What is the appropriate evaluation and management for a 27‑year‑old woman presenting with elevated testosterone?

Evaluation and Management of Elevated Testosterone in a 27-Year-Old Woman

A 27-year-old woman with elevated testosterone requires a systematic hormonal workup to identify the underlying cause—most commonly polycystic ovary syndrome (PCOS), but potentially indicating androgen-secreting tumors, congenital adrenal hyperplasia, or laboratory interference—followed by cause-specific management prioritizing fertility preservation and cardiovascular risk reduction. 1

Initial Diagnostic Approach

Confirm the Elevation and Rule Out Laboratory Error

• Repeat morning testosterone measurement on at least two separate occasions using liquid chromatography-mass spectrometry (LC-MS/MS) if available, as immunoassays are prone to interference from heterophile antibodies that can falsely elevate results 2, 3
• If clinical presentation doesn't match severely elevated testosterone (e.g., no virilization despite levels >2-3 SD above normal), suspect laboratory interference and request diethyl-ether extraction prior to immunoassay 4, 3
• Normal testosterone in reproductive-age women averages 14.1 ng/dL, with an upper limit around 28 ng/dL; commercial laboratory reference ranges (often up to 95 ng/dL) are inappropriately high and miss most cases of hyperandrogenemia 5

Comprehensive Hormonal Panel

Obtain the following tests between days 3-6 of the menstrual cycle (or at presentation if amenorrheic):

• LH and FSH levels (average of three measurements taken 20 minutes apart): LH/FSH ratio >2 suggests PCOS; elevated FSH >35 IU/L suggests ovarian failure 6, 1
• Prolactin (morning resting level, not post-ictal): levels >20 μg/L warrant pituitary imaging to exclude prolactinoma 6, 1
• Total testosterone: levels >2.5 nmol/L (approximately >72 ng/dL) are abnormal and require investigation 6
• Androstenedione: levels >10.0 nmol/L raise concern for adrenal or ovarian tumor 6
• DHEA-S: age-specific cutoffs (>3800 ng/mL for ages 20-29) suggest non-classical congenital adrenal hyperplasia 6
• 17-hydroxyprogesterone (early morning): screens for 21-hydroxylase deficiency causing congenital adrenal hyperplasia 2
• Mid-luteal progesterone (day 21 of 28-day cycle): <6 nmol/L indicates anovulation 6
• Fasting glucose and insulin: glucose/insulin ratio >4 or fasting glucose >7.8 mmol/L suggests insulin resistance associated with PCOS 6

Imaging Studies

• Transvaginal pelvic ultrasound (days 3-9 of cycle): >10 peripheral cysts of 2-8 mm diameter with thickened ovarian stroma confirms polycystic ovaries 6
• Pituitary MRI if LH is low or prolactin is elevated to identify pituitary adenomas 1
• Adrenal imaging (CT or MRI) if DHEA-S is markedly elevated or androstenedione >10.0 nmol/L to exclude androgen-secreting tumors 1

Common Etiologies and Red Flags

Polycystic Ovary Syndrome (Most Common)

• PCOS affects 4-6% of the general population but is the most common cause of hyperandrogenism and anovulatory infertility in young women 6, 4
• Characterized by LH/FSH ratio >2, mild testosterone elevation, insulin resistance, and polycystic ovaries on ultrasound 6
• Do not confuse PCOS with isolated polycystic ovaries (17-22% of normal women have polycystic appearance without hormonal abnormality or symptoms) 6

Androgen-Secreting Tumors (Urgent Evaluation Required)

• Testosterone levels >2-3 SD above normal (>150 ng/dL) with rapid onset of virilization demand immediate investigation for ovarian or adrenal tumors 4
• Ovarian steroid-cell tumors are rare but can produce extremely high testosterone without virilization in some cases due to selective peripheral tissue response 4
• Tumors >5 cm, inhomogeneous appearance, irregular margins, or local invasion require immediate referral to surgical oncology 2

Congenital Adrenal Hyperplasia

• Elevated 17-hydroxyprogesterone confirms 21-hydroxylase deficiency 2
• Markedly elevated DHEA-S (>3800 ng/mL in women aged 20-29) suggests adrenal androgen excess 6

Exogenous Androgens

• Always inquire about anabolic steroid use, testosterone supplementation, or performance-enhancing substances 1

Management Strategy

Fertility Preservation Considerations

• Prior to initiating any therapy, conduct comprehensive fertility assessment as treatment may further affect reproductive function 1
• Document menstrual pattern for at least 6 months: cycles <23 days (polymenorrhea), >35 days (oligomenorrhea), or no bleeding >6 months (amenorrhea) all warrant investigation 6

Cause-Specific Treatment

• PCOS: Refer to endocrinology and/or gynecology for management of insulin resistance, ovulation induction if fertility desired, and cardiovascular risk reduction 6
• Androgen-secreting tumors: Immediate surgical referral; testosterone normalizes within 24 hours post-resection 4
• Congenital adrenal hyperplasia: Initiate glucocorticoid therapy to suppress ACTH-driven androgen production 2
• Exogenous androgens: Discontinue immediately with gradual tapering to prevent withdrawal symptoms 1
• Hyperprolactinemia: Dopamine agonists for prolactinomas or address medication-induced causes 1

Monitoring and Follow-Up

• Recheck testosterone levels at 1-2 months after intervention to assess treatment efficacy 2
• Monitor complete blood count for polycythemia, as elevated androgens increase hemoglobin/hematocrit 1, 2
• Assess lipid profile and blood pressure regularly for cardiovascular risk 1, 2
• Monitor liver function tests if pharmacologic therapy is initiated 2

Critical Pitfalls to Avoid

• Do not rely on commercial laboratory reference ranges (often up to 95 ng/dL), which miss 84% of hyperandrogenemia cases; use evidence-based cutoff of 28 ng/dL 5
• Do not dismiss severely elevated testosterone without virilization as laboratory error without first excluding ovarian tumors, as selective peripheral tissue response can occur 4
• Do not overlook fertility implications; elevated testosterone suppresses ovulation through negative feedback on gonadotropins, and recovery may take 6+ months after treatment 1
• Do not measure testosterone at random times; always obtain early morning samples on at least two occasions for accuracy 2
• Do not skip assessment of menstrual regularity and ovulation status, as anovulation (low mid-luteal progesterone) is a key manifestation requiring intervention 6