Treatment of adrenal insufficiency in adults

Authors: Lynnette K Nieman, MD, Anthony DeSantis, MD

Section Editor: André Lacroix, MD
Deputy Editor: Katya Rubinow, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Dec 2023. | This topic last updated: Oct 09, 2023.

INTRODUCTION

Adrenal insufficiency is defined by inadequate cortisol production to meet physiologic needs. Primary
adrenal insufficiency (Addison disease) results from disorders of the adrenal cortex, whereas secondary and
tertiary adrenal insufficiency are due to dysfunction of the pituitary gland and the hypothalamus,
respectively. Adrenal insufficiency leads to diffuse symptoms, may become life-threatening (adrenal crisis),
and requires glucocorticoid replacement therapy. Primary adrenal insufficiency leads to both glucocorticoid
(cortisol) and mineralocorticoid (principally aldosterone) deficiency. In contrast, central (ie, secondary or
tertiary) adrenal insufficiency causes glucocorticoid, 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 both acute and chronic 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 disease)" and "Clinical manifestations of adrenal insufficiency in
adults" and "Diagnosis of adrenal insufficiency in adults".)

The management of adrenal insufficiency in children and in adults with classic congenital adrenal
hyperplasia is also reviewed separately. (See "Treatment of adrenal insufficiency in children", section on
'Adrenal hormone replacement therapy' and "Treatment of classic congenital adrenal hyperplasia due to
21-hydroxylase deficiency in adults", section on 'Continued adrenal hormone therapy'.)

ADRENAL CRISIS

Adrenal crisis is a life-threatening emergency that requires immediate treatment with parenteral
glucocorticoids and isotonic fluid administration ( table 1). Adrenal crisis denotes an episode of acute
adrenal insufficiency and should be considered in any patient with shock. In addition to hypotension,
patients commonly present with nonspecific signs and symptoms including nausea, vomiting, anorexia,
fever, fatigue, weakness, and confusion or loss of consciousness. If adrenal crisis is suspected, treatment
should be initiated immediately. Adrenal crisis occurs in patients with primary adrenal insufficiency and
central adrenal insufficiency, but it is very uncommon in patients with adrenal insufficiency due to
prolonged administration of exogenous glucocorticoids. (See "Clinical manifestations of adrenal
insufficiency in adults", section on 'Adrenal crisis'.)

Clinical data evaluating the management of adrenal crisis are limited. Our approach is consistent with
society guideline recommendations [1] and based on the pathophysiology of adrenal crisis, the
pharmacology of available treatment options, and clinical experience.

Emergency management — Adrenal crisis requires urgent diagnosis and intervention ( table 1).
Treatment of patients who present in possible adrenal crisis should never be delayed to perform diagnostic
tests. For all patients, initial treatment includes establishing intravenous (IV) access, isotonic fluid infusion,
and parenteral glucocorticoid therapy. Laboratory tests (including serum electrolyte and glucose levels)
should be sent. For patients without an established diagnosis of adrenal insufficiency, additional hormone
measurements (cortisol, corticotropin [ACTH], aldosterone, renin) should be obtained to facilitate the
diagnosis; however, these measurements do not alter emergency management and should never delay
treatment initiation. The precipitating cause of adrenal crisis (eg, bacterial infection, viral gastroenteritis,
trauma) should be determined and treated appropriately. (See "Clinical manifestations of adrenal
insufficiency in adults", section on 'Precipitating factors'.)

The detailed steps of initial emergency management include:

● Fluid resuscitation – After IV access is established with a large-gauge needle, we administer at least 1
liter of 0.9 percent saline or 5 percent dextrose in 0.9 percent saline within one hour. This fluid bolus
may need to be repeated, as patients with adrenal crisis usually require at least 2 to 3 liters of isotonic
fluids within the first 12 to 24 hours. Once the patient is volume resuscitated, maintenance fluids are
administered as for the general medical population, which is discussed elsewhere. (See "Maintenance
and replacement fluid therapy in adults", section on 'Maintenance fluid therapy'.)

We avoid hypotonic saline because it can worsen hyponatremia. Lactated Ringer solution also
theoretically may worsen hyponatremia, although clinical data are limited.

● Initial laboratory tests – Although initial laboratory tests are sent at the time of first clinical suspicion
for adrenal crisis, presumptive management should not be delayed pending results.

• All patients in adrenal crisis – In all patients in known or suspected adrenal crisis, we measure
serum creatinine, blood urea nitrogen (BUN), electrolyte, and glucose levels to evaluate for
hyponatremia, hyperkalemia, and hypoglycemia. (See "Hyponatremia and hyperkalemia in adrenal
insufficiency" and "Clinical manifestations of adrenal insufficiency in adults", section on 'Laboratory
findings'.)

• Additional testing for patients without a prior diagnosis of adrenal insufficiency – Prior to
initiation of glucocorticoid therapy, additional laboratory tests should be sent for patients without an
established diagnosis of adrenal insufficiency. For all patients without a prior diagnosis, we send a
 serum cortisol level to verify cortisol deficiency. When clinical suspicion is high for adrenal
insufficiency, we also measure plasma levels of ACTH, aldosterone, and renin to initiate the etiologic
evaluation. (See "Determining the etiology of adrenal insufficiency in adults", section on 'Establish
the level of defect'.)

● Glucocorticoid therapy – For patients who present in known or suspected adrenal crisis, we
recommend immediate administration of hydrocortisone (100 mg IV bolus), followed by 50 mg IV every
six hours (or 200 mg/24 hours as a continuous IV infusion) for the first 24 hours [2]. We then reduce the
hydrocortisone dose to 50 mg IV every 12 hours. Continued taper is guided by the patient's clinical
status. (See 'Subsequent management' below.)

We prefer hydrocortisone because it has both glucocorticoid and mineralocorticoid activity; this is
particularly important in patients with known primary adrenal insufficiency or those with serum
potassium >6.0 mEq/L and/or clear evidence of volume depletion, which may indicate
mineralocorticoid deficiency. If hydrocortisone is unavailable, alternatives include methylprednisolone
40 mg IV or dexamethasone 4 to 6 mg IV ( table 1).

● Mineralocorticoid therapy for patients with known or suspected primary adrenal insufficiency

• Concurrent hydrocortisone treatment – In patients with known or suspected primary adrenal

insufficiency (eg, based on the presence of hyperkalemia, skin hyperpigmentation, or overt volume
depletion), fludrocortisone is unnecessary during high-dose hydrocortisone therapy with isotonic
fluid administration. At doses ≥40 mg daily, hydrocortisone has sufficient mineralocorticoid activity
to serve as replacement therapy. In such patients, fludrocortisone should be resumed or initiated
during hydrocortisone taper when oral intake is possible. (See 'Patients with known adrenal
insufficiency' below.)

• Concurrent treatment with methylprednisolone or dexamethasone – In patients with known or

suspected primary adrenal insufficiency, we add oral fludrocortisone 0.2 mg daily during
methylprednisolone or dexamethasone therapy. Methylprednisolone has less mineralocorticoid
activity than hydrocortisone, and dexamethasone has none. Therefore, patients with primary
adrenal insufficiency usually require mineralocorticoid replacement. (See 'Patients with known
adrenal insufficiency' below.)

● Electrolyte management – Hyponatremia and hypoglycemia can evolve consequent to cortisol

deficiency, whereas the presence of hyperkalemia indicates mineralocorticoid as well as glucocorticoid
deficiency.

• Hyponatremia – If hyponatremia is present and the patient is known to have central adrenal
insufficiency, free thyroxine (T4) should be measured to exclude concurrent central hypothyroidism.
The serum sodium level should be monitored closely (eg, every two to six hours) until normalization.
Parenteral hydrocortisone therapy and isotonic fluid administration correct hyponatremia due to
adrenal insufficiency. If hyponatremia persists despite these interventions, it is not due to adrenal
 insufficiency, and additional evaluation is needed to determine the cause. (See "Diagnostic
evaluation of adults with hyponatremia".)

• Hyperkalemia – Parenteral hydrocortisone and volume replacement will correct hyperkalemia, and
additional intervention is not typically necessary. If present, hyperkalemia should correct within a
few hours of hydrocortisone initiation. If hyperkalemia persists, additional intervention and
evaluation for alternative causes are needed. (See "Causes and evaluation of hyperkalemia in adults"
and "Treatment and prevention of hyperkalemia in adults".)

• Hypoglycemia – Isotonic, dextrose-containing fluids should be administered to patients with known

or suspected hypoglycemia. Additional dextrose should be administered acutely if hypoglycemia is
severe enough to cause neuroglycopenia (ie, glucose <55 mg/dL [<3 mmol/L]). The glucose-raising
effect of supraphysiologic glucocorticoid treatment is potent, and correction of hypoglycemia is not
sufficient to confirm adrenal insufficiency as the underlying cause. (See "Hypoglycemia in adults with
diabetes mellitus", section on 'Reversing hypoglycemia' and "Hypoglycemia in adults without
diabetes mellitus: Clinical manifestations, causes, and diagnosis", section on 'Causes of
hypoglycemia'.)

Expected treatment response — If hypotension is caused by adrenal crisis, it should improve rapidly
(within a few hours) with parenteral glucocorticoid therapy and isotonic fluid administration. If hypotension
persists despite these interventions, the precipitating cause of the adrenal crisis may not be adequately
addressed, or the patient may have an alternative cause of hypotension and shock. (See "Clinical
manifestations of adrenal insufficiency in adults", section on 'Precipitating factors' and "Evaluation of and
initial approach to the adult patient with undifferentiated hypotension and shock", section on 'Common
conditions needing lifesaving interventions'.)

Subsequent management — After initial, emergency treatment of adrenal crisis, further adrenal hormone
replacement and evaluation depend in part on whether the patient has a prior diagnosis of adrenal
insufficiency. Assessment of the patient's volume status and urine output should guide subsequent fluid
administration. (See "Maintenance and replacement fluid therapy in adults".)

All patients require close outpatient follow-up within one to two weeks of hospital discharge for counseling,
assessment of risk factors for recurrent adrenal crisis, and, for patients without a known history of adrenal
insufficiency, further diagnostic evaluation.

Patients with known adrenal insufficiency — Once stable, patients with known adrenal insufficiency
generally transition to their home treatment regimen.

● Glucocorticoid therapy – We taper hydrocortisone over one to three days unless a major complicating
illness requires prolonged treatment with high-dose parenteral therapy. If the patient has ongoing
illness (eg, infection with moderate to severe symptoms, postsurgical complications), we first transition
to an oral stress dose regimen; otherwise, we resume the patient's usual maintenance regimen. Stress
dose and maintenance glucocorticoid regimens are discussed in detail below. (See 'Circumstances
 requiring glucocorticoid dose adjustment' below and 'Hydrocortisone (preferred glucocorticoid)'
below.)

● Mineralocorticoid therapy – For patients with known primary adrenal insufficiency, we reinitiate their
usual maintenance fludrocortisone dose when the hydrocortisone dose is tapered below 40 mg daily,
which confers mineralocorticoid activity roughly equivalent to 0.1 mg fludrocortisone [1].
Mineralocorticoid replacement therapy is rarely needed in patients with central adrenal insufficiency
and is reviewed in detail below. (See 'Mineralocorticoid replacement for selected individuals' below.)

Patients without known adrenal insufficiency — For patients without a prior diagnosis of adrenal
insufficiency, the initial serum cortisol level usually is available within a few hours and may help verify or
exclude cortisol deficiency. However, presumptive management of clinically suspected adrenal insufficiency
should not be delayed pending results. The interpretation of serum cortisol level in the setting of adrenal
crisis is reviewed separately. (See "Diagnosis of adrenal insufficiency in adults", section on 'Suspected
adrenal crisis'.)

● Glucocorticoid therapy

• Adrenal insufficiency likely or cannot be excluded – For patients in whom underlying adrenal
insufficiency is likely or cannot be excluded, we continue maintenance glucocorticoid replacement
until the patient undergoes further diagnostic evaluation, usually in the outpatient setting. (See
"Diagnosis of adrenal insufficiency in adults", section on 'ACTH stimulation tests'.)

Once the patient has stabilized, we taper hydrocortisone over one to three days, unless a major
complicating illness requires prolonged treatment with high-dose parenteral therapy. If the patient
has ongoing illness (eg, infection with moderate to severe symptoms, postsurgical complications),
we first transition to an oral stress dose regimen; otherwise, we initiate a maintenance
glucocorticoid replacement regimen. (See 'Circumstances requiring glucocorticoid dose adjustment'
below and 'Hydrocortisone (preferred glucocorticoid)' below.)

• Adrenal insufficiency excluded – For patients in whom underlying adrenal insufficiency is excluded,
we taper and discontinue hydrocortisone over one to three days.

● Patient education and counseling – Prior to hospital discharge, patients with known or suspected
adrenal insufficiency should receive counseling about glucocorticoid replacement, the risks of cortisol
deficiency, emergency measures, and circumstances requiring glucocorticoid dose adjustments. (See
'Patient education and safety' below.)

● Mineralocorticoid therapy for selected patients – If other initial diagnostic laboratory tests
(aldosterone, renin, ACTH) have not returned, we initiate maintenance mineralocorticoid replacement
with fludrocortisone empirically in patients who presented with hyperkalemia, skin hyperpigmentation,
or overt volume depletion; these are signs of mineralocorticoid deficiency and therefore may indicate
primary adrenal insufficiency. In these patients, we begin fludrocortisone when the hydrocortisone
 dose is tapered below 40 mg daily, which confers mineralocorticoid activity roughly equivalent to 0.1
mg fludrocortisone [1]. (See 'Mineralocorticoid replacement for selected individuals' below.)

In patients who did not present with hyperkalemia or volume depletion, we monitor blood pressure
and serum electrolyte levels closely during hydrocortisone taper and initiate fludrocortisone only if
indicated by hypotension, orthostasis, or hyperkalemia. Fludrocortisone dosing and treatment
monitoring are reviewed in detail below. (See 'Mineralocorticoid replacement for selected individuals'
below.)

If the diagnostic test results are available, they can be used to determine the presence of primary
adrenal insufficiency and attendant need for mineralocorticoid replacement. (See "Determining the
etiology of adrenal insufficiency in adults", section on 'Establish the level of defect'.)

● Additional diagnostic and etiologic evaluation – In patients with an indeterminate or low serum
cortisol level, we verify cortisol deficiency and, if indicated, determine its cause once the patient's
condition is stable. This evaluation is usually performed in the outpatient clinic setting and is reviewed
separately. (See "Diagnosis of adrenal insufficiency in adults" and "Determining the etiology of adrenal
insufficiency in adults".)

CHRONIC ADRENAL INSUFFICIENCY

Sequence of hormone replacement therapy

● Primary adrenal insufficiency – In patients with primary adrenal insufficiency, glucocorticoid and
mineralocorticoid replacement are started concurrently upon diagnosis ( algorithm 1). Selection of
initial glucocorticoid and mineralocorticoid regimens is reviewed below. (See 'Glucocorticoid
replacement for all patients' below and 'Mineralocorticoid replacement for selected individuals' below.)

In primary adrenal insufficiency, plasma dehydroepiandrosterone (DHEA and DHEA sulfate [DHEAS])
levels are usually low. The optimal use of DHEA therapy and its risk and benefits are uncertain. In
females with persistent symptoms suggestive of androgen deficiency, a therapeutic trial of androgen
replacement with DHEA may be offered. (See 'Androgen replacement therapy for selected females'
below.)

● Central adrenal insufficiency – In patients with central (ie, secondary or tertiary) adrenal insufficiency,
glucocorticoid replacement therapy is started upon diagnosis ( algorithm 1). Selection of an initial
glucocorticoid regimen is reviewed below. (See 'Glucocorticoid replacement for all patients' below.)

Once this regimen is optimized, we assess females for persistent symptoms suggestive of androgen
deficiency. If such symptoms are present, a therapeutic trial of androgen replacement with DHEA may
be offered. (See 'Androgen replacement therapy for selected females' below.)
 The initiation of glucocorticoid therapy requires additional considerations for patients with central
adrenal insufficiency. Such patients require evaluation for other pituitary hormone deficiencies [3]. In
patients with more than one pituitary hormone deficiency, glucocorticoid therapy should be initiated
prior to other hormone replacement therapies, particularly thyroid or growth hormone replacement.
The evaluation for hypopituitarism is reviewed separately. (See "Diagnostic testing for
hypopituitarism".)

• Concurrent hypothyroidism – In patients with hypopituitarism who also have secondary

hypothyroidism, glucocorticoid replacement must precede thyroid hormone replacement. Thyroid
hormone administration without adequate glucocorticoid replacement can precipitate adrenal crisis
through accelerated cortisol metabolism mediated by 11-beta-hydroxysteroid dehydrogenase type 2
(11-beta-HSD2).

• Concurrent growth hormone deficiency – In patients with hypopituitarism who also have growth
hormone deficiency, glucocorticoid replacement therapy must be optimized before initiation of
growth hormone therapy. Patients with corticotropin (ACTH) deficiency who receive suboptimal
glucocorticoid replacement are at risk for overt cortisol deficiency when growth hormone therapy is
initiated. This risk is due to the inhibitory effect of growth hormone on 11-beta-hydroxysteroid
dehydrogenase type 1 (11-beta-HSD1), the enzyme that converts cortisone to cortisol [4].

Glucocorticoid replacement for all patients — Cortisol deficiency is a feature of primary and central
adrenal insufficiency, so any form of adrenal insufficiency requires glucocorticoid replacement therapy.
Continual patient education and counseling are essential facets of management because cortisol deficiency
can be life-threatening, and glucocorticoid replacement regimens must be adjusted during periods of
stress. Rare patients can have partial central adrenal insufficiency, defined as normal basal cortisol
secretion with inadequate cortisol response to stress. In such patients, chronic daily glucocorticoid
replacement may not be necessary, but patients should be educated about signs of adrenal insufficiency
that may develop during stress and instructed on stress dose glucocorticoid management. Whenever
possible, these individuals should be under the care of a specialist experienced in the treatment of partial
central adrenal insufficiency. (See 'Patient education and safety' below and 'Circumstances requiring
glucocorticoid dose adjustment' below.)

Glucocorticoid replacement regimens are generally the same for patients with primary or central adrenal
insufficiency [5-7]. Chronic excess exposure to glucocorticoids can result in iatrogenic Cushing syndrome.
Therefore, a critical goal of replacement therapy is to provide adequate but not excessive glucocorticoid
exposure. Close monitoring for signs and symptoms of both over- and undertreatment is required for all
patients on glucocorticoid therapy. The optimal glucocorticoid dose for any patient is the lowest dose that
relieves symptoms of cortisol deficiency. (See 'Glucocorticoid therapy monitoring' below and "Epidemiology
and clinical manifestations of Cushing syndrome".)

In adults with adrenal insufficiency due to classic congenital adrenal hyperplasia, glucocorticoid therapy
has additional goals and is reviewed separately. (See "Treatment of classic congenital adrenal hyperplasia
due to 21-hydroxylase deficiency in adults", section on 'Continued adrenal hormone therapy'.)

Hydrocortisone (preferred glucocorticoid) — For most patients with adrenal insufficiency, we suggest
hydrocortisone for glucocorticoid replacement therapy [1]. Few data are available to guide the selection of
glucocorticoid replacement regimens. Consequently, regimens should be individualized with close
monitoring to ensure that treatment goals are met.

Rationale — Hydrocortisone is a short-acting agent and allows dose titration in small increments.
Dosing regimens also can be adjusted to provide variable glucocorticoid exposure over the course of a day.
Hydrocortisone is usually administered in two or three daily divided doses to better mimic the circadian
pattern of endogenous cortisol secretion, with an early morning peak and a bedtime nadir for individuals
who follow a natural circadian sleep-wake schedule.

When hydrocortisone therapy is unavailable, the short-acting agent cortisone acetate is a reasonable
alternative. (See 'Alternative short-acting therapy' below.)

For individuals with difficulty adhering to multiple daily hydrocortisone doses or those with persistent
symptoms on hydrocortisone regimens, once-daily therapy with prednisolone may provide greater ease of
dosing and symptom relief. (See 'Longer-acting agents for adherence challenges or persistent symptoms'
below.)

Initial dosing — We use an initial hydrocortisone dose of 15 to 25 mg daily divided in two or three
doses; alternatively, a calculated daily dose of 10 to 12 mg/m2 body surface area can be used. The first dose
should be administered in the morning upon waking, and the last dose is administered at least four to six
hours before bedtime [1]. Most regimens avoid mid-to-late evening doses because endogenous cortisol
production is minimal from approximately 6:00 PM to 3:00 AM.

● In a typical twice-daily regimen, approximately two-thirds of the total daily dose is taken in the morning
and one-third in the afternoon.

● Three times daily regimens entail decreasing doses in the morning, midday, and late afternoon (eg,
hydrocortisone 10, 5, and 2.5 mg taken at 7:00 AM, 12:00 PM, and 4:00 PM, respectively).

The bioavailability of hydrocortisone is nearly 100 percent, and serum cortisol concentrations rise rapidly in
the 30 minutes or so after ingestion. Thus, appropriate dosing can be predicted reasonably well, and
hydrocortisone can be taken immediately upon waking without a prolonged delay in effect. Body weight
and concurrent medications may influence selection of an initial hydrocortisone dose. (See 'Special
considerations for dosing' below.)

Dose titration

● Total daily dose – The initial hydrocortisone dose should be titrated as needed based on clinical
monitoring for evidence of under- or overtreatment. The ideal dose is the lowest total daily dose that
alleviates symptoms of cortisol deficiency. If indicated, dose adjustments should be small (eg, 2.5 to 5
 mg increments), and patients should be monitored closely during dose titration. In patients taking
fludrocortisone, the adequacy of mineralocorticoid replacement should be assessed before the
hydrocortisone dose is increased. (See 'Glucocorticoid therapy monitoring' below and
'Mineralocorticoid therapy monitoring' below.)

● Number of daily doses – For most patients, we initiate twice or three-times daily hydrocortisone
dosing. Although some patients do well on a single daily dose of hydrocortisone, we reserve single-
dose regimens for those who have difficulty adhering to the afternoon dose.

Some patients on a twice-daily regimen develop isolated early morning or late evening symptoms of
cortisol deficiency. In such patients, we add a third, small dose (eg, 2.5 mg) in the early evening without
increasing the total daily dose. Three times daily dosing may help alleviate symptoms of cortisol
deficiency and mimics the day-curve of cortisol seen in healthy volunteers [8]. Some patients may
benefit from a dosing frequency greater than three times daily for short-acting glucocorticoids [9]. As
an alternative strategy to alleviate early morning symptoms, patients may set an overnight alarm and
take the morning hydrocortisone dose a few hours prior to rising. Early morning symptoms can occur
because immediate-release, short-acting glucocorticoid therapy cannot replicate a normal, diurnal
rhythm, in which endogenous serum cortisol concentrations already would have reached or passed the
circadian peak before people would typically take the morning glucocorticoid dose. This transient early
morning cortisol deficiency probably accounts for the symptoms of fatigue, lassitude, mild nausea, and
headache that are often present upon waking and relieved within 30 to 60 minutes after the morning
hydrocortisone dose.

● Rationale for divided doses – In one study, quality of life and patient preference were greater with a
split dose regimen (20 mg at 7:00 AM and 10 mg at 7:00 PM) compared with a single total dose in the
morning or evening [10]. No studies have compared quality of life with two- versus three-dose daily
regimens. Smaller, divided doses of hydrocortisone also may help avoid excessive cortisol exposure
and adverse side effects of therapy [11]. Higher doses of hydrocortisone (those resulting in cortisol
levels ≥25 mcg/dL) exceed the binding capacity of corticosteroid-binding globulin (CBG) and lead to
increases in serum free cortisol followed by rapid filtration into urine [12]. In contrast, smaller, divided
hydrocortisone doses prevent this increase in free cortisol even when administered at the same total
daily dose [13].

Alternative regimens

Alternative short-acting therapy — Cortisone acetate is a short-acting glucocorticoid and is a

reasonable alternative to hydrocortisone for glucocorticoid replacement therapy. In some regions,
cortisone acetate is the only available short-acting glucocorticoid, and individual patients may prefer
cortisone acetate to hydrocortisone. Cost is another key consideration for choice of initial therapy.

An initial replacement regimen of cortisone acetate is 20 to 35 mg administered in two or three daily

divided doses (eg, 15, 5, and 2.5 mg). Like hydrocortisone, the first dose is administered immediately upon
waking, and the final dose is taken at least four to six hours before bedtime.
In contrast to hydrocortisone, cortisone acetate is a precursor that must undergo hepatic conversion to
cortisol via 11-beta-HSD1 and therefore could lead to more variability in dosing requirements. For this
reason, we prefer hydrocortisone as initial therapy. However, this potential limitation has not been studied
carefully.

Longer-acting agents for adherence challenges or persistent symptoms — Longer-acting

glucocorticoids may be useful for patients who have difficulty adhering to multiple daily dosing regimens
or those who experience severe symptoms of cortisol deficiency in the late evening or early morning on
short-acting glucocorticoid regimens. Longer-acting glucocorticoids provide a smoother physiological
effect and avoid the marked changes in serum glucocorticoid levels that occur with short-acting drugs
( table 2). Treatment options include the following:

● Prednisolone (preferred longer-acting agent) – If a longer-acting glucocorticoid is used for

replacement therapy, we prefer the intermediate-acting agent prednisolone. The usual oral
replacement dose for prednisolone is 3 to 5 mg daily, administered as either a single dose taken in the
morning upon waking or two divided doses (approximately 70 to 80 percent of the dose taken in the
morning and the remainder at bedtime).

● Prednisone – Prednisone is also an intermediate-acting glucocorticoid. The usual initial replacement

dose for prednisone is 5 mg administered orally once daily, and the typical dosing range is 2.5 to 7.5
mg daily. Like cortisone acetate, prednisone requires activation by 11-beta-HSD1 to confer biological
effects and could lead to more variability in dosing requirements. Prednisolone is therefore preferred
to prednisone if a longer-acting glucocorticoid is indicated.

● Dexamethasone – Dexamethasone is a long-acting glucocorticoid. The usual initial replacement dose

is 0.5 mg administered orally once daily, with a typical dosing range of 0.25 to 0.75 mg daily.
Dexamethasone has several limitations as glucocorticoid replacement therapy, including its long
duration of action, limited flexibility for dose titration, and variable interindividual metabolism, leading
to higher potential for overtreatment. Nonetheless, much of the clinical evidence supporting this
heightened risk of overtreatment is anecdotal and from an era when higher glucocorticoid doses were
commonly prescribed.

● Modified-release formulations (limited availability) – Modified-release forms of hydrocortisone are

commercially available in some regions of the world but not the United States. If available, modified-
release hydrocortisone is a reasonable alternative to immediate-release hydrocortisone. A once-daily
dual-release hydrocortisone tablet is authorized for use in the European Union. This formulation
combines an immediate-release coating with an extended-release core and provides a more
physiologic serum cortisol profile than three times daily hydrocortisone [14]. Like longer-acting
glucocorticoids, these formulations provide greater ease of dosing, while their modified release
enables better approximation of the circadian pattern of endogenous cortisol production. Short-term
data from randomized studies support the potential for modified-release hydrocortisone to impart
metabolic benefits (eg, lower body weight and blood pressure) relative to conventional therapy [15-17].
 A long-acting hydrocortisone formulation is authorized for use in the United Kingdom and European
Union for treatment of primary adrenal insufficiency specifically due to classic congenital adrenal
hyperplasia. The treatment of primary adrenal insufficiency in adults with classic congenital adrenal
hyperplasia is reviewed in detail separately. (See "Treatment of classic congenital adrenal hyperplasia
due to 21-hydroxylase deficiency in adults", section on 'Glucocorticoid therapy for all patients'.)

Special considerations for dosing

● Body weight – We generally initiate glucocorticoid therapy at the low end of the usual dosing range for
patients with lower body weight (eg, <75 kg) and at the high end for patients with higher body weight
(eg, >115 kg). (See 'Initial dosing' above.)

For some patients with low body weight (eg, <55 kg), a total daily dose as low as hydrocortisone 10 mg
is sufficient [18]. Pharmacokinetic studies are needed to better guide body weight-based glucocorticoid
dosing for adrenal insufficiency. As for any patient, we tailor treatment to achieve the lowest dose that
alleviates symptoms of cortisol deficiency. (See 'Glucocorticoid therapy monitoring' below.)

● Concomitant medications – Glucocorticoids are metabolized by the cytochrome P450 3A4 enzyme
(CYP3A4). Therefore, in patients taking medications that affect CYP3A4 activity, glucocorticoid regimens
may require dose adjustments [19,20]. Glucocorticoid doses may need to be increased in patients
taking drugs that induce CYP3A4 metabolism, such as phenytoin, barbiturates, rifampin,
phenobarbital, and mitotane [21-24]. In contrast, CYP3A4 inhibitors may require glucocorticoid dose
reductions to avoid excess exposure. Inhibitors of CYP3A4 include clarithromycin, erythromycin,
diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, and grapefruit ( table 3).

Glucocorticoid therapy monitoring — Glucocorticoid replacement therapy is monitored through clinical

assessments rather than biochemical tests. Patients should be assessed at least once every three months
early after diagnosis and during dose titration and at least once annually after a stable replacement
regimen is established. We suggest using the lowest glucocorticoid dose that relieves symptoms of cortisol
deficiency.

● Clinical assessment – Routine clinical assessments include measurement of blood pressure, heart
rate, and body weight, as well as detailed symptom queries about appetite, energy, daytime
somnolence, nausea, ability to concentrate, changes in body weight, and fatigue. At each visit, we ask
patients about therapy adherence as well as the need to administer additional glucocorticoid doses for
intercurrent illnesses or other stressors. Ongoing patient counseling is a critical facet of treatment
monitoring. (See 'Patient education and safety' below.)

• Evidence of undertreatment – Signs and symptoms that suggest undertreatment include lethargy,
subjective weakness, low blood pressure, nausea, weight loss, and poor appetite. Any of these could
indicate that the glucocorticoid dose is too low. When these signs or symptoms are present, we
increase the glucocorticoid dose by 2.5 to 5 mg and monitor the patient closely. If the signs or
 symptoms are not promptly (eg, within a week) improved, they are not due to cortisol deficiency, and
we resume the lower glucocorticoid dose.

Symptoms that occur only at a specific, predictable time of day (eg, early morning or late evening)
may indicate a need for a change in the timing or frequency of glucocorticoid dosing rather than an
increase in the total daily dose. (See 'Dose titration' above.)

• Evidence of overtreatment – Signs and symptoms suggestive of overtreatment include body

weight gain, increased blood pressure, impaired sleep, edema, facial plethora, and other
manifestations of Cushing syndrome. These are reviewed in detail separately. (See "Epidemiology
and clinical manifestations of Cushing syndrome", section on 'Categories of clinical manifestations'.)

For patients taking hydrocortisone or cortisone acetate with evidence of overtreatment, we reduce
the total daily dose in 2.5 to 5 mg increments. We monitor patients closely both for resolution of
signs or symptoms of overtreatment and for emergence of signs or symptoms of cortisol deficiency.
Chronic overtreatment can lead to complications of glucocorticoid excess including dysglycemia,
hypertension, dyslipidemia, and increased cardiovascular risk. Excessive glucocorticoid therapy also
may increase risk of osteoporosis [25,26].

● Limited role for biochemical assessment – We monitor treatment through clinical rather than
biochemical assessments (eg, measurement of plasma ACTH or cortisol concentration) [1]. Reports
suggest that clinical assessment alone works equally well [27]. Biochemical testing may be helpful in
rare circumstances of suspected glucocorticoid malabsorption (eg, individuals with persistent clinical
evidence of adrenal insufficiency despite progressive glucocorticoid dose titration). In such individuals,
we measure serum cortisol one hour after the morning dose of hydrocortisone [28].

In patients with primary adrenal insufficiency, measurement of early morning plasma ACTH
concentration is not necessary for routine monitoring but may help detect overreplacement. In such
patients, a low-normal or suppressed morning plasma ACTH concentration indicates glucocorticoid
overtreatment. However, an elevated concentration does not generally indicate undertreatment. Early
morning cortisol deficiency is evident with immediate-release hydrocortisone therapy and results in
plasma ACTH concentrations that are elevated two- to eightfold for several hours in the early morning,
with sustained elevation for several hours after the first hydrocortisone dose is taken [4,29,30]. In
patients with central adrenal insufficiency, measurements of plasma ACTH concentration are not
helpful, because levels are expected to be low and do not reflect tissue cortisol sufficiency.

Although some advocate the use of normative day-curve or single timepoint cortisol values to assess
the adequacy of hydrocortisone therapy [8,28], these have not been incorporated into routine clinical
practice.

Mineralocorticoid replacement for selected individuals

Primary adrenal insufficiency (all patients) — In patients with primary adrenal insufficiency, we assess
mineralocorticoid deficiency both clinically and through measurement of aldosterone and renin levels [1]. A
low aldosterone level with a plasma renin activity (PRA) above the upper limit of the reference range
confirms mineralocorticoid deficiency. Although virtually all patients with primary adrenal insufficiency
require mineralocorticoid replacement, rare patients with mild mineralocorticoid deficiency do not need
replacement therapy or achieve sufficient mineralocorticoid replacement through hydrocortisone therapy
alone.

Initial dosing — For patients with confirmed mineralocorticoid deficiency, we initiate fludrocortisone
0.05 to 0.1 mg daily. Selecting a dose within this range depends on the glucocorticoid replacement
regimen, as different agents have variable mineralocorticoid activity. Patients do not need to restrict their
dietary sodium intake during fludrocortisone therapy.

● For individuals taking hydrocortisone or cortisone acetate – For individuals taking hydrocortisone
or cortisone acetate, we generally choose an initial dose of fludrocortisone 0.05 mg daily because these
agents have some mineralocorticoid activity, and the lower fludrocortisone dose may be adequate. The
dose is then titrated based on both clinical and biochemical assessments, including PRA. In rare
patients, hydrocortisone alone is sufficient for mineralocorticoid replacement. Such individuals can
develop signs of mineralocorticoid overtreatment (eg, hypertension, hypokalemia) with fludrocortisone
doses as low as 0.05 mg twice weekly. (See 'Mineralocorticoid therapy monitoring' below.)

● For individuals taking prednisolone, prednisone, or dexamethasone – For individuals taking

prednisolone, prednisone, or dexamethasone, we start fludrocortisone 0.1 mg daily. Prednisolone and
prednisone have weaker mineralocorticoid activity than hydrocortisone and dexamethasone has none,
so higher fludrocortisone doses are usually needed with these agents. The initial fludrocortisone dose
is then titrated based on both clinical and biochemical assessments, including PRA. Patients receiving
dexamethasone may require up to 0.2 mg daily of fludrocortisone to lower their PRA to the upper
reference range [31,32]. (See 'Mineralocorticoid therapy monitoring' below.)

Dose adjustments for increased salt losses or primary hypertension — The fludrocortisone dose
and/or dietary sodium intake may need adjustment in individuals who regularly engage in vigorous
exercise, are exposed to warm climates, or develop primary hypertension during treatment.

● Vigorous exercise or warm climates – When increased salt losses occur, patients may need to
increase their dietary sodium intake and/or fludrocortisone dose to prevent symptoms of
mineralocorticoid deficiency. When patients engage in vigorous exercise, salt loss through perspiration
is transient, and increased fluid and dietary sodium intake alone is usually sufficient to prevent
symptoms of mineralocorticoid deficiency. Patients who engage in prolonged exercise (eg, long-
distance running or cycling) may need to increase the fludrocortisone dose on days when the exercise
is performed.

During the summer or in warmer climates when salt loss in perspiration increases throughout the day,
the fludrocortisone dose may need to be increased by 50 to 100 percent. We empirically increase the
 dose if a patient is routinely exposed to temperatures above approximately 29°Celsius (85°F).
Alternatively, salt tablets may be used to provide an additional 1 to 2 g sodium daily.

● Hypertension – In patients with primary adrenal insufficiency who develop primary hypertension
(formerly called "essential" hypertension), the initial approach is dietary sodium restriction and a
reduced dose of fludrocortisone [33,34]. Primary hypertension should only be diagnosed if
glucocorticoid and mineralocorticoid overtreatment are excluded as causes of blood pressure
elevation. (See 'Glucocorticoid therapy monitoring' above and 'Mineralocorticoid therapy monitoring'
below.)

Mineralocorticoid therapy usually cannot be discontinued without risking sodium depletion. Therefore,
if hypertension is not adequately managed on the reduced fludrocortisone dose, we continue
fludrocortisone and initiate antihypertensive treatment. If an antihypertensive medication is needed,
diuretics, eplerenone, or spironolactone should not be used, since they partly or completely
antagonize fludrocortisone action. First-line treatments include angiotensin II receptor blockers (ARBs)
and angiotensin-converting enzyme inhibitors (ACEs). Dihydropyridine calcium channel blockers are a
reasonable alternative.

Mineralocorticoid therapy monitoring — In patients with mineralocorticoid deficiency, both clinical

and biochemical assessments are needed to assess the adequacy of mineralocorticoid replacement
therapy. These assessments are performed at least every one to three months during treatment initiation
or dose adjustments and at least annually in individuals on stable replacement regimens.

● Clinical assessment – Clinical monitoring includes queries about symptoms of fatigue,

lightheadedness, nausea, muscle cramping, and salt craving. Routine monitoring also includes
measurement of supine and upright blood pressure and heart rate to assess for postural hypotension.
Hypertension and edema are signs of excessive mineralocorticoid replacement [33]. (See
"Pathophysiology and clinical features of primary aldosteronism", section on 'Clinical features'.)

● Biochemical assessment – Biochemical monitoring includes measurement of the serum sodium,

potassium, and creatinine concentrations and PRA. We adjust the fludrocortisone dose to lower the
PRA to the upper reference range [31,32]. If direct renin concentration (DRC) is measured instead of
PRA, targeting a DRC that is within the reference range or mildly elevated is reasonable.

We remeasure PRA three months after initiating fludrocortisone therapy or sooner if patients report
any signs or symptoms of under- or overtreatment. If indicated, we titrate the fludrocortisone dose in
0.05 mg increments as needed to achieve the target PRA. Once a stable fludrocortisone dose is
achieved, we measure PRA annually in all patients and whenever a patient develops signs or symptoms
of mineralocorticoid deficiency or excess. Normal morning PRA for seated, healthy individuals with a
typical dietary sodium intake ranges from approximately 1 to 4 ng/mL per hour (0.8 to 3 nmol/L per
hour).
 A PRA in the upper reference range usually is associated with a normal serum potassium level and
alleviation of symptoms of mineralocorticoid deficiency. However, if PRA remains elevated but the
patient is asymptomatic and the serum potassium is normal, the fludrocortisone dose should not be
increased to normalize PRA. In this setting, increasing the fludrocortisone dose imparts risk of
hypokalemia and edema [35]. (See "Assays of the renin-angiotensin-aldosterone system in adrenal
disease", section on 'Renin'.)

● Discerning between glucocorticoid- and mineralocorticoid mediated effects – The clinical signs
and symptoms of over- or undertreatment with glucocorticoid and mineralocorticoid therapy can
overlap. Biochemical measurements and careful clinical assessment can help distinguish between
glucocorticoid- or mineralocorticoid-mediated effects.

• Signs or symptoms of overtreatment – Edema and hypertension may indicate either

glucocorticoid or mineralocorticoid overtreatment. In such cases, the presence of hypokalemia
and/or a PRA that is below the upper third of the reference range suggest mineralocorticoid
overtreatment. Conversely, concurrent signs of glucocorticoid overtreatment (eg, weight gain,
increased appetite, impaired sleep) strongly suggest glucocorticoid rather than mineralocorticoid
overtreatment. In patients with primary adrenal insufficiency, an early morning plasma ACTH level
that is suppressed or in the lower third of the reference range further indicates glucocorticoid
overtreatment.

• Signs or symptoms of undertreatment – Lightheadedness, postural hypotension, nausea,

weakness, and fatigue may indicate either glucocorticoid or mineralocorticoid undertreatment. In
such cases, the presence of salt craving, hyperkalemia, and/or a PRA that is above the reference
range suggest mineralocorticoid undertreatment. Conversely, diminished appetite and weight loss
strongly suggest glucocorticoid undertreatment. In this setting, a plasma ACTH level is not helpful
for distinguishing between glucocorticoid and mineralocorticoid undertreatment.

Central adrenal insufficiency (rarely needed) — Mineralocorticoid replacement is rarely required in

patients with central adrenal insufficiency because ACTH is not the main physiological regulator of
aldosterone secretion. Rare patients with longstanding disease eventually may require replacement
therapy with fludrocortisone. Lightheadedness, weakness, salt craving, mild nausea, and postural
hypotension are signs and symptoms of mineralocorticoid deficiency. The diagnosis is confirmed with
findings of an elevated renin level or PRA and low aldosterone level. If indicated, replacement therapy with
fludrocortisone is the same as for individuals with primary adrenal insufficiency. (See 'Primary adrenal
insufficiency (all patients)' above.)

Androgen replacement therapy for selected females — In most forms of adrenal insufficiency, serum
concentrations of DHEA are extremely low, as the adrenal cortex is the primary source of androgens
including DHEA and DHEA sulfate (DHEAS). In selected females with adrenal insufficiency, androgen
replacement therapy may be beneficial for mood, quality of life, or libido.

Indications
 ● Females – We suggest a trial of DHEA treatment in females with adrenal insufficiency who have
significant symptoms of depression or anxiety, low libido or energy, or impaired sense of well-being
despite optimized glucocorticoid and mineralocorticoid (if applicable) therapy. We typically offer a
therapeutic trial to females with persistent mood symptoms or diminished energy or libido that affects
their quality of life. Although serious adverse effects have not been reported, the long-term safety of
DHEA therapy has not been established; we counsel all patients considering DHEA therapy about this
lack of long-term data.

The decision to initiate and continue androgen replacement therapy in such patients should be
individualized, as the clinical consequences of androgen deficiency and the response to androgen
replacement vary widely across individuals. Females with adrenal insufficiency due to classic congenital
adrenal hyperplasia are not candidates for DHEA therapy, as they have elevated rather than low
circulating androgen concentrations. (See "Genetics and clinical manifestations of classic congenital
adrenal hyperplasia due to 21-hydroxylase deficiency".)

● Males – In males, androgen replacement therapy is unnecessary; adrenal insufficiency does not result
in androgen deficiency in males because the testes are the predominant source of androgens. If males
with adrenal insufficiency have persistent symptoms of fatigue, low energy or libido, or reduced quality
of life, glucocorticoid and mineralocorticoid (if needed) regimens should be re-evaluated and
optimized. If symptoms continue, alternative causes for these symptoms should be investigated.

Approach to a therapeutic trial — For females who opt for a trial of androgen replacement therapy, we
typically start DHEA 25 to 50 mg once daily in the morning and adjust the dose based upon the serum
DHEA concentration, clinical response, and occurrence of adverse effects. We initiate a treatment trial of
three to six months and counsel patients that the therapeutic effects of DHEA may take months to evolve
( algorithm 1) [36]. (See 'Androgen therapy monitoring' below.)

● Assessment of clinical benefit – Clinical benefits, if they occur, should be evident by six months of
therapy. If no clear and enduring clinical benefit is evident after six months of treatment, DHEA therapy
is discontinued. If clinical benefit results but androgenic side effects emerge, the DHEA dose should be
reduced. DHEA has a long half-life and may be taken every second or third day if daily dosing confers
side effects [36]. Common androgenic side effects of DHEA therapy in women include oily skin,
hirsutism, acne, and increased sweating and odor [37].

● Biochemical monitoring – We measure on-treatment serum DHEAS concentrations in the morning,

prior to DHEA administration, and target a value in the middle of the reference range [1]. In most
women, DHEA 25 mg daily is sufficient to normalize the serum DHEAS concentration [38]. We avoid
DHEA doses higher than 50 mg daily. In females receiving concurrent growth hormone therapy, insulin-
like growth factor 1 (IGF-1) concentrations may rise and therefore also should be monitored [39]. Some
patients may require a reduction in growth hormone dose when taking DHEA [36].

● Potential benefits and risks of treatment – Although studies suggest that DHEA can modestly
improve some symptoms in females with adrenal insufficiency, existing evidence does not support the
 use of therapy in all females with adrenal insufficiency or in males. The best available data on DHEA
therapy in females with adrenal insufficiency are from a meta-analysis of 10 trials that found a small
improvement in health-related quality of life with DHEA treatment compared with placebo [37]. A small,
and perhaps trivial, beneficial effect was evident for depression but not for anxiety or sexual well-
being. Nonetheless, clinical trial data are heterogeneous, and individual patients may benefit from
therapy [36].

In the United States, lack of product quality control is a significant limitation to androgen replacement
therapy, as DHEA is considered a dietary supplement rather than a hormone preparation. Therefore,
DHEA supplements available commercially may not actually contain the advertised dose. This topic is
reviewed in detail separately. (See "Overview of herbal medicine and dietary supplements".)

In a 12-week crossover study in adults with primary and secondary adrenal insufficiency, DHEA
treatment (50 mg daily) did not impact metrics of arterial stiffness or endothelial function [40]. Limited
data also suggest that DHEA 50 mg daily does not affect insulin resistance, high sensitivity C-reactive
protein, physical performance, or body composition [40,41]. DHEA treatment may lead to a small
decrement in serum high-density lipoprotein (HDL) cholesterol concentration [42], but this has not
been a universal finding and any implications for cardiovascular risk are unknown.

Androgen therapy monitoring — We monitor DHEA therapy through both clinical assessments and
measurement of serum DHEA concentrations [1,38]. We perform these assessments every three months
during treatment initiation and dose titration and at least once annually in females on stable replacement
regimens. Symptom queries should include libido, mood, energy, and general sense of well-being. Patients
also should be monitored for evidence of adverse androgenic effects of therapy.

PATIENT EDUCATION AND SAFETY

Patient education — Patient education is a cornerstone of the management of adrenal insufficiency and
should include information about the physiology and clinical implications of cortisol deficiency, as well as
emergency precautions that all patients should follow ( table 4). Patient counseling should be ongoing
and reinforced at each clinic visit given the life-threatening nature and complexity of the disease. Patients
should be assured that they can lead active and vigorous lives provided they adhere to glucocorticoid
replacement therapy and follow the emergency precautions detailed below. The patient and at least one
household member or caregiver should be counseled 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

The major risk to patients with adrenal insufficiency is the lack of a normal serum cortisol response to
stress. Consequently, patients must receive extensive counseling to anticipate and recognize situations of
increased physiologic stress and to modify therapy accordingly. (See 'Circumstances requiring
glucocorticoid dose adjustment' below.)

Emergency precautions — Critical emergency precautions include the following:

● Every patient should wear a medical alert (Medic Alert) bracelet or necklace and carry the Emergency
Medical Information Card that is supplied with it or a similar medical information card (eg, European
Emergency Card). Both the medical alert bracelet and medical information card should indicate the
diagnosis, the patient's daily medications and doses, and the clinician to contact in case of emergency.

● Patients should be counseled in detail about "sick day rules," circumstances that require glucocorticoid
dose adjustments. These include illness, surgery, and other acute physiologic stressors. Patients also
should be counseled as to when they need to consult a clinician. (See 'Circumstances requiring
glucocorticoid dose adjustment' below.)

● Every patient should have injectable glucocorticoid, such as 100 mg vials of hydrocortisone, along with
needles and syringes for injection. Patients should assemble injection kits and keep them in a readily
accessible place known to all members of the household. If hydrocortisone powder is prescribed,
patients need vials of sterile 0.9 percent saline for drug reconstitution. Injectable hydrocortisone is also
available in a single-dose vial system that only requires mixing prior to injection. We instruct the
patient and one or more household members on how to reconstitute or mix and administer injectable
hydrocortisone. Hydrocortisone may be administered either through intramuscular or subcutaneous
injection. Subcutaneous injection confers a rapid increase in serum cortisol level, and patients may
prefer subcutaneous to intramuscular injection [43].

Injectable hydrocortisone should be administered if any of the following occur:

• An injury with substantial blood loss (more than a cup) or fracture

• Nausea and vomiting with inability to retain oral medications
• Symptoms of acute cortisol deficiency (eg, severe lightheadedness, nausea and vomiting, or
weakness)
• The patient is found unresponsive or with reduced consciousness

The entire dose of medication should be injected (100 mg of hydrocortisone), and the patient or
household member should seek medical help immediately after the injection. We counsel patients to
have a low threshold for injecting the hydrocortisone: if it might be necessary, it should be injected,
and medical attention should be sought.

Emergency precautions should be reviewed at each clinic visit, including verification that patients have
unexpired injectable hydrocortisone.

Circumstances requiring glucocorticoid dose adjustment — Cortisol secretion normally increases with
physiologic stressors including illness and surgery. For patients with adrenal insufficiency, such
circumstances require transient increases in glucocorticoid doses to prevent adrenal crisis. Few data are
available to guide these dose adjustments, which are generally based on stress physiology and clinical
experience. Glucocorticoid dose increases are not usually needed for psychological stress (eg, anxiety or
depression) or moderate exercise.

Acute illness

● Mild to moderate illness

• Minor illness – During minor illnesses, such as upper respiratory infections with general symptoms
and fever, patients should increase their glucocorticoid dose to two to three times the usual daily
dose for three days (known as the three-by-three rule). This can be done without consulting the
treating clinician. An increase in glucocorticoid dose is not necessary for mild symptoms (eg,
congestion) in the absence of fever.

The hydrocortisone dose adjustment should be implemented immediately upon the onset of
symptomatic illness. We counsel patients to double or triple the usual scheduled doses depending
on the severity of the illness ( table 4). For example, patients who normally take 10 mg of
hydrocortisone in the morning and 5 mg in the afternoon can take 20 to 30 mg of hydrocortisone in
the morning and 10 to 15 mg in the afternoon for three days. Doses at the higher end of this range
(ie, triple the usual dose) are indicated in the setting of fever >101°F or persistent nausea. If emesis
occurs, particularly if it prevents retention of oral glucocorticoid, the patient should administer
injectable glucocorticoid and immediately seek emergency care. (See 'Emergency precautions'
above.)

The increased dose will decrease fever and malaise and will not compromise the immune response.

• Persistent illness – If the illness worsens during the three days or if the patient cannot resume the
usual maintenance dose on the fourth day without symptoms of cortisol deficiency, the individual
should contact the treating clinician. Patients with persistent fever or worsening symptoms of illness
require in-person evaluation. In individuals with adrenal insufficiency, the threshold for
hospitalization should be low. Patients with nausea and vomiting who are unable to retain oral
medications should be counseled to administer injectable glucocorticoid therapy and immediately
seek emergency medical attention. (See 'Emergency precautions' above.)

• Illness requiring hospitalization – For patients with moderately severe illness (eg, community
acquired pneumonia) who require hospitalization but not intensive care, we administer 50 to 75 mg
hydrocortisone daily in divided doses (eg, 25 mg every 8 to 12 hours). This may be given orally if the
patient is alert and can tolerate oral medications. Once the underlying illness improves, we taper the
hydrocortisone dose over two to three days until the usual maintenance dose is resumed. If the
patient develops evidence of cortisol deficiency during taper, we resume the lowest dose that
alleviated symptoms.
 ● Critical illness (major trauma, illness requiring intensive care) – During critical illness,
hydrocortisone 100 mg (intravenous [IV] or intramuscular) and isotonic saline infusion should be
administered immediately. This should be followed by hydrocortisone 200 mg daily, delivered either as
a continuous infusion or 50 mg IV every six hours, with continuous isotonic fluid administration.
Patients also require cardiac monitoring and management of hypoglycemia and electrolyte
abnormalities as needed. The hydrocortisone dose is tapered as clinical status improves. (See 'Adrenal
crisis' above.)

Surgery — Glucocorticoid dosing during surgery primarily depends on the nature of the surgical
procedure ( table 4).

● Minor surgical stress – For minor surgical procedures such as herniorrhaphy, patients should receive
an extra dose of hydrocortisone 25 mg daily (or equivalent) on the day of surgery only with close
monitoring. The patient can return to the usual replacement dose the following day if clinical course is
uncomplicated [44,45].

● Moderate surgical stress – For moderate surgical stress (eg, cholecystectomy, joint replacement),
patients should receive divided IV doses equivalent to hydrocortisone 50 to 75 mg daily on the day of
surgery and the first postoperative day [44,45]. If the clinical course is uncomplicated, the usual dose
may be resumed on the second postoperative day with oral or IV formulations as appropriate.

● Major surgical stress – For major surgical procedures (eg, cardiac bypass), patients should receive
hydrocortisone 100 mg IV administered prior to the procedure followed by a total daily dose equivalent
to hydrocortisone 150 to 200 mg. This should be administered in divided doses (eg, 50 mg IV every six
to eight hours) for two to three days perioperatively [44]. If the postoperative course is uncomplicated,
a rapid taper (eg, daily dose reduction by 50 percent) to the usual maintenance dose can begin on
postoperative day 3 or 4.

● Postsurgical complications – If post-surgical complications develop, management of the

glucocorticoid taper depends on the severity of the complication. Glucocorticoid dosing should be
guided by the severity of illness or stress imparted by the complication. (See 'Acute illness' above.)

Fasting — Patients with adrenal insufficiency are at risk for complications due to fasting, which usually
occurs in the setting of religious observances such as Yom Kippur, Ramadan, or Fast Sunday. Glucocorticoid
replacement therapy is complicated both by the restriction on taking oral medications during the fasting
period and the slightly elevated physiologic stress caused by fasting.

Consistent with published recommendations for management during Ramadan [46], we typically ask
patients with adrenal insufficiency on short-acting glucocorticoid regimens to transition to prednisolone 5
mg once daily prior to the fast. During fasting, the prednisolone dose is taken immediately before initiation
of the fast (eg, at dawn during Ramadan). This strategy avoids the need for extended dosing intervals with
immediate-release hydrocortisone with the attendant risks of hypoglycemia or symptoms of acute cortisol
deficiency.
All patients should receive counseling on adequate hydration, sick day rules, when to urgently terminate
their fast, and when to administer an emergency injection of glucocorticoid. Patients at high risk for
complications should be advised to avoid fasting. Patients with primary adrenal insufficiency can maintain
their usual dose of fludrocortisone, also taken once daily prior to initiation of the fast.

Pregnancy and labor

● Pregnancy

• Glucocorticoid therapy – For pregnant individuals, we prefer hydrocortisone for glucocorticoid

replacement therapy [1]. Hydrocortisone is short-acting, does not require enzymatic activation, and
is metabolized by the placenta. It therefore provides the most predictable dosing with lowest risk of
glucocorticoid overexposure for the developing fetus. For individuals with adrenal insufficiency who
are taking other agents and contemplating pregnancy, we ask them to switch to hydrocortisone and
achieve a stable dosing regimen prior to conception.

- Early pregnancy (first and second trimester) – During early pregnancy, the patient's usual
glucocorticoid replacement dose is continued with monitoring for evidence of glucocorticoid
over- or undertreatment at least once every trimester. (See 'Glucocorticoid therapy monitoring'
above.)

In pregnant individuals, failure to achieve expected weight gain rather than overt weight loss is a
sign of undertreatment. Severe fatigue and postural hypotension also suggest undertreatment,
whereas hypertension and hyperglycemia may indicate overtreatment, particularly when present
during early pregnancy.

- Late pregnancy (third trimester) – In the third trimester, most patients require an increase in
the hydrocortisone dose of approximately 20 to 40 percent (eg, 2.5 to 10 mg daily) [3]. This
adjustment can be made empirically at pregnancy weeks 20 to 24 or as needed on the basis of
clinical course [34,47-49]. Most patients require this increased dose of hydrocortisone due to the
progressive rise in corticosteroid-binding globulin (CBG) particularly evident in late pregnancy.

- Severe nausea and vomiting – In patients with severe nausea and vomiting in the first trimester
who are unable to tolerate oral medications, intramuscular dexamethasone at a dose slightly
above physiologic replacement (eg, 1 mg daily) may be used. Dexamethasone should be
reserved for intractable vomiting and used for the shortest duration possible. Its use is usually
contraindicated during pregnancy as it is not inactivated by placental 11-beta-hydroxysteroid
dehydrogenase type 2 and can lead to excess glucocorticoid exposure for the developing fetus.

• Mineralocorticoid therapy – Dose adjustments for mineralocorticoid therapy are generally not
needed during pregnancy, but serum electrolytes and signs of volume depletion should be
monitored at each prenatal visit. If the reference range for pregnant individuals is used, plasma
renin activity (PRA) may provide an additional index of adequate fludrocortisone replacement. A PRA
 in the upper half of the reference range for pregnant individuals is a reasonable target. A PRA
suppressed to values less than those in pregnant individuals without adrenal insufficiency (ie, <20 to
25 ng/mL per hour supine or standing) is an indication of overtreatment [50-52].

The regulation of plasma volume during pregnancy is complex, with upregulation of both
aldosterone and the offsetting natriuretic actions of progesterone. Secondary hyperaldosteronism is
normal [53], with increased PRA and serum aldosterone concentrations [50,51]. Serum
concentrations of progesterone, which competes with aldosterone for binding to the
mineralocorticoid receptor in the kidney, are increased throughout pregnancy [54,55]. PRA and
serum aldosterone concentrations peak late in the third trimester [50].

● Labor and delivery – At the onset of labor, glucocorticoid therapy should be administered as for major
surgical stress. This consists of 100 mg hydrocortisone administered at the start of labor followed by
150 to 200 mg daily administered in divided doses every six to eight hours (eg, 50 mg every six hours).
After uncomplicated delivery, the hydrocortisone dose may be reduced to double the patient's
predelivery dose for one to two days followed by rapid taper to the patient's prepregnancy dose over
the following one to two days [49].

● Clinical outcomes – If recognized and treated appropriately, adrenal insufficiency rarely leads to
pregnancy complications [47]. 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 impaired fetal growth was common [56-58]. Most females adequately treated for
adrenal insufficiency now go through pregnancy, labor, and delivery without difficulty, and neonates
have a normal birth weight.

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 [59]. After glucocorticoids
became available for treatment, subsequent reports suggested that patients with autoimmune adrenal
insufficiency should have a normal lifespan and can lead fully active lives, including vigorous exercise
[48,59]. 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 [60]. The reasons for this
discrepancy are not understood, and further studies are needed to evaluate whether these patients have
premature mortality.

Some studies report significantly reduced subjective quality of life and increased rates of work disability in
patients with adrenal insufficiency [61-63]. A Norwegian study of 79 patients who answered a postal survey
showed impaired general health and vitality perception and an increase in reported fatigue. Working
disability at ages 18 to 67 years was 26 percent, compared with 10 percent in the corresponding general
Norwegian population [61]. 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 [62]. Improved therapies
that better mimic the normal diurnal pattern of cortisol production may help improve quality-of-life
outcomes for individuals with adrenal insufficiency.

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 disease (The Basics)" and "Patient education: Adrenal
crisis (The Basics)")

● Beyond the Basics topics (see "Patient education: Adrenal insufficiency (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

● Adrenal crisis – Adrenal crisis is a life-threatening emergency that requires immediate treatment
( table 1). Treatment must be initiated promptly for all patients with suspected adrenal crisis and
should never be delayed for diagnostic testing. The precipitating cause of adrenal crisis should be
identified and treated appropriately. (See 'Adrenal crisis' above and 'Emergency management' above.)

• Glucocorticoid treatment – Parenteral glucocorticoid therapy is required for acute adrenal crisis.
We suggest hydrocortisone rather than other glucocorticoids (Grade 2C). We administer
hydrocortisone as a 100 mg intravenous (IV) bolus followed by 50 mg IV every six hours (or 200
mg/24 hours as a continuous IV infusion) for the first 24 hours. If hydrocortisone is unavailable,
alternatives include methylprednisolone 40 mg IV and dexamethasone 4 to 6 mg IV ( table 1 and
table 2). However, since these agents have less mineralocorticoid activity than hydrocortisone,
fludrocortisone may also be needed in patients with known or suspected primary adrenal
 insufficiency. If hydrocortisone is given, mineralocorticoid replacement is not needed in the acute
setting. (See 'Emergency management' above.)

• Fluid and electrolytes – Patients with adrenal crisis require fluid resuscitation. We administer
isotonic fluid, typically saline (eg, 0.9 percent saline solution or 5 percent dextrose in 0.9 percent
saline), to correct hypovolemia and hyponatremia. Dextrose-containing fluids help correct confirmed
or suspected hypoglycemia. We begin with rapid infusion of 1 L over the first hour and typically give
at least 2 to 3 L within the first 24 hours. We monitor serum electrolyte and glucose levels closely.
(See 'Emergency management' above.)

• Subsequent treatment and monitoring – Hypotension, hyponatremia, or hyperkalemia that is

refractory to parenteral hydrocortisone and isotonic fluid administration suggests an etiology other
than adrenal crisis. Once the patient has stabilized, we taper hydrocortisone over one to three days
and convert to an oral stress dose or maintenance regimen once the patient can take oral
medications. Unless cortisol deficiency is excluded, we continue maintenance glucocorticoid
replacement until the patient undergoes outpatient evaluation. For patients with known or
suspected primary adrenal insufficiency, we begin fludrocortisone therapy when the hydrocortisone
dose is tapered below 40 mg daily. (See 'Subsequent management' above and "Diagnosis of adrenal
insufficiency in adults", section on 'Suspected adrenal crisis'.)

● Chronic adrenal insufficiency

• Glucocorticoid replacement – All individuals with adrenal insufficiency require glucocorticoid

replacement therapy. We use the lowest glucocorticoid dose that relieves symptoms of
glucocorticoid deficiency ( algorithm 1).

- Preferred therapy with hydrocortisone – In patients with chronic adrenal insufficiency, we

suggest replacement with hydrocortisone therapy rather than other glucocorticoids (Grade 2C).
Hydrocortisone is typically administered in two or three daily divided doses (total daily dose of 15
to 25 mg). These regimens can be adjusted to provide variable glucocorticoid exposure over the
course of a day and better replicate the normal circadian pattern of endogenous cortisol
secretion. The short-acting agent cortisone acetate (20 to 35 mg daily in two or three divided
doses) is a reasonable alternative, but dosing may be less predictable due to the need for
enzymatic activation. (See 'Hydrocortisone (preferred glucocorticoid)' above.)

- Adherence challenges or persistent symptoms – In individuals who have persistent symptoms

or difficulty adhering to multiple daily glucocorticoid doses, the longer-acting agent prednisolone
may be used. Longer-acting glucocorticoids may confer higher risk of overtreatment. (See
'Alternative regimens' above.)

• Mineralocorticoid replacement in patients with primary adrenal insufficiency – Virtually all

patients with primary adrenal insufficiency require mineralocorticoid replacement therapy, whereas
mineralocorticoid replacement is rarely needed in patients with central adrenal insufficiency. In
 patients with confirmed mineralocorticoid deficiency, we initiate fludrocortisone 0.05 to 0.1 mg daily.
We adjust the fludrocortisone dose to lower the plasma renin activity to the upper normal range.
(See 'Mineralocorticoid replacement for selected individuals' above.)

• Androgen replacement in selected females – For females with persistent symptoms of low mood,
diminished energy or libido, or reduced quality of life despite optimization of other hormone
replacement therapy, we suggest a trial of dehydroepiandrosterone (DHEA) therapy (Grade 2C). We
initiate therapy with DHEA 25 to 50 mg daily and monitor for clinical benefit. DHEA therapy should
not be used in males, in whom adrenal insufficiency does not lead to androgen deficiency. (See
'Androgen replacement therapy for selected females' above.)

• Patient safety – Cortisol deficiency can be life-threatening, so continual patient education and
counseling are essential facets of management for all patients with chronic adrenal insufficiency. All
patients should wear a medical alert bracelet and have emergency glucocorticoid injection kits. (See
'Patient education and safety' above.)

• Circumstances requiring glucocorticoid dose adjustment – The glucocorticoid dose must be

increased during illness, surgery, and other physiological stressors ( table 4). The extent and
duration of the dose increase depends on the severity of the stressor. Pregnant individuals require
close monitoring to assess the adequacy of both glucocorticoid and mineralocorticoid regimens.
(See 'Circumstances requiring glucocorticoid dose adjustment' above.)

ACKNOWLEDGMENT

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.

REFERENCES

1. 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; 101:364.

2. Taylor RL, Grebe SK, Singh RJ. Quantitative, highly sensitive liquid chromatography-tandem mass
spectrometry method for detection of synthetic corticosteroids. Clin Chem 2004; 50:2345.
3. Husebye ES, Pearce SH, Krone NP, Kämpe O. Adrenal insufficiency. Lancet 2021; 397:613.

4. Merza Z, Rostami-Hodjegan A, Memmott A, et al. Circadian hydrocortisone infusions in patients with

adrenal insufficiency and congenital adrenal hyperplasia. Clin Endocrinol (Oxf) 2006; 65:45.

5. Esteban NV, Loughlin T, Yergey AL, et al. Daily cortisol production rate in man determined by stable
isotope dilution/mass spectrometry. J Clin Endocrinol Metab 1991; 72:39.

6. Arafah BM. Medical management of hypopituitarism in patients with pituitary adenomas. Pituitary
2002; 5:109.
 7. Grossman AB. Clinical Review#: The diagnosis and management of central hypoadrenalism. J Clin
Endocrinol Metab 2010; 95:4855.

8. Mah PM, Jenkins RC, Rostami-Hodjegan A, et al. Weight-related dosing, timing and monitoring
hydrocortisone replacement therapy in patients with adrenal insufficiency. Clin Endocrinol (Oxf) 2004;
61:367.
9. Ekman B, Bachrach-Lindström M, Lindström T, et al. A randomized, double-blind, crossover study
comparing two- and four-dose hydrocortisone regimen with regard to quality of life, cortisol and ACTH
profiles in patients with primary adrenal insufficiency. Clin Endocrinol (Oxf) 2012; 77:18.

10. Riedel M, Wiese A, Schürmeyer TH, Brabant G. Quality of life in patients with Addison's disease: effects
of different cortisol replacement modes. Exp Clin Endocrinol 1993; 101:106.

11. Li Voon Chong JS, Sen J, Johnson Z, et al. Hydrocortisone replacement dosage influences intraocular
pressure in patients with primary and secondary hypocortisolism. Clin Endocrinol (Oxf) 2001; 54:267.

12. Derendorf H, Möllmann H, Barth J, et al. Pharmacokinetics and oral bioavailability of hydrocortisone. J
Clin Pharmacol 1991; 31:473.

13. Bliesener N, Steckelbroeck S, Redel L, Klingmüller D. Dose distribution in hydrocortisone replacement

therapy has a significant influence on urine free cortisol excretion. Exp Clin Endocrinol Diabetes 2003;
111:443.

14. Johannsson G, Nilsson AG, Bergthorsdottir R, et al. Improved cortisol exposure-time profile and
outcome in patients with adrenal insufficiency: a prospective randomized trial of a novel
hydrocortisone dual-release formulation. J Clin Endocrinol Metab 2012; 97:473.

15. Choudhury S, Lightman S, Meeran K. Improving glucocorticoid replacement profiles in adrenal

insufficiency. Clin Endocrinol (Oxf) 2019; 91:367.

16. Isidori AM, Venneri MA, Graziadio C, et al. Effect of once-daily, modified-release hydrocortisone versus
standard glucocorticoid therapy on metabolism and innate immunity in patients with adrenal
insufficiency (DREAM): a single-blind, randomised controlled trial. Lancet Diabetes Endocrinol 2018;
6:173.

17. Bannon CA, Gallacher D, Hanson P, et al. Systematic review and meta-analysis of the metabolic effects
of modified-release hydrocortisone versus standard glucocorticoid replacement therapy in adults with
adrenal insufficiency. Clin Endocrinol (Oxf) 2020; 93:637.
18. Debono M, Ross RJ. What is the best approach to tailoring hydrocortisone dose to meet patient needs
in 2012? Clin Endocrinol (Oxf) 2013; 78:659.

19. Arlt W. The approach to the adult with newly diagnosed adrenal insufficiency. J Clin Endocrinol Metab
2009; 94:1059.

20. Jacob, K, Trainer, PJ. Topiramate can induce hypoadrenalism in patients takingoral corticosteroid
replacement. BMJ 2009; 338:1788.

21. Elias AN, Gwinup G. Effects of some clinically encountered drugs on steroid synthesis and degradation.
Metabolism 1980; 29:582.
22. Kyriazopoulou V, Parparousi O, Vagenakis AG. Rifampicin-induced adrenal crisis in addisonian patients
receiving corticosteroid replacement therapy. J Clin Endocrinol Metab 1984; 59:1204.

23. Robinson BG, Hales IB, Henniker AJ, et al. The effect of o,p'-DDD on adrenal steroid replacement
therapy requirements. Clin Endocrinol (Oxf) 1987; 27:437.

24. Santen RJ, Lipton A, Kendall J. Successful medical adrenalectomy with amino-glutethimide. Role of
altered drug metabolism. JAMA 1974; 230:1661.

25. Peacey SR, Guo CY, Robinson AM, et al. Glucocorticoid replacement therapy: are patients over treated
and does it matter? Clin Endocrinol (Oxf) 1997; 46:255.

26. Løvås K, Gjesdal CG, Christensen M, et al. Glucocorticoid replacement therapy and pharmacogenetics
in Addison's disease: effects on bone. Eur J Endocrinol 2009; 160:993.

27. Arlt W, Rosenthal C, Hahner S, Allolio B. Quality of glucocorticoid replacement in adrenal insufficiency:
clinical assessment vs. timed serum cortisol measurements. Clin Endocrinol (Oxf) 2006; 64:384.

28. Rousseau E, Joubert M, Trzepla G, et al. Usefulness of Time-Point Serum Cortisol and ACTH
Measurements for the Adjustment of Glucocorticoid Replacement in Adrenal Insufficiency. PLoS One
2015; 10:e0135975.

29. Scott RS, Donald RA, Espiner EA. Plasma ACTH and cortisol profiles in Addisonian patients receiving
conventional substitution therapy. Clin Endocrinol (Oxf) 1978; 9:571.

30. Feek CM, Ratcliffe JG, Seth J, et al. Patterns of plasma cortisol and ACTH concentrations in patients with
Addison's disease treated with conventional corticosteroid replacement. Clin Endocrinol (Oxf) 1981;
14:451.

31. Smith SJ, MacGregor GA, Markandu ND, et al. Evidence that patients with Addison's disease are
undertreated with fludrocortisone. Lancet 1984; 1:11.

32. Oelkers W, Diederich S, Bähr V. Diagnosis and therapy surveillance in Addison's disease: rapid
adrenocorticotropin (ACTH) test and measurement of plasma ACTH, renin activity, and aldosterone. J
Clin Endocrinol Metab 1992; 75:259.

33. Jadoul M, Ferrant A, De Plaen JF, Crabbé J. Mineralocorticoids in the management of primary
adrenocortical insufficiency. J Endocrinol Invest 1991; 14:87.

34. Knowlton AI, Baer L. Cardiac failure in Addison's disease. Am J Med 1983; 74:829.

35. Flad TM, Conway JD, Cunningham SK, McKenna TJ. The role of plasma renin activity in evaluating the
adequacy of mineralocorticoid replacement in primary adrenal insufficiency. Clin Endocrinol (Oxf)
1996; 45:529.

36. Lang K, Burger-Stritt S, Hahner S. Is DHEA replacement beneficial in chronic adrenal failure? Best Pract
Res Clin Endocrinol Metab 2015; 29:25.

37. Alkataib, AA, Cosma, M, Elamin, MB, et al. J Clin Endocrinol Metab 2009; 94:3676.

38. Løvås K, Gebre-Medhin G, Trovik TS, et al. Replacement of dehydroepiandrosterone in adrenal failure:
no benefit for subjective health status and sexuality in a 9-month, randomized, parallel group clinical
 trial. J Clin Endocrinol Metab 2003; 88:1112.

39. van Thiel SW, Romijn JA, Pereira AM, et al. Effects of dehydroepiandrostenedione, superimposed on
growth hormone substitution, on quality of life and insulin-like growth factor I in patients with
secondary adrenal insufficiency: a randomized, placebo-controlled, cross-over trial. J Clin Endocrinol
Metab 2005; 90:3295.
40. Rice SP, Agarwal N, Bolusani H, et al. Effects of dehydroepiandrosterone replacement on vascular
function in primary and secondary adrenal insufficiency: a randomized crossover trial. J Clin Endocrinol
Metab 2009; 94:1966.

41. Dhatariya KK, Greenlund LJ, Bigelow ML, et al. Dehydroepiandrosterone replacement therapy in
hypoadrenal women: protein anabolism and skeletal muscle function. Mayo Clin Proc 2008; 83:1218.

42. Srinivasan M, Irving BA, Dhatariya K, et al. Effect of dehydroepiandrosterone replacement on

lipoprotein profile in hypoadrenal women. J Clin Endocrinol Metab 2009; 94:761.

43. Hahner S, Burger-Stritt S, Allolio B. Subcutaneous hydrocortisone administration for emergency use in
adrenal insufficiency. Eur J Endocrinol 2013; 169:147.

44. Salem M, Tainsh RE Jr, Bromberg J, et al. Perioperative glucocorticoid coverage. A reassessment 42
years after emergence of a problem. Ann Surg 1994; 219:416.

45. Coursin DB, Wood KE. Corticosteroid supplementation for adrenal insufficiency. JAMA 2002; 287:236.

46. Hussain S, Hussain S, Mohammed R, et al. Fasting with adrenal insufficiency: Practical guidance for
healthcare professionals managing patients on steroids during Ramadan. Clin Endocrinol (Oxf) 2020;
93:87.

47. Lindsay JR, Nieman LK. The hypothalamic-pituitary-adrenal axis in pregnancy: challenges in disease
detection and treatment. Endocr Rev 2005; 26:775.

48. Irvine WJ, Barnes EW. Adrenocortical insufficiency. Clin Endocrinol Metab 1972; 1:549.

49. Lebbe M, Arlt W. What is the best diagnostic and therapeutic management strategy for an Addison
patient during pregnancy? Clin Endocrinol (Oxf) 2013; 78:497.

50. Wu SJ, Tsai YL, Hsieh BS. Sequential changes in plasma renin activity and aldosterone level during
pregnancy. J Formos Med Assoc 1991; 90:932.

51. Fagundes VG, Lamas CC, Francischetti EA. Renin-angiotensin-aldosterone system in normal and
hypertensive pregnancy. Response to postural stimuli. Hypertension 1992; 19:II74.
52. Thomsen JK, Fogh-Andersen N, Jaszczak P, Giese J. Atrial natriuretic peptide (ANP) decrease during
normal pregnancy as related to hemodynamic changes and volume regulation. Acta Obstet Gynecol
Scand 1993; 72:103.

53. Corry DB, Tuck ML. Secondary aldosteronism. Endocrinol Metab Clin North Am 1995; 24:511.

54. Dörr HG, Heller A, Versmold HT, et al. Longitudinal study of progestins, mineralocorticoids, and
glucocorticoids throughout human pregnancy. J Clin Endocrinol Metab 1989; 68:863.
55. Funder JW. Aldosterone action: fact, failure and the future. Clin Exp Pharmacol Physiol Suppl 1998;
25:S47.

56. O'Shaughnessy RW, Hackett KJ. Maternal Addison's disease and fetal growth retardation. A case report.
J Reprod Med 1984; 29:752.

57. Wieacker P, Alexopoulos A, DeGregorio G, Breckwoldt M. [Pregnancy in Addison's disease]. Dtsch Med
Wochenschr 1989; 114:1117.

58. BRENT F. Addison's disease and pregnancy. Am J Surg 1950; 79:645.

59. DUNLOP D. EIGHTY-SIX CASES OF ADDISON'S DISEASE. Br Med J 1963; 2:887.

60. Bergthorsdottir R, Leonsson-Zachrisson M, Odén A, Johannsson G. Premature mortality in patients

with Addison's disease: a population-based study. J Clin Endocrinol Metab 2006; 91:4849.

61. Løvås K, Loge JH, Husebye ES. Subjective health status in Norwegian patients with Addison's disease.
Clin Endocrinol (Oxf) 2002; 56:581.

62. Hahner S, Loeffler M, Fassnacht M, et al. Impaired subjective health status in 256 patients with adrenal
insufficiency on standard therapy based on cross-sectional analysis. J Clin Endocrinol Metab 2007;
92:3912.

63. Ho W, Druce M. Quality of life in patients with adrenal disease: A systematic review. Clin Endocrinol
(Oxf) 2018; 89:119.

Topic 155 Version 30.0

© 2024 UpToDate, Inc. All rights reserved.