When is testosterone supplementation appropriate for treatment of hypogonadism?

When to Treat with Testosterone Supplementation

Testosterone replacement therapy should be initiated only when a patient has both biochemically confirmed hypogonadism (morning total testosterone <300 ng/dL on two separate occasions) AND specific symptoms of testosterone deficiency, particularly diminished libido and erectile dysfunction. 1

Diagnostic Requirements Before Treatment

Biochemical Confirmation

• Measure morning total testosterone (between 8-10 AM) on at least two separate days to confirm persistent hypogonadism, as single measurements are unreliable due to assay variability and diurnal fluctuation 1, 2
• Testosterone levels must be below 300 ng/dL (some guidelines use 275-350 ng/dL threshold) to establish hypogonadism 1
• Measure free testosterone by equilibrium dialysis and sex hormone-binding globulin (SHBG), especially in men with obesity or borderline total testosterone levels 1

Distinguish Primary from Secondary Hypogonadism

• Measure serum LH and FSH after confirming low testosterone to determine the type of hypogonadism 1
• Elevated LH/FSH with low testosterone indicates primary (testicular) hypogonadism 1
• Low or low-normal LH/FSH with low testosterone indicates secondary (hypothalamic-pituitary) hypogonadism 1
• This distinction is critical because testosterone therapy is absolutely contraindicated in men seeking fertility preservation—these men require gonadotropin therapy (hCG plus FSH) instead 1

Clinical Indications for Treatment

Primary Indication: Sexual Dysfunction

• The primary indication for testosterone therapy is diminished libido and erectile dysfunction in men with confirmed biochemical hypogonadism 1
• Testosterone produces small but significant improvements in sexual function (standardized mean difference 0.35) and quality of life 3, 1

Limited or No Benefit for Other Symptoms

• Testosterone therapy produces little to no effect on physical functioning, energy, vitality, or cognition, even in confirmed hypogonadism 3, 1
• Effect sizes for energy and fatigue are minimal (SMD 0.17), too small to be clinically meaningful 1
• Improvements in depressive symptoms are less-than-small (SMD -0.19) and not clinically significant 1

Absolute Contraindications

Do not initiate testosterone therapy in the following situations:

• Men actively seeking fertility preservation (use gonadotropin therapy instead) 1
• Active or treated male breast cancer 1
• Known or suspected prostate cancer 2
• Women who are pregnant (testosterone causes fetal harm) 2
• Untreated severe obstructive sleep apnea 1

Specific Clinical Scenarios

Classical Hypogonadism (Primary or Secondary)

• Treat all men with classical hypogonadism (Klinefelter's syndrome, anorchia, pituitary failure) who have inadequately low testosterone for their age 4
• These patients have unequivocal indications for lifelong testosterone replacement 4

Age-Related Low Testosterone

• Strongly recommend against testosterone therapy in men with age-related low-normal testosterone to improve energy, vitality, or physical function 1
• Approximately 20-30% of men over 60 have testosterone in the low-normal range, but this does not constitute a disease requiring treatment 1
• Only treat if testosterone is definitively low (<300 ng/dL) AND sexual symptoms are present 1

Obesity-Associated Secondary Hypogonadism

• First attempt weight loss through low-calorie diets and regular exercise, as this can improve testosterone levels without medication 3, 1
• Only initiate testosterone if hypogonadism persists after lifestyle modifications and sexual symptoms are present 1

Men with Chronic Liver Disease

• Testosterone can be given to hypogonadal men with cirrhosis only after discussion of theoretical risks of hepatocellular carcinoma 3
• Define hypogonadism using free testosterone index (total testosterone/SHBG ratio <0.3) since SHBG is often elevated in liver disease 3

Critical Pitfalls to Avoid

• Never diagnose hypogonadism based on symptoms alone without biochemical confirmation 1
• Never start testosterone without confirming the patient does not desire fertility 1
• Never use testosterone in eugonadal men (normal testosterone levels), even if symptomatic, for weight loss, muscle building, or cognitive enhancement 1
• Never attempt to diagnose type of hypogonadism while patient is on testosterone therapy, as exogenous testosterone suppresses LH/FSH and results will be misleading 1
• Approximately 20-30% of men receiving testosterone in the United States do not have documented low testosterone before treatment initiation—this violates evidence-based guidelines 1

Setting Realistic Expectations

Before initiating therapy, counsel patients that:

• Primary benefit is improvement in sexual function and libido 3, 1
• Minimal to no improvement expected in energy, mood, physical function, or cognition 3, 1
• Reevaluate symptoms at 12 months and discontinue testosterone if no improvement in sexual function, to prevent unnecessary long-term exposure without benefit 1