Additional signs and symptoms include weakness, tiredness, dizziness, low blood pressure that falls further when standing (orthostatic hypotension), cardiovascular collapse, muscle aches, nausea, vomiting, and diarrhea.

[12] High levels of cortisol inhibit the production of both CRH and ACTH, forming a negative feedback loop.

[2][3] In secondary and tertiary adrenal insufficiency, there is no effect on the production of aldosterone within the zona glomerulosa as this process is regulated by the renin–angiotensin–aldosterone system (RAAS), not ACTH.

[3] Adrenal insufficiency can also affect the zona reticularis and disrupt production of androgens, which are precursors to testosterone and estrogen.

[2][3] Cortisol increases blood sugar by inducing gluconeogenesis (glucose production) in the liver, lipolysis (fat breakdown) in adipose tissue, and proteolysis (muscle breakdown) in muscle while increasing glucagon secretion and decreasing insulin secretion in the pancreas.

[2] In primary adrenal insufficiency, the lack of negative feedback from cortisol leads to increased production of CRH and ACTH.

[14] Although the production of aldosterone occurs within the adrenal cortex, it is not induced by adrenocorticotropic (ACTH); instead, it is regulated by the renin–angiotensin–aldosterone system (RAAS).

[15] Deficiency of aldosterone leads to urinary loss of sodium and effective circulating volume, as well as retention of potassium.

[17] Minor causes of chronic adrenal insufficiency are systemic amyloidosis, fungal infections, hemochromatosis, and sarcoidosis.

[20] This may be isolated or in the context of autoimmune polyendocrine syndrome (APS type 1 or 2), in which other hormone-producing organs, such as the thyroid and pancreas, may also be affected.

[24] Destruction also occurs when the adrenal glands are involved in metastasis (seeding of cancer cells from elsewhere in the body, especially lung), hemorrhage (e.g. in Waterhouse–Friderichsen syndrome or antiphospholipid syndrome), particular infections which can spread to the adrenal cortex (tuberculosis, histoplasmosis, coccidioidomycosis), or the deposition of abnormal protein in amyloidosis.

[25] To form cortisol, the adrenal gland requires cholesterol, which is then converted biochemically into steroid hormones.

[verification needed] Of the synthesis problems, congenital adrenal hyperplasia is the most common (in various forms: 21-hydroxylase, 17α-hydroxylase, 11β-hydroxylase and 3β-hydroxysteroid dehydrogenase), lipoid CAH due to deficiency of StAR and mitochondrial DNA mutations.

[19] Some medications interfere with steroid synthesis enzymes (e.g. ketoconazole), while others accelerate the normal breakdown of hormones by the liver (e.g. rifampicin, phenytoin).

With prolonged suppression, the adrenal glands atrophy (physically shrink), and can take months to recover full function after discontinuation of the exogenous glucocorticoid.

[2] Cortisol levels typically peak in the morning; thus, low values indicate true adrenal insufficiency.

[2] If cortisol levels remain low following ACTH stimulation, then the diagnosis is primary adrenal insufficiency.

[2] If cortisol levels increase following ACTH stimulation, then the diagnosis is either secondary or tertiary adrenal insufficiency.

[2] Additional testing can include basal plasma ACTH, renin, and aldosterone concentrations, as well as a blood chemistry panel to check for electrolyte imbalances.

[2] For secondary and tertiary adrenal insufficiency, an MRI of the brain can be obtained to detect structural abnormalities such as masses, metastasis, hemorrhage, infarction, or infection.