What is the treatment for low testosterone (hypogonadism)?

Treatment for Low Testosterone (Hypogonadism)

Testosterone replacement therapy (TRT) is the first-line treatment for confirmed male hypogonadism, with transdermal testosterone gel (40.5 mg daily) preferred over intramuscular injections due to more stable day-to-day levels, though intramuscular testosterone cypionate (50-400 mg every 2-4 weeks) remains a cost-effective alternative. 1, 2

Diagnostic Confirmation Required Before Treatment

You must confirm both biochemical hypogonadism AND specific symptoms before initiating therapy:

• Measure morning total testosterone (8-10 AM) on two separate occasions, with levels <300 ng/dL establishing hypogonadism 1, 3
• Measure free testosterone by equilibrium dialysis in men with obesity or borderline total testosterone 1
• Measure LH and FSH to distinguish primary (testicular) from secondary (pituitary-hypothalamic) hypogonadism, as this critically determines treatment options 1, 3
• Primary symptoms justifying treatment are diminished libido and erectile dysfunction—not fatigue, low energy, or mood complaints 1, 4

The European Association of Urology explicitly warns against using symptoms or screening questionnaires alone without confirmed biochemical hypogonadism 1

Treatment Selection Algorithm

First-Line: Transdermal Testosterone Gel

• Start with transdermal testosterone gel 1.62% at 40.5 mg daily for most patients with confirmed hypogonadism 1
• Provides more stable day-to-day testosterone levels compared to injections 1
• Lower risk of erythrocytosis than injectable formulations 1
• Annual cost approximately $2,135 1

Alternative: Intramuscular Testosterone Cypionate

• Use testosterone cypionate 50-400 mg IM every 2-4 weeks when cost is a primary concern 1, 2
• Annual cost approximately $156, making it significantly more economical 1
• Peak levels occur 2-5 days post-injection, returning to baseline by days 10-14 1
• Measure testosterone levels midway between injections, targeting mid-normal range (500-600 ng/dL) 1
• Higher risk of erythrocytosis compared to transdermal preparations 1

Special Consideration: Clomiphene Citrate for Fertility Preservation

• Use clomiphene citrate instead of testosterone in men with secondary hypogonadism who desire fertility preservation 5, 6
• Stimulates endogenous testosterone production without suppressing spermatogenesis 5
• Particularly valuable for obesity-related hypogonadism where increased aromatization suppresses LH 5
• Not FDA-approved for male hypogonadism and ineffective for primary hypogonadism 5
• Switch to testosterone replacement if no response after 3 months 5

Alternative for Secondary Hypogonadism with Fertility Goals: Gonadotropin Therapy

• Use recombinant hCG plus FSH for men with secondary hypogonadism actively seeking fertility 1
• Testosterone therapy is absolutely contraindicated in men seeking fertility, as it causes azoospermia 1, 6

Expected Treatment Outcomes

Set realistic expectations with patients:

• Small but significant improvements in sexual function and libido (standardized mean difference 0.35) 1, 3
• Little to no effect on physical functioning, energy, vitality, or cognition, even in confirmed hypogonadism 1
• Minimal improvements in depressive symptoms (SMD -0.19) 1
• Modest improvements in metabolic parameters: fasting glucose, insulin resistance, triglycerides, and HDL cholesterol 1
• Improved bone mineral density in older men 1, 7

The American College of Physicians recommends discontinuing treatment if no improvement in sexual function occurs after 12 months 1

Monitoring Requirements

Initial Monitoring (First 2-3 Months)

• Check testosterone levels 2-3 months after treatment initiation or after any dose change 1
• For injectable testosterone, measure midway between injections 1

Long-Term Monitoring (Every 6-12 Months)

• Hematocrit monitoring: withhold treatment if >54% and consider phlebotomy in high-risk cases 1, 3
• PSA levels in men over 40 years, adjusting treatment if significant increases occur 1, 3
• Prostate examination to assess for benign prostatic hyperplasia symptoms 1
• Testosterone levels to ensure mid-normal range 1

Absolute Contraindications

Do not initiate testosterone therapy in:

• Men actively seeking fertility—use gonadotropins (hCG plus FSH) instead 1, 2
• Active or treated male breast cancer 1, 3
• Active or untreated prostate cancer 1, 3
• Erythrocytosis (hematocrit >50%) 3
• Untreated severe obstructive sleep apnea 1, 3
• Severe lower urinary tract symptoms (IPSS >19) 3
• Class III or IV heart failure 3
• Eugonadal men (normal testosterone levels), even if symptomatic—the European Association of Urology strongly recommends against this practice 1

Critical Pitfalls to Avoid

• Never diagnose hypogonadism based on symptoms alone—approximately 20-30% of men receiving testosterone in the U.S. lack documented low testosterone before treatment 1
• Never start testosterone without confirming the patient does not desire fertility, as it permanently compromises fertility during treatment 1
• Never attempt to diagnose primary vs. secondary hypogonadism while the patient is on testosterone therapy—gonadotropin levels will be misleadingly suppressed 1
• Never use testosterone for weight loss, muscle building in eugonadal men, or age-related decline without confirmed biochemical hypogonadism 1
• Never skip investigation for reversible causes in secondary hypogonadism (obesity, sleep apnea, medications, pituitary lesions) 1

Non-Pharmacological Interventions

Before or alongside pharmacological treatment:

• Weight loss through low-calorie diets can improve testosterone levels in men with obesity-associated secondary hypogonadism 1
• Regular physical activity and exercise should be encouraged 1
• Address reversible causes: sleep disorders, thyroid dysfunction, anemia, vitamin D deficiency, metabolic syndrome 1