OBJECTIVE: Since panhypopituitarism in patients with Sheehan's syndrome is due to massive pituitary necrosis with only minor hypothalamic involvement, we hypothesized that serum TSH levels would be low but its circadian rhythm preserved in these patients. DESIGN AND PATIENTS: Basal and TRH-stimulated mean afternoon (1500-1700 h) and nocturnal (0100-0300 h) TSH levels were determined in 10 patients with Sheehan's syndrome before and during T4/glucocorticoid replacement and in seven controls. MEASUREMENTS: Serum concentrations of T3, T4, free T4 (fT4) and cortisol were measured by radio-immunoassay; TSH, GH, PRL and LH were determined by immunofluorimetric assay. RESULTS: Afternoon TSH levels were markedly increased in Sheehan's syndrome patients compared with controls (3.3 +/- 1.0 vs 0.5 +/- 0.15 mU/l, respectively, P = 0.002). At night, TSH levels remained unchanged in Sheehan's syndrome patients (3.3 +/- 1.1 mU/l) but rose significantly in controls (1.1 +/- 0.34 mU/l, P = 0.016). The nocturnal TSH increment was significantly higher in controls than in patients (143 vs approximately 4.9%, respectively, P = 0.0001). In eight patients with normal serum fT4 levels during treatment, basal TSH levels decreased to 0.16 +/- 0.05 mU/l (P < or = 0.008), being barely detectable or undetectable in four patients. In the six patients with detectable TSH during treatment, nocturnal TSH increments were normal in four and blunted in two. There was a strong correlation between pre- and post-treatment basal TSH (r = 0.82, P = 0.012) and between pre- and post-treatment peak TSH after TRH (r = 0.91, P = 0.0017), but no significant correlation between TSH and thyroid hormone levels. The per cent ratio of peak TSH after TRH between treated patients and controls, an estimate of the relative size of the functional thyrotroph pool in Sheehan's syndrome patients, was 7%. CONCLUSIONS: Loss of TSH rhythm in Sheehan's syndrome is usually secondary to hormonal deficiency and results from maximally increased secretory activity of a decreased pool of thyrotrophs. The paradox of increased TSH levels and decreased thyroid function in Sheehan's syndrome could result from decreased TSH bioactivity and/or from a critically reduced thyrotroph population that fails to sustain sufficient TSH secretion in the face of rising serum thyroid hormone levels.