European Journal of Cancer 38 (2002) 1490–1494
`
`www.ejconline.com
`
`A low-dose adrenocorticotropin test reveals impaired adrenal
`function in cancer patients receiving megestrol acetate therapy
`
`I.G. Rona,*,1, V. Soyfera,b,1, D. Goldrayb, M.J. Inbara, Y. Weismanb
`aDepartment of Oncology, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, 6 Weizmann Street, 64239 Tel Aviv, Israel
`bBone Disease Unit, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, 6 Weizmann Street, 64239 Tel Aviv, Israel
`
`Received 1 May 2001; received in revised form 3 January 2002; accepted 23 January 2002
`
`Abstract
`
`Megestrol acetate (MA) has glucocorticoid activity and can induce significant secondary adrenal suppression. We designed this
`study to determine the extent of adrenal insufficiency in cancer patients receiving MA by utilising a sensitive low-dose adreno-
`corticotropin (ACTH) stimulation test. Adrenal function was assessed by a low-dose (0.625 mg) ACTH (1-24) stimulation test in 30
`patients receiving MA for metastatic cancer. 10 of the patients who failed this test underwent a standard (250 mg) test on another
`day. Adrenal function was also evaluated in 15 of the patients by measuring the excretion of free cortisol in 24-h urine samples.
`Peak serum cortisol levels following stimulation with low-dose (0.625 mg) ACTH (1-24) were < 18 mg/dl in 16 of 30 (53%) patients,
`of whom 9 had a basal serum cortisol level of < 5 mg/dl. Five of 16 poor responders to the low-dose test showed normal stimulation
`with the standard (250 mg) ACTH (1-24) test. Thus, adrenal insufficiency would fail to be detected by the standard high dose test in
`these patients. Patients who failed the low-dose ACTH (1-24) test had lower 24-h urinary free cortisol excretion (8.7  10.3 mg/24 h)
`than normal responders (35  12.7 mg/24 h). Impaired adrenal function is common in cancer patients receiving MA. The low-dose
`ACTH (1-24) test is apparently capable of revealing adrenal insufficiency undetected by the standard high-dose ACTH test. Patients
`receiving MA might have inadequate adrenal function during episodes of infection or after withdrawal of MA therapy and this may
`require prompt corticosteroid treatment. # 2002 Published by Elsevier Science Ltd.
`
`Keywords: Megestrol acetate; Adrenal insufficiency; ACTH test; Cortisol; Metastatic cancer
`
`1. Introduction
`
`Megestrol acetate (MA) is a synthetic progestational
`agent that has been used in the treatment of advanced
`breast and endometrial cancer since the mid-1970s [1,2].
`Since MA therapy can induce weight gain, it is also used
`for the management of AIDS-related cachexia [3]. An
`increasing number of reports have suggested that MA
`also has glucocorticosteroid activity. MA displayed
`considerable affinity towards the glucocorticoid receptor
`in various cells, as well as glucocorticoid-like activity
`both in vitro and in vivo [4–6]. The latter studies
`demonstrated that MA therapy may cause suppression
`of plasma adrenocorticotropin (ACTH) and cortisol
`
`* Corresponding author. Tel.: +972-3-697-3494; fax: +972-3-697-
`4828.
`E-mail address: dr-ron@zahav.net.il (I.G. Ron).
`1 Drs Soyfer and Ron contributed equally to this paper.
`
`levels which may lead to clinically significant adrenal
`insufficiency and, in some patients new-onset diabetes
`mellitus. Larger doses, longer durations or both of MA
`therapy may cause Cushingoid symptoms [4–8].
`For over three decades, the intravenous (i.v.) injection
`of a pharmacological dose (250 mg) of ACTH (1-24) has
`been used as a standard test in the initial assessment of
`adrenal function. However, studies in healthy volun-
`teers demonstrated that low doses (0.5–1 mg) of ACTH
`(1–24) are sufficient to stimulate release of cortisol from
`the adrenal gland that will meet the standard criteria for
`a satisfactory ACTH test result [9-13]. Indeed, it has
`been suggested that the low-dose ACTH test could be a
`sensitive method to detect subtle primary or secondary
`adrenal insufficiency that would be masked when the
`standard test is used [11–13].
`Weakness, fatigue, hypotension and vomiting which
`are common in patients with adrenal insufficiency are
`also common in patients with metastatic cancer or with
`AIDS. Furthermore, patients
`receiving MA who
`
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`

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`I.G. Ron et al. / European Journal of Cancer 38 (2002) 1490–1494
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`1491
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`develop asymptomatic adrenal insufficiency might have
`inadequate adrenal function if they become acutely ill.
`We conducted this study in order to delineate the
`extent of asymptomatic adrenal insufficiency in cancer
`patients receiving MA therapy, and to evaluate the
`possibility of its being a more sensitive method than the
`standard one for the detection of impaired adrenal
`function in these patients.
`
`2. Patients and methods
`
`2.1. Patients
`
`30 patients (22 females and 8 males, aged 54–86 years)
`who were receiving MA for metastatic cancer took part
`in this study. Their characteristics are described in
`Table 1. They were evaluated at the oncology outpatient
`service of
`the Tel Aviv Sourasky Medical Center.
`Patients who had been treated with oral corticosteroids
`during the 6 months preceding the study were excluded.
`
`None of our patients had metastatic involvement or
`destruction of the adrenal glands. The study protocol
`was approved by the ethics committee of the Tel Aviv
`Sourasky Medical Center and informed consent was
`obtained from the patients.
`
`2.2. Study protocol
`
`The low-dose ACTH (1–24) test was performed in all
`patients. A vial of 250 mg ACTH (1–24) (Cortrosyn,
`Orgenon International Oss, The Netherlands) was dilu-
`ted in sterile saline solution to a concentration of 0.625
`mg/ml. The solution was used immediately. An indwel-
`ling heparinized i.v. cannula was inserted into the fore-
`arm at 09.30 h. After a resting period of 60 min, 0.625
`mg/1.73 m2 ACTH (1–24) was administered as an i.v.
`bolus injection, and blood samples were obtained at 0,
`20, 30 and 45 min for the measurement of serum cortisol
`concentrations. The low-dose ACTH (1-24) test has
`been established in many laboratories, and its sensitiv-
`ity, specificity, accuracy and reproducibility have been
`
`Table 1
`Patients and tumour characteristics
`
`N
`
`Diagnosis
`
`Age
`(years)
`
`Gender
`
`Dose
`(mg/day)
`
`Duration of
`treatment
`(months)
`
`Response to
`low-dose
`ACTHa
`
`Baseline
`cortisol serum
`levels
`mg/dl
`
`Maximum
`cortisol serum
`levels
`mg/dl
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`26
`27
`28
`29
`30
`
`Ca of unknown origin
`Ca of breast
`Ca of endometrium
`Ca of lung
`Ca of breast
`Ca of unknown origin
`Ca of colon
`Ca of breast
`Ca of endometrium
`Ca of breast
`Ca of breast
`Ca of breast
`Ca of stomach
`Ca of breast
`Ca of stomach
`Ca of pancreas
`Ca of breast
`Ca of rectum
`Ca of breast
`Ca of pancreas
`Ca of breast
`Ca of breast
`Ca of breast
`Ca of breast
`Ca of breast
`Ca of pancreas
`Ca of lung
`Ca of breast
`Ca of breast
`Ca of stomach
`
`86
`67
`65
`76
`54
`55
`62
`62
`67
`63
`53
`81
`73
`61
`66
`54
`60
`84
`64
`70
`72
`65
`58
`76
`54
`81
`73
`61
`57
`72
`
`m
`f
`f
`f
`f
`f
`m
`f
`f
`f
`f
`f
`f
`f
`m
`m
`f
`f
`f
`m
`f
`f
`f
`f
`f
`m
`m
`m
`f
`f
`
`160
`160
`160
`160
`160
`160
`160
`160
`160
`160
`160
`160
`320
`160
`320
`320
`320
`160
`160
`160
`320
`160
`240
`160
`160
`160
`160
`160
`320
`160
`
`3
`48
`12
`> 6
`> 6
`> 6
`> 6
`5
`7
`6
`8
`6
`5
`2
`6
`6
`12
`4
`12
`3
`3
`3
`6
`> 6
`> 6
`8
`3
`2
`6
`3
`
`Ca, cancer.
`a Normal response to low-dose ACTH (+). Abnormal response to low-dose ACTH ().
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`+
`+
`+
`+
`+
`+
`+
`+
`+
`+
`+
`+
`+
`+
`
`5.8
`8.2
`3.9
`6.9
`2.0
`5.0
`1.0
`2.0
`5.0
`2.4
`3.6
`7.0
`0.3
`7.3
`7.4
`0.7
`10.6
`16.1
`5.5
`10.5
`11.7
`17.1
`12.6
`17.8
`12.4
`15.6
`25.4
`22.1
`27.2
`13.9
`
`12.0
`14.8
`11.8
`8.8
`11.0
`11.0
`3.0
`11.0
`7.0
`11.4
`7.5
`15.4
`3.0
`13.2
`13.7
`9.1
`18.5
`19.5
`20.7
`18.6
`20.8
`26.0
`19.1
`27.8
`23.1
`21.9
`31.4
`28.3
`29.4
`23.0
`
`

`
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`
`determined and compared with those of the previous
`gold standard high dose (250 mg) test. These data were
`published by various research groups [10,14], including
`four papers originating in our medical centre [11–13,15].
`These studies demonstrate that, in healthy people, doses
`of ACTH (1–24) of 0.5 to 1.0 mcg are sufficient to
`stimulate the release of cortisol from the adrenal gland
`that will meet the criterion for a satisfactory short
`ACTH test: when the highest serum cortisol recorded
`(peak value) during the test equalled or exceeded 18
`mcg/dl (500 nmol/l). This criterion is commonly advo-
`cated [9], was recently validated, and is the same as that
`used for many years as the high-dose (250 mcg) ACTH
`test.
`10 of the patients who failed to meet this criterion of a
`normal ACTH (1-24) test, underwent a standard (250
`mg) test 1–3 weeks later. Adrenal function was also
`evaluated in 15 patients by measuring the excretion of
`free cortisol in 24-h urine samples.
`
`2.3. Cortisol measurement
`
`Serum- and urinary-free cortisol concentrations were
`measured using
`a
`commercially
`available
`radio-
`immunoassay kit (coat-A-count, Diagnostic Products,
`Los Angeles, CA, USA), with intra-assay coefficients of
`variation of 3.2 and 7.2% for cortisol measurements in
`the serum and urine, respectively, and inter-assay coef-
`ficients of variation of 4.8 and 7.5%, respectively.
`
`2.4. Statistical analysis
`Data are expressed as means  standard deviations
`(S.D.). The results were analysed using an unpaired
`two-tailed Student’s test. Pearson’s correlation coeffi-
`cient and linear regression were used to evaluate the
`relationship between peak serum cortisol after injection
`of ACTH (1-24) and 24-h urinary excretion.
`
`3. Results
`
`3.1. ACTH test
`
`In 16 of 30 patients (53%), peak serum cortisol levels
`following stimulation with low-dose ACTH (1-24)
`(0.625 mg/1.73 m2 were less than 18 mg/dl and, of these,
`11 (37%) also had an incremental rise in cortisol of
`< 7.2 mg/dl ( < 200 nmol/l). Serum cortisol responses at
`20, 30 and 45 min to low-dose ACTH (1-24) were sig-
`nificantly lower in these 16 patients than in 14 patients
`who attained a normal peak cortisol level of > 18 mg/dl.
`Interestingly, treatment with the higher dose (320 mg)
`did not increase the suppression of the hypothalamic–
`pituitary–adrenal axis. Specifically, 14 of 23 patients
`who received 160 mg/day failed the low-dose ACTH
`test compared with 2 of 7 patients who received 320 or
`
`240 mg/day. 9 of these 16 patients had basal serum
`cortisol levels of < 5 mg/dl (138 nmol/l) (Fig. 1). All 14
`patients who responded normally to the low-dose
`ACTH test had basal cortisol levels of > 5 mg/dl.
`10 of the patients who failed to meet the criteria of a
`normal response to the low-dose ACTH (1-24) test
`(peak cortisol concentration < 18 mg/dl) underwent a
`standard 250 mg ACTH (1-24) test 1–3 weeks later: the
`responses were normal in 5 and abnormal in the other 5
`(Fig. 2). Thus,
`it appears that the low-dose ACTH
`(1-24) test is capable of revealing mild adrenal insuffi-
`ciency that would fail to be detected by the standard
`high-dose test.
`
`3.2. Urine free cortisol
`
`There was a positive correlation between the peak
`cortisol response to the low-dose ACTH (1-24) test and
`the urinary cortisol excretion (r=0.68; P < 0.0053)
`
`Fig. 1. Low-dose (0.625 mcg) ACTH (1-24) stimulation test in 30
`cancer patients receiving megestrol acetate (MA) therapy.  normal
`vs. & non-responders.
`
`Fig. 2. Standard (250 mcg) ACTH (1-24) stimulation test in 10
`patients who failed the low-dose ACTH test.  normal vs. & non-
`responders.
`
`

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`I.G. Ron et al. / European Journal of Cancer 38 (2002) 1490–1494
`
`1493
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`(Fig. 3). Furthermore, those patients who failed to pass
`the low-dose ACTH (1-24) test had lower 24-h urinary-
`free cortisol concentrations (8.7  10.3 mg/24 h) than the
`patients who responded normally (35  12.7 mg/24 h)
`(p < 0.001).
`
`4. Discussion
`
`Several recent reports have demonstrated that MA
`therapy in cancer and AIDS patients may cause sup-
`pression of the hypothalamic–pituitary–adrenal axis,
`which results in low-serum ACTH and cortisol levels
`followed by an inadequate or lack of a rise of serum
`control after a rapid corticotropin stimulation test
`[4,5,7]. However, low basal cortisol concentration tests
`and standard high-dose corticotropin stimulation tests
`are not sensitive enough to detect subtle or partial
`adrenal insufficiency in patients on MA therapy. Indeed,
`this study demonstrates that only 9 out of 16 patients
`who failed to pass the low-dose ACTH (1-24) test and
`who had abnormal low 24-h urinary free cortisol excre-
`tion had basal serum cortisol concentrations of < 5 mg/
`dl [16,17]. Furthermore, the standard (250 mg) ACTH
`(1-24) test provides information only about the ability
`of the adrenals to respond to unusual stimuli, but may
`not detect partial adrenal
`insufficiency. We used the
`low-dose (0.625 mg) ACTH (1-24) stimulation test in our
`current study and demonstrated that 5 of 16 of the
`patients on MA therapy who failed to meet the criteria
`of a satisfactory low-dose ACTH (1-24) test had a nor-
`mal response to the standard high dose test. This would
`indicate that the low-dose ACTH (1-24) test is capable
`of revealing mild adrenal insufficiency that would fail to
`be detected by the standard high-dose test. It should be
`noted that metastases to the adrenals may occur in cases
`of breast cancer, but the likelihood that it may cause
`
`Fig. 3. Relationship between the peak serum cortisol concentration
`following low-dose ACTH (1-24) stimulation and 24 h urinary-free
`cortisol. Patients who reached a serum cortisol peak of more than 18
`mg/dl after stimulation with 0.625 mg ACTH (1-24) and * poor
`responders.
`
`adrenal insufficiency is rather remote because the pro-
`cess would have to severely affect both adrenals.
`Although the suppression of the pituitary–adrenal–
`axis appears to be asymptomatic in most patients
`receiving MA, there are several reported cases of clini-
`cally symptomatic adrenal insufficiency [6,7]. Weakness,
`fatigue, hypotension and vomiting, which are common
`complaints and symptoms in patients with adrenal
`insufficiency, are also common in patients with meta-
`static cancer or with AIDS, thus the diagnosis of adre-
`nal insufficiency in patients receiving MA is frequently
`delayed unless there is a high degree of clinical suspicion
`or adrenal function tests are performed. Furthermore,
`patients receiving MA who develop mild asymptomatic
`adrenal
`insufficiency might have inadequate adrenal
`function during episodes of infection and, consequently,
`an increased likelihood of septic death [18]. The clinical
`significance of
`the low-dose ACTH test,
`therefore,
`appears to be early recognition of mild adrenal insuffi-
`ciency that might pose a danger in the presence of even
`mild stress. We conclude that patients taking MA
`should be followed carefully: those who respond poorly
`to low-dose ACTH stimulation during or after the
`withdrawal of MA therapy may require prompt treatment
`with corticosteroids when under stressful conditions.
`
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