# Adrenal Insufficiency - Primary and Secondary

## Adrenal Cortex Physiology Review

### Zones and Hormones

The adrenal cortex is organized into three histologically and functionally distinct zones, each producing a specific class of steroid hormones under unique regulatory control. The outermost zona glomerulosa synthesizes aldosterone, the principal mineralocorticoid, under the regulation of the renin-angiotensin-aldosterone system (RAAS) and serum potassium concentration. Critically, aldosterone production is not primarily dependent on ACTH, which explains why mineralocorticoid function is preserved in secondary adrenal insufficiency where ACTH is deficient but the RAAS axis remains intact. The middle zona fasciculata produces cortisol, the major glucocorticoid, under direct regulation by pituitary ACTH. Cortisol production is lost in both primary adrenal insufficiency (where the adrenal gland itself is destroyed) and secondary adrenal insufficiency (where ACTH stimulation is absent, leading to zona fasciculata atrophy). The innermost zona reticularis produces adrenal androgens, primarily dehydroepiandrosterone (DHEA), its sulfated form DHEA-S, and androstenedione, also under ACTH regulation. The mnemonic "GFR" (Glomerulosa, Fasciculata, Reticularis) paired with "Salt, Sugar, Sex" (from outer to inner) is a useful framework for remembering the zonal organization and hormonal products.

### Cortisol Physiology

Normal daily cortisol production is approximately 5-10 mg/m2/day, equivalent to roughly 15-25 mg of cortisol per day in adults. Cortisol secretion follows a robust circadian rhythm driven by the suprachiasmatic nucleus via corticotropin-releasing hormone (CRH), with peak levels occurring between 06:00 and 08:00 and the nadir between 23:00 and 01:00. Approximately 90% of circulating cortisol is protein-bound, with 75% bound to cortisol-binding globulin (CBG) and 15% to albumin; only the free fraction is biologically active. Cortisol metabolism occurs primarily in the liver through the enzymes 11-beta-hydroxysteroid dehydrogenase (11-beta-HSD) and cytochrome P450 3A4. The 11-beta-HSD system exists in two isoforms: 11-beta-HSD1 converts inactive cortisone to active cortisol (predominantly in the liver, amplifying local glucocorticoid action), while 11-beta-HSD2 inactivates cortisol to cortisone (predominantly in the kidney, protecting the mineralocorticoid receptor from cortisol activation).

## Primary Adrenal Insufficiency (Addison Disease)

### Etiology

The etiological spectrum of primary adrenal insufficiency varies by geographic region and clinical context. In developed countries, autoimmune adrenalitis accounts for 80-90% of cases, characterized by lymphocytic infiltration and progressive fibrosis of the adrenal cortex. Anti-21-hydroxylase antibodies are positive in over 90% of autoimmune cases and serve as a confirmatory serological marker. Autoimmune Addison disease frequently occurs in the context of autoimmune polyendocrine syndromes and may be associated with other autoimmune conditions including Hashimoto thyroiditis, type 1 diabetes, vitiligo, pernicious anemia, and premature ovarian insufficiency.

Infectious etiologies remain important globally. Tuberculosis is the most common cause of primary adrenal insufficiency in developing countries and characteristically produces bilateral adrenal calcification visible on imaging. Fungal infections including histoplasmosis, coccidioidomycosis, blastomycosis, and cryptococcosis can cause adrenal destruction, particularly in immunocompromised hosts. In HIV/AIDS, CMV adrenalitis, mycobacterial infection, and Kaposi sarcoma can all involve the adrenal glands.

Bilateral adrenal hemorrhage may occur in the setting of Waterhouse-Friderichsen syndrome (classically associated with meningococcal septicemia), anticoagulation therapy (heparin or warfarin), disseminated intravascular coagulation, antiphospholipid syndrome, post-surgical states, and trauma. Bilateral adrenal metastases from primary malignancies of the lung, breast, melanoma, kidney, or lymphoma can cause adrenal insufficiency, though more than 90% of both adrenal glands must be destroyed before clinical insufficiency manifests. Infiltrative diseases including amyloidosis, sarcoidosis, and hemochromatosis represent additional causes.

Several medications can cause adrenal insufficiency through various mechanisms: ketoconazole (inhibition of steroidogenesis), mitotane (direct adrenolytic action), etomidate (single-dose inhibition of 11-beta-hydroxylase), rifampin (acceleration of cortisol metabolism), and immune checkpoint inhibitors (autoimmune adrenalitis in approximately 0.7-1% of treated patients).

Genetic causes include congenital adrenal hyperplasia (with 21-hydroxylase deficiency being the most common form), adrenoleukodystrophy (an X-linked disorder of very long-chain fatty acid accumulation that affects boys and young men, for which VLCFA levels should be checked in all young males presenting with primary adrenal insufficiency), adrenal hypoplasia congenita (DAX1/NR0B1 mutations), Allgrove or Triple-A syndrome (the triad of achalasia, alacrima, and adrenal insufficiency), and familial glucocorticoid deficiency (MC2R or MRAP mutations).

### Clinical Features

The clinical presentation of primary adrenal insufficiency reflects the combined deficiency of glucocorticoids, mineralocorticoids, and adrenal androgens. Hyperpigmentation is the hallmark feature of primary adrenal insufficiency and does not occur in secondary disease. It results from the markedly elevated ACTH levels that accompany primary adrenal failure; ACTH is cleaved from the same precursor molecule (pro-opiomelanocortin, or POMC) as alpha-melanocyte-stimulating hormone, and the excess ACTH and related peptides activate melanocortin-1 receptors (MC1R) in the skin. Hyperpigmentation characteristically involves palmar creases, buccal mucosa, gums, scars, areolae, and areas of friction or pressure. Constitutional symptoms include fatigue, weakness, anorexia, weight loss, nausea, and abdominal pain. Hypotension and orthostatic hypotension result from the combined effects of cortisol and aldosterone deficiency. Salt craving occurs because aldosterone deficiency causes renal sodium wasting. Hyperkalemia is a distinguishing feature of primary adrenal insufficiency, reflecting impaired renal potassium excretion in the absence of aldosterone. Hyponatremia occurs through two mechanisms: cortisol deficiency causes impaired free water excretion via excess arginine vasopressin (AVP) secretion, and aldosterone deficiency causes direct sodium wasting. Hypoglycemia is more common in children, as cortisol serves as a counterregulatory hormone that opposes insulin action. Myalgias, arthralgias, and vitiligo (an associated autoimmune condition) may be present. In women, reduced axillary and pubic hair along with decreased libido reflect adrenal androgen deficiency, as the adrenal glands are a significant source of androgens in females.

<image>A clinical comparison diagram showing primary vs secondary adrenal insufficiency side by side. Left panel (Primary AI/Addison): show a patient figure with hyperpigmentation on palmar creases, buccal mucosa, and skin folds; label key features including: elevated ACTH, low cortisol, low aldosterone (with hyperkalemia), hyponatremia, salt craving, orthostatic hypotension, and adrenal atrophy on CT. Right panel (Secondary AI): show a patient figure with pale/alabaster skin; label: low ACTH, low cortisol, NORMAL aldosterone (no hyperkalemia), hyponatremia (from AVP excess), and possible features of panhypopituitarism. Between the panels, show a Venn diagram of shared features: fatigue, weakness, weight loss, nausea, hypoglycemia, hyponatremia. Use clinical illustration style with clear labeling.</image>

## Secondary Adrenal Insufficiency

### Etiology

Secondary adrenal insufficiency is far more common than primary disease, largely due to the widespread use of exogenous glucocorticoids. Chronic glucocorticoid administration suppresses CRH and ACTH secretion, leading to progressive atrophy of the zona fasciculata. Any dose exceeding prednisone 5 mg per day (or its equivalent) administered for more than 3 weeks carries the potential to suppress the hypothalamic-pituitary-adrenal (HPA) axis. The risk increases with higher dose, longer duration, greater potency, and systemic route of administration (systemic greater than inhaled greater than topical). Importantly, even non-systemic routes can produce clinically significant HPA suppression: inhaled fluticasone propionate at doses exceeding 500 mcg per day, potent fluorinated topical steroids under occlusion, and intra-articular or epidural steroid injections have all been documented to cause adrenal suppression. Recovery of the HPA axis after chronic glucocorticoid exposure takes weeks to months and may require up to 12 months, necessitating gradual taper and stress-dose coverage during the recovery period.

Pituitary and hypothalamic disease represent additional causes, including tumors, pituitary surgery, cranial radiation, Sheehan syndrome (postpartum pituitary necrosis), traumatic brain injury, lymphocytic hypophysitis, and infiltrative diseases. Immune checkpoint inhibitor-induced adrenal insufficiency may present as isolated ACTH deficiency or as a component of hypophysitis, and ACTH recovery is rare (occurring in fewer than 5% of cases), typically necessitating lifelong glucocorticoid replacement. Opioid-induced adrenal insufficiency is an increasingly recognized entity, with chronic opioid use suppressing CRH and ACTH secretion in up to 15-20% of patients receiving more than 30 mg morphine equivalents daily.

### Key Differences from Primary AI

| Feature | Primary AI (Addison) | Secondary AI |
|---|---|---|
| ACTH level | Elevated (>2x ULN) | Low or inappropriately normal |
| Hyperpigmentation | Present (ACTH/POMC excess) | Absent (pale/alabaster skin) |
| Aldosterone | Deficient (low) | Normal (RAAS-regulated) |
| Hyperkalemia | Present | Absent |
| Hyponatremia | Present (AVP excess + Na wasting) | Present (AVP excess only) |
| Mineralocorticoid replacement | Required (fludrocortisone) | Not needed |
| Most common cause | Autoimmune (80-90% in developed countries) | Exogenous glucocorticoids |
| Anti-21-hydroxylase antibodies | Positive (>90% autoimmune) | Negative |
| Adrenal crisis severity | More severe (no aldosterone) | May be less severe |

Several clinical features distinguish secondary from primary adrenal insufficiency. Hyperpigmentation is absent because ACTH levels are low rather than elevated. Hyperkalemia does not occur because the zona glomerulosa and aldosterone production are preserved, being regulated by the RAAS rather than ACTH. Hyponatremia may still occur, however, because cortisol deficiency itself impairs free water excretion through excess AVP secretion. Patients with secondary AI may have concurrent deficiencies of other pituitary hormones including central hypothyroidism, hypogonadism, and growth hormone deficiency. Adrenal crises may be less severe in secondary AI compared to primary disease because preserved aldosterone function provides a degree of hemodynamic stability.

## Diagnosis

### Screening Tests

The diagnostic evaluation begins with a morning cortisol level drawn between 08:00 and 09:00 (when cortisol should be at its circadian peak) paired with a simultaneous ACTH measurement. A morning cortisol below 3 mcg/dL (83 nmol/L) is strongly suggestive of adrenal insufficiency with a positive predictive value of approximately 97%. A cortisol between 3 and 15 mcg/dL is indeterminate and requires dynamic testing for definitive diagnosis. A cortisol above 15-18 mcg/dL generally excludes adrenal insufficiency with a negative predictive value of approximately 95%, though the exact threshold depends on the specific assay and clinical context. The simultaneous ACTH level provides immediate differentiation between primary disease (elevated ACTH, typically more than twice the upper limit of normal) and secondary disease (low or inappropriately normal ACTH in the setting of low cortisol).

### Dynamic Testing

The standard-dose cosyntropin (synthetic ACTH 1-24) stimulation test using 250 mcg administered intravenously or intramuscularly is the most widely used confirmatory test. Serum cortisol is measured at 0, 30, and 60 minutes after injection. A peak cortisol response exceeding 18 mcg/dL (500 nmol/L) at either the 30- or 60-minute time point represents a normal response and effectively excludes adrenal insufficiency. A peak below 18 mcg/dL confirms the diagnosis. This test is highly reliable for primary adrenal insufficiency but carries an important caveat for secondary AI: it may be falsely normal in the early stages (within 2-4 weeks) of a pituitary insult, before adrenal atrophy has had time to develop. It is also critical to recognize that cortisol assay variability is significant; newer liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays yield values 20-30% lower than traditional immunoassays, and assay-specific cut-offs may need to be applied.

The low-dose cosyntropin test (1 mcg intravenously) is considered more sensitive for detecting partial or early secondary adrenal insufficiency but poses technical challenges: the 250 mcg vial must be diluted, introducing risks of dosing error and loss of peptide through adherence to plastic surfaces. The same interpretation cut-off of 18 mcg/dL applies. The insulin tolerance test (ITT) remains the gold standard for diagnosing secondary adrenal insufficiency and growth hormone deficiency. Regular insulin at 0.1-0.15 units/kg is administered intravenously, and adequate hypoglycemia (glucose below 40 mg/dL) must be achieved to constitute a valid stimulus. A normal cortisol response is above 18-20 mcg/dL. Contraindications include seizure disorder, coronary artery disease, elderly age, and baseline cortisol below 5 mcg/dL. The overnight metyrapone test (metyrapone 30 mg/kg at midnight with measurement of 08:00 11-deoxycortisol) tests the entire HPA axis; a normal response is an 11-deoxycortisol level above 7 mcg/dL with cortisol below 5 mcg/dL, but the test carries a risk of precipitating adrenal crisis in patients with undiagnosed AI.

### Additional Testing

Additional investigations help establish the etiology and assess the completeness of adrenal dysfunction. Anti-21-hydroxylase antibodies are positive in over 90% of autoimmune Addison disease cases. Adrenal CT imaging may reveal enlarged adrenals (suggesting hemorrhage, infiltration, or metastasis), calcified adrenals (characteristic of tuberculosis or histoplasmosis), or small atrophic adrenals (consistent with autoimmune or chronic disease). Very long-chain fatty acids (VLCFA) should be measured to screen all males with primary AI for adrenoleukodystrophy. Plasma renin activity and aldosterone levels should be checked to confirm mineralocorticoid deficiency in primary AI (elevated renin with low aldosterone). DHEA-S levels are low in both primary and secondary AI and serve as a useful marker of adrenal androgen status.

<image>A diagnostic algorithm flowchart for adrenal insufficiency. Start with clinical suspicion (fatigue, hypotension, hyponatremia, hyperpigmentation, hypoglycemia). Step 1: Morning cortisol (08:00) + simultaneous ACTH. Branch: if cortisol <3 mcg/dL → AI confirmed → check ACTH. If cortisol 3-15 → cosyntropin stimulation test (250 mcg). If cortisol >15-18 → AI unlikely. Cosyntropin test branch: peak cortisol >18 mcg/dL → AI excluded (but consider low-dose cosyntropin or ITT if high clinical suspicion for early secondary AI). Peak cortisol <18 → AI confirmed → check ACTH. ACTH branch: ACTH high (>2x ULN) → Primary AI → check 21-hydroxylase antibodies, adrenal CT, VLCFA. ACTH low/normal → Secondary AI → pituitary MRI, evaluate for exogenous steroid use, other pituitary axes. Use decision diamond nodes with color-coded pathways.</image>

## Treatment

### Glucocorticoid Replacement

#### Daily Replacement

The goal of glucocorticoid replacement is to replicate physiological cortisol secretion as closely as possible, using the lowest effective dose to avoid the complications of chronic over-replacement. Hydrocortisone at 15-25 mg per day in 2-3 divided doses is the most physiologic option, with a typical regimen of 10 mg upon waking, 5 mg at midday, and 5 mg in the late afternoon (or a simplified 15 mg morning plus 5 mg early afternoon regimen). Cortisone acetate at 25-37.5 mg per day in 2-3 divided doses is an alternative that requires hepatic conversion to cortisol via 11-beta-HSD1. Prednisolone at 3-5 mg per day in 1-2 doses offers the convenience of its longer half-life, allowing once-daily dosing, though the peaks and troughs are less physiologic. Prednisone at 3-5 mg per day similarly requires hepatic conversion to its active form, prednisolone. Modified-release hydrocortisone (Plenadren) is a once-daily dual-release formulation designed to mimic the cortisol circadian rhythm, and some studies have shown improved metabolic parameters including BMI, HbA1c, and blood pressure, though its high cost limits widespread adoption. Dexamethasone is generally not recommended for chronic replacement because it is too potent, has too long a duration of action, is difficult to titrate, and causes disproportionate metabolic side effects; an exception is its short-term use when cosyntropin testing is planned, as dexamethasone does not interfere with cortisol assays.

#### Monitoring Glucocorticoid Replacement

There is no single reliable laboratory test for assessing the adequacy of glucocorticoid replacement; monitoring remains primarily clinical. Signs of under-replacement include persistent fatigue, weight loss, nausea, postural hypotension, and salt craving. Signs of over-replacement mirror the features of Cushing syndrome: central weight gain, insomnia, hyperglycemia, osteoporosis, and skin fragility, along with an increased risk of cardiovascular disease. Day curves involving multiple cortisol measurements throughout the day are used in some specialized centers but are not widely standardized. The guiding principle is to use the lowest effective dose that maintains clinical well-being while avoiding iatrogenic Cushingoid features.

### Mineralocorticoid Replacement (Primary AI Only)

Fludrocortisone at 0.05-0.2 mg daily is required exclusively in primary adrenal insufficiency, as the zona glomerulosa is preserved in secondary AI. Monitoring includes seated and standing blood pressure, serum potassium, and plasma renin activity, with the latter targeted to the upper-normal range. A suppressed renin suggests over-replacement. The dose should be increased if the patient has persistent orthostasis, hyperkalemia, or an elevated renin level, and decreased if hypertension, hypokalemia, suppressed renin, or peripheral edema develops. In hot climates or during vigorous exercise, a temporary increase in fludrocortisone dose may be needed to compensate for increased sodium losses through perspiration.

### DHEA Replacement

DHEA at 25-50 mg daily (available as a compounded prescription or over-the-counter supplement) should be considered in women with primary adrenal insufficiency who have persistent fatigue, depressed mood, or decreased libido despite optimal cortisol and fludrocortisone replacement. The evidence is mixed, with some studies demonstrating improved well-being and libido in women, while no consistent benefit has been shown in men. Monitoring includes DHEA-S levels (targeting the mid-normal female range) and surveillance for androgenic side effects such as acne and hirsutism.

### Stress Dosing ("Sick Day Rules")

#### Minor Illness (Fever, Viral Illness)

During minor illness with fever or viral symptoms, the daily hydrocortisone dose should be doubled or tripled for the duration of the illness. For example, a usual 20 mg per day dose would be increased to 40-60 mg per day in divided doses, returning to the normal dose upon recovery.

#### Moderate Illness (Vomiting, Unable to Take PO)

When the patient is unable to take oral medications due to vomiting, hydrocortisone 50-100 mg should be administered intramuscularly by self-injection, repeated every 8 hours if oral intake remains impossible. Emergency department evaluation is indicated if the patient does not improve within hours.

#### Major Stress/Surgery

| Stress Level | Example | Glucocorticoid Dosing |
|---|---|---|
| Minor stress (illness) | Fever, viral illness | Double or triple oral HC dose for duration of illness |
| Moderate stress (vomiting) | Unable to take PO | IM hydrocortisone 50-100 mg; repeat q8h if needed; seek ED |
| Minor surgery | Local anesthesia | Usual morning dose; no additional stress dosing |
| Moderate surgery | Joint replacement, cholecystectomy | HC 50 mg IV at induction → 25 mg q8h x 24-48h → resume oral |
| Major surgery | Cardiac, major abdominal | HC 100 mg IV at induction → 50 mg q8h x 48-72h → taper over 1-3 days |
| Critical illness / Sepsis | ICU, vasopressor-dependent | HC 50 mg IV q6h (200 mg/day); taper after vasopressors off |

Stress dosing for surgical procedures is graded by the severity of the physiological stress. For minor surgery under local anesthesia, the patient should take their usual morning dose and no additional stress dosing is needed. For moderate surgery (such as joint replacement or cholecystectomy), hydrocortisone 50 mg intravenously should be given at induction, followed by 25 mg every 8 hours for 24-48 hours, then resumption of the oral regimen. For major surgery (cardiac, major abdominal), hydrocortisone 100 mg intravenously is given at induction, followed by 50 mg every 8 hours for 48-72 hours, then tapered to oral over 1-3 days. During critical illness or septic shock, hydrocortisone 50 mg intravenously every 6 hours (200 mg per day) is administered per Surviving Sepsis Campaign guidelines, and tapering should not begin until vasopressors have been discontinued.

### Emergency Preparedness

All patients with adrenal insufficiency must carry a medical alert bracelet or necklace, an emergency hydrocortisone injection kit (100 mg for intramuscular administration), and an emergency information card or letter. Both the patient and close contacts should be trained in intramuscular injection technique. Written sick-day rules with specific dose adjustments should be provided. Standardized steroid emergency cards (developed in the UK and increasingly adopted internationally) improve emergency recognition and management. Annual adrenal crisis education refresher sessions are recommended, as crisis prevention is the most effective strategy for reducing morbidity and mortality.

## Adrenal Crisis

### Definition and Epidemiology

Adrenal crisis is a life-threatening state of acute cortisol deficiency that requires emergent intravenous glucocorticoids and fluid resuscitation. The incidence is approximately 5-10 adrenal crises per 100 patient-years among patients with known adrenal insufficiency, with a mortality rate of approximately 0.5 per 100 patient-years. The most common triggers include gastrointestinal illness with vomiting (which both prevents oral medication absorption and increases cortisol demand), infection, surgery, trauma, failure to implement stress dosing, abrupt withdrawal of chronic steroids, and adrenal hemorrhage.

### Clinical Features

The clinical presentation of adrenal crisis includes severe hypotension and hemodynamic shock that is characteristically refractory to fluids and vasopressors in the absence of glucocorticoid administration. Profound dehydration, hyponatremia, hyperkalemia (in primary AI), and hypoglycemia are typical laboratory findings. Gastrointestinal symptoms including nausea, vomiting, and severe abdominal pain may mimic an acute abdomen. Fever, altered mental status, obtundation, and coma may develop. The crisis may occur in a patient with known adrenal insufficiency who has encountered an intercurrent illness, or it may be the initial presentation of previously undiagnosed disease.

### Management

The management of adrenal crisis demands immediate action. Hydrocortisone 100 mg should be administered intravenously as a bolus without delay; diagnostic testing should never postpone treatment. This is followed by hydrocortisone 50 mg intravenously every 6-8 hours (or alternatively as a continuous infusion of 200 mg over 24 hours). Aggressive intravenous fluid resuscitation with 0.9% NaCl at 1-2 liters in the first 1-2 hours is initiated simultaneously, with continued fluid administration guided by hemodynamic response. Dextrose-containing fluids should be used if the patient is hypoglycemic. Identification and treatment of the precipitating factor, most commonly infection, is essential. Fludrocortisone is not needed during the acute crisis because hydrocortisone at stress doses (exceeding 50 mg per day) provides adequate mineralocorticoid activity. Tapering to maintenance replacement can begin when the patient is clinically improved and tolerating oral intake, typically over 1-3 days. It is critical to understand that hydrocortisone must be administered before or simultaneously with other resuscitative measures, as the vasopressor response is markedly impaired in the absence of cortisol.

## Glucocorticoid Withdrawal and HPA Axis Recovery

### HPA Axis Recovery After Exogenous Steroid Use

Adrenal suppression can occur with any systemic steroid use exceeding 3 weeks, with the degree of suppression dependent on dose and duration. The sequence of recovery follows a predictable pattern: CRH secretion recovers first, followed by ACTH secretion, and finally adrenal cortex reconstitution (specifically, regrowth of the zona fasciculata). This process takes weeks to months and in some cases may require up to 12-18 months. An important caveat is that a normal basal cortisol level during recovery does not guarantee an adequate stress response; the adrenal may be capable of basal cortisol production but lack the reserve to mount an appropriate response to physiological stress. The cosyntropin stimulation test may help assess recovery but can be falsely normal during the partial recovery phase.

### Taper Strategies

There is no universally validated tapering protocol; the approach must be individualized based on the underlying disease being treated and the duration of steroid use. A general approach for chronic use involves tapering to physiologic dose (equivalent to prednisone 5 mg or hydrocortisone 20 mg) over weeks to months as the underlying disease permits, then switching to hydrocortisone and tapering to 10 mg per day, at which point HPA axis testing can be performed. A morning cortisol above 10-15 mcg/dL measured after withholding glucocorticoids for 24 hours suggests recovery, and a cosyntropin stimulation test with a peak cortisol above 18 mcg/dL confirms adequate axis function. Stress dosing should be maintained during the taper period and for 6-12 months after complete cessation for patients who were on chronic steroids, as the stress response may recover more slowly than basal function.

## Key Clinical Pearls

- Hyperpigmentation is present ONLY in primary adrenal insufficiency (elevated ACTH/POMC); pale/alabaster skin is the hallmark of secondary AI; this is the single best bedside clue
- The cosyntropin stimulation test can be falsely normal in early/acute secondary AI (within 2-4 weeks of pituitary insult); if clinical suspicion is high, treat empirically and retest in 4-6 weeks
- ALL patients with primary AI require mineralocorticoid replacement (fludrocortisone); secondary AI does NOT (aldosterone is RAAS-regulated, not ACTH-dependent)
- Adrenal crisis is preventable with proper patient education; the most common trigger is GI illness with inability to absorb oral steroids; IM hydrocortisone self-injection is life-saving
- Screen all young males with primary AI for adrenoleukodystrophy (VLCFA levels); early diagnosis allows consideration of hematopoietic stem cell transplant or gene therapy before neurological deterioration
- Immune checkpoint inhibitor-induced adrenal insufficiency (either from hypophysitis or direct adrenalitis) rarely recovers; plan for lifelong glucocorticoid replacement

## References

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2. Rushworth RL, et al. "Adrenal Crisis." N Engl J Med. 2019;381(9):852-861.
3. Husebye ES, et al. "Adrenal Insufficiency." Lancet. 2021;397(10274):613-629.
4. Crowley RK, et al. "Clinical Insights into Adrenal Insufficiency." Postgrad Med J. 2012;88(1038):101-107.
5. Prete A, et al. "Prevention of Adrenal Crisis: Cortisol Responses to Major Stress Compared to Stress Dose Hydrocortisone Delivery." J Clin Endocrinol Metab. 2020;105(7):2262-2274.