My free testosterone is low on three separate morning labs while I’m taking an SSRI; what are the next steps to evaluate and treat?

Evaluation and Management of Confirmed Low Free Testosterone

Immediate Next Steps

When free testosterone is confirmed low on three separate morning measurements while taking an SSRI, you must first repeat total testosterone on two separate mornings (8–10 AM) to establish whether true biochemical hypogonadism exists, then measure LH and FSH to differentiate primary from secondary hypogonadism—this distinction is critical because it determines both treatment approach and fertility preservation options. 1, 2, 3

Diagnostic Algorithm

Step 1: Confirm Biochemical Hypogonadism

• Obtain two separate fasting morning total testosterone measurements (8–10 AM) using a liquid chromatography-tandem mass spectrometry assay certified by the CDC Hormone Standardization Program 4, 5
• Diagnosis requires both values < 300 ng/dL to establish true hypogonadism 1, 2, 3
• If total testosterone is 231–346 ng/dL (gray zone), proceed with free testosterone by equilibrium dialysis and calculate the free androgen index (total testosterone ÷ SHBG × 100); an FAI < 30 confirms true hypogonadism 1, 3

Step 2: Differentiate Primary vs. Secondary Hypogonadism

• Measure serum LH and FSH immediately after confirming low testosterone 1, 2, 3
• Low or inappropriately normal LH/FSH = secondary (hypothalamic-pituitary) hypogonadism 1, 2
• Elevated LH/FSH = primary (testicular) hypogonadism 1, 2
• This distinction has critical treatment implications: secondary hypogonadism can be treated with gonadotropin therapy to preserve fertility, whereas primary hypogonadism requires testosterone replacement which permanently suppresses spermatogenesis 1

Step 3: Complete Secondary Hypogonadism Workup (if LH/FSH are low-normal)

• Measure serum prolactin to screen for hyperprolactinemia 1, 3
• If prolactin > 1.5 × upper limit of normal, order pituitary MRI 1
• If testosterone < 150 ng/dL with LH/FSH < 1.5 IU/L, order pituitary MRI regardless of prolactin level 1
• Assess for reversible causes: obesity (BMI, waist circumference), metabolic syndrome (fasting glucose, HbA1c, lipid profile), hemochromatosis (iron saturation, ferritin), chronic systemic illness 1, 2

Step 4: Document Qualifying Symptoms

Testosterone therapy is justified only for diminished libido and erectile dysfunction—these are the only symptoms with proven responsiveness to treatment. 1, 6

• Fatigue, low energy, depressed mood, poor concentration, and reduced physical strength show minimal correlation with testosterone levels and do not improve reliably with replacement therapy 1
• Even in confirmed hypogonadism, testosterone produces little to no effect on energy (SMD 0.17), physical functioning, depressive symptoms (SMD -0.19), or cognition 1

SSRI-Specific Considerations

SSRIs can independently cause sexual dysfunction and may lower testosterone levels through multiple mechanisms, but this does not automatically justify testosterone therapy. 7

• One small study (n=5) showed dramatic improvement in SSRI-refractory depression with testosterone augmentation in hypogonadal men (mean testosterone 277 ng/dL), with HAM-D scores dropping from 19.2 to 4.0 by week 8 7
• However, this evidence is very limited (open-label, no control group) and should not drive treatment decisions in the absence of sexual symptoms 7
• If your primary complaints are fatigue and mood rather than sexual dysfunction, testosterone therapy is not indicated even with confirmed low levels 1

Treatment Decision Algorithm

If You Desire Fertility Preservation:

• Testosterone replacement is absolutely contraindicated because it causes prolonged, potentially irreversible azoospermia 1, 3
• For secondary hypogonadism: use gonadotropin therapy (recombinant hCG plus FSH) to restore both testosterone production and spermatogenesis 1
• For primary hypogonadism: testosterone replacement is the only option, but you must accept permanent fertility compromise 1

If Fertility is Not a Concern AND You Have Sexual Symptoms:

Transdermal testosterone gel 1.62% at 40.5 mg daily is the preferred first-line formulation because it produces stable day-to-day testosterone levels and carries a lower risk of erythrocytosis (15.4%) compared with injectable testosterone (43.8%). 1, 8

• Apply to clean, dry, intact skin of shoulders and upper arms once daily in the morning 8
• Wash hands immediately with soap and water after application 8
• Cover application site with clothing after gel dries 8
• Alternative: intramuscular testosterone cypionate/enanthate 100–200 mg every 2 weeks is more economical ($156/year vs. $2,135/year for gel) but has higher erythrocytosis risk 1

If You Have Only Non-Sexual Symptoms (Fatigue, Mood, Energy):

Do not initiate testosterone therapy, even with confirmed low levels, because the evidence shows no meaningful benefit for these symptoms. 1

• Expected improvement in fatigue/energy is negligible (SMD 0.17) 1
• Depressive symptoms show less-than-small improvement (SMD -0.19) 1
• Physical functioning and cognition are unaffected 1
• Consider addressing the SSRI itself or other reversible causes of your symptoms 1

Pre-Treatment Requirements

Before starting testosterone, you must complete:

• Baseline hematocrit/hemoglobin (absolute contraindication if > 54%) 1
• PSA for men > 40 years (PSA > 4.0 ng/mL requires urologic evaluation and negative prostate biopsy) 1
• Digital rectal examination to assess for prostate abnormalities 1
• Confirm you do not desire fertility 1

Monitoring Schedule

• 2–3 months after initiation: measure testosterone (midway between injections for injectables), hematocrit, PSA 1, 8
• Every 3–6 months during first year: repeat testosterone, hematocrit, PSA, lipid profile, digital rectal exam 1
• Annually thereafter once stable 1
• Withhold treatment if hematocrit > 54% and consider phlebotomy in high-risk cases 1
• Refer to urology if PSA rises > 1.0 ng/mL in first 6 months or > 0.4 ng/mL per year thereafter 1

Expected Outcomes

Set realistic expectations: testosterone therapy produces only small improvements in sexual function (SMD 0.35) with no meaningful benefit for energy, mood, physical function, or cognition. 1

• If sexual function does not improve after 12 months, discontinue therapy to avoid unnecessary long-term exposure to potential risks 1
• Quality-of-life improvements are modest and confined to sexual function domains 1

Critical Pitfalls to Avoid

• Never diagnose hypogonadism on symptoms alone or a single testosterone measurement 1, 2, 3
• Never skip LH/FSH testing after confirming low testosterone—this distinction guides treatment and fertility counseling 1, 2, 3
• Never initiate testosterone without confirming the patient does not desire fertility 1, 3
• Never prescribe testosterone for weight loss, energy enhancement, or athletic performance—these are not evidence-based indications 1
• Never assume the SSRI is irrelevant—consider whether switching or discontinuing the SSRI might address both sexual and mood symptoms without testosterone 7