The pituitary-adrenal axis is known to be stimulated during the acute-phase response. As cytokines play a central role in mediating the constellation of host response occurring during the acute-phase response it was of interest to assess the ability of cytokines to stimulate ACTH secretion from normal pituitary cells in culture. We used human recombinant interleukin-1β and -α (hrlL1β, hrlL1α) and human recombinant tumor necrosis factor α (hrTNFα) to analyze the ability of these cytokines to induce ACTH secretion from normal rat anterior pituitary cells in culture. We also investigated the possible roles of prostaglandin E₂ (PGE₂) and cAMP in the cellular transduction mechanism. After 3 days of incubation primary cultures of rat anterior pituitary cells were stimulated for 24 h with either hrlL1β, hrlL1α or hrTNFα alone or with the addition of dexamethasone or indomethacin. The culture media were analyzed for ACTH, PGE₂ and cAMP content. At doses ranging from 0.03 to 30 nM, hrlL1β stimulated the release of ACTH and PGE₂ in a dose-dependent manner. In contrast, at doses ranging from 3 to 60 nM, hrTNFα was unable to stimulate ACTH secretion although it stimulated PGE₂ synthesis. Time-course experiments demonstrated that hrlL1β (3 nM) stimulates ACTH production over a period of 8, 16 and 24 h, but not after a period of 4 h. In these experiments, hrlL1β failed to cause any change in the secretions of growth hormone and luteinizing hormone. In hrlL1β-stimulated cells, indomethacin (10 mM) completely inhibited PGE₂ production without significantly affecting ACTH release, whereas dexamethasone (50 nM), which also inhibited PGE₂ production, partially inhibited ACTH secretion. Finally indomethacin blocked the hrlL1β-induced cAMP accumulation obtained after 24 h, without significantly affecting hrlL1β-induced ACTH release. The results obtained with hrlL1α were similar to those obtained with hrlL1β. In conclusion, although hrlL1β, hrlL1α and hrTNFα stimulate PGE₂ synthesis, only hrlL1β and hrlL1α stimulate ACTH release from normal rat anterior pituitary cells in culture. The stimulation is partially inhibited by dexamethasone and the cellular transduction mechanism involved in this ACTH release does not depend on PGE₂ or cAMP. These results confirm the interaction between the endocrine and the immune systems. They suggest that the monokine-induced stimulation of the pituitary-adrenal axis may represent a potent negative feedback mechanism through which the immune system avoids an overshoot of the inflammatory and febrile effect stimulated during the acute-phase response.

Objective: To investigate the effects of long-term GH in GH-deficient adults, as predicted by IGF-I levels. Methods: Patients received GH, 5 mg/kg per day for 1 month and 10 mg/kg per day for another 12-30 months. Changes in body composition, cardiac structure/function, serum lipids and quality of life were measured. Results: There was a significant increase in lean body mass (LBM) (2.21 kg; P , 0.0001) after 6 months, which was sustained throughout treatment. A larger increase occurred in males than females (2.97 vs 1.19 kg; P , 0.0001). Total fat mass was reduced (2.56 kg; P , 0.0001 (3.26 kg males, 1.63 kg females)). Responsiveness to GH varied greatly, but LBM changes correlated with IGF-I changes (P , 0.004). Furthermore, thinner patients experienced greater and progressive LBM increases. There was an increase in ejection fraction (3.85^9.95%; P ¼ 0.0002) after 6 months, sustained to 18 months. These cardiac effects were equal for males and females, and did not correlate with IGF-I levels. Serum low-density lipoprotein/high-density lipoprotein ratios decreased within 6 months, and were sustained thereafter. Quality of life improved significantly after 6 months, an effect that was sustained/enhanced as treatment continued. No major adverse events were identified. Conclusions: Improved body composition is both reflected by IGF-I changes and predicted inversely by baseline adiposity. Other effects of GH replacement on cardiac function, dyslipidaemia and quality of life, however, do not correlate with circulating IGF-I concentrations. Our findings validate the importance of sustained GH therapy, but caution on the interpretation of IGF-I levels in monitoring the longterm effects of GH treatment.

Abstract. Both arginine vasopressin (AVP) and angiotensin II (All) potentiate the corticotropin-releasing activity of CRF41 via a potentiation of CRF41-induced cAMP production. In perfused rat anterior pituitary cells, AII (10−8 mol) showed a transitory 2-fold increase in its ACTH-releasing activity, when tested after application extract of rat stalk median eminence. In order to determine whether this facilitating effect on All corticotropin-releasing activity occurred through cAMP-dependent mechanisms, the ACTH-releasing activity of All was tested after stimulation with CRF41, AVP or forskolin, three secretagogues with known effects on cAMP production. When given 16 min after CRF41, 10 μg/l, All (10−8 mol) showed a significant increase (210%) in its ACTH-releasing activity, which returned to the normal level when All-stimulation was repeated at 32 min (121%) and 48 min (100%). Similarly, forskolin, 3 × 10−6 mol, produced a significant transitory increase (208%) in the subsequent All-induced ACTH release whereas AVP, 10 μg/l and 100 μg/l, had no effect on the following ACTH response to All. These results suggest that the All-induced ACTH secretion – which is cAMP independent – nevertheless may be modulated by previously stimulation of the cAMP pathway.