What is the optimal dosage of pregnenolone for replacement in primary adrenal insufficiency?

Pregnenolone is NOT Recommended for Primary Adrenal Insufficiency

Pregnenolone has no established role in the treatment of primary adrenal insufficiency and is not part of standard replacement therapy. The evidence-based treatment consists exclusively of glucocorticoid and mineralocorticoid replacement, with possible DHEA supplementation in select cases.

Standard Replacement Therapy for Primary Adrenal Insufficiency

Glucocorticoid Replacement (Essential)

• Hydrocortisone 15-25 mg daily in divided doses is the cornerstone of treatment 1, 2
• Typical dosing schedule: 10 mg upon waking, 5 mg at noon, and 2.5-5 mg in late afternoon 1
• Alternative: Cortisone acetate 25-37.5 mg daily in divided doses 1
• Prednisolone 4-5 mg daily should only be used when hydrocortisone is not tolerated or compliance is problematic 3

Mineralocorticoid Replacement (Essential for Primary AI)

• Fludrocortisone 50-200 μg (0.05-0.2 mg) once daily is mandatory for all patients with primary adrenal insufficiency 1, 2
• Taken as a single morning dose upon awakening 4
• Higher doses up to 500 μg daily may be needed in children, younger adults, or during the third trimester of pregnancy 1, 4
• Dose adjusted based on serum electrolytes, blood pressure, and clinical symptoms (salt cravings, orthostatic hypotension, peripheral edema) 4

Optional DHEA Supplementation

• DHEA 25-50 mg daily may improve mood, fatigue, well-being, and sexuality in women with adrenal insufficiency 5
• This represents the closest evidence-based approach to replacing adrenal androgens/precursors, though large Phase III trials are still lacking 5

Why Pregnenolone is Not Used

The available guidelines and research evidence make no mention of pregnenolone as a therapeutic agent in adrenal insufficiency. The adrenal gland produces multiple hormones, but replacement therapy focuses on:

1. Cortisol replacement (the essential glucocorticoid) 1, 2
2. Aldosterone replacement via fludrocortisone (essential in primary AI) 1, 4
3. Possibly DHEA (for androgen/precursor replacement in select patients) 5

Pregnenolone, while a precursor to all steroid hormones, is not converted efficiently to cortisol or aldosterone when given exogenously in patients with adrenal insufficiency, making it therapeutically ineffective for this condition.

Critical Monitoring and Pitfalls

• Under-replacement with mineralocorticoids is common and sometimes inappropriately compensated for by over-replacement with glucocorticoids 1
• This practice predisposes patients to recurrent adrenal crises despite apparent adequate glucocorticoid dosing 3
• Annual monitoring should include serum electrolytes, blood pressure, and screening for other autoimmune disorders 1
• All patients require education on stress dosing and should carry injectable hydrocortisone 100 mg for emergency use 1, 2