INTRODUCTION — Primary adrenal insufficiency (Addison's disease) is due to adrenocortical disease, while secondary and tertiary adrenal insufficiency are due to disorders of the pituitary gland (corticotropin [ACTH] secretion) or the hypothalamus (corticotropic-releasing hormone secretion), respectively. Primary adrenal insufficiency is associated with both cortisol and mineralocorticoid deficiency. In contrast, secondary and tertiary adrenal insufficiency are associated with cortisol, but not mineralocorticoid deficiency, because aldosterone is regulated primarily by the renin-angiotensin system, which is independent of the hypothalamus and pituitary. This distinction accounts for the different clinical presentation and management of these disorders.
The management of all forms of adrenal insufficiency is reviewed here. The causes, clinical manifestations, and diagnosis of adrenal insufficiency in adults are reviewed separately. (See "Causes of primary adrenal insufficiency (Addison's disease)" and "Clinical manifestations of adrenal insufficiency in adults" and "Diagnosis of adrenal insufficiency in adults".)
ADRENAL CRISIS — Adrenal crisis refers to acute adrenal insufficiency; it is most common in patients with primary adrenal insufficiency, but may also occur in those with secondary or tertiary adrenal insufficiency. It is a life-threatening emergency that requires immediate treatment (table 1).
In patients with primary adrenal insufficiency, the major clinical features of adrenal crisis are volume depletion and hypotension, resulting mainly from mineralocorticoid deficiency.
While secondary or tertiary adrenal insufficiency (isolated glucocorticoid deficiency) does not lead to volume depletion, it decreases vascular tone, which leads to hypotension. Thus, adrenal crisis occurs less frequently in patients with secondary or tertiary adrenal insufficiency. When they do have adrenal crisis, it tends to be during acute stress, or with acute cortisol deficiency due to pituitary infarction or after surgical cure of Cushing's syndrome. (See "Clinical manifestations of adrenal insufficiency in adults", section on 'Secondary/tertiary adrenal insufficiency'.)
Adrenal crisis may also occur in patients who are abruptly withdrawn from exogenous glucocorticoids. (See "Clinical manifestations of adrenal insufficiency in adults".)
The biochemical features of adrenal crisis in primary adrenal insufficiency include hyperkalemia and hyponatremia. Hyponatremia occurs because of mineralocorticoid deficiency and also due to inappropriate secretion of antidiuretic hormone (vasopressin) that is caused by cortisol (not aldosterone) deficiency. In these patients, combined mineralocorticoid and glucocorticoid deficiency lead to urinary sodium loss, plasma volume depletion with increased serum urea. (See "Hyponatremia and hyperkalemia in adrenal insufficiency".)
Patients with pure cortisol deficiency (eg, secondary or tertiary adrenal insufficiency) have slightly increased blood volume, dilutional hyponatremia, less urinary sodium loss, and no hyperkalemia.
Management — Adrenal crisis requires urgent diagnosis and intervention (table 1).
●Treatment of patients who present in possible adrenal crisis should not be delayed while diagnostic tests are performed. Blood for serum cortisol, corticotropin (ACTH), aldosterone, renin, and serum chemistry should be drawn and therapy initiated immediately. The serum chemistry results guide initial treatment; the hormone values return later and are used to confirm the diagnosis (cortisol and aldosterone) or evaluate the differential diagnosis (ACTH and renin).
●1 to 3 liters of 0.9 percent saline solution or 5 percent dextrose in 0.9 percent saline (to correct possible hypoglycemia) should be infused intravenously (IV) within the first 12 to 24 hours based on assessment of volume status and urine output.
●Hypotonic saline should not be used because it can worsen the hyponatremia.
Choice of glucocorticoid — For patients who present with adrenal crisis, we suggest administration of hydrocortisone (100 mg IV bolus), followed by 50 mg IV every 6 hours (or 200 mg/24 hours as a continuous IV infusion for the first 24 hours) [1]. If hydrocortisone is unavailable, alternatives include methylprednisolone and dexamethasone (table 1 and table 2). This can rapidly decrease the inappropriate vasopressin production with increased clearance of free water and correction of hyponatremia.
●In contrast to glucocorticoid replacement, mineralocorticoid replacement is not necessary acutely because it takes several days for its sodium-retaining effects to appear, and adequate sodium replacement can be achieved by IV saline alone. However, in patients with known primary adrenal insufficiency or those with potassium >6.0 mEq/L, hydrocortisone is preferred because of its mineralocorticoid activity.
●After the initial bolus, hydrocortisone 50 mg IV bolus is administered every six hours until stabilization of vital signs and capacity to eat and take medication orally.
●Unless there is a major complicating illness, parenteral glucocorticoid therapy can be tapered over one to three days and changed to an oral stress or maintenance dose.
Diagnostic tests — After initial treatment, the precipitating cause of the adrenal crisis (as an example, bacterial infection, viral gastroenteritis) should be sought and appropriately treated.
Once the patient's condition is stable, the diagnosis can be confirmed in patients not known to have adrenal insufficiency with a short ACTH stimulation test. This should be followed by tests to determine the cause of the adrenal insufficiency. (See "Diagnosis of adrenal insufficiency in adults".)
CHRONIC ADRENAL INSUFFICIENCY — One of the important components of therapy in chronic adrenal insufficiency is patient education (table 3). The patient should be told that they can lead an active and vigorous life as long as they take replacement therapy and follow a few common-sense precautions. The patient and responsible family members should be instructed about:
●The nature of the hormonal deficit and the rationale for treatment
●Maintenance medications and adjustment during minor illnesses
●When to consult a clinician
●When and how to inject a glucocorticoid for emergencies
Glucocorticoid regimens — The ideal glucocorticoid replacement therapy would:
●Mimic the endogenous cortisol rhythm, with a nadir at bedtime and peak values in the early morning before waking.
●Have little interindividual variability in metabolism, so that the correct dose could be predicted.
●Be amenable to easy dose titration.
●Be easily monitored.
●Minimize the risk of overtreatment, resulting in iatrogenic Cushing's syndrome (obesity, osteoporosis, facial plethora). (See 'Monitoring dose' below and "Epidemiology and clinical manifestations of Cushing's syndrome".)
Unfortunately, there are no head-to-head comparisons of various glucocorticoid replacement regimens. Various regimens have been advocated, using short-acting (cortisone acetate or hydrocortisone) or long-acting (prednisone/prednisolone, dexamethasone) agents (table 2).
Optimal choice: Short-acting glucocorticoids — We suggest replacement with a short-acting glucocorticoid, hydrocortisone, in two or three divided doses as the glucocorticoid of choice for the management of chronic primary adrenal insufficiency [2]. We suggest using the lowest glucocorticoid dose that relieves symptoms of glucocorticoid deficiency.
Short-acting regimens roughly mimic the normal diurnal rhythm. The bioavailability of hydrocortisone is nearly 100 percent, and serum cortisol concentrations rise rapidly in the 30 minutes or so after ingestion. However, after a large dose, the ability of corticosteroid-binding globulin (CBG) to bind cortisol is exceeded (it cannot bind any more cortisol at around 25 mcg/dL) [3]. As a result, the serum free cortisol increases, and is rapidly filtered into the urine, resulting in a rapid decline in serum total cortisol concentrations to 25 mcg/dL (690 nmol/L), after which the decline slows (average plasma half-life about 95 minutes). One study found elevated urinary free cortisol (UFC) for 24 hours after a single 25 mg hydrocortisone dose, but a decrease to the reference range, when the 25 mg daily dose was given in five 5 mg doses [4].
To become biologically active, cortisone must undergo hepatic conversion to cortisol. It is either largely unabsorbed or not metabolized after intramuscular administration [5]. Because of these shortcomings, hydrocortisone is generally considered to be the better choice for a short-acting glucocorticoid regimen.
In general, the replacement dose of glucocorticoid is aimed at replacing the missing cortisol or its equivalent. The average daily secretion rate of cortisol in normal subjects is 2.7 to 14 mg/m2/day [6], and the range of replacement doses is wider due to interindividual variation in metabolism of the steroids and the fact that a single dose is less effective than the same amount of steroid administered in multiple doses. Based on the known secretion rate, we recommend a total daily hydrocortisone dose of 10 to 12 mg/m2.
Because of its short half-life, the total daily dose of hydrocortisone is divided into two or three doses. Thrice daily administration mimics the day-curve of cortisol seen in healthy volunteers [7]. A typical twice-daily regimen consists of taking about two-thirds of the total dose upon arising in the morning and one-third in the afternoon to simulate the normal cortisol circadian rhythm. Three times daily regimens use decreasing doses in the morning, early afternoon, and late afternoon/early evening (eg, 10/5/2.5 mg). Most regimens avoid evening doses, because normal subjects secrete little cortisol from about 6 PM to 3 AM.
Authors recommend a variety of replacement doses, including 5 mg/m2 given thrice daily, 10 mg morning, and 5 mg in the afternoon [8], 20 mg total dose [9], and 15 to 25 mg daily given in two or three divided doses [10]. Hydrocortisone has some mineralocorticoid activity, so fludrocortisone replacement (if needed) must be decreased appropriately. Hydrocortisone dose recommendations are similar for patients with secondary adrenal insufficiency [11-13]. (See "Treatment of hypopituitarism", section on 'ACTH deficiency'.)
The interaction of concurrent medications that alter CYP3A4 metabolism of glucocorticoids should be considered when choosing the dose, as it may require adjustment [14,15].
While some patients do well on single-dose administration, we use a split dose when initiating therapy. A single dose should only be used if patients are not compliant with the afternoon dose. In one study, quality of life and patient preference were greatest during three weeks with a split dose regimen (20 mg at 0700h and 10 mg at 1900h) rather than a single total dose in the morning or evening [16]. There are no studies comparing quality of life of two versus three dose regimens.
Advantages of hydrocortisone include the potential for fine dose adjustments using various tablet strengths. Additionally, one study found that smaller fractionated doses of hydrocortisone (10 mg twice daily) avoided increased intraocular pressure found with a higher dose (20 mg and 10 mg split dose) [17].
A disadvantage of hydrocortisone therapy is the fact that a normal diurnal rhythm cannot be truly replicated: at the time of the morning dose, endogenous serum cortisol concentrations would normally already be at or after the circadian peak. This transient early morning adrenal insufficiency probably accounts for the symptoms of fatigue, lassitude, mild nausea, or headache that are often present upon awakening and that are relieved within 30 to 60 minutes after taking the morning dose of hydrocortisone. Some patients find it helpful to take their initial dose of hydrocortisone in the early morning and go back to sleep for a few hours. However, slow-release preparations in development may address this problem [18-20].
A once-daily dual-release hydrocortisone tablet based on an immediate-release coating combined with an extended-release core is being investigated as an alternative to standard twice or three times daily dosing for patients with adrenal insufficiency. In one report, patients taking the once-daily tablet had a more physiologic serum cortisol profile, and lower body weight and blood pressure when compared with those taking an equivalent dose of hydrocortisone administered as a three times daily regimen [21]. Another strategy being investigated is a hydrocortisone ultradian pump [22].
Long-acting glucocorticoids — Longer-acting agents such as prednisone, prednisolone, or dexamethasone provide a smoother physiological effect and avoid the marked changes in serum glucocorticoid levels that occur with short-acting drugs. It is not known if this is clinically important. The usual oral daily replacement doses are 0.5 mg and 5 mg for dexamethasone and prednisone, respectively. Some patients require 2.5 or 7.5 mg for prednisone or 0.25 or 0.75 mg for dexamethasone (table 2).
Long-acting agents may be useful in patients who are non-compliant with multiple daily dose schedules, or in those with severe late-evening or early morning symptoms that are not ameliorated by three-times daily hydrocortisone. Disadvantages of long-acting agents include the variable inter-individual metabolism of dexamethasone and, as a result, an inability to predict the correct dose. As a result, patients may be over-treated.
Patients with obesity and those who metabolize glucocorticoids more rapidly than average may need higher doses; children or small adults and patients who metabolize glucocorticoids less rapidly than average may need lower doses. The dexamethasone dose may need to be increased in patients taking drugs that accelerate hepatic steroid metabolism, such as phenytoin, barbiturates, rifampin, and mitotane [23-26].
Monitoring dose — We suggest using the lowest glucocorticoid dose that relieves symptoms of glucocorticoid deficiency and avoids signs and symptoms of glucocorticoid excess. (See "Epidemiology and clinical manifestations of Cushing's syndrome", section on 'Clinical manifestations'.)
Symptom assessment
●The dose may be too low if symptoms of apparent glucocorticoid deficiency are present. If, however, increasing the dose does not promptly relieve the symptoms, then they have other causes and the lower steroid dose should be resumed.
●The dose may be too high if excessive weight gain, facial plethora or other symptoms or signs of Cushing's syndrome are present. (See "Epidemiology and clinical manifestations of Cushing's syndrome", section on 'Clinical manifestations'.)
Osteoporosis is more likely with excessive glucocorticoid therapy [27,28]. Increased bone loss in women, but not men, with treated primary adrenal insufficiency was reported in one study [29] and in men but not women in another [30]. Comparison of bone loss in patients treated with daily hydrocortisone 30 mg or prednisone 7.5 mg (doses that are higher than the recommended maintenance doses) found no difference in one study, but lower bone mineral density with prednisone in another [31,32]. (See "Clinical features and evaluation of glucocorticoid-induced osteoporosis", section on 'Epidemiology and risk factors'.)
A study of nine patients receiving three different regimens in random order suggested that morning dexamethasone 0.1 mg/15 kg body weight had adverse effects on serum markers of bone turnover as compared with hydrocortisone 10 mg/5 mg or 10/5/5 mg split doses [33]. Although this issue remains unresolved, it does highlight the importance of avoiding excessive doses of glucocorticoid, and may suggest that long-acting glucocorticoids are more likely to reduce bone mineral density. (See "Clinical features and evaluation of glucocorticoid-induced osteoporosis", section on 'Epidemiology and risk factors'.)
Plasma ACTH
●A low normal or suppressed morning plasma corticotropin (ACTH) concentration indicates excessive glucocorticoid replacement in patients with primary adrenal insufficiency. The early morning adrenal insufficiency with hydrocortisone results in plasma ACTH concentrations that are two to eight times higher than normal for several hours in the early morning and for several hours after the cortisol is taken [34-36]. ACTH levels were significantly lower compared with conventional oral therapy, but remained about twofold elevated in two patients receiving hydrocortisone infusion [36]. Measurements of plasma ACTH are not helpful in patients with secondary insufficiency, in whom levels are expected to be low.
●While some advocate use of normative day-curve cortisol values to assess the adequacy of hydrocortisone therapy [7], other reports suggest that clinical assessment alone works equally well [37].
Mineralocorticoid replacement — Most patients with primary adrenal insufficiency eventually require mineralocorticoid replacement to prevent sodium loss, intravascular volume depletion, and hyperkalemia. Fludrocortisone (9-alpha-fluorohydrocortisone), a potent synthetic mineralocorticoid, is given orally in a usual dose of 0.1 mg/day. A lower dose (such as 0.05 mg/day) may be sufficient in patients receiving hydrocortisone, which has some mineralocorticoid activity. Rare patients are sufficiently replaced with hydrocortisone alone and become hypertensive, hypokalemic with even 0.05 mg Florinef twice a week. Many patients receiving prednisone or dexamethasone require up to 0.2 mg/day of fludrocortisone to lower their plasma renin activity to the upper normal range [38,39]. (See 'Monitoring' below.)
The mineralocorticoid dose may have to be increased in the summer, when salt loss in perspiration increases, especially if the patient is routinely exposed to temperatures above about 29ºC (85ºF). Salt intake should be liberal, especially when exercising.
Primary hypertension (formerly called "essential" hypertension) in patients with primary adrenal insufficiency should be treated by dietary sodium restriction and a lower dose of fludrocortisone [40,41]. Mineralocorticoid therapy usually cannot be discontinued without risking sodium depletion. If an antihypertensive drug is needed, diuretic drugs and spironolactone should not be used, since they simply counteract the action of fludrocortisone.
Mineralocorticoid replacement is rarely required in patients with secondary adrenal insufficiency because ACTH is not the main physiological regulator of aldosterone release.
Monitoring — The adequacy of mineralocorticoid replacement should be monitored by asking about symptoms of postural hypotension and measuring supine and upright blood pressure and pulse, serum potassium, and plasma renin activity (PRA). Hypertension, edema, and hypokalemia are signs of excessive mineralocorticoid replacement [40].
We suggest adjusting the fludrocortisone dose to lower the PRA to the upper normal range [38,39]. Normal morning plasma renin activity for seated subjects ranges from about 1 to 4 ng/mL per hour (0.8 to 3.0 nmol/L per hour). (See "Assays of the renin-angiotensin-aldosterone system in adrenal disease", section on 'Plasma renin activity'.)
It is useful to measure PRA annually in all patients and in:
●Newly diagnosed patients, until they are on a stable dose of mineralocorticoids.
●Patients with symptoms consistent with mineralocorticoid deficiency such as salt craving and intermittent mild nausea who have otherwise normal findings on physical examination.
In asymptomatic patients with normal serum electrolyte concentrations but high PRA, the fludrocortisone dose should not be raised to normalize PRA. Although one might predict that this would be a physiologic dose (normal PRA in an asymptomatic, normokalemic patient), patients may develop hypokalemia and edema [42]. (See "Pathophysiology and clinical features of primary aldosteronism".)
Androgen replacement (DHEA) — Many women with adrenal insufficiency describe a decrease in quality of life in spite of adequate glucocorticoid and mineralocorticoid replacement. This observation has led to interest in finding additional therapies, in particular, androgens, to improve well-being.
The adrenal cortex is the primary source of androgen in the form of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). In women with adrenal insufficiency, serum concentrations of DHEA are extremely low. Therefore, DHEA has been studied as a therapy to improve mood and quality of life.
Mood/quality of life — Clinical trial data suggest that in women with primary adrenal insufficiency, replacement with 50 mg of DHEA daily may be beneficial for outcomes such as mood and psychological well-being.
In women with secondary adrenal insufficiency, DHEA appears to have a modest beneficial effect on psychological well-being. However, the available data are from women with panhypopituitarism, who have combined adrenal and ovarian androgen deficiency. No data are available in women with isolated ACTH deficiency, a very rare disorder.
The best available data on the effect of DHEA on mood and quality of life in women with adrenal insufficiency comes from a meta-analysis of 10 randomized, placebo-controlled trials [43]. When compared with placebo, DHEA resulted in a small improvement in health-related quality of life. There was also a small beneficial effect on depression, but no significant effect on anxiety or sexual well-being.
Other effects — Twelve-week crossover studies of patients with primary and secondary adrenal insufficiency did not find significant improvements in vascular markers in males and females (arterial stiffness and endothelial function) or metabolic markers (lipids, HOMA-IR, high sensitivity CRP, adiponectin, plasminogen activator inhibitor-1), physical performance, body composition, protein metabolism, or muscle mitochondrial biogenesis in women receiving DHEA 50 mg daily [44-46].
Adverse effects — In the meta-analysis, most, but not all, studies reported common androgenic side effects including oily skin, hirsutism, acne, and increased sweating and odor [43]. Although serious adverse effects were not reported, the long-term safety of DHEA therapy has not been established.
Other adverse effects, including decreases in serum high-density lipoprotein (HDL) concentrations, have been reported.
Suggested approach — There is insufficient evidence to recommend therapy in all patients with adrenal insufficiency, particularly men. In women with adrenal insufficiency (primary or secondary), we suggest DHEA therapy only for those who have significantly impaired mood or sense of well-being despite optimal glucocorticoid and mineralocorticoid replacement. We typically start with 25 to 50 mg daily for three to six months and adjust the dose based upon the clinical response (improvement in libido, sense of well-being, and androgenic side effects). Adverse effects and biochemical monitoring are discussed separately.
If no obvious benefit has been seen after six months or if adverse effects occur, we discontinue DHEA. In the United States, this approach is severely limited by the lack of product quality control, as DHEA is considered to be a dietary supplement rather than a hormone preparation. Therefore, DHEA supplements available commercially may not actually contain the advertised dose. This topic is discussed in detail separately.
Considerations in secondary adrenal insufficiency
●Patients with secondary adrenal insufficiency should receive evaluation and adequate replacement for other pituitary hormone deficiencies. Replacement of thyroid hormone without replacement of glucocorticoids can precipitate acute adrenal insufficiency.
●Patients with hypopituitarism who have partial or total ACTH deficiency and are receiving suboptimal cortisol or cortisone replacement may be at risk of developing symptoms of cortisol deficiency when growth hormone therapy is initiated. This is due to the inhibitory effect of growth hormone on 11-beta-hydroxysteroid dehydrogenase type 1, the enzyme that converts cortisone to cortisol [36].
Special considerations — Cortisol secretion normally increases with the stress of illness and surgery. This fact has prompted the usual clinical practice of giving higher doses of glucocorticoid to patients with adrenal insufficiency in these situations. Unfortunately, there is little information about how much additional glucocorticoid is needed.
Emergency precautions — The major risk to the patient with adrenal insufficiency is the lack of a normal serum cortisol response to stress and, in patients with primary adrenal insufficiency, of a normal renin-angiotensin-aldosterone response to hypovolemia. Consequently, the patient must anticipate these situations and be prepared to modify therapy to meet these needs.
Every patient should wear a medical alert (Medic Alert) bracelet or necklace and carry the Emergency Medical Information Card that is supplied with it. Both should indicate the diagnosis, the daily medications and doses, and the clinician to call in the event of an emergency.
Each patient should have injectable glucocorticoid, such as 100 mg vials of hydrocortisone (Solu-Cortef) or 4 mg vials of dexamethasone, along with vials of sterile 0.9 percent normal saline and syringes. The patient and one or more responsible family or household members should be instructed on how to reconstitute and inject the medication subcutaneously or intramuscularly anywhere on the patient's body if any of the following occur:
●An injury with substantial blood loss (more than a cup) or fracture
●Nausea and vomiting and inability to retain oral medications
●Symptoms of acute adrenal insufficiency
●The patient is found unresponsive
The entire dose of medication should be injected (100 mg of hydrocortisone or 4 mg dexamethasone). Patient and family instruction should include the need to get medical help immediately after the injection. The patient should be instructed to have a low threshold for injecting the glucocorticoid: if it might be necessary, it should be injected and medical attention should be sought. It is unlikely, however, that a patient will need the injectable glucocorticoid more than two or three times a year, and most patients go for years without using it.
Illness — During minor illnesses, such as upper respiratory infections, the patient can increase the dose of glucocorticoid to two to three times the usual daily dose for three days without consulting a clinician (known as the 3 x 3 rule). The increased dose will decrease fever and malaise and will not compromise the immune response. If the illness becomes worse during the three days or if the patient cannot resume the usual maintenance dose on the fourth day, one should consult a clinician to determine if other treatment (eg, antibiotics) is indicated.
As described below, patients with nausea and vomiting who are unable to retain oral medications should have a low threshold for injecting glucocorticoid. Further medical attention should then be sought. (See 'Emergency precautions' above.)
Surgery — The appropriate dose and timing of glucocorticoids for patients undergoing surgery is controversial. Early reports of death after surgery led to a recommendation to give glucocorticoids in doses equivalent to 1000 mg of hydrocortisone daily [47]. This is clearly in excess of the increased production of up to 200 mg daily. Prolonged postoperative pharmacologic glucocorticoid therapy can mask symptoms and signs of infection and cause undesirable side effects. For example, traditional doses of 300 to 400 mg hydrocortisone for a few days can cause significant hypokalemia and edema. (See "The management of the surgical patient taking glucocorticoids".)
Current recommendations for glucocorticoid supplementation at surgery take into account the severity of the operation and suggest lower daily doses [47,48]. For minor procedures such as herniorrhaphy, a dose equivalent to hydrocortisone 25 mg is suggested for the day of operation only, with a return to the usual replacement dose on the second day. For moderate surgical stress (eg, cholecystectomy, joint replacement), divided intravenous (IV) doses equivalent to hydrocortisone 50 to 75 mg are suggested on the day of surgery and the first postoperative day, with a return to the usual dose on the second postoperative day (using oral or IV preparation as appropriate). The authors suggest a total daily dose equivalent to 100 to 150 mg hydrocortisone for major surgical procedures (eg, cardiac bypass) given in divided doses for two to three days, then returning to the usual dose. Alternatively, the dose used on the day of surgery can be halved on postoperative day one. (See "The management of the surgical patient taking glucocorticoids".)
Fasting — Similar to patients with diabetes mellitus, patients with adrenal insufficiency are more likely to have complications as a result of fasting during Ramadan. Clinical recommendations for the approach to these patients, including risk stratification, medication management, monitoring for complications, and patient education have now been published [49]. Patients considered to be at high risk for complications are encouraged to find a modified approach to fasting. Patients on hydrocortisone should be transitioned to a single dose of prednisone or prednisolone, administered at dawn with the patient's daily dose of fludrocortisone. It is essential that patients receive instructions on hydration, sick day rules, when to urgently terminate their fast, and when to give themselves an emergency injection of glucocorticoids.
Critical illness — Adrenal cortisol secretion increases during critical illness, but the increase may not be detected if only total serum cortisol concentrations are measured. Some critically ill patients may have "functional adrenal insufficiency," but there is currently no consensus on diagnostic criteria or indications for treatment. This topic is discussed in detail separately. (See "Initial testing for adrenal insufficiency: Basal cortisol and the ACTH stimulation test" and "Glucocorticoid therapy in septic shock in adults".)
PREGNANCY — Pregnancy complicated by primary adrenal insufficiency has been reported in about 100 women [50]. Before glucocorticoid replacement therapy became available, pregnancy in women with primary adrenal insufficiency was associated with a maternal mortality rate as high as 35 to 45 percent and fetal growth retardation was common [51-53]. At present, most women adequately treated for adrenal insufficiency go through pregnancy, labor, and delivery without difficulty, and babies achieve a normal birth weight. The usual glucocorticoid and mineralocorticoid replacement doses are continued; an occasional woman requires slightly more glucocorticoid in the third trimester [41,50,54].
●During labor, adequate saline hydration and 25 mg hydrocortisone should be administered intravenously (IV) every six hours.
●At the time of delivery, or if labor is prolonged, hydrocortisone should be administered IV in a dose of 100 mg every six hours or as a continuous infusion.
●After delivery, the dose can be tapered rapidly to maintenance within three days [55].
An occasional woman with severe nausea and vomiting in the first trimester may require intramuscular dexamethasone at a slightly increased dose (1 mg daily).
The regulation of plasma volume during pregnancy is complex. Secondary hyperaldosteronism is normal [56], associated with increased plasma renin activity and serum aldosterone concentrations [57,58]. Serum concentrations of progesterone, which competes with aldosterone for binding to the type 1 corticosteroid (mineralocorticoid) receptor in the kidney and has a natriuretic effect, are increased throughout pregnancy [59,60]. Plasma atrial natriuretic peptide concentrations reach their nadir late in the third trimester [61], when plasma renin activity and serum aldosterone concentrations reach their peak [57].
There are no studies of mineralocorticoid requirement during pregnancy in women with adrenal insufficiency. Patients should be followed closely throughout pregnancy for electrolyte abnormalities and signs of volume depletion. Plasma renin activity may be used as an index of adequate fludrocortisone dose, but should not be suppressed to values less than those in pregnant women without adrenal insufficiency (ie, 20 to 25 ng/mL per hour supine or standing) [57,58,61].
PROGNOSIS — The prognosis for patients with adrenal insufficiency was poor before the availability of glucocorticoids, with more than 80 percent of patients dying within two years after diagnosis [62]. Subsequent reports after glucocorticoids became available for treatment suggested that patients with autoimmune adrenal insufficiency should have a normal life-span and can lead a fully active life, including vigorous exercise [54,62]. By contrast, a study based on the Swedish death registry found that patients with adrenal insufficiency have a twofold higher mortality rate than the background population [63]. The reasons for this discrepancy are not understood and further studies are needed to evaluate whether these patients have premature mortality.
Studies report significantly reduced subjective quality of life and increased rates of work disability in patients with adrenal insufficiency [64-66]. A Norwegian study of 79 patients who answered a postal survey showed impaired general health and vitality perception and an increase in reported fatigue. Self-perception of physical functioning was low in women. Working disability at ages 18 to 67 years was 26 percent, compared with 10 percent in the corresponding general Norwegian population [64]. A German study reported increased depression scores and reduced quality of life scores in 210 patients, 18.3 percent of whom did not work because of disability [65]. It is possible that improved therapy that better mimics the normal diurnal cortisol rhythm or additional therapy with dehydroepiandrosterone (DHEA) might ameliorate this problem, but data are not available to address this.
One study noted the presence of heart failure in 7 of 22 patients with long-standing primary adrenal insufficiency receiving conventional treatment after a mean of 26 years [41]. However, the causal relationship, if any, to the adrenal insufficiency or its therapy is unclear.
Linear growth and pubertal development proceed normally in correctly (ie, adequately but not overly) treated children with adrenal insufficiency [67,68]. As noted, over-replacement can lead to bone loss and osteoporosis [30,31].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Adrenal insufficiency".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Addison's disease (The Basics)" and "Patient education: Adrenal crisis (The Basics)")
●Beyond the Basics topics (see "Patient education: Adrenal insufficiency (Addison's disease) (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Adrenal crisis – Adrenal crisis is a life-threatening emergency that requires immediate treatment (table 1). It is essential that treatment of patients who present in possible adrenal crisis not be delayed while diagnostic tests are performed. (See 'Adrenal crisis' above.)
•The goal of therapy is treatment of hypotension and reversal of electrolyte abnormalities and of cortisol deficiency. Large volumes (1 to 3 liters) of 0.9 percent saline solution or 5 percent dextrose in 0.9 percent saline should be infused intravenously (IV) to correct hypovolemia and hyponatremia associated with mineralocorticoid deficiency and/or syndrome of inappropriate antidiuretic hormone secretion (SIADH). (See 'Management' above.)
•For patients who present with adrenal crisis, we administer hydrocortisone (100 mg IV bolus), followed by 50 mg IV every 6 hours (or 200 mg/24 hours as a continuous IV infusion for the first 24 hours). If hydrocortisone is unavailable, alternatives include methylprednisolone and dexamethasone (table 1 and table 2). (See 'Choice of glucocorticoid' above.)
•Mineralocorticoid administration is not necessary in the acute setting. (See 'Management' above.)
●Chronic primary adrenal insufficiency
•For the management of chronic primary adrenal insufficiency, we suggest replacement with hydrocortisone in two or three divided doses (total dose of 10 to 12 mg/m2/day) as the glucocorticoid of choice (Grade 2C). A daily dose of dexamethasone or prednisone may also be used (table 3). (See 'Glucocorticoid regimens' above.)
•The vast majority of patients with primary adrenal insufficiency eventually require mineralocorticoid replacement with fludrocortisone. We suggest adjusting the fludrocortisone dose to lower the plasma renin activity to the upper normal range (Grade 2C). (See 'Mineralocorticoid replacement' above.)
•We suggest dehydroepiandrosterone (DHEA) therapy only in women with impaired mood or sense of well-being despite optimal glucocorticoid and, if needed, mineralocorticoid replacement (Grade 2C). However, this approach is limited by the lack of reliable source of this compound in some countries. (See 'Androgen replacement (DHEA)' above.)
●Monitoring glucocorticoid dose – We suggest using the lowest glucocorticoid dose that relieves symptoms of glucocorticoid deficiency. In patients with secondary adrenal insufficiency, measurement of early morning plasma corticotropin (ACTH) concentration is not helpful because values are expected to be low. In patients with primary adrenal insufficiency, measurement of early morning plasma ACTH concentration is not necessary for routine monitoring, but may detect over-replacement, in which case the value will be in the low-normal range. (See 'Monitoring dose' above.)
●Special considerations
•Minor illness – For minor illnesses, we suggest two to three times the usual maintenance glucocorticoid dose for three days (known as the 3 x 3 rule) (Grade 2C). (See 'Special considerations' above and 'Illness' above.)
•Surgical procedures or severe illness – For surgical procedures or severe illness, we suggest coverage with graded doses of hydrocortisone or its equivalent, as noted above. (See 'Surgery' above.)
•Emergency preparedness – All patients should wear a medical alert bracelet and have supplies for emergency glucocorticoid injections. (See 'Emergency precautions' above.)
DISCLOSURE — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.
