Why would a woman have an elevated serum testosterone of 2.8 ng/mL?

Elevated Testosterone in Women: Differential Diagnosis

A testosterone level of 2.8 ng/mL (280 ng/dL) in a woman is markedly elevated—approximately 10-fold higher than the upper limit of normal—and demands urgent investigation for an androgen-secreting tumor, particularly an ovarian steroid cell tumor, as this level far exceeds what is seen even in severe hyperandrogenic conditions like PCOS.

Understanding Normal Testosterone Ranges in Women

The normal testosterone range in healthy premenopausal women is quite narrow and substantially lower than what is reported in this case:

• Normal range: 15-46 ng/dL (0.15-0.46 ng/mL) for a typical 30-year-old woman, with the 95th percentile at approximately 46 ng/dL 1
• Upper limit of normal: Approximately 28 ng/dL (0.28 ng/mL) based on mean + 2 standard deviations in women without hyperandrogenic signs 2
• Bimodal distribution: Healthy women have testosterone levels of 0.4-2.0 nmol/L (approximately 11-58 ng/dL), while healthy men range from 8.8-30.9 nmol/L, with the lower male range being 4-5 fold higher than the upper female range 3

Your patient's level of 2.8 ng/mL (280 ng/dL) is approximately 6-10 times the upper limit of normal for women.

Differential Diagnosis by Testosterone Level

Very High Testosterone (>200 ng/dL or >2-3 SD above normal)

This patient falls into this category and requires immediate evaluation for:

• Ovarian steroid cell tumor (SCT): These rare sex cord-stromal tumors actively secrete androgens and are clinically malignant in 25-43% of cases 4
• Other androgen-secreting tumors: Ovarian or adrenal neoplasms 4, 5

Moderate Elevation (50-200 ng/dL)

• Severe hirsutism: Mean testosterone 49.0 ng/dL 2
• Congenital adrenal hyperplasia: Levels above normal female range but below male range 3

Mild Elevation (28-50 ng/dL)

• Mild hirsutism: Mean testosterone 38.4 ng/dL 2
• Polycystic ovary syndrome (PCOS): Levels above normal female range but still well below male range 3
• Menstrual dysfunction alone: Mean testosterone 17.9 ng/dL 2

Critical Diagnostic Pitfalls

Laboratory Interference Must Be Excluded First

Before pursuing invasive workup, verify the result is not due to laboratory interference:

• Repeat testosterone measurement after diethyl-ether extraction prior to immunoassay to eliminate interfering substances 4
• Some women can have extremely elevated testosterone levels without virilization signs due to selective peripheral tissue response, but laboratory interference is more common 4
• Commercial laboratory reference ranges (often listing upper limits of 95 ng/dL) are inappropriately high and miss most cases of hyperandrogenemia 2

Clinical Presentation May Not Match Laboratory Values

Importantly, very high testosterone levels do not always cause virilization:

• A documented case exists of a woman with testosterone >200 ng/dL from an ovarian SCT who had no virilization signs, only secondary amenorrhea and infertility 4
• This reflects selective peripheral target-tissue response to androgens 4
• Do not dismiss markedly elevated testosterone simply because virilization is absent

Immediate Workup Algorithm

1. Confirm the result: Repeat testosterone with diethyl-ether extraction if available 4

2. Assess for rapid virilization: Deepening voice, clitoromegaly, male-pattern baldness, increased muscle mass (though may be absent) 4

3. Pelvic imaging: Transvaginal ultrasound or pelvic MRI to evaluate for ovarian masses 4

4. Additional hormones:

   • DHEAS to assess adrenal contribution 2, 5
   • LH and FSH 5
   • 17-hydroxyprogesterone if congenital adrenal hyperplasia suspected 5

5. Adrenal imaging: CT abdomen if DHEAS markedly elevated or no ovarian source identified 5

Other Causes of Testosterone Elevation (Less Likely at This Level)

• Iatrogenic: Testosterone therapy (gel, patch, injection) - verify medication history 6, 7
• Exogenous androgen exposure: Supplements, partner's testosterone gel transfer 7
• Oophorectomy/adrenalectomy: Causes deficiency, not elevation 5
• Premature ovarian failure, Turner's syndrome: Associated with low testosterone 5

Expected Post-Treatment Response

If an androgen-secreting tumor is identified and resected:

• Testosterone should normalize within 24 hours post-surgery 4
• Menstruation typically resumes within one month 4
• This rapid normalization confirms the tumor as the source 4