Mitotane (o.pDDD, Lysodren) is used to treat adrenortical carcinoma and Cushing syndromes. It is catabolised into o.pDDA and o.pDDE. It is lowly protein-bound but its tropism for lipids is high. It has multiple side effects on the digestive gut increasing alkaline phosphatases and cholesterol. Patients treated with mitotane have been described as having decreased FT4 levels without any signs of hypothyroidism. We wanted to know whether this is due to an analytical interference in the FT4 assay or a true disruption in the thyroid axis and FT4 metabolism.
We retrospectively investigate the sera of 31 patients (22 adrenortical carcinoma, nine Cushing syndromes) assaying o.pDDD and o.pDDE (liquid chromatography); TSH, FT4, FT3, albumin, cholesterol, triglycerides (Cobas Roche); TBG (AdviaCentaur Siemens); rT3 (RIA, IDS). Statistical analysis was performed using Staview software (Spearman correlation ρ, P significant if <0.005).
In vitro, the addition of increasing amounts of o.pDDD (140 mg/l) and o.pDDE (0.510 mg/l) in serum had no significant influence on FT4, FT3 and TSH serum assay. In vivo, we confirmed that FT4 were slightly decreased under mitotane although not significantly (−0.16, P=0.24) while TSH and FT3 were normal. o.pDDD levels were negatively correlated with rT3 levels (−0.36, P=0.013) and positively correlated with TBG levels (+0.43, P=0.0016). FT4 levels were not influenced by albumin or lipids.
Our results show that o.pDDD and o.pDDE has no influence on FT4, FT3, and TSH assay in serum. The lack of correlation between TSH and FT4 levels is not in favour of a decreased pituitary production of TSH. Mitotane may increase TBG, thus decreasing FT4 levels but in a moderate way. The increase in rT3 levels while FT3 levels are unchanged suggests that mitotane may induce desiodases. Our results point out that the hepatic actions of mitotane may interfere with thyroid hormones physiology.