What is the management approach for a female of reproductive age with elevated bioavailable testosterone (hyperandrogenism)?

Management of Elevated Bioavailable Testosterone in Reproductive-Age Females

In a reproductive-age female with elevated bioavailable testosterone, immediately perform endocrinologic evaluation including LH, FSH, DHEA-S, 17-hydroxyprogesterone, and prolactin to identify the underlying cause, then treat based on etiology—most commonly PCOS requiring combined oral contraceptives with or without spironolactone, while urgently excluding androgen-secreting tumors if testosterone exceeds twice the upper limit of normal. 1, 2

Initial Diagnostic Workup

Hormone Panel Assessment

• Measure LH and FSH levels to distinguish between ovarian versus central causes of androgen excess 2
• Obtain serum prolactin if LH is low or low-normal, as hyperprolactinemia can present with hyperandrogenism and oligomenorrhea 2, 3
• Check DHEA-S levels when testosterone is elevated, as DHEA-S >600 mg/dL (16.3 μmol/L) suggests adrenal cortical adenoma 2, 4
• Measure early morning 17-hydroxyprogesterone (17-OHP) to screen for non-classical congenital adrenal hyperplasia (21-hydroxylase deficiency), which commonly presents with elevated androgens 2, 3
• Assess ACTH levels to determine if excess androgen production originates from adrenal versus ectopic sources 2

Clinical Red Flags Requiring Urgent Evaluation

• Testosterone levels >2-3 SD above normal reference range warrant immediate investigation for androgen-secreting tumors, despite the low positive predictive value (9%) of this threshold 5, 6
• Rapid onset of virilization (clitoromegaly, voice deepening, male-pattern baldness) indicates possible ovarian or adrenal tumor requiring immediate imaging 7, 3
• Total testosterone >8.7 nmol/L (250 ng/dL) has 100% sensitivity but only 9% positive predictive value for neoplasm, necessitating imaging when present 5

Differential Diagnosis Algorithm

Most Common: Polycystic Ovary Syndrome (PCOS)

• Diagnose PCOS in adult females when 2 of 3 criteria are met: (1) androgen excess (clinical or biochemical), (2) ovulatory dysfunction (oligo- or anovulation), or (3) polycystic ovaries on ultrasound 7
• In adolescent females, diagnosis requires hyperandrogenism (clinical or biochemical) plus persistent oligomenorrhea 7
• PCOS accounts for the majority of hyperandrogenic presentations in reproductive-age women 5, 8

Less Common Etiologies to Exclude

• Non-classical congenital adrenal hyperplasia (NCCAH): Elevated basal or ACTH-stimulated 17-OHP, or significant decrease in testosterone and DHEA-S with 2-day dexamethasone suppression test 3
• Cushing's disease: Recent onset hyperandrogenism with signs of hypercortisolism; exclude with overnight dexamethasone suppression test or 24-hour urinary free cortisol 3
• Androgen-secreting tumors: Very high testosterone levels with rapid virilization; requires pelvic ultrasound for ovarian masses and adrenal CT for adrenal masses 2, 5
• Hyperprolactinemia: Mild hyperandrogenism with recent oligomenorrhea; measure prolactin and repeat if elevated to exclude spurious elevation 3

Management Based on Etiology

PCOS Management

• First-line pharmacologic therapy: 17β-estradiol-based combined oral contraceptives (17βE + nomegestrol acetate or 17βE + dienogest) are preferred formulations for treating hirsutism and hyperandrogenism 1
• Add spironolactone as the recommended anti-androgen, either alone or combined with oral contraceptives for enhanced efficacy in treating hirsutism 1
• Consider metformin if metabolic abnormalities or insulin resistance are present, as it reduces testosterone levels and improves insulin sensitivity 1
• Implement lifestyle modifications including weight loss and increased physical activity, which can reduce testosterone levels in patients with metabolic causes 1

Metabolic Screening and Monitoring

• Screen for metabolic complications including lipid profile and glucose tolerance testing, as elevated testosterone is associated with cardiovascular risk factors and insulin resistance 1
• Evaluate for insulin resistance and metabolic syndrome, which are commonly associated with hyperandrogenism 1
• Monitor complete blood count for polycythemia, as elevated androgens increase hemoglobin/hematocrit 2
• Assess blood pressure regularly for cardiovascular risk, particularly with prolonged androgen excess 2

Tumor Management

• Refer immediately to pediatric endocrinology and surgical oncology if androgen-secreting tumor is suspected, especially for tumors >5 cm, inhomogeneous appearance, irregular margins, or local invasion 2
• Perform open adrenalectomy for suspected malignant or androgen-secreting tumors prone to rupture 2
• Use laparoscopic adrenalectomy for benign adenomas when feasible, with postoperative corticosteroid supplementation required until HPA axis recovery 2

Congenital Adrenal Hyperplasia Management

• Initiate glucocorticoid therapy to suppress excessive ACTH-driven androgen production in confirmed cases of congenital adrenal hyperplasia 2

Important Caveats

Laboratory Interpretation Pitfalls

• Avoid measuring random testosterone levels; obtain early morning samples on at least two separate occasions for accuracy 2
• When clinical presentation doesn't match laboratory values, suspect laboratory interference and consider diethyl ether extraction prior to immunoassay 6, 4
• Normal testosterone with clear hyperandrogenic symptoms (hirsutism, acne) requires careful interpretation, as SHBG is reduced with obesity, metabolic syndrome, or family history of diabetes 4
• Elevated testosterone with marked SHBG elevation may result from medications with estrogenic effects (tamoxifen, raloxifene), hyperthyroidism, or liver disease 4

Fertility Considerations

• Avoid progestins with anti-androgenic effects in patients with documented low testosterone or sexual dysfunction, as these may worsen hypoandrogenism 1
• For patients desiring fertility, metformin and lifestyle modifications are preferred over combined oral contraceptives 1

Follow-Up Monitoring

• Recheck testosterone, DHEA, and DHEA-S levels at 1-2 months after intervention to assess treatment efficacy 2
• Measure liver function tests if pharmacologic therapy is initiated 2