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 IST (nnIST)], and tumoral
pituitary TSH hypersecretion [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
hyperthyroidism 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.