The slow clearance, prolonged half-life, and high serum concentration of thyroxine (T4) are largely due to strong binding by the principal plasma thyroid hormone-binding proteins, thyroxine-binding globulin (TBG), transthyretin (TTR), and albumin. These proteins, which shield the hydrophobic thyroid hormones from their aqueous environment, buffer a stable free T4 concentration for cell uptake. Free rather than bound T4 is subject to homeostatic control by the hypothalamic-pituitary thyroid axis. Although it is not a protease inhibitor, sequence analysis identifies TBG as a member of the serine protease inhibitor (serpin) family of proteins. Proteolytic cleavage of TBG appears to be a mechanism for site-specific release of T4 independently of homeostatic control. TBG probably facilitates the transport of maternal T4 and iodide to the fetus, although this remains to be proven. High-affinity cellular binding sites for TTR have been described; however, their function and that of choroid plexus synthesis of TTR and transport of T4 into the cerebrospinal fluid remain unclear. Albumin, with the lowest T4 affinity and fastest T4 release of the major T4-binding proteins may promote quick exchange of T4 with tissue sites. The affinity of albumin for T4 is increased by histidine substitution for arginine 218 in the most common form of dysalbuminemic hyperthyroxinemia. However, proline and alanine substitutions at the same site have a similar effect, suggesting that arginine 218 interferes with T4 binding.

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The reported failure of serum TSH to rise in response to the low serum T3 of severe systemic illness may be due to the known stress inhibition of TSH secretion. We therefore measured TSH and total and free thyroid hormones during the course of recovery from severe illness. During recovery, TSH increased at a time when T3 was rising but still below normal (mean TSH during recovery, 6.5 +/- 0.8 SEM microU/ml, n = 41 vs. normal, 2.5 +/- 0.2 SEM microU/ml; n = 31; P less than 0.001), TSH concentrations were negatively correlated with total and free T3 and less strongly correlated with total T4 but not with free T4. Average TSH concentrations were also significantly elevated in severely ill patients with hypothermia that was unrelated to cold exposure (mean TSH, 5.6 +/- 1.3 microU/ml; n = 11; P less than 0.005). The T3 concentrations in these sera were lower than those of other severely ill patients. Thus, during recovery from severe illness and during hypothermia not induced by cold, the relationship between serum T3 and TSH is qualitatively similar to that seen in primary hypothyroidism and may imply a pituitary response to a deficiency of thyroid hormone.

The distribution of thyroid hormones between free solution and their several protein-binding sites during pregnancy was studied under physiological conditions of temperature and pH. Single serum specimens were obtained from individual women at different stages of pregnancy. During the first 5 weeks of pregnancy, mean serum free T4 and free T3 concentrations were 50% higher than in nonpregnant women or women during the third trimester. Free T4 was increased significantly throughout the first trimester, but because of wide variance, free T3 was significantly above control values only during the first 5 weeks. Free T4 and free T3 concentrations decreased to control levels in the third trimester. These changes in free T4 concentrations are consistent with a weak thyrotropic action of hCG, which attained maximal concentrations early in the first trimester and then decreased markedly in the second and third trimesters. TRH testing of women scheduled for abortion in the first and second trimesters revealed marked inhibition of TSH response to TRH in those first trimester women who had elevated free T4 concentrations. The percent free T4 did not decrease during the first 5 weeks, but then declined progressively to term as T4-binding globulin (TBG) affinity, defined as the product of the capacity and affinity constant, progressively increased. T4 bound to TBG (T4-TBG) increased from early in the first trimester to term, and then decreased in postterm pregnancy and postpartum. T4 bound to prealbumin (T4-PA) and to albumin (T4-Alb) decreased significantly in the third trimester compared with either control or first trimester concentrations. The concentration of free T3 was positively correlated with T4-PA (r = 0.25) and T4-Alb (r = 0.31), but not with free T4 (r = 0.18) or T4-TBG (r = -0.30) concentrations. These results suggest that 1) only the high concentrations of hCG present in the first trimester of pregnancy have a thyrotropic effect in excess of normal levels of TSH, and this can be sufficient to suppress the TSH response to TRH; 2) hepatic TBG secretion continues to respond to the continuously rising estrogen levels throughout pregnancy; and 3) T4-PA and T4-Alb, but not free T4 or T4-TBG, are possible precursors for the extrathyroidal generation of T3.