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ORIGINAL ARTICLE
Safety and specificity of the growth hormone suppression testin patients with diabetes
Pedro Weslley Rosario • Maria Regina Calsolari
Received: 12 February 2014 / Accepted: 26 April 2014
� Springer Science+Business Media New York 2014
Abstract The purpose of this study was to evaluate the
safety of the oral glucose tolerance test (OGTT) and its
capacity to suppress growth hormone (GH) in diabetic
patients without acromegaly. A total of 135 diabetic patients
submitted to the OGTT for GH suppression were studied.
The following selection criteria were applied: age between
20 and 70 years; body mass index C18.5 and B27 kg/m2;
absence of kidney, liver, or thyroid disease; no use of
estrogens, androgens, corticosteroids, or levothyroxine.
Adequate suppression of GH was defined as a nadir below the
cut-off established for a sample of 200 normoglycemic
subjects (\0.25 lg/L for men, \0.74 lg/L for premeno-
pausal women, and\0.5 lg/L for postmenopausal women).
Acromegaly was diagnosed in five patients. Among the 130
diabetic patients without known pituitary disease or a clinical
suspicion of acromegaly, 95.5 % of men, 94 % of pre-
menopausal women, and 96.6 % of postmenopausal women
presented adequate GH suppression (vs 97.5 % of normo-
glycemic controls). In all patients without acromegaly, the
lowest GH levels (nadir) were achieved after the adminis-
tration of glucose and not during baseline measurement.
None of the patients had acute complications [ketoacidosis,
hyperosmolar state, and symptomatic marked hyperglyce-
mia ([300 mg/dL)] on the day of the test and up to 3 days
thereafter. We demonstrated the safety of the OGTT and its
capacity to suppress GH in diabetic patients without
acromegaly. In addition, we suggest the adoption of a pro-
tocol to prevent possible risks of the OGTT in patients with
diabetes.
Keywords Growth hormone � Suppression test �Diabetes � Acromegaly
Introduction
The oral glucose tolerance test (OGTT) for growth hormone
(GH) suppression continues to be recommended for the
diagnosis of acromegaly, at least in subjects without an
exuberant phenotype and/or only slightly elevated IGF-1,
and for the evaluation of disease activity in patients treated
only by surgery [1]. Many authors do not perform the OGTT
in patients with diabetes because of safety reasons and low
specificity (i.e., the absence of GH suppression should be
common in diabetic patients without acromegaly). This
restriction is even found in some consensuses: (i) ‘‘extreme
caution should be exercised when employing this test in
patients with glucose intolerance’’ [2]; (ii) ‘‘diabetic patients
should not be submitted to the OGTT’’ [3]; (iii) ‘‘OGTT must
not be performed in patients with overt diabetes’’ [4]; (iv)
‘‘apart from an obvious lack of control, in a diabetic who is
only weakly hyperglycemic, OGTT is best avoided’’ [5];
(v) ‘‘glucose loading should be avoided if glucose is higher
than 140 mg/dL since complete GH suppression would be
expected in the presence of hyperglycemia of this magni-
tude’’ [6]; and (vi) ‘‘OGTT is unreliable in diabetes where
loss of normal GH suppression may be seen’’ [7].
Little is known about the safety of the OGTT and its
capacity to suppress GH, measured by sensitive assays, in
diabetic patients without acromegaly [8, 9]. This infor-
mation is important since diabetes is common among
P. W. Rosario (&)
Postgraduation Program, Instituto de Ensino e Pesquisa da Santa
Casa de Belo Horizonte, Rua Domingos Vieira, 590, Santa
Efigenia, Belo Horizonte, MG CEP 30150-240, Brazil
e-mail: [email protected]
P. W. Rosario � M. R. Calsolari
Endocrinology Service, Santa Casa de Belo Horizonte,
Belo Horizonte, MG, Brazil
123
Endocrine
DOI 10.1007/s12020-014-0282-2
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patients with excess GH production. There are studies
reporting the results of the OGTT for diabetic patients in
whom acromegaly was confirmed or for known acrome-
galic patients submitted to different treatment modalities,
as recently reported by Reimondo et al. [10], without
information of specificity (i.e., in patients without acro-
megaly). Even these studies provide no information about
the safety of the OGTT in diabetic patients.
Marked hyperglycemia can interfere not only with GH
concentrations, but also with IGF-1 levels (underestimated)
[3–6]. Therefore, laboratory assessment of acromegaly
(GH and IGF-1) should be performed after reasonable
metabolic compensation.
The objective of the present study was to evaluate the
safety of the OGTT and its capacity to suppress GH in
diabetic patients without acromegaly (specificity).
Patients and methods
A total of 135 diabetic patients (known diagnosis) sub-
mitted to the OGTT for GH suppression due to the fol-
lowing reasons were studied: (i) 41 patients without known
pituitary disease or a clinical suspicion investigated in a
study on acromegaly screening [11] and with elevated IGF-
1; (ii) two patients without a clinical suspicion of acro-
megaly investigated because of pituitary adenoma and
elevated IGF-1; (iii) two patients with a clinical suspicion
of acromegaly; and (iv) 90 patients without known pituitary
disease or a clinical suspicion of GH hypersecretion
selected for the study. The study was approved by the
Ethics Committee of our institution.
Adequate suppression of GH was defined as a nadir below
the cut-off established for a sample of 200 normoglycemic
subjects, corresponding to the 97.5th percentile of the results
[\0.25 lg/L for men (n = 80), \0.74 lg/L for premeno-
pausal women (n = 70), and\0.5 lg/L for postmenopausal
women (n = 50)] [12]. To guarantee the reliability of the
comparison, in addition to the same GH assay, the same
selection criteria were applied [12]: (i) age between 20 and
70 years (excluding pregnant women); (ii) body mass index
(BMI) C18.5 and B27 kg/m2; (iii) absence of kidney, liver,
or thyroid disease (these conditions were ruled out based on
anamnesis and serum measurement of creatinine, alanine
transaminase, aspartate transaminase, alkaline phosphatase,
c-glutamyl-transferase, bilirubins, and TSH); and (iv) no use
of estrogens, androgens, corticosteroids, or levothyroxine.
The protocol for the OGTT shown in Table 1 was
followed in all the patients
GH was measured with a chemiluminescence assay (Im-
mulite, Diagnostic Products Corporation, Los Angeles, CA).
The standard provided by the kit was calibrated against the
World Health Organization (WHO) 2nd International
Standard (IS) 98/574. The results are expressed as lg/L.
Data were presented as median and range. The Fisher’s
exact test or X2 test was used to detect differences in the
proportions between groups. The Spearman correlation test
was used to analyze the correlation of plasma glucose and
HbA1c levels with nadir GH. A P value \ 0.05 was con-
sidered to be statistically significant.
Results
Seventy men and 65 women, ranging in age from 22 to
67 years (median 45 years), with a BMI of 20.2–27 kg/m2
(median 24.8 kg/m2), and duration of diabetes of
2–10 years (median 6 years), were studied. All of the
patients used oral hypoglycemic agents and 54 also used
insulin. HbA1c levels ranged from 6.6 to 9.2 % (median
7.5 %). Plasma glucose levels before the OGTT (fasting)
ranged from 86 to 160 mg/dL (median 120 mg/dL) and
were C126 mg/dL in 60 patients. Acromegaly was diag-
nosed in five patients (Table 2).
Among the 130 diabetic patients without known pituitary
disease or a clinical suspicion of acromegaly, 95.5 % of men
(n = 67), 94 % of premenopausal women (n = 33), and
96.6 % of postmenopausal women (n = 30) presented ade-
quate GH suppression (versus, by definition, 97.5 % of
normoglycemic controls [12]). Nadir GH \ 0.4 lg/L [1, 3,
5–7] was seen in all men (controls and diabetics), in 68.6 %
of normoglycemic women versus 63.6 % of premenopausal
diabetic women, and in 84 % of controls versus 80 % of
postmenopausal diabetic women. All normoglycemic sub-
jects [12], as well as men and postmenopausal women with
Table 1 Protocol for the oral glucose tolerance test
After the patient presented fasting capillary blood glucose
B160 mg/dL for two consecutive days, the test was scheduled
for the next day
Plasma glucose was obtained on the day of the test, at 7:30 am,
after a fast of approximately 10 h. Only if glucose B160 mg/dL
was the test initiated. In the case of patients using insulin, the
dose of slow-acting insulin was administered normally
Time 0: measurement of GH followed by the oral administration
of 75 g anhydrous glucose. Measurement of GH after 30, 60, 90,
and 120 min. The patient remained at rest during the test
After the last collection, capillary blood glucose was measured and
correction with ultra-rapid-acting insulin was performed if
[180 mg/dL. The patient was advised to take his usual diabetes
medication and to measure capillary glucose throughout the day
(before and after meals and at bedtime), correcting with ultra-
rapid-acting insulin if [180 mg/dL
On the day after the test, the patient returned to his usual
medications and orientations
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diabetes, had nadir GH \ 1 lg/L. One of the 33 premeno-
pausal women with diabetes (3 %) had nadir GH [ 1 lg/L
(1.25 lg/L) and mildly elevated IGF-1 [1.3 9 ULN (upper
limit of normal)]. In this patient, acromegaly was excluded
based on the absence of any clinical suspicion and adenoma
by magnetic resonance imaging and because she developed
no symptoms and IGF-1 was 0.95 9 ULN after 1 year.
In all the patients without acromegaly (n = 130), including
patients with glucose levels[126 mg/dL immediately before
the OGTT (n = 60), the lowest GH levels (nadir) were
achieved after the administration of glucose and not during
baseline measurement.
No correlation was observed between plasma glucose or
HbA1c, obtained immediately before the test and nadir
GH.
Following the protocol shown in Table 1, none of the
patients had acute complications [ketoacidosis, hyperos-
molar state, and symptomatic marked hyperglycemia
([300 mg/dL)] on the day of the test and up to 3 days
thereafter. Glucose levels at the end of the test ranged from
122 to 272 mg/dL (median 172 mg/dL) and were
[180 mg/dL (need for correction with ultra-rapid insulin)
in 55 patients (40.7 %).
The characteristics and results of the diabetic patients
without acromegaly are shown in Table 3.
Discussion
Despite the sensitivity and specificity of serum IGF-1 for
the diagnosis of acromegaly and for the definition of dis-
ease activity after therapy, the GH suppression test con-
tinues to be useful and recommended in some situations
[1]. Since many patients with acromegaly have associated
diabetes, determination of the safety and specificity of this
test in diabetic patients, which was the objective of this
study, is important. Although there are other tests for the
diagnosis of acromegaly and/or evaluation of disease
activity, such as TRH [13] and galanin [14], these tests are
only considered when the OGTT cannot be performed,
since normative data and information about the accuracy of
these alternative tests are limited [13].
Few studies have evaluated GH suppression during an
OGTT in diabetic patients (without acromegaly). In addi-
tion, these studies involved a small number of patients,
were conducted before the current requirements for GH
Table 2 Data of the five
patients with acromegaly
ULN upper limit of normal
range, MRI magnetic resonance
imaginga Immunohistochemistry
confirmed GH-positive pituitary
adenoma
Gender Age
(years)
Reason for investigation IGF-1
(9 ULN)
Nadir
GH (lg/L)
MRI Management
Female 50 Participating in a
study on acromegaly
screening
1.8 0.9 Macroadenoma Surgerya
Male 64 Pituitary adenoma 1.6 1.1 Macroadenoma Surgerya
Female 44 Pituitary adenoma 1.5 1.4 Macroadenoma Surgerya
Male 38 Clinical suspicion
of acromegaly
2.5 10.2 Macroadenoma Octreotide
Male 52 Clinical suspicion
of acromegaly
2 8.1 Microadenoma Surgerya
Table 3 Data of the diabetic
patients without acromegaly
BMI body mass index, OGTT
oral glucose tolerance testa Adequate suppression of GH
was defined as a nadir below the
cut-off established for a sample
of normoglycemic subjects,
corresponding to the 97.5th
percentile of the results
Results Men (n = 67) Premenopausal
women (n = 33)
Postmenopausal
women (n = 30)
Age [range (median, years)] 28–67 (43) 26–50 (36) 53–67 (59)
BMI [range (median, kg/m2)] 23.5–27 (25.5) 20.2–26 (24) 22–27 (24.6)
Duration of diabetes [range (median, years)] 2–8 (5) 3–10 (6) 2–10 (6)
HbA1c [range (median, %)] 7–9 (8) 6.7–9.2 (7.6) 6.6–8.5 (7.4)
Plasma glucose before the OGTT
[range (median, mg/dL)]
92–160 (124) 88–160 (120) 86–156 (118)
Plasma glucose before the OGTT [ 126 mg/dL 30 (44.8 %) 15 (45.4 %) 13 (43.3 %)
Nadir GH [range (median, lg/L)] 0.05–0.3 (0.12) 0.06–1.25 (0.3) 0.05–0.68 (0.23)
Nadir GH \ 0.4 lg/L 67 (100 %) 21 (63.6 %) 24 (80 %)
Adequate suppression of GHa 64 (95.5 %) 31 (94 %) 29 (96.6 %)
Glucose levels at the end of the test
[range (median, mg/dL)]
122–272 (168) 125–268 (176) 124–260 (164)
Glucose levels [180 mg/dL at the
end of the test
26 (39 %) 14 (42.4 %) 12 (40 %)
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assays, and did not evaluate the safety of the test [8, 9]. The
results of the present study suggest that the OGTT is able to
adequately suppress GH in diabetic patients without acro-
megaly, at least when the patient is reasonably compen-
sated, without the observation of a significant difference
compared to normoglycemic subjects (high specificity).
Therefore, the lack of GH suppression should be consid-
ered even in diabetic patients. We call attention to the fact
that only one premenopausal woman without acromegaly
had nadir GH [ 1 lg/L and none of the men had a nadir
[0.4 lg/L.
The exact mechanism whereby a glucose overload sup-
presses GH secretion is still unclear, but seems to be related
to an increase in somatostatinergic tone and does not
involve the inhibition of GHRH release [15]. In contrast to
the hypothesis that hyperglycemia itself is able to suppress
GH secretion [6], we observed that even in the 60 patients
with glucose levels [126 mg/dL before the administration
of glucose, GH suppression only occurred after its admin-
istration. In fact, spontaneous secretion of GH seems to be
increased in diabetic patients and has a direct correlation
with HbA1c [16]. In addition, it is well established that GH
suppression occurs even in subjects who do not present
hyperglycemia during the OGTT [12]. Therefore, the rapid
increase in glucose or even other mechanisms associated
with oral glucose overload (e.g., the release of intestinal
hormones) seem to be more important for GH suppression
than hyperglycemia itself. Serial measurement of GH at the
same time as the OGTT, but without administration of
glucose, may show how much of the reduction in GH
concentrations observed during the OGTT would be
attributed to spontaneous secretion of this hormone or to the
suppressive effect of oral glucose [8, 17].
The strengths of the present study are the number of
patients studied, the use of a sensitive GH assay in
accordance with current recommendations, comparison
with a normoglycemic control group, and the adoption of a
protocol designed to minimize possible risks of the OGTT.
In conclusion, we demonstrated the safety of the OGTT
and its capacity to suppress GH in diabetic patients without
acromegaly. In addition, we suggest the adoption of a
protocol (Table 1) to prevent possible risks of the OGTT in
patients with known diabetes.
Disclosure There is no potential conflict of interest relevant to this
article.
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