What are the treatment options for hypogonadism (low testosterone)?

Treatment Options for Low Testosterone (Hypogonadism)

Transdermal testosterone gel (40.5 mg daily applied to shoulders and upper arms) is the recommended first-line treatment for confirmed hypogonadism, offering stable testosterone levels and ease of use, though intramuscular testosterone injections (50-400 mg every 2-4 weeks) remain a highly effective and more economical alternative. 1, 2

Diagnostic Confirmation Required Before Treatment

Before initiating any testosterone therapy, you must confirm hypogonadism with:

• Two separate morning (8-10 AM) total testosterone measurements below 300 ng/dL 1, 3
• Presence of specific symptoms, particularly diminished libido, erectile dysfunction, or decreased sense of vitality 1
• Measurement of LH and FSH levels to distinguish primary (elevated LH/FSH) from secondary (low/normal LH/FSH) hypogonadism, as this critically impacts treatment selection and fertility preservation 1

Critical pitfall: Never diagnose hypogonadism based on symptoms alone without confirmed biochemical testing, as approximately 20-30% of older men have low-normal testosterone that does not constitute disease requiring treatment. 1

First-Line Treatment Options

Transdermal Testosterone Gel (Preferred Initial Therapy)

Transdermal testosterone gel 1.62% at 40.5 mg daily (2 pump actuations) applied to shoulders and upper arms is the preferred first-line formulation. 1, 2

Advantages:

• Provides stable day-to-day testosterone levels without the peaks and troughs of injections 1, 4
• Easy application with good skin tolerability 4
• Preferred by 71% of patients for convenience, ease of use, and non-staining of clothes 4
• Can be adjusted in 20.25 mg increments based on testosterone levels measured at 14 and 28 days 2

Disadvantages:

• Significantly higher cost: $2,135.32 annually versus $156.24 for intramuscular injections 5, 4
• Risk of secondary transfer to partners or children through skin contact—patients must wash hands immediately after application and cover application sites with clothing 2

Monitoring: Check testosterone levels at 2-3 months, targeting mid-normal range (500-600 ng/dL), then every 6-12 months once stable 1

Intramuscular Testosterone Injections (Cost-Effective Alternative)

Testosterone cypionate or enanthate 50-400 mg administered every 2-4 weeks intramuscularly. 1, 6

Advantages:

• Highly cost-effective at $156.24 annually 5, 4
• Preferred by 53% of patients, primarily due to lower cost 7
• No risk of secondary transfer to others 4

Disadvantages:

• Peak serum levels occur 2-5 days after injection with return to baseline by days 10-14, causing fluctuations in mood and sexual function in some men 1
• Higher risk of erythrocytosis (elevated hematocrit) compared to transdermal preparations 1
• Requires office visits or self-injection training 1

Monitoring: Measure testosterone levels midway between injections, targeting 500-600 ng/dL 1

Testosterone Patches (Alternative Transdermal Option)

Androderm patches applied to back, abdomen, upper thighs, or upper arms provide stable testosterone levels. 4

Advantages:

• Stable day-to-day levels similar to gels 4
• No risk of secondary transfer 4

Disadvantages:

• Potential for skin rash or irritation at application site 4
• Less preferred by patients compared to gels 4

Alternative Treatment for Fertility Preservation

Clomiphene Citrate (Off-Label for Secondary Hypogonadism)

For men with secondary hypogonadism who desire fertility preservation, clomiphene citrate is the preferred alternative as it stimulates endogenous testosterone production without suppressing spermatogenesis. 8

Key indications:

• Men with secondary (hypogonadotropic) hypogonadism with functioning pituitary glands 8
• Men with obesity-related hypogonadism where increased aromatization suppresses LH 8
• Any man actively seeking fertility, as testosterone therapy causes azoospermia 1, 8

Advantages:

• Preserves or improves spermatogenesis 8
• Lower risk of polycythemia compared to testosterone 8
• Achieves similar outcomes for sexual function and quality of life as testosterone 8

Limitations:

• Not FDA-approved for male hypogonadism 8
• Ineffective for primary hypogonadism 8
• Should be switched to testosterone if no response after 3 months 8

Critical contraindication: Never use clomiphene in men with primary testicular failure—check baseline LH and FSH first. 8

Gonadotropin Therapy (For Fertility Restoration)

For men with secondary hypogonadism seeking fertility, recombinant hCG plus FSH is mandatory, and testosterone therapy is absolutely contraindicated. 1

• Combined hCG and FSH therapy provides optimal outcomes for fertility preservation 1
• Testosterone must be discontinued with 2-4 week washout before initiating gonadotropin therapy 1

Expected Treatment Outcomes

Realistic Benefits of Testosterone Therapy

Sexual function improvements:

• Small but significant improvements in sexual function and libido (standardized mean difference 0.35) 5, 1
• Most effective for erectile dysfunction, decreased sex drive, and sexual satisfaction 5

Limited or no benefits:

• Little to no effect on physical functioning, energy, vitality, or cognition in older men 5, 1
• Little to no improvement in depressive symptoms 5, 1
• Small improvements in vitality and fatigue only 5

Metabolic improvements:

• Improvements in fasting plasma glucose, insulin resistance, triglyceride levels, and HDL cholesterol 1
• Potential improvement in bone mineral density 1
• May help correct mild anemia 1

Critical counseling point: Reevaluate symptoms at 12 months and discontinue testosterone if no improvement in sexual function is seen, as continued therapy without benefit exposes patients to unnecessary risks. 1

Absolute Contraindications to Testosterone Therapy

Never initiate testosterone therapy in:

• Men actively seeking fertility preservation (use gonadotropins instead) 1
• Active male breast cancer 1
• Active or treated prostate cancer (though evidence is evolving) 1
• Untreated severe obstructive sleep apnea 1
• Eugonadal men (normal testosterone levels), even if symptomatic 1

Monitoring Requirements During Treatment

Mandatory monitoring parameters:

• Hematocrit: Check periodically and withhold treatment if >54%; consider phlebotomy in high-risk cases 1
• PSA levels: Monitor in men over 40 years; adjust treatment if significant increases occur 1
• Prostate examination: Assess for benign prostatic hyperplasia symptoms 1
• Testosterone levels: At 2-3 months, then every 6-12 months once stable, targeting mid-normal range (500-600 ng/dL) 1

Potential Risks and Side Effects

Common adverse effects:

• Erythrocytosis (elevated hematocrit), particularly with injectable testosterone 1, 6
• Fluid retention and potential worsening of congestive heart failure 6
• Benign prostatic hyperplasia symptoms 1
• Gynecomastia, acne or oily skin 1
• Testicular atrophy and infertility due to suppression of spermatogenesis 1

Serious potential risks:

• Venous thromboembolic events including deep vein thrombosis and pulmonary embolism 6
• Uncertain cardiovascular risk with Peto odds ratio of 1.22 for cardiovascular events 1
• Long-term safety data are lacking, particularly for men aged 18-50 years 1

Treatment Selection Algorithm

Step 1: Confirm diagnosis

• Two morning testosterone levels <300 ng/dL plus specific symptoms 1, 3

Step 2: Assess fertility desires

• If fertility desired → Use clomiphene citrate or gonadotropin therapy (hCG + FSH), NOT testosterone 1, 8
• If fertility not a concern → Proceed to Step 3

Step 3: Choose testosterone formulation based on:

• If cost is primary concern → Intramuscular testosterone cypionate/enanthate 50-400 mg every 2-4 weeks 5, 1
• If convenience and stable levels preferred → Transdermal testosterone gel 1.62% at 40.5 mg daily 1, 4, 2
• If patient refuses injections and cost is not prohibitive → Transdermal gel or patches 4

Step 4: Monitor and adjust

• Check testosterone at 2-3 months, target 500-600 ng/dL 1
• Monitor hematocrit, PSA, and symptoms 1
• Reassess at 12 months; discontinue if no improvement in sexual function 1

Important Clinical Caveats

Discontinuation rates are high (30-62%), suggesting many patients do not find sustained benefit or experience intolerable side effects. 5

Age-related hypogonadism: The FDA has not established safety and efficacy of testosterone therapy in men with "age-related hypogonadism" or "late-onset hypogonadism." 2

Never use testosterone for:

• Weight loss in eugonadal men 1
• Improving cognition, vitality, or physical strength in aging men with normal testosterone 1
• Cardiometabolic improvement in men without confirmed hypogonadism 1