What is the appropriate evaluation and treatment approach for a woman with elevated testosterone levels?

Evaluation and Management of Elevated Testosterone in Women

Initial Diagnostic Approach

Women with elevated testosterone require immediate comprehensive hormonal evaluation to distinguish between benign conditions like PCOS and potentially malignant androgen-secreting tumors, with the urgency and extent of workup determined by the degree of testosterone elevation and presence of virilization. 1, 2

Risk Stratification Based on Testosterone Level

The absolute testosterone level guides diagnostic urgency:

• Testosterone >5 nmol/L (approximately >150 ng/dL): This threshold is associated with virilization and demands prompt investigation to exclude androgen-producing tumors 2
• Testosterone >2-3 SD above normal reference range: Typically associated with hyperandrogenic signs, menstrual irregularities, and rapid onset of virilization requiring immediate workup 3
• Mild elevations: More consistent with PCOS, the most common cause of hyperandrogenism in premenopausal women 2, 4

Red Flag Features Requiring Urgent Evaluation

Certain clinical presentations mandate aggressive investigation for neoplastic pathology:

• Rapid onset of symptoms (developing over weeks to months rather than years) 4
• Overt virilization: clitoromegaly, deepening voice, male-pattern baldness, increased muscle mass 2, 5
• Postmenopausal onset of hyperandrogenic symptoms 2, 5
• Severe biochemical disturbances with markedly elevated testosterone 4

Comprehensive Hormonal Panel

Measure the following hormones to localize the source of androgen excess: 1, 2

• Luteinizing hormone (LH) and follicle-stimulating hormone (FSH): Helps distinguish between primary gonadal disorders versus central causes 1, 6
• Prolactin levels: Particularly important if LH is low or low-normal, as this may indicate a pituitary tumor causing secondary hormonal dysregulation 1, 6
• Dehydroepiandrosterone sulfate (DHEAS) and androstenedione: Elevated levels suggest adrenal source of androgen excess 2, 5
• 17-hydroxyprogesterone (17-OHP): Early morning levels screen for congenital adrenal hyperplasia, specifically 21-hydroxylase deficiency 6
• Estradiol levels: Evaluates for aromatization of excess androgens 1, 6

Critical Pitfall: Laboratory Interference

In women with very elevated testosterone levels but absent clinical manifestations of virilization, suspect laboratory interference. 3 Diethyl ether extraction prior to immunoassay is a useful technique when other methods fail to detect interference 3. This selective peripheral tissue response can cause suppression of ovulation and menstruation without virilization 3.

Imaging Studies Based on Hormonal Results

Ovarian Imaging

Transvaginal ultrasound or pelvic MRI should be performed when:

• Testosterone is markedly elevated with normal or mildly elevated DHEAS 1, 2
• Clinical suspicion for ovarian source exists 2

Important caveat: Pure testosterone-secreting adrenal adenomas can occur even with normal DHEAS and androstenedione levels 7. Therefore, evaluate both ovaries AND adrenals in all women with virilization, particularly during menopause, even if DHEAS and androstenedione are normal 7.

Adrenal Imaging

CT or MRI of adrenal glands is indicated when:

• DHEAS is significantly elevated 2, 5
• Testosterone is markedly elevated despite normal ovarian imaging 7
• 17-OHP suggests adrenal pathology 6

Pituitary Imaging

Pituitary MRI should be ordered if:

• LH is low or low-normal with elevated testosterone 1
• Prolactin is elevated, suggesting prolactinoma or other sellar masses 1, 6

Differential Diagnosis by Clinical Context

Premenopausal Women

Most common causes in order of frequency:

1. Polycystic ovary syndrome (PCOS): Most common cause, typically with mild testosterone elevation 2, 4
2. Nonclassic congenital adrenal hyperplasia: Screened with early morning 17-OHP 6, 4
3. Ovarian hyperthecosis: Can cause virilization 2, 5
4. Androgen-secreting ovarian tumors: Rare (1-3 per 1000 patients with hirsutism), comprising <0.5% of all ovarian tumors 5
5. Exogenous testosterone or anabolic steroids: Requires detailed medication and supplement history 1, 6

Postmenopausal Women

Postmenopausal onset of hyperandrogenic symptoms is a red flag requiring aggressive investigation 2, 5:

1. Androgen-secreting ovarian tumors: More common than adrenal tumors in this population 5
2. Adrenal adenomas or carcinomas: Less common than ovarian tumors but important to exclude 7, 5
3. Ovarian hyperthecosis: Can present or worsen after menopause 2, 5
4. Worsening of previously undiagnosed PCOS: Relative androgen excess associated with menopausal transition 2, 5

Treatment Approach Based on Etiology

Androgen-Secreting Tumors

Surgical resection is the definitive treatment:

• Bilateral oophorectomy for ovarian tumors or when source cannot be lateralized 5
• Adrenalectomy for adrenal tumors: laparoscopic approach for benign adenomas, open surgery for suspected malignancy >5 cm or with concerning features 6
• Postoperative corticosteroid supplementation required after adrenalectomy until HPA axis recovery 6

Expected outcomes: Testosterone levels should normalize within 24 hours post-surgery, with resumption of menstruation within one month in premenopausal women 3

Exogenous Testosterone/Anabolic Steroids

Immediately discontinue all exogenous testosterone or anabolic steroids with gradual tapering to prevent withdrawal symptoms 1, 6. Counsel on cardiovascular risks 6. Recovery of normal spermatogenesis typically requires 6 months or longer after cessation 1.

Congenital Adrenal Hyperplasia

Initiate glucocorticoid therapy to suppress excessive ACTH-driven androgen production 6.

Hyperprolactinemia

Treatment depends on etiology: dopamine agonists for prolactinomas, or addressing medication-induced causes 1. Refer to endocrinology for management 1.

Medical Management When Surgery Not Indicated

For women unfit for surgery or when source is unidentified:

• GnRH agonists/analogues or antagonists have been reported 5
• Antiandrogen therapy for mild to moderate symptoms 2

Monitoring and Follow-Up

Laboratory Surveillance

Regular monitoring should include: 1, 6

• Testosterone levels: Recheck at 1-2 months after intervention, then every 3-6 months initially, annually once stable 1, 6
• Complete blood count: Monitor for polycythemia, as elevated androgens increase hemoglobin/hematocrit 1, 6
• Lipid profile: Assess cardiovascular risk regularly 1, 6
• Liver function tests: If pharmacologic therapy is initiated 6

Cardiovascular Risk Assessment

Elevated testosterone not only causes virilizing effects but also leads to hypercholesterolemia, insulin resistance, hypertension, and cardiac disease 5. Monitor blood pressure and lipid profiles closely 1, 6.

Fertility Considerations

Counsel patients about fertility implications, as elevated testosterone can suppress spermatogenesis and ovulation through negative feedback on gonadotropins 1, 3. For women interested in fertility, reproductive health evaluation should be performed prior to any treatment that might further compromise fertility 8.

Common Diagnostic Pitfalls to Avoid

• Do not rely solely on DHEAS and androstenedione to localize androgen source: Pure testosterone-secreting adrenal tumors can occur with normal adrenal androgens 7
• Avoid measuring random testosterone levels: Obtain early morning samples on at least two separate occasions for accuracy 6
• Do not overlook adrenal imaging in postmenopausal women with virilization: Even when ovaries appear normal on imaging 7, 5
• Do not delay investigation when testosterone is markedly elevated: Androgen-secreting tumors can be malignant in 25-43% of cases 3