MULTIPHASIC THYROTROPIN RESPONSES TO THYROID-HORMONE ADMINISTRATION IN MAN

The magnitude and temporal pattern of serum TSH suppression after sing le or multiple doses of thyroid hormone (T-3, T-4, or triiodothyroacet ic acid) were studied using third and fourth generation TSH assays (se nsitivities, 0.01 and 0.001 mU/L, respectively). A constant T-3 dose ( 263 mu g iv) administered at a uniform clock time (1200 h) produced id entical serum TSH suppression patterns, (percent of control TSH vs. ho urs) in euthyroid and hypothyroid subjects. The percent log TSH vs. lo g time plot revealed three temporally distinct linear suppression phas es: phase 1, a rapid TSH suppression, onset 1 h and lasting for 10-20 h; phase 2, slower suppression, onset between 10 and 20 h and lasting for 6-8 weeks; and phase 3, an invariable low TSH level (<0.01 mU/L) w ith chronic T-3 suppression (100 mu g four times a day). TSH escaped m aximal suppression at a similar serum T-3 level in both euthyroid and hypothyroid subjects (2.9 +/- 0.2 vs. 3.5 +/- 0.5 nmol/L, respectively ; P > 0.9), despite different basal serum T-3 values (2.0 +/- 0.1 vs. 0.6 +/- 0.1 nmol/L, respectively; P < 0.01). Two milligrams of triiodo thyroacetic acid or 2 mg T-4 given iv at 1200 h produced TSH suppressi on patterns similar to T-3. The phase 1 suppression varied with the cl ock time of T-3 administration, (steeper responses were seen at 2400 v s. 1200 h), whereas phase 2 responses were unaltered. This study shows that thyroid hormone suppression of TSH is a complex, biphasic, nonli near process, which is reproducible and independent of thyroid status or the thyroid hormone analog used. It is hypothesized that phase 1 re flects inhibition of release of preformed hormone, whereas phase 2 lik ely reflects inhibition of de novo synthesis and/or thyrotroph storage of TSH. In contrast, phase 3 secretion seems to represent basal const itutive TSH release, which may have relevance to the role of thyroid h ormone-suppressive therapy in the treatment of patients with benign or neoplastic thyroid disease.