How should I evaluate and manage a 54-year-old man with borderline low total testosterone, low‑normal free testosterone, and mildly elevated prolactin?

Evaluation and Management of Borderline Hypogonadism with Mild Hyperprolactinemia

This patient requires immediate pituitary MRI and prolactin-lowering therapy with cabergoline before considering testosterone replacement, as his prolactin-to-testosterone ratio of 0.062 (20.1÷322) and clinical presentation suggest possible prolactinoma despite "normal-range" testosterone.

Diagnostic Interpretation

Understanding the Hormonal Pattern

• The total testosterone of 322 ng/dL sits just above the diagnostic threshold of 300 ng/dL, but this single borderline value does not exclude hypogonadism—repeat morning measurement (8-10 AM) is mandatory to confirm persistent levels below 300 ng/dL on two separate occasions. 1, 2

• The free testosterone of 7.1 pg/mL is frankly low (normal range typically 50-200 pg/mL), creating a discordance with the borderline-low total testosterone that strongly suggests true biochemical hypogonadism. 1, 3

• The prolactin of 20.1 ng/mL exceeds the upper limit of normal (typically 15 ng/mL in men) and represents mild hyperprolactinemia that can suppress gonadotropin secretion and testosterone production. 4, 5

Critical Red Flag: Prolactin-to-Testosterone Ratio

• The prolactin-to-testosterone ratio of 0.062 (20.1÷322) approaches the 0.10 threshold that predicts pituitary abnormalities with 90% sensitivity in hypogonadal men with mild hyperprolactinemia (15.1-50 ng/mL). 6

• Men with prolactinomas can present with testosterone levels in the "normal range" (≥260 ng/dL) yet still experience hypogonadal symptoms—in one series, 55% of such men had symptoms despite testosterone levels averaging 391 ng/dL. 7

• Pituitary MRI is indicated immediately because the combination of borderline-low testosterone, low free testosterone, and elevated prolactin carries a 28% probability of demonstrating a pituitary abnormality. 6

Required Diagnostic Workup

Immediate Laboratory Tests

• Repeat morning total testosterone (8-10 AM) on a second occasion to confirm persistent hypogonadism, as single measurements are insufficient due to diurnal variation and assay variability. 1, 2

• Measure LH and FSH to distinguish primary (elevated gonadotropins) from secondary (low or low-normal gonadotropins) hypogonadism—this distinction is mandatory before initiating any treatment. 1, 4, 2

• Confirm free testosterone by equilibrium dialysis (gold standard) or calculated free testosterone using the Vermeulen formula, as direct immunoassays are unreliable. 1, 3

• Measure sex hormone-binding globulin (SHBG) to interpret the discordance between borderline total testosterone and low free testosterone. 1, 2

Pituitary Imaging

• Order pituitary MRI with gadolinium contrast immediately, as the prolactin-to-testosterone ratio of 0.062 and clinical presentation warrant imaging regardless of whether testosterone falls definitively below 300 ng/dL on repeat testing. 6

• The 28% prevalence of pituitary abnormalities in this clinical scenario justifies upfront imaging rather than empiric testosterone therapy. 6

Treatment Algorithm

If Pituitary MRI Shows Prolactinoma or Microadenoma

First-line therapy is cabergoline, not testosterone replacement:

• Initiate cabergoline 0.25-0.5 mg twice weekly to lower prolactin and restore the hypothalamic-pituitary-gonadal axis. 7, 8, 5

• Cabergoline normalizes testosterone in 83% of men with prolactinomas, increasing levels by an average of 2.5 ng/dL (250 ng/dL) within 8-12 weeks. 7

• In men with baseline testosterone 260-520 ng/dL and prolactinomas, cabergoline increased testosterone from 391 to 642 ng/dL (Δ = 251 ng/dL) and resolved hypogonadal symptoms in 83% of cases. 7

• Testosterone therapy is contraindicated until prolactin is controlled, as exogenous testosterone will suppress LH/FSH and worsen the underlying pituitary dysfunction. 1, 5

If Pituitary MRI is Normal

Proceed with standard hypogonadism evaluation:

• If repeat morning testosterone remains <300 ng/dL on two occasions AND LH/FSH are low or low-normal, diagnose secondary (hypogonadotropic) hypogonadism. 1, 4, 2

• Address the mild hyperprolactinemia (prolactin 20.1 ng/mL) even without a visible adenoma, as functional hyperprolactinemia can suppress gonadotropins—consider a trial of cabergoline 0.25 mg twice weekly. 7, 8

• If testosterone normalizes with prolactin lowering, continue cabergoline and monitor; testosterone replacement becomes unnecessary. 7, 8

• If testosterone remains <300 ng/dL despite normalized prolactin, proceed with testosterone replacement therapy only after confirming the patient does not desire fertility. 1, 5

Fertility Considerations

Absolute Contraindication to Testosterone Therapy

• Never initiate testosterone replacement without first confirming the patient does not desire fertility, as exogenous testosterone suppresses spermatogenesis and causes prolonged, potentially irreversible azoospermia. 1, 5

• If fertility is desired or uncertain, use gonadotropin therapy (hCG plus FSH) to stimulate endogenous testosterone production and preserve spermatogenesis. 1, 4

• Cabergoline preserves fertility while normalizing testosterone in men with hyperprolactinemia, making it the preferred initial approach. 7, 8

Testosterone Replacement (If Indicated After Above Workup)

When to Initiate Testosterone Therapy

• Testosterone replacement is appropriate only if:
  1. Repeat morning testosterone <300 ng/dL on two occasions 1, 2
  2. Prolactin is normalized (either spontaneously or with cabergoline) 7, 5
  3. Pituitary MRI excludes adenoma or other pathology 6, 5
  4. Patient does not desire fertility 1, 5
  5. Specific symptoms are present: diminished libido and erectile dysfunction 1, 2

Expected Outcomes

• Testosterone therapy produces small but significant improvements in sexual function (standardized mean difference 0.35) and modest quality of life improvements, primarily in sexual domains. 1

• Testosterone therapy provides little to no benefit for physical functioning, energy, vitality, depressive symptoms, or cognition, even in confirmed hypogonadism. 1, 2

• Reevaluate at 12 months and discontinue testosterone if no improvement in sexual function, as continued therapy without benefit exposes the patient to unnecessary risks. 1

Preferred Formulation

• Transdermal testosterone gel 1.62% at 40.5 mg daily is first-line, providing stable day-to-day levels and lower erythrocytosis risk (15.4%) compared to injectable testosterone (43.8%). 1

• Target mid-normal testosterone levels (500-600 ng/dL) during treatment. 1, 2

Monitoring Requirements

• Hematocrit at baseline, 2-3 months, then every 6-12 months—withhold therapy if >54% and consider phlebotomy. 1, 2

• PSA at baseline and periodically in men over 40 years—refer for urologic evaluation if PSA increases >1.0 ng/mL in first 6 months or >0.4 ng/mL per year thereafter. 1, 2

• Testosterone levels at 2-3 months after initiation, then every 6-12 months once stable. 1, 2

Critical Pitfalls to Avoid

• Never start testosterone without first obtaining pituitary MRI in a patient with elevated prolactin and borderline-low testosterone, as this can mask a prolactinoma and delay appropriate treatment. 6, 5

• Never diagnose hypogonadism on a single testosterone measurement—two morning values are required due to diurnal variation and assay variability. 1, 2

• Never omit LH/FSH testing once low testosterone is confirmed, as the distinction between primary and secondary hypogonadism fundamentally changes management and fertility counseling. 1, 4, 2

• Never initiate testosterone without confirming the patient does not desire fertility, as this causes irreversible suppression of spermatogenesis. 1, 5

• Never expect meaningful improvements in energy, physical function, or mood from testosterone therapy—these are not evidence-based indications. 1, 2