What is the recommended treatment for hypogonadism using testosterone replacement therapy (TRT)?

Testosterone Replacement Therapy for Hypogonadism

Initiate testosterone replacement therapy only in men with confirmed biochemical hypogonadism (morning total testosterone <300 ng/dL on two separate occasions) AND corresponding symptoms—particularly diminished libido and erectile dysfunction—never based on symptoms alone. 1

Diagnostic Confirmation Requirements

Before starting treatment, you must establish hypogonadism through specific laboratory criteria:

• Measure morning total testosterone between 8-10 AM on at least two separate days, confirming levels below 300 ng/dL (some guidelines use 275-350 ng/dL threshold) 1, 2, 3
• Measure free testosterone by equilibrium dialysis and sex hormone-binding globulin (SHBG) in men with obesity or suspected binding protein alterations 1, 2
• After confirming low testosterone, measure LH and FSH to distinguish primary hypogonadism (elevated gonadotropins indicating testicular failure) from secondary hypogonadism (low/normal gonadotropins indicating hypothalamic-pituitary dysfunction) 1, 2

Critical pitfall to avoid: Never attempt to diagnose the type of hypogonadism while a patient is already on testosterone therapy, as exogenous testosterone suppresses the hypothalamic-pituitary-gonadal axis and renders gonadotropin measurements meaningless. 1

First-Line Treatment Selection

Start with transdermal testosterone gel 1.62% at 40.5 mg daily (2 pump actuations) applied once daily in the morning to shoulders and upper arms. 1, 2, 3 This formulation is preferred over intramuscular injections because it provides more stable day-to-day testosterone levels and lower risk of erythrocytosis. 1, 2

Alternative for Cost-Conscious Patients

If cost is the primary concern, use intramuscular testosterone cypionate or enanthate 100-200 mg every 2-3 weeks (annual cost approximately $156 versus $2,135 for transdermal gel). 1 However, counsel patients that injectable testosterone causes peak levels at days 2-5 and returns to baseline by days 13-14, resulting in more fluctuation in symptoms and higher risk of erythrocytosis compared to transdermal preparations. 1

Dose Titration Protocol

Measure testosterone levels at 14 days and 28 days after treatment initiation or dose adjustment, then every 6-12 months once stable. 1, 2

For transdermal gel patients:

• Target mid-normal testosterone levels (500-600 ng/dL) 1
• If pre-dose morning testosterone >750 ng/dL: Decrease by 20.25 mg (1 pump actuation) 3
• If 350-750 ng/dL: Continue current dose 3
• If <350 ng/dL: Increase by 20.25 mg (1 pump actuation) 3
• Maximum dose is 81 mg daily (4 pump actuations) 3

For injectable testosterone patients:

• Measure levels midway between injections 1
• Adjust dose to achieve mid-normal values (500-600 ng/dL) 1

Expected Treatment Outcomes

Set realistic expectations with patients about what testosterone therapy can and cannot achieve:

Benefits with strong evidence:

• Small but significant improvements in sexual function and libido 4, 1, 2, 5
• Improvements in insulin sensitivity in men with type 2 diabetes and metabolic syndrome 4
• Improvements in bone mineral density, muscle strength, and symptoms of frailty 4
• Small improvements in quality of life, particularly vitality and mental health domains 1, 5

Limited or no benefits:

• Little to no effect on physical functioning, energy, or vitality in older men 1, 2
• Little to no improvement in depressive symptoms 1
• Inconsistent effects on erectile dysfunction (particularly in men refractory to PDE5 inhibitors) 4
• No benefit for cognition 1, 2

Discontinue treatment if no improvement in sexual function after 12 months, as this indicates the patient is unlikely to benefit from continued therapy. 1, 2

Monitoring Requirements

Monitor the following parameters every 6-12 months once stable: 1, 2

• Hematocrit: Withhold treatment if >54% and consider phlebotomy in high-risk cases 1
• PSA in men over 40 years: Adjust treatment if significant increases occur 1
• Prostate examination: Assess for benign prostatic hyperplasia symptoms 1
• Sexual symptoms and metabolic parameters 2

Erythrocytosis is more common with injectable testosterone than transdermal preparations, so monitor hematocrit more closely in patients using intramuscular formulations. 1, 2

Absolute Contraindications

Never initiate testosterone therapy in the following situations:

• Men actively seeking fertility preservation: Testosterone suppresses spermatogenesis and causes azoospermia. Instead, use gonadotropin therapy (hCG plus FSH) which stimulates the testes directly and can restore both testosterone levels and fertility. 1, 2, 6
• Active male breast cancer 1
• Active or untreated prostate cancer (though evidence is evolving) 1
• Eugonadal men (normal testosterone levels), even if symptomatic or seeking weight loss, cardiometabolic improvement, cognition enhancement, or vitality improvement 1, 2

Special Population: Secondary Hypogonadism in Young Men Desiring Fertility

For men with secondary hypogonadism who desire fertility, use gonadotropin therapy (hCG with or without FSH) as first-line treatment instead of testosterone. 1 This approach can achieve both fertility restoration and normal testosterone levels, whereas testosterone therapy permanently compromises fertility by suppressing the hypothalamic-pituitary-gonadal axis. 1

Application Instructions for Transdermal Gel

Apply to clean, dry, intact skin of shoulders and upper arms only—never to abdomen, genitals, chest, armpits, or knees. 3

Wash hands immediately with soap and water after application and cover application sites with clothing after gel dries to prevent secondary exposure to women and children. 3 Virilization has been reported in children secondarily exposed to testosterone gel. 3

Wash application sites thoroughly with soap and water before any skin-to-skin contact with others. 3

Evolving Contraindications

Recent level 1 evidence suggests that severe lower urinary tract symptoms and untreated obstructive sleep apnea may not be absolute contraindications as previously thought, though caution is still warranted. 4 The 2010 Endocrine Society guidelines considered these conditions contraindications, but trials since 2010 have challenged this dogma. 4

Critical Pitfalls to Avoid

• Never diagnose hypogonadism based on symptoms alone without laboratory confirmation 1, 2
• Never start testosterone without confirming the patient does not desire fertility 1
• Never assume age-related decline in young men without investigating for reversible secondary causes 1
• Never measure only 74.72% of newly prescribed patients had testosterone measured in the preceding 12 months, which is inadequate 4