Testosterone Replacement Therapy for Hypogonadism
Transdermal testosterone formulations are the recommended first-line treatment for testosterone replacement therapy (TRT) in individuals with hypogonadism due to their stable hormone levels and lower risk of adverse effects compared to intramuscular injections. 1, 2
Diagnosis of Hypogonadism
- Diagnosis requires low testosterone levels (<300 ng/dL) in at least two separate morning measurements AND presence of corresponding symptoms such as decreased libido, fatigue, and mood changes 1, 2
- Assessment should include morning total testosterone concentration drawn between 8 AM and 10 AM, as well as free testosterone level by equilibrium dialysis and sex hormone-binding globulin level, especially in men with obesity 2
- Serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations should be measured to distinguish primary (testicular) from secondary (pituitary-hypothalamic) hypogonadism 2
Treatment Options
First-Line: Transdermal Formulations
- Transdermal formulations (gels, patches) provide stable testosterone levels and avoid fluctuations observed with intramuscular injections 1, 2
- Target mid-normal physiological values (500-600 ng/dL) 2
- Lower risk of polycythemia (3-18%) compared to injections (up to 44%) 1
- Apply to clean, dry, intact skin of the shoulders and upper arms only 3
Alternative: Intramuscular Injections
- Testosterone cypionate or enanthate administered every 2-3 weeks 2
- More economical option ($156.24 annually) compared to topical gels/creams ($2,135.32 annually) 1
- Peak serum levels occur 2-5 days after injection, with return to baseline usually observed 10-14 days after injection 2
- Target mid-normal value (500-600 ng/dL) when measured midway between injections 2
Important Limitations
- Oral testosterone formulations are specifically contraindicated by the FDA for "age-related hypogonadism" not associated with structural or genetic etiologies 1, 3
- Safety and efficacy of testosterone therapy in men with "age-related hypogonadism" have not been established 3
Monitoring Protocol
- Test testosterone levels 2-3 months after treatment initiation and/or after any dose adjustment 1, 2
- Once stable levels are confirmed, monitor every 6-12 months 2
- Evaluate symptoms within 12 months of starting treatment 1
- Monitor PSA and prostate function, especially in men over 40 years old 1
- Monitor hematocrit to detect polycythemia, which is less common with transdermal formulations 1, 2
Expected Benefits
- Improved sexual functioning and quality of life, though effect sizes may be small 4, 2
- Potential improvements in fasting plasma glucose, insulin resistance, triglyceride levels, and HDL cholesterol 2
- Little to no effect on physical functioning, depressive symptoms, energy and vitality, or cognition in older men 4
Potential Risks and Side Effects
- Secondary exposure risk with topical formulations - patients must wash hands immediately after application and cover application sites with clothing after the gel has dried 3
- Erythrocytosis (higher risk with injections) 1, 2
- Fluid retention, benign prostatic hyperplasia, sleep apnea, gynecomastia, acne or oily skin, and testicular atrophy 2, 5
- Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE) 3, 5
- Possible increased risk of myocardial infarction and stroke 3
- Fertility suppression due to negative feedback on the hypothalamic-pituitary-gonadal axis 6
Special Considerations
- TRT is specifically indicated for primary hypogonadism (congenital or acquired) and hypogonadotropic hypogonadism (congenital or acquired) 3
- The European Association of Urology specifically recommends against using testosterone therapy in eugonadal individuals 7
- Long-term efficacy and safety data are limited, particularly for men aged 18 to 50 years 4, 8
- Weight loss through low-calorie diets can improve testosterone levels in men with obesity-associated secondary hypogonadism 2