Clinical and molecular studies of a thyrotropin-secreting pituitary adenoma

A 40-year-old woman, who had previously received radioactive iodine for hyperthyroidism, presumably due to Graves’ disease, subsequently was found to have inappropriately elevated serum TSH and α-subunit levels and a pituitary adenoma. Detailed clinical studies revealed marked serum TSH elevations (˜100 mU/L) with no circadian variation, but with 7 pulses/24 h. Serum α-subunit levels averaged 2.5 μg/L, with 13 pulses/24 h. Neither serum TSH nor α-subunit responded to TRH stimulation, nor did serum TSH change during dopamine infusion, but α-subunit levels did decline slightly. In contrast, during somatostatin infusion, serum TSH declined to 30% of baseline levels, while α-subunit levels did not change. Pituitary adenoma tissue obtained at the time of transsphenoidal surgery immunostained weakly with anti-TSHβ serum and strongly with anti-α-subunit serum. Northern blot analysis of RNA isolated from the tumor revealed TSHβ and α-subunit mRNA levels of normal length, while primer extension analysis showed a major initiation site for the TSHβ gene that appeared to be identical in the tumor and normal pituitary tissue. A second minor upstream start site was detected in the tumor, but it represented less than 1% of transcription compared to the major downstream start site. We conclude that the tumor secreted TSH and asubunit in an abnormal and discordant fashion, but that the TSH gene initiation site appeared to be normal and, therefore, did not explain the observed secretory abnormalities.