What causes elevated Dehydroepiandrosterone sulfate (DHEA-S) levels?

Causes of Elevated DHEA-S Levels

Elevated Dehydroepiandrosterone sulfate (DHEA-S) levels are most commonly caused by non-classical congenital adrenal hyperplasia, polycystic ovary syndrome (PCOS), adrenal tumors, and certain medication effects. 1

Primary Causes of Elevated DHEA-S

Adrenal Pathology

• Adrenal tumors

  • Adrenocortical carcinoma (ACC) - can cause markedly elevated DHEA-S levels 1
  • Non-hyperfunctioning adrenal adenomas - can paradoxically cause elevated DHEA-S 2
  • Rule out adrenal tumors when DHEA-S is significantly elevated (>3800 ng/ml in ages 20-29, >2700 ng/ml in ages 30-39) 1

• Congenital adrenal hyperplasia (CAH)

  • Non-classical congenital adrenal hyperplasia is a common cause 1, 3
  • Typically presents with other signs of androgen excess (hirsutism, acne, menstrual irregularities) 3
  • Poorly controlled CAH patients may have normal or elevated DHEA-S levels 4

Reproductive/Metabolic Disorders

• Polycystic ovary syndrome (PCOS)
  • Common cause of elevated DHEA-S in women (affects 4-6% of general female population) 1
  • Often presents with menstrual irregularity, hirsutism, acne, and obesity 1
  • Characterized by hyperandrogenic chronic anovulation 1

Medication and Supplement Effects

• Medication interactions
  • Some medications may interfere with DHEA-S metabolism 3
  • Glucocorticoid therapy can suppress DHEA-S levels (important to note when interpreting results) 4

Genetic/Transport Abnormalities

• Transporter protein defects
  • Mutations in efflux transporters like breast cancer-resistance protein (BCRP) 5
  • Mutations in steroid sulfatase (STS) gene 5
  • These can impair normal DHEA-S clearance, leading to accumulation

Clinical Evaluation of Elevated DHEA-S

When to Suspect and Test for Elevated DHEA-S

• Clinical presentations warranting testing:
  • Hirsutism, acne, or male pattern baldness in women 1
  • Menstrual irregularities (oligomenorrhea, amenorrhea) 1
  • Virilization (clitoromegaly, deepening voice) 3
  • Truncal obesity with metabolic abnormalities 1
  • Infertility 1
  • In prepubertal children: premature adrenarche, early pubic/axillary hair 1

Diagnostic Workup

1. Initial laboratory assessment:

   • DHEA-S levels (age-specific reference ranges are important) 1
   • Other androgens: testosterone, androstenedione 1
   • LH/FSH ratio (>2 suggests PCOS) 1
   • 17-OH-progesterone (elevated in CAH) 1, 3

2. Imaging studies when DHEA-S is significantly elevated:

   • Adrenal CT or MRI to rule out adrenal tumors 1
   • Pelvic ultrasound if PCOS is suspected 1

3. Additional testing:

   • Dexamethasone suppression test to differentiate between adrenal tumor and hyperplasia 5
   • Glucose/insulin testing if PCOS or metabolic syndrome suspected 1

Clinical Significance and Management

• Elevated DHEA-S is associated with increased risk of metabolic complications 3
• While once thought to be protective against cardiovascular disease, research has not confirmed this association in women 6
• Treatment should target the underlying cause:
  • For PCOS: lifestyle modifications, hormonal therapy 1
  • For CAH: appropriate glucocorticoid replacement 3, 4
  • For adrenal tumors: surgical intervention may be necessary 2

Important Caveats

• DHEA-S levels naturally decline with age 7
• Reference ranges are age and sex-specific 1
• Overtreated CAH patients may have abnormally suppressed DHEA-S levels 4
• Isolated elevation of DHEA-S without clinical symptoms may not require treatment 1
• Heterozygous mutations in transport proteins may cause unexpectedly high DHEA-S levels even without tumors 5

Understanding the cause of elevated DHEA-S is crucial for appropriate management and to prevent potential long-term health consequences related to androgen excess.