The response of luteinizing hormone to a single injection of synthetic LRH was established in 6 women and 7 men following an intramuscular dose of 0.2mg or 0.1mg. Significant increases of serum LH were observed in 30 min. Pretreatment with metyrapone for one day (4.5 g/sugject injection of synthetic LRH (0.1 MG/SUBJECT). Seven women, 21-48 years of age who were treated with prednisolone for a least 11/2 months were examined for responsiveness of the anterior pituitary to a single injection of synthetic LRH (0.2 MG). The secretion of LH was markedly suppressed and maximal serum levels of LH WERE OBSERVED 90 MIN FOLLOWING LRH injection.

Circadian periodicity of the hypothalamic content of corticotropin-releasing factor (CRF) was determined in normal and adrenalectomized male rats, using the intrapituitary micro-injection method. It was found that the CRF activity in the rat hypothalamus showed a definite circadian variation, having the peak value at 6 p.m. and the minimum at 8 a.m. under the lighting schedule used here (light between 6 a.m. and 7 p.m. followed by 11 h of darkness). A close temporal relationship with a definite phase shift was observed between the CRF activity and plasma corticosterone level. The finding thus supports the concept that the circadian rhythm of the pituitary-adrenal axis is a direct reflection of the rhythmicity of CRF activity in the median eminence. Furthermore, the persistent periodicity observed in the CRF activity in the absence of circulating corticosterone suggests that the dominating mechanism for the control of the circadian rhythm of CRF activity is of neural origin, being independent of the negative feedback mechanism.

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Negative feedback in the hypothalamic-pituitary-adrenal axis by exogenous glucocorticoids has been well established, but it is still in doubt whether ACTH-releasing factor (CRF) activity in the hypothalamus is inhibited by endogenous glucocorticoids under conditions of stress. In our first experiment, CRF activity in the hypothalamus of rats was significantly increased, 2 min after onset of immobilization, for 2 min; a rapid drop of CRF activity followed immediately. On the other hand, the concentration of plasma corticosterone changed more slowly; it was increased at 5 min, and showed a progressive further increase until 17 min after the administration of the immobilization stress. A high plateau level persisted for the next 8 min, after which the concentration of plasma corticosterone fell, reaching the control level at 40 min. In order to test for negative feedback inhibition by endogenous glucocorticoids in the hypothalamic-pituitary-adrenal axis, a 2nd immunobilization stress was administered to rats 5 or 23 min after the 1st stress, and hypothalamic CRF activity and plasma corticosterone were examined after the 2nd stress. When the 2nd stress was applied 5 min after the start of the 1st stress, during the phase of a gradual increase of endogenous glucocorticoids, CRF activity was not increased 2 min after the 2nd stress. In contrast, an increase of CRF activity and plasma corticosterone was observed when the 2nd stress was administered 23 min after the onset of the 1st stress, during the phase of a high plateau level of endogenous plasma corticosterone. These data suggest that CRF activity in the hypothalamus is governed by a fast feedback, rate-sensitive mechanism.

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Only a few reports have appeared which have attempted to determine whether the naturally occurring steroid, corticosterone, has the same site of action in the hypothalamus-pituitary-adrenal axis as the synthetic steroid, dexamethasone. The present studies help to define the site of inhibition of both corticosterone and dexamethasone on the hypothalamus-pituitary-adrenal axis. Infusion of 20 or 202 µg corticosterone over 6 h significantly reduced hypothalamic CRF (corticotropin-releasing factor) content, whereas it did not reduce plasma ACTH levels in normal rats. This finding indicates the possibility that the infusion of corticosterone may decrease the hypothalamic CRF content by reducing CRF production or enhancing intracel-lular and/or extracellular CRF degradation. On the other hand, infusion of 20 µg dexamethasone for 6 h to normal rats significantly decreased plasma ACTH levels, but did not alter the hypothalamic CRF content. This finding indicates that dexamethasone may inhibit the release or/and production of ACTH in the anterior pituitary. In addition, relatively large doses of corticosterone (504 µg/rat) and dexamethasone (202 µg/rat) may suppress CRF content and ACTH release at the level of both the hypothalamus and anterior pituitary.

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