What are the implications and treatment options for elevated testosterone levels in females?

Elevated Testosterone in Females: Clinical Implications and Management

Obtaining testosterone levels in women in nonresearch settings is not recommended according to current guidelines, as there is no well-defined clinical syndrome of androgen deficiency or excess that warrants routine testing. 1, 2

Clinical Significance of Elevated Testosterone

Diagnostic Considerations

High testosterone levels in females typically indicate underlying pathology that requires investigation, with levels >2-3 standard deviations above normal reference ranges (>2.0 nmol/L or approximately >0.6 ng/mL) warranting urgent evaluation. 3, 4

The bimodal distribution of testosterone between sexes is clear:

• Normal female range: 0.4-2.0 nmol/L 4
• Normal male range: 8.8-30.9 nmol/L 4
• Females with PCOS remain below normal male range despite elevation 4

Common Etiologies

When testosterone is markedly elevated in females, consider:

• Polycystic ovary syndrome (PCOS) - most common cause, typically shows mild elevations 3
• Ovarian steroid-cell tumors - rare but associated with very high levels and may present without virilization signs 3
• Congenital adrenal hyperplasia - elevated but still below normal male range 4
• Laboratory interference - must be excluded when clinical presentation doesn't match laboratory values 3

Clinical Manifestations

The relationship between testosterone and symptoms follows a parabolic curve, with optimal levels around 0.4-0.6 ng/mL free testosterone; both low and high levels correlate with depression and reduced well-being. 5

High testosterone may cause:

• Virilization signs: hirsutism, acne, androgenic alopecia 6
• Menstrual irregularities: oligomenorrhea or amenorrhea 3
• Infertility and anovulation 3
• Aggressive behavior and depression 5
• Increased libido 5

Critical pitfall: Some women with extremely elevated testosterone may show selective peripheral tissue response, manifesting infertility and amenorrhea without virilization, which can delay diagnosis of serious conditions like ovarian tumors. 3

Diagnostic Approach

Laboratory Evaluation

When elevated testosterone is suspected:

1. Confirm with repeat testing - spurious elevations occur 3
2. If clinical-laboratory discordance exists, perform diethyl-ether extraction prior to immunoassay to exclude laboratory interference 3
3. Measure total testosterone as first-line test 3
4. Check LH, FSH, and estradiol to characterize hormonal pattern 5

Four-level hormone classification scheme for interpretation: 5

• Low estradiol-low testosterone: osteoporosis, depression, obesity
• High estradiol-low testosterone: obesity, decreased libido
• High testosterone-low estradiol: aggression, depression, increased libido, substance abuse
• High estradiol-high testosterone: type 2 diabetes risk, breast cancer, cardiovascular risk

Imaging

For testosterone levels >2-3 SD above normal with rapid onset or virilization, obtain pelvic ultrasound or MRI to evaluate for ovarian tumors. 3

Treatment Considerations

When Testosterone Reduction is Indicated

For hyperandrogenic states (hirsutism, acne, PCOS), antiandrogenic progestins may be useful in peri- and postmenopausal women. 5

Individual dosing schemes balancing side effects and beneficial effects are absolutely necessary due to substantial interindividual variability in testosterone plasma values. 5

Surgical Management

Ovarian steroid-cell tumors require surgical resection; testosterone levels normalize within 24 hours post-surgery, with menstruation resuming within one month. 3

Important note: Steroid-cell tumors are clinically malignant in 25-43% of cases, requiring appropriate oncologic follow-up. 3

Monitoring Parameters

For women with elevated testosterone being treated:

• Assess for resolution of menstrual irregularities 3
• Monitor for improvement in fertility if desired 3
• Evaluate for regression of virilization signs (though some changes like voice deepening may be irreversible) 6
• Screen for metabolic complications including insulin resistance and cardiovascular risk factors 5

Safety Considerations

Short-term studies up to 2 years show that testosterone at upper normal female range does not increase risk of hepatotoxicity, endometrial hyperplasia, or behavioral hostility. 6

No adverse cardiovascular effects including changes in blood pressure, blood viscosity, arterial vascular reactivity, hypercoagulable states, or polycythemia have been demonstrated in women with physiologic testosterone levels. 6

However, long-term safety data for elevated testosterone in women is lacking, and chronic hyperandrogenic states require ongoing monitoring for metabolic and cardiovascular complications. 6, 5