Pituitary (2008) 11:115–120
DOI 10.1007/s11102-008-0105-7
Growth hormone deficiency in children
Erick J. Richmond Æ Alan D. Rogol
Published online: 19 April 2008
Ó Springer Science+Business Media, LLC 2008
Abstract The foundation for the diagnosis of growth
hormone (GH) deficiency in childhood must be auxology,
that is, the comparison of the child’s growth pattern to that
of established norms for gender and ethnicity. It is only in
those growing considerably more slowly than average that
testing for GHD makes sense. Assessment of laboratory
tests, whether static, for example, the measurement of
growth factors or their binding proteins, or dynamic, for
example, secretagogue-stimulated GH secretion is confir-
matory. One must be cognizant of the assay used to
determine GH, for there may be a 3-fold difference in
the concentration of GH among commercially-available
assays. Controversy still exists concerning the measure-
ment of spontaneous GH release and whether sex-steroid
priming is appropriate in prepubertal children. Imaging
analysis may prove helpful in some children with con-
genital GHD or to detect a space-occupying lesion in the
area of the hypothalamus and pituitary. The final diagnosis
is based on multiple parameters and occasionally on a
E. J. Richmond
Pediatric Endocrinology, National Childreńs Hospital, San Jose,
Costa Rica
e-mail: erichmondp@hnn.sa.cr
E. J. Richmond
School of Medicine, Pediatrics and Pediatric Endocrinology,
University of Costa Rica, San Jose, Costa Rica
A. D. Rogol (&)
Pediatric Endocrinology, University of Virginia, 685 Explorers
Road, Charlottesville, VA 22911-8441, USA
e-mail: adrogol@comcast.net
A. D. Rogol
Riley Hospital, Indiana University School of Medicine,
Indianapolis, IN, USA
therapeutic trial of GH therapy to determine if there is a
significant acceleration of growth velocity.
Keywords Growth hormone
Provocative testing

Growth hormone deficiency
Insulin like growth factors
Introduction
The proper means for establishing a diagnosis of growth
hormone deficiency (GHD) continues to be highly con-
troversial. The foundation for the diagnosis of GHD in
childhood must be auxology, that is, a comparison of the
child’s growth pattern to established norms.
Candidates for the evaluation of the GH-IGF-IGFBP
axis include: (1) severe short stature (height SDS \ -
3SD), (2) severe growth deceleration (height velocity\ -2
SD), (3) less severe short stature (height SDS between -2
and -3 SDS) and growth deceleration (height velocity\-
1 SD), (4) history of brain tumor, cranial irradiation, or
other organic pituitary abnormality and (5) radiologic
evidence of abnormality of the pituitary.
Assessment of pituitary growth hormone (GH) produc-
tion is difficult because GH secretion is pulsatile, with the
consistent surges during stages 3 and 4 of sleep. The reg-
ulation of GH secretion is complex, involves multiple
peptides and neurotransmitters, GHRH and somatostatin
are the most important hypothalamic proteins. Ghrelin, a
peptide that is synthesized in the fundus of the stomach, as
well as in the hypothalamus, heart, lung and adipose tissue,
is an endogenous ligand of the growth hormone secreta-
gogue receptor. Spontaneous GH secretion varies
significantly with gender, age and pubertal status, factors
that should be considered during the evaluation of the GH
axis status.
123
116
Between normal pulses of GH secretion, serum GH
levels are often low, below the limits of sensitivity of most
conventional assays. Thus, measurement of a single serum
GH level is not helpful in diagnosing GHD.
Measurement of growth factor concentrations
The most commonly used screening tests [1, 2] to evaluate
GHD are insulin-like growth factor-1 (IGF-1) and insulin-
like growth factor-binding protein-3 (IGFBP-3) levels.
IGF-1 has limited sensitivity because of significant overlap
with normal values [3]. Low levels of IGF-1 may be found
in normal children, mainly in those less than 5 years of age.
About 50% of low levels of IGF-1 are not associated with
GHD, but with low energy intake and less commonly GH
receptor and post-receptor defects.
Low serum IGF-1 levels with normal GH secretory
dynamics may be indicative of other disorders associated with
growth failure such as: [1] poor nutrition [2] inadequate
spontaneous GH secretion, and [3] psychosocial growth fail-
ure. Serum IGFBP-3 levels are less nutritionally dependant
than IGF-1, and low levels are suggestive of GH deficiency.
The correlation between IGF-axis determinations and
measures of spontaneous GH secretion remains imperfect.
Even in healthy normal children, the correlation between
24-h GH secretion and serum IGF-1 and IGFBP-3 levels is
modest (r = 0.78 and r = 0.62, respectively [4]. Smith and
coworkers reported an 18% discordance between measures
of IGFBP-3 and provocative GH response [5]. Determi-
nation of low levels of IGF-1 and/or IGFBP-3 in a short
child usually warrants a thorough evaluation of the hypo-
thalamic-pituitary function with stimulation tests.
Growth hormone assays
Determination of circulating GH concentrations in serum
plays a key role in the diagnosis of GH deficiency. Methods
Table 1 Growth hormone stimulation tests
Test Dose
Arginine 0.5 g/kg I.V., over 30 min, maximum of 40 g
L-Dopa 125 mg if weight \13.5 kg
250 mg if weight 13.5–31.5 kg
500 mg if weight [31.5 kg
GHRH 1 or 2 mg/kg I.V. infusion over 1 min
Glucagon 0.03 mg/kg, maximum of 1 mg IM/SC
ITT 0.05–0.1 IU/kg I.V. bolus
Clonidine 5 mcg/kg, maximum of 250 mcg
Abbreviation: ITT, insulin tolerance test; GHRH, growth hormone releasing hormone
123
Pituitary (2008) 11:115–120
of measuring GH still lack standardization and the devel-
opment of newer popular assays, including some monoclonal
antibody-based assays, has demonstrated that there is sig-
nificant variability among the results reported by different
laboratories. The GH concentration reported in a specific
patient’s sample mainly depends on the method used by the
laboratory [6]. Some measure only the 22 kD monomeric
GH and others measure multiple isoforms of pituitary GH.
Consideration for the units and reference values given
by the laboratory are of importance when interpreting test
results. There is a recent consensus for GH to be reported in
mass units; in the near future, leading endocrine journals
will only accept for publication manuscripts with GH data
in mass units [7].
Growth hormone stimulation tests
Stimulation tests have often been divided into screening
tests (exercise, fasting, levodopa, and clonidine), which are
characterized by ease of administration, low toxicity, and
low specificity and definitive tests (arginine, insulin and
glucagon). To improve specificity, stimulation tests may be
combined or performed sequentially [8, 9].
Conventionally, a serum GH level of 10 ng/ml indicates
adequate GH response to pharmacological stimulation and
is considered sufficient to exclude the diagnosis of GHD.
At the present time, the generally recognized criterion for
GHD are GH levels to of less than 10 ng/ml, or other,
specific assay dependent limits to two different pharma-
cologic stimulation of GH secretion.
Although stimulation GH testing has been the founda-
tion for the diagnosis of GHD, its use has a number of
limitations, including: testing is nonphysiologic, the defi-
nition of abnormal response is arbitrary, results are age-
dependant, the role of sex steroid priming is not adequately
defined, GH assays are of limited accuracy (see above),
tests have poor reproducibility, tests are expensive,
uncomfortable and carry some risk [10, 11]. Table 1 shows
Timing peak of GH Side effect
30–60 min Late hypoglycemia
30–120 min Nausea, emesis, headache
15–30 min Flushing
2–3 h Late hypoglycemia
30–60 min Severe hypoglycemia
60 min Drowsiness, hypotension
Pituitary (2008) 11:115–120
some of the more commonly used protocols for the
assessment of GH secretion.
A consensus guideline for the diagnosis and treatment of
GH deficiency in childhood and adolescence by the Growth
Hormone Research Society [12] established that there is no
gold standard for the diagnosis of GHD and suggested that
in a child with slow growth, whose history and auxology
are consistent with GHD, testing for GH/IGF-1 deficiency
requires the measurement of IGF-1 and IGFBP-3 levels as
well as GH stimulation testing (after hypothyroidism has
been excluded).
In suspected isolated GHD, two GH stimulation tests are
required. In those with a defined CNS pathologic process,
history of irradiation, multiple pituitary hormone defi-
ciency, or a genetic defect, one GH test will generally
suffice. These recommendations underscore the importance
of good clinical judgment rather than specific tests as the
key to the diagnosis of GHD.
Arginine and combined arginine-L-Dopa test
The arginine stimulant works by inhibiting somatostatin
release and dopamine acts through a-adrenergic mecha-
nisms to stimulate GHRH release, consequently, the
combined test thus stimulates GH secretion by two separate
mechanisms [13–15]. This combined protocol has fewer
false positive results than when either agent is administered
alone [16–18]. This test is commonly used when a second
pharmacological test for GH is necessary. Arginine may be
used as a single GH stimulus in the same way as described
here, but without the addition of L-Dopa.
Prior to the administration of the pharmacological
stimulus, the patient should be fasting after midnight or
following bedtime snack. It is mandatory to have L-Dopa
prepared for administration before admitting the patient for
the test, since the availability of this agent is problematic in
many centers.
After the baseline serum sample is obtained, arginine
HCL (0.5 g/kg to a maximum of 40 g) is administered IV
over a 30-min period. If the combined arginine-L-Dopa
protocol is used, L-Dopa is administered orally immedi-
ately after the baseline serum sample is collected.
Then arginine is administered. The recommended dose
of L-Dopa is as follow: (1) 125 mg for children less than
13.5 kg; (2) 250 mg for children between 13.5 kg and
31.5 kg; and (3) 500 mg for children over 31.5 kg. Blood
samples for GH determination should be taken at 0, 30, 60,
90, and 120 min. [17, 18].
With this protocol the maximum GH peak is expected
60 min after starting the arginine infusion. After L-Dopa
stimulation, GH reaches a peak at approximately 45 min.
Frequent side effects with this protocol are nausea and
117
vomiting. It is recommended that the patient be recumbent
and water be given throughout the test [19–21].
Clonidine stimulation test
Clonidine is an alpha 2-adrenergic agonist that increases
the growth hormone releasing hormone secretion, and
inhibits somatostatin release. This stimulus is one of the
best choices to avoid positive results. Children who fail to
secrete GH in response to stimulation with clonidine, sel-
dom secrete GH in response to any other GH stimuli
[22, 23].
The patient should receive nothing by mouth for at least
four to 6 h prior to the test and is generally off all other
medications. After the baseline blood sample is obtained,
clonidine is administered at a dose of 5 mcg/kg, to a
maximum of 250 mcg. Samples for GH assay should be
obtained at 0, 30, 60 and 90. With this test the maximal GH
secretion is expected in the 60 min sample. The GH peak
usually is greater than peak response to other tests (except
with GHRH stimulation).
Clonidine is an agent used to lower blood pressure;
consequently, blood pressure should be monitored at 0, 30,
60, and 90 min after clonidine administration. In young
children, clonidine frequently causes drowsiness, which
may last for several hours. Patients should have a place to
lie down and may be allowed to sleep throughout the
procedure. Drowsiness may prolong fasting period and
may cause hypoglycemia. Subjects must be encouraged to
eat or drink after the test is finished. Water may be fre-
quently offered to the patient throughout the test [24, 25].
Growth hormone releasing hormone test
The ability of the pituitary to secrete growth hormone can
be assessed directly with administration of GHRH [26–29].
Due to fluctuations in somatostatin secretion, there is great
variability in the GH response. Thus, inhibitors of the
endogenous somatostatin such as pyridostigmine and
arginine have been used to enhance the GH response and to
reduce the intra-and inter-individual variability. If a patient
secretes GH in response to GHRH but not to pharmaco-
logical stimuli that function within the hypothalamus, then
a defect at the hypothalamic level is suggested.
The test should be performed in the morning after an
overnight fast. GHRH at a dose of 1 mcg/kg is infused over
a period of 1 min. The patient may experience some
flushing immediately after the IV infusion. Serum samples
should be obtained at 0, 15, 30, and 60 min. The 90 min
sample is no longer recommended, since the GH peak
occurs within the first hour; most often 15–30 min after the
stimulus. The mean GH peak level in normal children has
123
118
been reported as 28 mcg/l, which is a much higher peak
compared with those observed in other tests [30].
Most individuals with idiopathic GH deficiency have a
defect in hypothalamic regulation of pituitary GH secre-
tion. Hence, most patients secrete GH in response to
GHRH, but do not secrete GH in response to normal
physiological processes. High endogenous or exogenous
levels of somatostatin block the effect of GHRH.
Combined GHRH-arginine test
The combination of these two agents results in a potent
growth hormone release. This test is used as an alternative
to the insulin tolerance test in children and adults [31, 32].
After an overnight fast, GHRH is given IV at a dose of
1 mcg/kg at time 0 and arginine, at a dose of 0.5 g/kg
(maximum of 40 g), IV infusion is given from time 0 min
to 30 min. Serum samples for GH analysis are obtained at
0, 15, 30, 45, 60, 90, and 120 min.
This combination test stimulates GH to a greater extent
than the traditional GHRH test. In normal children, GH
response has been reported to be in the range of 19–
120 mcg/l [30]. This GHRH-arginine combined test is very
informative in children with multiple pituitary deficiencies.
Glucagon test
This test is a very good option for small children and
infants. Glucagon induces GH secretion by stimulating
endogenous insulin secretion to compensate for elevated
serum glucose levels [33, 34]. It is a good substitute for the
insulin tolerance test that may be risky in newborns and
small children.
After an overnight fast, glucagon is administered intra-
muscularly or subcutaneously at a dose of 0.03 mg/kg to a
maximum of 1 mg. Serum samples should be drawn at 0, 1,
2, 2.5 and 3 h after administration of glucagon. The max-
imal GH peak occurs in most patients between 2 and 3 h
after the stimuli. Young children may develop nausea and
vomit during the course of this test.
L-Dopa stimulation test for growth hormone secretion
L-Dopa stimulates GHRH release via an alpha-adrenergic
mechanism and also inhibits GH secretion mediated by
beta-adrenergic receptors, an effect which can be blocked
by propranolol [16, 35]. L-Dopa is no longer available in
the United States. In some centers, the combination of
carbidopa/levodopa is used for GH stimulation, but there
are only few studies with this combined test [19, 36].
After an overnight fast L-Dopa is given orally immedi-
ately after the baseline blood sample is obtained. The dose
is as follows: (1) 125 mg if weight\13.5 kg; (2) 250 mg if
123
Pituitary (2008) 11:115–120
weight 13.5–31.5 kg; and (3) 500 mg if weight [31.5 kg.
Blood samples are obtained at 0, 30, 60, 90, and 120 min
after administration of L-Dopa. In about one-third of chil-
dren, nausea is observed. Less frequently, vomiting,
vertigo, fatigue and headache are reported.
Insulin hypoglycemia test
This test, also called Insulin Tolerance Test (ITT), is
considered the gold standard, but is risky and must be done
under appropriate surveillance [37]. The mechanism of
stimulation is the counter-regulatory response to insulin-
induced hypoglycemia [38, 39]. Patient should be fasting
after midnight. Strict surveillance by an experienced nurse
and/or physician is mandatory. Calibrated glucose monitor
at bedside, an IV line with saline solution and 25 ml
syringes filled with 50%-glucose-solution should be pre-
pared prior to the initiation of the test.
In children over 4 years of age, to start the protocol,
0.1 unit/kg of regular insulin should be administered IV.
For younger children, a dose of 0.05 unit/kg is usually
sufficient. However, if used for infants, the dose must be
one tenth (0.01 unit/kg) and must be administered under
careful observation.
Blood samples for GH analysis should be obtained at 0,
15, 30, 45, 60, and 90 min after the insulin dose. Serum
glucose levels must be evaluated at the bedside at each
time point during the protocol. For the test to be valid, the
blood glucose level must decrease by 50% of the initial
value or to less than 40 mg/dl. However more severe
hypoglycemia must be avoided because it can lead to sei-
zures, coma or death.
Clinical symptoms such as sweating, tremor tachycar-
dia, and nervousness are indicative that adequate
hypoglycemia has occurred and those symptoms usually
abate by the next scheduled blood sample, if the symptoms
progress and the patient shows lethargy, loss of con-
sciousness or seizure; the test is interrupted and terminated
by the immediate IV administration of glucose from the
previously prepared syringes (dose of 1 g/kg). If this
occurs, do not stop collecting serum samples according to
the protocol. Upon completion of the test, a meal high in
carbohydrate is offered to the patient. The patient must be
monitored until serum glucose levels return to normal.
The GH peak occurs approximately 20 min after the
glucose nadir. In some patients the GH peak is delayed.
Thus, a 90 min blood sample is recommended. Children
with GH deficiency frequently have enhanced response to
insulin, thus making them more likely to have an episode
of severe hypoglycemia. The adrenal cortisol reserve can
also be confirmed during this test. If cortisol reserve is
adequate, then, at least one sample will have a cortisol
level over 20 mcg/dl.
Pituitary (2008) 11:115–120
Priming with sex steroids
A considerable proportion of prepubertal children with
slow growth have subnormal GH levels during stimulation,
although GH insufficiency can be excluded by either after
repeated testing or upon retesting at puberty [40]. Since sex
steroids cause the increase in GH secretion during puberty,
it can be assumed that exposing prepubertal children to sex
steroids (priming) facilitates GH release in these patients
and thus makes retesting unnecessary or avoid false clas-
sification. For priming boys, several protocols has been
suggested, one commonly used is the administration of
100 mg depot testosterone between 7 and 10 days before
the actual GH stimulation test, although some studies have
shown that more doses of testosterone improve the quality
of the priming [41]. For girls and boys, some endocrinol-
ogists prime with estradiol or ethinyl-estradiol, one
protocol is as follows: a daily dose of micronized estradiol
(1 or 2 mg), for 3 days, prior to starting the growth hor-
mone stimulation test [42]. Also, only one dose of ethinyl-
estradiol at 40 mcg/m2 2 days before the test, has been
proven adequate to enhance GH secretion [43].
Not all agree that sex-hormone priming is required; for
the concern is the spontaneous GH release in prepubertal
children who do not have endogenous sex steroids.
Summary
The diagnosis of GH deficiency is primarily one of disor-
dered growth as detected by auxology. It is only in those
growing well below average that testing for GH deficiency
makes sense. IGF-1 and IGF-BP3 levels are helpful in most
patients with short stature, but in some circumstances it is
mandatory to perform GH stimulation tests to confirm or
discard GH deficiency. The insulin stimulation test (ITT) is
currently used infrequently because it is risky and must be
performed only under appropriate surveillance. Other
stimulation tests, including arginine and glucagon are used
more frequently by clinicians.
One must not only be concerned with the specific tests
as noted above but by the method of analysis for GH
itself. This can be problematic since there are very few
test-specific cutoffs for many of the commercial and/or
proprietary assays. Thus, the final diagnosis is based on
multiple parameters and occasionally on a clinical trial of
GH therapy in which the outcome of a marked increase in
height velocity is the pharmacodynamic effect of GH that
‘‘proves’’ the putative diagnosis. Imaging studies of the
hypothalamic-pituitary area may be helpful in the evalua-
tion of the severity and prognosis of the GH deficiency
with the position of the neurohypophysis an important
consideration.
119
References
1. Ranke MB, Schweizer R, Lindberg A et al (2004) Insulin-like
growth factors as diagnostic tools in growth hormone deficiency
during childhood and adolescence: the KIGS experience. Horm
Res 62:17–25. doi:10.1159/000080754
2. Jensen RB, Jeppesen KA, Vielwerth S et al (2005) Insulin-like
growth factor I (IGF-I) and IGF-binding protein 3 as diagnostic
markers of growth hormone deficiency in infancy. Horm Res
63:15–21. doi:10.1159/000082456
3. Strasburger CJ, Bidlingmaier M (2005) How robust are labora-
tory measures of growth hormone status? Horm Res 64:1–5. doi:
10.1159/000087745
4. Hasegawa Y, Hasegawa T, Aso T et al (1992) Usefulness and
limitation of measurement of insulin-like growth factor binding
protein-3 (IGFBP-3) for diagnosis of growth hormone deficiency.
Eur J Endocrinol 39:585–591
5. Smith WJ, Underwood LE, Busby WH et al (1993) Use of
insulin-like growth factor-binding protein-2 (IGFBP-2), IGFBP-
3, and IGF-I for assessing growth hormone status in short chil-
dren. J Clin Endocrinol Metab 77:1294–1299. doi:10.1210/jc.
77.5.1294
6. Bidlingmaier M, Strasburger CJ (2007) Growth hormone assays:
current methodologies and their limitations. Pituitary 10:115–
119. doi:10.1007/s11102-007-0030-1
7. Wieringa GE, Trainer PJ (2007) Commentary: harmonizing
growth hormone measurements: learning lessons for the future. J
Clin Endocrinol Metab 92:2874–2875. doi:10.1210/jc.2007-0750
8. Fass B, Lippe BM, Kaplan SA (1979) Relative usefulness of three
growth hormone stimulation screening tests. Am J Dis Child
133:931–933
9. Guyda HJ (2000) Growth hormone testing and the short child. Pe-
diatr Res 48:579–580. doi:10.1203/00006450-200011000-00003
10. Gandrud LM, Wilson DM (2004) Is growth hormone stimulation
testing in children still appropriate? Growth Horm IGF Res
14:185–194. doi:10.1016/j.ghir.2003.11.003
11. Ghigo E, Bellone J, Aimaretti G et al (1996) Reliability of pro-
vocative tests to assess growth hormone secretory status. Study in
472 normally growing children. J Clin Endocrinol Metab
81:3323–3327. doi:10.1210/jc.81.9.3323
12. Growth Hormone Research Society (2000) Consensus guidelines
for the diagnosis and treatment of growth hormone (GH) defi-
ciency in childhood and adolescence: summary statement of the
GH research society. GH research society. J Clin Endocrinol
Metab 85:3990–3993. doi:10.1210/jc.85.11.3990
13. Alba-Roth J, Muller OA, Schopohl J et al (1988) Arginine
stimulates growth hormone secretion by suppressing endogenous
somatostatin secretion. J Clin Endocrinol Metab 67:1186–1189
14. Root AW, Saenz-Rodriguez C, Bongiovanni AM et al (1969) The
effect of arginine infusion on plasma growth hormone and insulin
in children. J Pediatr 74:187–197. doi:10.1016/S0022-3476(69)
80066-1
15. Merimee TJ, Rabinowitz D, Fineberg SE (1969) Arginine-initi-
ated release of human growth hormone. Factors modifying the
response in normal man. N Engl J Med 280:1434–1438
16. Mauras N, Walton P, Nicar M et al (2000) Growth hormone
stimulation testing in both short and normal statured children: use
of an immunofunctional assay. Pediatr Res 48:614–618. doi:
10.1203/00006450-200011000-00010
17. Weldon VV, Gupta SK, Haymond MW et al (1973) The use of
L-DOPA in the diagnosis of hyposomatotropism in children.
J Clin Endocrinol Metab 36:42–46
18. Weldon VV, Gupta SK, Klingensmith et al (1975) Evaluation of
growth hormone release in children using arginine and L-dopa in
123
120
combination. J Pediatr 87:540–544. doi:10.1016/S0022-3476
(75)80816-X
19. Philippi H, Pohlenz J, Grimm W et al (2000) Simultaneous stim-
ulation of growth hormone, adrenocorticotropin and cortisol with
L-dopa/L-carbidopa and propranolol in children of short stature.
Acta Paediatr 89:442–446. doi:10.1080/080352500750028168
20. Collu R, Brun G, Milsant F et al (1978) Reevaluation of levo-
dopa-propranolol as a test of growth hormone reserve in children.
Pediatrics 61:242–244
21. Reiter EO, Martha PM (1990) Pharmacological testing of growth
hormone secretion. Horm Res 33:121–126
22. Lanes R, Hurtado E (1982) Oral clonidine-an effective growth
hormone-releasing agent in prepubertal subjects. J Pediatr
100:710–714. doi:10.1016/S0022-3476(82)80569-6
23. Huang C, Banerjee K, Sochett E et al (2001) Hypoglycemia
associated with clonidine testing for growth hormone deficiency.
J Pediatr 139:323–324. doi:10.1067/mpd.2001.116276
24. Lanes R, Recker B, Fort P (1985) Low-dose oral clonidine. A
simple and reliable growth hormone screening test for children.
Am J Dis Child 139:87–88
25. Fraser NC, Seth J, Brown NS (1983) Clonidine is a better test for
growth hormone deficiency than insulin hypoglycaemia. Arch Dis
Child 58:355–358
26. Takano K, Hizuka N, Asakawa K et al (1984) Plasma growth
hormone (GH) response to GH-releasing factor in normal chil-
dren with short stature and patients with pituitary dwarfism. J
Clin Endocrinol Metab 58:236–241
27. Butenandt O (1989) Diagnostic value of growth hormone-
releasing hormone tests in short children. Acta Paediatr Scand
349:93–99
28. Martha PM, Blizzard RM, McDonald JA et al (1988) A persistent
pattern of varying pituitary responsivity to exogenous growth
hormone (GH)-releasing hormone in GH-deficient children: evi-
dence supporting periodic somatostatin secretion. J Clin
Endocrinol Metab 67:449–454
29. Maghnie M, Salati B, Bianchi S et al (2001) Relationship
between the morphological evaluation of the pituitary and the
growth hormone (GH) response to GH-releasing hormone plus
arginine in children and adults with congenital hypopituitarism. J
Clin Endocrinol Metab 86:1574–1579. doi:10.1210/jc.86.4.1574
30. Ghigo E, Bellone J, Aimaretti G et al (1996) Reliability of pro-
vocative tests to assess growth hormone secretory status. Study in
472 normally growing children. J Clin Endocrinol Metab
81:3323–3327. doi:10.1210/jc.81.9.3323
31. Ham JN, Ginsberg JP, Hendell CD et al (2005) Growth hormone
releasing hormone plus arginine stimulation testing in young
123
Pituitary (2008) 11:115–120
adults treated in childhood with cranio-spinal radiation therapy.
Clin Endocrinol (Oxf) 62:628–632. doi:10.1111/j.1365–2265.
2005.02272.x
32. Maghnie M, Cavigioli F, Tinelli C et al (2002) GHRH plus
arginine in the diagnosis of acquired GH deficiency of childhood-
onset. J Clin Endocrinol Metab 87:2740–2744. doi:
10.1210/jc.87.6.2740
33. Leong KS, Walker AB, Martin I et al (2001) An audit of 500
subcutaneous glucagon stimulation tests to assess growth hor-
mone and ACTH secretion in patients with hypothalamic-
pituitary disease. Clin Endocrinol (Oxf) 54:463–468. doi:
10.1046/j.1365-2265.2001.01169.x
34. Mitchell ML, Sawin CT (1972) Growth hormone response to
glucagon in diabetic and nondiabetic persons. Isr J Med Sci 8:867
35. Collu R, Leboeuf G, Letarte J et al (1975) Stimulation of growth
hormone secretion by levodopa-propranolol in children and
adolescents. Pediatrics 56:262–266
36. Schonberger W, Ziegler R, Brodt B et al (1976) GH secretion
after oral application of L-dopa and L-carbidopa. Eur J Pediatr
122:195–200. doi:10.1007/BF00463737
37. Shah A, Stanhope R, Mathew D (1991) Hazards of pharmaco-
logical tests of growth hormone secretion in childhood. BMJ
304:173–174
38. Kaplan SL, Abrams CA, Bell JJ et al (1968) Growth and growth
hormone. I. Changes in serum level of growth hormone following
hypoglycemia in 134 children with growth retardation. Pediatr
Res 2:43–63. doi:10.1203/00006450-196801000-00005
39. Root AW, Rosenfield RL, Bongiovanni AM et al (1967) The
plasma growth hormone response to insulin-induced hypoglyce-
mia in children with retardation of growth. Pediatrics 39:844–852
40. Gonc EN, Yordam N, Kandemir N et al (2001) Comparison of
stimulated growth hormone levels in primed versus unprimed
provocative tests. Effect of various testosterone doses on growth
hormone levels. Horm Res 56:32–37. doi:10.1159/000048087
41. Couto-Silva AC, Trivin C, Adan L et al (2005) Management of
boys with short stature and delayed puberty. J Pediatr Endocrinol
Metab 18:807–813
42. Martinez AS, Domene HM, Ropelato MG et al (2000) Estrogen
priming effect on growth hormone (GH) provocative test: a useful
tool for the diagnosis of GH deficiency. J Clin Endocrinol Metab
85:4168–4172. doi:10.1210/jc.85.11.4168
43. Marin G, Domene HM, Barnes KM et al (1994) The effects of
estrogen priming and puberty on the growth hormone response to
standardized treadmill exercise and arginine-insulin in normal
girls and boys. J Clin Endocrinol Metab 79:537–541