Low Cortisol Levels (Hypocortisolism), Adrenal Insufficiency

Cortisol is one of the sterol hormones known as glucocorticoids secreted by the outer cortex of the adrenal gland. These small glands sit on top of each kidney and secrete several important hormones. Cortisol is known to have a wide range of effects on carbohydrate, protein and fat metabolisms as well as regulates the inflammatory process in response to injury and the body’s immunity. It is also considered as one of the stress hormones in that it is secreted in large quantities over a long period of time when the body is under stress.

Cortisol secretion is large regulated by the hormone ACTH (adrenocorticotropin hormone) secreted from the pituitary gland. Low cortisol levels stimulate the hypothalamus to release corticotropin-releasing factor (CRF) which then acts on the anterior pituitary to stimulate ACTH secretion. High cortisol levels reduces CRF secretion which in turn decreases ACTH secretion.

In order to understand the effect of low cortisol levels it is important to first be familiar with the functions of this hormone. This is discussed further under the functions of cortisol. Another group of hormones also secreted from the adrenal cortex is known as the mineralocorticoids which regulate blood pressure and the fluid-electrolyte balance in the body. The main mineralocorticoid is aldosterone. Low cortisol levels are often accompanied by low aldosterone levels as well if the adrenal gland is diseased. The adrenal glands also produce small amounts of androgens (male sex hormones) which are present in both males and females and also contributes to the clinical presentation.

What is hypocortisolism?

Hypocortisolism is the deficiency of circulating cortisol in the body due to an underactive adrenal cortex. This condition is known by several other names including adrenocortical hypofunction or simply as adrenal insufficiency and aldosterone deficiency may or may not also be present. The androgen levels may also be lower than normal but this is more prominent in women.

Causes of Hypocortisolism

Adrenocortical insufficiency may be either primary or secondary. In primary adrenocortical insufficiency, also known as Addison’s disease, the low cortisol and/or aldosterone levels can be attributed to pathology within the the adrenal cortex itself and may be accompanied by low aldosterone levels. Primary insufficiency may be divided into acute or chronic. In secondary adrenocortical insufficiency, the low cortisol levels are due to low ACTH levels as a result of pituitary pathology and the adrenal gland itself is intact. Therefore aldosterone levels are normal while only cortisol is low.

Primary Adrenocortical insufficiency

Primary adrenocortical insufficiency can be acute or chronic.
The acute form is known as an adrenal crisis or Addisonian crisis where there is existing adrenal insufficiency and there is suddenly a need for greater quantities of cortisol. The adrenal glands are unable to compensate and an adrenal crisis develops. It may also be seen with glucocorticoid therapy which is suddenly discontinued or if there is any cause of massive adrenal hemorrhage which immediately and almost completely compromises normal adrenal functioning.
The chronic form, known as Addison’s disease, may be due to a wide range of causes and is an uncommon condition overall. Clinical features are only seen when most (about 90%) of the adrenal tissue is destroyed thereby preventing early diagnosis and intervention. Since the pathology is within the adrenal gland resulting in destruction of the cortical tissue, aldosterone and androgen levels are also diminished.

The anterior pituitary attempts to increase cortisol secretion by secreting large quantities of ACTH. In the process a large amount of pro-opiomelanocortin (POMC) is also secreted which is a precursor to both ACTH and MSH (malnocyte-stimulating hormone). MSH is responsible for skin pigmentation and high levels contribute to the overall presentation of Addison’s disease.

Causes of chronic primary adrenocortical insufficiency includes :

  • Autoimmune conditions known as autoimmune adrenalitis are the most common cause of adrenocortical insufficiency. Here the immune system attacks the adrenal tissue and while the exact cause is not always known, it may occur in two clinical settings :
    • Autoimmune polyendocrine syndrome type 1 (APS1) caused by a mutation of the gene that regulates autoimmune function. Many glands are targeted simultaneously including the parathyroid gland and gonads.
    • Autoimmune polyendocrine syndrome type 2 (APS2) is seen in early adulthood and occurs in combination with type 1 diabetes or hypothyroidism (underactive thyroid gland).
  • Infections particularly those due to tuberculosis (TB)  and fungi are prominent causes of primary chronic adrenocortical insufficiency. HIV/AIDS patients are at a greater risk of developing these infections along with certain viral and other mycobacterial infections which may not usually affect an immunocompetent patient.
  • Cancer of the adrenal gland is primarily due to metastasis from distant sites like lung and breast. Other sites may include malignancies from the gastrointestinal tract and skin (malignant melanoma). Lymphoma and leukemia also need to be considered.  In HIV/AIDS, Kaposi sarcoma may involve the adrenal gland.
  • Genetic causes involve congenital disorders like adrenal hypoplasia which is an underdevelopment of the adrenal gland from birth.
  • Other causes include :
    • Bilateral surgical removal of the adrenal glands (adrenalectomy)
    • Intra-adrenal hemorrhage (massive hemorrhage may result in and adrenal crisis)
    • Amyloidosis
    • Hemochromatosis

Secondary Adrenocortical Insufficiency

In secondary adrenocortical insufficiency the disease mechanism lies with the pituitary gland or hypothalamus. If the hypothalamus does not stimulate the anterior pituitary by the means of CRF and/or if the anterior pituitary does not secrete ACTH, cortisol secretion from the adrenal glands will be minimal. The feedback mechanism is compromised and there is inadequate stimulation thereby causing low cortisol levels. Usually aldosterone levels are not affected and POMC secretion which contributes to skin pigmentation is not raised.

The anterior pituitary or hypothalamus may be diseased and under-functioning due to infection, infarction, cancer or radiation therapy. ACTH deficiency may occur on its own with an underactive pituitary gland or it may be part of panhypopituitarism where the secretion of all the anterior pituitary hormones are diminished.

Signs and Symptoms of Adrenal Insufficiency

Low cortisol levels may cause :

  • Hypoglycemia – low blood glucose levels
  • Muscle weakness
  • Fatigue
  • Weight loss
  • Muscle aches and joint pains
  • Nausea, vomiting and diarrhea
  • Irritability and depression
  • Lack of appetite

With primary adrenocortical insufficiency the low levels of aldosterone and androgens may cause the following symptoms :

  • Hypotension
  • Dehydration
  • Salt craving
  • Loss of pubic hair and armpit hair (androgen deficiency)

The high levels of melanocyte-stimulating hormone in Addison’s disease may cause darkening of the skin (hyperpigmentation). This is more pronounced on sun-exposed areas and pressure points like the knees, elbows, neck and knuckles. It is usually absent in secondary adrenal insufficiency.

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