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), followed by non-classic congenital adrenal hyperplasia, adrenal tumors (benign or malignant), and rarely, defects in steroid metabolism or transport.

Primary Causes

Polycystic Ovary Syndrome (PCOS)

• PCOS is the most frequent cause of elevated DHEAS in women, with approximately 20-30% of PCOS patients demonstrating excess adrenal androgen production 1
• Elevated DHEAS is found in 33% of young PCOS women (ages 20-29), and is more prevalent in non-classic PCOS phenotypes (B and C) compared to classic phenotype A 2
• Women with elevated DHEAS in PCOS typically have higher testosterone and androstenedione levels, indicating generalized hyperandrogenism 2
• PCOS patients with elevated DHEAS appear to have a generalized exaggeration in adrenal steroidogenesis in response to ACTH stimulation, though they lack overt hypothalamic-pituitary-adrenal axis dysfunction 1

Non-Classic Congenital Adrenal Hyperplasia

• Subtle defects in adrenal steroidogenesis are found in approximately 61% of hirsute women undergoing ACTH stimulation testing 3
• The most common enzyme deficiencies include 3β-hydroxysteroid dehydrogenase, 21-hydroxylase, and 11β-hydroxylase deficiencies 3
• These inherited defects can result in a PCOS-like phenotype with elevated DHEAS 1
• ACTH stimulation testing is essential for diagnosis, as basal DHEAS levels alone are not predictive of underlying enzyme deficiencies 3

Adrenal Tumors

• Androgen-secreting adrenal tumors (benign adenomas or malignant carcinomas) present with virilization symptoms including hirsutism, voice deepening, and oligomenorrhea/amenorrhea in women 4
• Approximately 60% of adrenocortical carcinomas present with evidence of adrenal steroid hormone excess 4
• Very high DHEAS levels (markedly elevated above normal range) are typical for adrenal tumors and warrant imaging evaluation 5
• Malignancy should be suspected when tumors are larger than 4-5 cm, have irregular margins, are internally heterogeneous, or show local invasion 4

Other Endocrine Disorders

• Elevated DHEAS occurs in 34% of oligomenorrheic women and 19% of ovulatory infertile women 6, 7
• Hirsute women show elevated DHEAS in 60% of cases, making it a clinically useful marker of adrenal androgen secretion 7
• When combined with unbound testosterone measurements, 82% of hirsute women demonstrate androgen excess 7

Rare Causes

Steroid Metabolism and Transport Defects

• Heterozygous mutations in steroid sulfatase (STS) gene or breast cancer resistance protein (BCRP) transporter can result in very high DHEAS levels without tumor presence 5
• These defects impair DHEAS hydrolysis or cellular transport, leading to accumulation 5

Clinical Approach to Elevated DHEAS

Initial Evaluation

• Measure serum testosterone, androstenedione, and DHEAS together, as isolated DHEAS elevation without clinical context may be misleading 3
• Assess for clinical hyperandrogenism: hirsutism, acne, androgenic alopecia, menstrual irregularities, and infertility 4
• Basal steroid levels alone are not helpful in differentiating causes and may be misleading 3

When to Pursue Further Testing

• Very high DHEAS levels (markedly above normal range) warrant imaging with CT or MRI to exclude adrenal tumors 5
• For moderate elevations with clinical hyperandrogenism, perform ACTH stimulation testing to identify enzyme deficiencies 3
• Consider measuring 17-hydroxyprogesterone for 21-hydroxylase deficiency screening 4
• Dexamethasone suppression testing can help distinguish adrenal from ovarian sources, with marked DHEAS decrease within 2 weeks indicating adrenal origin 7

Age-Related Considerations

• DHEAS levels decline by approximately 40% from the twenties to thirties, making age-specific reference ranges critical for interpretation 2
• Studies using heterogeneous age populations may show inconsistent prevalence rates of DHEAS elevation 2

Important Caveats

• Routine endocrinologic testing is not indicated for most acne patients; reserve testing for those with clinical signs of hyperandrogenism 4
• Obesity, insulin levels, and ovarian secretions play limited roles in increased adrenal androgen production in PCOS 1
• The exact cause of adrenal androgen excess in PCOS remains unclear but likely reflects inherited exaggeration in androgen biosynthesis 1
• Paradoxically, elevated DHEAS may be protective against cardiovascular risk in women, though this relationship in PCOS is unknown 1