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Adrenal Insufficiency and Cushing’s

Editor’s Note: The Guideline Committee of The Endocrine Society determined that a guideline on the Diagnosis and Treatment of Primary Adrenal Insufficiency would be highly beneficial. Thus, a task force of experts was formed and following an extensive literature review process to identify evidence in the medical literature, reached a consensus on the guideline. The panel was chaired by Dr. Stefan R. Bornstein and task force participants were Drs. Bruno Allolio, Wiebke Arlt, Andreas Barthel, Andrew Don-Wauchope, Gary D. Hammer, Eystein S. Husebye, Deborah P. Merke, M. Hassan Murad, Constantine A. Stratakis and David J. Torpy*. The full guideline, co-sponsored by the European Society of Endocrinology and the American Association for Clinical Chemistry, was published in J Clin Endocrinol Metab, February 2016, 101(2):364 –389. While some of this guideline does not apply to Cushing’s patients post-surgery, we asked Dr. Torpy for an article discussing adrenal insufficiency after treatment for Cushing’s and the areas of the guidelines that do apply to Cushing’s patients after successful treatment.


Following successful surgical treatment for Cushing’s, either by removal of a pituitary tumor, one or both adrenal glands or ectopic tumor, most patients are adrenal insufficient (cannot make cortisol) for a period of time. Cortisol is essential to life so patients require replacement with a glucocorticoid, such as hydrocortisone or sometimes prednisone. Most patients recovering from Cushing’s require replacement medication only until their body is able to produce adequate cortisol. There is no standard protocol for “tapering” steroid dose during this time period, thus patients need to work closely with their doctor. Most patients regain normal cortisol production within 12 to 18 months following surgical treatment. During times of illness and surgery the body requires additional cortisol, therefore, in these circumstances the dosage of replacement medication needs to be increased.


Primary adrenal insufficiency, also known as Addison’s disease, involves conditions that affect the adrenal glands, such as a bilateral adrenalectomy. Autoimmune destruction of adrenal tissue is the leading cause of adrenal insufficiency in the adult population. Patients with primary adrenal insufficiency due to bilateral adrenalectomy require replacement with both glucocorticoid (hydrocortisone) and mineralocorticoid (aldosterone) usually with fludrocortisone (Florinef).

Secondary (or central) adrenal insufficiency is used to describe situations where damage of the pituitary gland or hypothalamus impairs secretion of adrenocorticotropic hormone (ACTH), thus appropriate levels of cortisol are not produced by the adrenal glands. This situation arises in most Cushing’s patients following successful surgery for a pituitary tumor, a unilateral adrenal tumor or an ectopic tumor. These patients maintain the ability to produce the mineralocorticoid, aldosterone, and do not require mineralocorticoid fludrocortisone (Florinef) replacement. In some patients, extensive pituitary surgery or radiation treatment damages the normal pituitary tissue and patients require lifelong full or partial glucocorticoid replacement medication.

While on replacement glucocorticoid medication, patients should be aware that other medications, such as Phenytoin, Carbamazepine and Mitotane and the supplement St John’s Wort, may increase the metabolism of glucocorticoids requiring an increase in glucocorticoid dose. Also, initiation of T4 (thyroxine) thyroid or growth hormone (GH) medication may require an increase in glucocorticoid replacement dose. Patients should also be aware that licorice and grapefruit juice increase the aldosterone-like effect of hydrocortisone and should be avoided.

Regardless of whether adrenal insufficiency is primary or secondary, or whether the patient is expected to recover normal pituitary and adrenal function, patient education on increasing replacement medication during illness and taking prompt action in case of an adrenal crisis, is the same.


The symptoms of adrenal insufficiency include fatigue, dizziness or light-headedness on standing, reduced appetite, abdominal discomfort and weight loss. Routine laboratory tests may show low sodium and high potassium levels.

An adrenal crisis denotes a much more severe situation, a medical emergency, where there is an abrupt development of severe weakness, a tendency to fall on standing, nausea, vomiting and abdominal pain, back pain, confusion and hypotension (low blood pressure) consistent with shock. The blood sodium and potassium abnormalities are much more frequent than is seen in adrenal insufficiency. The treatment of adrenal crisis is urgent and the administration of a glucocorticoid, usually hydrocortisone 100mg, is generally given intravenously or intramuscularly. Such treatment is life-saving.

Prevention of adrenal crisis is an important subject. There is a 5-10% annual risk of adrenal crisis in patients with primary adrenal insufficiency, although this risk is probably lower in patients with secondary adrenal insufficiency following successful treatment for Cushing’s syndrome. Importantly, patients need to be aware of circumstances where they may be at risk of adrenal crisis. These circumstances include times when glucocorticoid replacement is abruptly stopped or where the body requires additional glucocorticoid to deal with stress. While some patients may resist increasing their replacement dose, patients should err on the side of caution as increasing the replacement dose for a few days does no harm and under dosing can be very dangerous.

Sick day rule 1: Home management of illness with fever*

The standard daily replacement dose of oral glucocorticoids should be doubled when the patient experiences fever or illness requiring bed rest and when requiring antibiotics for an infection. More specifically, hydrocortisone replacement doses should be doubled when patients have a fever >38°C; 100.4°F. The dose should be tripled for fevers >39°C; 102.2°F. The dose increase should be sustained until recovery, usually 2 to 3 days. During this time, increased consumption of electrolyte-containing fluids as tolerated is recommended.

Sick day rule 2: Unable to tolerate oral medication due to gastroenteritis or trauma*

In case of severe illness, trauma, persistent vomiting, and if needed when fasting for a procedure, adult and adolescent patients should inject 100mg of hydrocortisone intramuscularly or subcutaneously. Following the initial injection, patients should present to the Emergency Department as fluids are often needed. In children, refer to the complete guideline as the dose depends on age and body weight.

Minor to moderate surgical stress*

Prior to minor surgical procedures, such as dental procedures with local anesthesia, the patient can double the daily replacement dose. For dental work requiring sedation, the doubled daily dose can be administered intravenously prior to the procedure. For moderate surgical procedures, such as cholecystectomy or joint replacement a hydrocortisone dose of 50–75 mg/24 hours should be maintained in adults and adolescents usually for 1 to 2 days.

Major surgery with general anesthesia, trauma, delivery, or disease that requires intensive care*

Prior to major surgery, such as cardiopulmonary bypass 100mg of hydrocortisone should be injected iv, followed by continuous iv infusion of 200 mg hydrocortisone/24h; alternatively 50 mg every 6 hours iv or im. The same applies to trauma or very serious illness. For children, please refer to the complete guideline. Weight-appropriate continuous iv fluids with 5% dextrose and 0.2 or 0.45% NaCl should be continued. Depending on the clinical state, rapid tapering of the replacement hydrocortisone dose and a switch to oral replacement is recommended.

*Modified with permission of The Endocrine Society from Tables 3 & 4 in J Clin Endocrinol Metab, February 2016, 101(2):364 –389 doi: 10.1210/jc.2015-1710 [Adapted from I. Bancos, et al: Diagnosis and management of adrenal insufficiency. Lancet Diabetes Endocrinol. 2015;3:216–226 (122), with permission. © Elsevier Limited and from B. Allolio: Extensive expertise in endocrinology: adrenal crisis. Eur J Endocrinol. 2015;172:R115–R124 (126), with permission. © Endocrine Society]

Adrenal crisis management

Initial symptoms of an impending crisis are often fatigue, nausea, weakness and sometimes vomiting or dizziness on standing. Onset of symptoms consistent with adrenal crisis should lead to an increase in the dose of oral glucocorticoid replacement. Often glucocorticoids cannot be administered orally because of vomiting. In this situation an injection of hydrocortisone intramuscularly is required. This injection can be given at home with appropriate training.

The use of hydrocortisone subcutaneously, produces prompt, only slightly delayed elevation of cortisol compared to an intramuscular injection. It has been tested in patients with Addison’s disease but not yet in those with an adrenal crisis. The advantage is that subcutaneous injection is far easier for patients and care givers.

After injection, or if injection is not available, patients should present immediately to an Emergency Department. Sometimes treatment is delayed even after presentation to an Emergency Department. Carrying a ‘steroid card’, leaflet or this article is useful as it indicates the need for prompt administration of glucocorticoids in an adrenal crisis.

Another alternative for glucocorticoid delivery is the use of glucocorticoid-containing suppositories, useful in situations where there is vomiting. However, these cannot be used successfully when diarrhea is present. Table 1 summarizes management of an acute adrenal crisis in a hospital setting and can be shared with medical staff. Table 2 summarizes precautions that patients should be aware of and discuss with their physician.


A period of secondary adrenal insufficiency is expected after treatment of prolonged high cortisol levels from Cushing’s. Therefore, glucocorticoid replacement is routine after Cushing’s treatment. Over time, recovery from adrenal insufficiency, usually occurring more than six months after treatment of Cushing’s, can be confirmed with morning cortisol levels and glucocorticoid replacement can be weaned.

When results are vague or further documentation is required, an ACTH-stimulation test can help clarify the diagnosis. This dose of ACTH is 250mcg for a diagnosis of all primary adrenal insufficiency. Some physicians believe a lower dose of ACTH, namely 1mcg, is more sensitive in secondary adrenal insufficiency diagnosis. Importantly, the presence of primary adrenal insufficiency is associated with ACTH elevation in association with low cortisol. However, in contrast, secondary adrenal insufficiency is associated with low or inappropriately normal levels of ACTH in blood.


Many patients who have been treated for Cushing’s, except those who have had a bilateral adrenalectomy, will ultimately be able to stop glucocorticoid replacement. However, in some cases glucocorticoid replacement is long-term. The long-term management of glucocorticoid replacement requires careful clinical observation and review by a physician experienced in glucocorticoid replacement at least every 6 to 12 months. Blood tests do not provide a reliable basis for adjusting glucocorticoid dose.

Glucocorticoids doses are based on body size. Hydrocortisone dosing is generally in the range of 15 to 25mg daily or 20 to 35mg daily of cortisone acetate usually in two divided oral doses daily. Generally a higher dose is given in the morning in an attempt to achieve cortisol levels closer to that seen in patients without adrenal insufficiency. Prednisone generally administered once daily (3 to 6mg per day) can also be given.

Patients need to be monitored closely for the possibility of excess glucocorticoid replacement which would become evident with increasing bodyweight particularly an increase in abdominal girth, skin thinning, the development of thin bones and alterations such as reduced sleep. Glucocorticoid replacement levels that are too low may result in weight loss, dizziness and low blood pressure on standing. The aim is to avoid either excessive or inadequate glucocorticoid replacement doses. When this is achieved, glucocorticoid replacement is not associated with immune impairment. There is a substantial variation in cortisol production between individuals so that the ideal glucocorticoid replacement dose cannot be predicted and the response to therapy needs to be monitored.

Most individuals on glucocorticoid replacement experience a good quality of life and function. A substantial minority of patients, particularly those with primary adrenal insufficiency, have reported reduced quality of life and wellbeing, particularly in relation to fatigue. The explanation for this phenomenon is likely to vary in different patients and is a subject of ongoing research.

Cortisol levels typically rise during pregnancy. The current guidelines suggest individual monitoring and an increase in hydrocortisone dose particularly in the third trimester. Stress doses of hydrocortisone are required during labor.


Aldosterone is replaced in patients with primary adrenal insufficiency. The replacement synthetic hormone is fludrocortisone (Florinef). A typical daily dose of fludrocortisone is 0.05 to 0.2mg given in the morning. Monitoring of aldosterone replacement is based on clinical assessment including restoration of normal blood pressure and reduced salt hunger, re-establishing normal sodium and potassium levels and the presence of normal plasma renin levels. Renin is a kidney derived hormone which stimulates aldosterone production from the adrenal glands. If the fludrocortisone dose is too low, renin levels are too high and this indicates a need for a higher dose of fludrocortisone. If the fludrocortisone dose is too high, renin levels are suppressed. Over-replacement with fludrocortisone can lead to high blood pressure and low potassium. Patients should not restrict their salt intake and if high blood pressure develops, a decrease in fludrocortisone dose can be considered.


Patients with primary adrenal insufficiency often have very low DHEA (dehydroepiandrosterone) levels. DHEA levels can also be low in secondary adrenal insufficiency patients. DHEA is an adrenal steroid intermediate which can be metabolized to androgens such as testosterone or estrogen. Its potential role as a third adrenal steroid replacement has been investigated in a number of trials. A clinically meaningful response to DHEA replacement is not universal.

Currently the guidelines have suggested a trial of DHEA replacement in women with adrenal insufficiency and low libido or depressive symptoms and/or reduced energy levels despite optimized glucocorticoid and mineralocorticoid replacement. A trial of six months should be sufficient to determine if the patient is going to respond. DHEA levels are typically monitored by measurement of morning blood DHEAS levels before the morning dose and these can be tested before and after a trial of DHEA. The long-term benefits and risks of DHEA treatment are not established.

By Dr. David Torpy, Winter, 2016

Editor’s Note: Dr. David Torpy is a Consultant Endocrinologist at the Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, SA, Australia.

You can read the entire guideline at the Endocrine Society Guideline website.

Table I: Acute Adrenal Crisis

  • Rapid infusion of 1000 mL isotonic saline within the first hour or 5% glucose in isotonic saline, followed by continuous iv isotonic saline guided by individual patient needs
  • Hydrocortisone 100 mg iv immediately followed by hydrocortisone 200 mg/d as a continuous infusion for 24 h, reduced to hydrocortisone 100 mg/d the following day
  • Children, rapid bolus of normal saline (0.9%) 20 mL/kg. Can repeat up to a total of 60 mL/kg within 1 h for shock.
  • Children, hydrocortisone 50–100 mg/m2 bolus followed by hydrocortisone 50–100 mg/m2/d divided q 6 h
  • For hypoglycemia: dextrose 0.5–1 g/kg of dextrose or 2–4 mL/kg of D25W (maximum single dose 25 g) infused slowly at rate of 2 to 3 mL/min. Alternatively, 5–10 mL/kg of D10W for children <12 y old
  • Cardiac monitoring: Rapid tapering and switch to oral regimen depending on clinical state

Abbreviation: D10W, 10% dextrose solution; D25W, 25% dextrose solution.

Table reprinted in part with permission of The Endocrine Society from Table 3 in J Clin Endocrinol Metab, February 2016, 101(2):364 –389 doi: 10.1210/jc.2015-1710 [Adapted from B. Allolio: Extensive expertise in endocrinology: adrenal crisis. Eur J Endocrinol. 2015;172:R115–R124 (126), with permission. © Endocrine Society.]

Table II: Adrenal Insufficiency

  • Patients should carry an up to date steroid emergency card
  • Patients should wear a medical alert bracelet or necklace stating “Adrenal insufficiency – needs steroids!” This is particularly useful if the patient is confused or unable to describe their need for a glucocorticoid injection.
  • Patients should ensure that they always have a sufficient supply of hydrocortisone and fludrocortisone (accounting for possible sick days)
  • Patients should carry a hydrocortisone emergency injection kit (vials of 100 mg hydrocortisone sodium, syringes, needles); alternatively, also hydrocortisone or prednisolone suppositories
  • Patients (parents, partners) need to be taught to administer an injectable glucocorticoid preparation
  • Patients should go to the hospital after emergency injection as fluids are almost always needed.
  • Patients should carry a leaflet (or this article) with information on adrenal crisis and hospitalization to be shown to health care staff; clearly advise regarding the need to inject 100 mg hydrocortisone immediately iv or im, followed by continuous infusion of 200 mg/24 h
  • Patients should carry an emergency phone number for the endocrine specialist team
Modified with permission of The Endocrine Society from Table 4 in J Clin Endocrinol Metab, February 2016, 101(2):364 –389 doi: 10.1210/jc.2015-1710 [Adapted from I. Bancos, et al: Diagnosis and management of adrenal insufficiency. Lancet Diabetes Endocrinol. 2015;3:216–226 (122), with permission. © Elsevier Limited.]

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