Secondary Hyperthyroidism due to Thyrotropin Hypersecretion: Study of Pituitary Tumor Morphology and Thyrotropin Chemistry and Release*

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Abstract
A 57-yr-old male presented with hyperthyroidism (serum T4, 18 μg/dl) intractable by subtotal thyroidectomy. Workup 1 yr after thyroid surgery showed elevated values of plasma TSH (480 /μU/ml), αTSH (68 ng/ml), T4 (15.9 μg/dl), T3 (230 ng/ml), and thyroid function index (1.25) as well as an enlarged sella. A large pituitary tumor (8.4 g) was partially removed by frontal craniotomy. Postoperatively, plasma TSH was 81 juU/ml and a-TSH was 13.5 ng/ml, whereas /β-TSH rose from 0.5 to 8.0 ng/ml. However, hyperthyroidism persisted and had to be controlled by methimazole. It ceased after reoperation (TSH, 2.1 /μU/ml; T4, ¼1 μg/dl). Plasma TSH concentration was unresponsive to TRH (400 fig, iv), T3 (25 jug, four times daily), bromocryptine (10 mg, orally), metoclopramide (10 mg, orally), and iv somatostatin (500 /μg/h). TRH-induced PRL release was normal, but it was suppressed by bromocryptine and somatostatin. Six fractions of tumor TSH (TSHT) were found by electrofocussing, with isoelectric points at pH 4.8, 5.2-6.2, 6.8, 7.5, 8.2, and 8.7. Identity with TSH-MRC 68/38 was shown for fraction II, representing 16.3% of total TSHT. Immunoreactivity and bioactivity were almost identical for fractions I and II, whereas for fractions III-V bioactivity was only 35-50% of the estimated immunoreactivity. The apparent molecular weights, as estimated by gel filtration, were 38,000-44,000 (fractions I-V), 34,000 (fraction VI), and 22,000-25,000 (fractions I, II, and VI) daltons, respectively. On Concanavalin A-Sepharose, TSH-r behaved as a glycoprotein. Immunohistochemically, tumor cells showed abundant TSH immunoreactivity and were intermingled with somatotrophs and a very few ACTH and a-MSH cells. It is concluded that 1) TSHT was released by the tumor autonomously, 2) TSHT was responsible for the development of secondary hyperthyroidism, 3) TSHr consisted of a variety of polypeptides which only in part represented regular TSH, and 4) measurement of TSH subunits could provide a tool to diagnose a pituitary TSH-producing tumor (β-TSH) and to follow recovery after surgery (/-TSH).