What causes elevated testosterone levels?

Causes of Elevated Testosterone

Elevated testosterone levels can result from various pathological conditions including androgen-secreting tumors of the adrenal glands or ovaries, congenital adrenal hyperplasia, and exogenous testosterone administration. Understanding the etiology is crucial for proper management and preventing potential complications.

Pathological Causes

Androgen-Secreting Tumors

• Adrenal tumors:

  • Adrenocortical adenomas can secrete pure testosterone, though this is extremely rare 1
  • These tumors may not elevate other adrenal androgens like DHEAS or androstenedione 1
  • Can respond to gonadotropin stimulation in some cases 2

• Ovarian tumors:

  • Hilar cell tumors
  • Ovarian stromal tumors
  • Often present with rapidly progressive virilization, particularly in postmenopausal women 3

Congenital Adrenal Hyperplasia (CAH)

• Most commonly due to 21-hydroxylase deficiency (CYP21A2 gene mutations) 4
• Leads to accumulation of 17-hydroxyprogesterone (17OHP) which is converted to androgens
• Involves multiple pathways:
  • Conventional pathway: 17OHP → androstenedione → testosterone → DHT
  • Backdoor pathway: 17OHP → DHT (bypassing testosterone)
  • 11-oxyandrogens pathway: androstenedione → 11β-hydroxyandrostenedione → 11-ketotestosterone 4

Polycystic Ovary Syndrome (PCOS)

• Most common cause of hyperandrogenism in women of reproductive age
• Characterized by hyperandrogenemia, oligo/anovulation, and polycystic ovaries
• Testosterone levels are typically elevated but usually not as high as with androgen-secreting tumors 3

Iatrogenic Causes

Exogenous Testosterone Administration

• Testosterone replacement therapy
• Anabolic steroid use
• Gender-affirming hormone therapy

Diagnostic Approach

Laboratory Assessment

1. Total testosterone measurement:

   • Values >8.7 nmol/L (250 ng/dL) in women warrant further investigation 3
   • Consider free testosterone measurement as it represents the metabolically active fraction 5

2. Additional hormone testing:

   • DHEAS (adrenal androgen marker)
   • Androstenedione
   • 17-hydroxyprogesterone (for CAH)
   • LH/FSH (to assess gonadal axis)
   • Prolactin (elevated levels may indicate pituitary tumors) 6

Imaging Studies

• Adrenal imaging: CT scan or MRI for suspected adrenal tumors
• Ovarian imaging: Transvaginal ultrasound for ovarian pathology
• Pituitary MRI: If hyperprolactinemia is present 6

Clinical Pearls and Pitfalls

Important Considerations

• The source identification of hyperandrogenemia based solely on testosterone, DHEAS, and androstenedione levels is limited 1
• Normal DHEAS does not rule out an adrenal source of testosterone excess 1
• Evaluate both ovaries and adrenal glands in women with virilization, particularly during menopause 1

Warning Signs for Neoplasms

• Rapid onset and progression of virilization
• Very high testosterone levels (>250 ng/dL in women)
• Postmenopausal presentation of new-onset hyperandrogenism

Monitoring Testosterone Levels

• In patients on testosterone therapy, regular monitoring is essential:
  • Hemoglobin/hematocrit: Baseline and every 3-6 months initially, then annually 7
  • PSA (in men >40 years): Baseline and every 3-6 months for the first year, then annually 7
  • Intervention is required if hematocrit exceeds 54% (dose reduction or temporary discontinuation) 7

By systematically evaluating patients with elevated testosterone using appropriate laboratory and imaging studies, clinicians can identify the underlying cause and implement appropriate management strategies to prevent complications related to hyperandrogenism.