What causes elevated Dehydroepiandrosterone (DHEA) sulfate levels?

Causes of Elevated DHEA Sulfate Levels

The most common causes of elevated dehydroepiandrosterone sulfate (DHEAS) levels include non-classical congenital adrenal hyperplasia, polycystic ovary syndrome (PCOS), adrenal tumors, and certain genetic variants affecting DHEAS metabolism or transport. 1

Primary Causes

Congenital Adrenal Hyperplasia

• Non-classical congenital adrenal hyperplasia should be ruled out in patients with elevated DHEAS, particularly when levels exceed age-specific thresholds (>3800 ng/ml for ages 20-29, >2700 ng/ml for ages 30-39) 1
• Patients with poorly controlled congenital adrenal hyperplasia due to 21-hydroxylase deficiency may have normal or elevated DHEAS levels 2
• Adequately treated patients with congenital adrenal hyperplasia typically show suppressed DHEAS levels 2

Adrenal Tumors

• Very high DHEAS levels are typically associated with adrenal tumors 3
• Diagnostic workup should include imaging studies (ultrasonography, MRI) to exclude adrenal masses when DHEAS levels are significantly elevated 3
• Dexamethasone suppression testing can help differentiate between functional causes and tumors 4

Polycystic Ovary Syndrome (PCOS)

• Approximately 20-30% of women with PCOS demonstrate excess adrenal precursor androgen production, with elevated DHEAS as a marker 5
• PCOS patients with elevated DHEAS appear to have a generalized exaggeration in adrenal steroidogenesis in response to ACTH stimulation 5
• The pathogenesis involves acceleration of pulsatile gonadotropin-releasing hormone secretion, insulin resistance, and downstream metabolic dysregulation 1

Cushing's Disease

• Patients with Cushing's disease (ACTH-dependent Cushing's syndrome) typically have normal or elevated DHEAS levels 6
• In contrast, patients with adrenal adenomas causing Cushing's syndrome usually have suppressed DHEAS levels 6
• ACTH appears to be the major determinant of DHEAS secretion 6

Genetic and Transport-Related Causes

• Genetic variants affecting steroid sulfatase (STS) can lead to impaired DHEAS metabolism 3
• Mutations in transporter proteins, such as breast cancer-resistance protein (BCRP), may affect DHEAS efflux and contribute to elevated levels 3
• Combinations of heterozygous mutations in both STS and BCRP genes have been associated with very high DHEAS levels 3

Diagnostic Approach

Initial Evaluation

• Assess for clinical signs of hyperandrogenism: hirsutism, acne, menstrual irregularities, androgenetic alopecia, infertility 1
• In prepubertal children, look for early-onset body odor, axillary or pubic hair, accelerated growth, advanced bone age, and genital maturation 1
• In postpubertal females, evaluate for infrequent menses, hirsutism, androgenetic alopecia, infertility, polycystic ovaries, clitoromegaly, and truncal obesity 1

Laboratory Testing

• A typical hormone-screening panel should include free and total testosterone, DHEAS, androstenedione, luteinizing hormone, and follicle-stimulating hormone 1
• Consider additional testing for growth hormone, insulin-like growth factor, lipid levels, insulin, sex hormone binding globulin, free androgen index, prolactin, estrogen, and progesterone in selected cases 1
• Rule out non-classical congenital adrenal hyperplasia with appropriate testing 1

Imaging Studies

• Pelvic ultrasound may be indicated to evaluate for polycystic ovaries in females 1
• Adrenal imaging (CT or MRI) should be considered when DHEAS levels are very high to exclude adrenal tumors 3, 4

Clinical Implications

• Elevated DHEAS levels may be protective against cardiovascular risk in the general population, though the role in PCOS patients remains unclear 5
• Identifying the underlying cause of elevated DHEAS is important for appropriate management and treatment of associated conditions 1
• In patients with suspected hypercortisolism, measuring plasma aldosterone and renin activity is important to evaluate for concomitant hyperaldosteronism 7

By systematically evaluating patients with elevated DHEAS levels and considering these potential causes, clinicians can determine the appropriate diagnostic workup and management strategy.