What oral options (testosterone undecanoate, clomiphene citrate, dehydroepiandrosterone) can be used to treat male hypogonadism, including typical dosing and monitoring requirements?

Oral Medications for Male Hypogonadism

Oral testosterone undecanoate (JATENZO) is the only FDA-approved oral testosterone formulation for male hypogonadism, with typical dosing of 225 mg twice daily, achieving eugonadal testosterone levels in 87% of patients without dose titration. 1, 2

Available Oral Treatment Options

Testosterone Undecanoate (JATENZO)

Dosing and Administration:

• Start at 225 mg twice daily with food 1, 2
• Dose adjustments of 75 mg/dose at weeks 4 and 8 based on serum testosterone levels 1
• Measure testosterone 4-6 hours after morning dose for monitoring 3
• Target mid-normal testosterone range (450-600 ng/dL) 3

Efficacy:

• 87% of patients achieve eugonadal testosterone concentrations (300-1140 ng/dL) 1
• Mean serum testosterone approximately 489-628 ng/dL 2
• Significant improvements in libido, sexual function, lean body mass (+3.2 kg), and bone density 2
• Small but significant improvement in mental health and mood parameters 1

Monitoring Requirements:

• Testosterone levels at 2-3 months, then every 6-12 months once stable 3
• Hematocrit monitoring—withhold if >54% 3
• PSA monitoring in men over 40 years 3
• Blood pressure monitoring (expect 3-5 mmHg systolic increase) 2

Contraindications:

• Active desire for fertility preservation (causes azoospermia) 3
• Active or treated male breast cancer 3
• Hematocrit >54% 3
• Recent cardiovascular events within 3-6 months 3

Clomiphene Citrate (Off-Label)

Mechanism and Indications:

• Stimulates endogenous testosterone production by blocking estrogen feedback 3
• Only effective in secondary hypogonadism (low/low-normal LH and FSH) 3
• Preferred when fertility preservation is desired 4, 3

Dosing:

• 25-50 mg three times per week 3
• Achieves mid-normal testosterone levels (500-600 ng/dL) within 6 weeks in obese secondary hypogonadal men 3

Advantages:

• Preserves or improves spermatogenesis (unlike testosterone therapy) 3
• Effective in obesity-associated secondary hypogonadism 3

Limitations:

• Off-label use; not FDA-approved for male hypogonadism 3
• Ineffective in primary hypogonadism (elevated LH/FSH) 3
• Moderate-quality evidence only 3

DHEA (Dehydroepiandrosterone)

DHEA is NOT recommended for hypogonadism treatment. 3

• Produced by adrenal glands, not testes 3
• Does not aid in diagnosing or treating hypogonadism 3
• Should not be included in diagnostic workup or treatment algorithms 3

Treatment Selection Algorithm

Step 1: Confirm Diagnosis

• Two morning testosterone measurements (8-10 AM) <300 ng/dL 3
• Measure LH and FSH to distinguish primary vs. secondary hypogonadism 3
• Assess for specific symptoms (diminished libido, erectile dysfunction) 3

Step 2: Assess Fertility Desires

• If fertility desired: Use clomiphene citrate (secondary hypogonadism) or gonadotropin therapy 3, 4
• Testosterone therapy is absolutely contraindicated if fertility preservation is a goal 3

Step 3: Choose Formulation

• Oral testosterone undecanoate: Convenient twice-daily dosing, no skin transfer risk 1, 2
• Transdermal gel: More stable levels, lower erythrocytosis risk (15.4% vs 43.8% with injections) 3
• Injectable testosterone: Most economical ($156/year vs $2,135/year for transdermal), but higher erythrocytosis risk 3

Step 4: For Obesity-Associated Hypogonadism

• First attempt weight loss through hypocaloric diet and exercise before initiating testosterone 3
• Consider clomiphene citrate if secondary hypogonadism persists 3

Critical Pitfalls to Avoid

• Never use oral methyltestosterone—severe hepatotoxicity risk with cholestasis, jaundice, and hepatic tumors 5
• Never start testosterone without confirming patient does not desire fertility—causes prolonged azoospermia 3
• Never diagnose hypogonadism on symptoms alone—requires two morning testosterone measurements <300 ng/dL 3
• Never use testosterone in eugonadal men for weight loss, energy, or athletic performance 3
• Do not expect meaningful improvements in physical function, energy, or cognition—testosterone produces only small improvements in sexual function (standardized mean difference 0.35) 3, 1

Expected Outcomes

Proven Benefits:

• Small but significant improvements in sexual function and libido 1, 2
• Modest quality of life improvements, primarily in sexual domains 1
• Improved bone density and lean body mass 2

Minimal or No Benefit:

• Physical functioning, energy, vitality 3
• Depressive symptoms, cognition 3
• Athletic performance or muscle building in eugonadal men 3