Hair Cortisol Measurement in Mitotane-Treated Adrenocortical Cancer Patients
Authors Affiliations
L. Manenschijn1*, M. Quinkler2*, E. F. C. van Rossum1
1 Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
2 Department of Clinical Endocrinology, Charité Campus Mitte, Charité University Medicine Berlin, Berlin, Germany
Key words
hair cortisol
· adrenal insufficiency
glucocorticoid replacement therapy
cortisol
Abstract
▼
The only approved drug for the treatment of adrenocortical cancer (ACC) is mitotane. Mito- tane is adrenolytic and therefore, hydrocorti- sone replacement therapy is necessary. Since mitotane increases cortisol binding globulin (CBG) and induces CYP3A4 activity, high doses of hydrocortisone are thought to be required. Eval- uation of hydrocortisone therapy in mitotane- treated patients has been difficult since there is no good marker to evaluate hydrocortisone therapy. Measurement of cortisol in scalp hair is a novel method that offers the opportunity to measure long-term cortisol levels. Our aim was to evaluate whether hair cortisol measurements could be useful in evaluating recent hydro- cortisone treatment in mitotane-treated ACC patients. Hair cortisol levels were measured in 15 mitotane-treated ACC patients on hydrocor-
tisone substitution and 96 healthy individuals. Cortisol levels were measured in 3 cm hair seg- ments, corresponding to a period of 3 months. Hair cortisol levels were higher in ACC patients compared to healthy individuals (p<0.0001). Seven ACC patients (47%) had hair cortisol levels above the reference range. None of the patients had hair cortisol levels below normal. In contrast to hydrocortisone doses (B=0.03, p=0.93), hair cortisol levels were associated with BMI (B=0.53, p=0.042). There was no correlation between hair cortisol levels and hydrocortisone doses (B=0.41, p=0.13). Almost half of the ACC patients had high hair cortisol levels, suggesting long-term over-substitution of hydrocortisone in some of the patients, whereas none of the patients was under-substituted. Hair cortisol measurements might be useful in long-term monitoring hydro- cortisone treatment in mitotane-treated ACC patients.
received 30.07.2013 accepted 10.02.2014
Bibliography
DOI http://dx.doi.org/ 10.1055/s-0034-1370961 Published online: March 13, 2014 Horm Metab Res 2014; 46: 299-304 @ Georg Thieme Verlag KG Stuttgart . New York ISSN 0018-5043
Correspondence M. Quinkler, MD Clinical Endocrinology Charité Campus Mitte Charité University Medicine Berlin Charitéplatz 1 10117 Berlin Germany Tel .: +49/30/4505 14152
Fax: +49/30/4505 14958 marcus.quinkler@charite.de
Introduction
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Adrenocortical cancer (ACC) is a rare malignancy that occurs in approximately 0.5-2 per million persons per year [1,2]. The only curative treat- ment is radical surgery [3]. However, even after initial curative surgery, 40% of the patients have recurrent disease or distant metastases within 2 years [4]. Adrenolytic therapy with mitotane [1,1-dichloro-2-(o-chlorophenyl)-2-(p-chloroph- enyl)ethane (o’p’-DDD)] is the primary treatment for patients with advanced ACC [3], either as monotherapy or in combination with cytotoxic chemotherapy. Mitotane is the only approved drug for ACC and has been shown to extend dis- ease-free survival [5], although this has been questioned [6-9]. Mitotane is also recommended in an adjuvant setting after R0 resection of the primary tumor and with a high risk of relapse
(Ki67>10%) by an international panel of interna- tional experts [10]. Mitotane is a steroidogenesis inhibitor at different enzymatic steps, which con- centrates in the adrenal glands and is thought to provoke mitochondrial degeneration and destruc- tion of the adrenal cortex [11]. However, the pre- cise mechanisms of action remain still unknown. It is suggested that serum concentrations of mito- tane should exceed 14mg/l to increase the likeli- hood for an antitumoral response, and kept below 20mg/l to avoid side effects [12,13]. However, often this concentration is not achieved, due to the low bioavailability caused by its low absorp- tion rate and its lipophilic nature [14]. The aim of reaching target serum concentrations is also hampered by many side effects of mitotane treat- ment. Up to 80% of the patients have gastrointes- tinal side effects including nausea, vomiting, abdominal discomfort and diarrhoea. About 40% develop neurological symptoms such as dizziness, dysesthesia, sedation, and ataxia [15,16].
*Both authors contributed equally to this work.
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Mitotane affects all adrenocortical zones, therefore it is neces- sary to replace glucocorticoids and sometimes mineralocorti- coids during mitotane treatment. However, mitotane is a strong inducer of hepatic CYP3A4 activity [17,18] and increases corti- sol binding globulin (CBG) [15], resulting in an increased cortisol metabolism and reduced free, active cortisol [19-23]. Therefore, normal hydrocortisone replacement therapy (approximately 20 mg/day) as used in adrenal insufficiency, is not sufficient in ACC patients on mitotane and higher dosages (40-80 mg/day) are necessary [24,25]. The monitoring of hydrocortisone substi- tution under mitotane treatment is difficult. One study sug- gested that free cortisol measurement may offer additional information in the follow-up of ACC patients on mitotane, espe- cially in the subgroup of patients with Cushing’s syndrome [15]. This marker indeed may overcome some of the complications in the interpretation of measured cortisol in serum or in saliva; however, it only reflects acute free cortisol levels of minutes to hours. Therefore, the monitoring of hydrocortisone dose has relied on clinical symptoms until now. However, the clinical symptoms of cortisol deficiency show extensive overlap with side effects of mitotane. Therefore, the differentiation between symptoms of adrenal insufficiency and mitotane-induced side effects is difficult. The value of measurement of cortisol in serum or urine is rather limited, since these methods measure total or unconjugated cortisol (excretion) and do not reflect chronic unbound, free cortisol levels. In addition, these measurements reflect only a short time frame, and serum levels are also influ- enced by the time of intake of hydrocortisone and may be affected by acute stress (e.g., imaging that may detect tumor progression) in case of some residual adrenal function.
In the past few years, a novel method to measure long-term cor- tisol has been developed by extraction of cortisol from scalp hair [26]. This measurement has been well validated by several groups [26-31]. Since scalp hair grows with an average rate of 1 cm per month, a hair segment of 1 cm reflects mean cortisol levels of 1 month. Cortisol measurements in scalp hair have been shown to represent long-term cortisol levels in health and disease [32]. Retrospective timelines of hair cortisol levels cor- responded with clinical course in patients with Cushing’s syn- drome [29,33,34], cyclic Cushing’s syndrome [33], and Addison’s disease [29,35]. In healthy individuals, hair cortisol levels were positively correlated with BMI and waist circumference, sug- gesting that hair cortisol measurements reflect cortisol expo- sure [29,36,37]. Furthermore, hair cortisol levels were elevated in individuals with chronic stress such as unemployment and chronic pain [31,38]. All these studies together show that the measurement of cortisol in hair is a reliable marker of long-term cortisol levels [32].
Our aim was to study whether hair cortisol measurements could be useful in the long-term evaluation of hydrocortisone substi- tution in mitotane treated ACC patients and whether high dose hydrocortisone replacement as commonly used in clinical prac- tice results in normal long-term cortisol levels in these patients.
Patients and Methods
▼
Patients
Patients with histologically confirmed adrenocortical carci- noma, treated with mitotane, who were seen at the endocrine outpatient clinic of the Charité Campus Mitte, Berlin in the
period July-December 2011, were asked to participate in this study. Data on tumor size and ENSAT stage at diagnosis and the current status of disease were collected, together with mitotane serum levels, body mass index (BMI), and hydrocortisone dosage of the period corresponding to the hair sample collection. This study was approved by the local medical ethics committee and all participants gave written informed consent.
Mitotane was given orally, and was started usually with an “intermediate dose regimen”. Briefly, mitotane was adminis- tered at a starting dose of 1.0 g/day and increased in case of good gastrointestinal tolerance every 2 days by 0.5 g until a daily dose of 4.5 g/day was reached. Further adjustment of dosage was per- formed according to blood mitotane concentrations (aim: con- centrations between 14 and 20 mg/l) and tolerability. All patients received the same mitotane formulation (Lysodren, 500 mg tab- lets) that was purchased from Laboratoire HRA Pharma. Patients were followed up every 3 months including physical examina- tion, routine laboratory evaluation, hormonal workup, and monitoring of mitotane concentrations. For measurement of the latter, plasma samples were shipped to Lysosafe Service (HRA Pharma) and plasma levels were determined by Atlanbio Bioa- nalysis (Saint-Nazaire, France).
Healthy individuals
We collected hair samples of 96 healthy individuals (age 18-65 years) with BMI 18.5-24.9 kg/m2 and no abdominal obes- ity. The reference range of hair cortisol was calculated as mean±1.96*SD and was 9.9-75.9 pg cortisol per mg hair. Detailed information of this group of healthy individuals has been previously described [33,36].
Hair collection
Hair samples were collected from the posterior vortex of the scalp. A lock of approximately 100-150 hairs was cut off as close to the scalp as possible. The 3 cm most proximal to the scalp were used in the measurements, which correspond to the 3-month period prior to hair sample collection.
Hair preparation
The hair preparation method has been extensively described in previous reports [26,29]. In brief, a minimum of 10 mg hair was weighed, put in a glass vial and cut into very small pieces. Meth- anol was added to the hairs to extract cortisol during an over- night extraction (16h) in a shaking water bath at 52℃. Afterwards, the methanol was transferred to a clean glass tube and evaporated under a stream of nitrogen until completely dry, after which the samples were resolved in phosphate buffered saline (PBS pH 8.0).
Cortisol measurement
Cortisol was measured in the hair extract with a commercially available ELISA kit (DRG), which was originally developed to measure salivary cortisol. Cross reactivity of the kit’s antibodies with other steroids was reported as follows: corticosterone (29.00%), cortisone (3.00%), 11-deoxycortisol (<1.00%), 17-OH progesterone (<0.50%), other hormones (<0.10%). Intra-assay variation was below 5% and interassay variation was below 8% as stated by the manufacturer. The low end detection limit for this assay is 1.5 nmol/l. Recovery of the assay was tested and described elsewhere [29].
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| ACC patients | Healthy individuals | |
|---|---|---|
| Number | 15 | 96 |
| Number of women, n (%) | 11 (73.3%) | 53 (55.2%) |
| Age (years) - median (range) | 49 (25-82) | 32 (19-61) |
| Body mass index (kg/m2) - median (range) | 26.0 (18.5-29.9) | 22.5 (18.5-24.8) |
| Age at diagnosis (years) - median (range) | 46 (24-74) | |
| ENSAT stage at diagnosis | ||
| Stage 1 - n (%) | 1 (6.7%) | |
| Stage 2 - n (%) | 11 (73.3%) | |
| Stage 3 - n (%) | 2 (13.3%) | |
| Stage 4 - n (%) | 1 (6.7%) | |
| Tumor size at diagnosis (cm) - median (range) | 10.5 (4.5-21.5) | |
| Hormone production at diagnosis | ||
| No, n (%) | 6 (40.0%) | |
| Cortisol, n (%) | 3 (20.0%) | |
| Aldosterone, n (%) | 1 (6.7%) | |
| Androgens (precursors), n (%) | 3 (20.0%) | |
| Multiple hormones, n (%) | 2 (13.3%) | |
| Time since diagnosis (months) - median (range) | 47 (2-187) | |
| Metastasis at hair collection, n (%) | 8 (53.3%) | |
| Therapy at hair collection | ||
| Mitotane monotherapy, n (%) | 12 (80.0%) | |
| Streptozotocin + mitotane, n (%) | 2 (13.3%) | |
| Gemcitabine + capecitabine + mitotane, n (%) | 1 (6.7%) | |
| Serum mitotane levels (mg/l) - median (range) | 11.5 (0.8-18.4) | |
| Daily hydrocortisone intake (mg) - median (range) | 53.3 (0-60) |
Statistical analysis
Statistical tests were performed using SPSS version 17.0 and Graphpad version 5.0. A p-value <0.05 was considered statisti- cally significant. The Mann-Whitney U-test was used to test for statistical significant difference between groups. Associations between hair cortisol levels, hydrocortisone dosage, and BMI were tested using linear regression analysis.
Results
▼ Clinical characteristics of the ACC patients and healthy individu- als are shown in . Table 1. Most patients were in ENSAT stage 2 (73.3%) at the moment of ACC diagnosis. Median time since diagnosis to the moment of hair sample collection was 47 months (range 2-187 months). None of the patients had a clear Cushingoid appearance at diagnosis, but 5 of them had slight cortisol overproduction at the time of diagnosis of ACC. Two patients had solely mild cortisol overproduction and 3 patients had slight overproduction of multiple hormones including corti- sol at the time of diagnosis. At the moment of hair sample collec- tion, none of these patients had remaining cortisol overproduction and hair cortisol levels were not different between patients with and without a history of cortisol produc- ing ACC (p=0.43).
Hair cortisol levels were significantly higher in mitotane treated ACC patients with hydrocortisone substitution (p<0.0001) com- pared to healthy individuals. Seven out of the 15 ACC patients (47%) had hair cortisol levels above the upper limit of normal for healthy individuals (75.9 pg/mg hair), which ranged from 85.4 pg/mg hair to 445.2 pg/mg hair ( Fig. 1). In 3 patients with elevated hair cortisol levels mitotane treatment was only recently started (“intermediate dose regimen”) and the dosage was progressively increased in the 3 months period. In these
· Stable hydrocortisone substitution
A Not stable hydrocortisone substitution
o Mitotane progressively increased
= Mitotane stopped
w Healthy controls
1 000
Hair cortisol (pg/mg hair)
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ACC (n=15)
HC (n=96)
patients increased hydrocortisone replacement therapy was started at the same time as mitotane, to prevent adrenal insuf- ficiency (open circles · Fig. 1, 2). Two patients were not on sta- ble hydrocortisone substitution (closed squares · Fig. 1, 2). One of these patients underwent surgery for recurrent disease with increased hydrocortisone dosage around the period of the sur- gery. The other patient had frequent symptoms of nausea and vomiting, which resulted in multiple short-term hydrocortisone dosage elevations. Two patients (closed circles · Fig. 1, 2) were on stable hydrocortisone substitution and had stable mitotane
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· Stable hydrocortisone substitution
A Not stable hydrocortisone substitution
O Mitotane progressively increased
Mitotane stopped
1 000
Hair cortisol (pg/mg hair)
316
&
100
32
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3
1
0
10
20
30
40
50
60
70
Daily Hydrocortisone (mg)
1 000
Hair cortisol (pg/mg hair)
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BMI (kg/m2)
serum levels. These patients had only mildly elevated cortisol levels. Six of the 8 patients with normal hair cortisol levels were on stable hydrocortisone substitution and had stable mitotane serum levels (closed dots · Fig. 1, 2). The other 2 patients with normal cortisol levels had stopped mitotane treatment before or during the 3 month period corresponding to the hair sample (closed squares · Fig. 1, 2).
Hair cortisol levels did not correlate with the mean hydrocorti- sone daily dosage of the 3 months corresponding with the hair cortisol timeframe (B=0.41, p=0.13) ( Fig. 2). In ACC patients, hair cortisol levels were positively correlated with BMI (B=0.53, p=0.04) (· Fig. 3). There was no correlation between hydrocor- tisone daily dosage and BMI (B =- 0.03, p=0.93). During the hair cortisol timeframe (3 months) no adrenal crisis occurred, which might have required i. v. hydrocortisone application.
Discussion
▼
Monitoring hydrocortisone substitution during mitotane treat- ment is known to be a problem. Nowadays, the hydrocortisone dose is adjusted if patients have symptoms and clinical signs of hypo- or hypercortisolism. A marker to evaluate hydrocortisone substitution in these patients, even retrospectively, would be helpful for the physician. The traditional methods to measure cortisol are not optimal to use in the evaluation of hydrocorti- sone substitution in mitotane treated ACC patients. Serum total cortisol levels cannot be used since mitotane raises CBG [15,23]. Measurement of cortisol excretion in 24-h urine collection might be a potential useful method, but the collection of multi- ple 24-h urine samples may be problematic and difficulties in 24-h urine collections are well reported [39]. In addition, mito- tane induces hepatic CYP3A4, which results in a rapid inactiva- tion of cortisol [22]. Cortisol in saliva or free cortisol in urine might be better; however, they only reflect acute free cortisol levels of minutes to hours. Another method that has been con- sidered as a possible useful marker is the measurement of adrenocorticotropic hormone (ACTH) in serum. However, ACTH is rapidly degraded by plasma proteases, which complicates the interpretation of serum values [40]. Furthermore, patients with cortisol producing ACC, might have persistent suppression of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in sup- pressed ACTH levels. In these cases, suppressed serum ACTH lev- els do not reflect hydrocortisone over-replacement but a long-term suppressed HPA-axis [41].
In our study, we used a novel method to measure cortisol in scalp hair to evaluate the long-term hydrocortisone substitution in mitotane-treated ACC patients. Measurement of cortisol in scalp hair has been shown to reflect long-term cortisol exposure with 1cm of hair corresponding to a period of 1 month [26,29,33,34]. In this study we show that hair cortisol levels are significantly higher in some mitotane-treated ACC patients (47%) on hydrocortisone substitution compared to physiological levels of hair cortisol in controls, suggesting that these patients received too much hydrocortisone in the previous weeks. The positive correlation between hair cortisol and BMI supports the notion that these patients might be over-substituted, since an increase in specifically abdominal fat is a key feature of hyper- cortisolism [42]. However, we did not study other aspects of glu- cocorticoid action, which might be influenced by elevated cortisol levels.
Recently, 2 novel large studies were published [43,44], also showing that hair cortisol is strongly related to BMI, metabolic syndrome, as well as cardiovascular diseases. In previous studies it was already shown that hydrocortisone levels can be reliably measured in hair of patients with Addison’s disease on regular hydrocortisone replacement therapy [29,35].
Importantly, none of the patients had hair cortisol levels below the lower limit of normal, suggesting that no patient was chron- ically undertreated and threatened by adrenal crisis by under- replacement. A problem in the treatment of ACC patients with mitotane is to distinguish between mitotane side effects and cortisol deficiency, since both conditions result in similar symp- toms. The measurement of cortisol in scalp hair may provide useful information regarding the cortisol exposure in the previ- ous weeks in these patients, and might be used by the physician to judge retrospectively whether the patient has been under- or overtreated with hydrocortisone.
Interestingly, we did not find a correlation between daily hydro- cortisone substitution dosage and hair cortisol levels. In con- trast, in patients with primary and secondary adrenal insufficiency it has been shown that hair cortisol levels corre- sponded with daily hydrocortisone dosage [35]. The lack of cor- relation between hair cortisol levels and hydrocortisone substitution in mitotane treated patients can be explained by the CYP3A4 inducing effect of mitotane, resulting in an increased metabolism of hydrocortisone. However, the lack of correlation between hydrocortisone dose and hair cortisol levels might also be caused by the relatively low number of individuals with this rare disease.
The measurement of cortisol in scalp hair has been well vali- dated in the past years and has been shown to be a reliable method to measure long-term cortisol exposure, both in health and disease [26,29,31,33-38]. A very recent study showed that hair cortisol measurement strongly correlated with the meta- bolic syndrome and its components in a large cohort of 1258 subjects [44]. Hair sample collection is easy and noninvasive, and samples can be stored in envelopes and send via mail, which makes it a simple and suitable method to use in patients. How- ever, patients on chemotherapy with EDP (etoposid, doxoru- bicin, and cisplatin) face the problem of chemotherapy-induced hair loss and this novel method cannot be used in these patients. There are several limitations of our study. First, our patient group is small and heterogeneous. However, ACC is a rare disease and therefore it is difficult to obtain large homogeneous groups of patients. Still, there is the need to validate our data in a future larger cohort. Second, although studies using hair cortisol meas- urements are emerging, there are still a lot unknown facts about the use of hair for cortisol measurements. It is not clear how and where cortisol is incorporated in the hairs. In addition, the effects of chronic disease and mitotane treatment on hair growth rate are not known. However, in patients with Cushing’s syn- drome and Addison’s disease, hair cortisol timelines corre- sponded very well to the clinical course when assuming a hair growth rate of 1 cm per month [29,33,34]. This suggests that there is not a major influence of hyper- or hypocortisolism on hair growth rate. A characteristic of hair cortisol measurement is that it provides only retrospective data, however even this might help the physician to find the correct individual dosage of hydro- cortisone.
In conclusion, our study is the first that shows that hair cortisol measurements can be used to retrospectively evaluate hydro- cortisone substitution in mitotane treated ACC patients. We showed that almost half of the patients had hair cortisol above the upper limit of normal, which suggests that they are over- substituted, whereas no patients seemed under-substituted. Furthermore, hair cortisol levels, but not daily hydrocortisone dose, were positively associated with BMI, suggesting that hair cortisol levels may be a better indicator of cortisol exposure in mitotane treated ACC patients than daily hydrocortisone dose. This novel method can contribute significantly in the evaluation of hydrocortisone substitution in ACC patients on mitotane; especially ruling out previous under-replacement and thus giv- ing some clue for adjusting replacement in the future.
Acknowledgements
▼
This study was supported by a grant from the Netherlands Organisation for Scientific Research (NWO grant number
916.96.069). We thank Kathrin Zopf and Christiane Friedrich, both Clinical Endocrinology, Charité Campus Mitte, Berlin, Ger- many, for help with the patients.
Conflicts of Interest
▼
The authors declare that they have no conflicts of interest in the authorship or publication of this contribution.
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