INHIBITION OF PITUITARY-ADRENAL SECRETION BY A CORTICOTROPIN-RELEASING HORMONE ANTAGONIST IN HUMANS

Corticotropin releasing hormone (CRH) is the primary modulator of ACTH release from the pituitary, and a neuromodulator in limbic and autono mic brain regions. Dysfunction of CRH-mediated neurotransmission is em erging as a critical mechanism in several disorders. Therefore, modula tion of CRH availability at receptor sites is a potentially powerful t herapeutic tool. Inhibitory analogues of CRH have been tested in roden ts and primates, but their safety and hormonal effects in humans are u nknown. We administered a CRH-antagonist, alpha-helical-CRH-(9-41) to six individuals. Each received two intravenous infusions: 50 mu g kg(- 1) on day 1, and 100 mu g kg(-1) on the following morning. These doses block both endocrine and central effects of CRH in experimental anima ls. ACTH, cortisol, electrolytes, glucose and autonomic parameters wer e monitored in comparison with control values. Infusion of CRH antagon ist did not alter heart rate, blood pressure, temperature or plasma el ectrolytes and glucose. Pre-infusion plasma ACTH levels averaged 26.8 +/- 6.7 pg ml(-1) on day 1, and 29.0 +/- 5.8 pg ml(-1) on day 2. Post- infusion values were 11.8 +/- 2 and 11.5 +/- 2.4 pg ml(-1), significan tly lower than pre-infusion levels. Plasma cortisol levels, which aver aged 21.4 +/- 4 mu g dl(-1) on the first morning and 22.9 +/- 4.2 on t he second, also decreased significantly after CRH antagonist infusions (to 14.0 +/- 2.9 mu g dl(-1) on day 1, and 13.9 +/- 3.0 mu g dl(-1) o n day 2). Hormonal changes were transient, and circadian rhythm was no t affected. Though not measured formally, euphoria, anxiety or somnole nce were not observed. In conclusion, CRH antagonist administration to adults reduces hormonal secretion by pituitary corticotrophs, with re sulting decrease in plasma ACTH and cortisol.