Hypogonadism Assessment and Treatment Plan
Initial Diagnostic Workup
Confirm biochemical hypogonadism with two separate morning (8-10 AM) total testosterone measurements showing levels <300 ng/dL before initiating any treatment. 1, 2
Essential Laboratory Tests
- Morning total testosterone (8-10 AM) on two separate occasions to establish persistent hypogonadism 1, 2
- Free testosterone by equilibrium dialysis in men with obesity or borderline total testosterone, as low SHBG can falsely lower total testosterone while free testosterone remains normal 1, 2
- Sex hormone-binding globulin (SHBG) to distinguish true hypogonadism from SHBG-related decreases 1
- Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) to differentiate primary (elevated LH/FSH) from secondary hypogonadism (low or inappropriately normal LH/FSH) 1, 2
Additional Workup for Secondary Hypogonadism
If LH/FSH are low or inappropriately normal with low testosterone:
- Serum prolactin to rule out prolactinoma 3
- Iron saturation to exclude hemochromatosis 3
- Consider pituitary MRI if prolactin elevated or other pituitary dysfunction suspected 3
- Rule out reversible causes: medications (opioids, glucocorticoids), acute illness, obesity, metabolic disorders 2
Baseline Safety Monitoring
- Hematocrit/hemoglobin before initiating therapy 1
- PSA in men >40 years 1, 2
- Prostate examination to assess for BPH symptoms 2
Treatment Algorithm
Step 1: Determine Fertility Intentions
Testosterone therapy is absolutely contraindicated in men actively seeking fertility, as it suppresses spermatogenesis and causes azoospermia that may take months to years to reverse. 1, 2
For Men Seeking Fertility Preservation:
- Gonadotropin therapy is mandatory 1, 2
- Start with hCG 500-2500 IU subcutaneously or intramuscularly 2-3 times weekly to stimulate endogenous testosterone production 2, 4
- Add FSH (recombinant or highly purified urinary) if needed to optimize spermatogenesis 2, 4
- Combination hCG plus FSH for 12-24 months promotes testicular growth in nearly all patients, spermatogenesis in ~80%, and pregnancy rates ~50% 4
- Alternative: Clomiphene citrate 25-50 mg daily as off-label treatment to stimulate endogenous testosterone while preserving fertility 5, 6
For Men NOT Seeking Fertility:
Proceed to testosterone replacement therapy (TRT) as outlined below.
Step 2: Select Testosterone Formulation
Transdermal testosterone gel 1.62% at 40.5 mg daily (2 pump actuations or one 40.5 mg packet) is the preferred first-line formulation due to stable day-to-day testosterone levels and lower erythrocytosis risk. 1, 2, 7
First-Line: Transdermal Testosterone Gel
- Dose: 40.5 mg testosterone daily, applied to clean, dry, intact skin of shoulders and upper arms 2, 7
- Do NOT apply to abdomen, genitals, chest, armpits, or knees 7
- Advantages: More stable testosterone levels, lower erythrocytosis risk compared to injections 1
- Disadvantages: Higher cost (~$2,135/year), risk of secondary exposure to women/children 1, 7
- Critical safety: Wash hands immediately with soap and water after application; cover application sites with clothing after gel dries; wash application site thoroughly before skin-to-skin contact with others 7
Alternative: Intramuscular Testosterone Injections
- Dose: Testosterone cypionate or enanthate 50-400 mg every 2-4 weeks (NOT weekly, as this exceeds standard practice and increases supraphysiologic levels) 1, 2
- Advantages: Significantly lower cost (~$156/year), preferred by some patients 1
- Disadvantages: Peak levels at days 2-5, return to baseline by days 13-14 causing fluctuations; higher erythrocytosis risk 1
- Monitoring: Measure testosterone midway between injections, targeting mid-normal value (500-600 ng/dL) 1
Third-Line: Testosterone Undecanoate
- Dose: 750 mg initially, repeat at 4 weeks, then every 10 weeks 1
- Advantages: Fewer yearly injections, more stable levels 1
Step 3: Set Realistic Treatment 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
Proven Benefits:
- Sexual function and libido: Small but significant improvement (SMD 0.35) 1
- Quality of life: Modest improvements, primarily in sexual function domains 1
- Metabolic parameters: Improvements in fasting glucose, insulin resistance, triglycerides, HDL cholesterol 1, 2
- Bone mineral density: Potential improvement 1
- Mild anemia: May help correct 1
Minimal or No Benefits:
- Physical functioning: Little to no effect 1
- Energy and vitality: Minimal improvement (SMD 0.17) 1
- Depressive symptoms: Less-than-small improvement (SMD -0.19) 1
- Cognition: No effect 1
Step 4: Monitoring Schedule
Initial Monitoring (2-3 months after starting or dose adjustment):
- Testosterone levels (morning for gel; midway between injections for IM) targeting 500-600 ng/dL 1, 2
- Hematocrit: Withhold treatment if >54% and consider phlebotomy 1, 2
- PSA in men >40 years: Adjust treatment if significant increases 1, 2
- Prostate examination: Assess for BPH symptoms 2
Ongoing Monitoring (every 6-12 months once stable):
- Same parameters as initial monitoring 1, 2
- Reevaluate symptoms at 12 months: Discontinue testosterone if no improvement in sexual function to prevent unnecessary long-term exposure without benefit 1
Step 5: Dose Adjustment
Testosterone gel can be adjusted between 20.25 mg (1 pump actuation) and 81 mg (4 pump actuations) based on pre-dose morning testosterone levels at 14 and 28 days after starting or dose adjustment. 7
For IM testosterone, adjust dose or frequency based on mid-cycle testosterone levels targeting 500-600 ng/dL 1
Absolute Contraindications to Testosterone Therapy
- Active desire for fertility preservation (use gonadotropins instead) 1, 2
- 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
- Pregnancy in female partners (risk of virilization from secondary exposure) 7
Adjunctive Therapies
For Erectile Dysfunction:
Combine testosterone with PDE5 inhibitors (sildenafil, tadalafil) for optimal results, as testosterone is required for complete PDE5 inhibitor efficacy. 1, 2
For Obesity-Associated Secondary Hypogonadism:
Weight loss through low-calorie diets and regular exercise should be attempted first, as this can reverse obesity-associated hypogonadism by improving testosterone levels without medication. 1, 2
Critical Pitfalls to Avoid
- Never start testosterone without confirming the patient does not desire fertility 1
- Never diagnose hypogonadism based on symptoms alone without biochemical confirmation 1
- Never use testosterone in eugonadal men (normal testosterone levels), even if symptomatic, as this violates evidence-based guidelines 1
- Never attempt to diagnose primary vs. secondary hypogonadism while patient is on testosterone, as exogenous testosterone suppresses LH/FSH and results will be misleading 1
- Never skip repeat morning testosterone measurement, as single measurements are insufficient due to assay variability and diurnal fluctuation 1, 2
Potential Adverse Effects
- Erythrocytosis: Higher risk with injectable testosterone; monitor hematocrit and withhold if >54% 1, 2, 7
- Fluid retention: Use caution in cardiac, renal, or hepatic disease 7
- BPH worsening: Monitor for lower urinary tract symptoms 2, 7
- Gynecomastia: Most common with gonadotropin therapy due to increased estradiol 4
- Testicular atrophy: Expected with exogenous testosterone 1
- Acne or oily skin 1
- Sleep apnea: May worsen in those with risk factors 7
- Cardiovascular events: Some postmarketing studies show increased risk of MI and stroke, though data are conflicting 1
- Venous thromboembolism: DVT and PE reported with testosterone products 7
Special Populations
Men with Diabetes:
- Testosterone therapy may improve insulin resistance, glycemic control, and HbA1c by ~0.37% 1
- Optimize diabetes management concurrently; consider intensifying therapy with GLP-1 agonist or SGLT2 inhibitor 1
- Monitor blood glucose closely as testosterone may decrease insulin requirements 7
Men with Cirrhosis:
- Transdermal testosterone can be given only after discussing theoretical risks of hepatocellular carcinoma 1
- Use free testosterone index (total testosterone/SHBG ratio <0.3) to define hypogonadism in this population 1