What is the evaluation and management approach for a 38-year-old woman with hyperandrogenism (elevated androgen levels), specifically a Dehydroepiandrosterone sulfate (DHEA-S) level of 311 micrograms per deciliter (ug/DL)?

DHEA-S 311 μg/dL in a 38-Year-Old Woman

A DHEA-S level of 311 μg/dL in a 38-year-old woman is within normal range and does not indicate adrenal pathology, but requires evaluation of total and free testosterone as first-line tests to assess for hyperandrogenism, with DHEA-S serving only as a second-line marker. 1

Interpretation of This DHEA-S Level

• This DHEA-S value (311 μg/dL) falls well below the threshold of concern for adrenal tumors, which typically present with DHEA-S levels exceeding 600 μg/dL 1, 2
• Age-adjusted interpretation is critical, as DHEA-S peaks between ages 20-30 years and declines steadily thereafter, making this level appropriate for a 38-year-old woman 1
• In polycystic ovary syndrome (PCOS), only 8-33% of patients demonstrate elevated DHEA-S, and this marker has poor specificity compared to testosterone measurements 1

Required First-Line Testing

You must measure total testosterone (TT) and free testosterone (FT) using liquid chromatography-tandem mass spectrometry (LC-MS/MS) as your initial diagnostic approach, not DHEA-S alone 1, 3

• Total testosterone measured by LC-MS/MS demonstrates 74% sensitivity and 86% specificity for hyperandrogenism 3, 1
• Calculated free testosterone shows superior diagnostic accuracy with 89% sensitivity and 83% specificity 3, 1
• If LC-MS/MS is unavailable, calculate the free androgen index (FAI = total testosterone/SHBG ratio) as an alternative 1
• Avoid direct immunoassay methods for free testosterone due to poor accuracy at low serum concentrations 1

Clinical Assessment Priorities

Evaluate for these specific clinical features that indicate hyperandrogenism severity:

• Red flag features requiring urgent evaluation: rapid onset of symptoms (developing over weeks to months), virilization signs (clitoromegaly, deepening voice, male-pattern baldness), or postmenopausal onset 1, 4
• Hirsutism using modified Ferriman-Gallwey scoring (≥6 indicates hyperandrogenism) 1, 5
• Persistent or treatment-resistant acne, particularly truncal distribution 1
• Menstrual irregularities including oligomenorrhea (cycles >35 days or <8 cycles/year) or amenorrhea 1, 5
• Metabolic signs including acanthosis nigricans (indicating insulin resistance) and central obesity 1

Diagnostic Algorithm

Step 1: Morning testosterone testing

• Measure total testosterone and free testosterone by LC-MS/MS in the morning due to diurnal variation 1
• If TT >250 ng/dL (8.7 nmol/L), this suggests possible androgen-secreting tumor and requires imaging 5

Step 2: Second-line testing (only if TT/FT normal but clinical suspicion remains)

• Measure androstenedione (A4) with 75% sensitivity and 71% specificity 1
• DHEA-S serves as a second-line test, not first-line 1
• Check SHBG, as fluctuations affect interpretation (decreased with obesity, metabolic syndrome, or diabetes risk) 1, 2

Step 3: Exclude other endocrine disorders

• Measure TSH to rule out thyroid disease 1
• Measure prolactin to exclude hyperprolactinemia 1
• Perform fasting glucose and 2-hour oral glucose tolerance test for insulin resistance screening 1
• Check 17-hydroxyprogesterone if considering nonclassic congenital adrenal hyperplasia 1

Common Diagnostic Pitfalls

• Do not use DHEA-S as a screening test for hyperandrogenism—it has the poorest diagnostic accuracy among androgen markers (75% sensitivity, 67% specificity) 3, 1
• The positive predictive value of elevated DHEA-S for adrenal tumors is extremely low due to the rarity of these neoplasms (affecting only 2.3% of hyperandrogenic patients) 5
• DHEA-S >600 μg/dL (16.3 μmol/L) indicates adrenal source and raises concern for adrenocortical carcinoma, but levels below this threshold do not exclude PCOS or other causes 1, 2
• Clinical evaluation alone often suffices for identifying patients requiring imaging, making routine DHEA-S measurement not cost-effective as a screening tool 5

Most Likely Diagnosis

• PCOS accounts for 95% of hyperandrogenism cases and affects 10-13% of women globally 1
• PCOS diagnosis requires both clinical/biochemical hyperandrogenism AND ovulatory dysfunction—isolated findings are insufficient 1
• Only 20-33% of PCOS patients show elevated DHEA-S when using age-adjusted reference ranges 1

Management Approach

• Combined oral contraceptives (COCs) serve as first-line treatment for hyperandrogenism, effectively regulating menstrual cycles and reducing androgen levels 1
• Screen for and manage metabolic complications, particularly insulin resistance 1
• Implement lifestyle modifications including diet and exercise for overweight/obese patients 1
• Address psychological impact of hyperandrogenism symptoms as part of comprehensive care 1