What are the treatment options for hypogonadism (low testosterone)?

Treatment Options for Low Testosterone (Hypogonadism)

Diagnostic Confirmation Required Before Any Treatment

Before initiating any therapy, confirm hypogonadism with two separate morning (8-10 AM) total testosterone measurements below 300 ng/dL, accompanied by specific symptoms—particularly diminished libido and erectile dysfunction. 1, 2

• Measure serum LH and FSH after confirming low testosterone to distinguish primary (testicular) from secondary (hypothalamic-pituitary) hypogonadism, as this distinction is critical for treatment selection and fertility preservation 1
• In men with obesity, also measure free testosterone by equilibrium dialysis and sex hormone-binding globulin (SHBG), as obesity-related reductions in SHBG can create "pseudo-hypogonadism" where total testosterone appears low but the patient is actually eugonadal 1, 3
• Elevated LH/FSH with low testosterone indicates primary hypogonadism; low or low-normal LH/FSH with low testosterone indicates secondary hypogonadism 1

First-Line Treatment Selection Algorithm

For Men Desiring Fertility Preservation (Any Age)

Testosterone therapy is absolutely contraindicated in men seeking fertility, as it suppresses spermatogenesis and causes azoospermia. 1, 4

• Use gonadotropin therapy (recombinant hCG plus FSH) as first-line treatment for secondary hypogonadism with fertility preservation goals 1
• This approach stimulates the testes directly, restoring both testosterone levels and fertility potential 1
• Primary hypogonadism patients cannot benefit from gonadotropins and must choose between fertility (no treatment) or symptom relief (testosterone with permanent fertility compromise) 1

For Men NOT Seeking Fertility

Step 1: Consider Reversible Causes First (Especially in Obesity-Related Hypogonadism)

In men with obesity and secondary hypogonadism, weight loss through low-calorie diets and regular exercise should be attempted before pharmacologic therapy, as this can substantially reverse testosterone reductions and is more effective than testosterone treatment for non-specific symptoms. 1, 3

• Weight loss, smoking cessation, increased physical activity, and avoiding excess alcohol improve sexual function and testosterone levels 5, 6
• Optimize management of sleep apnea, depression, type 2 diabetes, and rationalize concomitant medications that may suppress testosterone 6, 3
• These lifestyle modifications produce more meaningful improvements in overall health than testosterone therapy alone in obesity-related cases 3

Step 2: Pharmacologic Treatment Options

For confirmed hypogonadism requiring pharmacologic therapy, transdermal testosterone gel is the preferred first-line formulation due to more stable day-to-day testosterone levels. 1

Option A: Transdermal Testosterone Gel (First-Line)

• Starting dose: 40.5 mg daily (testosterone gel 1.62%) applied to shoulders and upper arms 1, 2
• Dose range: 20.25 mg to 81 mg daily, titrated based on pre-dose morning testosterone levels at 14 and 28 days 2
• Target mid-normal testosterone levels (500-600 ng/dL) 1
• Annual cost approximately $2,135, but provides convenience and stable levels 1
• Lower risk of erythrocytosis compared to injectable testosterone 1
• Critical warning: Children must avoid contact with unwashed or unclothed application sites due to risk of virilization 2

Option B: Intramuscular Testosterone (Cost-Effective Alternative)

• Testosterone cypionate or enanthate 50-400 mg every 2-4 weeks intramuscularly 1, 4
• Peak levels occur 2-5 days post-injection, returning to baseline by days 10-14 1
• Measure testosterone levels midway between injections, targeting 500-600 ng/dL 1
• Annual cost approximately $156, making it significantly more economical 1
• Higher risk of erythrocytosis (up to 44%) compared to transdermal preparations 1
• Some patients prefer this due to lower cost and less frequent administration 1

Option C: Clomiphene Citrate (Off-Label, Fertility-Preserving Alternative)

For men with secondary hypogonadism who wish to preserve fertility but need symptom relief, clomiphene citrate is an effective off-label alternative that stimulates endogenous testosterone production without suppressing spermatogenesis. 7, 6

• Particularly valuable for obesity-related hypogonadism where increased aromatization suppresses LH 7
• Achieves similar improvements in sexual function and quality of life as testosterone replacement while maintaining fertility 7
• Lower risk of polycythemia compared to testosterone 7
• Not FDA-approved for male hypogonadism and not effective for primary hypogonadism 7
• Switch to testosterone replacement if no response after 3 months 7

Monitoring Requirements During Treatment

• Check testosterone levels at 2-3 months after initiation or dose change, then every 6-12 months once stable 1
• Monitor hematocrit periodically; withhold treatment if >54% and consider phlebotomy 1, 4
• Monitor PSA in men over 40 years 1
• Assess for benign prostatic hyperplasia symptoms 1
• Reevaluate symptoms at 12 months and discontinue testosterone if no improvement in sexual function, as continued treatment without benefit exposes patients to unnecessary risks 1

Expected Treatment Outcomes (Setting Realistic Expectations)

Testosterone therapy produces small but significant improvements in sexual function and libido (standardized mean difference 0.35), but little to no effect on physical functioning, energy, vitality, or cognition. 1

• Sexual function and desire improve modestly 5, 1
• Minimal improvements in energy and fatigue (SMD 0.17) 1
• Less-than-small improvements in depressive symptoms (SMD -0.19) 1
• Small quality of life improvements, primarily driven by sexual symptom relief 1
• Potential improvements in fasting glucose, insulin resistance, triglycerides, and HDL cholesterol 1
• Improved bone mineral density 1

Absolute Contraindications to Testosterone Therapy

• Active desire for fertility preservation 1, 4
• Active male breast cancer 1, 4
• Prostate cancer on active surveillance or androgen deprivation therapy 5, 1
• Untreated severe obstructive sleep apnea 1
• Hematocrit >54% 1

Adjunctive Therapies for Sexual Dysfunction

For erectile dysfunction in hypogonadal men, combine PDE5 inhibitors (sildenafil, tadalafil) with testosterone therapy for optimal results. 5, 1

• PDE5 inhibitors are first-line for erectile dysfunction and can be used with testosterone 5
• Studies show testosterone addition to PDE5 inhibitors improves outcomes in men with low testosterone 5
• PDE5 inhibitors are contraindicated with oral nitrates due to dangerous blood pressure reduction 5
• Pelvic floor muscle training may improve sexual function in some populations 5

Critical Pitfalls to Avoid

• Never start testosterone without confirming both biochemical hypogonadism (<300 ng/dL on two occasions) and specific symptoms—approximately 20-30% of men receiving testosterone in the US lack documented low testosterone before treatment 1
• Never use testosterone in eugonadal men for weight loss, muscle building, energy, or cognitive enhancement—this violates evidence-based guidelines and exposes patients to harm without benefit 1
• Never diagnose hypogonadism based on symptoms or screening questionnaires alone without biochemical confirmation 1
• Never attempt to diagnose primary vs. secondary hypogonadism while patient is on testosterone therapy—requires washout period of 2-4 weeks 1
• Never assume age-related decline justifies treatment in older men without confirmed hypogonadism and sexual symptoms 1