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From: The Rheumatologist, February 2011

The Evolution of Glucocorticoids

Hench lecturer highlights complexities of these steroid hormones’ signaling mechanisms

by Gretchen Henkel

The Evolution of Glucocorticoids

ATLANTA—In a densely packed lecture at the 2010 ACR/ARHP Annual Scientific Meeting, George P. Chrousos, MD, of the Athens University Medical School (AUMS) in Athens, Greece, mapped our expanding knowledge of glucocorticoids, their mechanisms of action, and regulatory effects on the body [Note: This session was recorded and is available via ACR SessionSelect at www.rheumatology.org.].

Dr. Chrousos, this year’s Hench Lecture Award recipient, is chair of the Department of Pediatrics at AUMS, and previously was chief of the Pediatric and Reproductive Endocrinology Branch of the National Institute of Child Health and Human Development. He also holds a professorship in Pediatrics at Georgetown University and is one of the world’s preeminent authorities on the hypothalamic-pituitary-adrenal (HPA) axis, most notably its relationship to stress-induced pathology.

Accepting the plaque from the Hench Society, Dr. Chrousos said he was honored to be giving a lecture in Dr. Hench’s name. “I would call Philip Showalter Hench a benefactor to the world,” he remarked, referring to Hench’s discovery, with Drs. Edward C. Kendall and Tadeus Reichstein, of cortisone and its healing powers, for which they were awarded the 1950 Nobel Prize in Physiology or Medicine.

Astounding Numbers, Variety

Dr. Chrousos began his lecture by placing glucocorticoids within the context of evolution. Glucocorticoids are steroid hormones that exert their actions through specific receptors, multifunctional domain proteins that operate as ligand-dependent transcription factors.1 These hormones are major adaptive response mediators whose signaling system interacts with other cell signaling systems, and which are essential for maintaining the homeostasis of many of the body’s complex functions, including immune and stress responses. Glucocorticoid receptors (GRs) belong to a class of nuclear receptors generated approximately 400 million years ago from duplications of two ancestral genes, those of the estrogen and the corticosteroid receptors; the latter finally evolved into the glucocorticoid and the mineral corticoid receptors.

Discoveries about glucocorticoid signaling mechanisms in the past 15 years now necessitate a broader view of these vital hormones and their key roles in the body. “You have to think of the human organism as a collection of different tissues that can respond differently to glucocorticoids, either in a glucocorticoid-hypersensitive or -resistant fashion,” Dr. Chrousos noted. Indeed, his earlier work identifying the familial or sporadic generalized glucocorticoid resistance (Chrousos) syndrome has served as a model for subsequent studies investigating the diverse roles that these steroid hormones play in the regulation of several thousand genes in a cell, representing up to 20% of the expressed genome.2

“In our genome, we have between 1,000 and 2,000 binding sites for hormone-activated glucocorticoid receptors dispersed in the chromatin of our cells,” Dr. Chrousos said. “What’s interesting is that the availability of these binding sites for interacting with the GR-glucocorticoid complex depends on the chromatin landscape, which is tissue- and cell type–specific. This explains, to some extent, why the GR has a certain effect on one tissue and a totally different effect on another.” Thus, even though the signaling system is the same, the landscape of the landing site is not. So the cells recognize these signals differently, resulting in a different glucocorticoid effect.

Intensifying the complexity, Dr. Chrousos and colleagues, as well as other groups, have shown that there are at least 16 GR isoforms, eight of which produce isoforms of the “classic” GR alpha and eight of the GR beta. While GR alpha binds to cortisol, GR beta does not bind glucocorticoids, but is able to heterodimerize with GR alpha, decreasing its effectiveness. Thus, the activity of the alpha receptor is moderated by the beta receptor. GRs, he said, are much more stochastic in their effects than originally thought.

You have to think of the human organism as a collection of different tissues that can respond differently to glucocorticoids, either in a glucocorticoid-hypersensitive or -resistant fashion.

—George P. Chrousos, MD

Pervasive Actions

Dr. Chrousos then summarized other recent discoveries about glucocorticoids’ actions, which include regulation of metabolism and the immune response. For example, a recent study in rats found differences in genomic response to the administration of dexamethasone, depending on the animals’ gender.3 While the majority of the genes responded similarly in the two genders, this sexually dimorphic effect was seen in a significant subset of genes consisting of either stimulation or suppression.

Dr. Chrousos’ team studied the effects of glucocorticoids given to patients with acute respiratory distress syndrome and followed the physiological chain of events resulting in control of inflammation. In those given glucocorticoids, plasma levels of TNF alpha, IL-1, and IL-6 decreased, as did nuclear levels of nuclear factor kappa B (NF-κB), normally high in the cell nucleus of inflamed cells. As such, the GR receptors were able to displace NF-κB from the cell nucleus and inflammation came under control.4

Concordance with Circadian Rhythms

Interestingly, Dr. Chrousos noted, the way in which researchers approach their work has changed over the past 30 years, resulting in new discoveries. As a fellow in the 1980s, he recalled, it was “anathema” to engage in any non-hypothesis-driven research. In those “politically correct” times, he said, such studies were labeled “fishing expeditions.”

And yet, today, “discovery-driven research,” as these expeditions have now been relabeled, is acceptable. By applying discovery-driven methods, Dr. Chrousos and his colleagues have begun to uncover additional properties of GR signaling. He highlighted one such “expedition” begun 15 years ago, when he and his team decided to use pieces of the GR as “bait” to see what kinds of proteins would interact within the cell.

One of the most interesting things they found was that one component of the GR bound to the CLOCK transcription factor, an important molecule that regulates day and night activity of an organism. They also discovered that glucocorticoid actions are coupled to the body’s circadian rhythms. For example, the CLOCK transcription factor produces part of the 24-hour oscillations of the genome through altering the activity of the glucocorticoid receptor. Cortisol secretion is typically high at around 8 a.m., peaks again at lunchtime, and then decreases each evening. Examining 24-hour oscillations in the sensitivity of circulating white cells to glucocorticoids, Dr. Chrousos observed that their response to cortisol is an inverse one: In the morning, when cortisol levels are high, the body’s tissues are resistant to its effects. In the evening, when cortisol levels are low, tissues are hypersensitive.

There are many examples of pathology due to the aberrant coupling of the CLOCK and the HPA axis, such as chronic stress, when the body is subjected to chronically high levels of endogenous cortisol, and in such diseases as Cushing’s disease. Likewise, in people who do night-shift work or travel across time zones frequently, the decoupling of CLOCK and the HPA axis can lead to functional hypercortisolism and serious health consequences, such as developing metabolic syndrome (possibly leading to diabetes mellitus type 2), atherosclerosis, and cardiovascular disease. These are just some of the ways by which glucocorticoids, when hypersecreted or hyperfunctional because of uncoupling with tissue sensitivity, can cause premature aging, collection of visceral fat, and loss of muscle.

Earlier, Dr. Chrousos used Hooke’s Law of Physics to illustrate the parallels between GR signaling and pressure exerted on metal. Just as with a metal rod, the body can withstand and bend with the “pressure” of dealing with stress hormones. For the most part, he noted, “we are resilient to perturbations.” But if the tipping point is crossed, returning to homeostasis will not be possible. Cacostasis ensues.5 We now know that glucocorticoid over- or under-secretion or, respectively, tissue hypersensitivity or resistance play significant roles in the genesis of many disorders, including metabolic syndrome, diabetes type II, inflammatory and allergic disorders, depression, and insomnia. Humans, according to Dr. Chrousos, consist of multiple systems self-organized into a whole. “And in complex systems, too much or too little is associated with poor performance; everything in moderation is very important.”

Future Implications

At the conclusion of the lecture, moderator Steven R. Goldring, MD, of the Hospital for Special Surgery in New York City, said that given the different functions of the glucocorticoid receptors in different tissues, these might present an ideal system for developing selective glucocorticoid receptor modulators.

Dr. Chrousos concurred that what is now known about the physiology and molecular biology of glucocorticoid signaling suggests that these kinds of targeted compounds will, indeed, be developed. There are some molecules being studied preclinically, he reported. “I’m sure that eventually we will have synthetic steroids that will be specific for specific conditions. They are going to be here in a few years.” Until then, the glucocorticoid signaling system will continue to reveal its complexities.

Gretchen Henkel is a freelance journalist based in California.

References

  1. Chrousos GP, Kino T. Glucocorticoid signaling in the cell. Expanding clinical implications to complex human behavioral and somatic disorders. Ann N Y Acad Sci. 2009;1179:153-166.
  2. Charmandari E, Kino T. Chrousos syndrome: A seminal report, a phylogenetic enigma and the clinical implications of glucocorticoid signalling changes. Eur J Clin Invest. 2010;40:932-942.
  3. Chrousos GP. Stress and sex versus immunity and inflammation. Sci Signal. 2010;3:pe36.
  4. Meduri GU, Muthiah MP, Carratu P, Eltorky M, Chrousos GP. Nuclear factor-kappaB- and glucocorticoid receptor alpha- mediated mechanisms in the regulation of systemic and pulmonary inflammation during sepsis and acute respiratory distress syndrome. Neuroimmunomodulation. 2005;12:321-338.
  5. Chrousos GP. Stress and disorders of the stress system. Nat Rev Endocrinol. 2009;5:374-381.

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