Effects of mitotane on the hypothalamic–pituitary–adrenal axis in patients with adrenocortical carcinoma

Reimondo, Giuseppe; Puglisi, Soraya; Zaggia, Barbara; Basile, Vittoria; Saba, L.; Perotti, Paola; Francia, Silvia De; Volante, Marco; Zatelli, Maria Chiara; Cannavò, Salvatore; Terzolo, Massimo

doi:10.1530/eje-17-0452

Cited by 32 publications

(28 citation statements)

References 28 publications

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“…Reduction of pituitary ACTH secretion by mitotane has been described previously as a potential etiology for HPA axis suppression. Reimondo et al found that mitotane-treated patients with adrenal insufficiency had lower ACTH levels than patients with primary adrenal insufficiency of other etiologies [15]. In our cohort, this finding was also present but not consistent among patients.…”

Section: Discussioncontrasting

confidence: 64%

“…It also reduces adrenal steroidogenesis by inhibiting key mitochondrial enzymes like CYP11B, which reduces the conversion of hormone precursors into active hormones such as cortisol [11][12][13][14]. It was also found that mitotane could potentially interfere with pituitary function by comparing adrenocorticotropic hormone (ACTH) levels between patients treated with mitotane for ACC and patients with primary adrenal insufficiency (autoimmune or post-adrenalectomy) [15]. Basal values and post-CRH stimulation test (100 mcg) both showed a statistically significant decrease in ACTH levels in patients treated with mitotane, which suggests that this drug might have inhibitory effects at diverse levels of the hypothalamic-pituitary-adrenal (HPA) axis.…”

Section: Introductionmentioning

confidence: 99%

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Recovery of Adrenal Insufficiency Is Frequent After Adjuvant Mitotane Therapy in Patients with Adrenocortical Carcinoma

Poirier

Gagnon

Terzolo

et al. 2020

Cancers

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Mitotane is a steroidogenesis inhibitor and adrenolytic drug used for treatment of adrenocortical cancer (ACC). Mitotane therapy causes adrenal insufficiency requiring glucocorticoid replacement in all patients. However, it is unclear whether chronic therapy with mitotane induces complete destruction of zona fasciculata and whether hypothalamic-pituitary-adrenal (HPA) axis can recover after treatment cessation. Our objective was to assess the HPA axis recovery in a cohort of patients after cessation of adjuvant mitotane therapy for ACC. We retrospectively reviewed patient files with stage I-II-III ACC in two referral centers in Canada and Italy. Data on demographics, tumor characteristics, hormonal profile, and HPA axis were collected. Data from 23 patients with pathologically proven ACC treated with adjuvant mitotane for a minimum of two years were analyzed. Eight patients were males and 15 were females and the median age was 41 years old (range 18 to 73). After mitotane cessation, 18/23 (78.3%) patients achieved a complete HPA axis recovery while 3/23 (13.0%) were unable to tolerate glucocorticoid withdrawal despite having normal hormonal test values and 2/23 (8.7%) never achieved recovery. The mean time interval between mitotane cessation and HPA axis recovery was 2.7 years. A high proportion of patients achieved HPA axis recovery following cessation of mitotane adjuvant therapy. However, complete recovery was often delayed up to 2.5 years and regular assessment of the hormonal profile is required.

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Section: Discussioncontrasting

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Recovery of Adrenal Insufficiency Is Frequent After Adjuvant Mitotane Therapy in Patients with Adrenocortical Carcinoma

Poirier

Gagnon

Terzolo

et al. 2020

Cancers

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“…after 2-3 weeks or in case they experience adrenal insufficiency), because impairment of glucocorticoid effectiveness is rarely observed within the first few weeks. Due to the increased clearance and increased cortisol-binding globulin (268,270,271,272) with increasing mitotane plasma levels and based on clinical symptoms, the total hydrocortisone replacement dose will usually increased to a typical total daily dose of 50 mg in two or three divided doses. However, some patients require daily dosages up to 100 mg.…”

Section: R92 We Recommend Monitoring Of Blood Concentration Of Mitmentioning

confidence: 99%

“…However, some patients require daily dosages up to 100 mg. There is no reliable laboratory marker to guide the optimal dosage of hydrocortisone (271), which has to be based on clinical judgment similar to the management of patients with adrenal insufficiency (208). Mitotane-induced increase in cortisol-binding globulin may confound interpretation of serum cortisol measurement.…”

Section: R92 We Recommend Monitoring Of Blood Concentration Of Mitmentioning

confidence: 99%

European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors

Fassnacht

Dekkers

Else

et al. 2018

European Journal of Endocrinology

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867

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Adrenocortical carcinoma (ACC) is a rare and in most cases steroid hormone-producing tumor with variable prognosis. The purpose of these guidelines is to provide clinicians with best possible evidence-based recommendations for clinical management of patients with ACC based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. We predefined four main clinical questions, which we judged as particularly important for the management of ACC patients and performed systematic literature searches: (A) What is needed to diagnose an ACC by histopathology? (B) Which are the best prognostic markers in ACC? (C) Is adjuvant therapy able to prevent recurrent disease or reduce mortality after radical resection? (D) What is the best treatment option for macroscopically incompletely resected, recurrent or metastatic disease? Other relevant questions were discussed within the group. Selected Recommendations: (i) We recommend that all patients with suspected and proven ACC are discussed in a multidisciplinary expert team meeting. (ii) We recommend that every patient with (suspected) ACC should undergo careful clinical assessment, detailed endocrine work-up to identify autonomous hormone excess and adrenal-focused imaging. (iii) We recommend that adrenal surgery for (suspected) ACC should be performed only by surgeons experienced in adrenal and oncological surgery aiming at a complete en bloc resection (including resection of oligo-metastatic disease). (iv) We suggest that all suspected ACC should be reviewed by an expert adrenal pathologist using the Weiss score and providing Ki67 index. (v) We suggest adjuvant mitotane treatment in patients after radical surgery that have a perceived high risk of recurrence (ENSAT stage III, or R1 resection, or Ki67 >10%). (vi) For advanced ACC not amenable to complete surgical resection, local therapeutic measures (e.g. radiation therapy, radiofrequency ablation, chemoembolization) are of particular value. However, we suggest against the routine use of adrenal surgery in case of widespread metastatic disease. In these patients, we recommend either mitotane monotherapy or mitotane, etoposide, doxorubicin and cisplatin depending on prognostic parameters. In selected patients with a good response, surgery may be subsequently considered. (vii) In patients with recurrent disease and a disease-free interval of at least 12 months, in whom a complete resection/ablation seems feasible, we recommend surgery or alternatively other local therapies. Furthermore, we offer detailed recommendations about the management of mitotane treatment and other supportive therapies. Finally, we suggest directions for future research.

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“…Moreover, it may be of interest to evaluate the changes of 27OHC levels after mitotane exposition in other cell lines also, focusing on the endocrine glands other than adrenals (i.e., pituitary) that are affected by mitotane both in vitro [28,29] and in vivo [30,31].…”

Section: Discussionmentioning

confidence: 99%

Involvement of 27-Hydroxycholesterol in Mitotane Action on Adrenocortical Carcinoma

Germano

Rossin

Leoni

et al. 2020

Cells

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Adrenocortical carcinoma (ACC) is a rare cancer with poor prognosis. Mitotane, the standard treatment for ACC, impairs adrenocortical steroid biosynthesis and cholesterol metabolism. In the H295R cell line, a standard ACC in vitro model, mitotane was previously reported to enhance the production of some oxysterols. To verify the possible mechanistic involvement of oxysterols in the anti-ACC effect of mitotane, a gas chromatography mass spectrometry (GC-MS) profiling of oxysterols and the main cholesterol precursors was carried out in H295R cells. Among the oxysterols detected in mitotane-treated cells, 27OHC was markedly produced, as well as lanosterol and lathosterol cholesterol precursors. In this cell model, mitotane was confirmed to affect mitochondrial transmembrane potential and induce apoptosis. Such cytotoxic effects were perfectly matched by H295R cell treatment with a single identical micromolar amount of 27OHC. The mitotane-dependent strong increase in 27OHC was confirmed in vivo, in the plasma of ACC patients under treatment with the drug. Moreover, lanosterol, lathosterol, desmosterol and, to a minor extent, 24-hydroxycholesterol and 25-hydroxycholesterol plasma levels were significantly increased in those patients. The cytotoxic effect of mitotane on ACC cells may be partly related to the increased intracellular level of 27OHC induced by the drug itself.

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Effects of mitotane on the hypothalamic–pituitary–adrenal axis in patients with adrenocortical carcinoma

Cited by 32 publications

References 28 publications

Recovery of Adrenal Insufficiency Is Frequent After Adjuvant Mitotane Therapy in Patients with Adrenocortical Carcinoma

Recovery of Adrenal Insufficiency Is Frequent After Adjuvant Mitotane Therapy in Patients with Adrenocortical Carcinoma

European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors

Involvement of 27-Hydroxycholesterol in Mitotane Action on Adrenocortical Carcinoma

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