What is the appropriate dosage and administration for prescribing testosterone replacement therapy?

How to Prescribe Testosterone Replacement Therapy

For most hypogonadal men, transdermal testosterone gel (50-100 mg daily) should be the first-line therapy due to stable physiologic testosterone levels and patient convenience, with intramuscular injections reserved for those with cost constraints or adherence issues. 1

Patient Selection and Diagnosis

Before prescribing testosterone, confirm hypogonadism with:

• Morning total testosterone drawn between 8-10 AM on at least 2 separate occasions showing frankly low levels 1
• Free testosterone by equilibrium dialysis (particularly important in obesity) 1
• Sex hormone-binding globulin level in patients with obesity 1
• LH and FSH levels to distinguish primary (testicular) from secondary (pituitary-hypothalamic) hypogonadism 1

If secondary hypogonadism is confirmed (low testosterone with low LH/FSH), further workup should include serum prolactin, iron saturation, pituitary function testing, and MRI of the sella turcica to identify underlying causes 1.

Formulation Selection Algorithm

First-Line: Transdermal Gel Preparations

Transdermal testosterone gels produce the most stable testosterone levels and highest patient satisfaction. 1

Specific dosing options:

• AndroGel 1%: Start 50 mg daily, titrate to 100 mg daily 1
• AndroGel 1.62%: Start 40.5 mg daily (2 pump actuations), titrate between 20.25-81 mg daily 2
• Testim 1%: Start 50 mg daily, titrate to 100 mg daily 1
• Fortesta 2%: Start 40 mg daily, titrate between 10-70 mg daily 1

Application instructions: Apply to clean, dry, intact skin of the upper arms and shoulders (NOT abdomen, genitals, chest, or axillae). Cover with clothing after drying. Avoid swimming/showering for minimum 2 hours after application. 2

Critical safety warning: Children and women must avoid contact with unwashed or unclothed application sites due to risk of virilization. Patients must wash hands immediately after application and cover sites with clothing. 2

Second-Line: Intramuscular Injections

For cost-sensitive patients or those with poor adherence to daily regimens:

Short-acting esters (more fluctuating levels):

• Testosterone enanthate or cypionate: 100-200 mg every 2 weeks OR 50 mg weekly 1
• Administered intramuscularly in thighs (self-injection) or gluteal region (by provider) 1
• Major disadvantage: Fluctuating serum testosterone with peaks and valleys, spending significant time in both supratherapeutic and subtherapeutic ranges 1

Long-acting ester (more stable levels):

• Testosterone undecanoate: 750 mg initially, followed by 750 mg after 4 weeks, then 750 mg every 10 weeks 1
• Gluteal intramuscular injection only 1
• Provides fewer yearly injections with less fluctuation 1
• Warning: Risk of injection-associated pulmonary oil microembolism; restricted access in United States 1

Alternative Formulations

Transdermal patches:

• Androderm: 2-6 mg daily applied to back, abdomen, upper thighs, or upper arms 1
• Advantage: No transference risk 1
• Disadvantage: High rate of skin irritation and poor patch adherence 1

Subcutaneous pellets:

• Testopel: 150-450 mg every 3-6 months implanted subcutaneously in hips 1
• Advantage: Long-lasting with stable levels 1
• Disadvantage: Requires incision, risk of pellet extrusion and infection 1

Buccal tablets:

• Striant: 30 mg twice daily applied to buccal mucosa 1
• Disadvantage: Poor adherence, gum irritation, taste changes 1

Monitoring Protocol

Initial Monitoring

Measure testosterone levels 2-3 months after treatment initiation or any dose change. 1

Timing of measurements varies by formulation:

• Intramuscular injections: Measure midway between injections, targeting mid-normal value (500-600 ng/dL) 1
• Transdermal preparations: Can measure at any time, though peak values occur 6-8 hours after patch application. Gel concentrations vary substantially and unpredictably. 1
• Testosterone gel 1.62%: Adjust dose based on pre-dose morning total serum testosterone: decrease if >750 ng/dL, continue if 350-750 ng/dL, increase if <350 ng/dL 2

Long-Term Monitoring

Once stable levels confirmed, monitor every 6-12 months 1:

• Testosterone levels to maintain therapeutic range
• Hematocrit/hemoglobin to detect erythrocytosis (monitor more frequently with injections) 1
• PSA and prostate examination to monitor for prostate changes 1
• Lipid panel for cardiovascular risk assessment 1

Safety Considerations

Cardiovascular Risk

The FDA required labeling changes in 2015 warning of possible increased risk of heart attack and stroke with testosterone preparations. 1 Some evidence suggests intramuscular injections carry greater cardiovascular risk than gels, potentially related to time spent in supratherapeutic and subtherapeutic ranges. 1 However, multiple professional societies support testosterone use in appropriately selected patients, citing cardiometabolic benefits. 1

Erythrocytosis Risk

Injections carry significantly higher erythrocytosis risk than transdermal preparations. In comparative studies, 43.8% of patients on intramuscular testosterone enanthate developed elevated hematocrit (>52%) versus 15.4% on transdermal patches. 1 Dose-dependent erythrocytosis occurs in 2.8-17.9% of gel users depending on dose. 1 If erythrocytosis develops, institute dosage reduction, withhold testosterone temporarily, or perform therapeutic phlebotomy. 1

Prostate Monitoring

Testosterone is contraindicated in men with known or suspected prostate cancer or breast carcinoma. 2 While testosterone replacement increases prostate volume to levels equivalent to eugonadal men (mainly in first 6 months), it does not typically worsen voiding symptoms or cause urinary retention at higher rates than placebo. 1 Monitor patients with BPH for worsening signs and symptoms. 2

Secondary Exposure Prevention

Cases of virilization in children from secondary exposure have been reported in postmarketing surveillance. 2 Signs include penile/clitoral enlargement, pubic hair development, increased erections and libido, aggressive behavior, and advanced bone age. 2 Strict adherence to application precautions is mandatory. 2

Contraindications

Absolute contraindications:

• Carcinoma of breast or prostate 2
• Pregnancy (testosterone causes virilization of female fetus) 2