Mitotane Has an Estrogenic Effect on Sex Hormone-Binding Globulin and Corticosteroid-Binding Globulin in Humans

Nader, Nader D.; Raverot, Gérald; Emptoz-Bonneton, Agnès; Déchaud, H.; Bonnay, M; Baudin, Éric; Pugeat, Michel

doi:10.1210/jc.2005-2157

Cited by 76 publications

(64 citation statements)

References 22 publications

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“…In vitro studies showed that mitotane increases the synthesis of steroid binding protein (26,27). In our study, SHBG was markedly increased, whereas in males free T was decreased and LH was increased.…”

Section: Hormonal Parameterssupporting

confidence: 49%

Comparison of two mitotane starting dose regimens in patients with advanced adrenocortical carcinoma

Kerkhofs¹,

Baudin²,

Terzolo³

et al. 2013

EJEA

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Context: Mitotane is the only approved drug for treatment of adrenocortical carcinoma. Its pharmacokinetic properties are not fully elucidated and different dosing regimens have never been compared head to head.Objective: The objective of the study was to investigate the relationship between mitotane dose and plasma concentration comparing two dosing regimens. Patients/Interventions: Forty mitotane-naïve patients with metastatic adrenocortical carcinoma were assigned to a predefined low-or highdose regimen by the local investigator. Thirty-two patients could be evaluated in detail.Main Outcome Measure: The difference in median mitotane plasma levels between both treatment groups was measured. Conclusions: The high-dose starting regimen resulted in neither significantly different mitotane levels nor a different rate of adverse events, but concomitant chemotherapy influenced these results. Thus, for mitotane monotherapy the high-dose approach is favorable, whereas for combination therapy a lower dose seems reasonable.

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Section: Hormonal Parameterssupporting

confidence: 49%

Comparison of two mitotane starting dose regimens in patients with advanced adrenocortical carcinoma

Kerkhofs¹,

Baudin²,

Terzolo³

et al. 2013

EJEA

Self Cite

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“…It causes an increase in many binding globulins, including cortisol-binding globulin (CBG), which results in elevated plasma cortisol levels (152,153,154). For this reason, total serum cortisol level cannot be used to monitor the response to treatment or development of hypoadrenalism (152).…”

Section: European Journal Of Endocrinologymentioning

confidence: 99%

THERAPY OF ENDOCRINE DISEASE: Steroidogenesis enzyme inhibitors in Cushing's syndrome

Daniel

Newell‐Price

2015

European Journal of Endocrinology

111

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Steroidogenesis enzyme inhibitors are the mainstay of medical therapy in Cushing's syndrome (CS). Ketoconazole (KTZ) and metyrapone are the most commonly used agents. Although there is considerable experience of their use in individual specialist centres, these drugs have not been rigorously tested in prospective clinical trials. Clinicians face uncertainties and concerns with respect to the safety profile of these agents, and best means to monitor effect. We review steroidogenesis inhibitors in the management of CS, including older agents (KTZ, metyrapone, etomidate and mitotane) and those currently under development (LCI699, non-racemic KTZ), and offer a practical approach for their use in clinical practice.

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“…This CYP3A4 induction can also, together with suppression of 11b-hydroxylase and cholesterol side chain cleavage, lead to hypocortisolism (Touitou et al 1978, Ghataore et al 2012. The adrenolytic effect of mitotane on the healthy contralateral adrenal, as well as enhanced production of cortisol-binding globuline in mitotane treated patients, also play a role in the occurrence of hypocortisolism (Nader et al 2006), which should be prevented by supraphysiological hydrocortisone replacement therapy.…”

Section: Current Therapeutic Strategiesmentioning

confidence: 99%

Future directions in the diagnosis and medical treatment of adrenocortical carcinoma

Creemers¹,

Hofland²,

Korpershoek³

et al. 2015

Endocrine-Related Cancer

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Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis. Discrimination between ACCs and adrenocortical adenomas (ACAs) remains challenging, with the current gold standard being the Weiss score, consisting of several histopathological characteristics. However, new markers like Ki67, a marker for proliferation, and the staining of reticulins are promising not only as it comes to identifying malignancy but also as prognostic markers in patients with ACC. Currently, surgery is still the only curative treatment for ACC. Mitotane, an adrenolytic drug, is used in the adjuvant setting and in case of metastatic or advanced disease. Patients with progressive disease are frequently treated with mitotane, alone or in combination with etoposide, doxorubicine and cisplatin. Radiotherapy is indicated in selected cases. The low response rates and high toxicity of the systemic therapies emphasize the need for markers that enable the identification of responders and non-responders. Consequently, research is focusing on predictive factors varying from the expression of DNA repair genes to clinical patient characteristics. Subgroups of ACC with different prognosis have been identified based on transcriptome characteristics. As a conclusion from large molecular studies, ACCs appear to harbor many abnormalities compared to ACAs. Altered pathways driving ACC pathogenesis include the IGF, TP53 and the Wnt signaling pathway, allowing these as new potential targets for medical therapy. However, despite efforts in preclinical and clinical studies investigating efficacy of targeting these pathways, most novel therapies appear to be effective in only a subset of patients with ACC. New treatment concepts are therefore urgently needed.

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Mitotane Has an Estrogenic Effect on Sex Hormone-Binding Globulin and Corticosteroid-Binding Globulin in Humans

Abstract: Mitotane increased SHBG/CBG gene expression and liver production by mechanisms requiring the presence of ERalpha.

Cited by 76 publications

References 22 publications

Comparison of two mitotane starting dose regimens in patients with advanced adrenocortical carcinoma

Comparison of two mitotane starting dose regimens in patients with advanced adrenocortical carcinoma

THERAPY OF ENDOCRINE DISEASE: Steroidogenesis enzyme inhibitors in Cushing's syndrome

Future directions in the diagnosis and medical treatment of adrenocortical carcinoma

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