Sex Hormone-Binding Globulin Measurement in Patients with Inappropriate Secretion of Thyrotropin (IST): Evidence against Selective Pituitary Thyroid Hormone Resistance in Nonneoplastic IST*

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Abstract
The differential diagnosis of the various forms of inappropriate secretion of TSH (IST), i.e. generalized thyroid hormone resistance (GRTH), selective pituitary resistance [non-neoplastic 1ST (nnIST)], and tumoral pituitary TSH hyperse-cretion [neoplastic IST (nIST)], mainly rests on clinical observation, skull imaging, and measurement of several parameters assessing peripheral thyroid hormone effects. Clinically, patients with GRTH usually display compensated hypothyroidism, while those with nnIST or nIST are hyperthyroid. Since sex hormone-binding globulin (SHBG) measurement has been shown to be a reliable parameter in distinguishing between euthyroid and hyperthyroid states, we evaluated serum SHBG levels in 39 patients with IST (7 with GRTH, 15 with nnIST, and 17 with nIST). The results were compared to those in 68 normal subjects, 76 hyperthyroid patients, and 31 hypothyroid patients. SHBG levels in patients with either GRTH or nnIST were similar to those in controls or hypothyroid patients [GRTH, 40.5 ± 11.8 (±SD) nmol/L (range, 26.4–57.5); nnIST, 29.7 ± 12.8 nmol/L (range, 6.8–46.8); controls, 36.7 ± 21.7 nmol/L (range, 5.4–96.5); hypothyroid, 30.8 ± 14.4 nmol/L (range, 10.4–63.3)]. On the contrary, SHBG levels in patients with either overt hyperthy-roidism or nIST were significantly higher than those in the above groups [hyperthyroid, 149 ± 111 nmol/L (range, 48–557); nIST, 99.5 ± 54.7 nmol/L (range, 21.6–259)]. The apparent overlap of SHBG values between hyperthyroid patients and controls almost completely disappeared when comparisons were made with control groups matched for age and sex. Additional indices of peripheral thyroid hormone action (basal metabolic rate, cardiac systolic time intervals, and Achilles' reflex time) were normal in patients with GRTH, while they were in the hyperthyroid range in patients with nnIST and nIST. After successful treatment of hyperthyroidism, SHBG levels normalized in patients with nIST, but they did not change in patients with nnIST. In conclusion, the measurement of SHBG in patients with IST is useful in differentiating the neoplastic form from that due to thyroid hormone resistance, but it fails to distinguish between generalized and pituitary resistance to thyroid hormone action. Moreover, the present data suggest that the resistance to thyroid hormone action in patients with nnIST is not selective at the thyrotroph cell level, but also involves the hepatic SHBG-synthesizing cells, thus supporting the view that the various forms of thyroid hormone resistance could represent a continuum of the same defect with variable expression in different tissues.