OBJECTIVE: Thyroid hormones (THs) perform essential roles in pituitary function. They regulate anterior pituitary hormone secretion and are also key determinants of pituitary cell proliferation and differentiation. The critical role of deiodinase enzymes, which serve as prereceptor regulators of TH action, remains largely unexplored. Three deiodinase enzymes metabolize active and inactive THs and thereby determine tissue concentrations of the biologically active ligand, tri-iodothyronine (T3). We hypothesized that aberrant expression of deiodinase enzymes and/or altered enzyme activity in pituitary tumours may change tissue concentrations of THs and influence their growth and secretory characteristics. STUDY DESIGN AND PATIENTS: We studied 105 pituitary tumours and 10 normal pituitaries for expression of deiodinase enzyme mRNAs encoding types 1 (D1), 2 (D2) and 3 (D3) using real-time RT-PCR. Enzyme activity data from 20 pituitary samples were also obtained. RESULTS: Pituitary tumours expressed significantly increased D3 mRNA (6.5-fold, P <0.0005) compared with normal pituitaries. D2 mRNA was also increased 2.6-fold (P = 0.005) in pituitary tumours compared with normals. The rare TSH-secreting pituitary tumour subtype expressed a 13.1-fold excess of D3 mRNA and reduced D2 mRNA (0.1-fold of normal pituitaries). D2 mRNA expression in ACTH-secreting tumours was similarly reduced to 0.1-fold that in normal pituitaries. CONCLUSIONS: Pituitary adenomas express abnormal levels of deiodinase enzymes compared to normal pituitaries. These abnormalities may have functional consequences on pituitary tumour growth. In the case of TSH-secreting pituitary adenomas, the observed pattern of deiodinase mRNA expression may explain the 'resistance' of this tumour type to TH feedback.