What is the treatment for hypogonadism (low sex hormone levels)?

Treatment for Hypogonadism

Testosterone replacement therapy (TRT) is the first-line treatment for confirmed male hypogonadism, with transdermal testosterone gel (40.5 mg daily) preferred over intramuscular injections due to more stable testosterone levels and lower erythrocytosis risk. 1, 2

Diagnostic Confirmation Required Before Treatment

• Measure morning total testosterone (8-10 AM) on two separate occasions, with levels <300 ng/dL confirming biochemical hypogonadism 1, 2, 3
• Obtain free testosterone by equilibrium dialysis and sex hormone-binding globulin (SHBG), especially in obese men where total testosterone may be falsely low 1
• Measure LH and FSH to distinguish primary hypogonadism (elevated LH/FSH) from secondary hypogonadism (low or low-normal LH/FSH), as this determines treatment options 1, 2, 3
• Both biochemical confirmation AND specific symptoms (diminished libido, erectile dysfunction, decreased vitality) are required - never treat based on symptoms alone 1, 2

Treatment Selection Algorithm

Step 1: Assess Fertility Desires

If patient desires fertility preservation:

• Testosterone therapy is absolutely contraindicated - it suppresses spermatogenesis and causes azoospermia that may take months to years to reverse 1, 2, 3, 4
• For secondary hypogonadism: Start gonadotropin therapy with hCG 500-2500 IU subcutaneously 2-3 times weekly, add FSH if needed after testosterone normalizes 2, 3, 5, 6
• For primary hypogonadism: Gonadotropins will not work as testes cannot respond; assisted reproductive technologies may be required 2

If patient does not desire fertility:

• Proceed to testosterone replacement therapy 2, 3

Step 2: Select Testosterone Formulation

First-line: Transdermal testosterone gel 1.62% at 40.5 mg daily 1, 2, 3

• Advantages: Stable day-to-day testosterone levels, lower erythrocytosis risk compared to injections 1
• Disadvantages: Higher cost ($2,135/year), requires daily application, risk of transfer to contacts 1

Second-line: Intramuscular testosterone cypionate or enanthate 100-200 mg every 2 weeks 1, 4

• Advantages: Lower cost ($156/year), less frequent dosing 1
• Disadvantages: Peak levels at days 2-5 with return to baseline by days 10-14, higher erythrocytosis risk 1
• FDA-approved dosing: 50-400 mg every 2-4 weeks 1, 4

Third-line: Testosterone undecanoate 750 mg initially, repeat at 4 weeks, then every 10 weeks 1

• Advantages: Fewer yearly injections, more stable levels 1

Monitoring Requirements

Initial monitoring at 2-3 months after starting therapy: 1, 2, 3

• Testosterone levels (target mid-normal 500-600 ng/dL; for injections, measure midway between doses) 1
• Hematocrit (withhold treatment if >54%, consider phlebotomy) 1, 2, 3
• PSA in men over 40 years 1, 2, 3

Ongoing monitoring every 6-12 months once stable: 1, 2

• Same parameters as initial monitoring 1, 2
• Assess for lower urinary tract symptoms and perform prostate examination 2, 3

Expected Treatment Outcomes

Realistic benefits to discuss with patients:

• Small but significant improvements in sexual function and libido (standardized mean difference 0.35) 1, 2
• Modest quality of life improvements, primarily in sexual function domains 1, 2
• Little to no effect on physical functioning, energy, vitality, or cognition 1, 2
• Minimal improvements in depressive symptoms (SMD -0.19) 1
• Potential metabolic improvements: fasting glucose, insulin resistance, triglycerides, HDL cholesterol 1, 3

Reevaluate at 12 months and discontinue if no improvement in sexual function 1, 2

Absolute Contraindications to Testosterone Therapy

• Active desire for fertility preservation 1, 2, 3, 4
• Active or treated male breast cancer 1, 2, 4
• Hematocrit >54% 2, 3
• Untreated severe obstructive sleep apnea 2
• Eugonadal men (normal testosterone levels), even if symptomatic - testosterone should never be used for weight loss, cardiometabolic improvement, cognition, vitality, or physical strength in men with normal testosterone 1, 2

Special Populations

Obese men with secondary hypogonadism:

• First attempt weight loss through low-calorie diets and regular exercise - this can reverse obesity-associated hypogonadism by improving testosterone levels 1, 2, 3
• If lifestyle modifications fail and patient remains symptomatic with confirmed low testosterone, proceed to TRT 3

Men with diabetes:

• Optimize diabetes management concurrently with TRT 1
• Consider intensifying diabetes therapy with GLP-1 receptor agonist or SGLT2 inhibitor for cardiovascular benefits 1
• TRT may improve insulin resistance and reduce HbA1c by approximately 0.37% 1

Elderly men:

• Primary indication is sexual dysfunction - do not use TRT to improve energy, vitality, physical function, or cognition 1
• Higher risk of erythrocytosis and cardiovascular events 1
• If no improvement in sexual function after 12 months, discontinue treatment 1

Potential Risks and Side Effects

• Erythrocytosis (higher risk with injectable testosterone) 1, 2, 4, 7
• Fluid retention, potential worsening of benign prostatic hyperplasia 1, 4
• Gynecomastia 1, 7, 4
• Acne or oily skin 1
• Testicular atrophy and infertility 1
• Sleep apnea potentiation 1, 7
• Venous thromboembolic events (DVT, PE) 4
• Theoretical risk of prostate cancer stimulation (evidence evolving) 1

Critical Pitfalls to Avoid

• Never start testosterone without confirming the patient does not desire fertility - this causes irreversible suppression of spermatogenesis 1, 2, 3
• Never diagnose hypogonadism based on symptoms alone - biochemical confirmation with two low morning testosterone measurements is mandatory 1, 2
• Never prescribe testosterone to eugonadal men - approximately 20-30% of men receiving testosterone in the US do not have documented low testosterone 1
• Never attempt to diagnose primary vs. secondary hypogonadism while patient is on testosterone - requires washout of 2-4 weeks before measuring LH/FSH 1
• Never assume age-related decline justifies treatment - diagnosis requires both low testosterone AND specific symptoms 1, 2

Alternative Treatments for Specific Scenarios

For men with secondary hypogonadism not desiring fertility who cannot tolerate TRT:

• Clomiphene citrate (off-label) to stimulate LH, FSH, and endogenous testosterone 8, 9
• Aromatase inhibitors (off-label) - limited use due to osteopenia risk 8, 9

For erectile dysfunction with confirmed hypogonadism:

• Combine TRT with PDE5 inhibitors (sildenafil, tadalafil) for optimal results 1, 3