What is the recommended approach for primary care testosterone replacement therapy (TRT) in patients with hypogonadism?

Primary Care Testosterone Replacement Therapy

Diagnostic Confirmation Required Before Treatment

Testosterone replacement therapy should only be initiated in men with confirmed biochemical hypogonadism (morning total testosterone <300-350 ng/dL on two separate occasions) AND corresponding symptoms—never based on symptoms alone. 1, 2, 3

Essential Diagnostic Steps

• Obtain morning serum total testosterone between 8-10 AM on at least two separate days to confirm levels below the normal range 1, 2, 3
• Measure free testosterone by equilibrium dialysis and sex hormone-binding globulin (SHBG) in men with obesity or when binding protein alterations are suspected 1, 2
• Once low testosterone is confirmed, measure luteinizing hormone (LH) and follicle-stimulating hormone (FSH) to distinguish primary (testicular failure with elevated gonadotropins) from secondary hypogonadism (hypothalamic-pituitary dysfunction with normal/low gonadotropins) 1, 2

Key Symptoms to Assess

• Diminished libido and erectile dysfunction 2
• Reduced sense of vitality and fatigue 2
• Depressive symptoms 1, 2
• Weight loss or reduced bone mineral density 1

Treatment Selection and Initiation

First-Line Formulation Choice

Transdermal testosterone gel is preferred for initial therapy due to more stable day-to-day testosterone levels, though intramuscular injections are a reasonable alternative when cost is a primary concern. 2

Transdermal Testosterone Gel

• Starting dose: 40.5 mg testosterone (2 pump actuations) applied once daily in the morning to clean, dry, intact skin of shoulders and upper arms only 3
• Apply to shoulders and upper arms—never to abdomen, genitals, chest, armpits, or knees 3
• Patients must wash hands immediately with soap and water after application and cover application sites with clothing after gel dries 3
• Annual cost approximately $2,135 2

Intramuscular Testosterone Injections

• Testosterone cypionate or enanthate 100-200 mg every 2-3 weeks 2
• Peak levels occur 2-5 days post-injection, returning to baseline by 10-14 days 2
• Annual cost approximately $156 2
• Higher risk of erythrocytosis compared to transdermal preparations 2, 3

Monitoring Protocol

Initial Monitoring Phase

• Measure pre-dose morning testosterone at 14 days and 28 days after treatment initiation or any dose adjustment 2, 3
• For injectable testosterone, measure levels midway between injections, targeting mid-normal range (500-600 ng/dL) 2
• For transdermal gel, target pre-dose levels of 350-750 ng/dL 3

Dose Adjustments for Transdermal Gel

• If testosterone >750 ng/dL: Decrease by 20.25 mg (1 pump actuation) 3
• If testosterone 350-750 ng/dL: Continue current dose 3
• If testosterone <350 ng/dL: Increase by 20.25 mg (1 pump actuation) 3
• Dose range: 20.25 mg (minimum) to 81 mg (maximum) daily 3

Long-Term Monitoring

• Once stable testosterone levels achieved, monitor every 6-12 months 2
• At each visit, assess: 1
  • Hematocrit (discontinue if >54% and consider phlebotomy in high-risk cases)
  • Prostate-specific antigen (PSA)
  • Sexual symptoms (typically improve by 3 months)
  • Metabolic parameters

Absolute Contraindications

Do not prescribe testosterone therapy in the following situations: 1, 3

• Men seeking fertility (TRT suppresses spermatogenesis) 1
• Active or treated male breast cancer 1, 3
• Known or suspected prostate cancer 3
• Eugonadal men (normal testosterone levels) 1, 2
• Women who are pregnant 3

Expected Outcomes and Realistic Expectations

Proven Benefits

• Improved sexual function and libido in hypogonadal men, particularly those with mild erectile dysfunction (use as first-line treatment) 1, 2
• Improvements in fasting glucose, insulin resistance, triglycerides, and HDL cholesterol 2
• Small improvements in quality of life 2

Limited or No Benefits

Do not use testosterone therapy for the following indications, as evidence shows little to no benefit: 1

• Weight reduction and cardiometabolic status improvement 1
• Improving cognition, vitality, or physical strength in aging men 1
• Physical functioning in elderly men 2
• Depressive symptoms (use conventional therapies instead) 1

Critical Safety Warnings

Secondary Exposure Risk

Children and women must avoid contact with unwashed or unclothed application sites—virilization has been reported in children secondarily exposed to testosterone gel. 3

• Patients must wash application site thoroughly with soap and water before any anticipated skin-to-skin contact 3
• Cover application sites with clothing after gel dries 3

Cardiovascular and Hematologic Risks

• Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, reported with testosterone therapy 3
• Some postmarketing studies show increased risk of myocardial infarction and stroke with testosterone replacement 3
• Erythrocytosis is more common with injectable testosterone than transdermal preparations 2, 3

Other Potential Adverse Effects

• Fluid retention (caution in cardiac, renal, or hepatic disease) 3
• Worsening of benign prostatic hyperplasia symptoms (though generally safe except in severe LUTS) 1
• Sleep apnea exacerbation in at-risk patients 3
• Testicular atrophy and infertility 3

Special Populations

Men Desiring Fertility

For secondary hypogonadism patients seeking fertility, use gonadotropin therapy (hCG with or without FSH) instead of testosterone—TRT is absolutely contraindicated. 1

Lifestyle Modifications

Weight loss through low-calorie diets and regular physical activity should be recommended for all patients with obesity-associated hypogonadism, though testosterone increases are modest (1-2 nmol/L). 1

• Combining lifestyle modifications with testosterone therapy may yield better outcomes than either alone 1

Treatment Discontinuation

If no improvement in sexual function after 12 months of therapy, discontinue treatment. 2