Secondary Adrenal Insufficiency

How to Cite This Chapter: Rodríguez-Gutiérrez R, Mancillas-Adame LG, Gonzalez-Nava V, Dorsey-Treviño EG, Bednarczuk T, Płaczkiewicz-Jankowska E, Kasperlik-Załuska AA. Secondary Adrenal Insufficiency. McMaster Textbook of Internal Medicine. Kraków: Medycyna Praktyczna. Accessed August 15, 2022.
Last Updated: January 26, 2018
Last Reviewed: August 7, 2019
Chapter Information

Definition, Etiology, PathogenesisTop

Secondary adrenal insufficiency is a clinical syndrome caused by a long-term deficit of adrenal cortex hormones due to adrenocorticotropic hormone (ACTH) deficiency.

Most frequent causes: Inhibition of ACTH secretion by long-term glucocorticoid therapy, large tumors of the pituitary and craniopharyngiomas, neurosurgical treatment of pituitary and parasellar tumors, autoimmunization.

Less frequent causes: Pituitary infarction, postpartum pituitary necrosis (Sheehan syndrome: see Hypopituitarism), infiltrative and posttraumatic lesions.

Clinical FeaturesTop

Symptoms are as in Addison disease but usually develop much more slowly and are less severe. The key difference is reduced skin pigmentation, especially of the nipple areolae, due to ACTH and melanocyte-stimulating hormone (MSH) deficits. Electrolyte disturbances (particularly hyperkalemia) are not frequent (secretion of mineralocorticoids is usually not impaired, as it depends to a greater degree on the renin-angiotensin system than on ACTH). Hypoglycemia is more common and hyponatremia may develop due to cortisol deficiency. Symptoms of an underlying condition are present.


Diagnostic Tests

1. Hormone tests:

1) Low cortisol levels (<138 nmol/L [5 microg/dL]) and low ACTH levels (<2.2 pmol/L [10 pg/mL]) in blood samples collected simultaneously in the morning (the key feature); low cortisol levels in the evening (an early manifestation). The tests listed below are usually performed in specialized settings:

2) 24-hour urinary excretion of free cortisol or 17-hydroxycorticosteroids (17-OHCS) is usually decreased.

3) Low serum dehydroepiandrosterone sulfate (DHEAS) levels.

4) Serum gonadotropin and thyroid-stimulating hormone (TSH) levels are normal or not elevated despite low peripheral hormones in isolated secondary adrenal insufficiency (in isolated ACTH deficit) and decreased in hypopituitarism.

5) The short stimulation test with 250 microg of synthetic ACTH involves the administration of synthetic human ACTH (cosyntropin [INN tetracosactide] 0.25 mg IV or IM) and measurements of serum cortisol levels at baseline, 30 minutes, and 60 minutes to reveal a delayed increase in cortisol levels in secondary adrenal insufficiency. Adrenal reserve test, if done (stimulation with long-acting synthetic ACTH; see Primary Adrenal Insufficiency), reveals a gradual 2- to 4-fold increase in free cortisol or 17-OHCS levels in 24-hour urine and confirms secondary adrenal insufficiency.

6) The corticotropin-releasing hormone (CRH) stimulation test (stimulation of ACTH and cortisol secretion using CRH): Administer 100 microg (or 1 microg/kg) of synthetic CRH IV. Measure serum ACTH levels before CRH administration and at 15, 30, 60, and 90 minutes after the administration; measure serum cortisol levels at baseline and at 30, 60, 90, and 120 minutes after the administration. Under normal conditions, serum ACTH levels increase 2 to 4 times and serum cortisol levels increase by >552 nmol/L (20 microg/dL) (or >276 nmol/L [10 microg/dL] above the baseline value). Absence of response confirms secondary (pituitary) adrenal insufficiency.

2. Imaging studies: Magnetic resonance imaging (MRI) or computed tomography (CT) may reveal an empty or partially empty sella resulting from prior lymphocytic pituitary hypophysitis or a tumor of the hypothalamus-pituitary region.


1. High-sodium diet.

2. Glucocorticoid replacement: Hydrocortisone, usually at doses lower than in Addison disease (5-20 mg/d orally), most frequently in 2 or 3 divided doses (aim at reproducing the circadian cortisol secretion rhythm).Evidence 1Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias and indirectness of some studies.Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016 Feb;101(2):364-89. doi: 10.1210/jc.2015-1710. Epub 2016 Jan 13. Review. PubMed PMID: 26760044; PubMed Central PMCID: PMC4880116.

3. Mineralocorticoid replacement is not necessary in most cases, because aldosterone secretion is regulated by the renin-angiotensin-aldosterone system. In patients with long-standing disease lasting many years, the mineralocorticoid requirement may be similar as in primary adrenal insufficiency due to degenerative changes in the adrenal glands.

4. Adrenal androgen replacement: Consider oral dehydroepiandrosterone (DHEA) at a dose of 5 to 10 mg/d in the morning in women and 25 to 50 mg/d in men (evaluate the prostate before treatment).

Special ConsiderationsTop


Indications for hydrocortisone during surgeryEvidence 2Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias (observational studies) and indirectness of outcomes measured.Salem M, Tainsh RE Jr, Bromberg J, Loriaux DL, Chernow B. Perioperative glucocorticoid coverage. A reassessment 42 years after emergence of a problem. Ann Surg. 1994 Apr;219(4):416-25. Review. PubMed PMID: 8161268; PubMed Central PMCID: PMC1243159.: Prior glucocorticoid therapy (in our practice we use an approximate threshold for oral glucocorticoids of prednisone or equivalent ≥7.5 mg for >2-3 weeks in the past year); prior surgical resection of a hormonally functioning adrenal tumor (secondary adrenal insufficiency develops in the contralateral adrenal gland due to chronic inhibition of ACTH secretion); secondary adrenal insufficiency of another origin.

On the day of surgery, our approach is to administer hydrocortisone 100 mg as an IV infusion during surgery followed by 50 mg IM or IV every 8 hours or a continuous infusion of 200 mg over 24 hours. On day 1 after surgery, administer 50 mg IM or IV every 8 to 12 hours, and in case of a blood pressure decrease add 100 mg as an IV infusion. On day 2 after surgery, administer 50 mg IM or IV in the morning, and in case of a blood pressure decrease add 100 mg as an IV infusion. Starting from day 3 after surgery (or earlier if the patient tolerates fluids well), switch to oral hydrocortisone. In case of surgical complications, such as infection, maintain a higher hydrocortisone dose (eg, 50 mg IV tid to qid) and delay switching to oral treatment.


Adrenal insufficiency caused by glucocorticoid treatment may be reversible. Appropriately treated isolated secondary adrenal insufficiency is not life-threatening and does not affect life expectancy. In patients with overt hypopituitarism, the prognosis depends on disturbances caused by deficiencies of other pituitary hormones (see Hypopituitarism).

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