Does elevated testosterone qualify for a diagnosis of hyperandrogenism in a female?

Does Elevated Testosterone Qualify for Hyperandrogenism in This 17-Year-Old Female?

Yes, this patient's elevated free testosterone (14 pg/mL) and total testosterone (92 ng/dL) meet criteria for biochemical hyperandrogenism, though the diagnosis requires integration with clinical features and exclusion of other causes. 1

Diagnostic Criteria for Biochemical Hyperandrogenism

Elevation of free or total testosterone above adult female normative values is a key diagnostic feature of biochemical hyperandrogenism. 2 The 2023 International PCOS Guidelines recommend using total testosterone (TT) and free testosterone (FT) as first-line laboratory tests to assess biochemical hyperandrogenism, with TT having 74% sensitivity and 86% specificity, while FT demonstrates 89% sensitivity and 83% specificity. 3, 1

Laboratory Interpretation in This Case

• Free testosterone of 14 pg/mL is elevated above typical adult female reference ranges (normal approximately 0.3-1.9 pg/mL depending on assay), confirming biochemical hyperandrogenism 1, 2
• Total testosterone of 92 ng/dL is elevated above typical adult female ranges (normal approximately 15-70 ng/dL), further supporting the diagnosis 1, 4
• DHEAS of 391 μg/dL is within normal limits (normal range approximately 35-430 μg/dL), making primary adrenal causes less likely 1, 4
• SHBG of 44.5 nmol/L is normal (normal range approximately 30-100 nmol/L), which means the elevated free testosterone reflects true androgen excess rather than decreased binding protein 4, 5

Critical Methodological Consideration

The accuracy of this diagnosis depends entirely on the assay method used. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) should be utilized for measuring testosterone, as direct immunoassays have limited accuracy at the low concentrations seen in females. 3, 1 If the testosterone was measured by direct immunoassay and results are inconsistent with clinical presentation, the test should be rechecked using LC-MS/MS. 3

Clinical Context in Adolescents

Why This Case is Complex

This 17-year-old presents diagnostic challenges specific to adolescence:

• Normal pubertal changes overlap with PCOS features, making diagnosis difficult in this age group 2
• She has mild facial acne but no hirsutism or virilization, which represents incomplete clinical hyperandrogenism 1, 6
• Regular 28-day cycles argue against classic PCOS, though heavy flow and cramping suggest possible ovulatory dysfunction 7, 2
• The cyclical mood symptoms could reflect normal hormonal fluctuation rather than pathologic androgen excess 2

Additional Clinical Signs to Assess

The American Academy of Dermatology recommends evaluating for these specific features of hyperandrogenism: 1

• Hirsutism (excessive terminal hair in male-pattern distribution) - absent in this patient
• Androgenic alopecia (male-pattern hair loss) - not mentioned
• Clitoromegaly - not mentioned but should be assessed
• Truncal obesity - not mentioned but relevant given metabolic implications
• Acanthosis nigricans (dark velvety skin patches indicating insulin resistance) - should be assessed 1

Differential Diagnosis Requiring Exclusion

Most Likely: Polycystic Ovary Syndrome (PCOS)

PCOS accounts for 95% of hyperandrogenism cases and affects 10-13% of women globally. 1 However, diagnosis in adolescents requires caution due to overlap with normal puberty. 8, 2

Rotterdam criteria require at least 2 of 3 findings: 7, 8

1. Hyperandrogenism (clinical or biochemical) - ✓ Present (biochemical)
2. Ovulatory dysfunction (oligomenorrhea/anovulation) - Questionable (regular cycles but heavy flow/cramping)
3. Polycystic ovary morphology on ultrasound - Not mentioned

Important: Ultrasound Should NOT Be Used as Primary Criterion in Adolescents

The Endocrine Society recommends against using ultrasound as a primary diagnostic criterion in adolescents <8 years post-menarche due to high false-positive rates from normal multi-follicular ovaries in this age group. 8 Biochemical hyperandrogenism provides more reliable confirmation.

Other Causes to Rule Out

• Nonclassic congenital adrenal hyperplasia (NCCAH): Check early morning 17-hydroxyprogesterone (17-OHP); if >200 ng/dL, perform ACTH stimulation test 1, 2
• Hyperprolactinemia: Measure prolactin to exclude this cause of menstrual irregularity and hyperandrogenism 1, 7
• Thyroid disease: Check TSH as thyroid dysfunction can present similarly 1, 2
• Cushing's syndrome: Consider if clinical features present (striae, central obesity, moon facies) 1
• Androgen-secreting tumor: Very unlikely given moderate testosterone elevation (<200 ng/dL) and gradual onset, but if testosterone >200 ng/dL or DHEAS >600 μg/dL, imaging is mandatory 1, 4
• Exogenous androgen use: Inquire about supplements, medications, or performance-enhancing substances 1

Recommended Diagnostic Algorithm

Immediate Next Steps

1. Confirm the testosterone measurement was performed using LC-MS/MS - if not, repeat with this methodology 3, 1
2. Measure morning testosterone (between 8-10 AM) due to diurnal variation 1
3. Complete hormonal panel: 1, 7, 2
   • 17-hydroxyprogesterone (early morning, follicular phase)
   • Prolactin
   • TSH
   • LH and FSH (already done: FSH 5.58 - need LH for ratio)
4. Assess ovulatory status: Measure mid-luteal progesterone (day 21 of cycle); progesterone >30 nmol/L confirms ovulation 5
5. Screen for metabolic complications: Fasting glucose, 2-hour oral glucose tolerance test, fasting lipid panel 1, 7

If Second-Line Testing Needed

If clinical suspicion remains high despite borderline testosterone, consider: 1

• Androstenedione (A4): 75% sensitivity, 71% specificity
• Repeat DHEAS if concern for adrenal source persists

Clinical Significance and Management Implications

Why This Diagnosis Matters

Even with mild clinical manifestations, biochemical hyperandrogenism warrants attention because: 7, 2

• Metabolic complications including insulin resistance and diabetes risk require screening and management 1, 7
• Cardiovascular risk increases with PCOS-related metabolic syndrome 1
• Fertility implications may emerge if ovulatory dysfunction develops 1
• Psychological impact from acne and potential progression of symptoms affects quality of life 1, 7

Treatment Considerations

Treatment should not be withheld during ongoing diagnostic evaluation if symptoms are distressing to the patient. 2

• Combined oral contraceptives (COCs) are first-line treatment for hyperandrogenism, effectively regulating cycles and reducing androgen levels 1, 7
• Lifestyle modifications (diet and exercise) are essential if overweight/obese 1
• Acne treatment can proceed with standard dermatologic approaches while evaluation continues 2
• Antiandrogens (spironolactone, cyproterone acetate) may be considered for persistent symptoms 6

Critical Pitfalls to Avoid

1. Do not diagnose PCOS prematurely in adolescents - maintain longitudinal follow-up as pubertal changes evolve 8, 2
2. Do not rely on direct immunoassay testosterone results - insist on LC-MS/MS methodology 3, 1
3. Do not use ultrasound as primary diagnostic criterion in adolescents <8 years post-menarche 8
4. Do not ignore metabolic screening - insulin resistance and diabetes risk require assessment even with mild symptoms 1, 7
5. Do not dismiss patient concerns about acne - substantial effect on self-esteem warrants treatment 2

Addressing the Ferritin Finding

The ferritin of 1024 ng/mL is markedly elevated (normal approximately 12-150 ng/mL in females) and requires separate investigation, as this suggests either: [@general medical knowledge@]

• Acute or chronic inflammation
• Hemochromatosis or iron overload (though patient is taking iron supplements, which is contradictory)
• Liver disease
• Malignancy (less likely given age and presentation)

This finding is unrelated to hyperandrogenism but requires urgent evaluation with repeat ferritin off iron supplementation, iron studies (serum iron, TIBC, transferrin saturation), liver function tests, and inflammatory markers. [@general medical knowledge@]