What is the primary treatment for a patient with confirmed hypogonadism (low testosterone)?

Treatment for Low Testosterone (Hypogonadism)

Testosterone replacement therapy (TRT) is the primary treatment for confirmed hypogonadism, with transdermal testosterone gel (40.5 mg daily) as the preferred first-line formulation due to more stable day-to-day testosterone levels compared to intramuscular injections. 1

Diagnostic Confirmation Required Before Treatment

Before initiating any treatment, you must confirm both biochemical hypogonadism and specific symptoms:

• Measure morning total testosterone (8-10 AM) on two separate occasions, with levels <300 ng/dL establishing hypogonadism 1
• Measure free testosterone by equilibrium dialysis in men with obesity, diabetes, or borderline total testosterone, as low SHBG can artificially lower total testosterone while free testosterone remains normal 1
• Measure LH and FSH to distinguish primary (elevated LH/FSH) from secondary (low/low-normal LH/FSH) hypogonadism, as this distinction has critical treatment implications for fertility preservation 1

The primary symptoms warranting treatment are diminished libido and erectile dysfunction 1. Symptoms like fatigue, low energy, depressed mood, or cognitive complaints show minimal to no benefit from testosterone therapy, even with confirmed hypogonadism 1.

First-Line Treatment: Transdermal Testosterone Gel

Start with transdermal testosterone gel 1.62% at 40.5 mg applied once daily to the upper arms and shoulders 1. This formulation is preferred over intramuscular injections because:

• Provides stable day-to-day testosterone levels without the peaks and troughs seen with injections 1
• Lower risk of erythrocytosis (15.4% vs 43.8% with intramuscular injections—a nearly 3-fold difference) 2
• Minimizes mood and energy fluctuations due to stable testosterone levels 2

The primary disadvantage is cost: transdermal formulations cost approximately $2,135 annually versus $156 for intramuscular testosterone 1. However, the cardiovascular and hematologic safety profile favors transdermal preparations, particularly in elderly patients or those with cardiovascular risk factors 2.

Alternative: Intramuscular Testosterone Injections

If cost is the primary concern, use testosterone cypionate or enanthate 100-200 mg intramuscularly every 2 weeks 1, 3. This is the most economical option but carries significant drawbacks:

• 43.8% risk of erythrocytosis compared to 15.4% with transdermal preparations 2
• Fluctuating testosterone levels with peaks at days 2-5 and return to baseline by days 10-14, causing mood and sexual function shifts in some men 1
• Potentially higher cardiovascular risk due to time spent in both supratherapeutic and subtherapeutic ranges 2

Measure testosterone levels midway between injections (days 5-7), targeting mid-normal values of 500-600 ng/dL 1.

Special Consideration: Fertility Preservation

If the patient desires fertility now or in the future, testosterone therapy is absolutely contraindicated 1. Exogenous testosterone suppresses the hypothalamic-pituitary-gonadal axis, causing azoospermia that can be prolonged and potentially irreversible 1.

For men with secondary hypogonadism who desire fertility, use gonadotropin therapy (recombinant hCG plus FSH) instead 1. This directly stimulates the testes, restoring both testosterone production and spermatogenesis without suppressing the pituitary 1.

Alternative to Testosterone: Clomiphene Citrate

For men with secondary hypogonadism who wish to preserve fertility, clomiphene citrate 25-50 mg three times weekly is an effective alternative 4. Clomiphene stimulates endogenous testosterone production without suppressing spermatogenesis 4.

Advantages of clomiphene include:

• Preserves fertility by maintaining or improving spermatogenesis 4
• Lower risk of polycythemia compared to testosterone replacement 4
• Cost-effective at approximately $156 annually for generic formulations 4

Clomiphene is only effective in secondary hypogonadism with functioning pituitary glands—it will not work in primary testicular failure 4. Measure LH and FSH before initiating clomiphene to confirm secondary hypogonadism 4.

Expected Treatment Outcomes

Set realistic expectations with patients:

• Small but significant improvements in sexual function and libido (standardized mean difference 0.35) 1
• Modest quality of life improvements, primarily in sexual function domains 1
• Little to no effect on physical functioning, energy, vitality, depressive symptoms, or cognition 1
• Minimal improvements in fatigue (standardized mean difference 0.17) 1

Reevaluate symptoms at 12 months and discontinue testosterone if no improvement in sexual function is seen, to prevent unnecessary long-term exposure to potential risks without benefit 1.

Monitoring Requirements

Initial Monitoring (First 3 Months)

• Measure testosterone levels at 2-3 months after treatment initiation or dose change, targeting mid-normal range (500-600 ng/dL) 1
• Check hematocrit/hemoglobin at 2-3 months to assess for erythrocytosis 1

Long-Term Monitoring (Every 6-12 Months)

• Testosterone levels every 6-12 months once stable 1
• Hematocrit monitoring—withhold treatment if >54% and consider phlebotomy in high-risk cases 1
• PSA levels in men over 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
• Digital rectal examination to assess for prostate abnormalities 1

Absolute Contraindications to Testosterone Therapy

Do not initiate testosterone therapy in men with: 1

• Active desire for fertility preservation (use gonadotropins instead)
• Active or treated male breast cancer
• Hematocrit >54%
• Untreated severe obstructive sleep apnea
• Recent cardiovascular events within past 3-6 months

Management of Erythrocytosis on Testosterone Therapy

Erythrocytosis is the most common serious adverse effect, particularly with injectable testosterone:

• Hematocrit 50-52%: Continue current therapy with closer monitoring, consider dose reduction if trending upward 1
• Hematocrit 52-54%: Reduce testosterone dose by 25-50%, consider switching from injectable to transdermal formulation 1
• Hematocrit >54%: Withhold testosterone therapy immediately, consider therapeutic phlebotomy in high-risk patients 1

If erythrocytosis develops on injectable testosterone, switch to transdermal gel or patch, which provides more stable levels and lower erythrocytosis risk 2.

Critical Pitfalls to Avoid

• Never start testosterone without confirming the patient does not desire fertility, as suppression of spermatogenesis can be prolonged and potentially irreversible 1
• Never diagnose hypogonadism based on symptoms alone—biochemical confirmation with two morning testosterone measurements is mandatory 1
• Never use testosterone therapy in eugonadal men (normal testosterone levels), even if symptomatic, for weight loss, cardiometabolic improvement, cognition, vitality, or physical strength 1
• Never ignore mild erythrocytosis (hematocrit 50-52%) in elderly patients or those with cardiovascular disease, as even modest elevations increase blood viscosity and thrombotic risk 1
• Never continue full-dose testosterone when hematocrit exceeds 54%—this is an absolute indication to withhold therapy 1

Lifestyle Modifications as Adjunctive Therapy

For men with obesity-associated secondary hypogonadism, attempt weight loss through low-calorie diets and regular exercise before initiating testosterone, as 5-10% weight loss can significantly increase endogenous testosterone production 1. This approach is particularly valuable in obese men where increased aromatization of testosterone to estradiol suppresses LH secretion 1.