Failure to produce adequate levels of cortisol, or adrenal insufficiency, can occur for different reasons.
The problem may be due to a disorder of the adrenal glands themselves (primary adrenal insufficiency) or to inadequate
secretion of ACTH by the pituitary gland (secondary adrenal insufficiency).
Primary Adrenal Insufficiency
Most cases of Addison's disease are caused by the gradual destruction of the adrenal cortex, the outer layer of
the adrenal glands, by the body's own immune system. About 70 percent of reported cases of Addison's disease are
due to autoimmune disorders, in which the immune system makes antibodies that attack the body's own tissues or
organs and slowly destroy them. Adrenal insufficiency occurs when at least 90 percent of the adrenal cortex has
been destroyed. As a result, often both glucocorticoid and mineralocorticoid hormones are lacking. Sometimes only
the adrenal gland is affected, as in idiopathic adrenal insufficiency; sometimes other glands also are affected,
as in the polyendocrine deficiency syndrome.
The polyendocrine deficiency syndrome is classified into two separate forms, referred to as type I and type II.
Type I occurs in children, and adrenal insufficiency may be accompanied by underactive parathyroid glands, slow
sexual development, pernicious anemia, chronic candida infections, chronic active hepatitis, and, in very rare
cases, hair loss. Type II, often called Schmidt's syndrome, usually afflicts young adults. Features of type II
may include an underactive thyroid gland, slow sexual development, and diabetes mellitus. About 10 percent of patients
with type II have vitiligo, or loss of pigment, on areas of the skin. Scientists think that the polyendocrine deficiency
syndrome is inherited because frequently more than one family member tends to have one or more endocrine deficiencies.
Tuberculosis (TB) accounts for about 20 percent of cases of primary adrenal insufficiency in developed countries.
When adrenal insufficiency was first identified by Dr. Thomas Addison in 1849, TB was found at autopsy in 70 to
90 percent of cases. As the treatment for TB improved, however, the incidence of adrenal insufficiency due to TB
of the adrenal glands has greatly decreased.
Less common causes of primary adrenal insufficiency are chronic infections, mainly fungal infections; cancer cells
spreading from other parts of the body to the adrenal glands; amyloidosis; and surgical removal of the adrenal
glands. Each of these causes is discussed in more detail below.
Secondary Adrenal Insufficiency
This form of Addison's disease can be traced to a lack of ACTH, which causes a drop in the adrenal glands' production
of cortisol but not aldosterone. A temporary form of secondary adrenal insufficiency may occur when a person who
has been receiving a glucocorticoid hormone such as prednisone for a long time abruptly stops or interrupts taking
the medication. Glucocorticoid hormones, which are often used to treat inflammatory illnesses like rheumatoid arthritis,
asthma, or ulcerative colitis, block the release of both corticotropin-releasing hormone (CRH) and ACTH. Normally,
CRH instructs the pituitary gland to release ACTH. If CRH levels drop, the pituitary is not stimulated to release
ACTH, and the adrenals then fail to secrete sufficient levels of cortisol.
Another cause of secondary adrenal insufficiency is the surgical removal of benign, or noncancerous, ACTH-producing
tumors of the pituitary gland (Cushing's disease). In this case, the source of ACTH is suddenly removed, and replacement
hormone must be taken until normal ACTH and cortisol production resumes. Less commonly, adrenal insufficiency occurs
when the pituitary gland either decreases in size or stops producing ACTH. This can result from tumors or infections
of the area, loss of blood flow to the pituitary, radiation for the treatment of pituitary tumors, or surgical
removal of parts of the hypothalamus or the pituitary gland during neurosurgery of these areas.
This e-pub was written by Eileen K. Corrigan of NIDDK's Office of Health Research Reports. The
draft was reviewed by Dr. George P Chrousos, National Institute of Child Health and Human Development, Dr. Judith
Fradkin, National Institute of Diabetes and Digestive and Kidney Diseases, and by Dr. Richard Horton, University
of Southern California Medical Center.
NIH Publication No. 90-3054
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