STUDIES OF TWO THYROTROPHIN‐SECRETING PITUITARY ADENOMAS: EVIDENCE FOR DOPAMINE RECEPTOR DEFICIENCY

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Abstract
SUMMARY: Of 22 previously reported patients with TSH‐secreting pituitary adenomas challenged with dopamine agonists, 18 showed no decrease in serum TSH. There have been few in‐vitro studies of these rare tumours so the mechanism of the dopaminergic resistance has remained obscure. We describe two further patients with thyrotrophinomas; the first was thyrotoxic (T3 6.1 nmol/l, TSH 7 mU/l) and the second was diagnosed after radioiodine for presumed Graves’disease. The second patient had an α‐subunit: TSH molar ratio less than unity (0.27). In‐vivo TSH responses to TRH, bromocriptine and domperidone were compared with those of the resected tumour cells in vitro, the latter studied using a continuous perifusion system. Dopamine receptors were sought in membranes from each tumour using a radioreceptor assay employing 3H‐spiperone. Patient 1 showed significant increases in serum TSH (7 to 13 mU/l) and α‐subunit (18.7 to 385 ng/ml) after 200 μg TRH (i.v.) but patient 2 showed no such increases (TSH: 69 to 72 mU/l, α‐subunit: 4.9 to 5.2 ng/ml). Neither patient showed a change in serum TSH following bromocriptine 2.5 mg (orally) or domperidone 10 mg (i.v.), though serum PRL responded normally. Serum TSH from patient 1 was of apparently normal molecular size but increased bioactivity (B/I ratio 3.8) and that from patient 2 was of increased molecular size but reduced bioactivity (B/I ratio 0.1). Tumour cells from each patient immunostained for TSHβ and α‐subunit, and secreted TSH in vitro. The first showed dose‐dependent TSH release after TRH (1–100 ng/ml) which could not be inhibited by dopamine (5 μmol/l) but the second was unresponsive to TRH in vitro. Neither tumour showed inhibition of TSH release by dopamine (5 μmol/l) or bromocriptine (0.01–10 nmol/l) and neither contained membrane‐bound dopamine receptors. The results suggest that the dopaminergic resistance typical of most TSH‐secreting pituitary adenomas may be due to altered or absent membrane‐bound dopamine receptors.