Secondary adrenal insufficiency is caused by the processes occurring outside adrenal glands: pituitary causes, drugs, genetic causes.These disease processes causes the decreased production of adrenocorticotrophic hormone (ACTH).

• Hypothalamus produces corticotropin releasing hormone (CRH) that stimulates pituitary gland‘s corticotrophs to release adrenocorticotrophic hormone ( ACTH).
• Anterior pituitary gland‘s corticotroph cells produce ACTH that in turn stimulates adrenal cortex‘s zona glomerulosa to produce cortisol.
• Cortisol is produced by zona glomerulosa of the adrenal gland and provides feedback to pituitary and hypothalamus.

• Secondary adrenal insufficiency is caused by the processes occurring outside adrenal glands: pituitary causes, drugs, and genetic causes.
• These disease processes causes the decreased production of adrenocorticotrophic hormone (ACTH).
• Chronic steroid therapy causes suppression of hypothalamic pituitary adrenal axis (HPA) axis.
• In some cases of adrenal insufficiency, hyponatremia is seen due to an abnormal increase in antidiuretic hormone(ADH) which in turn caused due to deficiency of cortisol due to decreased excretion of free water. The feedback loop causes secretion of corticotropin-releasing hormone (CRH), again an ADH secretagogue. There is a negative feedback on CRH and ACTH by cortisol. In adrenal insufficiency, this effect is removed and cortisol inhibits ADH excretion directly showing the reciprocal relation of ADH increase when cortisol is low. ADH inappropriate secretion leads to more water absorption leading to hyponatremia.^[1]

• Secondary adrenal insufficiency is also caused by genetic disorders.
  • Combined pituitary hormone deficiency (CPHD)
  • Proopiomelanocortin deficiency (POMC)^[2]

• POMC deficiency is transmitted in autosomal recessive transmission pattern.
• Genes involved in the pathogenesis of POMC deficiency include POMC gene.
• Genes involved in the pathogenesis of CPHD include PROP-1 where ACTH deficiency occurs in the end after GH, Prolactin, TSH, and LH/FSH deficiencies. Other genes in CPHD include HESX1, LHX3, LHX4 and SOX3.

• Hypopituitarism
• Adrenal crisis
• Adrenal hemorrhage
• Hyponatremia

• The gross pathology features are dependent on the cause. For the gross pathology, when secondary adrenal insufficiency is caused by hypopituitarism, click here.

• The microscopic pathology features are dependent on the cause. For the microscopic pathology when the cause is hypopituitarism, click here.