What are the causes of elevated dehydroepiandrosterone sulfate (DHEAS) in women?

Causes of Elevated DHEAS in Women

Elevated DHEAS in women is most commonly caused by polycystic ovary syndrome (PCOS), occurring in approximately 20-33% of PCOS patients, followed by non-classic congenital adrenal hyperplasia, adrenal tumors, and rarely, genetic defects in steroid metabolism or transport. 1, 2

Primary Causes

Polycystic Ovary Syndrome (PCOS)

• PCOS is the leading cause of elevated DHEAS in reproductive-age women, with 20-30% of PCOS patients demonstrating excess adrenal precursor androgen production 2
• The prevalence varies by race: 20% in White women and 33% in Black women with PCOS when adjusted for age and race-specific normative values 1
• Elevated DHEAS is more prevalent in non-classic PCOS phenotypes (B and C) compared to classic phenotype A, with approximately 33% of non-classic PCOS patients showing elevated levels 1, 3
• DHEAS elevation in PCOS represents a generalized exaggeration in adrenal steroidogenesis in response to ACTH stimulation, though without overt hypothalamic-pituitary-adrenal axis dysfunction 2
• When DHEAS is elevated in PCOS, it is typically accompanied by higher testosterone and androstenedione levels, indicating generalized hyperandrogenism 3

Non-Classic Congenital Adrenal Hyperplasia (NCAH)

• Mild enzymatic defects in adrenal steroidogenesis account for a substantial proportion of elevated DHEAS cases 4
• The most common defects include:
  • 3β-hydroxysteroid dehydrogenase deficiency (most frequent finding on ACTH stimulation testing) 4, 5
  • 21-hydroxylase deficiency 4
  • 11β-hydroxylase deficiency 4
• Approximately 61% of hirsute women show subtle defects in adrenal steroidogenesis on ACTH stimulation testing 4
• Importantly, basal DHEAS levels do not predict which patients have enzymatic defects: 13 patients with defective steroidogenesis had normal DHEAS levels, while 5 of 11 patients with elevated DHEAS had no enzymatic defects 4

Adrenal Tumors

• Very high DHEAS levels (typically >700 μg/dL) are characteristic of DHEAS-producing adrenal tumors, particularly adrenocortical carcinoma (ACC) 1
• ACC is responsible for more than half of androgen hypersecretion cases presenting with virilization 1
• When ACC is suspected, additional testing should include testosterone, 17β-estradiol, 17-OH progesterone, androstenedione, 17-OH pregnenolone, 11-deoxycorticosterone, progesterone, and estradiol 1

Anovulatory Disorders

• Elevated DHEAS occurs in 50% of euprolactinemic anovulatory infertility patients, with 77% of these women being non-hirsute 5
• The prevalence increases with severity: 19% in ovulatory infertile women, 34% in oligomenorrheic patients, and 60% in hirsute women 6

Rare Genetic Causes

• Heterozygous mutations in steroid sulfatase (STS) gene combined with variants in breast cancer resistance protein (BCRP) transporter can cause markedly elevated DHEAS through impaired efflux transport 7
• These genetic defects are extremely rare and typically present with very high DHEAS levels without tumor evidence 7

Important Clinical Considerations

Age-Related Factors

• DHEAS values are strongly age-dependent: levels peak between 20-30 years of age and decline by approximately 40% from the twenties to thirties 1, 3
• DHEAS has more diagnostic value in premenopausal than postmenopausal women due to this age-related decline 1

Diagnostic Approach

• DHEAS should be considered a second-line diagnostic marker for hyperandrogenism, not a first-line test 1
• The 2023 International PCOS Guidelines recommend measuring DHEAS only when first-line androgens (total testosterone, free testosterone, or FAI) are negative but clinical suspicion remains high 1
• DHEAS has poorer specificity (67%) compared to testosterone (86%) or FAI (85%) for diagnosing hyperandrogenism, leading to risk of overdiagnosis 1

Common Pitfalls

• Basal DHEAS levels alone cannot differentiate between ovarian and adrenal sources of androgen excess and may be misleading 4
• Normal DHEAS does not exclude adrenal enzymatic defects—ACTH stimulation testing is required for definitive diagnosis 4, 5
• Elevated DHEAS does not necessarily indicate progression to overt disease or require intervention unless accompanied by clinical symptoms 2

Factors That Do NOT Significantly Influence DHEAS

• Obesity, insulin levels, glucose levels, and ovarian secretions play limited roles in increased DHEAS production in PCOS 2
• Plasma ACTH, total cholesterol, LDL, and HDL cholesterol levels do not correlate with elevated DHEAS 5