing factor
hGH: human growth hormone
This report describes clinical and laboratory findings in
four children who manifested pituitary dysfunction
several years after conventional external irradiation to
tumors of the central nervous system, eye, or ear.

Vol. 89, No. 4, pp. 553-559

554 Richards et al.
1 CASE 3
Fig. 1. Diagrammatic representation of radiation fields for each of four patients as described in the text. Case 3 had two
different fields, as described.
PATIENTS AND METHODS
Four children were referred for evaluation of short
stature. Hypothalamic and pituitary function was assessed
by: evaluation of the capacity to secrete growth hormone
by provocative testing with insulin, arginine, and
L_dopa 5. 6; ACTH and adrenocortical function by deter-
mination of plasma cortisol before and 60 minutes after
administration of 0.1 U / k g crystalline insulin intrave-
nously. 7 Measurements of plasma thyrotropin were made
after an intravenous bolus of 200 ~g synthetic thyrotropin-
releasing factor, using Medical Research Council Stan-
dard 68/38. ~ Plasma LH and FSH were measured before
and after intravenous administration of 100/~g synthetic
luteinizing hormone releasing factor (LRF), using hLH
(LER-960) and hFSH (LER-869) as standards for
radioimmunoassay. ~ (LRF and TRF were generously
provided by Dr. R. Guillemin of the Salk Institute, La
Jolla, Calif.) Plasma protactin was measured during the
TRF test, by means of human prolactin standard (No.
201-195-1), kindly supplied by Dr. U. J. Lewis of Scripps
Research Foundation, La Jolla, Calif. 16' 11 Bone age was,
evaluated by using the standards of Greulich and Pyle. 1~
Case 1 was well until 8 1/2 months of age, at which time
the right eye was enucleated for retinoblastoma. The
The Journal of Pediatrics
October 1976
~ ] t
,@~._)
CASE 3 CASE 4
pathologic specimen confirmed the diagnosis with exten-
sion into the dura of the optic nerve. Irradiation was given
to the right orbit, using Cobalt-60 (fields: wedged antero-
posterior and lateral 4 x 5.5 cm) (Fig. 1) with 5,490 rads
to the tumor bed and approximately 4,050 rads to the
hypothalamic-pituitary area. In retrospect, a diminution
of growth rate may have occurred by 5 years of age (Fig.
2A). At 8 1/2 years, when he was evaluated for growth
failure, his weight was 4.8 SD below the mean value for
age. Pertinent clinical and laboratory data are shown in
Tables I and II. After therapy with human growth
hormone (hGH), 2 mg three times a week, intramuscu-
larly, the growth rate was 6.2 cm/yr (normal) compared
with 2.1 before therapy.
Case 2 was first evaluated at 5 10/12 years for clumsi-
ness, weakness, involuntary movements of the left side of
the body, drooling from the left side of the mouth,
strabismus, and temper tantrums. Positive physical
findings were bilateral sixth and seventh cranial nerve
palsies, left hemiballismus, marked bilateral ataxia, and
increased deep tendon reflexes on the left. Pneumoen-
cephalogram, ventriculogram, and arteriogram confirmed
the clinical impression of a midbrain tumor. Irradiation
was started with 5,060 fads to the tumor area (36 fractions
Volume 89 Delayed onset of hypopituitarism 555
Number 4

Table I. Pertinent clinical data

Case 4..
Case 1: Case 2: Case 3." Rhabdomyosarcoma
Diagnosis Retinoblastoma Midbrain tumor Medulloblastoma right middle ear

Irradiation
Age (yr) 10 mo 6 4 8
Height (SD)* Mean -2 --I Mean
Dose (fads) 4,050 5,060 4,500 5,200
Growth evaluation
Age (yr) 8 6/12 13 5/12 10 14 3/12
Height (SD)* --4.8 -2.7 -3.6 -3.4
Age at onset of diminished growth 5 8 7 9

*Standard deviation from the mean value for height for age.

Table II. Laboratory data

Laboratory data Case l l Case 2 l Case 3 l Case 4 Normal values

Cortisol
Before insulin 17 tI ND 13 Increase of 10/Lg/dl or peak
After insulin 32 22 17 > 20/~g/dl
T~ 9.1 9.1 6.2 2.3 5.3-14.5/tg/dl
TSH
Before TRF < 0.5 < 5 ND 7.1 < 10./~U/ml
After TRF 9.6 9.6 28.6 > 7/~U/ml rise
Prolactin
Before TRF 5.1 11.2 ND 10.3 < 20 ng/ml
After TRF 12.7 20.8 37.3
Growth hormone (maximum)
After insulin 0_8 < 0.4 [.5 > 7 ng/mI
After arginine 1.0 < 0.4 2.3 > 7 ng/ml
After L-dopa 4.2 2.8 < 1.0t 1.4 > 7 ng/ml
LH (ng/ml)
Before LRF 0.75 1.3 1.0
After LRF 1.15 2.7 ND 1.7
FSH (ng/ml)
Before LRF 0_7 1.1 ND 1.7
After LRF 1.65 1.4 3.5
Bone age (yr) at endocrine evaluation 5 1/2 12. 1/2 13

ND = not done.
*Prepubertal children have an increase in LH of < 1.5 ng/ml after LRF. Pubertal children have a rise of > 1.5 ng/ml. The change from a prepubertal to a
pubertal response usually occurs before there are physical signs of puberty. The mean rise in FSH after LRF is 1.5 ng/ml without any differencebetween
pubertal and prepubertal children.
]-Tested on two occasions.

in 42 days, using a 1 meV x-ray unit; fields were 9 x 9 cm
right and left lateral skull (Fig. 1). Neurologic a b n o r m a l -
ities resolved gradually over the next two years and there
was no evidence o f recurrent disease. At a b o u t 11 years, it
was noticed that he was not growing normally (Fig. 2B). A
review o f growth data indicated that growth may have
slowed by 6 years. At 13 5/12 years, his height was 2.7 SD
below the m e a n value for age. The genitals were those o f a
boy in early puberty: testes 3 x 2 cm and penis 6 x 2,5
cm. There were a few pubic hairs, but no axillary hair
(Tables I and II). A diagnosis of growth h o r m o n e defi-
ciency was made.
Case 3 was a 4-year-old boy who had ataxia, headaches,
and vomiting for six weeks prior to his first admission. On
physical examination, the h e a d tilted to the left and
rotated to the right. He also had bilateral p a p i l l e d e m a and
an unsteady gait, A posterior fossa mass was seen on
ventriculogram and removed; the pathologic diagnosis
was medulloblastoma. Postoperative irradiation included
5,500 rads to the posterior fossa, 4,500 rads to the
55 6 Richards et al. The Journal of Pediatrics
October 1976

200"
.,.S.. so
SD
15-

/~/..." . - - 1 SD
160"
/ / //"~
../".i.- 10-

r 120-
/~~W Increment
(cm/year) AI
/..
80-
TH
HORMONE
S-
" /
RADIATION
t
RADIATION
>--,:_i',
-iHGg?MWgNH E
40
"~ 4 6 8 10 1~2 114. 1~5 1'8 o "~ 4 ~ ~ 1'0 ll2 14 1~5 18
Age (years), AGE (years)
Fig. 2A. Linear growth (left) and growth velocity (right) for Case 1. Growth hormone therapy was begun at 8 10/12 yr.
Linear growth is height (cm) vs chronologic age (yr): . . . . 1SD above and/or below mean height at any given age; =
2.5 SD above and/or below mean height at any given age. Growth velocity is cm/yr plotted vs chronologic age. - - =
mean growth velocity; horizontal bars = period of time for which growth rate is calculated. Growth rate for this period
can be read from vertical axis at the level of the horizontal bar. The dashed line connects the midpoints of each
period.

HEIGHT 15-
200- + 21/2 SD
+ 1 SD
--1 SD
160 - / ." ..'/-21/2SD
lO-

r 120" //2.-'" GR?.W.TH

,/,Sfi
i~ HORMONE (era/year)

""" 0 5-
80- D!ATI N
RAD,A:,ON GROW: \
HORMONE \
40
"~ 71 ~ ~ l b I'2 1~4 1'6 1'8 0 1'8
Age (years) Age (years)
Fig 2B. Linear growth (left) and growth velocity (right) for Case 2. Growth hormone therapy was given for six months
beginning at 14 10/12 years without any significant change in growth rate. See legend, Fig. 2A, for explanation
graphs.

remainder of the intracranial contents, and 4,000 fads to
the spinal cord (fields: 17 x 6.5 cm opposed field skull,
11 x 8 cm opposed posterior fossa, and 20 x 4 cm and
5.4 cm postero-anterior (Fig. 1). Growth may have been
slow as early as 7 years. At 10 years of age, when he was
evaluated for growth failure, significant findings included
height 3.6 SD below the mean value for age (Fig. 2C),
posterior alopecia below the occipital protuberance, penis
4 cm in length, testes 2.5 x 1.5 bilaterally, and upper-to-
lower segment ratio of 1.03 (Tables l and II). Urinary 17-
ketosteroids were 0.9 rag/24 hrs and urinary 17-hydroxy-
corticosteroids were 1.7 m g / 2 4 hrs.
Case 4 had been well until 8 years of age when she
developed right ear pain and right facial palsy. A diag-
nosis of rhabdomyosarcoma of the right middle ear was
made. Over a period of one year she received vincristine,
actinomycin D, cyclophosphamide, and 5,200 Cobalt-60
irradiation to the tumor area (fields: 8 x 7 cm over the
Volume 89 Delayed onset of hypopituitarism 55 7
Number 4

200- 15~
SD ~r
///'/,-- 1 SD
160- ..4/; so
S- /Y 10-
cm 120- Height
/;U..2r 4 " Increment
/,:,r (cm/year)
/(,7," 5-
80-

40
' RADIATION

o
??,,ON ~ lb 1~ 1~,
,!
~ ~ ~ lb 12 14 16 1'8
AGE .(years) Age (years)
Fig. 2C. Linear growth (left) and growth velocity (right) for Case 3. See legend of Fig. 2A for explanation of
graphs.

200- 15-

160- -- 1 SD
J.-'" .-"~--21/2 SD
10-
Height
cm 120- Increment
('cm/year)
2; 't 5-
80- ////~ RADIATION
, ,- ,,,/,,
'~ / \ /\

40 , , RADIATION ; ,
'2 4 ~) 8 10 ll2 1~l 1()118 0 2 4 6 8 10 12 14 16 18
Age (years) Age (years)
Fig. 2D. Linear growth (left) and growth velocity (right) for Case 4. See legend of Fig. 2A for explanation of
graphs.

external auditory canal) (Fig. 1). At about 12 years of age,
a decrease in growth was noted (Fig. 2D). Growth appears
to have slowed by 9 years. At 14 3/12 years, she was
evaluated for short stature, at which time height was 3.4
SD below the mean value for age. There was no breast
development or pubic hair, and the right facial palsy
persisted (Tables I and II).
DISCUSSION
Each patient showed both clinical and laboratory
evidence of hypothalamic-pituitary dysfunction related to
irradiation. Because of the location of the original tumor
and the nature of the operation performed, neither the
underlying pathology nor surgical intervention adequate-
ly accounts for the hypothalamic-pituitary deficiency.
Although Case 3 had evidence of increased intracranial
pressure, the transitory nature of this abnormality makes
it unlikely that intracranial hypertension alone cvuld
account for the growth hormone deficiency in this patient.
The earliest clinical finding in each patient was a decrease
in the rate of growth.
In evaluating children who have had irradiation to the
central nervous system, assessment of growth is critical. In
our patients, short stature was not noticed until several
years after irradiation.
In retrospect, a decrease in growth rate could have been
558 Richards et aL
discerned earlier by careful evaluation of sequential
growth rates. An insidious diminution of growth rate one
or more years after irradiation should be viewed as a sign
of possible growth hormone deficiency. Patients also
should be studied carefully for evidence of other hypo-
physiotropic-pituitary deficiencies.
Case 4 had a low plasma thyroxine and basal TSH and
a normal pituitary TSH reserve by TR~ testing. The
normal evaluation of plasma TSH evoked by TRF
suggests that the patient had tertiary or hypothalamic
hypothyroidism and the hypothalamus rather than the
pituitary was the main site of injury. In addition, she had a
subnormal increase in plasma cortisol following insulin-
induced hypoglycemia (Table II), indicating impaired
ACTH reserve. Her plasma gonadotropin roeasurements
after LRF did not increase to the levels expected in a 14-
year-otd girl, which we interpreted as evidence of dimin-
ished readily releasable gonadotropin reserve for her
chronologic and bone age.
Delayed onset of hormonal deficiencies rarely has been
reported as a complication of irradiation; however, the
true prevalence of postirradiation hypothalamic-pituitary
deficiency is probably much higher than published
reports indicate. All four patients Were evaluated for short
stature, and each had a history of irradiation to extrahy-
pothalamic-pituitary neoplasms. Growth hormone defi-
ciency was documented in all; one also had evidence of
diminished reserve of other hypothalamic hypophysio-
tropic hormones. In each instance, the hypothalamic and
pituitary were within the treatment field and received a
dose of radiation that was considered to be within the safe
tolerance limit. Irradiation and not the underlying
disease, however, seemed to be the cause of the later onset
of hypothalamic-pituitary hormone deficiencies.
Tan and Kunaratnam~ described a 23-year-old woman
who had irradiation for nasopharyngeal carcinoma at age
12, and clinical evidence of growth hormone and gonad-
otropin deficiency. Larkins and Martin ~ reported two
patients with hypopituitarism after irradiation for carci-
noma of the nasopharynx and maxillary sinus, respective-
ly; both patients had evidence of hypothyroidism, hypo-
gonadism, and cortisol deficiency. One patient had docu-
mented growth hormone deficiency and there was
evidence for hypothalamic rather than pituitary damage
in one: he had an elevation of plasma TSH after intrave-
nous T R F and an increase in plasma cortisol values in
response to vasopressin but not to hypoglycemia. These
findings are similar to those of our Case 4. Fuks and
Glatstein 2 discuss a boy with growth hormone deficiency~
documented eight years after irradiation for rhabdomyo-
sarcoma of the nasopharynx. Recently, Shalet and
colleagues 3 noted impaired growth hormone responses to
The Journal of' Pediatrics
October 1976
provocative stimuli in 10 children who had surgery,
irradiatign, and chemotherapy for intracranial tumors
that did not involve the hypothalamic or pituitary
area.
The prevalence of growth hormone deficiency after
hypothalamic-pituitary irradiation may be greater than
published reports indicate. In adults, growth hormone
deficiency may have no obvious clinical manifestations;
thus provocative testing is required to determine the true
incidence of this complication. Few patients have been
evaluated prior to irradiation of the head to detect
hypothalamic-pituitary hormonal deficiencies caused by
the original disease process, or periodically after irradia-
tion. Advances in radioimmunoassay techniques and the
availability of synthetic hypothalamic releasing factors for
assessing the secretory reserve of pituitary hormones now
permit a more accurate assessment of these deficiencies.
The long-term effects of external irradiation to the
hypothalamic-pituitary axis are unknown. Several au-
thors 1~-1"have concluded that doses of 3,000 to 6,000 rads
to this area are safe and without significant clinical
sequelae in children; only a few cases of hypopituitarism
have been reported following these doses, including one
of our patients previously mentioned. 17 The true risk of
pituitary hypofunction following external irradiation,
especially in the child can be obtained only by prospective
study before and after radiotherapy to the central nervous
system. The possibility of other subtle neurologic dysfunc-
tion, such as disabilities of learning, should also be
considered in the long-term care of children who have
received central nervous system irradiation. In addition,
primary hypothyroidism 2 may result from irradiation
when the thyroid is included in the treatment field.
We recommend that children should have the pituitary
gland and hypothalamus shielded from irradiation, if
such shielding does not compromise treatment, and that
careful assessment of growth and hypothalamic-pituitary
function and tests be done before and especially at annual
intervals after irradiation of the head. In view of the latent
period between treatment and the onset of clinical mani-
festations, the physician must be aware of the possibility
of progressive loss of pituitary function.
ADDENDUM
Since this manuscript was submitted, an additional four
patients have been studied. The results are summarized in
Table A.
In addition, pituitary and/or hypothalamic dysfunction
was found in 14 of 15 adult patients studied at least eight
years after irradiation for various tumors of the head and
neck (Samaan NA, and Bakdash MM: Ann Intern Med
83:771, 1975).
Volume 89 Delayed onset o f hypopituitarism 559
Number 4

T a b l e A. Additional patients with post-irradiation h y p o p i t u i t a r i s m

Growth
irradiation Evaluation Onset of GH Cortisol
diminished after Response response Response
At At growth insulin, to TRF to to L R F
age Ht Dose age Ht approximate arginine, I hypo-
Patient Sex Diagnosis (yr) (SD) (rad) (yr) (SD) age L-dopa PRL I TSH glycemia LH FSH

G.C. M Medulloblastoma 7 -3.5 4,250 11-2/12 -4.8 9 + N ~* N N N

G.B. M Aneurysmal bone 9-8/12 + 1 3,858 10-11/12 Mean 10-1/2 + N N N N N
cyst of
sphenoid
G.P. F Esthesioneuroblas- 13-4/12--1 5,730 17-7/12 --1.5 '[ N N N N N
toma of
nasopharynx
J.C. F Medulloblastoma 4 -2.8 4,500 8-9/12 --4.7 7 ~ N N N N N

*Baseline TSH of 10/~U/mlwith peak level of 123, consistent with compensated primary hypothyroidism. Plasma T4 6.4/~g/dl.

We are indebted to Dr. O. C. Green for clinical and laboratory
data for Case 3.
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1. Tan BC, and Kunaratnam N: Hypopituitary dwarfism
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2. Fuks Z, and Glatstein E: Long-term effects of external
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3. Shalet SM, Beardwell CG, Morris-Jones PH, and Pearson
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4. Larkins RG, and Martin FIR: Hypopituitarism after extra-
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