Cortisol Physiology & Cushing's Syndrome

Cortisol is the primary glucocorticoid secreted by the zona fasciculata of the adrenal cortex. Its secretion is triggered by Adrenocorticotropic Hormone (ACTH), which is released by the anterior pituitary. ACTH and cortisol secretion is pulsatile and circadian; levels are highest upon waking and decline to reach their lowest levels around bedtime – thus, we need to be aware of a person's sleep schedule when assessing these hormone levels. On top of this baseline rhythm, stress and other factors trigger additional release of ACTH and cortisol. Cortisol receptors are located throughout the body, in many tissue types; physiologic roles include dampening the immune/inflammatory responses and mobilizing fat, protein, and carbohydrates from the cells to maintain energy homeostasis. Cushing's Syndrome = Elevated levels of cortisol, aka, hypercortisolism We categorize hypercortisolism as ATCH-dependent (in which elevated cortisol is caused by elevated ACTH) and, ACTH-independent (in which elevated cortisol is not caused by elevated ACTH). Most cases of Cushing's syndrome are due to the use of exogenous glucocorticoids (which is, by definition, ACTH-independent). Exogenous Cushing's syndrome/Iatrogenic Cushing's syndrome. When hypercortisolism is suspected, and glucocorticoid administration is not the cause, we need to rule out physiologic causes and certain medical conditions that raise cortisol levels, which include: pregnancy, alcoholism, anorexia, obesity, depression, and uncontrolled diabetes. Stress is a key trigger for cortisol secretion; chronic physical and/or psychosocial stress and subsequent hypercortisolism can have widespread negative health effects. HPA axis – the hypothalamus, pituitary gland, and adrenal gland, which rests upon the kidney. Neurosecretory cells originate in the paraventricular nucleus of the hypothalamus, and that their axons terminate on capillaries of the hypothalamic-pituitary portal system. Various types of endocrine cells reside in the anterior pituitary; we label the corticotrophs with a C, and show the nearby capillaries that deliver hormones to the blood supply. The hypothalamus secretes Corticotropin-Releasing Hormone (CRH, formerly known as corticotropin-releasing factor, CRF) into the neurosecretory cells, which deliver it to the anterior pituitary. Upon reaching the corticotrophs, CRH triggers their release of Adrenocorticotrophic Hormone (ACTH). ACTH leaves the pituitary and travels in the bloodstream to the cortex of the adrenal gland, where it triggers cortisol (and androgen) release. Cortisol travels in the blood to various body tissues.

• Most of the cortisol in the blood, approximately 85%, is bound to plasma proteins; hence, it has a long half-life. * Urine free cortisol and salivary cortisol, which we often use to measure cortisol levels, is not bound to these plasma proteins.

Regulation of the HPA axis: Stress is a key trigger for CRH release from the hypothalamus – including physical and psychosocial stressors.

• This makes sense, since cortisol regulates metabolism to maintain energy homeostasis. In times of stress, our body's energy use increases, and cortisol helps to increase energy availability.
• CRH is also released in response to low levels of circulating cortisol, and, to ADH (aka, vasopressin).

Cortisol has a negative feedback effect at both the hypothalamus and at the pituitary, where it blocks the release of CRH and ACTH, respectively. Dexamethasone, which is a synthetic glucocorticoid, mimics these negative feedback effects. As we'll see, it may be used to help diagnose Cushing's syndrome. Immune, inflammatory, and metabolic effects Suppression of inflammatory and immune responses:

• It does this via multiple pathways; for example, write that cortisol inhibits pro-inflammatory mediators such as monocytes, neutrophils, and cytokines.
• At physiologic levels, this effect protects us from over-active inflammatory and immune responses that cause tissue damage.
• However, indicate that too much suppression of these responses can increase our susceptibility to infection.

Increases carbohydrate metabolism: Increases gluconeogenesis in the liver and decreasing insulin resistance and utilization by other body tissues, such as skeletal muscle.

• Thus, blood glucose levels increase.
• Excessive cortisol exposure can lead to hyperglycemia.

Increases protein metabolism and decreases protein stores in the tissues (note that this does not happen in the liver).

• Since skeletal muscle is a primary protein storage site, we use it as our example to show that cortisol decreases protein synthesis and increases protein metabolism.
• These processes result in increased amino acid substrates for gluconeogenesis in the liver; thus, this is another way to increase energy availability.
• However, chronic exposure to elevated cortisol leads increased muscle fiber degradation and loss skeletal muscle mass.

Increases fat metabolism: Increases lipolysis, which generates free fatty acids to fuel gluconeogenesis (again, increasing energy availability).

• Despite increasing lipolysis, hypercortisolism is associated with increased weight gain and obesity.
• This is because cortisol induces hypertrophy (enlargement of fat cells due to fatty acid synthesis) and hyperplasia (increased formation of mature adipose cells).

Increases bone resorption Influences bone remodeling by increasing bone resorption and reducing the formation of new bon* tissue.

• Thus, chronic exposure to elevated cortisol can result in osteoporosis and increased vulnerability to bone fractures.

To screen for hypercortisolism, we can take 24-hour urine samples, midnight salivary samples, or try a dexamethasone suppression test (recall that dexamethasone is a synthetic glucocorticoid that mimics cortisol – thus, it should suppress the HPA axis). If the results of these tests reveal cortisol within the normal range, or suppressed from the dexamethasone, we can exclude Cushing's syndrome. If cortisol levels are elevated and/or not suppressed by the dexamethasone test, then we can say that Cushing's syndrome is likely. Now, we have to figure out what's causing the hypercortisolism – is it due to elevated ACHT, or something else? To determine this, we'll measure plasma ACTH levels. If plasma ACTH levels are low/suppressed, there may be a cortisol-secreting adrenal tumor; we'll want to do imaging tests to investigate this.

• We'd expect to find a tumor in one adrenal gland and atrophy of the other (atrophy is due to lack of stimulation by ACTH, which is inhibited by negative feedback of cortisol on the HPA axis).

Adenomas are more common than carcinomas, and carcinomas are more likely to secrete androgens along with cortisol. Be aware that bilateral macro- and micro-nodular adrenal hyperplasias, though rare, can also cause ACTH-independent Cushing's syndrome. We need to rule out exogenous glucocorticoids and other physiologic and medical causes, as we mentioned in the introduction, as potential sources of ACTH-independent hypercortisolism. If plasma ACTH is elevated/not suppressed, hypercortisolism is ACTH-dependent – the adrenal gland is releasing cortisol in response to excessive stimulation by ACTH. Now, we need to determine the source of the excess ACTH. There are a few ways we can do this; we'll use inferior petrosal sampling in our example. If we find central ACTH levels are higher than peripheral levels, the cause is likely a pituitary tumor secreting ACTH – this is called Cushing's Disease, and typically involves an adenoma.

• This is the most common form of endogenous (non-iatrogenic) Cushing's Syndrome.
• In these patients, the HPA axis is dysfunctional, and is no longer responsive to negative feedback from cortisol.
• Furthermore, the HPA axis is no longer responsive to stressors that would typically stimulate the release of additional ACTH (likely because CRH secretion has been suppressed by chronic hypercortisolism).
• Secretion of thyrotropin, gonadotropin, and growth hormone are also suppressed.
• Treatment involves removal of the pituitary tumor, which can reverse these effects in many, but not all, patients. Some patients may require bilateral adrenalectomy.

• In these cases, be aware of a potential complication called Nelson syndrome (aka, corticotroph tumor progression), in which a pituitary tumor develops, producing headaches, elevated ACTH levels, and hyperpigmentation.

If we find central ACTH levels less than or equal to peripheral levels, the source is likely an ectopic (non-pituitary) tumor.

• Small cell lung cancer and bronchial tumors are often to blame, although tumors in other tissues can also secrete ectopic ACTH.

Click for Diagrams of the HPA axis in these scenarios. Be aware that not all patients will exhibit these signs and symptoms, and they can vary by etiology. "Moon facies" describes the rounded shape of the face and neck that can develop as a result of fat accumulation on the sides of the face. Central, aka, truncal obesity is common, with a so-called "buffalo hump" due to fat redistribution and accumulation between the shoulders in the upper back. As you may have guessed from our earlier discussion on the roles of cortisol, patients with Cushing's syndrome are prone to muscle, bone, and skin atrophy and weakness. Muscle atrophy is particularly apparent in the extremities, so patients' limbs appear disproportionately thin, and their bones may be more prone to fracture. Red or purple striae in the skin, particularly on the abdomen, breasts, thighs, and buttocks; these are the result of increased subcutaneous fat and the loss of collagen and other structural components of the skin. Patients may also bruise more easily. Hypertension is caused via multiple effects, including increased cardiac contractility and increased extracellular fluid volume. Hyperglycemia is common, and may progress to diabetes mellitus, because cortisol increases gluconeogenesis and insulin resistance. Immunosuppression increases vulnerability to infectious diseases that require robust B- and T-cell-mediated immune responses (for example, tuberculosis and fungal infections). Patients may experience emotional or psychiatric disturbances, such as irritability or impaired memory. The excess androgen secretion associated with some forms of Cushing's syndrome (i.e., adrenal tumors) can cause hirsutism and menstrual irregularities. In children, hypercortisolism can impair linear growth via negative effects on bone growth and impaired secretion of growth hormone and thyroid stimulating hormone.