Welcome back from your second and last intermission. I trust the wait wasn’t too long. In today’s post, I’ll be concentrating on how cortisol is regulated by the body, and how these regulatory systems are shaped by immune activation.
There is a happy medium where hormone concentrations within a defined lower and upper limit result in the best health outcomes. However, go outside those boundaries for extended periods and unfortunate things begin to happen as we saw in the first act with both adrenal insufficiency and cortisol excess.
Some of you may have noted how similar the symptoms of glucocorticoid overload are to syndrome X or metabolic syndrome. First explained by Gerald Reaven, an American endocrinologist and professor at Standford University School of Medicine, metabolic syndrome has many of the same symptoms as Cushing’s syndrome: abdominal obesity, elevated blood pressure, high fasting blood glucose, raised triglyceride levels, high LDL and low HDL cholesterol levels.
You are not alone if this thought crossed your mind. For a while now, some researchers have defined metabolic syndrome as a form of Cushing’s syndrome. (1) (2) However, where Cushing’s patients consistently display elevations in plasma cortisol, persons with metabolic syndrome typically do not. (3)
I believe there is a good explanation for these observations. However, before I get to that, I really need to cover how cortisol is regulated by the body.
The Hypothalamic-Pituitary-Adrenal (HPA) axis
Whenever the brain perceives stress, including the stress of infection, corticotropin releasing hormone (CRH) is secreted by the paraventricular nucleus of the hypothalamus. This hormone then travels to the pituitary where it acts on receptors in the anterior lobe of this gland.
In response, the pituitary releases adrenocorticotropic hormone (ACTH). ACTH acts by binding ACTH receptors in the adrenal glands. This in turn stimulates secretion of cortisol. Free, unbound cortisol is now able to attach to receptors in a variety of sites throughout the body.
The increase in plasma cortisol concentrations reacts back on the brain not only to inhibit further release of CRH by the hypothalamus, but also of ACTH from the pituitary. In other words, a rise in plasma cortisol calls forth a decrease in the hormones that caused the adrenals to secrete it in the first place.
However, if there is a pituitary tumor as in Cushing’s disease, this feedback loop is never closed. Instead, the pituitary gland continues to pump out ACTH oblivious to signals that cortisol is already at high levels.
In other cases, tumors that are not part of this HPA-axis can also release ACTH to stimulate cortisol release. For example, some small-cell lung carcinomas do this. However, it’s well beyond the scope of today’s post to explain the many ways this axis can be affected by tumors.
However, the HPA-axis isn’t the only way cortisol is regulated by the body. For that, we need to look at another system, this one having to do with the metabolism of cortisol within cells.
The Cortisol-Cortisone Shunt
This, ladies and gents, illustrates the cortisol-cortisone shunt, which, if you ask me, kinda sounds like a funky dance. I promise to make this as painless as possible…..really I do.
Recall that cortisol bound to a protein might as well not exist as far as the body is concerned. Bound cortisol is biologically inactive.
But there is another way for the body to inactivate cortisol, and that is by converting it to cortisone. Cortisone is also biologically inactive. But why, I’m sure some of you are wondering, would the body do this? Patience my dears, patience.
Cellular enzymes exist that can not only convert active cortisol to inactive cortisone, but can reverse the process by changing cortisone back to cortisol. These enzymes are 11β-HSD1 and 11β-HSD2. Both are shown in the two yellow ovals of this graphic.
These abbreviations, by the way, stand for 11β-hydroxysteroid dehydrogenase type 1 and 11β-hydroxysteroid dehydrogenase type 2. If you think that’s a mouthful, try typing it!
OK, let’s start with the type 2 whatchamacallit thingy first, shall we? The burgundy blob on the right represents the kidneys, and attached to the kidneys are the adrenals, site of cortisol production and release.
And what you’re seeing illustrated here is that cortisol is converted from its active form to cortisone by 11β-HSD2 within kidney cells. Also seen here is that kidney tissue expresses mineralocorticoid receptors.
See the box in the lower center part of this illustration? The one that starts with kidney, colon, etc.? Those are sites that contain mineralocorticoid receptors. This isn’t an exhaustive list by the way, but good enough for today’s purposes.
Recall that cortisol not only binds to glucocorticoid receptors, but also to mineralocorticoid receptors. And interestingly enough, cortisol has a higher affinity for mineralocorticoid than for glucocorticoid receptors.
But this presents a wee bit of a problem for the kidneys and us, as binding to these receptors can mimic the actions of aldosterone. Aldosterone is another hormone produced by the adrenals involved in blood pressure regulation.
Aldosterone plays this role by acting on the sodium, potassium and water retention system in the kidneys. Dysregulation of this system by this hormone is a major contributor to hypertension.
If 11β-HSD2 did not convert cortisol to inactive cortisone in kidney cells, cortisol would bind to these receptors causing a chronic increase in blood pressure. So 11β-HSD2 plays a very critical role in preventing cortisol from doing this. However, when plasma cortisol levels are high, the inactivating function of 11β-HSD2 can be overwhelmed leading to chronically high blood pressure.
Cortisone can be converted back to cortisol by the enzymatic actions of 11β-HSD1. This is seen on the left-hand side of this graphic where the liver is represented. The overwhelming majority of this enzyme’s action, but by no means all, occurs here.
In the liver, cortisone is reconverted to cortisol and the free hormone is once again capable of binding to both glucocorticoid and mineralocorticoid receptor sites throughout the body. See the box in the upper-left-hand corner? These are some of the tissues that express glucocorticoid receptors. But again, this list is by no means exhaustive.
OK, so what I want you to take away from all this is that the cellular enzymes 11β-HSD1 and 11β-HSD2 have opposite actions when it comes to cortisol metabolism. All things being equal, if 11β-HSD1 enzymatic activity is predominant, more cortisol will be generated from inactive cortisone within cells and tissue. Conversely, if there is more 11β-HSD2 activity, the opposite happens.
Immune Activation and Cortisol Secretion
Many of you are already familiar with this graphic from my post The Gut-Brain Axis: How Endotoxemia and “Leaky Gut” Impact the Hypothalamic-Pituitary-Adrenal Axis. There is no need for me to once again explain what I covered in that post, other than to say that this graphic is missing a very, very important player, namely tumor necrosis factor alpha (TNF-α), the cytokine introduced to you in the second act of this ballet.
In the green box where you see the cytokines interleukin 1 (IL-1) and interleukin 6 (IL-6) represented, TNF-α should also be listed. It, like IL-1 and IL-6, acts directly on the hypothalamus to cause the release of CRH.
This activation of the HPA-axis is, however, self-limiting because of the feedback loop I mentioned above. So in gut dysbiosis, one can argue that stimulation of this axis is apt to occur acutely and not chronically, with digestion of food and drink being a precipitating factor.
Note also in this graphic that the immune system acts on the adrenals by producing what is known as prostaglandin E2 (PGE2). Prostaglandins are lipid compounds produced from certain polyunsaturated fatty acids (PUFAs). In the case of PGE2, that fatty acid is arachidonic acid, an omega 6 PUFA.
Immune cells like monocytes and macrophages produce large quantities of PGE2 when activated by bacterial toxins from the gut. Immune neutrophils also produce PGE2s, but in moderate amounts. So this is another way the adrenals can be stimulated to secrete cortisol when pathogens breach the gut wall.
Immune Activation and the Cortisol-Cortisone Shunt
However, immune activation from a leaky gut does not only impact the adrenals via the HPA axis or PGE2 generation. Pro-inflammatory cytokines like TNF-α and IL-1 also lead to an increased expression of the intracellular 11β-HSD1 enzyme that converts inactive cortisone to active cortisol. (7) (8) (9)
Now, what’s important to remember is that this conversion is taking place within cells, not outside them. In other words, where stimulation of the HPA axis and increases in PGE2 formation are likely to be noticeable as elevations in plasma cortisol when measured by a saliva, blood or urine test, what occurs within cells cannot be detected by these same tests. The only way to note an increase in 11β-HSD1 enzymatic activity would be by tissue biopsy.
And this means that if a standard test for cortisol doesn’t register systemic elevations in this hormone, that doesn’t mean that intracellular concentrations are not high. On the contrary, a lot of recent research has shown that an increased conversion of cortisone to cortisol within cells may be the key to unraveling the mystery of metabolic syndrome.
In rodents, inhibition of or genetic deficiency in 11β-HSD1 improves insulin sensitivity in the liver and fat tissue. It also slows production of glucose by the liver, changes the lipid profile of these rodents to one that is “heart healthy”, reduces or reverses accumulation of fat in the liver and causes fat to be stored as less dangerous subcutaneous fat and not pro-inflammatory visceral fat. (10) (11) (12) (13) (14)
Conversely, mice genetically bred to overexpress this same enzyme in their fat tissue become obese, develop high blood pressure, show a lipid profile conducive to heart disease and are insulin resistant. (15) Mice who are bred to selectively overexpress 11β-HSD1, but only in the liver, do not become obese. However, they exhibit insulin resistance, develop fatty livers, hypertension and an atherogenic cholesterol profile. (16).
In humans with type 2 diabetes, inhibition of 11β-HSD1 also lowers plasma glucose levels and cholesterol markers for heart disease. Inhibition has also shown promise in reducing high blood pressure. (17) (18) (19) This improvement in blood pressure is no doubt due to less cortisol attaching to the mineralocorticoid receptors in the kidneys.
TNF-α also induces a decrease in 11β-HSD2, the enzyme that converts cortisol to inactive cortisone. This too would affect the kidneys’ regulation of blood pressure.
As we saw in act two, this up-regulation of cortisol metabolism makes biological sense as a way to counterbalance immune activation. The anti-inflammatory actions of cortisol also aid in the eventual resolution of the immune response.
But what if acute immune activation doesn’t resolve? Well, then we have chronic immune activation, and along with it comes the potential for chronic conversion of cortisone to cortisol within a whole host of tissues: the liver, muscles, kidneys, fat, arteries, central nervous system, etc.
This suggests that metabolic syndrome is just another form of glucocorticoid excess, but one that is more likely to affect the cortisol-cortisone shunt rather than the HPA-axis. It is for this reason that plasma cortisol concentrations can appear normal in those who have type 2 diabetes or are morbidly obese, yet within cells generation of cortisol remains elevated. And with its elevation, many of the effects of glucocorticoid excess become obvious.
I’ve reprinted this chart from the first act illustrating the myriad effects glucocorticoids like cortisol have on immune cells, including macrophage cells represented in the upper-right-hand corner in orange and labeled MΦ. What I want to emphasize is how low doses of cortisol, and that includes cortisol generated within cells, augments the inflammatory actions of these immune cells.
Secretion of inflammatory cytokines by these macrophages induces an increase in the enzymatic actions of 11β-HSD1, that in turn causes cortisone to be converted to cortisol. And that reacts back on these same macrophages to cause them to release even more inflammatory cytokines.
This feed-forward system is prevalent in many tissue types, but seems particularly active in visceral, as opposed to subcutaneous, fat. This turns this type of adipose tissue into a chronic generator of both cortisol and inflammatory cytokines.
Because of this, a lot of research has been devoted to either inhibiting the actions of cytokines like TNF-α, or suppressing the up-regulation of 11β-HSD1 within cells. I don’t want to discount these efforts, but these approaches carry some risks.
For example, should a drug be developed that reliably inhibits the actions of 11β-HSD1, I think it’s safe to predict that runaway immune responses with all their attendant risks would be a serious side effect. And indeed, studies in mice bear out this pro-inflammatory prediction. (21) (22)
As far as TNF-α is concerned, there are already drugs in use to inhibit its actions. These agents are being used to treat autoimmune disorders like rheumatoid arthritis, for example. However, such therapy also poses serious risks, as does all immune-suppressive therapy. Some of those risks are outlined in this paper.
I have argued from the start that gut dysbiosis is often the source of the immune activation and consequent cortisol release and metabolism that underlies many chronic disease states. Would it not make more sense to shut off the source of that activation and not suppress either immune function or inhibit cortisol metabolism? I believe so.
This hypothesis of gut dysbiosis setting in motion the inflammatory-cortisol ballet can explain why diet can have such a profound effect on health. We can predict that those foods and drinks that nourish beneficial gut flora, and by doing so support gut wall integrity, would be expected to inhibit this inflammatory cascade.
Conversely, those foods and drinks that damage these organisms, and by doing so compromise gut wall integrity, would be expected to increase the number of times this “ballet” is performed as well as its duration.
Now, no one should take this to mean that I’m discounting the role psychological stress plays in the onset of disease. Far from it.
The research is pretty clear that chronic psychological stress increases the risk for many diseases, including cardiovascular disease. (23) (24) As I’ve written, psychological stress is more than capable of negatively impacting the health of our gut bacteria as well as compromising gut-barrier function.
Health is more than what you put or don’t put in your mouth. Having a loving family and good friends, being financially secure, engaging in daily exercise, utilizing stress-reduction techniques—all are important to good health. And a major reason is because they all keep the stress response in check.
But I would argue that someone who also suffers from gut dysbiosis is at a far greater disadvantage when it comes to handling the stresses of life than someone who doesn’t. For in such situations, any psychological stress is piled on top of an immune and hormonal system that is already chronically activated. The added stress just ensures that this inflammatory-cortisol ballet is transformed into an exhausting dance akin to what we saw in the movie They Shoot Horses, Don’t They?.
Gut dysbiosis and the inflammatory-cortisol cascade provoked by this, negatively affects emotional well-being and the ability to handle the challenges of everyday life. It is not in the least bit unusual to note improvements in mental health and outlook in those who successfully overcome their gut issues. Never forget that the gut-brain axis is a two-way street.
The inflammatory-cortisol ballet can explain many of the disparate symptoms seen in those suffering from various forms of gut dysbiosis.
For example, let’s consider someone with confirmed metabolic syndrome. They are obese, have elevated fasting blood glucose, high triglyceride levels, high LDL levels, suffer from hypertension, osteopenia and insomnia. In other words, they manifest many of the symptoms of cortisol excess we read about in act one.
In this situation, inflammation, or to be more precise, inflammatory cytokines like TNF-α, IL-1 and IL-6 are causing an increase in intracellular cortisol metabolism separate and apart from any transient cortisol spikes from stimulation of the HPA-axis. And this immune activation is being caused in response to lipopolysaccharides (LPSs) and other gut components (yeast, gram-positive bacteria, etc.) coming through the gut wall due to increased intestinal permeability.
Now inflammation is clearly driving cortisol secretion and metabolism. However in this case, what is most noticeable are the dance steps of Margot Cortisol Fonteyn, not those of Rudolf Inflammatory Nureyev. In other words, the symptoms of glucocorticoid excess are in the forefront, yet the underlying immune activation that’s driving the entire process is hidden from view.
Now what if we really cranked up gut permeability? Would the results be the same?
Let’s say we look at another person with a very severe drinking problem, say they consume at least a fifth of whiskey per day. And let’s also say that this person is a heavy cigarette smoker, on the order of two to three packs a day. You can tell they’re heavy smokers by looking at the yellowed and rotting teeth populating their mouth, a sure sign of oral dysbiosis.
Due to their oral dysbiosis, many of these mouth pathogens are swallowed daily. Given how binge drinking reliably raises stomach acid pH, many of these bacteria happily make their way to the gut undisturbed. Here they displace beneficial bacteria, adhere to the gut wall, and with the help of alcohol’s metabolite, acetaldehyde, make sure that their host’s gut resembles a sieve. In other words, they too have gut dysbiosis but on another level entirely.
As in the case of the person with metabolic syndrome, cortisol is being released from the adrenals in response to translocating gut pathogens and immune activation. And the same goes for conversion of cortisone to cortisol within cells. But this person’s immune system is really pumping out copious amounts of cytokines to deal with the bacterial onslaught.
In this case, unlike in our first example, we are more apt to notice the dance moves of Rudolf Inflammatory Nureyev rather than those of Margot Cortisol Fonteyn.
And indeed, our smoking alcoholic is extremely gaunt and pasty looking. The reason for this is that their body is undergoing a form of cachexia. (25) Partly caused by the anorexic effect these inflammatory cytokines have on appetite, but also due to sped up metabolism and overall catabolism. Any compensatory weight-enhancing effects cortisol would normally have—increase in hunger and slow down in metabolic rate due to euthyroid sick syndrome—are swamped by the intense inflammatory response.
Yes, Margot Cortisol Fonteyn is still leaping and pirouetting like mad. However in this case, her inflammatory dance partner is out dancing her, and poor Margot just can’t keep up, let alone rein him in.
Should our alcoholic smoker never attain sobriety, a heart attack, pneumonia, cirrhosis, or cancer will dispatch him or her to that great distillery and tobacco farm in the sky.
This imbalance between immune activation and the anti-inflammatory actions of cortisol may also explain why reducing, yet not entirely eliminating, increased intestinal permeability can paradoxically result in weight gain for some ex alcoholics and/or smokers. The weight-enhancing effects of cortisol now come to the forefront, while the anorexic effects of inflammatory cytokines recede.
Of course, genetics also plays an important role in how this dance is performed. For example, in people who are efficient at producing cortisol in response to immune activation, the effects of glucocorticoid excess would be more apparent than in low cortisol responders. And if, as in the rodent study I cited above, the 11β-HSD1 enzyme is overexpressed in the human liver, but underexpressed in fat cells, metabolic syndrome would be noticeable, but without the typical weight gain seen in most people with this disorder.
The time has come to bring the curtain down on our inflammatory-cortisol ballet and bid our dancers a good night. No doubt many of you have had more than enough of my ballet metaphors.
I trust, however, that I’ve conveyed to you how disturbances in intestinal bacterial populations and gut-barrier function can set in motion a dance whose wide-ranging effects on the body is best avoided. I also hope I’ve done some justice to those scientists who for decades have pointed the finger at the stress response as the best explanation for metabolic syndrome.
That this disorder closely resembles Cushing’s syndrome is no accident. Where many have been led astray is in believing that plasma cortisol levels have to be consistently raised in order for it to be treated as a form of glucocorticoid excess. What we saw in this post is that even absent HPA-axis stimulation, activation of the cortisol-cortisone shunt by inflammatory cytokines in response to gut dysbiosis results in the same symptomatology.
I believe it’s time to acknowledge that metabolic syndrome is just another form of Cushing’s syndrome, Pseudo-Cushing’s if you will. It’s also time for researchers to concentrate on how diet, drugs and psychological stress affect the source of chronic immune activation, i.e. the gut and its community of bacteria and fungi. Otherwise, any hope of preventing or curing metabolic syndrome remains just that, hope. And as important as hope is to the human spirit, it’s not a particularly effective strategy for keeping us healthy.
Gardner, D.G. & Shoback, D. (2011). Greenspan’s Basic and Clinical Endocrinology (9th ed.). China: McGraw-Hill.
Melmed, S., Polonsky, K. S., Larsen, P. R., & Kronenberg, H. M. (2011). Williams Textbook of Endocrinology (12th ed.). Philadelphia: Saunders Elsevier.
Owen, J. A., Punt, J., Strandford, S. A., & Jones, P. P. (2013). Kuby Immunology (7th ed.). New York: W.H. Freeman and Company.