Endocrine System ORGAN SYSTEMS

Adrenal insufficiency (AI)

Inadequate ­glucocorticoid production owing to destruction of the adrenal cortex or lack of adrenocorticotropic hormone stimulation.

Inadequate ­glucocorticoid production owing to destruction of the adrenal cortex or lack of adrenocorticotropic hormone stimulation.


Adrenal gland endocrinology:

Three classes of steroid hormone are produced by the adrenal cortex after uptake of precursor cholesterol from the plasma: mineralocorticoids, glucocorticoids and sex steroids
  • Zona glomerulosa | Mineralocorticoids (aldosterone and deoxycorticosterone): Aldosterone secretion is principally under the control of the renin–angiotensin–aldosterone system and its action leads to enhanced uptake of sodium in the distal renal tubule following binding to the mineralocorticoid receptor.
  • Zona fasciculata | Glucocorticoids (cortisol and corticosterone): Secreted in response to stimulation by adrenocorticotrophic hormone (ACTH) and have wide-ranging effects mediated by the glucocorticoid receptors.
  • Zona reticularis | Androgens (sex steroids)

Hypothalamic-pituitary-adrenal (HPA) axis:

Basal and stress-inputs to the hypothalamic parvocellular nuclei lead to an increase in the neurocrine factor corticotrophin-releasing hormone (CRH) release into the hypophysical-portal veins.
Hypothalamic-pituitary-adrenal axis
The hypothalamic-pituitary-adrenal axis: Inputs from the hypothalamic circadian rhythm generator in the suprachiasmatic nucleus (SCN) and neural stress pathways in the central nervous system (CNS) control the activity of the corticotrophin-releasing hormone (CRH) neuronal cell bodies in the paraventricular nucleus. These neurons are also capable of synthesizing arginine vasopressin (AVP), which can augment the pituitary response to CRH. CRH (and AVP) are released into the portal circulation in capillaries in the median eminence and drain onto the anterior pituitary where they stimulate the pituitary corticotrophs to release adrenocorticotropic hormone (ACTH). ACTH stimulates the zona fasciculata (ZF) and zona reticularis (ZR) via the MC2R (melanocortin 2 receptor, also known as the ACTH receptor). This G-protein coupled receptor increases intracellular cAMP release, which activates StAR-mediated cholesterol transport into the mitochondria (the rate-limiting step of steroidogenesis). Once cholesterol reaches the inner mitochondrial (Mito) membrane, it is acted on by the first steroidogenic enzyme, and then by subsequent sequential enzymes in the smooth endoplasmic reticulum (SER) and Mito with cortisol as an end product. Cortisol is released into the plasma compartment where it binds reversibly to corticosteroid-binding globulin (CBG; also known as cortisol-binding globulin). As CBG-bound plasma cortisol enters the capillaries in target tissue, it dissociates from CBG and diffuses into the target cell. In the pituitary and hypothalamus, negative feedback inhibition is exerted with the binding of cortisol to glucocorticoid (GR) and mineralocorticoid (MR) receptors. | Raff, H., Sharma, S. T., & Nieman, L. K. (2014). Physiological basis for the etiology, diagnosis, and treatment of adrenal disorders: Cushing’s syndrome, adrenal insufficiency, and congenital adrenal hyperplasia. Comprehensive Physiology, 4(2), 739–769.

CRH acutely stimulates the corticotrophs of the anterior pituitary to increase the release of already stored adrenocorticotrophic hormone (ACTH) into the pituitary venous effluent that, through the inferior petrosal sinuses, drains into the internal jugular veins. CRH also stimulates the synthesis of new ACTH by activating gene transcription for the precursor molecule proopiomelanocortin (POMC) and its post-translational processing to ACTH and other byproducts (including melanocyte-stimulating hormone (MSH)).

ACTH synthesis from large protein proopiomelanocortin (POMC)
The large protein proopiomelanocortin (POMC) is produced by transcription and translation of the POMC gene. Adrenocorticotropic hormone is then produced by posttranslational processing. Note that other products of POMC can be produced (for example, beta and gamma-lipotropic hormone [LPH], N-terminal POMC fragment [N-POC], and melanocyte-stimulating hormone [M]). Also notice that ACTH contains the sequence of MSH within it. Ectopic ACTH-secreting tumors can perform the same processing but often produce large amounts of precursors (particularly pro-ACTH). | Raff H, Findling JW. A physiologic approach to diagnosis of the Cushing syndrome. Ann Intern Med. 2003;138:980–991.


Adrenal insufficiency. In primary adrenal insufficiency, the adrenal cortex is typically destroyed (indicated by an X). This relieves the hypothalamus of cortisol negative feedback such that, presumably, corticotrophin-release hormone (CRH) is increased, although sampling portal vein blood is not possible in humans. The loss of negative feedback at the pituitary leads to a large increase in plasma ACTH. In secondary adrenal insufficiency, adequate ACTH secretion is lost (indicated by an X) resulting in suboptimal plasma ACTH and adrenal atrophy. | Raff, H., Sharma, S. T., & Nieman, L. K. (2014). Physiological basis for the etiology, diagnosis, and treatment of adrenal disorders: Cushing’s syndrome, adrenal insufficiency, and congenital adrenal hyperplasia. Comprehensive Physiology, 4(2), 739–769.

Primary adrenal insufficiency “Addison disease”:

Occurs when there is a pathology affecting the adrenal gland itself
  • Autoimmune destruction (M/C cause of primary adrenal insufficiency, 70% cases)
  • Congenital adrenal hyperplasia (CAH)
  • X-linked adrenoleukodystrophy (ALD)
  • Drugs inhibiting steroidogenesis (etomidate, ketoconazole, fluconazole, or metyrapone)
  • Infectious (HIV, syphilis, tuberculosis):
    • Tuberculosis: M/C infectious cause of Addison’s disease in India
  • Adrenal hemorrhage

Secondary adrenal insufficiency:

Results from a decreased level of adrenocorticotropic hormone (ACTH) released from the pituitary gland leading to atrophy due to prolonged deprivation of the adrenal cortex of corticotrophic stimulation
  • Hypopituitarism (inadequate ACTH secretion)
  • Pituitary surgery/irradiation
  • Pituitary apoplexy
  • Sheehan’s syndrome (peripartum pituitary apoplexy and necrosis)
  • Infiltrating tumors
  • Infections

Tertiary adrenal insufficiency:

High levels of glucocorticoids (endogenous/exogenous) which decrease hypothalamic CRH synthesis and secretion and also block the trophic and ACTH-secretagogue actions of CRH on anterior pituitary cells. This leads to decrease in size, and eventually, number of corticotroph cells
  • Iatrogenic adrenal insufficiency (M/C cause of adrenal insufficiency): Abrupt cessation of high-dose glucocorticoid therapy
  • Cushing’s syndrome: Endogenous glucocorticoid hypersecretion
Plasma ACTH in adrenal insufficiency
Plasma ACTH in patients with untreated primary and secondary adrenal insufficiency, and in patients on chronic pharmacological glucocorticoid therapy: Notice that plasma ACTH is often within the reference range (blue shading) in patients with secondary adrenal insufficiency. | Raff, H., Sharma, S. T., & Nieman, L. K. (2014). Physiological basis for the etiology, diagnosis, and treatment of adrenal disorders: Cushing’s syndrome, adrenal insufficiency, and congenital adrenal hyperplasia. Comprehensive Physiology, 4(2), 739–769.


General features:

Most common symptoms in any cause of adrenal insufficiency are related to glucocorticoid insufficiency
  • Related to glucocorticoid insufficiency:
    • Non-specific features: General malaise, fatigue, weakness
    • Gastrointestinal symptoms: Nausea, vomiting, abdominal pain, and diarrhea alternating with constipation
  • Hyponatremia (related to both mineralocorticoid deficiency and increased vasopressin action due to cortisol deficiency, as cortisol directly inhibits neurohypophysial vasopressin secretion)

Primary adrenal insufficiency:

Clinical symptoms of adrenal insufficiency include weakness, fatigue, anorexia, abdominal pain, weight loss, orthostatic hypotension, salt craving, and characteristic hyperpigmentation of the skin occurring with primary adrenocortical failure.
  • Hyperpigmentation of skin (92-100% cases) (elevated ACTH derived from the same precursor as for melanocyte-stimulating hormone (MSH))
  • Related to mineralocorticoid deficiency and hypovolemia:
    • Postural dizziness, hypotension/orthostasis
    • Dehydration, salt craving
    • Hyperkalemia
  • Adrenal calcification
  • Vitiligo (8-20%)
The Calgary Guide |
Hyperpigmentation in Addison's disease
Hyperpigmentation in the neck and chest region | Sarkar, S. B., Sarkar, S., Ghosh, S., & Bandyopadhyay, S. (2012). Addison’s disease. Contemporary clinical dentistry, 3(4), 484–486.

Associated endocrine and autoimmune disorders:

Associated endocrine and autoimmune disorders:
Frequency of concomitant endocrine and autoimmune diseases in patients with autoimmune AD. *other: chronic mucocutaneous candidiasis, hypoparathyroidism, alopecia. | Ferreira, L., Silva, J., Garrido, S., Bello, C., Oliveira, D., Simões, H., Paiva, I., Guimarães, J., Ferreira, M., Pereira, T., Bettencourt-Silva, R., Martins, A. F., Silva, T., Fernandes, V., Pereira, M. L., & Adrenal Tumors Study Group of the Portuguese Society of Endocrinology (2017). Primary adrenal insufficiency in adult population: a Portuguese Multicentre Study by the Adrenal Tumours Study Group. Endocrine connections, 6(8), 935–942.

Central (secondary & tertiary) adrenal insufficiency:

Clinical features of secondary/tertiary AI are similar to those of primary adrenal insufficiency with a few exceptions. The clinical presentation and treatment of tertiary adrenal insufficiency is similar to secondary adrenal insufficiency and a formal distinction between the two forms is not needed for clinical management.
  • Hyperpigmentation (as ACTH is not increased)
  • Dehydration & hyperkalaemia and ↓ hypotension (as mineralocorticoids production by zona glomerulosa is mostly preserved and renin-angiotensin-aldosterone system is intact)
  • Signs of other pituitary hormone deficiencies
  • Delayed puberty
  • Headaches, visual field deficits
  • Hypoglycaemia (more common in central AI due to concomitant growth hormone insufficiency than in isolated ACTH deficiency)
The Calgary Guide |


Adrenal crisis (AC):

Precipitated by a serious infection, acute stress, bilateral adrenal infarction or hemorrhage. Cortisol and aldosterone deficiencies contribute to hypotension, orthostasis, and shock; however, adrenal crisis is more likely to occur in primary adrenal insufficiency compared with secondary adrenal insufficiency.
  • Shock (primary clinical manifestation) (hypotension due to mineralocorticoid deficiency)
  • Nonspecific symptoms: Anorexia, nausea, vomiting, abdominal pain, weakness, fatigue, lethargy, confusion or coma.
Pathophysiology of adrenal crisis.
Amrein, K., Martucci, G., & Hahner, S. (2018). Understanding adrenal crisis. Intensive care medicine, 44(5), 652–655.


Clinical diagnosis of adrenal insufficiency can be confirmed by demonstrating inappropriately low cortisol secretion, determining whether the cortisol deficiency is secondary or primary and, hence, dependent or independent of ACTH deficiency, and detecting the cause of the disorder.

  • ACTH stimulation test (screening test): Useful for screening for both primary and established secondary adrenal insufficiency. The test may not be abnormal in early secondary adrenal insufficiency because it takes time for the adrenal to atrophy and lose sensitivity to a pharmacological dose of ACTH
  • CRH stimulation test: Differentiate between secondary and tertiary forms of adrenal insufficiency. In both conditions, the cortisol levels are low at baseline and after CRH administration. There is little or no ACTH response to CRH in secondary adrenal insufficiency while in the tertiary form, there is a delayed and exaggerated increase in ACTH after CRH with a subnormal plasma cortisol response
Algorithm for the initial investigation of adrenal insufficiency. | +ve = positive; -ve = negative; Abs = antibodies; ACTH = adrenocorticotropic hormone; CT = computerised tomography; MRI = magnetic resonance imaging | Pazderska, A., & Pearce, S. H. (2017). Adrenal insufficiency – recognition and management. Clinical medicine (London, England), 17(3), 258–262.

Insulin tolerance test (ITT):

Gold standard test for secondary adrenal insufficiency but it is a dangerous test with significant risk of neuroglycopenia so not routinely performed. Insulin-induced hypoglycemia is useful to evaluate the integrity of the HPA axis since hypoglycemia leads to an increase in hypothalamic CRH and pituitary ACTH release. in healthy subjects. In patients with a loss of adrenocortical function (for whatever reason), the cortisol response will be inadequate.
Typical plasma glucose, ACTH, and cortisol response to insulin-induced hypoglycemia in a healthy subject and a patient with secondary adrenal insufficiency (hypopituitarism). Notice there is a small increase in ACTH and cortisol in this patient with secondary adrenal insufficiency indicating there are still a few remaining functioning pituitary corticotrophs. | Raff, H., Sharma, S. T., & Nieman, L. K. (2014). Physiological basis for the etiology, diagnosis, and treatment of adrenal disorders: Cushing’s syndrome, adrenal insufficiency, and congenital adrenal hyperplasia. Comprehensive Physiology, 4(2), 739–769.


Treatment of adrenal insufficiency, regardless of the cause, is to replace the missing cortisol in as physiological a pattern as possible. Because cortisol is normally secreted in a circadian rhythm, it is most common to give cortisol (hydrocortisone) by mouth in a circadian pattern.

Hormone replacement therapy:

Lifelong hormone therapy with glucocorticoids and mineralocorticoids
  • Hydrocortisone (glucocorticoid) (first-line hormonal treatment)
  • 9-αfluorocortisol (fludrocortisone) (mineralocorticoid agonist): Replace endogenous aldosterone in primary adrenal insufficiency
    • Patients with secondary adrenal insufficiency usually do not require mineralocorticoid replacement (again, because the renin-angiotensin-aldosterone system is intact)

Iatrogenic adrenal insufficiency

Secondary adrenal insufficiency will rapidly ensue if the glucocorticoid therapy is abruptly stopped. This is due to the long-term suppression of the endogenous HPA axis. Patients receiving glucocorticoid therapy for extended periods of time are counseled extensively on this fact. As a result, patients have to be slowly weaned from chronic glucocorticoid therapy
Risk of discontinuation of chronic pharmacological glucocorticoid therapy
Pattern of the recovery of ACTH from the pituitary and cortisol from the adrenal after discontinuation of chronic pharmacological glucocorticoid therapy: First both plasma ACTH and cortisol are suppressed when weaning starts. As the dose of glucocorticoid therapy is tapered, the hypothalamic-pituitary unit starts to recover. As a result, plasma ACTH begins to increase and starts the process of “waking up” the atrophied adrenal cortex. As plasma ACTH continues to increase, adrenal function starts to recover leading to an increase in plasma cortisol. | Felig P, Frohman L. Endocrinology and Metabolism 4/e. McGraw-Hill; New York: 2001. p. 627. Figure 14–11.

Adrenal crisis:

  • Fluid resuscitation with intravenous (IV) normal saline (to correct volume depletion)
  • Dextrose (to correct hypoglycemia)
  • Hormone replacement (correct lack of circulating glucocorticoid)


Types of adrenal insufficiency, its epidemiology, mechanisms, diagnosis and management as well as specific strategies to prevent and treat adrenal crises. | Adrenal insufficiency. Nat Rev Dis Primers 7, 18 (2021).

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