What is the recommended approach for a patient considering testosterone as part of Hormone Replacement Therapy (HRT) for hypogonadism?

Testosterone as Part of Hormone Replacement Therapy for Hypogonadism

For men with confirmed hypogonadism (morning total testosterone <300 ng/dL on two separate occasions) AND specific symptoms—particularly diminished libido and erectile dysfunction—testosterone replacement therapy should be initiated, with transdermal gel as the preferred first-line formulation due to more stable testosterone levels, though intramuscular injections are a reasonable cost-effective alternative. 1, 2

Diagnostic Confirmation Requirements

Before initiating testosterone therapy, you must establish both biochemical and clinical hypogonadism:

• Measure morning total testosterone (between 8-10 AM) on at least two separate days, with levels <300-350 ng/dL confirming biochemical hypogonadism 1, 2, 3
• In men with obesity, diabetes, or borderline total testosterone, measure free testosterone by equilibrium dialysis and sex hormone-binding globulin (SHBG), as low SHBG can artificially lower total testosterone while free testosterone remains normal 1, 2
• Once low testosterone is confirmed, measure LH and FSH to distinguish primary hypogonadism (elevated LH/FSH indicating testicular failure) from secondary hypogonadism (low/normal LH/FSH indicating hypothalamic-pituitary dysfunction)—this distinction is critical for fertility preservation 1, 2, 3

Critical pitfall to avoid: Never diagnose hypogonadism based on symptoms alone without confirmed low testosterone levels, as approximately 20-30% of men receiving testosterone in the United States lack documented biochemical hypogonadism before treatment initiation 1

Primary Indications and Expected Benefits

The strongest evidence supports testosterone therapy for:

• Sexual dysfunction: Small but significant improvements in sexual function and libido (standardized mean difference 0.35), with benefits typically seen within 3-6 months 1, 2, 3
• Erectile dysfunction: Testosterone improves response to PDE5 inhibitors (sildenafil, tadalafil), and approximately 36% of men with ED have hypogonadism 1

Set realistic expectations: Testosterone therapy produces little to no effect on physical functioning, energy, vitality, depressive symptoms, or cognition, even in confirmed hypogonadism 1, 2, 3. The effect sizes for energy/fatigue (SMD 0.17) and mood (SMD -0.19) are clinically insignificant 1.

Treatment Selection Algorithm

First-Line: Transdermal Testosterone Gel

Transdermal testosterone gel 1.62% is the preferred initial formulation due to more stable day-to-day testosterone levels and lower risk of erythrocytosis compared to injections 1, 2, 4:

• Starting dose: 40.5 mg testosterone (2 pump actuations or one 40.5 mg packet) applied once daily in the morning to shoulders and upper arms 4
• Dose range: Can be adjusted between 20.25 mg (minimum) and 81 mg (maximum) based on testosterone levels 4
• Application instructions: Apply to clean, dry, intact skin of shoulders and upper arms only—never to abdomen, genitals, chest, armpits, or knees 4
• Annual cost: Approximately $2,135 1, 3

Critical safety warning: Children and women must never touch areas where testosterone gel has been applied, as secondary exposure can cause virilization in children (early puberty, enlarged genitals) and unwanted facial/body hair growth in women 4. Patients must wash hands thoroughly with soap and water after application and cover application sites with clothing once dry 4.

Alternative: Intramuscular Testosterone Injections

Intramuscular testosterone cypionate or enanthate is a reasonable alternative when cost is the primary concern 1, 2, 3:

• Dosing: 100-200 mg every 2 weeks or 50-100 mg weekly 1, 3
• Pharmacokinetics: Peak levels occur 2-5 days after injection, with return to baseline by days 10-14 1
• Annual cost: Approximately $156 (significantly lower than transdermal) 1, 3
• Disadvantage: Higher risk of erythrocytosis (up to 44%) compared to transdermal preparations 1, 3

Monitoring Requirements

Initial Monitoring (First 3 Months)

• Measure testosterone levels at 2-3 months after treatment initiation or dose adjustment 1, 3
• For injectable testosterone, measure levels midway between injections (days 5-7), targeting mid-normal values of 500-600 ng/dL 1, 3
• For transdermal gel, measure pre-dose morning testosterone at approximately 14 days and 28 days after starting treatment 4

Long-Term Monitoring (Every 6-12 Months)

Once stable testosterone levels are achieved, monitor the following every 6-12 months 1, 2, 3:

• Testosterone levels: Target mid-normal range (500-600 ng/dL) 1, 3
• Hematocrit/hemoglobin: Withhold treatment if hematocrit >54% and consider phlebotomy in high-risk cases 1, 2, 3
• PSA levels (in men >40 years): Refer for urologic evaluation if PSA increases >1.0 ng/mL in first 6 months or >0.4 ng/mL per year thereafter 1, 3
• Digital rectal examination: Assess for prostate abnormalities 1, 3
• Clinical symptom response: Particularly sexual function and libido 1, 2

Discontinue therapy if no improvement in sexual function after 12 months, as this prevents unnecessary long-term exposure to potential risks without benefit 1, 2.

Absolute Contraindications

Testosterone therapy is absolutely contraindicated in the following situations 1, 2:

• Active desire for fertility preservation: Testosterone suppresses spermatogenesis and causes azoospermia—use gonadotropin therapy (hCG plus FSH) instead 1, 2, 3
• Active or treated male breast cancer 1, 2
• Prostate cancer (though evidence is evolving) 1
• Hematocrit >54% 1, 2
• Untreated severe obstructive sleep apnea 1
• Recent cardiovascular events (within 3-6 months): Delay initiation until stable 1

Special Clinical Scenarios

Obesity-Associated Secondary Hypogonadism

Before initiating testosterone therapy, attempt weight loss through low-calorie diets and regular exercise, as this can improve testosterone levels without medication 1, 2, 3. Excessive aromatization of testosterone to estradiol in adipose tissue causes estradiol-mediated negative feedback suppressing pituitary LH secretion 1.

Secondary Hypogonadism with Fertility Concerns

Gonadotropin therapy (recombinant hCG plus FSH) is mandatory for men with secondary hypogonadism who desire fertility preservation, as testosterone is absolutely contraindicated 1, 2, 3. Men with secondary hypogonadism can achieve both fertility restoration and normal testosterone levels with gonadotropin therapy, whereas primary hypogonadism patients can only receive testosterone replacement therapy, which permanently compromises fertility 1.

Men with Diabetes

Testosterone therapy may improve insulin resistance, glycemic control, and HbA1c (reduction of approximately 0.37%) in hypogonadal men with type 2 diabetes 1. Consider intensifying diabetes therapy concurrently with testosterone treatment 1.

Common Pitfalls to Avoid

• Never start testosterone in eugonadal men (normal testosterone levels), even if symptomatic or for weight loss, cardiometabolic improvement, cognition, vitality, or physical strength 1, 2
• Never diagnose hypogonadism based on symptoms alone without confirmed low testosterone levels on two separate occasions 1, 2
• Never start testosterone without confirming the patient does not desire fertility, as this causes irreversible suppression of spermatogenesis 1, 2
• Never draw testosterone levels at peak (days 2-5) or trough (days 13-14) for injectable testosterone—measure midway between injections 1
• Never assume age-related decline in young men—investigate for secondary causes of hypogonadism, as reversible conditions must be addressed first 1