What are the implications of elevated Dehydroepiandrosterone (DHEA)-Sulfate levels?

Elevated DHEA-Sulfate: Clinical Implications

Elevated DHEA-S indicates adrenal androgen excess and requires systematic evaluation to exclude adrenal tumors, non-classical congenital adrenal hyperplasia, and polycystic ovary syndrome, with the diagnostic approach guided by the degree of elevation and clinical presentation. 1, 2

Primary Diagnostic Considerations

The clinical significance depends critically on the magnitude of elevation and associated symptoms:

Immediate Exclusion of Serious Pathology

• Obtain adrenal CT or MRI to exclude adrenal tumor, particularly when DHEA-S exceeds age-specific thresholds (>3800 ng/mL for ages 20-29, >2700 ng/mL for ages 30-39). 1, 2
• Very high DHEA-S levels are typical for adrenal tumors and require urgent imaging evaluation. 3
• Perform dexamethasone suppression testing if tumor is suspected—adrenal tumors typically do not suppress. 3

Rule Out Non-Classical Congenital Adrenal Hyperplasia

• Non-classical CAH must be ruled out first, particularly when DHEA-S exceeds age-specific thresholds, as this represents an inherited enzyme deficiency (most commonly 21-hydroxylase or 3β-ol dehydrogenase-isomerase). 2, 4
• ACTH stimulation testing reveals exaggerated responses of DHEA-S and 17-OH pregnenolone in approximately 34% of patients with elevated DHEA-S. 4
• Inherited enzyme defects account for only a small fraction of women with hyperandrogenism, but must be excluded. 5

Clinical Assessment for Androgen Excess

Signs and Symptoms to Evaluate

In prepubertal children, look for: 2

• Early-onset body odor
• Premature axillary or pubic hair
• Accelerated growth velocity
• Advanced bone age
• Genital maturation

In postpubertal females, assess for: 1, 2

• Hirsutism (excessive male-pattern hair growth)
• Acne
• Androgenetic alopecia (male-pattern baldness)
• Menstrual irregularities
• Clitoromegaly
• Voice deepening
• Increased muscle mass

Additional endocrine features: 1

• Truncal obesity
• Hypertension
• Glucose intolerance

Laboratory Evaluation

Initial hormone panel should include: 2

• Free and total testosterone
• Luteinizing hormone (LH)
• Follicle-stimulating hormone (FSH)
• Sex hormone binding globulin (SHBG)
• Free androgen index

Additional testing in selected cases: 2

• Insulin and glucose for metabolic assessment
• 17-hydroxyprogesterone if CAH suspected

Imaging studies: 1

• Pelvic ultrasound in women to evaluate for ovarian pathology (polycystic ovaries)

Most Common Cause: Polycystic Ovary Syndrome

• Moderate elevations are most commonly associated with PCOS (affecting 4-6% of women) or non-classical CAH. 1
• Elevated DHEA-S occurs in 34% of oligomenorrheic patients and 60% of hirsute women. 6
• Approximately 20-30% of PCOS women demonstrate excess adrenal precursor androgen production. 5
• DHEA-S has moderate diagnostic accuracy for PCOS with pooled sensitivity and specificity around 70-75%. 1
• Clinical diagnosis based on menstrual irregularity, hirsutism, acne, and obesity is often sufficient for moderate elevations with PCOS features. 1
• PCOS involves accelerated pulsatile GnRH secretion, insulin resistance, and metabolic dysregulation. 2

Mechanism in PCOS

• Women with PCOS and elevated DHEA-S have a generalized exaggeration in adrenal steroidogenesis in response to ACTH stimulation, without overt hypothalamic-pituitary-adrenal axis dysfunction. 5
• Extra-adrenal factors (obesity, insulin, glucose, ovarian secretions) play a limited role in increased adrenal androgen production. 5
• Substantial heritabilities of DHEA-S have been found, suggesting an inherited exaggeration in androgen biosynthesis. 5

Treatment Approach

For PCOS-Related Elevation

Weight loss is first-line for overweight or obese patients with PCOS-related elevation. 1

Hormonal contraceptives regulate menstrual cycles and reduce androgen effects. 1

Metformin or other insulin-sensitizing agents if insulin resistance is present. 1

Anti-androgen therapy (spironolactone) for persistent hirsutism or acne. 1

Dexamethasone Suppression

• A single daily dose of 0.5 mg dexamethasone at bedtime results in marked decrease in serum DHEA-S within 2 weeks in hirsute patients with elevated levels. 6
• This can be used therapeutically in select cases, though not first-line for PCOS. 6

Monitoring Strategy

Repeat DHEA-S measurements every 3-6 months until normalized or stable. 1

Monitor clinical symptoms of androgen excess and assess treatment response. 1

Long-term follow-up for persistent elevations to detect evolving pathology. 1

Special Considerations

Infertility Patients

• Elevated DHEA-S is found in 50% of euprolactinemic anovulatory infertility patients, with 77% being nonhirsute. 4
• Serum DHEA-S is frequently elevated in anovulatory infertile patients and should be measured during evaluation. 4
• When combined with unbound testosterone measurement, 82% of hirsute women have demonstrable androgen excess. 6

Premature Adrenarche

• Regular monitoring without specific treatment is recommended, with follow-up every 6-12 months to monitor growth velocity, bone age, and pubertal development. 1
• Evaluate further if signs of true central puberty develop. 1

Cardiovascular Considerations

• Paradoxically, elevated DHEA-S levels appear protective against cardiovascular risk in women (as in men), though the role in PCOS remains unknown. 5

Common Pitfalls

• Do not assume all elevated DHEA-S is benign PCOS—always exclude adrenal tumors with imaging when levels are significantly elevated. 1, 3
• Do not overlook non-hirsute patients—77% of women with elevated DHEA-S and anovulation are nonhirsute. 4
• Measure unbound testosterone in addition to DHEA-S—unbound testosterone is most frequently elevated in hirsute women and provides complementary diagnostic information. 6
• Consider genetic causes—rare transporter protein defects can cause very high DHEA-S without tumors. 3