The adrenal cortex makes glucocorticoids and androgens in its zona fasciculata and zona reticularis, and mineralocorticoids in the outer zona glomerulosa. Glucocorticoid output depends on ACTH from the anterior pituitary, which in turn depends on CRH from the hypothalamus. Adrenal insufficiency of any level is a failure somewhere along this chain, and in all three forms the same sequence unfolds: the gland or its regulators first lose reserve, meaning the ability to raise hormone output above the basal level, so only a major stressor causes a crisis, and later they lose basal secretion, so the patient becomes constantly symptomatic.
Loss of reserve, then loss of basal secretion
In primary adrenal insufficiency, whatever the cause, the clinical manifestations begin only once more than 90% of the adrenal cortex is destroyed. While enough cells remain, the patient is in a normal condition at rest, because only the reserve of the cortex is diminished; in this stage only a major stressor can cause an adrenal crisis. As destruction continues, the gland eventually loses even basal glucocorticoid secretion, and from that point the patient is constantly symptomatic.
In secondary and tertiary adrenal insufficiency the same sequence runs one level higher, in the pituitary or the hypothalamus: the early stages bring loss of the reserve of ACTH or CRH while basal secretion is still sufficient, and only later does basal secretion fail and the patient become symptomatic.
The difference between the forms lies in which hormones are lost.
In secondary and tertiary adrenal insufficiency, the lack of enough ACTH or CRH causes loss of cells in the zona fasciculata and the zona reticularis, which produce glucocorticoids and androgens. These patients therefore show glucocorticoid and androgen deficiency, while mineralocorticoid secretion stays normal: aldosterone is driven mainly by the renin–angiotensin system rather than by ACTH, so it is not affected by a pituitary or hypothalamic lesion.
Which diseases destroy the adrenal cortex, or interrupt ACTH or CRH, and so start this sequence is the question of cause.