What is the approach to testosterone replacement therapy (TRT) for individuals with hypogonadism?

Testosterone Replacement Therapy for Hypogonadism

Testosterone replacement therapy (TRT) should only be initiated for men with confirmed hypogonadism due to specific medical conditions affecting the testes, pituitary gland, or brain, not for age-related low testosterone alone. 1

Diagnostic Criteria and Patient Selection

• TRT is indicated only for:

  • Primary hypogonadism (testicular failure): conditions like cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter's syndrome, chemotherapy, or toxic damage 2
  • Hypogonadotropic hypogonadism: LHRH deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation 2

• Diagnosis requires:

  • Morning serum testosterone measurements on at least two separate days showing consistently low levels 1
  • Presence of symptoms associated with hypogonadism

Contraindications

Absolute contraindications to TRT include:

• Prostate cancer
• Male breast cancer
• Desire for fertility in the near future
• Severe obstructive sleep apnea (OSA)
• Uncontrolled congestive heart failure (CHF)
• Hematocrit >54% 1

Recent evidence suggests that severe lower urinary tract symptoms (LUTS) and untreated OSA may not be absolute contraindications to TRT as previously thought 3.

Treatment Options and Administration

Several TRT formulations are available:

• Transdermal (gels): Apply to clean, dry skin of upper arms and shoulders daily
• Intramuscular injections: Administered every 1-4 weeks depending on formulation
• Buccal, nasal, and subdermal options 4

Dosing protocol:

1. Start with recommended initial dose (e.g., 40.5 mg testosterone gel applied daily) 2
2. Titrate dose based on pre-dose morning serum testosterone at 14 and 28 days after starting treatment 2
3. Target testosterone levels between 450-600 ng/dL 1

Monitoring Protocol

Follow-up schedule:

• 4-6 weeks after initiating therapy
• Every 3-6 months during the first year
• Yearly thereafter if stable 1

At each follow-up visit, assess:

• Symptomatic response to treatment
• Testosterone levels
• Hematocrit or hemoglobin levels
• Voiding symptoms
• Digital rectal examination and PSA levels 1

Benefits and Risks

Benefits of TRT (with certainty of evidence):

• Small but significant improvements in sexual function (moderate-certainty) 1
• Small improvements in quality of life (low-certainty) 1
• Small improvements in depressive symptoms (low-certainty) 1
• Potential improvements in bone mineral density and muscle strength 3

Risks and adverse effects:

• Secondary exposure risk to children and women (virilization) 2
• Erythrocytosis (dose-dependent: 2.8% at 5 mg/day to 17.9% at 100 mg/day) 1
• Fluid retention 1
• Suppression of spermatogenesis 1
• Potential cardiovascular effects (controversial evidence) 3, 5

Cardiovascular Risk Considerations

The cardiovascular safety of TRT remains controversial:

• FDA issued a Safety Announcement in 2015 cautioning against TRT use for age-related hypogonadism due to possible increased risk of heart attack and stroke 3
• Some retrospective studies show increased cardiovascular risk 3
• Other studies suggest potential cardiovascular benefits in certain populations 3
• Most level 1 evidence trials show no difference in cardiovascular adverse events compared to placebo 3

Special Populations

For men with metabolic syndrome or type 2 diabetes:

• TRT may improve insulin sensitivity and biometric parameters in men with metabolic syndrome 3
• Effects on insulin sensitivity in men with type 2 diabetes remain inconclusive 3

For men with fertility concerns:

• Consider alternative treatments like selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), or human chorionic gonadotropin (hCG) 1
• Clomiphene citrate may preserve fertility and improve sperm parameters 1

Common Pitfalls to Avoid

• Diagnosing hypogonadism based on a single testosterone measurement
• Failing to measure free testosterone in obese patients
• Overlooking secondary causes of hypogonadism
• Initiating therapy without proper baseline evaluation
• Not monitoring for adverse effects, particularly hematocrit elevation
• Using testosterone for "age-related hypogonadism" without structural or genetic etiology 1

TRT is a long-term therapy requiring careful patient selection, appropriate dosing, and vigilant monitoring to maximize benefits while minimizing risks. The decision to initiate TRT should be based on confirmed hypogonadism due to specific medical conditions, not simply age-related decline in testosterone levels.