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 autonomic brain regions. Dysfunction of CRH-mediated neurotransmission is emerging as a critical mechanism in several disorders. Therefore, modulation of CRH availability at receptor sites is a potentially powerful therapeutic tool. Inhibitory analogues of CRH have been tested in rodents and primates, but their safety and hormonal effects in humans are unknown. We administered a CRH-antagonist, alpha-helical-CRH-(9-41) to six individuals. Each received two intravenous infusions: 50 micrograms kg-1 on day 1, and 100 micrograms kg-1 on the following morning. These doses block both endocrine and central effects of CRH in experimental animals. ACTH, cortisol, electrolytes, glucose and autonomic parameters were monitored in comparison with control values. Infusion of CRH antagonist did not alter heart rate, blood pressure, temperature or plasma electrolytes 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, significantly lower than pre-infusion levels. Plasma cortisol levels, which averaged 21.4 +/- 4 micrograms dl-1 on the first morning and 22.9 +/- 4.2 on the second, also decreased significantly after CRH antagonist infusions (to 14.0 +/- 2.9 micrograms dl-1 on day 1, and 13.9 +/- 3.0 micrograms dl-1 on day 2). Hormonal changes were transient, and circadian rhythm was not affected. Though not measured formally, euphoria, anxiety or somnolence were not observed. In conclusion, CRH antagonist administration to adults reduces hormonal secretion by pituitary corticotrophs, with resulting decrease in plasma ACTH and cortisol