We have retrospectively studied 41 patients with hypothalamic-pituitary disease and central hypothyroidism associated with hypopituitarism. Sixteen patients had nonsecreting pituitary macroadenoma, whereas different sellar and suprasellar pathologies affected all other patients. Pretreatment thyrotropin (TSH) level (mean ± standard error of the mean [SEM]) was 2.04 ± 0.25 mU/L (normal, 0.4-4), and gradually decreased to 0.51 ± 0.19 mU/L (range, 0.009-3.38) by treatment with levothyroxine in a mean dose of 86 ± 6 μg/d. TSH was suppressed by thyroid replacement to less than 0.5 mU/L in 80% of patients. Mean baseline free thyroxine (FT4) was 7.55 ± 0.51 pmol/L (normal, 11.8-24.6) and gradually increased with thyroid hormone to 15.19 ± 1.0 pmol/L, whereas total thyroxine (TT4) increased from 57.4 ± 2.6 to 104.4 ± 5.0 nmol/L (normal, 77-154). Mean pretreatment total triiodothyronine (TT3) was 1.44 ± 0.09 nmol/L (normal, 1.1-2.7), and was not altered by treatment. Thyrotropin-releasing hormone (TRH) test was performed in 20 patients before thyroid replacement, and mean baseline and peak TSH levels were 1.33 ± 0.3 and 7.14 ± 1.62 mU/L, respectively. In 5 subjects TSH was stimulated to 6 mU/L or more, whereas in 5 others TSH was not affected. Based on linear regression of logarithm (Ln) TSH against FT4, a leftward shift of the TSH/FT4 ratio was demonstrated in patients with central hypothyroidism compared to 17 patients with primary hypothyroidism. Plotting measurements of TSH against FT4 for 6 individuals with central hypothyroidism showed different regression slope for each patient. Suppression of TSH by thyroid replacement to levels below 0.1 mU/L predicted euthyroidism in 92% of cases, compared to 34% when TSH was above 1 mU/L (p < 0.0001). In conclusion, in central hypothyroidism baseline TSH is usually within normal values, and is further suppressed by exogenous thyroid hormone as in primary hypothyroidism, but to lower levels. Thus, insufficient replacement may be reflected by inappropriately elevated TSH levels, and may lead to dosage increment.