Testosterone Therapy for Hypogonadism
Diagnostic Requirements Before Treatment
Testosterone therapy should only be initiated in men with both confirmed biochemical hypogonadism (morning total testosterone <300 ng/dL on two separate occasions measured between 8-10 AM) and specific symptoms, particularly diminished libido and erectile dysfunction. 1
Essential Diagnostic Steps
- Measure morning total testosterone (8-10 AM) on at least two separate occasions to confirm persistent hypogonadism, as single measurements are unreliable due to assay variability and diurnal fluctuation 1
- If testosterone is low-normal or borderline, measure free testosterone by equilibrium dialysis and sex hormone-binding globulin (SHBG) levels, especially in men with obesity 1
- Once low testosterone is confirmed, measure serum LH and FSH to distinguish primary (testicular) from secondary (hypothalamic-pituitary) hypogonadism 1
- Elevated LH/FSH with low testosterone = primary hypogonadism
- Low or low-normal LH/FSH with low testosterone = secondary hypogonadism 1
This distinction is critical because it determines fertility preservation options and treatment selection 1
Treatment Selection Algorithm
Step 1: Assess Fertility Desires
Testosterone therapy is absolutely contraindicated in men actively seeking fertility preservation, as it suppresses spermatogenesis and causes azoospermia. 1
For men desiring fertility with secondary hypogonadism: Use gonadotropin therapy (recombinant hCG plus FSH) as first-line treatment instead of testosterone 1, 2
For men with primary hypogonadism desiring fertility: Testosterone therapy permanently compromises fertility; gonadotropins are the only option 1
Step 2: Choose Testosterone Formulation (If Fertility Not Desired)
Transdermal testosterone gel (1.62% at 40.5 mg daily) is the preferred first-line formulation due to more stable day-to-day testosterone levels and lower risk of erythrocytosis compared to injections. 1, 3
Transdermal Preparations (Preferred)
- Provide stable testosterone levels without the peaks and troughs of injections 1
- Lower risk of erythrocytosis (3-18%) compared to injections (up to 44%) 3
- Annual cost approximately $2,135 1
- Preferred by some patients for convenience and ease of use 1
Intramuscular Injections (Alternative)
- FDA-approved dosing: testosterone cypionate 50-400 mg every 2-4 weeks 4
- Peak serum levels occur 2-5 days after injection, with return to baseline by days 10-14 1
- More economical option with annual cost of $156 1, 3
- Higher risk of erythrocytosis compared to transdermal preparations 1
- Should be administered deep in the gluteal muscle 4
Absolute Contraindications
Do not initiate testosterone therapy in the following situations: 1
- Men actively seeking fertility preservation (use gonadotropins instead) 1
- Active or treated male breast cancer 1
- Eugonadal men (normal testosterone levels), even if symptomatic or seeking weight loss, cardiometabolic improvement, cognition enhancement, vitality, or physical strength 1
- Active prostate cancer (though evidence is evolving) 1
Monitoring Requirements
Initial Monitoring
- Check testosterone levels 2-3 months after treatment initiation and after any dose change 1
- For intramuscular injections: Measure levels midway between injections, targeting a mid-normal value (500-600 ng/dL) 1
- For transdermal preparations: Morning levels should be in the mid-normal range 1
Ongoing Monitoring
- Once stable levels are confirmed, monitor testosterone every 6-12 months 1
- Check hematocrit periodically and withhold treatment if >54%; consider phlebotomy in high-risk cases 1
- Monitor PSA levels in men over 40 years and adjust treatment if significant increases occur 1
- Assess for benign prostatic hyperplasia symptoms through prostate examination 1
- Reevaluate symptoms at 12 months and discontinue testosterone if no improvement in sexual function is seen 1
Expected Treatment Outcomes
Realistic Benefits
- Small but significant improvements in sexual function and libido (standardized mean difference 0.35) 1
- Modest improvements in quality of life, particularly in vitality, social functioning, and mental health domains 1
- Improvements in fasting plasma glucose, insulin resistance, triglyceride levels, and HDL cholesterol 1
- Potential improvement in bone mineral density 1
- May help correct mild anemia 1
Limited or No Benefits
- Little to no effect on physical functioning, energy, vitality, or cognition 1
- Minimal improvements in depressive symptoms (SMD -0.19) 1
- No benefit for muscle building in eugonadal men 1
The European Association of Urology explicitly states that testosterone therapy should not be used in eugonadal men for weight loss, cardiometabolic improvement, cognition, vitality, or physical strength in aging men 1
Critical Pitfalls to Avoid
- Never start testosterone without confirming the patient does not desire fertility 1
- Never diagnose hypogonadism based on symptoms alone without laboratory confirmation 1, 5
- Never attempt to diagnose the type of hypogonadism (primary vs. secondary) while the patient is on testosterone therapy, as results will be misleading; testosterone must be discontinued with adequate washout (2-4 weeks) before diagnostic testing 1
- Never assume age-related decline in young men without investigating for secondary causes of hypogonadism, as reversible conditions must be addressed first 1
- Approximately 20-30% of men receiving testosterone in the United States do not have documented low testosterone levels before treatment initiation, violating evidence-based guidelines 1
Special Populations
Elderly Men with Symptomatic Hypogonadism
- The American College of Physicians recommends testosterone therapy primarily to improve sexual function, not for energy, vitality, physical function, or cognition 1
- Low testosterone in elderly men is defined as total testosterone <275 ng/dL with associated symptoms 1
Men with Obesity-Associated Secondary Hypogonadism
- First attempt weight loss through low-calorie diets and regular exercise, as this can improve testosterone levels without medication 1
- Increased aromatization of testosterone to estradiol in adipose tissue causes estradiol-mediated negative feedback suppressing pituitary LH secretion 1
Men with Diabetes
- Measure morning total testosterone using an accurate assay in diabetic men with symptoms or signs of hypogonadism 1
- Also measure free or bioavailable testosterone levels in diabetic men with total testosterone near the lower limit 1