Abstract
The secretion of glucocorticoids (GCs) is a classic endocrine response to stress. Despite that, it remains controversial as to what purpose GCs serve at such times. One view, stretching back to the time of Hans Selye, posits that GCs help mediate the ongoing or pending stress response, either via basal levels of GCs permitting other facets of the stress response to emerge efficaciously, and/or by stress levels of GCs actively stimulating the stress response. In contrast, a revisionist viewpoint posits that GCs suppress the stress response, preventing it from being pathologically overactivated. In this review, we consider recent findings regarding GC action and, based on them, generate criteria for determining whether a particular GC action permits, stimulates, or suppresses an ongoing stress-response or, as an additional category, is preparative for a subsequent stressor. We apply these GC actions to the realms of cardiovascular function, fluid volume and hemorrhage, immunity and inflammation, metabolism, neurobiology, and reproductive physiology. We find that GC actions fall into markedly different categories, depending on the physiological endpoint in question, with evidence for mediating effects in some cases, and suppressive or preparative in others. We then attempt to assimilate these heterogeneous GC actions into a physiological whole.
The Decline and Modern Revision of Glucocorticoid Physiology
OVER THE past half century, an extraordinary range of glucocorticoid (GC)1 effects upon target tissues have been uncovered. When first studied in the 1930s by Hans Selye, one of the founders of the study of stress, GCs were a topic for the physiologist. Few contemporary endocrinologists view GC actions as part of a coherent physiological picture, or see the need to do so. Today the focus is on the molecular and cell biology of GC action, e.g., GC receptors as ligand-activated transcription factors or GC-induced apoptosis in lymphocytes.
Two broad explanations have been offered for the decline of GC physiology as a discipline (1):
1. Disparate and new GC actions emerged (notably the antiinflammatory actions reported in 1949) (2), which did not fit into the existing paradigm of stress physiology, namely that GCs enhanced the response to stress. Many physiologists either dismissed these effects by declaring them to be pharmacological or ignored them (3, 4) (despite the antiinflammatory effects accounting for more research and publications on GCs after 1949 than all the traditional physiological effects together).
2. Selye, one of the most prolific champions of GC physiology, turned out to be profoundly wrong about critical features of the physiology that he espoused. His claim throughout the early 1940s that GC excess could cause arthritis, allergies, and collagen-related disorders was shattered by the discovery of GC’s antiinflammatory actions.
This debacle discouraged further attempts to make physiological sense of GC actions. Instead, attention moved to the dramatic new clinical applications of these hormones and, eventually, to their cellular and molecular actions.
A consequence of this withering of GC physiology was that it seemed irrelevant to ask the question that dominated earlier research—how do GCs help in surviving stressors? An earlier review (1) aimed to restore the integrative role of GC physiology by means of a new paradigm to encompass the disparate actions of GCs and remove the unconvincing physiological/pharmacological dichotomy. The authors proposed that GCs, rather than enhancing the stress response, through their suppressive actions limit its size and contribute to recovery from it. To quote (1):
“We propose that: (a) the physiological function of stress induced increases in GC levels is to protect not against the source of stress itself, but against the normal defense reactions that are activated by stress; and (b) the GCs accomplish this function by turning off those defense reactions, thus preventing them from overshooting and themselves threatening homeostasis.”
Unknown to the authors of Ref. 1, a paper by Marius Tausk in 1951 (5) published in the periodical of a pharmaceutical firm, included the germ of this idea, which unfortunately did not enter the regular literature. Tausk illustrated his thought pithily by comparing stress to a fire and the role of GCs to that of preventing water damage rather than putting out the fire.
The permissive and suppressive effects of GCs have been suggested to complement each other, the former preparing or priming defense mechanisms for action and the latter, limiting the actions (6). The present review represents a synthesis of the classical view of Selye (that stress-induced secretion of GCs enhances and mediates the stress response), of Ingle (that basal GC levels are permissive of the stress response; 3), and of the emphasis on GCs as limiting the stress response and contributing to the recovery from it (1, 5, 6). The goals of the review are 4-fold: 1) to define the ways in which GCs influence the response to stress; 2) to propose criteria by which to discriminate between these roles in particular cases; 3) to apply those criteria to a broad spectrum of GC actions as organized by physiological systems, extending the analysis into areas not contemplated previously; 4) to attempt a synthesis of the physiological implications and evolution of these GC actions and establish why particular combinations of them make biological sense. As an important caveat, while we are reviewing a considerable body of facts (i.e., a large percentage of the literature concerning the physiology of GC actions) that are generally accepted within the endocrine community, our interpretations and emphases represent a very personal perspective.
Conclusions
Emerging from this survey of GC actions in stress is a picture of extraordinary diversity, whether viewed in terms of the target cells, the metabolic pathways, or the physiological functions that GCs regulate. How those diverse actions are coordinated to protect the organism from specific challenges to homeostasis has been the theme of our analysis. Now we turn to some of the broader implications of our findings.
Although we have not tried to be comprehensive, within our limited goal of discussing GCs only in relation to stress, we have encountered most of the textbook GC actions. (Among the significant exceptions are GC functions in development and parturition, and in bone and ion metabolism). Included implicitly in our survey are even major clinical applications of GCs, since the suppressive actions underlie GC use in treatment of inflammatory and immune disorders, and the permissive actions probably underlie GC use in treatment of adrenal insufficiency (1, 6). Thus, not only are GCs essential for surviving stress, but most GC actions appear to have a role in stress, whether or not they have alternative roles. For example, as discussed, GC effects on carbohydrate metabolism are important both in the prototypical stress of a chase, and in day-to-day regulation of food disposal and blood glucose levels.
This review reaffirms the importance of the permissive actions of GCs. The evolution of the role in stress of permissive actions, rooted in basal GC levels, may well have been separate from that of suppressive (and stimulatory) actions, which are consequences of stress-induced levels of GCs. Key to the suppressive actions must have been the linkage between stress and the ensuing surge in GCs, and key, in turn, to that linkage must have been central nervous system (or comparably central) control of GC secretion. Such control mechanisms appear in all vertebrates including fish, in which cortisol plays the two roles that in mammals are exercised independently by mineralocorticoids and GCs, and may also exist in much more primitive species (see Refs. 439–441). Out of earlier roles of GCs in regulating osmotic and ion balance via such organs as gills during transfer from salt to fresh water and back—which might be regarded as a stressor, and is accompanied in some species of fish by elevation of GC levels (439, 440)—other tissues and functions may have become attuned to periodic surges in GC levels. Eventually, after GCs were relieved of their osmoregulatory role by aldosterone [with the aid of 11b-HSD and the renal-based renin-angiotensin system, and of separate GRs and MRs (442)], GCs could be harnessed to protect against a wider range of stressors and aid in recovery from the various stress responses.
A second major emphasis of this review has been the potential importance of what we have termed preparative functions of GCs. This view has relied heavily upon an ethological perspective, on the assumption that an understanding of stressors and stress responses in natural settings provides an important complement to the traditional study of stress physiology in the laboratory (cf. Ref. 327). We suspect that an ethological perspective will be useful for appreciating the evolution and larger physiological context of other facets of endocrinology as well. As a caveat though, it is always critical to appreciate an ethological setting within the framework of an organism, rather than the perception of the human studying that organism. A circumstance that might, to a human observer, appear to represent a stressful challenge to homeostasis might merely represent a normative life history stage for an animal with adequate metabolic reserves. For example, king penguins which, as a normal part of nesting behavior during the peak of the Antarctic winter, fast for weeks on end without a rise in GC levels (443).
This review also emphasizes the differences between the physiological role of GCs in surviving natural stressors and the pathological effects of prolonged GC elevation. GC physiology should be thought of as the salutary responses (be they mediating or suppressive) to noxious stimuli, whereas GC pathology occurs when the natural recovery phase to a noxious stimulus is prevented from occurring.
Finally, both this and our earlier review (1) noted the tendency of GC endocrinologists in recent decades to view the multitude of GC actions as reflecting a patchwork quilt of often unconnected pharmacological actions. We hope that the present review will stimulate further research within a framework of GC actions constituting a coherent, albeit complex and heterogeneous, physiological whole.