What is the role of testosterone in the body and how is low testosterone treated?

Role of Testosterone in the Body and Treatment of Low Testosterone

Testosterone treatment should only be initiated in men with age-related low testosterone who have sexual dysfunction and want to improve sexual function, using intramuscular formulations as first-line therapy due to lower cost with similar effectiveness and safety compared to transdermal options. 1

Physiological Role of Testosterone

Testosterone is a critical hormone in male physiology with multiple important functions:

• Responsible for development and maintenance of male sex organs and secondary sex characteristics including facial/body hair growth, deepening of voice, and male pattern fat distribution 2
• Promotes protein anabolism and decreases protein catabolism, improving nitrogen balance when sufficient calories and protein are available 2
• Stimulates production of red blood cells by enhancing erythropoietic stimulation factor 2
• Essential for muscle mass development and maintenance, bone density, and physical strength 3, 4
• Critical for reproductive health, affecting libido, erectile function, and spermatogenesis 3, 4
• Influences mood and cognitive function 3

Age-Related Testosterone Decline

• Serum testosterone levels begin declining in men starting in their mid-30s at an average rate of 1.6% per year 1
• Approximately 20% of men older than 60,30% of men older than 70, and 50% of men older than 80 years have low testosterone levels 1
• Syndromic low testosterone (defined as at least 3 sexual symptoms with total testosterone <320 ng/dL) is less prevalent 1

Diagnosis of Low Testosterone

• No universally accepted threshold exists for testosterone levels below which symptoms occur 1
• Morning total testosterone concentration should be drawn between 8-10 AM 1
• In men with obesity, free testosterone by equilibrium dialysis should be measured 1
• If testosterone levels are low, they should be repeated, and luteinizing hormone (LH) and follicle-stimulating hormone (FSH) should be measured to distinguish primary from secondary hypogonadism 1

Treatment Recommendations

When to Treat

• Testosterone treatment is recommended only for men with age-related low testosterone with sexual dysfunction who want to improve sexual function 1
• Testosterone treatment is NOT recommended to improve energy, vitality, physical function, or cognition in men with age-related low testosterone 1
• FDA requires labeling of testosterone medications to state they are approved only for use in persons with low testosterone due to known causes 1

Treatment Options

• Intramuscular formulations (testosterone cypionate or enanthate) are recommended as first-line therapy due to significantly lower cost with similar effectiveness and safety compared to transdermal options 1
• Intramuscular testosterone can be given at intervals of two to four weeks 2
• Transdermal options (gels, patches) provide more stable day-to-day testosterone levels but are more expensive 1
• Patient preferences may influence choice: some prefer topical gels for convenience and ease of use, while others prefer injections due to lower cost 1

Monitoring Treatment

• Symptoms should be reevaluated within 12 months and periodically thereafter 1
• Treatment should be discontinued if there is no improvement in sexual function 1
• Testosterone levels should be tested 2-3 months after treatment initiation to ensure normal levels are achieved 1

Benefits and Risks

Benefits

• Small improvement in sexual function and erectile function 1
• Less-than-small improvements in vitality, fatigue, and depressive symptoms 1
• May improve vascular endothelial function, muscle strength, and bone health 3, 4

Risks and Side Effects

• No evidence of increased risk for serious adverse events or withdrawals due to adverse events 1
• Low-certainty evidence shows small to no difference in adverse cardiovascular events 1
• No increased risk observed for mortality, prostate cancer, or venous thromboembolism in observational studies, though long-term safety data is limited 1
• Most studies excluded men with recent cardiovascular disease 1

Special Considerations

• In men with obesity and low total testosterone, free testosterone measurement is essential as some may have normal free testosterone levels due to low sex hormone-binding globulin 1
• In men with obesity and hypogonadism, testosterone replacement has shown favorable results including weight loss, improved glucose control, insulin sensitivity, and body composition 1

Treatment Algorithm

1. Confirm low testosterone with morning total testosterone measurements on at least two occasions
2. Measure free testosterone in men with obesity
3. Determine if patient has sexual dysfunction and desires improvement
4. If yes to #3, discuss potential benefits, harms, costs, and preferences
5. If treatment is initiated, use intramuscular formulations (testosterone cypionate or enanthate) as first-line
6. Reevaluate symptoms within 12 months
7. Discontinue treatment if no improvement in sexual function
8. Do not initiate testosterone for improving energy, vitality, physical function, or cognition