At what testosterone level would you consider initiating testosterone replacement therapy with injections in patients with hypogonadism?

Testosterone Injection Initiation Threshold

Initiate testosterone replacement therapy when morning total testosterone is below 300 ng/dL on at least two separate fasting morning measurements (drawn between 8-10 AM), confirmed with a frankly low free testosterone level by equilibrium dialysis, in the presence of hypogonadal symptoms. 1, 2

Diagnostic Algorithm

Initial Assessment Requirements

• Measure morning total testosterone between 8-10 AM on at least two separate days to confirm levels below the normal range (300-800 ng/dL) 1, 2
• Obtain free testosterone by equilibrium dialysis - this is essential, particularly in patients with obesity where sex hormone-binding globulin may be low, potentially giving falsely low total testosterone with normal free testosterone 1
• Measure sex hormone-binding globulin to interpret total testosterone accurately 1

Confirmatory Testing

If initial testosterone levels are subnormal:

• Repeat the morning testosterone measurement to confirm persistently low levels 1
• Measure serum LH and FSH to distinguish primary (testicular) from secondary (pituitary-hypothalamic) hypogonadism 1
• If LH/FSH are low (secondary hypogonadism), obtain serum prolactin, iron saturation, consider pituitary function testing and MRI of sella turcica 1

Symptom Requirements

Treatment should only be initiated when biochemical hypogonadism is accompanied by symptoms, including:

• Decreased energy 1
• Reduced libido 1
• Decreased muscle mass 1
• Loss of body hair 1
• Hot flashes, gynecomastia, or infertility 1

Critical Threshold Details

The specific testosterone level of <300 ng/dL is recommended by the American Urological Association as the threshold to categorize a man as hypogonadal 1. However, the evidence shows that:

• Most clinical trials enrolled patients with total testosterone ≤300 ng/dL 1
• Eleven trials used even lower thresholds of <275 ng/dL 1
• Only 13 trials required two fasting morning testosterone levels, and only 2 required both measurements to be ≤300 ng/dL 1

Special Consideration for Obesity

In patients with obesity, treatment should be considered only when morning free testosterone by equilibrium dialysis is frankly low on at least 2 separate assessments 1. This is because obesity-related decreases in testosterone are frequently due to low sex hormone-binding globulin, and these patients may have normal free testosterone despite low total testosterone 1.

Formulation Selection for Injections

While transdermal preparations are generally preferred for most patients due to more stable testosterone levels, testosterone injections offer specific advantages 1:

• Avoid daily administration requirements 1
• Advantageous in patients with reduced disease-management skills or resources 1
• More cost-effective than transdermal preparations 1

Injectable Dosing

For testosterone enanthate or cypionate: 100-200 mg every 2 weeks or 50 mg weekly 1, 2

• Doses above 400 mg per month are rarely required 2
• Injections more frequently than every 2 weeks are rarely indicated 2

For testosterone undecanoate: 750 mg initially, followed by 750 mg at 4 weeks, then 750 mg every 10 weeks 1

Monitoring After Initiation

• Check testosterone levels 2-3 months after treatment initiation or any dose change 1
• For injections, measure levels midway between injections, targeting mid-normal values (500-600 ng/dL) 1
• Once stable levels confirmed, monitor every 6-12 months 1

Critical Safety Caveat

There is conflicting evidence regarding cardiovascular safety of testosterone therapy 1. The FDA required labeling changes in 2015 regarding possible increased risk of heart attack and stroke 1. Some evidence suggests testosterone injections may carry greater cardiovascular risk than gels, potentially related to fluctuations between supratherapeutic and subtherapeutic ranges 1. However, multiple professional societies support testosterone use when appropriately indicated, and these cardiovascular concerns may reflect high-risk patient populations rather than the therapy itself 1.

Never initiate testosterone therapy in eugonadal individuals - this is explicitly recommended against by the European Association of Urology 3.