Over the past year and a half, I’ve spent much my time on this blog detailing the various dietary practices and other conditions that can impair intestinal-barrier function, and for good reason. While our intestines are located within us, as far as the body is concerned, this environment is actually external to it.
And what I mean by this is that while we must rely on our digestive system to break down and absorb the food and drink we ingest, improper breaching of the gut wall by food macromolecules, parasites, bacteria, yeast and viruses will always provoke a defensive response from the body. It is for this very reason that the majority of our immune cells are located along the length of the gastrointestinal tract.
For example, bacteria that are beneficial to our health and survival when confined to the lumen or gut wall turn pathogenic when they flood into the bloodstream because of intestinal perforation. Conversely, organisms like Candida albicans, Clostridia difficile and Klebsiella pneumoniae can happily exist in our digestive tract for a lifetime causing us no problems whatsoever, as long as they are kept in check by friendly gut flora and prevented from reaching systemic circulation.
I’ve explained how the membrane that surrounds gram-negative bacteria (lipopolysaccharide; LPS) is uniquely effective in initiating and maintaining chronic immune activation should these bacteria breach the gut wall. I’ve also detailed how these inflammatory reactions can activate what is known as the hypothalamic-pituitary-adrenal (HPA) axis leading to cortisol release.
However, activation of the HPA axis is not the only way endotoxins, and the immune reactions to them, affect cortisol concentrations. There is another pathway that has elicited great interest among researchers. I will introduce you to that pathway in act two.
What’s important to remember is that interactions between the immune and hormonal systems are not unidirectional. Not only do inflammatory cytokines affect cortisol secretion and its metabolism, cortisol also shapes immune function. Indeed, one of the major uses of synthetic cortisol-like medications is to tamp down inflammatory immune responses.
To use a metaphor, cortisol is an active dance partner of inflammation and the cytokines that drive immune responses. It often moves left when inflammation moves right, back when the other moves front–like Swan Lake, but with more Sturm und Drang.
This dance is extremely complex and not always balanced. There are times when the anti-inflammatory actions of cortisol hold sway, and yet other periods when inflammation is in firm control of the choreography much to the detriment of the body and its various organs.
While the actions between the two can be mainly described as oppositional, there are times when their effects are synergistic. Adding to this ballet’s complexity is the fact that rarely are these performers alone on stage. Both are accompanied by other hormonal and immune partners who collectively shape the ebb and flow of immune activation, function and hormonal responses.
Today’s post will introduce you to the first major performer in this so-called ballet: cortisol. I will be covering what this hormone is and what effects it has on various bodily systems. How inflammatory immune responses shape its genesis and metabolism will be left to subsequent posts in this series.
Many effects caused by cortisol excess cannot be entirely divorced from an immune system that often drives or counters these processes. Nor should we forget the effect that intense psychological stress has on cortisol release. That stress is more than capable of initiating disruptions in both intestinal-barrier function and composition of native gut flora populations; and this alone can spark inflammatory cascades.
In other words, what you’re about to read can not always be blamed solely on cortisol and other glucocorticoids. Disentangling where the actions of these agents end and where those of inflammation begin can be extremely difficult.
Even in situations where tumors are clearly the cause of elevations in cortisol secretion as in Cushing’s disease, we may be fooling ourselves if we believe that once the tumor is removed all will be well. Often it is, but in other cases it is not. And this is most likely because of gut flora shifts and disruptions to intestinal-barrier function from previous cortisol excess that persists long after surgical intervention has ended.
Most of what follows is courtesy of two textbooks in my personal library: Greenspan’s Basic and Clinical Endocrinology, Ninth Edition and Williams Textbook of Endocrinology, 12th Edition. Should anyone reading this be in the market for a good endocrinology resource, I recommend the latter as the more comprehensive of the two, although Greenspan’s has a lot going for it. I might add that should you opt to shell out the big bucks for the Williams Textbook, you may want to also spring for a back brace as this tome tips the scales at a hefty ten pounds (4.54 kg).
What Is Cortisol?
Cortisol is a steroid hormone produced in the zona fasciculata of the adrenal glands. It is more formally known as hydrocortisone.
Other hormones produced by the zona fasciculata are the androgens: androstenedione, DHEA and DHEA sulfate. These serve as precursors to testosterone and dihydrotestosterone.
All steroid hormones are derived from cholesterol. While low-density lipoprotein (LDL) cholesterol is considered to be the main substrate for cortisol synthesis, recent research suggests that high-density lipoprotein (HDL) is more important to its formation. (1)
Cortisol is classified as a glucocorticoid. And what, pray tell are glucocorticoids?
Well, the name derives from their ability to regulate glucose levels in the blood, namely by increasing them in opposition to insulin’s action of lowering blood-sugar levels.
Broadly speaking, glucocorticoids are steroid hormones able to bind to glucocorticoid receptors (GR) expressed in a large array of cells and tissues. However, as you’ll soon read, these aren’t the only receptors that glucocorticoids bind to.
As mentioned, glucocorticoids have powerful anti-inflammatory effects that modern medicine has utilized to create a number of synthetic corticosteroids for use in autoimmune and inflammatory conditions like rheumatoid arthritis, ulcerative colitis, lupus, allergies, etc. Common corticosteroids include hydrocortisone, prednisone, dexamethasone, fludrocortisone and beclomethasone.
Cortisol is also popularly referred to as the stress hormone, although other hormones are involved in the fight or flight response like adrenaline and norepinephrine. Typically, however, when people are warning about the hazards of chronic stress, it’s cortisol they’re mostly referring to even if they’re not aware of it.
Many of the effects of cortisol excess I’ll be covering today are also experienced by those taking synthetic glucocorticoid medications. Nonetheless, there is variability in how immune function, blood pressure, glucose levels, etc. are affected both between different synthetic corticosteroids and endogenously produced cortisol.
And that brings me to a warning for anyone now on these medications. While the use of glucocorticoids entails some serious side effects as you’ll soon read, this should not be used as an excuse to stop their use without consulting your physician.
The use of synthetic glucocorticoids, like any hormone-replacement therapy, causes suppression in the body’s production of said hormone, in this case cortisol. As a result, stopping these drugs abruptly can lead to a condition known as adrenal fatigue.
Symptoms of adrenal failure can include any or all of the following:
- extreme weakness, tiredness, fatigue
- abdominal pain
- weight loss
- high calcium levels
- high potassium levels
- low sodium levels
- salt craving
- dizziness when standing from a seated position
- muscle or joint pain
- low blood pressure
- low blood sugar or hypoglycemia
It can take six to nine months after discontinuation of these drugs for the adrenals to again secrete adequate levels of cortisol. Consultation with a qualified doctor is absolutely vital should the decision be made to stop their use. A schedule that gradually tapers their dosage will have to be adhered to for an extended period to avoid this outcome.
Don’t say I didn’t warn you!
I’d like to think that what follows is fairly comprehensive, but I kinda doubt it. The more I learn about glucocorticoids, the more surprised I am about the wide-ranging effects they have on the body. I’m sure future research will uncover more ways bodily systems are affected by their actions.
Much of what we know about glucocorticoid excess has been learned by examining those who suffer from Cushing’s syndrome. This syndrome, not to be confused with the more narrowly defined pituitary-dependent Cushing’s disease, covers most cases of glucocorticoid excess, including those caused by the use of synthetic corticosteroids.
I say most because as I will argue at a later date, one other type of cortisol excess remains to be included under the general heading of Cushing’s syndrome. But as I said, that discussion is for another day.
Free and Bound Cortisol
Cortisol and androgens are released in a free, unbound state by the adrenals. However, once these hormones enter circulation, they are bound by proteins.
Cortisol mainly binds to a protein known as transcortin or corticosteroid-binding globulin (CBG). It also binds to albumin, but to a lesser extent.
Cortisol bound to a protein is biologically inactive. So when you read through the following effects, keep in mind that these are caused by free or unbound glucocorticoids.
Under normal conditions, approximately 10% of circulating cortisol is unbound and active. As for the rest, about 75% is bound to CBG with the remainder to albumin.
I will be using the words glucocorticoid, corticosteroid and cortisol interchangeably for what follows. However as I stated earlier, while the effects of glucocorticoids are broadly similar, there is marked variability between them.
For example, the anti-inflammatory action of the synthetic glucocorticoid fludrocortisone is 12 times that of naturally occurring cortisol. The HPA-suppressing effect of prednisone is four times that of cortisol. Nonetheless, for purposes of today’s post, I’m ignoring these differences to give you a broad overview of the impact these agents have on the body.
OK, with all that out of the way, let’s see what those effects are:
Protein, Fat and Blood Glucose Metabolism
All glucocorticoids inhibit deoxyribonucleic acid (DNA) synthesis in cells external to the liver. They also inhibit the actions of ribonucleic acid (RNA). As both of these are necessary for protein synthesis, their inhibition by cortisol increases the breakdown of protein in muscle.
This breakdown causes an increase in the glucogenic amino acids necessary for accelerated production of glucose in the liver. And while suppressed in peripheral tissue, protein synthesis is stimulated in the liver.
In adipose tissue, elevated glucocorticoid levels increase breakdown of stored fat (lipolysis). This causes an increase in glycerol levels which is also used by the liver to produce glucose. Lipolysis also causes an elevation in free fatty acids, so-called because they are no longer bound to their glycerol backbone. They also cause a rise in plasma triglyceride levels.
Ironically, while lipolysis is stimulated by glucocorticoids like cortisol, a classic outcome of elevated glucocorticoid levels is weight gain and obesity. So while cortisol acts to break down fat to increase production of glucose, it also increases the propensity to pack on the pounds or kilos, and in the worst way possible–as visceral fat.
Studies in animals and humans have shown that elevations in stress and the stress hormone cortisol consistently leads to stimulation of the appetite centers in the brain. Stress activation also has depressive effects on metabolism. This increase in calories ingested against a decline in calories expended accounts for the propensity to gain weight in those experiencing elevations in both serum and tissue glucocorticoid concentrations.
With substrates from both muscle and fat now readily available due to the catabolic actions of glucocorticoids, a dramatic increase in the liver’s production of glucose occurs. This is achieved by a process known as gluconeogenesis.
This is mainly brought about because glucocorticoids call forth a dramatic increase in two liver enzymes necessary for this to occur: glucose-6-phosphatase and phosphoenolpyruvate kinase.
Not only is production of glucose raised, but so too the deposition of glycogen in the liver. Glycogen is the polysaccharide storage form of glucose.
To prevent insulin from countering these effects by shuttling glucose into peripheral cells, cortisol and other glucocorticoids actively inhibit glucose uptake by muscle and fat tissue. Glucocorticoids also enhance the action of other hormones like the catecholamines (adrenaline, norepinephrine, dopamine) and glucagon that also act to counter insulin’s action in peripheral tissue.
The result of all of this is insulin resistance. The higher production of glucose by the liver, combined with increased resistance to the effects of insulin, causes blood glucose levels to rise and stay elevated as long as glucocorticoids remain biologically active.
The pancreas, however, continues to pour out insulin in a futile attempt to bring down blood-glucose levels. But the signal goes unheard, both in peripheral tissue and in the liver where insulin would normally act to shut off gluconeogenesis. Thus diabetes can be an outcome of glucocorticoid excess.
When it comes to who has the upper-hand, glucocorticoids, catecholamines, and glucagon consistently trump insulin. This makes perfect evolutionary sense.
Our very survival as a species depends on our ability to fight or take flight when confronted by external threats. Cortisol, catecholamines and glucagon are required to fuel these responses.
Under such conditions, the actions of insulin are clearly counterproductive. An increase in blood sugar, not its diminution, is what is needed to supply quick energy to the brain and muscles to power these reactions
But external threats are not the only perils faced by our species. Internal threats from increased intestinal permeability and translocating gut pathogens, for example, also elicit similar hormonal reactions due to immune activation.
So when it comes to determining the hierarchy of hormones, it should be fairly obvious that while cortisol opposes the actions of insulin, and insulin opposes the actions of cortisol, when the body is under threat–acute or chronic, external or internal–it is cortisol that grabs the lead role.
Skin and Connective Tissue
In skin and connective tissue, glucocorticoids inhibit both DNA synthesis and cell division reducing production of collagen. In those experiencing chronically elevated cortisol levels, the skin on the back of the hand can become quite thin and takes on a wrinkled appearance that resembles crumpled cigarette paper.
Easy bruising of the skin with minor trauma is also a pervasive side effect. Acne is also common, with outbreaks appearing on the face, chest and back.
Glucocorticoids directly inhibit bone formation. In youth, cortisol excess can stunt growth. Nevertheless, due to an increase in load-bearing weight, a decline in bone-mineral density is typically averted before reaching adulthood.
In adults, osteopenia and osteoporosis are very common outcomes of chronic glucocorticoid excess. In those on synthetic corticosteroid therapy for longer than twelve months, fully 50% will go on to develop osteroporosis.
A small part of this group will go on to develop a condition known as osteonecrosis or avascular necrosis. This side effect produces a very rapid breakdown of bone that primarily affects the hip, leading to pain and collapse. Hip replacement is the only remedy. Osteonecrosis can affect people at any age, and has been documented to occur on relatively low doses of corticosteroids.
Another result of glucocorticoids on bone metabolism has to do with calcium. These agents inhibit absorption of calcium from the digestive tract and accelerate excretion of the same in urine.
Because of induced low calcium or hypocalcemia, the parathyroid glands kick into high gear to correct the imbalance. Parathyroid hormone also causes bone to be broken down to raise levels of calcium in the blood.
Glucocorticoids reliably increase blood pressure. First by increasing sensitivity to agents like the catecholamines and angiotensin II. Secondly, by decreasing nitric oxide dilation of smooth muscle cells in the vasculature.
Glucocorticoid excess, along with certain kinds of inflammatory cytokines, can down-regulate an enzyme that normally prevents cortisol from binding to mineralocorticoid receptors (MR) in the kidneys. Activation of these receptors is responsible for sodium retention and potassium loss. Interestingly, glucocorticoids have a higher affinity for mineralocorticoid over glucocorticoid receptors.
Glucocorticoids have quite powerful anti-inflammatory effects, which is why they are widely used in medicine to treat all manner of inflammatory conditions. Now, as I wrote in relation to omega 3s in my post on polyunsaturated fats, whenever you read the word anti-inflammatory, you should automatically interpret this to mean immune suppressing. Plainly speaking, glucocorticoids are anti-inflammatory because they suppress certain immune functions.
The broad effect glucocorticoids have on immune cells is well beyond my ability to explain them in a single blog post. Suffice it say that these effects are wide-ranging, and there are still many questions left unanswered about how they are produced.
This illustration comes from a paper entitled: The kaleidoscope of glucocorticoid effects on immune system. As can be gleaned from this illustration, these effects impact a large variety of immune cell types and the signaling proteins some of these cells produce.
Most of the effects are suppressive as indicated by the truncated red arrows. Moreover, note that anti-inflammatory Treg cells are stimulated by these agents.
However, I want to point your attention to the cell type seen in the upper-right-hand section that is labeled MΦ and is colored bright orange. Do you see it?
This represents macrophage cells. Their name derives from the Greek for ‘big eaters’, and that is precisely what they do. They eat or phagocytose cellular debris or pathogens, either as stationary cells like resident Kupffer cells in the liver, or as mobile immune cells drawn to the site of an infection.
Macrophage activity is either stimulated or inhibited by glucocorticoids depending on their concentration. This illustrates that cortisol can augment inflammatory immune reactions under certain conditions, and therefore does not universally act in an immune-suppressive manner.
Needless to say, these powerful immune-shaping effects can dramatically dial down inflammation. However, these same effects also increase susceptibility to catching things like the cold, flu or tuberculosis. This explains the common association seen between high-stress levels and increased susceptibility to infection.
Apart from viral and bacterial infections, fungal infections of the skin, nails and bowel are also a common occurrence in those on glucocorticoid medications or experiencing chronically elevated endogenous cortisol production. Susceptibility to wound infections also occurs, while wound healing is delayed.
Central Nervous System
Glucocorticoids can have pronounced effects on the brain and mood. Recall that cortisol and most other glucocorticoids have a high affinity for both glucocorticoid and mineralocorticoid receptors. Both types of receptors are expressed in the brain, including the hippocampus, hypothalamus, cerebellum and cortex.
Glucocorticoids are well-known for causing the death of brain and central nervous system cells or neurons. For this reason, there is great interest in studying glucocorticoid excess as a precipitating factor in impaired cognitive function, neurodegenerative diseases and Alzheimer’s.
In those diagnosed with Cushing’s syndrome, about 50% report some mood or psychiatric disorder. Some of the disorders reported are depression, fatigue, paranoia, anxiety, overt psychosis, insomnia, irritability, apathy and euphoria. Again, how much of this is due directly to glucocorticoids and how much is due to inflammatory immune activation that often accompanies their presence is yet to be determined.
Memory and cognitive function are often impaired in those experiencing higher glucocorticoid levels. Feelings of being spaced out and having a hard time concentrating are often seen in this group.
Glucocorticoids raise pressure in the eyes. Combined with genetic predisposition, these hormones are capable of initiating development of glaucoma.
Cataracts are also a known side effect of elevated glucocorticoid levels. No doubt this has something to do with chronic elevations in blood glucose and free fatty acids as cataracts are also quite common in those with pre- or full-blown type-2 diabetes.
Long-term use of glucocorticoids increases the chance of developing peptic ulcers. Glucocorticoids increase triglyceride levels. As hypertriglyceridemia is a risk factor for developing pancreatitis, those on long-term glucocorticoid therapy are at higher risk of developing this disorder.
Glucocorticoids consistently increase intestinal permeability and endotoxemia. One hypothesis holds that effects on mast cells lining the digestive tract is the reason for this occurrence. (2)
Another theory holds that their general immune-suppressing actions can permit the out-of-control growth of pathogens like Candida albicans and gram-negative bacteria in the digestive tract. This could conceivably allow these pathogens to crowd out beneficial gut flora, and compromise intestinal-barrier function by initiating inflammatory responses at the level of the gut wall.
Another mechanism is disturbance to intestinal motility due to depressed thyroid hormone metabolism that predisposes to small bowel infection. I describe why below.
Whatever the mechanism(s), glucocorticoid’s ability to disrupt gut-barrier function, intestinal movement and gut flora populations can initiate and sustain a cycle of gut dysbiosis, endotoxemia, inflammation and chronic cortisol secretion that can make resolving gastrointestinal disturbances very difficult.
Glucocorticoids reliably suppress thyroid hormone function and metabolic rate. Some of this effect is due to direct inhibition of the pituitary gland’s secretion of thyroid-stimulating hormone (TSH).
However, while this is mainly true for acute glucocorticoid spikes brought about by the rapid onset of infection, chronic glucocorticoid excess is more likely to have tissue-specific effects on thyroxine (T4) conversion to its more biologically active triiodothyronine (T3) form.
Glucocorticoids also down-regulate peripheral T3 receptors and increase levels of biologically inactive reverse T3. This explains why euthyroid sick syndrome is commonly seen in those diagnosed with Cushing’s syndrome.
Declines in metabolic rate will cause gastrointestinal issues like constipation, delayed stomach emptying and gastroesophageal reflux disease (GERD). It will also predispose to development of small intestinal fungal and bacterial overgrowth (SIFBO) as slowed intestinal movement can lead to migration of predominantly gram-negative bacteria from the colon into the small intestine.
Glucocorticoids suppress gonadotropin-releasing hormone (GnRH). GnRH is released by the hypothalamus and causes the pituitary to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH).
In women, LH stimulates secretion of progesterone and estrogen. A surge in LH in the mid-menstrual cycle is responsible for ovulation. In men, LH stimulates testicular cells to produce testosterone.
FSH in women stimulates maturation of ovary follicles. In men, this hormone is important for maintaining production of viable sperm.
Disruption in GnRH secretion is therefore an important cause of infertility in both men and women. This explains why psychological stress is often associated with difficulties in becoming pregnant.
Glucocorticoid excess also delays onset of puberty in young girls. It also causes the absence of menstrual cycles in women of reproductive age; a condition known as amenorrhea.
Glucocorticoids increase blood levels of LDL cholesterol and triglycerides. However, they lower blood concentrations of HDL.
As mentioned, the prevailing view had been that LDL served as the main substrate for cortisol synthesis. It now appears that HDL is the preferred source.
This would suggest that reductions in HDL may be partly explained by an accelerated conversion of this lipid to cortisol. This would further imply that the typical pattern seen in those diagnosed with metabolic syndrome of high LDL cholesterol, high triglycerides and low HDL may actually be an outcome of cortisol activation.
The well-known fact that those suffering from Cushing’s syndrome and Cushing’s disease experience higher rates of heart disease than the general population speaks to the role stress hormones play in the genesis of this disorder. Moreover, given the reality that increases in glucocorticoid levels rarely, if ever, occur without concurrent immune activation, implies that both are intimately involved in the onset of cardiovascular disease.
Well, that pretty much covers the effects glucocorticoids have on the body, although I’m sure there are things I’ve missed. In the next post, I’ll shift focus to how the immune system interacts with cortisol.
Gardner, D.G. & Shoback, D. (2011). Greenspan’s Basic & 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.