What is the recommended treatment for hypogonadism with low testosterone levels?

Testosterone Treatment for Hypogonadism

Testosterone replacement therapy is indicated for men with confirmed hypogonadism, specifically those with primary hypogonadism (testicular failure) or secondary hypogonadism (pituitary-hypothalamic dysfunction), and should be initiated when morning free testosterone is frankly low on at least two separate assessments. 1, 2

Diagnosis and Evaluation

Before initiating treatment, proper diagnosis is essential:

• Measure morning total testosterone concentration between 8 AM and 10 AM on at least two separate days 2
• Measure free testosterone by equilibrium dialysis and sex hormone-binding globulin level, especially in obese patients 2
• If testosterone levels are low, measure luteinizing hormone (LH) and follicle-stimulating hormone (FSH) to distinguish between:
  • Primary hypogonadism: Low testosterone with elevated LH/FSH
  • Secondary hypogonadism: Low testosterone with normal/low LH/FSH 2, 1

For secondary hypogonadism, further evaluation may include:

• Serum prolactin and iron saturation
• Pituitary function testing
• MRI of the sella turcica to identify potential causes 2

Treatment Options

Transdermal Preparations (First-line)

• Testosterone gel (1% or 1.62%):

  • Apply daily to shoulders and upper arms (not abdomen or genitals)
  • Starting dose: 40.5 mg daily (for 1.62% gel)
  • Advantages: Stable testosterone levels, convenient, preferred by many patients 2, 1
  • Caution: Risk of transfer to others through skin contact 1

• Testosterone patches:

  • Apply daily to non-scrotal skin
  • Disadvantages: Skin irritation, adhesion issues 2

Injectable Preparations

• Testosterone enanthate or cypionate:

  • Typically administered every 1-2 weeks
  • Advantages: Lower cost ($156.24 vs $2135.32 annually for transdermal) 2
  • Disadvantages: Fluctuating testosterone levels, injection discomfort 2

• Testosterone undecanoate injections:

  • Administered every 10-14 weeks
  • Advantages: Fewer injections, more stable levels 3

Other Formulations

• Implantable testosterone pellets
• Buccal and nasal preparations 4

Monitoring and Dose Adjustment

• Check testosterone levels 2-3 months after treatment initiation or dose change 2
• For transdermal preparations: Target normal range (300-800 ng/dL)
• For injections: Measure midway between injections, targeting mid-normal range (500-600 ng/dL) 2
• Once stable, monitor every 6-12 months 2
• Adjust dose based on pre-dose morning testosterone levels:

  • 750 ng/dL: Decrease dose

  • 350-750 ng/dL: Maintain dose
  • <350 ng/dL: Increase dose 1

Benefits and Limitations

Testosterone therapy has shown benefits for:

• Sexual function and quality of life (small improvements) 2
• Improvements in body composition (increased lean mass, decreased fat mass) 2
• Metabolic parameters in men with obesity and hypogonadism 2

However, evidence shows limited or no benefit for:

• Physical functioning
• Depressive symptoms (unless depression is present at baseline)
• Energy and vitality
• Cognitive function 2

Safety Considerations

• Long-term safety data is limited 2
• Observational studies show no increased risk for mortality, cardiovascular events, prostate cancer, or venous thromboembolism 2
• Most studies excluded men with recent cardiovascular disease 2
• Monitor for potential adverse effects including polycythemia, sleep apnea exacerbation, and prostate changes

Important Caveats

• FDA approval is specifically for primary or secondary hypogonadism, not for "age-related hypogonadism" 1
• Many men receive testosterone without proper testing or for non-specific symptoms 2
• Testosterone use has tripled in recent years, often exceeding appropriate indications 2
• Treatment discontinuation rates range from 30-62%, suggesting variable satisfaction 2

Clinical Pitfalls to Avoid

1. Treating without confirming low testosterone on at least two morning measurements
2. Failing to measure free testosterone in obese patients (who may have low total but normal free testosterone)
3. Not distinguishing between primary and secondary hypogonadism
4. Initiating treatment without proper evaluation for underlying causes
5. Inadequate monitoring of testosterone levels and potential adverse effects
6. Using testosterone for non-specific symptoms of aging without confirmed hypogonadism

By following this structured approach to diagnosis and treatment, clinicians can appropriately manage hypogonadism while minimizing risks and optimizing patient outcomes.