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corticoids. Withdrawal of the corticoids enhances both the release and 

 synthesis of ACTH, its predominant effect being on the synthesis (Fortier, 

 1959a, b) . The steroids appear to act on the pituitary itself, but they may 

 act also on the hypothalamic centers, or on the releasing mechanism or 

 mechanisms themselves, or even may act to some extent on the adrenal 

 gland directly (Birmingham and Kurlents, 1958). However, the corticoids 

 evidently are not capable of blocking the release of ACTH in response to all 

 types of tissue damage, unless the steroids are present in very large quan- 

 tities. It has been suggested in the case of tissue damage, such as burns, 

 that substances are released from the site of the injury (Hume, 1953; 

 Woodbury, 1958; Share and Stadler, 1958), which are able to stimulate 

 directly the release of ACTH by direct action on the pituitary, although 

 final proof of such a suggestion is lacking. It is unlikely that histamine, 

 epinephrine, serotonin or a variety of other compounds which are released 

 during tissue-breakdown are responsible for directly stimulating the release 

 of ACTH (Sandberg et al, 1953; Guillemin, 1955; Guillemin et al, 1957; 

 Woodbury, 1958) as has been suggested. Nervous impulses from the site 

 of injury cannot be responsible for initiating the release of ACTH following 

 injury, as complete denervation of the part or transection of the cord fails 

 to block the release of ACTH (Hume, 1953). The mechanism by which 

 adrenocorticotropin is released following tissue damage needs to be deter- 

 mined. 



Finally, there is evidence that two or more substances from the hypo- 

 thalamus may regulate different activities of the adrenal cortex. Slusher 

 (1958) has shown that lesions in one region of the hypothalamus will block 

 the usual fall in adrenal ascorbic acid which follows cortical stimulation 

 without preventing the release of cortical steroids. On the other hand, 

 lesions in a nearby region can prevent the release of corticoids without pre- 

 venting the fall in ascorbic acid. Guillemin ct al, (1958) have shown that 

 there may be a functional separation of corticoid secretion from ascorbic 

 acid depletion. These investigators found that a marked secretion of corti- 

 coids could occur in the absence of detectable changes in adrenal ascorbic 

 acid concentration when both variables were measured simultaneously fol- 

 lowing stimulation by ACTH in hypophysectomized rats. Finally, there is 

 other evidence which suggests that the factors controlling cortical hyper- 

 trophy (adrenal weight factor: AWF) and ascorbic acid (ascorbic acid 

 factor: AAF) reduction are separate entities and may respond differentially 

 to different stimuli (Nowell, 1959) . Nowell (1959) has suggested that stim- 

 ulation of the release of various ACTH factors from the pituitary may in- 

 volve different mechanisms for different stimuli; for example, emotional 

 stimuli may require activation of the hypothalamic centers, whereas adre- 

 nal regeneration may not require hypothalamic activity. 



