Guideline Summary: Management of Primary Adrenal Insufficiency (Addison’s Disease)

Overview of Replacement Therapy

• Lifelong glucocorticoid replacement with hydrocortisone 15–25 mg daily in 2–3 divided doses (largest dose on waking) plus mineralocorticoid replacement with fludrocortisone 50–200 µg daily, together with comprehensive patient education on stress dosing and emergency management to prevent adrenal crises. 1

Glucocorticoid Replacement

Preferred Agent and Dosing

• Hydrocortisone is the glucocorticoid of choice because it most closely mimics physiological cortisol and has a short half‑life that permits dose titration. 2
• Standard adult dosing is 15–25 mg per day, divided into two or three oral doses; the highest dose is given immediately after awakening. 3
• In pediatric patients, hydrocortisone is dosed at ≈ 8 mg/m² body‑surface‑area per day, divided into three to four doses. 2

Alternative Options

• Cortisone acetate 20–35 mg daily (divided 2–3 doses) may be used when hydrocortisone is unavailable. 1
• Prednisolone 3–5 mg daily (once or twice daily) can be considered for patients with adherence difficulties, acknowledging its less physiological profile. 1
• Dexamethasone should be avoided for routine replacement because its long half‑life hampers titration and it carries a high risk of Cushingoid side effects even with modest overdosing. 1

Rationale

• Physiologic cortisol production is only 5–6 mg/m², yet replacement doses of 15–25 mg are required because oral hydrocortisone cannot reproduce the normal pulsatile (≈ 3‑hour) peaks or circadian rhythm that drive cortisol’s metabolic, immune, and cognitive actions. 2
• Long‑acting synthetic glucocorticoids (e.g., prednisolone, dexamethasone) are linked to greater adverse metabolic effects and reduced quality of life. 2

Mineralocorticoid Replacement

• All patients with confirmed aldosterone deficiency should receive fludrocortisone, initiating at 50–100 µg daily and maintaining within a 50–200 µg daily range. 1
• Sodium restriction must be avoided; adequate dietary salt is essential for mineralocorticoid efficacy. 1
• Monitoring relies primarily on clinical signs (salt craving, postural hypotension indicating under‑replacement; edema or hypertension indicating over‑replacement) together with serum sodium/potassium and plasma renin activity measurements. 1
• If hypertension persists despite dose reduction, antihypertensive therapy may be added while continuing fludrocortisone. 1
• When hydrocortisone doses reach ≥ 50 mg per day during stress or illness, fludrocortisone should be temporarily discontinued because high‑dose hydrocortisone provides sufficient mineralocorticoid activity; fludrocortisone is restarted only after hydrocortisone is tapered below 50 mg daily. 4

Monitoring and Dose Adjustment

• Glucocorticoid doses are adjusted solely on clinical response; routine cortisol or ACTH measurements are not useful for chronic replacement guidance. 1
• Indicators of under‑replacement include fatigue, nausea, poor appetite, weight loss, postural hypotension, and generalized weakness. 1
• Indicators of over‑replacement include weight gain, hyperglycemia, hypertension, fluid retention, insomnia, and Cushingoid features. 1

Stress Dosing and Emergency Management

• All patients must receive education on increasing glucocorticoid doses during physiological stress (illness, surgery, trauma) and be equipped with a steroid emergency card and a 100‑mg hydrocortisone intramuscular kit for emergencies. 1

Stress‑Dosing Protocols

• Minor illness (e.g., low‑grade fever, upper‑respiratory infection): double the usual daily hydrocortisone dose for the duration of the illness. 3
• Moderate illness (e.g., gastroenteritis, urinary‑tract infection): triple the usual dose (minimum 60 mg daily in adults), divided into three doses until recovery, then taper over 48 hours back to maintenance. 4
• Severe illness or adrenal crisis: give an immediate IV bolus of 100 mg hydrocortisone, followed by 50–100 mg every 6–8 hours (or 200 mg continuous infusion over 24 h) together with aggressive IV saline resuscitation. 1
• Major surgery: maintain triple the usual oral dose for at least 48 hours post‑operatively, extending up to one week if recovery is complicated. 4

Post‑Stress Tapering

• After resolution of acute stress dosing, transition to double the maintenance dose for 48 hours before returning to baseline. 4
• For postoperative or prolonged illness, maintain the doubled dose for up to one week before a gradual taper. 4
• Abrupt discontinuation of high‑dose therapy must be avoided; a bridging taper is required to prevent withdrawal and ensure adequate coverage. 4

DHEA Replacement (Selective Use in Women)

• A trial of DHEA 25–50 mg daily may be considered in women with persistent low libido, depressive symptoms, or low energy despite optimized glucocorticoid and mineralocorticoid therapy; continue for six months and discontinue if no sustained benefit is observed. 1
• Baseline morning DHEA‑sulfate levels should be measured before initiating therapy, aiming for a mid‑normal range. 1

Screening for Associated Autoimmune Conditions

• Routine monitoring for autoimmune thyroid disease is recommended, as it frequently co‑exists with primary adrenal insufficiency (autoimmune polyendocrine syndrome type 2). 1
• Periodic screening for other autoimmune disorders (type 1 diabetes, celiac disease, vitiligo, pernicious anemia) should be performed based on clinical suspicion. 1

Special Populations

• Pregnancy: women with Addison’s disease require close, trimester‑specific monitoring for signs of glucocorticoid over‑ or under‑replacement. 1
• Pediatric patients: use hydrocortisone 8 mg/m² per day divided into three to four doses; hypoglycemia is a critical warning sign and warrants immediate evaluation and treatment. 2

Drug Interactions and Dose Adjustments

• CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine) may accelerate cortisol metabolism, necessitating an increase in hydrocortisone dose. 5
• CYP3A4 inhibitors (certain antifungals, protease inhibitors) may require hydrocortisone dose reduction to avoid over‑replacement. 5
• Proton‑pump inhibitors such as lansoprazole do not significantly affect hydrocortisone metabolism and therefore do not require dose adjustment. 6

Common Pitfalls and Prevention

• Delayed diagnosis: nonspecific symptoms (fatigue, nausea, weight loss) often lead to diagnostic delay; the triad of hyperpigmentation, hyponatremia, and hyperkalemia is highly specific for primary adrenal insufficiency and should prompt immediate testing. 5
• Inadequate stress‑dosing education: infections are the most common trigger for adrenal crisis; patients must understand that gastrointestinal illness can impair oral drug absorption and that intramuscular hydrocortisone should be used when oral intake is compromised. 6
• Over‑replacement: use of long‑acting glucocorticoids or excessive hydrocortisone doses raises cardiovascular, metabolic, and bone‑health risks; the therapeutic goal is the lowest effective dose guided by clinical parameters, not hormone levels. 2
• Premature fludrocortisone restart: fludrocortisone must not be resumed until hydrocortisone has been tapered below 50 mg daily after stress dosing, as higher hydrocortisone doses provide intrinsic mineralocorticoid activity. 4

Fludrocortisone Therapy and Adjunctive Management in Primary Adrenal Insufficiency

Mineralocorticoid Replacement (Fludrocortisone)

• In adults and adolescents with primary adrenal insufficiency, fludrocortisone is taken once daily in the morning because aldosterone follows a circadian rhythm similar to cortisol. 7
• The recommended daily dose ranges from 0.05 mg to 0.20 mg (50–200 µg), adjusted according to individual fluid and electrolyte intake and losses. 7
• Sodium restriction should be avoided; patients are advised to maintain normal salt intake and may need temporary dose increases of 50–100 % or additional dietary salt in hot climates or when sweating excessively. 7
• When patients are treated with prednisolone (which has limited mineralocorticoid activity) rather than hydrocortisone, a higher fludrocortisone dose is often required; dexamethasone provides no mineralocorticoid effect and therefore does not require fludrocortisone supplementation. 7

Monitoring Mineralocorticoid Therapy

• Clinical assessment—including inquiry about salt cravings or light‑headedness, measurement of sitting and standing blood pressure, and inspection for peripheral edema (low sensitivity)—is used to gauge adequacy of fludrocortisone replacement. 7
• Adequate replacement is indicated by overall well‑being, normal serum electrolytes, and blood pressure without postural hypotension. 7
• Plasma renin activity that lies in the upper normal reference range serves as a useful biochemical marker of appropriate mineralocorticoid dosing. 7
• Patients should avoid licorice and grapefruit juice, both of which can potentiate the mineralocorticoid effect of hydrocortisone and lead to excess volume retention. 7
• Concomitant use of phenytoin accelerates fludrocortisone metabolism, often necessitating a higher replacement dose. 7

Management of Hypertension in Primary Adrenal Insufficiency

• Development of hypertension warrants evaluation of both fludrocortisone and glucocorticoid doses, as overtreatment with either agent can precipitate elevated blood pressure. 7
• If hypertension persists after dose optimization and the patient is euvolemic, first‑line pharmacologic therapy includes angiotensin‑II receptor blockers or angiotensin‑converting enzyme inhibitors to counteract excess angiotensin‑II–mediated vasoconstriction. 7
• A dihydropyridine calcium‑channel blocker may be employed as second‑line therapy when additional blood‑pressure control is needed. 7
• Diuretics should be avoided, and aldosterone‑receptor antagonists such as spironolactone or eplerenone are contraindicated in this population. 7

DHEA Replacement in Women with Primary Adrenal Insufficiency

• A trial of dehydroepiandrosterone (DHEA) 25–50 mg daily can be considered for women who, despite optimized glucocorticoid and mineralocorticoid therapy, continue to experience low libido, depressive symptoms, or low energy. 7
• The trial should last up to six months; if no sustained clinical benefit is observed, DHEA should be discontinued. 7
• Monitoring involves measuring a morning serum DHEAS level before initiating DHEA, aiming for a value in the mid‑normal reference range. 7
• A systematic review and meta‑analysis found no substantial clinical benefit of routine DHEA supplementation, indicating that current evidence is insufficient to support its widespread use (low‑quality evidence). 7
• Nevertheless, some individual studies have reported improvements in libido and restoration of pubarche in women with adrenal insufficiency receiving DHEA. 7