What are the indications for testosterone therapy in adult males with diagnosed hypogonadism?

Indications for Testosterone Therapy

Testosterone therapy is indicated exclusively for adult males with confirmed biochemical hypogonadism (morning total testosterone <300 ng/dL on two separate occasions) who have specific symptoms—primarily diminished libido and erectile dysfunction—and is absolutely contraindicated in men seeking fertility preservation. 1, 2, 3, 4

Diagnostic Requirements Before Initiating Therapy

The diagnosis of hypogonadism requires both biochemical confirmation and clinical symptoms—neither alone is sufficient 1, 2, 4:

• Measure morning total testosterone (drawn between 8-10 AM) on at least two separate occasions, with levels consistently <300 ng/dL required for diagnosis 2, 3, 4
• In men with borderline total testosterone or conditions affecting sex hormone-binding globulin (obesity, aging, diabetes), measure free testosterone by equilibrium dialysis to confirm true hypogonadism 2, 4
• Measure serum LH and FSH to distinguish primary hypogonadism (elevated LH/FSH) from secondary hypogonadism (low or low-normal LH/FSH), as this distinction has critical treatment implications for fertility preservation 2, 5, 4

Primary Clinical Indications

FDA-Approved Indications

Testosterone therapy is FDA-approved only for replacement in males with conditions associated with deficiency or absence of endogenous testosterone 3:

• Primary hypogonadism: Testicular failure from cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter's syndrome, chemotherapy, or toxic damage (alcohol, heavy metals) 3
• Secondary hypogonadism: Gonadotropin or LHRH deficiency from pituitary-hypothalamic injury due to tumors, trauma, or radiation 3

Symptom-Based Indications

The primary indication for testosterone therapy is sexual dysfunction (diminished libido and erectile dysfunction) in men with confirmed biochemical hypogonadism 1, 2, 6:

• Testosterone therapy produces small but significant improvements in sexual function (standardized mean difference 0.35) and sexual activity 1, 6
• Improvements in libido and sexual desire are consistently demonstrated across trials 2, 6, 7
• Erectile dysfunction improves modestly, though combination therapy with PDE5 inhibitors produces superior outcomes 2

Limited or No Benefit for Other Symptoms

The American College of Physicians explicitly recommends against initiating testosterone therapy to improve energy, vitality, physical function, or cognition in men with age-related low testosterone 1:

• Physical function: Little to no improvement (SMD 0.15) 1
• Energy and vitality: Less-than-small improvement (SMD 0.17) that is clinically insignificant 1, 2
• Depressive symptoms: Minimal improvement (SMD -0.19) in men without baseline depression 1, 2
• Cognitive function: No demonstrated benefit 1

Absolute Contraindications

Testosterone therapy is absolutely contraindicated in the following situations 2, 8, 3, 4:

• Active desire for fertility preservation—testosterone suppresses spermatogenesis and causes prolonged azoospermia; gonadotropin therapy (hCG plus FSH) must be used instead 2, 8, 4
• Active or treated male breast cancer 2, 8, 4
• Prostate cancer (though evidence is evolving, current guidelines maintain this contraindication) 2, 4
• Hematocrit >54% 2, 8, 4
• Untreated severe obstructive sleep apnea 2, 4
• Recent cardiovascular events (myocardial infarction or stroke within 6 months) 8, 4
• Uncontrolled heart failure 4

Special Populations and Considerations

Age-Related Low Testosterone

The FDA explicitly states that testosterone products are NOT approved for age-related hypogonadism (also called late-onset hypogonadism) 1, 3:

• Approximately 20-30% of men over 60 have low testosterone levels, but this does not constitute a disease requiring treatment without specific symptoms 1, 2
• The European Association of Urology strongly recommends against testosterone therapy in eugonadal men, even for weight loss, cardiometabolic improvement, cognition, vitality, or physical strength 2

Obesity-Associated Secondary Hypogonadism

Before initiating testosterone therapy, attempt weight loss through low-calorie diets and regular exercise, as this can improve testosterone levels without medication 2:

• Increased aromatization of testosterone to estradiol in adipose tissue causes estradiol-mediated negative feedback, suppressing pituitary LH secretion 2
• Weight loss may restore testosterone levels to normal range in some men 2

Men with Diabetes

In diabetic men with symptoms of hypogonadism, measure morning total testosterone using an accurate assay, and measure free or bioavailable testosterone in those with total testosterone near the lower limit 2:

• Testosterone therapy may improve insulin resistance, glycemic control, and HbA1c (reduction of approximately 0.37%) 2
• Improvements in lipid profile (reduced triglycerides, improved HDL cholesterol) are expected 2

Critical Clinical Algorithm

Follow this stepwise approach 2, 4:

1. Confirm symptoms: Primarily diminished libido and erectile dysfunction; other symptoms (fatigue, mood changes) are supportive but insufficient alone
2. Measure morning testosterone twice: Both measurements must be <300 ng/dL
3. Measure free testosterone if total testosterone is borderline (275-350 ng/dL) or patient has obesity/diabetes
4. Measure LH and FSH: Distinguish primary from secondary hypogonadism
5. Assess fertility desires: If patient desires fertility now or in near future, testosterone is contraindicated—use gonadotropin therapy instead
6. Screen for contraindications: Check hematocrit, PSA (if age >40), perform digital rectal exam, assess cardiovascular history
7. Set realistic expectations: Discuss that primary benefit is sexual function improvement; minimal to no benefit for energy, mood, or physical function
8. Initiate therapy: Transdermal testosterone gel (40.5 mg daily) is first-line due to stable levels and lower erythrocytosis risk; intramuscular testosterone (100-200 mg every 2 weeks) is more economical alternative
9. Monitor at 2-3 months: Check testosterone levels (target mid-normal 500-600 ng/dL), hematocrit, and PSA
10. Reassess at 12 months: If no improvement in sexual function, discontinue therapy

Common Pitfalls to Avoid

• Never diagnose hypogonadism based on symptoms alone without biochemical confirmation on two separate occasions 1, 2
• Never start testosterone without confirming the patient does not desire fertility, as suppression of spermatogenesis can be prolonged 2, 8
• Never assume age-related decline justifies treatment—the FDA has not approved testosterone for this indication 1, 3
• Never prescribe testosterone to improve energy, vitality, or physical function as primary goals—evidence shows minimal to no benefit 1
• Never skip measurement of LH and FSH—distinguishing primary from secondary hypogonadism has critical implications for fertility preservation and treatment selection 2, 5, 4