We have investigated the role of circulating glucocorticoids in the suppression of the hypothalamic-pituitary-thyroid (HPT) axis following lipopolysaccharide (LPS) injection in rats. Intraperitoneal injection of LPS (2.5 mg/kg) suppressed paraventricular nucleus thyrotropin-releasing hormone (TRH) mRNA, pituitary thyroid-stimulating hormone (TSH) mRNA and plasma triiodothyronine. In these animals LPS also increased paraventricular nucleus corticotropin-releasing hormone (CRH) mRNA, pituitary proopiomelanocortin (POMC) mRNA and plasma corticosterone levels. To investigate the role of plasma corticosterone in the suppression of the HPT axis, we clamped the plasma corticosterone level at morning baseline level by bilateral adrenalectomy and corticosterone pellet implantation. Ten days after surgery, LPS injection evoked a dramatic increase in CRH mRNA and POMC mRNA. Despite the lack of change in plasma corticosterone in the corticosterone-clamped rats, LPS was still able to suppress TRH and TSH mRNA levels in both corticosterone-clamped and sham-operated rats. These data indicate that in response to LPS, suppression of the HPT axis occurs and is independent of the LPS-induced increase in plasma corticosterone.