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European Journal of Endocrinology (2017) 157 265–270 ISSN 0804-4643

CLINICAL STUDY

Reduced epinephrine reserve in response to insulin-induced


hypoglycemia in patients with pituitary adenoma
Shinya Morita1, Michio Otsuki1, Maki Izumi1, Nobuyuki Asanuma1, Shuichi Izumoto2, Youichi Saitoh2,
Toshiki Yoshimine2 and Soji Kasayama1
Department of 1Medicine and 2Neurosurgery, Osaka University Graduate School of Medicine (C-4), 2-2 Yamada-oka, Suita, Osaka 565-0871,
Japan (Correspondence should be addressed to S Kasayama; Email: [email protected])

Abstract
Objective: Hypoglycemia induces rapid secretion of counterregulatory hormones such as
catecholamine, glucagon, cortisol, and GH. Insulin-induced hypoglycemia is used for evaluating
GH–IGF-I and ACTH– adrenal axes in patients with pituitary disorders. The aim of this study was to
determine whether the response of catecholamine secretion to hypoglycemia is disrupted in patients
with pituitary adenoma. Methods: The study population comprised 23 patients with pituitary
adenoma (non-functioning adenoma or prolactinoma). An insulin tolerance test was performed and
serum catecholamines as well as plasma GH and serum cortisol were measured.
Results: The study patients showed diminished response of plasma epinephrine to insulin-induced
hypoglycemia. With the cutoff level of peak epinephrine for defining severe impairment set at 400
pg/ml, more patients with secondary adrenal insufficiency showed severe impairment of the
epinephrine response than did those without it. Peak epinephrine levels to insulin-induced
hypoglycemia were significantly correlated with peak cortisol levels. In patients with secondary
hypothyroidism, secondary hypogonadism, GH deficiency, or diabetes insipidus, the prevalence of
severe impairment of the epinephrine response was similar to that in patients without these
deficiencies.
Conclusions: Impaired epinephrine secretion in response to insulin-induced hypoglycemia was
frequently observed in patients with pituitary adenoma. This disorder was especially severe in
patients with secondary adrenal insufficiency.

European Journal of Endocrinology 157 265–270

Introduction loss of the counterregulatory response to hypoglycemia


as well as pituitary insufficiency and central diabetes
Glucose counterregulatory mechanisms in response to insipidus (14). In addition, pediatric and adult patients
hypoglycemia consist of rapid secretion of adreno- with craniopharyngioma have been shown to have a
corticotropin (ACTH), growth hormone (GH), defect in sympathoadrenal counterregulation (15, 16).
glucagon, epinephrine, and norepinephrine (1, 2). In However, it is not known whether the counterregulatory
patients with type 1 diabetes mellitus, insulin treatment response of catecholamines to hypoglycemia is
increases the risk of severe hypoglycemia (3). In disrupted in patients with pituitary adenomas.
addition, defective glucose counterregulation is Therefore, we studied the responses of catecholamine
sometimes associated with diabetic patients, and secretion in response to insulin-induced acute
becomes a cause for hypoglycemia unawareness (4), hypoglycemia in patients with pituitary adenoma, who
while single or recurrent episodes of hypoglycemia had a variety of hypothalamic–pituitary hormone
have been shown to impair sympatho- adrenal disorders.
responses to a subsequent episode of hypogly- cemia
(5, 6). Moreover, patients with insulinoma often also
have a lowered glycemic threshold for the activation
of glucose counterregulation (7). Patients and methods
The brainventromedial hypothalamus (VMH) has
been shown to sense hypoglycemia and trigger the Patients
release of counterregulatory hormones (8–12).
The study population consisted of 23 patients with
Corticotropin- releasing hormone (CRH) acting via diagnosed pituitary adenoma. Among 90 such patients
CRH receptor 1 has been found to play an important visiting Osaka University Hospital between December
role in the sympathoa- drenal downregulation in a 2003 and January 2007, the study patients were
rodent model of antecedent hypoglycemia (13). It has randomly selected after exclusion of patients with
further been reported that a patient with hypothalamic ACTH- or GH-producing adenoma. Seven patients
sarcoidosis suffered complete

q 2007 Society of the European Journal of Endocrinology DOI: 10.1530/EJE-07-


0176 Online version via www.eje-
online.org
266 S Morita and EUROPEAN JOURNAL OF ENDOCRINOLOGY (2017) 157
others
were males and sixteen females, their mean age at the 0.05 unit/kg body weight of insulin was injected to
time of this study was 55 years (range, 20–76 years), induce hypoglycemia. During the endocrine tests, the
and their body mass index was 24.3G2.9 kg/m 2. patients were keeping spine position.
Eighteen patients had clinically non-functioning ade- Secondary adrenal insufficiency was diagnosed if
nomas and five patients had prolactinomas. The the peak serum cortisol response was !200 mg/l
diagnosis of these tumors was made by enhanced during the insulin tolerance test (ITT) (17, 18) and if
magnetic resonance imaging and was confirmed by early morning (0800 h) serum cortisol levels were !
transsphenoidal surgery or craniotomy in 21 of the 80 mg/l and 24-h urinary-free cortisol levels were
patients. Table 1 shows the clinical characteristics of low (!30 mg/24 h). Secondary hypothyroidism was
the study population. All patients gave their informed indicated by low free L-thyroxine (T4) concentrations
consent, and the investigation was performed in (!8 ng/l) with normal or low thyrotropin (TSH)
accordance with the principles of the Declaration of levels (1, 2). Secondary hypogonadism was identified
Helsinki as revised in 2000. in premenopausal women by menstrual disturbances,
low estradiol levels (!20 pg/ ml) with normal or low
Endocrine evaluation follicle-stimulating hormone (FSH) and luteinizing
hormone (LH) levels, and in postmenopausal women
All patients were hospitalized. Endocrine evaluation by relatively low FSH and LH levels. In men,
tests were performed between 0800 and 1000 h. All secondary hypogonadism was indicated by low
medi- cations were allowed to be taken after the testosterone levels (!3 mg/l) with low or normal FSH
endocrine evaluation tests ended. After a 15 min rest, and LH levels (17, 18). A diagnosis of GH deficiency
regular insulin (0.1 unit/kg body weight) was was based on a peak GH response of !5 mg/l at ITT
administered intravenously in a single injection. Blood (17, 18), and a diagnosis of diabetes insipidus on the
samples were obtained for measurements of pituitary presence of a markedly large dilute urine volume
hormones, cortisol, epinephrine, and norepinephrine at (O2.5–3 l per 24 h) with low urine osmolality (!300
the time of injection, and 15, 30, 60, 90, and 120 min mmol/kg) (17, 18). Patients who had been diagnosed
after the injection. When hypoglycemia (blood with secondary adrenal insufficiency, secondary
glucose levels hypothyroidism, and/or diabetes insipidus had been
!40 mg/dl or half of basal levels) was not receiving replacement therapy with appropriate doses
obtained within 30 min after the insulin injection, an of hydrocortisone, T4, and/or desmopressin. No patient
additional with GH deficiency had

Table 1 Type and size of pituitary adenoma, defective pituitary hormones, replaced hormones therapy, and previous surgery in the study
population.

Duration of
Patient Hormone Size of tumor Defective pituitary Replaced replacement Previous
no Age/sex produced (mm) hormone(s) hormone(s) therapy surgery
1 21/M NF 22 ACTH, GH, TSH, H, T4, DDAVP 60 months TSS, craniotomy
LH/FSH, AVP
2 31/F NF 30 None None None
3 50/F NF 23 GH, TSH, LH/FSH, AVP DDAVP 1 month None
4 56/F NF 38 ACTH, GH, TSH, LH/FSH None TSS
5 56/F NF 32 GH, LH/FSH None TSS
6 57/F NF 12 GH None None
7 58/F NF 25 GH, TSH, LH/FSH None None
8 58/F NF 29 GH, TSH, LH/FSH T4 60 months TSS
9 59/F NF 26 ACTH, GH None None
10 62/M NF 25 GH, LH/FSH None None
11 62/M NF 24 GH None None
12 62/F NF 70 GH None Craniotomy
13 65/F NF 13 ACTH, GH, TSH, LH/FSH H, T4 1 month None
14 71/M NF 38 ACTH, GH, TSH H 1 month None
15 72/F NF 32 LH/FSH None TSS
16 74/M NF 18 GH, LH/FSH Tes 12 months TSS
17 75/M NF 28 ACTH, GH, TSH, LH/FSH None None
18 76/F NF 31 GH, TSH, LH/FSH, AVP DDAVP 1 month TSS
19 20/F Prolactin 21 LH/FSH None None
20 30/F Prolactin 13 LH/FSH None None
21 43/F Prolactin 11 LH/FSH None None
22 53/M Prolactin 20 LH/FSH None None
23 62/F Prolactin 23 ACTH, GH, LH/FSH None None

NF, non-functioning; DDAVP, desmopressin; H, hydrocortisone; T 4, L-thyroxine; Tes, testosterone; TSS, transsphenoidal surgery. The size of the tumor is
shown as the maximal diameter.
www.eje-online.org
received GH replacement therapy, and only one male
patient with secondary hypogonadism had received
testosterone replacement.

Hormone assays
All hormones were assayed in the Clinical Laboratory
of Osaka University Hospital. GH, ACTH, free T4, free
tri- iodothyronine, and cortisol were measured by
means of RIA. Prolactin, LH, and FSH were measured
by means of enzyme-immunoassay, TSH by
electrochemilumines- cence immunoassay, epinephrine
and norepinephrine by high performance liquid
chromatography, and plasma glucose with the glucose
oxidase method.

Statistical analysis
Peak epinephrine secretion of patients with different
pituitary hormone disorders was compared using the c2
test. The StatView computer program (Version 5.0 for
Windows; Abacus Concepts, Berkeley, CA, USA) was
used for statistical analyses. P!0.05 was
considered statistically significant.

Results
Figure 1 Epinephrine (top) and norepinephrine (bottom) responses
Subjects to insulin-induced hypoglycemia in 23 patients with pituitary
adenoma. The shaded area represents the meanGS.E.M. values for
Table 1 shows characteristics of the tumors, defective normal subjects (Ref. (19)). To convert the values for epinephrine
pituitary hormones, replaced hormones therapy, and and norepinephrine to nanomoles per liter, multiply by 0.0005458
previous surgery in the study population. The maximal and 0.005910 respectively.
diameter of the tumors ranged from 11 to 70 mm. Out
of the 23 patients, 22 had anterior and/or posterior
controls (150–570 pg/ml) and were within control
pituitary hormones deficiencies; four patients showed
signs of panhypopituitarism, and three of central ranges in the other 18 patients, while secretory
diabetes insipidus. All five patients with prolactinoma responses of plasma norepinephrine were ambiguous.
had hypogonadism. Three patients had been receiving
hydrocortisone at 10 or 20 mg daily after breakfast, Relationship between epinephrine responses at
while three patients had been receiving T 4 at 25 or ITT and defective pituitary hormones of the
75 mg daily after breakfast. No patient had DHEA study patients
replacement therapy. Desmopressin had been adminis-
tered to three patients with central diabetes insipidus. With the cutoff level of peak epinephrine at ITT for
Eight of the study patients had previously received identifying severe impairment set at 400 pg/ml, more
transsphenoidal surgery or craniotomy. There were no patients with secondary adrenal insufficiency showed
patients with prolactinoma who had been treated with severe impairment of the epinephrine response than
dopamine agonist. those without it (Fig. 2 and Table 2). On the other
hand, patients with secondary hypothyroidism, sec-
ondary hypogonadism, GH deficiency, and/or diabetes
Catecholamines responses to insulin-induced insipidus showed a similar prevalence of severe
hypoglycemia
impairment of the epinephrine response as those
Plasma epinephrine and norepinephrine responses to without these abnormalities. Peak epinephrine levels
ITT are shown in Fig. 1. Baseline plasma epinephrine at ITT were significantly correlated with peak cortisol
levels were within control ranges (!170 pg/ml) in all levels (RZ0.506, PZ0.014; Fig. 3). In contrast, there
patients. However, all patients showed a diminished was no correlation of the peak epinephrine levels with
response of plasma epinephrine to insulin-induced the peak GH levels (RZ0.072, PZ0.745) and the
hypoglycemia. Baseline plasma norepinephrine levels lowest plasma glucose levels (RZK0.147, PZ0.503)
were considerably lower in five of the patients than in at ITT.
Figure 2 Peak epinephrine levels during
the insulin tolerance test in 23 patients with
pituitary adenoma. The patients were
divided to subgroups according to pituitary
hormonal deficiencies. To convert the
values for epinephrine to nanomoles per
liter, multiply by 0.0005458.

Discussion adrenomedullary hypofunction was observed in


patients with 21-hydroxylase deficiency (24, 25) and
Insulin-induced acute hypoglycemia is a well-known those with isolated glucocorticoid deficiency (26). In
stimulus for the secretion of GH and ACTH from the these patients, plasma epinephrine concentrations at
pituitary gland (17, 18). This stimulus has therefore baseline and in response to stimuli such as exercise,
been used for the diagnosis of GH deficiency and upright posture and cold pressure, were reduced (24–
secondary adrenal deficiency in patients with suspected 26). Adrenomedullary dysfunction was characterized
hypopituitarism (17, 18). Besides GH and ACTH/ by incomplete formation of the adrenal medulla and a
cortisol, other counterregulatory hormones such as depletion of secretory vesicles in chromaffin cells (24).
epinephrine, norepinephrine, and glucagon, also play Basal and post-exercise plasma epinephrine levels
pivotal roles in recovery from hypoglycemia (1, 2). were also found to be reduced in children with ACTH
Glucose counterregulation deficiency has been found deficiency (27). In our study, peak epinephrine levels
to be associated with diabetes mellitus (3–5), at ITT were correlated with peak cortisol levels, but
insulinoma (7), hypothalamic sarcoidosis (14), not with peak GH levels. These results suggest that
craniopharyngioma secondary adrenal insufficiency could be an important
(15, 16), and psychological stress (20). Deficiencies in
glucose counterregulatory hormones have been shown
Table 2 Prevalence of severe impairment of the epinephrine
to vary, depending on the background disease: response to insulin-induced hypoglycemia.
responses of glucagon and GH were impaired in
diabetic patients
(21), those of GH, cortisol, glucagon, epinephrine, and
norepinephrine in a patient with hypothalamic sarcoi- Peak epinephrine !400 R400
dosis (14), and those of cortisol, epinephrine, and level at ITT (pg/ml) (pg/ml) P
norepinephrine in a patient with psychological stress maintenance of adrenomedullary chromaffin cells and
(20). Of the 23 patients with pituitary adenoma their production of epinephrine (22, 23). In fact,
enrolled in our study, all showed diminished plasma Secondary adrenal insufficiency
epinephrine response to insulin-induced acute (K) 9 (39%) 7 (30%) 0.036
hypoglycemia. Reduction in the epinephrine reserve (C) 7 (30%) 0 (0%)
Secondary hypothyroidism
thus occurred with very high frequency in these (K) 8 (35%) 6 (26%) 0.106
patients. Unfortu- nately, neuroglycopenic symptoms (C) 8 (35%) 1 (4%)
during insulin- induced hypoglycemia were not GH deficiency
accurately recorded in some patients. Thus, in the (K) 3 (13%) 3 (13%) 0.226
present study, we failed to reveal the relationship
between these symptoms and the diminished plasma
epinephrine response.
Glucocorticoids are required for the survival and
(C) 13 (57%) 4 (17%)
Secondary
hypogonadism
(K) 5 (22%) 1 (4%) 0.394
(C) 11 (48%) 6 (26%)
Diabetes insipidus
(K) 13 (57%) 7 (30%) 0.219
(C) 3 (13%) 0 (0%)

ITT, insulin tolerance test.


1-mediated activation and CRH receptor

Figure 3 Correlation of peak epinephrine levels with peak cortisol


levels during the insulin tolerance test in 23 patients with pituitary
adenoma. To convert for epinephrine and cortisol to nanomoles
per liter, multiply by 0.0005458 and 2.759 respectively.

cause of the reduction in epinephrine reserve observed


in our patients with pituitary adenoma. In our study,
seven patients had secondary adrenal insufficiency,
three of whom had been treated with replacement of
hydrocortisone. Diminished epinephrine response was
observed similarly in the patients with secondary
adrenal insufficiency, irrespective of hydrocortisone
replacement. Thus, glucocorticoid replacement therapy
is suggested not to ameliorate the epinephrine response
to insulin-induced hypoglycemia. However, all
patients, only seven of whom had secondary adrenal
insuffi- ciency, showed diminished epinephrine
response to the hypoglycemic stimulus, so it is unlikely
that secondary adrenal insufficiency per se is the direct
cause of the reduction in epinephrine reserve. Prolactin
has been shown to stimulate catecholamine synthesis in
rat hypothalamic cells (28). There were no patients
with prolactin deficiency in our study, suggesting that
prolactin deficiency is not involved in the decreased
epinephrine reserve.
When severe impairment of the epinephrine
response was defined as a peak epinephrine level of !
400 pg/ml, more patients with secondary adrenal
insufficiency showed severe impairment than those
without it. Secondary hypothyroidism, secondary
hypogonadism, GH deficiency, and diabetes
insipidus, on the other hand, were not significantly
associated with prevalence of severe impairment of
the epinephrine response. As the order of
diminishing pituitary function associated with
pituitary compression is GH before the other tropic
hormones, with ACTH and TSH usually being the
last hormones to show functional loss (17), our
results seem to indicate that a spread of deficient
pituitary hormones is associated with the severity of
reduction in the epinephrine reserve. The activation
of glucose counter- regulation mechanisms starts
with the sensing of hypoglycemia by the VMH to
trigger the release of counterregulatory hormones
(8–12). In rat experi- mental models, this
counterregulation was found to be largely
determined by the interaction between CRH receptor
2-mediated suppression in the VMH (29). The 3 White NH, Skor DA, Cryer PE, Levandoski LA, Bier DM &
sum total of these findings may lead the Santiago JV. Identification of type 1 diabetic patients at increased
risk for hypoglycemia during intensive insulin therapy. New
speculation that the balance between CRH England Journal of Medicine 1983 308 485–491.
receptors 1 and 2 is impaired in the VMH of 4 Gerich JE, Mokan M, Veneman T, Korytkowski M & Mitrakou A.
most patients with pituitary adenoma and that the Hypoglycemia unawareness. Endocrine Reviews 1991 12 356–371.
extent of this impairment is more severe in
patients with a wider deficiency of pituitary
hormones. In contrast to plasma epinephrine,
which is derived almost exclusively from the
adrenal medulla, plasma norepinephrine,
predominantly derived from sym- pathetic nerve
endings acting as neurotransmitter, was within
normal ranges at baseline in 18 of the 23 patients
with pituitary adenoma. Norepinephrine
responses to insulin-induced hypoglycemia were
only marginal in these patients. Similar
norepinephrine reserve to that in control subjects
have been found in patients with 21-hydroxylase
deficiency and/or with isolated glucocorticoid
deficiency (24–26). However, increased
norepinephrine secretion has been demon-
strated in patients with Addison’s disease (30)
and in those who had undergone bilateral
adrenalectomy (24), suggesting that some
compensatory increases occur during
sympathetic nerve activity. Similar compen-
sation in basal sympathetic nerve activity may
also
occur in patients with pituitary adenoma.
In this study, we show for the first time that
impaired epinephrine secretion in response to
insulin-induced hypoglycemia is frequently
observed in patients with pituitary adenoma. From
the present study and the previous studies on
patients with hypothalamic sarcoi- dosis or
craniopharyngioma (14–16), defense
mechanisms against hypoglycemia are thought to
be disrupted to various extents in patients with
pituitary or hypothalamic disorders. Defects in the
secretion of GH and ACTH may be involved in
failure to recover rapidly from hypoglycemia in
patients who are deficient in these hormones.
However, reductions in the epinephrine reserve may
lead to defects in the defense against acute
hypoglycemia in patients with pituitary and
hypothalamic disorders, even though they may not
show any pituitary hormone deficiency.
Furthermore, the absence of the sympathoadrenal
symptoms of hypoglycemia may confound a
diagnosis of hypoglycemia.

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