Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1583
Address all correspondence and requests for reprints to: Dr. G. P. Chrousos, National Institutes of Health, Building 10, Room 9D42, Bethesda, Maryland 20892-1583. E-mail: chrousog{at}mail.nih.gov.
Glucocorticoids are one of the most pervasive hormones in the human organism (1, 2). These steroid molecules reach all tissues, including the brain, readily penetrate the cell membrane, and interact with ubiquitous cytoplasmic/nuclear glucocorticoid receptors (GRs), through which they exert markedly diverse actions. In a first glimpse, using DNA microarray technology, we found that approximately 20% of the expressed human leukocyte genome was positively or negatively affected by glucocorticoids (3). This is many-fold the proportion of genes that change in the transformation of a normal cell to a tumor cell and involves an amazingly wide array of functions, including every aspect of resting and stress-related homeostasis (3, 4). The pervasive nature of glucocorticoids, the rapid advances in our general knowledge of the human genome, and the massive amount of information that increasingly accumulates dictate a new model of thinking and testing of hypotheses regarding the actions of these hormones and their involvement in human physiology and pathophysiology.
In this issue of JCEM, Wuest et al. (5) present a convincing association between the hypothalamic-pituitary-adrenal (HPA) axis response to a standardized socioemotional stimulus and polymorphisms of the GR gene. This study follows others using a similar rationale and examining HPA axis indices and other end points, such as arterial blood pressure, body mass index and markers of the metabolic syndrome, and bone mineral density (reviewed in Ref.5). These studies have had some overlap and mostly concordant results but have also shown inconsistencies. This should have been expected because they were performed in a limited number of subjects in different ethnic populations, and because the altered GR would have been expected to function differently in the context of different genetic backgrounds characterized by different genes with differing epistatic effects on the ability of the GR to exert its actions (6).
Empirically, experimentally, and intuitively, physicians and scientists have made major advances in the general understanding of glucocorticoids and their involvement in human pathophysiology and in using these hormones extensively and effectively in the treatment of a wide spectrum of human diseases (1, 2). As the end product of the HPA axis, glucocorticoids are literally involved in every organ system of the human organism, in almost every physiological, cellular, and molecular network, and in many crucial modules of these networks (2, 3, 6). Furthermore, glucocorticoids participate in a pivotal fashion in the unfolding of vital biological programs using synchronously or in tandem several networks, including the behavioral and physical response to stress, the inflammatory reaction, the sickness syndrome, and the process of sleep, as well as long-term functions such as growth and reproduction (4, 6). As it happens with many other homeostatic systems, too much, as well as too little, of HPA axis and/or glucocorticoid activity signify pathology (e.g. Cushing syndrome vs. Addison disease, respectively) (7, 8, 9). Because the responsiveness of the target tissues to glucocorticoids is crucial for the end effect of these hormones, similar pathology may result from hypersensitivity or resistance to these hormones, respectively (8) (Table 1). However, because the brain and the pituitary are also targets for glucocorticoids, and because the organism strives for homeostasis in time-integrated free cortisol exposure, any generalized change in the glucocorticoid signaling system would be followed by corrective, compensatory changes in the activity of the HPA axis. However, absence of complete compensation, be it slightly excessive or deficient, could result in allostasis and target tissue pathology, as occurs in chronically stressed or depressed individuals (9, 10). But this has been known for a number of years. The key question follows below.
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From the above, it is apparent that the way to proceed further in understanding the roles of polymorphisms of multiple genes related to the HPA axis and the glucocorticoid signaling system in human physiology and pathophysiology will be to study large populations of normal subjects, including adequate numbers of representative racial and ethnic subpopulations, as well as populations of patients afflicted by states and diseases that may result from dysfunction of this system, which are summarized in Table 2. Once we have defined the crucial genes and polymorphisms, the numbers of which we predict will be large but technically manageable, we could use new existing and constantly improving methods to screen for changes in the entire gene networks of choice that, in the appropriate context, could predict the relative risk for developing common disorders in which cortisol plays a significant role, such as visceral obesity along with its various and varying degrees of metabolic syndrome manifestations, arterial hypertension, autoimmune allergic and inflammatory disorders, and psychiatric states. Also, granted that a large subgroup of this gene network plays a major role in regulating immune function, this information could be useful in predicting vulnerability to certain infections and tumors. Finally, this knowledge might help individualize medications and doses for subjects with the above conditions in a rational way, an effort in which the pharmaceutical industry has already made a major investment.
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Footnotes
Abbreviations: GR, Glucocorticoid receptor; HPA, hypothalamic- pituitary-adrenal.
Received November 17, 2003.
Accepted November 24, 2003.
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