At what testosterone level is treatment for hypogonadism recommended?

Testosterone Treatment Threshold

Testosterone replacement therapy should be initiated when morning total testosterone is below 300 ng/dL on at least two separate fasting morning measurements, confirmed in the presence of hypogonadal symptoms. 1, 2, 3

Diagnostic Algorithm

Step 1: Confirm Low Testosterone Levels

• Measure fasting morning total testosterone (between 8-10 AM) on at least two separate days to confirm levels below 300 ng/dL 1, 2, 3
• Morning measurements are critical because testosterone levels naturally fluctuate throughout the day, with peak levels occurring in the morning 1
• Both measurements must be below 300 ng/dL to support the diagnosis 2, 3

Step 2: Confirm with Free Testosterone (When Indicated)

• Obtain free testosterone by equilibrium dialysis, particularly in patients with obesity where sex hormone-binding globulin may be low, potentially giving falsely low total testosterone with normal free testosterone 2
• This is essential when evaluating low total testosterone clinically in a man with obesity 1

Step 3: Assess for Hypogonadal Symptoms

• Treatment requires both biochemical confirmation AND presence of symptoms 2, 3
• Key symptoms to assess include: decreased libido, decreased spontaneous erections, erectile dysfunction, decreased physical stamina and strength, depressed mood, fatigue, increased visceral adiposity, sleep disturbance, and poor concentration/memory 4, 5
• Physical findings may include testicular or muscle atrophy 4

Treatment Threshold Stratification

The evidence supports a stratified approach based on testosterone levels:

Testosterone <230 ng/dL

• Usually benefits from testosterone replacement therapy in symptomatic men 1
• This represents clear-cut hypogonadism requiring treatment 1

Testosterone 231-300 ng/dL

• Consider a 4-6 month trial in symptomatic men after careful risk-benefit discussion 1
• This falls within the diagnostic threshold but represents the lower end of the treatment spectrum 1

Testosterone 301-350 ng/dL (Gray Zone)

• A 4-6 month trial may be considered in symptomatic men after careful risk-benefit discussion 1
• Testosterone >350 ng/dL typically does not require replacement therapy 1
• Research suggests that men with sexual symptoms of hypogonadism and low-normal testosterone levels (301+ ng/dL) may respond well to TRT, with 73.6% reporting improvement in erectile function 6

Testosterone >350 ng/dL

• Typically does not require replacement therapy 1
• The European Association of Urology explicitly recommends against initiating testosterone therapy in eugonadal individuals 2

Critical Caveats and Pitfalls

Common Diagnostic Errors

• Up to 25% of men receiving testosterone therapy do not meet diagnostic criteria for testosterone deficiency 1
• Substantial proportions of U.S. men receive testosterone therapy without having testosterone levels tested before initiation 4
• Approximately 20% of men who had their testosterone level measured before initiating therapy had a level above 300 ng/dL 4

Age-Related Considerations

• Recognize that testosterone levels naturally decline with age, but this doesn't automatically indicate pathology requiring treatment 1
• The increase in testosterone use in the United States has tripled in recent years, with much of the increase in men with nonspecific symptoms who have low-normal testosterone for no apparent reason other than older age or comorbid conditions such as obesity 4

Contraindications to Treatment

• Do not prescribe testosterone to men currently trying to conceive, as it interrupts normal spermatogenesis 1
• Do not commence testosterone therapy for 3-6 months in patients with a history of cardiovascular events 1
• Avoid in men with prostate cancer, polycythemia, thrombophilia, and severe cardiovascular disease 7

Treatment Goals and Monitoring

Target Testosterone Range

• Target total testosterone levels in the middle tertile of the normal reference range (450-600 ng/dL) 1
• The goal is normalization of total testosterone levels combined with improvement in symptoms 1
• Use minimal dosing necessary to drive testosterone levels to the normal physiologic range of 450-600 ng/dL 1

Initial Monitoring

• Check testosterone levels 2-3 months after treatment initiation or any dose change 1, 2
• For injectable testosterone: measure levels midway between injections, targeting mid-normal values (500-600 ng/dL) 1, 2
• For transdermal preparations: levels can be measured at any time, with peak values occurring 6-8 hours after application 1

Ongoing Monitoring

• Once stable levels are confirmed, monitor every 6-12 months 1
• If patients do not experience symptomatic relief after reaching target testosterone levels, or remain testosterone deficient despite symptom improvement, testosterone therapy should be stopped 1

FDA-Approved Dosing (Testosterone Enanthate)

• Initial dosing ranges from 50-400 mg every 2-4 weeks for male hypogonadism 3
• Total doses above 400 mg per month are generally not required due to the prolonged action of the preparation 3
• Injections more frequently than every two weeks are rarely indicated 3

Cardiovascular Safety Considerations

• The FDA has required labeling to inform healthcare professionals and patients of a possible increased risk of heart attack and stroke with testosterone preparations 1, 2
• Low testosterone levels have been associated with increased all-cause and cardiovascular mortality in multiple prospective studies, with hazard ratios ranging from 1.24 to 7.1 4
• Patients on testosterone therapy should be advised to report any possible cardiovascular symptoms during routine follow-up visits 1