Notes
Cortisol Physiology
Sections
Key Points
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
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.
Cortisol Regulation
First, we show the 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.
Physiologic Roles of Cortisol
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.
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