High Cortisol Levels (Hypercortisolism, Cushing Syndrome)

The Hormone Cortisol

Cortisol is the main type of glucocorticoid – a group of hormones secreted by the outer cortex portion of the adrenal glands that sit on top of each kidney. These glucocorticoids are sterol hormones and cortisol (hydrocortisone) is a natural corticosteroid.

Cortisol secretion is almost entirely controlled by the hormone ACTH – adrenocorticotropin hormone – secreted by anterior pituitary and acts on the adrenal cortex to stimulate cortisol secretion. ACTH secretion in the pituitary gland is in turn controlled by corticotropin-releasing factor (CRF) from the hypothalamus. If the cortisol levels in the blood are too high, it inhibits CRF from the hypothalamus and ACTH from the anterior pituitary. The direct negative feedback mechanism ensures that the adrenal glands do not secrete anymore cortisol.

In order to understand the effects of high cortisol levels it is important to have a knowledge of the functions of cortisol.

Functions of Cortisol

Cortisol is one of the most versatile hormones in the body having a wide range of effects. The functions of cortisol includes its effects on nutrients (carbohydrate, protein and fat) metabolism, on inflammatory processes in the body and its effects on the immune system.

Carbohydrate Metabolism

Cortisol promotes gluconeogenesis, a process that causes amino acids (breakdown products of protein) to be converted into glucose. At the same time it reduces the utilization of glucose by the cells. Both these effects increase the blood glucose levels. Cortisol can also reduce the effect of insulin which should decrease the blood glucose levels. The glucose levels if more than 50% of normal is referred to as adrenal diabetes.

Protein Metabolism

Cortisol decreases protein stores in the cells by reducing protein synthesis within the cells and promoting protein breakdown. This causes protein depletion in most tissues. However the liver cells are stimulated to produce more protein and this also increases the blood proteins. At the same time, the protein that is “recalled” is ultimately used for gluconeogenesis as explained above under carbohydrate metabolism.

Fat Metabolism

Cortisol causes fatty acids to be mobilized from the adipose tissues (fat stores) and stimulates the cells to use these fats for energy production. This spares the glucose even further as discussed under carbohydrate metabolism. However this shift does not cause fat loss in the long term but rather the effects of high cortisol will increase fat stores in certain areas like the chest and back.

Inflammation and Immunity

Cortisol can block the various stages of inflammation thereby stopping the inflammatory process or even preventing it from starting up. Therefore it is a natural anti-inflammatory in the body. Cortisol also reduces the concentration of certain white blood cells like eosinophils and lymphocytes which may also reduce inflammation but at the same time the immunity is partly compromised.

What is Cushing Syndrome?

Cushing syndrome is a condition associated with higher than normal levels of cortisol in the bloodstream. It is also known by other terms including :

• hypercortisolism (excess cortisol)
• hyperadrenalism (overactive adrenal gland) which may also involve the mineralocorticoids and androgens from the adrenal cortex or epinephrine and norepinephrine from the adrenal medulla.
• adrenocortical hyperfunction (overactivity of the adrenal cortex) which may also involve the mineralocorticoids and androgens from adrenal cortex

In Cushing syndrome, there is also extra androgens secreted by the adrenal cortex. The effects of excess androgens are more prominent in women. An excess of cortisol will exaggerate its effects as described above and this is harmful to the body in the long term. This is potentially life threatening depending on the severity and duration of the condition. Sometimes the levels of cortisol and ACTH are elevated and the clinical effects of Cushing syndrome are apparent but the disease does not have the same detrimental effects as Cushing syndrome. This is known as pseudo-Cushing syndrome.

Causes of High Cortisol Levels

The causes of high cortisol levels may be divided into endogenous or exogenous causes. Endogenous causes refers to any conditions or diseases that leads to an excess of cortisol production and secretion within the body. Exogenous causes refers to the administration of cortisol into the body.

Endogenous Causes

Most of the endogenous causes are a consequence of one or more of the following processes :

• growth of the adrenal cortex causing the secretion of more cortisol
• growth of the anterior pituitary causing a greater secretion of ACTH which stimulate cortisol secretion
• abnormal activity of the hypothalamus (rarely a tumor) that secretes more CRF which then stimulates ACTH secretion
• ACTH-secreting tumor located elsewhere in the body other than the pituitary gland which increases ACTH levels

Endogenous causes can be further divided into ACTH-dependent and ACTH-independent factors. This means that the causes of excess cortisol secretion is due to the action of ACTH or it occurs without the overactivity of ACTH.

ACTH-Dependent

• Pituitary adenoma secreting ACTH (most common cause)
• Pituitary hyperplasia – enlargement of the anterior pituitary usually due to excess CRH (rare)
• Ectopic corticotropin due to an ACTH-secreting tumor usually from cancers of the bronchus or lung

ACTH-Indepenent

• Adrenal adenoma (benign)
• Adrenal carcinoma (malignant ~ cancer)
• Genetic mutations
  • McCune-Albright syndrome (GNAS1 gene)
  • Primary pigmented nodular adrenal disease (PDE8B and PDE11 genes)
• Bilateral macronodular adrenal hyperplasia (there is also an ACTH-independent variety)

Exogenous Causes

This is the administration of glucocorticoids usually seen with corticosteroid therapy. It is also known as iatrogenic Cushing syndrome. Administration of ACTH may also cause a similar effect.

• Chronic glucocorticoid therapy
• ACTH therapy

Pseudo-Cushing Syndrome

This may be due to :

• Excess alcohol
• Severe depression
• Obesity not related to Cushing syndrome (primary obesity)

Signs and Symptoms of High Cortisol Levels

The clinical features are non-specific meaning that it does not only occur in Cushing syndrome and on its own it is not conclusive for high cortisol levels. Due to diverse effects of cortisol, many systems in the body will be compromised due to excess level of the hormone.

Body Shape, Skin and Hair

• Obesity particularly on the upper body (chest,  back, neck and face). The fat deposition be very pronounced on the back  between the shoulders (buffalo hump) and face (moon face).
• Striae which are pink to purple (may also appear dark brown) stretch marks on the arms, breast, lower abdomen, buttocks and thighs.
• Bruises and the skin is thin heals poorly.
• Plethora which is the red flushing of the skin particularly on the face.
• Acne
• Thinning hair
• Hirsuitism – excessive hair growth particularly on the face

Muscles and Bones

• Muscle weakness and wasting.
• Osteoporosis which is fragile bones leading to easy fractures.
• Loss of height due to compression fractures.
• Back pain

Reproductive System

• Menstrual irregularities in women
• Infertility
• Erectile dysfunction in men
• Diminished libido

Blood and Vessels

• Hypertension – high blood pressure
• Hyperglycemia – high blood glucose levels
• Hyperlipidemia – high cholesterol and triglyceride levels
• Hyperinsulinemia – high insulin levels in the blood due to insulin resistance

Mental

• Irritability and anxiety
  
• Depression
• Psychosis

Eyes

• Cataracts
• Exopthalmus – abnormal bulging of the eyeball

General

• Severe fatigue
• Increased thirst often leading to excessive urination