What are the causes of undetectable Dehydroepiandrosterone sulfate (DHEAS) levels in a female in her fifties?

Causes of Undetectable DHEAS in a Female in Her Fifties

Undetectable DHEAS levels in a woman in her fifties most commonly indicate primary adrenal insufficiency (PAI), though secondary adrenal insufficiency and age-related physiologic decline are also important considerations. 1, 2

Primary Adrenal Insufficiency (Most Important Cause)

Primary adrenal insufficiency is the most critical diagnosis to exclude when DHEAS is undetectable, as it carries significant morbidity and mortality risk if untreated. 1

• Low DHEAS is a characteristic finding in PAI, occurring alongside low cortisol, elevated ACTH, and low aldosterone 3
• PAI results in complete loss of adrenal androgen secretion, causing severe androgen deficiency particularly in women 1
• Look specifically for: salt cravings, lightheadedness, orthostatic hypotension, hyperpigmentation (elevated ACTH), fatigue, weight loss, and hypoglycemia 1
• Measure morning cortisol, ACTH, aldosterone, and electrolytes (hyponatremia, hyperkalemia) to confirm diagnosis 1
• If PAI is confirmed, glucocorticoid and mineralocorticoid replacement are essential; DHEA replacement (25 mg daily) should be offered as a 6-month trial for persistent low libido or low energy despite optimized replacement 1, 3

Secondary Adrenal Insufficiency

Secondary adrenal insufficiency from pituitary dysfunction causes decreased DHEAS even more frequently than decreased cortisol levels. 2

• DHEAS levels are decreased in 95% of patients with secondary adrenal insufficiency, while cortisol is low in only 85% 2
• The frequency of decreased DHEAS is significantly higher than decreased cortisol, making DHEAS a sensitive marker for deficient ACTH secretion 2
• Evaluate for pituitary pathology: history of pituitary tumor, surgery, radiation, head trauma, or postpartum hemorrhage (Sheehan syndrome) 2
• Measure ACTH (will be low or inappropriately normal), prolactin, TSH, LH, FSH, and consider pituitary MRI 2
• Unlike PAI, secondary adrenal insufficiency does not cause hyperpigmentation or mineralocorticoid deficiency 2

Age-Related Physiologic Decline

DHEAS levels decline profoundly with age, and women in their fifties naturally have substantially lower levels than younger women, though "undetectable" suggests pathology beyond normal aging. 4, 5

• DHEAS secretion decreases progressively with age in all individuals 4, 5
• In healthy women over 90 years, DHEAS levels are five-fold lower than in young controls (geometric mean 364-521 ng/mL vs 2824 ng/mL) 6
• However, truly undetectable levels (below assay detection limits) in a woman in her fifties are abnormal and warrant investigation for adrenal insufficiency 1, 3
• Normal age-related decline should still yield measurable DHEAS levels in the 30-39 age range reference of >2700 ng/mL, declining further but remaining detectable in the fifties 1

Other Considerations

Certain medications and conditions can suppress adrenal androgen production, though they rarely cause completely undetectable levels. 1

• Chronic glucocorticoid therapy (oral prednisone) suppresses ACTH and adrenal androgen production 1
• Severe chronic illness or critical illness can suppress adrenal function 1
• Hypopituitarism from any cause affects DHEAS before cortisol 2

Diagnostic Approach

Measure morning cortisol and ACTH simultaneously with DHEAS to differentiate primary from secondary adrenal insufficiency. 1, 3, 2

• If cortisol is low and ACTH is elevated: primary adrenal insufficiency 1
• If both cortisol and ACTH are low: secondary adrenal insufficiency 2
• Check electrolytes, aldosterone, and renin to assess mineralocorticoid status 1
• Consider ACTH stimulation test if diagnosis is uncertain 1
• Evaluate for autoimmune causes (21-hydroxylase antibodies), tuberculosis, or other infiltrative diseases in PAI 1

Clinical Significance

Women with undetectable DHEAS and confirmed adrenal insufficiency require lifelong hormone replacement and education about stress dosing to prevent adrenal crisis. 1

• Untreated adrenal insufficiency is life-threatening 1
• DHEA replacement (10-50 mg daily, typically 25 mg) should be guided by morning DHEAS, androstenedione, and testosterone levels maintained in the normal range 1, 3
• Continue DHEA only if clinically effective after 6 months, as long-term benefits have limited evidence 1, 3