Evidence of a corticotropin-releasing hormone pulse generator in the macaque hypothalamus

Abstract

The secretion of hormones from the hypothalamic-pituitary axis is, in general, characterized by an episodic pattern of release. In the adrenal axis, ACTH and cortisol levels in peripheral blood display irregularly pulsatile ultradian patterns that are superimposed on the well characterized circadian rhythm. While it is generally accepted that CRH is released from the hypothalamus in a similar manner, very few studies have actually examined the temporal release of CRH. To examine the temporal release of CRH directly, we have established an in vitro perifusion system using the hemisectioned macaque hypothalamus. Perifusate samples were collected at 10-min intervals for 20 h and assayed for CRH by RIA. In control animals, a very regular, pulsatile pattern of hormone release was present, with a pulse interval of 90 +/- 11 min. Although this interval closely approximates the average pulse interval of ACTH and cortisol in the human, the regular pattern revealed in our study has not been demonstrated previously in the adrenal axis in vivo and suggests that factors outside the hypothalamus play a major role in controlling adrenal hormone levels. When hypothalami were perifused with dexamethasone added to the culture medium, no change in pulsatile activity was detected, indicating that a site outside of the hypothalamus may function as the primary center of feedback inhibition by adrenal glucocorticoids in the central nervous system. Because the very regular pulses of CRH that we observed bear striking similarity to the circhoral pulses of GnRH, we speculate that CRH may play a more subordinate role in regulating the adrenal axis and that other releasing factors and/or feedback effects at the pituitary level may be more important in the generation of the irregularly pulsatile, circadian patterns of ACTH and cortisol seen in peripheral blood.