The causes of adrenal insufficiency divide by the level at which the hormone axis fails: the adrenal cortex in the primary form, the pituitary in the secondary form, and the hypothalamus in the tertiary form.
Epidemiology
Primary adrenal insufficiency mostly occurs between the ages of 30 and 50 and is more common in women, with a prevalence of 90-140 per million in Europe and an incidence of 4-6 new cases per million per year. Secondary adrenal insufficiency is more common than the primary form, with a prevalence of 150-280 cases per million of population, mostly occurring in the sixth decade of life in women.
Primary Adrenal Insufficiency
The main cause of primary adrenal insufficiency has changed over time; from the 1950s onward, about 80-90% of cases are due to autoimmune adrenalitis, which is isolated in 40% of cases and part of the autoimmune polyendocrinopathy syndrome (APS), in which autoimmunity involves several endocrine glands, in 60% of cases.
Addison’s disease, or autoimmune adrenalitis. In more than 90% of cases, Addison’s disease is associated with cell-mediated destruction of the adrenal cortex, mediated by autoantibodies against the 21-hydroxylase enzyme. Certain genetic polymorphisms predispose to it: HLA-DR3-DQ2 and HLA-DR4-DQ8, and variants of other genes such as PTPN22 and CTLA4.
Adrenoleukodystrophy. Adrenoleukodystrophy is an X-linked disorder that affects the ABCD1 gene, which is involved in the β-oxidation of very long chain fatty acids (VLCFAs). Accumulation of VLCFA in the cells of the adrenal cortex damages the cells and leads to primary adrenal insufficiency.
Hemorrhagic infarction. Infarction of the adrenal gland can occur through hemorrhagic conditions and adrenal vein thrombosis. Other causes of hemorrhagic infarction of the adrenal glands are coagulopathies, heparin-induced thrombocytopenia, Waterhouse-Friderichsen syndrome caused by meningococcemia, and Pseudomonas aeruginosa.
Infectious adrenalitis. The common infectious causes that can lead to adrenalitis and primary adrenal insufficiency are Mycobacterium avium complex, cytomegalovirus infection in HIV-positive patients, and syphilis.
Drug-induced adrenal insufficiency. The drugs implicated are:
- anti-epileptic drugs
- sedative drugs
- anti-mycotic drugs
- phenytoin
- barbiturate
- rifampin
- tyrosine kinase inhibitors
Other causes of primary adrenal insufficiency are bilateral adrenal metastasis, primarily from lung, stomach, breast, and colon cancer, and infiltrative disorders such as primary bilateral lymphoma of the adrenal gland, amyloidosis, and hemochromatosis.
Secondary Adrenal Insufficiency
In the secondary form the lesion lies in the pituitary and ACTH secretion falls. The causes are grouped below by disease category, with the mechanism of each; the genetic disorders are named by the gene that is mutated.
| Disease category | Specific condition | Pathogenetic mechanism |
|---|---|---|
| Space-occupying lesions or trauma | Pituitary tumors (adenomas, cysts, craniopharyngiomas, ependymomas, meningiomas, rarely carcinomas) or trauma (pituitary stalk lesions) | Decreased ACTH secretion |
| Pituitary surgery or irradiation for pituitary tumors, tumors outside the HPA axis, or leukemia | Decreased ACTH secretion | |
| Infections or infiltrative processes | Lymphocytic hypophysitis, hemochromatosis, tuberculosis, meningitis, sarcoidosis, actinomycosis, histiocytosis X, Wegener’s granulomatosis | Decreased ACTH secretion |
| Vascular | Pituitary apoplexy | Decreased ACTH secretion |
| Sheehan’s syndrome (peripartum pituitary apoplexy and necrosis) | Decreased ACTH secretion | |
| Genetic disorders | HESX homeobox 1 (HESX1) | HESX1 gene mutations |
| Orthodenticle homeobox 2 (OTX2) | OTX2 gene mutations | |
| LIM homeobox 4 (LHX4) | LHX4 gene mutations | |
| PROP paired-like homeobox 1 (PROP1) | PROP1 gene mutations | |
| SRY (sex-determining region Y)-box 3 (SOX3) | SOX3 gene mutations | |
| T-box 19 (TBX19) | TBX19 gene mutations | |
| Congenital proopiomelanocortin (POMC) deficiency | POMC gene mutations | |
| Prader-Willi syndrome (PWS) | Deletion or silencing of genes in the imprinting center for PWS |
Tertiary Adrenal Insufficiency
The most common cause of tertiary adrenal insufficiency, which is based on low production and secretion of CRH from the hypothalamus, is chronic use of synthetic glucocorticoids. The other causes are grouped below by disease category; the drug-induced rows include, besides glucocorticoid therapy and Cushing’s syndrome (in which the body itself makes too much glucocorticoid), drugs that block glucocorticoid action in the tissues.
| Disease category | Specific condition | Pathogenetic mechanism |
|---|---|---|
| Space-occupying lesions or trauma | Hypothalamic tumors (craniopharyngiomas or metastasis from lung or breast cancer) | Decreased CRH secretion |
| Hypothalamic surgery or irradiation for central nervous system or nasopharyngeal tumors | Decreased CRH secretion | |
| Infections or infiltrative processes | Lymphocytic hypophysitis, hemochromatosis, tuberculosis, meningitis, sarcoidosis, actinomycosis, histiocytosis X, Wegener’s granulomatosis | Decreased CRH secretion |
| Trauma | Injury (fracture of the skull base) | Decreased CRH secretion |
| Drug-induced adrenal insufficiency | Glucocorticoid therapy (systemic or topical) or endogenous glucocorticoid hypersecretion (Cushing’s syndrome) | Decreased CRH and ACTH secretion |
| Mifepristone | Tissue resistance to glucocorticoids through impairment of glucocorticoid signal transduction | |
| Antipsychotics (chlorpromazine), antidepressants (imipramine) | Inhibition of glucocorticoid-induced gene transcription |
Whether the lesion sits in the adrenal gland, the pituitary or the hypothalamus decides which hormones are lost, and so what the patient feels and shows.