Oral Testosterone Therapy for Hypogonadism: Critical Considerations
Oral testosterone undecanoate is FDA-approved for hypogonadism but carries a black box warning for blood pressure increases and cardiovascular risk, making it a second- or third-line option reserved for patients who cannot tolerate or refuse transdermal or injectable formulations. 1
FDA-Approved Oral Formulations and Their Limitations
Testosterone undecanoate capsules (JATENZO, TLANDO) are the only FDA-approved oral testosterone formulations available in the United States, using self-emulsifying drug delivery systems and lymphatic absorption to avoid first-pass hepatic metabolism 1, 2
The FDA explicitly contraindicates oral testosterone undecanoate for "age-related hypogonadism" not associated with structural or genetic etiologies due to cardiovascular risks 1
Oral testosterone undecanoate carries a black box warning for blood pressure increases that can elevate the risk of major adverse cardiovascular events (MACE), including non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death 1
Dosing requires twice-daily administration with food (starting dose 200 mg twice daily), with serum testosterone monitoring 7 days after initiation and dose adjustments ranging from 100 mg once daily to 400 mg twice daily 1
Why Oral Testosterone Is Not First-Line Therapy
Transdermal testosterone gel is recommended as first-line therapy by the European Association of Urology, starting at 40.5 mg daily, due to stable day-to-day testosterone levels and lower risk of erythrocytosis (3-18% vs up to 44% with injections) 3, 4
Intramuscular testosterone (cypionate or enanthate) is preferred over oral formulations when cost is a concern, with annual costs of $156.24 for injections versus $2,135.32 for transdermal preparations, and oral formulations likely falling in the higher cost range 3, 4, 5
Injectable testosterone provides similar clinical effectiveness to oral formulations with small but significant improvements in sexual function (standardized mean difference 0.35) and quality of life 6, 3
Diagnostic Requirements Before Any Testosterone Therapy
Two separate morning total testosterone measurements below 300 ng/dL (drawn between 8 AM and 10 AM) are required to establish biochemical hypogonadism before initiating any testosterone formulation 3, 7
Measure serum LH and FSH after confirming low testosterone to distinguish primary (elevated LH/FSH) from secondary (low or low-normal LH/FSH) hypogonadism, which has critical treatment implications including fertility preservation 3, 7
The primary indication for testosterone therapy is diminished libido and sexual dysfunction, not fatigue, energy, physical function, or cognition, where testosterone produces minimal to no benefit 6, 3, 5
Absolute Contraindications to Oral Testosterone
Carcinoma of the breast or known/suspected prostate cancer 1
Pregnancy (testosterone causes virilization of female fetus) 1
Active desire for fertility preservation (testosterone suppresses spermatogenesis; use gonadotropin therapy instead) 3
Untreated severe obstructive sleep apnea 3
Pre-Treatment Safety Screening for Oral Testosterone
Document baseline blood pressure and ensure adequate control before initiating oral testosterone undecanoate due to black box warning for BP increases 1
Measure baseline hematocrit or hemoglobin to monitor for erythrocytosis during treatment 3, 7
Perform digital rectal examination and measure PSA in men over 40 years, with PSA >4.0 ng/mL requiring urologic evaluation and documented negative prostate biopsy before initiating therapy 3, 7
Assess cardiovascular risk factors and established cardiovascular disease, as oral testosterone increases MACE risk in these populations 1
Monitoring Requirements for Oral Testosterone
Check serum testosterone 7 days after starting treatment or dosage adjustment, 3-5 hours after the morning dose, targeting mid-normal values (500-600 ng/dL) 3, 1
Monitor blood pressure periodically and treat new-onset hypertension or exacerbations of pre-existing hypertension 1
Monitor hematocrit periodically and withhold treatment if >54%, considering phlebotomy in high-risk cases 3
Monitor PSA levels in men over 40 years, with urologic referral for biopsy if PSA increases >1.0 ng/mL during the first 6 months or >0.4 ng/mL per year thereafter 3
Re-evaluate symptoms at 12 months and discontinue testosterone if no improvement in sexual function, to prevent unnecessary long-term exposure to cardiovascular risks without benefit 3
Clinical Algorithm for Formulation Selection
Step 1: Confirm biochemical hypogonadism (two morning testosterone <300 ng/dL) and presence of diminished libido or erectile dysfunction 3, 5
Step 2: Assess cardiovascular risk factors and blood pressure control—if significant cardiovascular disease or uncontrolled hypertension, oral testosterone is relatively contraindicated 1
Step 3: If patient refuses injections and cannot tolerate transdermal preparations (skin irritation, transfer concerns), consider oral testosterone undecanoate as second-line option 1, 2
Step 4: If cost is a primary concern, intramuscular testosterone (100-200 mg every 2 weeks) is more economical than oral formulations 3, 4, 5
Step 5: If patient desires fertility preservation, testosterone therapy (any formulation) is absolutely contraindicated—use gonadotropin therapy (hCG plus FSH) instead 3
Expected Treatment Outcomes with Oral Testosterone
Small but significant improvements in sexual function and libido (standardized mean difference 0.35) 6, 3
Little to no effect on physical functioning, energy, vitality, or cognition, even in confirmed hypogonadism 6, 3, 5
Minimal improvements in depressive symptoms (standardized mean difference -0.19), though most men in studies did not have baseline depression 6
Potential improvements in fasting plasma glucose, insulin resistance, triglyceride levels, and HDL cholesterol 3
Common Pitfalls to Avoid
Never prescribe oral testosterone based on symptoms alone without confirmed biochemical hypogonadism (two measurements below 300 ng/dL)—approximately 20-30% of men receiving testosterone in the United States violate this guideline 3, 5
Never start oral testosterone without confirming the patient does not desire fertility, as testosterone causes prolonged azoospermia 3
Never use oral testosterone in men with "age-related hypogonadism" without structural or genetic etiologies, as this is an FDA contraindication due to cardiovascular risks 1
Never assume oral testosterone is equivalent to transdermal or injectable formulations in safety profile—the black box warning for blood pressure increases is unique to oral testosterone undecanoate 1