is there any relationship between imatinib mesylate medication and hypothalamic-pituitary-adrenal...

Is there any relationship between imatinib mesylatemedication and hypothalamic-pituitary-adrenal axisdysfunction?

O. Bilgir,1 L. Kebapcilar,1 F. Bilgir,2 I. Sarı,1 P. Oner,1 B. Karaca,3 I. Alacacioglu4

Introduction

Imatinib mesylate [tyrosine kinase (TK) inhibitor] is

a novel medication, which gives new insights in the

treatment of Abelson proto-oncogene (BCR-ABL)

positive chronic myelogenous leukaemia (CML) (1).

TK is not only present in the product of BCR-ABL

fusion gene protein but also present in the other

essential pathways of the body. One important activ-

ity is present in the hypothalamic-hypophysis-adrenal

(HPA) axis. Janus kinase ⁄ signal transducers and acti-

vators of the transcription (JAK2-STAT) pathway is

essential in the secretion and action of both cortico-

tropin-releasing hormone and pro-opiomelanocortin

(POMC) via processing adrenocorticotropic hor-

mone (ACTH) (2). Furthermore, steroid secretion

needs ACTH ⁄ cyclic adenosine monophosphate

(cAMP) signalling that shows its effect via JAK2-

phosphatidylinositol 3-kinase (PI3K) ⁄ protein kinase

B (Akt), and phosphodiesterase (PDE) 3-cAMP path-

way to regulate P450scc expression (3).

There are many tests to evaluate function of the

HPA axis, including glucagon stimulation test (GST),

and low dose short synacthen test (LDSST) (4–6).

Age, gender and underlying growth hormone defi-

ciency do not effect ACTH and cortisol responses to

GST. is independent of gender, age or underlying

growth hormone deficiency (4). LDSST is another

reliable choice of determining adrenal cortisol reserve

(6).

The aim of the present report was to evaluate

HPA axis in patients treated with imatinib mesylate

because TK enzyme is also widely present in the cor-

tisol secretion pathway. Chronic fatigue is a common

and unexplained side effect of imatinib therapy and

it is interesting to speculate whether there is any

correlation the effect of imatinib mesylate therapy on

the glucocorticoid secretion in CML subjects and it

SUMMARY

Background: Imatinib mesylate [tyrosine kinase (TK) inhibitor] is a novel medica-

tion in the treatment of chronic myelogenous leukaemia (CML). TK is also essential

in hypothalamo-pituitary-adrenal (HPA) axis. Purpose: The aim of this study was

to evaluate HPA axis in patients treated with imatinib. Twenty-five patients were

included in this study. Methods: Glucagon stimulation test (GST) and low-dose

(1 lg) adrenocorticotropin test (LDSST) were used to assess the HPA gland axis.

Results: Seventeen (68%) subjects had impaired peak response when a cortisol

cut-off value is accepted as 500 nmol ⁄ L. Twelve (48%) out of 17 subjects also

failed to show a response to LDSST. Therefore, 12 patients (48%) were defined as

HPA deficient. Only two of these 25 patients had morning serum cortisol

< 200 nmol ⁄ l (7.22 lg ⁄ dl), and failed the GST and ⁄ or LDSST, indicating that the

majority had partial glucocorticoid deficiency. If the cut-off presume for LDSST is

from 500 to 600 nmol ⁄ l, 16 patients (64%) would have failed both the GST and

LDSST. Conclusion: Our results indicate an increased prevalence of subclinical glu-

cocorticoid deficiency in patients receiving imatinib mesylate for CML. Therefore

under stressed conditions, such as intercurrent illness state, overt and untreated

partial glucocorticoid deficiency in CML patients become life threatening.

What’s known• Imatinib mesylate (tyrosine kinase inhibitor) is a

novel medication in the treatment of BCR-ABL

positive chronic myelogenous leukaemia.

• Tyrosine kinase is essential in hypothalamo-

pituitary-adrenal (HPA) axis.

• Chronic fatigue is a common and unexplained

side effect of imatinib therapy.

What’s new• Glucagon stimulation test (GST) and low-dose

(1 lg) short synacthen test (LDSST) assays were

used to evaluate the hypothalamic-pituitary-

adrenal axis in leukaemia patients treated with

the BCR-ABL tyrosine kinase inhibitor imatinib.

• The results obtained suggest impaired hormone

responses in the hypothalamic-adrenal axis.

• Under stressed conditions, such as intercurrent

illness state, overt and partial untreated partial

glucocorticoid deficiency in CML patients may

become life threatening.

1Internal Medicine Department,

Bozyaka Training and Research

Hospital, Izmir, Turkey2Internal Medicine, Seyfi

Demirsoy State Hospital, Izmir,

Turkey3Biochemistry, Bozyaka Training

and Research Hospital, Izmir,

Turkey4Internal Medicine, Ataturk

Training and Research Hospital,

Izmir, Turkey

Correspondence to:

Levent Kebapcilar,

Internal Medicine Department,

Bozyaka Training and Research

Hospital, 123 ⁄ 4 street no: 10

A flat: 4, Izmir, Turkey

Tel.: + 905054482857

Fax: + 902322505050 1391

Email:

[email protected]

Disclosures

No conflicts of interest to

declare.

OR IG INAL PAPER

ª 2009 The AuthorsJournal compilation ª 2009 Blackwell Publishing Ltd Int J Clin Pract, January 2010, 64, 1, 45–50doi: 10.1111/j.1742-1241.2008.01856.x 45

still remains unknown and has not been evaluated to

date.

Subjects and methods

There were 34 CML (BCR-ABL positive) patients

treated with imatinib in our clinic. We contacted

32 of them and invited to the study. Four patients

refused to participate and three patients were dis-

carded because of older age. Twenty-five patients

were eligible for inclusion in the study. This study

was approved by the Institutional Review Board of

Bozyaka Training and Research Hospital, Izmir,

and informed consent was obtained from each

patient.

Exclusion criteriaPatients over 75 or under 15 years of age at the

time of testing, pregnant women, patients with

hypothyroidism, traumatic brain injury and renal

or hepatic insufficiency, patients who had under-

gone surgery, patients who had received central

nervous system irradiation previously, patients on

glucocorticoid therapy, patients undergoing antide-

pressant treatment and patients who were in the

accelerated and blastic phase of CML were

excluded from the study. Twenty-five patients (15

male patients and 10 female patients, mean age,

50.84 ± 13.28 years; range, 29–75 years) who were

receiving imatinib mesylate therapy for CML (ini-

tially BCR-ABL positive subjects) were included in

this study.

Glucagon stimulation test, LDSST and determina-

tion of basal cortisol levels were performed in all

patients, during the morning hours (8–9 am) and in

fasting state. There were at least 2 days interval

between GST and LDSST.

Glucagon stimulation testTwenty-five CML patients underwent GST (1 mg or

1.5 mg i.m. in subjects > 90 kg). Basal serum cortisol

levels were determined before glucagon administra-

tion and after 30, 60, 90, 120, 150, 180, 210 and

240 min of glucagon administration (5).

Low-dose adrenocorticotropin testLow dose of ACTH (1 lg i.v.) was administered and

serum cortisol levels were measured after 30 min, as

previously described (6). Our current policy is to add

1000 lg ACTH to 1000 ml of 0.9% saline. One milli-

litre of it is then used for i.v. injection. Preferably, a

1-ml syringe connected directly to a needle is used to

inject the solution into a vein; this should be carried

out because additional plastic tubing may reduce the

amount of ACTH delivered, as described (7). Our

practice has been to discard the solution at the end of

each day.

Parameters of hypothalamic-pituitary-adrenocortical insufficiency• Patients with basal serum cortisol levels between

100 and 200 nmol ⁄ l (serum cortisol level at 8:00–

9:00 hours; 3.61–7.72 lg ⁄ dl) are considered as ACTH

deficient (8–10).

• According to GST, impaired response is accepted

as a peak cortisol level < 18 lg ⁄ dl (500 nmol ⁄ l)(11). Subnormal cortisol response to LDSST is

defined as a peak cortisol < 18 lg ⁄ dl (500 nmol ⁄ l)(6,11). Subnormal LDSST is also defined as a peak

cortisol < 21.6 lg ⁄ dl (600 nmol ⁄ l) which was shown

HPA axis deficiency more accurately in recently

reports (12,13).

Analytical methodsSerum cortisol concentrations were measured by

chemiluminescent enzyme immunoassay (Immulite,

Diagnostic Products Corp., Los Angeles, CA, USA

with an intra-assay coefficient variation (CV) of

5.7% and an interassay CV of 7.8%. Normal blood

cortisol levels are 138–635 nmol ⁄ l (5–23 lg ⁄ dl) in

our laboratory.

Statistical analysisDescriptive statistics was performed using frequencies

and percentages. The Spearman’s rho correlation was

used to determine relationships between parameters.

The statistical analysis was carried out by using

Statistical Package of Social Science (spss), version

13.0 (SPSS Inc., Chicago, IL, USA). A p-value of

< 0.05 was considered as statistically significant.

Results

Twenty-five patients with CML in chronic phase who

were treated with imatinib enrolled in the study (15

male patients and 10 female patients). The median

ages of the patients were 50.84 ± 13.28 years (range:

29–75 years). The mean disease duration of the

patients was 43.68 ± 28.43 months. The imatinib

treatment duration (time interval between the last

dose and the initiation of imatinib) was 34.36 ±

20.62 months (range: 3–71 months).

Evaluation of hypothalamic-pituitary-adrenocortical axisA Glucagon stimulation test was performed on all

patients and cortisol levels were determined. There

were 17 patients (Table 1; Figure 1; 68%; 10 males,

seven females) with impaired hypothalamo-pituitary-

adrenal (HPA) axis.

46 Does imatinib cause glucocorticoid deficiency?

ª 2009 The AuthorsJournal compilation ª 2009 Blackwell Publishing Ltd Int J Clin Pract, January 2010, 64, 1, 45–50

According to LDSST cut-off 500 (18 lg ⁄ dl)Low dose short synacthen test was subnormal in 12

patients (48%; three males, nine females). Twelve

(48%) patients revealed subclinical glucocorticoid

insufficiency who had impaired GST and LDSST

response (Table 1; Figure 1). There were five subjects

who had subnormal GST and LDSST response. Only

eight patients (Table 1; Figure 1) had normal cortisol

response to GST and LDSST combinations (32%).

According to LDSST cut-off 600 nmol ⁄ l(21.6 lg ⁄ dl)Twenty patients (Table 1; Figure 1) had a serum cor-

tisol response to LDSST < 600 nmol ⁄ l (80%). There

were 16 patients (64%) who had abnormal GST and

LDSST (Table 1; Figure 1). Only four patients had

normal cortisol response to GST and LDSST combi-

nations (16%).

Subclinical partial glucocorticoid deficiencyPartial glucocorticoid deficiency was defined based on

the following laboratory findings: Basal cortisol

‡ 200 nmol ⁄ l and the presence of either impaired

GST (15 subjects; 60%) or LDSST response (10 sub-

jects; 40%) (Table 1). When a cut-off value of LDSST

is accepted as < 600 nmol ⁄ l, 18 out of 25 subjects

(Table 1; 72%) had partial impairment response.

Table 1 The number of subjects with glucocorticoid

insufficiency by using different diagnostic tests

Number of

subjects (%)

Basal cortisol level

Below 200 nmol ⁄ l 2 (8)

Above 200 nmol ⁄ l 23 (92)

Response to GST (cortisol level of 500 nmol ⁄ l)Below 500 nmol ⁄ l 17 (68)

Above 500 nmol ⁄ l 8 (32)

Response to LDSST (cortisol level of 500 nmol ⁄ l)Below 500 nmol ⁄ l 12 (48)

Above 500 nmol ⁄ l 13 (52)

Response to LDSST (cortisol level of 600 nmol ⁄ l)Below 600 nmol ⁄ l 20 (80)

Above 600 nmol ⁄ l 5 (20)

Impaired GST and LDSST

(with a cut off value of 500 nmol ⁄ l)12 (48)


(with a cut off value of 600 nmol ⁄ l)16 (64)


(with a cut off value of 500 nmol ⁄ l)and basal cortisol level of below

200 nmol ⁄ l (overt)

2 (8)

GST, glucagon stimulation test; LDSST, low-dose (1 lg)

adrenocorticotropin test.

40

30

20

10

10 15

#

∗

##

20 25

Peak cortisol response to LDSST (μg/dl)

Pea

k co

rtis

ol r

esp

on

se t

o G

ST

(μg

/dl)

30 3518 21.6

18

Figure 1 Peak serum cortisol response to glucagon stimulation test (GST) vs. 30 min serum cortisol response to low-dose

(1 lg) adrenocorticotropin test (LDSST) in 25 chronic myelogenous leukaemia (CML) patients treated with imatinib

mesylate. Note that ‘#’ indicates LDSST with a cut off value of 18 lg ⁄ dl, ‘##’ with a cut off 21.6 lg ⁄ dl and ‘*’ indicates

GST with a cut off value of 18 lg ⁄ dl

Does imatinib cause glucocorticoid deficiency? 47


Overt glucocorticoid deficiencyOnly two of these 25 patients showed overt glucocor-

ticoid deficiency in our group (Table 1). Overt glu-

cocorticoid deficiency was defined based on the

following laboratory findings: Impaired GST and ⁄ or

LDSST response (with a cut off value of 500 nmol ⁄ l)and basal cortisol level of below 200 nmol ⁄ l.

Correlations

There were no correlations with the cortisol response

and age, gender, imatinib dose and the treatment

duration (p > 0.05). Spearman’s correlation coeffi-

cients between GST and LDSST were r = 0.65;

p £ 0.001 (with a cut off value of 500 nmol ⁄ l) and

r = 0.51; p = 0.009 (with a cut off value of

600 nmol ⁄ l). Spearman’s correlation coefficient

between cut off value of 500 and 600 nmol ⁄ l for

LDSST was r = 0.48; p = 0.015.

Discussion

Our results showed that CML patients who have

received imatinib are at high risk of subclinical ACTH

and cortisol deficiency. We assessed HPA axis by

novel methods such as GST and LDSST. Seventeen of

twenty-five patients with an impaired response to

GST (68%). With the combination of these tests (cut-

off limit for 500 nmol ⁄ l), only eight subjects (32%)

showed normal response. On the other hand, 12

patients (48%) failed both GST and LDSST response

(cut-off 500 nmol ⁄ l; 18 lg ⁄ dl) and found to be clearly

glucocorticoid deficient. But the number of patients

increased to 16 (64%) in LDSST administered subjects

when a cut-off value 600 nmol ⁄ l (21.6 lg ⁄ dl) was

accepted as abnormal. The combination of these tests

[GST and LDSST response (cut-off 600 nmol ⁄ l;21.6 lg ⁄ dl)] also revealed that 64% of the patients

had abnormal cortisol response. There are two previ-

ous reports (12,13), suggesting the cut-off value of

600 nmol ⁄ l for LDSST is more reliable than a cut off

value of 500 nmol ⁄ l. One of these studies reported a

high percent of sensitivity and specificity (100% and

80% respectively) in the reliable determination of

cortisol deficiency (12).

Only two of these 25 patients (8%) showed overt

glucocorticoid deficiency in our group. There was an

increased frequency of partial glucocorticoid defi-

ciency (10 patients, 40%; with a cut-off 500 nmol ⁄ land 18 patients, 72%; with a cut-off 600 nmol ⁄ l for

LDSST and 15 patients, 60%; for GST). It is note-

worthy that patients with partial glucocorticoid defi-

ciency are prone to clinical glucocorticoid deficiency

under stress conditions such as intercurrent illness

(9). Therefore, it is important that imatinib treated

patients need to be screened for glucocorticoid insuf-

ficiency especially during stress conditions.

Chronic myelogenous leukaemia is caused by hae-

matopoietic progenitor cells that possess the Phila-

delphia chromosome, which encodes chromosome

9,22 translocation resulting in the BCR-ABL fusion

protein TK (1). The JAK2 and STAT families of sig-

nal transduction molecules play a critical role in the

pathogenesis of CML (14–16). Tyrosine phosphoryla-

tion of JAK2 by BCR-ABL was inhibited by the Abl

TK inhibitor, in a dose-dependent manner (15). In a

recent report, it was shown that imatinib mesylate

had an inhibitory effect on the cells expressing JAK2,

STAT5 and cKIT proteins (17) other than CML sub-

jects. JAK2 ⁄ STAT pathway is also essential in hypo-

thalamic-hypophysis-adrenal axis. In this pathway,

leukaemia inhibitory factor (LIF) is also essential,

which is secreted by the pituitary cells (18). LIF cyto-

kine binding the common gp130 receptor subunit

and functioning through the activation of the intra-

cellular JAK2 ⁄ STAT pathway, induce POMC synthe-

sis and ACTH release (18–20). The ACTH acts

primarily to promote the production and secretion

of the glucocorticoid cortisol. ACTH ⁄ cAMP signal-

ling showed its effect via JAK2-PI3K ⁄ Akt-PDE3-

cAMP pathway to regulate P450scc expression and

consequential steroid secretion (3). It is important to

report that there are a large number of TK enzymes

in the body, but imatinib is specific for the TK

domain in ABL (the Abelson proto-oncogene), c-kit

and platelet-derived growth receptor. No study has

reported about the effects of imatinib on TK related

to HPA axis.

One may speculate that this observation (high per-

centage of glucocorticoid deficiency) may be a result

of chronic illness. However, in a report, Gallagher

et al. (21) showed that subjects with CML do not

have depressed corticoid production. Furthermore,

they also reported an increased hydrocortisone pro-

duction. Also existing pathways such as tumour

necrosis factor-a, vasoactive intestinal polypeptide

(22,23) other than pituitary ⁄ adrenal axis for the acti-

vation of adrenal cortex were rising in CML patients

(24,25).

One interesting finding of our study is the lack of

correlations between the glucocorticoid deficiency

and the disease and dose duration of imatinib. In

our study, the duration varied considerably among

the patients from 3 to 71 months and glucocorticoid

deficiency appears to occur rapidly and it is persis-

tent in those with imatinib treatment.

LimitationsThere are a number of limitations of our study. One

of them is the limited number of subjects. The other



limitation is the lack of an insulin tolerance test

(ITT) which is the gold standard for assessing the

HPA-axis. ITT was not performed in subjects

because the data regarding ACTH response to hypo-

glycaemia are not suitable for older participants as

mentioned before especially for our CML patients.

However, we performed our study by using glucagon

stimulation test, which is a reliable alternative to ITT

for the diagnosis of glucocorticoid insufficiency

(5,26–29). Moreover, to support our findings, we

also performed LDSST, which is a reliable diagnostic

tool in search of glucocorticoid deficiency (6,30).

The use of LDSST rather than 250 lg cosyntropin

i.v. in the assessment of suspicious adrenocortical

dysfunction gives better results and LDSST is essen-

tially equivalent to insulin-induced hypoglycaemia or

the metyrapone test (31). Maybe the most important

limitation is that a group which did not receive

imatinib mesylate therapy for CML was not enrolled

for the study. Imatinib mesylate was used by a large

number of CML patients and was used as a first-line

treatment (32) to decrease the progression of the dis-

ease and nearly all of BCR-ABL (+) CML patients

were receiving this therapy in our clinic. The current

study, unfortunately, does not have a control group

who were treated with other medications. Control

group might be patients treated with other treat-

ments were not enrolled in the study. Therefore, this

study did not definitively show that the HPA axis is

inhibited by imatinib treatment and because of

aforementioned reasons, our results indicate an

increased prevalence of subclinical glucocorticoid

deficiency in patients receiving imatinib mesylate for

CML. Thus a new study with larger number of

patients and with control groups are needed to con-

firm our results and investigate the effects of imati-

nib on TK related to HPA axis.

Conclusion

Our results indicate an increased prevalence of sub-

clinical glucocorticoid deficiency in patients receiving

imatinib mesylate for CML. It may be useful in

screening these patients for glucocorticoid deficiency

especially under stress conditions.

References

1 Deininger MW, Druker BJ. Specific targeted therapy of chronic

myelogenous leukemia with imatinib mesylate. Pharmacol Rev

2003; 55: 401–23.

2 Ray DW, Ren SG, Melmed S. Leukemia inhibitory factor (LIF)

stimulates proopiomelanocortin (POMC) expression in a cortico-

troph cell line. Role of STAT pathway. J Clin Invest 1996; 97:

1852–9.

3 Hsu HT, Chang YC, Chiu YN, Liu CL, Chang KJ, Guo IC.

Leptin interferes with adrenocorticotropin ⁄ 3¢,5¢-cyclic adenosine

monophosphate (cAMP) signaling, possibly through a Janus kinase

2-phosphatidylinositol 3-kinase ⁄ Akt-phosphodiesterase 3-cAMP

pathway, to down-regulate cholesterol side-chain cleavage cyto-

chrome P450 enzyme in human adrenocortical NCI-H295 cell line.

J Clin Endocrinol Metab 2006; 91: 2761–9.

4 Bottner A, Kratzsch J, Liebermann S et al. Comparison of adrenal

function tests in children – the glucagon stimulation test allows

the simultaneous assessment of adrenal function and growth hor-

mone response in children. J Pediatr Endocrinol Metab 2005; 18:

431–2.

5 Leong KS, Walker AB, Martin I, Wile D, Wilding J, MacFarlane IA.

An audit of 500 subcutaneous glucagon stimulation tests to assess

growth hormone and ACTH secretion in patients with hypotha-

lamic-pituitary disease. Clin Endocrinol (Oxf) 2001; 54: 463–8.

6 Thaler LM, Blevins LS Jr. The low dose (1-lg) adrenocorticotropin

stimulation test in the evaluation of patients with suspected central

adrenal insufficiency. J Clin Endocrinol Metab 1998; 83: 2726–9.

7 Murphy H, Livesey J, Espiner EA, Donald RA. The low dose

ACTH test – a further word of caution. J Clin Endocrinol Metab

1998; 83: 712–3.

8 Watts NB, Tindall GT. Rapid assessment of corticotropin reserve

after pituitary surgery. JAMA 1988; 259: 708–11.

9 Agha A, Liew A, Finucane F et al. Conventional glucocorticoid

replacement overtreats adult hypopituitary patients with partial

ACTH deficiency. Clin Endocrinol (Oxf) 2004; 60: 688–93.

10 Dilckstein G, Spigel D, Arad E, Shechner C. Adrenocorticotropin

stimulation test: effects of basal cortisol level, time of day, and sug-

gested new sensitive low dose test. J Clin Endocrinol Metab 1991;

72: 773–8.

11 Inder WJ, Hunt PJ. Glucocorticoid replacement in pituitary sur-

gery: guidelines for perioperative assessment and management. J

Clin Endocrinol Metab 2002; 87: 2745–50.

12 Abdu TA, Elhadd TA, Neary R, Clayton RN. Comparison of the

low dose short synacthen test (1 lg), the conventional dose short

synacthen test (250 lg), and the insulin tolerance test for assess-

ment of the hypothalamo-pituitary-adrenal axis in patients with

pituitary disease. J Clin Endocrinol Metab 1999; 84: 838–43.

13 Doi SA, Lasheen I, Al-Humood K, Al-Shoumer KA. Relationship

between cortisol increment and basal cortisol: implications for the

low-dose short adrenocorticotropic hormone stimulation test. Clin

Chem 2006; 52: 746–9.

14 Xie S, Lin H, Sun T, Arlinghaus RB. JAK2 is involved in c-Myc

induction by Bcr-Abl. Oncogene 2002; 21: 7137–46.

15 Xie S, Wang Y, Liu J et al. Involvement of JAK2 tyrosine phos-

phorylation in Bcr-Abl transformation. Oncogene 2001; 20: 6188–

95.

16 Klejman A, Schreiner SJ, Nieborowska-Skorska M et al. The Src

family kinase Hck couples BCR ⁄ ABL to STAT5 activation in mye-

loid leukemia cells. EMBO J 2002; 21: 5766–74.

17 Le Tourneau C, Faivre S, Raymond E. New developments in mult-

itargeted therapy for patients with solid tumours. Cancer Treat Rev

2008; 34: 37–48.

18 Akita S, Webster J, Ren SG et al. Human and murine pituitary

expression of leukemia inhibitory factor: novel intrapituitary regu-

lation of adrenocorticotropin synthesis and secretion. J Clin Invest

1995; 95: 1288–98.

19 Auernhammer CJ, Melmed S. Leukemia-inhibitory factor-neuroim-

mune modulator of endocrine function. Endocr Rev 2000; 21: 313–

45.

20 Chesnokova V, Auernhammer CJ, Melmed S. Murine leukemia

inhibitory factor gene disruption attenuates the hypothalamo-pitu-

itary-adrenal axis stress response. Endocrinology 1998; 139: 2209–

16.

21 Gallagher TF, Hellman L, Zumoff B, Miller DG. Steroid hormone

metabolism in chronic myelogenous leukemia. Blood 1965; 25:

743–8.

Does imatinib cause glucocorticoid deficiency? 49


22 Gonzalez-Hernandez JA, Ehrhart-Bornstein M, Spath-Schwalbe E,

Scherbaum WA, Bornstein SR. Human adrenal cells express tumor

necrosis factor-alpha messenger ribonucleic acid: evidence for

paracrine control of adrenal function. J Clin Endocrinol Metab

1996; 81: 807–13.

23 Bornstein SR, Haidan A, Ehrhart-Bornstein M. Cellular communi-

cation in the neuro-adrenocortical axis: role of vasoactive intestinal

polypeptide (VIP). Endocr Res 1996; 22: 819–29.

24 Duncombe AS, Heslop HE, Turner M et al. Tumor necrosis factor

mediates autocrine growth inhibition in a chronic leukemia. J

Immunol 1989; 143: 3828–34.

25 O’Dorisio MS, O’Dorisio TM, Cataland S, Balcerzak SP. Vasoactive

intestinal polypeptide as a biochemical marker for polymorphonu-

clear leukocytes. J Lab Clin Med 1980; 96: 666–72.

26 Spathis GS, Bloom SR, Jeffcoate WJ et al. Subcutaneous glucagon

as a test of the ability of the pituitary to secrete GH and ACTH.

Clin Endocrinol 1974; 3: 175–86.

27 Rao RH, Spathis GS. Intramuscular glucagon as a provocative

stimulus for the assessment of pituitary function: growth hormone

and cortisol responses. Metabolism 1987; 36: 658–63.

28 Orme SM, Price A, Weetman AP, Ross RJ. Comparison of the

diagnostic utility of the simplified and standard i.m. glucagons

stimulation test. Clin Endocrinol 1998; 49: 773–8.

29 Arvat E, Maccagno B, Ramunni J et al. Glucagon is an ACTH

secretagogue as effective as hCRH after intramuscular administra-

tion while it is ineffective when given intravenously in normal sub-

jects. Pituitary 2000; 3: 169–73.

30 Crowley S, Hindmarsh PC, Holownia P, Honour JW, Brook CG.

The use of low doses of ACTH in the investigation of adrenal

function in man. J Endocrinol 1991; 130: 475–9.

31 Tordjman K, Jaffe A, Grazas N, Apter C, Stern N. The role of the low

dose (1 lg) adrenocorticotropin test in the evaluation of patients

with pituitary diseases. J Clin Endocrinol Metab 1995; 80: 1301–5.

32 Kantarjian HM, Cortes JE, O’Brien S et al. Imatinib mesylate ther-

apy in newly diagnosed patients with Philadelphia chromosome-

positive chronic myelogenous leukemia: high incidence of early

complete and major cytogenetic responses. Blood 2003; 101: 97–

100.

Paper received June 2008, accepted July 2008



is there any relationship between imatinib mesylate medication and hypothalamic-pituitary-adrenal...

Documents