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

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 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.

Lack of effects of circulating thyroid hormone levels on serum leptin concentrations

“…However, recent data failed to demonstrate a direct role for estrogens in leptin regulation (27), but other reports indicated that variations in serum androgens cause leptin synthesis to be partially inhibited. Since both hypo-and hyperthyroidism cause variations in circulating sex hormone-binding globulin (28,29), as well as in peripheral sex hormone metabolism, the putative increase in or the relative prevalence of circulating androgenic compounds in female patients with thyroid disorders may account for the difference in SDS found in female patients.…”

Triiodothyroacetic acid in health and disease

“…In a subgroup of RTHβ patients, TA 3 is able to decrease TSH and consequently the high serum T 4 and T 3 levels. Since the thyromimetic effects of TA 3 itself do not fully compensate the reduction in endogenous TH levels, it alleviates the thyrotoxic symptoms including tachycardia, goiter, excessive sweating and behavioral problems (BeckPeccoz et al 1983, Lind & Eber 1986, Faglia et al 1987, Salmela et al 1988, Kunitake et al 1989, Smallridge et al 1989, Beck-Peccoz et al 1990, Aguilar Diosdado et al 1991 Crino et al 1992, Dulgeroff et al 1992, Ueda et al 1996, Darendeliler & Basx 1997, Radetti et al 1997, CliftonBligh et al 1998, Persani et al 1998, Asteria et al 1999, Kong et al 2005, Torre et al 2005, Wu et al 2006, Gurgel et al 2008, Santos et al 2008, Guran et al 2009, Anzai et al 2012, Ferrara et al 2012, Ramos-Prol et al 2013, Stagi et al 2014, Chatzitomaris et al 2015, Xue et al 2015. However, some patients do not respond to TA 3 treatment, which is assumed to depend on the type or location of the mutation (Hamon et al 1988, Persani et al 1998.…”

Increased Sex Hormone-Binding Globulin Levels in Children and Adolescents with Thyrotoxicosis

“…Studies have described SHBG in children and adults with THR and found that it was possible to distinguish patients with inappropriate TSH production (pituitary TSH-producing adenomas) from patients with THR. However, specificity was low in terms of distinguishing pituitary resistance from more generalized forms of THR [21,22]. …”