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Massive evidence has now accumulated which indicates that the pituitary-adrenal cortical system responds sensitively to psychological influences. This evidence represents converging and reinforcing findings from diverse studies of many species, including man. It involved the use of many methods of eliciting, isolating, and evaluating emotional disturbances, relatively direct and specific biochemical measurements of endocrine activity, and control measures that permit exclusion of concomitant physical variables. It also appears that the principal experimental or methodological factors which were involved in the relatively few conflicting findings reported in this field have now been largely identified, eliminated, or adequately taken into consideration.There is no longer room for reasonable doubt as to the validity of the basic conclusion that psychological stimuli are capable of influencing the level of pituitary-adrenal cortical activity. It now appears to be time to consolidate our grasp of the knowledge that is firmly established in this field and to review the implications in order that we may logically decide the most likely directions for fruitful future work along these lines.Some of the general biological conclusions emerging from the work covered in this review may be summarized as follows:Psychological influences are among the most potent natural stimuli known to affect pituitary-adrenal cortical activity.The remarkable sensitivity of 17-OHCS levels even to relatively subtle, everyday psychological influences suggests that the central nervous system exerts a constant “tonicity” upon this endocrine system, in much the same fashion as has been previously demonstrated for the autonomic and skeletal muscular effector systems.Elevation of 17-OHCS levels is not related to a highly specific affective state, but rather appears to reflect a relatively undifferentiated state of emotional arousal or involvement, perhaps in anticipation of activity or coping.The elements of novelty, uncertainty, or unpredictability are particularly potent influences in eliciting 17-OHCS elevations.Intense, disorganizing emotional reactions with behavioral breakdown are associated with unusually marked 17-OHCS elevations.Psychological factors may either raise or lower the level of pituitary-adrenal cortical activity. Some important variables to consider in relation to the direction of 17-OHCS response are the quality of the emotional reaction, the style and effectiveness of psychological defenses, and whether the threat is of an acute or chronic nature.Marked individual differences in pituitary-adrenal cortical response to any given situation have been a striking and consistent feature of psychoendocrine studies. Definition of the multiple determinants, psychological and other, of these individual differences is a major goal in the future development of psychoendocrine research. The organization of psychological defenses has been shown to be an especially important factor to consider in the study of this problem.The measurement of 17-OHCS levels provides the behavioral scientist with a sensitive, objective index of a physiological reflection of emotional state that represents a balance between forces promoting affective arousal or distress versus those of a protective or defensive nature which prevent, minimize, or counteract arousal or distress.Experience in psychoendocrine research on the pituitary-adrenal cortical system has also yielded a number of important conclusions concerning methodological principles, which have been discussed at some length. These principles deserve wider recognition and should be useful in the future refinement of psychoendocrine research in general.It is perhaps also important to realize that the recent burgeoning development of psychoendocrine research owes both its conception and support largely to psychiatry, and that the dissemination of psychoendocrine data has remained largely within the psychiatric literature -as clearly revealed by the inspection of the bibliography for this paper. The many fruitful psychoendocrine approaches to a variety of basic issues in psychiatry which have now been delineated, as reviewed recently, 133 are gradually gaining recognition; thus it is likely that psychoendocrine approaches will be incorporated into psychiatric research programs to an even greater degree in the future as general awareness of their power and potential grows.While the concept of psychological influences upon endocrine function has, in general, been readily accepted by behavioral scientists, it has, however, made very little headway as yet into other biological fields-particularly physiology and internal medicine. While psychoendocrine concepts may not yet provide the immediate promise of research tools and approaches for these fields as they do in the case of psychiatry, they have profound implications for the study and understanding of physiological integration and must, inescapably, be eventually incorporated into physiological thought. It may be true that the participation of psychological factors in endocrine regulation temporarily “muddies the waters” from the viewpoint of physiological theory, by complicating the servomechanism formulation of endocrine regulation, but this is not by any means the first instance in physiology in which a higher-level regulatory mechanism has been found to be superimposed upon a lower-level mechanism.It should also be recognized that there are practical implications involved which the biological investigator concerned with measurement of metabolic or physiological functions in the conscious animal or human can no longer afford to ignore. There is clearly now a burden on such investigators to minimize extraneous environmental and psychological stimuli and to take necessary control measures to rule out the possibility that observed bodily responses are related to psychological or emotional reactions. What really appears to be needed, in fact, is a closer two-way relationship between psychoendocrinology and physiology. The endocrine glands are regulated in life by both physical and psychological stimuli, in varying combinations, and at present the psychoendocrinologist is perhaps as much in danger of ignoring physical or constitutional factors as the physiologist is of ignoring psychological factors in the experimental study and conceptualization of endocrine regulation.A principal reason for including this review in the present series is to give an impression of the overwhelming weight of evidence for the superimposition of psychological mechanisms upon endocrine regulation. Definitive support for this conclusion in the case of the pituitary-adrenal cortical system should reasonably be expected to minimize contention over drawing similar conclusions for other endocrine systems if evidence along similar lines is obtained, even though it be on a smaller scale. It is also suggested that the evolution of psychoendocrine research on the pituitary-adrenal cortical system provides us with a valuable guide to the lines that similar research on other endocrine systems must very likely follow. Finally, a review of the extensive work on this system brings out the relative paucity of studies on most of the other endocrine systems.