Should an adult male patient with low free testosterone levels treat the condition?

Should Adult Males with Low Free Testosterone Treat the Condition?

Yes, but only if you have confirmed biochemical hypogonadism (morning total testosterone <300 ng/dL on two separate occasions) AND specific symptoms—primarily diminished libido and erectile dysfunction—should you initiate testosterone replacement therapy. 1, 2

Diagnostic Requirements Before Treatment

You must confirm true hypogonadism through a systematic approach:

• Measure morning total testosterone (8-10 AM) on at least two separate occasions to establish persistent hypogonadism, as single measurements are unreliable due to assay variability and diurnal fluctuation 1, 2, 3

• Measure free testosterone by equilibrium dialysis in addition to total testosterone, especially when total testosterone is borderline (231-346 ng/dL), as 26.3% of men over 60 have normal total testosterone but low free testosterone 2, 4

• Measure sex hormone-binding globulin (SHBG) to distinguish true hypogonadism from SHBG-related decreases in total testosterone—men with obesity often have low total testosterone due solely to low SHBG but normal free testosterone, and these men do NOT require treatment 2, 4

• Measure LH and FSH levels to distinguish primary (testicular) from secondary (pituitary-hypothalamic) hypogonadism, which has critical treatment implications for fertility preservation 1, 2, 3

Who Should Actually Be Treated?

The primary indication for testosterone therapy is sexual dysfunction—specifically diminished libido and erectile dysfunction 1, 2. The American College of Physicians' comprehensive evidence review demonstrates:

• Small but significant improvements in sexual function (standardized mean difference 0.35) and erectile function (SMD 0.27) 1, 2, 5

• Modest quality of life improvements, primarily driven by sexual function domains rather than energy or mood 1, 2

Do NOT expect meaningful benefits for:

• Physical functioning (SMD 0.14-0.15)—essentially no effect 1, 2
• Energy and vitality (SMD 0.17)—less than small improvement 1, 2, 5
• Depressive symptoms (SMD -0.19)—minimal effect 1, 2, 5
• Cognition—no proven benefit 1, 2

The European Association of Urology explicitly recommends against testosterone therapy in eugonadal men, even for weight loss, cardiometabolic improvement, cognition, vitality, or physical strength 2

Critical Fertility Consideration

If you desire fertility preservation, testosterone therapy is absolutely contraindicated 2, 3. Exogenous testosterone suppresses spermatogenesis and causes prolonged azoospermia. Instead:

• Men with secondary hypogonadism seeking fertility must receive gonadotropin therapy (recombinant hCG plus FSH), which stimulates the testes directly and restores both testosterone production and spermatogenesis 2

• Men with primary hypogonadism cannot respond to gonadotropin stimulation and can only receive testosterone replacement, which permanently compromises fertility 2

Treatment Selection Algorithm

First-line: Transdermal testosterone gel 1.62% at 40.5 mg daily 2, 4

• Provides stable day-to-day testosterone levels
• Preferred by 71% of patients for convenience and ease of use 2, 5
• Annual cost: $2,135 2, 5

Alternative: Intramuscular testosterone cypionate or enanthate

• Dosing: 100-200 mg every 2 weeks or 50 mg weekly 2
• Annual cost: $156—significantly more economical 2, 5
• Higher risk of erythrocytosis compared to transdermal preparations 1, 2
• Peak levels occur days 2-5, return to baseline by days 10-14 2

Target testosterone levels: 500-600 ng/dL (mid-normal range) 2, 4

Absolute Contraindications

Do NOT initiate testosterone therapy if:

• Active desire for fertility preservation 2, 3
• Active or treated male breast cancer 2, 3
• Prostate cancer 2, 3
• Hematocrit >54% (or >50% per some guidelines) 2, 3, 6
• PSA >4.0 ng/mL without urologic evaluation 3, 6
• Untreated severe obstructive sleep apnea 2, 3
• Recent major cardiovascular event (within 3-6 months) 2, 7
• Uncontrolled heart failure 3, 6

Mandatory Monitoring Requirements

Before initiating therapy:

• Baseline hematocrit/hemoglobin 2, 3
• PSA level and digital rectal examination in men over 40 2, 3
• Fasting glucose to exclude diabetes 2

During therapy:

• Testosterone levels at 2-3 months, then every 6-12 months once stable 1, 2, 4
• For injectable testosterone, measure levels midway between injections (days 5-7), NOT at peak or trough 2
• Hematocrit periodically—withhold treatment if >54% and consider phlebotomy 2, 4, 3
• PSA monitoring—refer for urologic evaluation if PSA increases >1.0 ng/mL in first 6 months or >0.4 ng/mL per year thereafter 2

Special Populations

Men with obesity-associated secondary hypogonadism:

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

Men with borderline testosterone (231-346 ng/dL):

• Consider a 3-6 month trial of testosterone therapy after careful discussion of risks and benefits 2, 8
• Continue beyond 6 months only if clinical benefit is demonstrated 2

When to Discontinue Treatment

Reevaluate symptoms at 12 months and discontinue testosterone if no improvement in sexual function occurs, to prevent unnecessary long-term exposure to potential risks without benefit 2, 5

Common Pitfalls to Avoid

• Never diagnose hypogonadism based on symptoms alone—screening questionnaires lack specificity 2
• Never start testosterone without confirming the patient does not desire fertility—this causes irreversible azoospermia 2
• Never draw testosterone levels at peak (days 2-5) or trough (days 13-14) for injectable testosterone—measure midway between injections 2
• Never assume testosterone will improve energy, physical function, or cognition—evidence shows minimal to no benefit for these outcomes 1, 2
• Nearly 20-30% of men receiving testosterone in the US do not have documented low testosterone levels before treatment initiation—this violates evidence-based guidelines 2