What is the recommended treatment for an adult male with symptoms suggestive of hypogonadism and laboratory-confirmed low total and free testosterone levels?

Treatment for Adult Male Hypogonadism with Low Total and Free Testosterone

For an adult male with symptoms of hypogonadism and laboratory-confirmed low total and free testosterone levels, initiate testosterone replacement therapy using either transdermal testosterone gel 1.62% at 40.5 mg daily or intramuscular testosterone cypionate/enanthate 100-200 mg every 2 weeks, after confirming the diagnosis with two separate morning measurements and ruling out contraindications. 1, 2, 3, 4

Diagnostic Confirmation Required Before Treatment

Before initiating therapy, you must confirm:

• Two separate morning total testosterone measurements (drawn between 8-10 AM) showing levels <300 ng/dL 1, 2, 5, 6
• Free testosterone by equilibrium dialysis is frankly low, particularly important when total testosterone is borderline or in men with obesity 7, 1
• Measure LH and FSH levels 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 7, 1, 6
• Document specific symptoms including diminished libido, erectile dysfunction, reduced energy, decreased muscle mass, or hot flashes 1, 2, 5

If secondary hypogonadism is confirmed with low LH/FSH, further workup should include serum prolactin, iron saturation, pituitary function testing, and potentially MRI of the sella turcica to identify reversible causes 7, 1

First-Line Treatment Selection

Preferred Option 1: Transdermal Testosterone Gel

• Transdermal testosterone gel 1.62% at 40.5 mg daily (2 pump actuations) applied to shoulders and upper arms 1, 2, 3
• Provides more stable day-to-day testosterone levels compared to injections 1, 2
• Dose can be adjusted between 20.25 mg (1 pump) and 81 mg (4 pumps) based on monitoring 3
• Annual cost approximately $2,135 1
• Critical warning: Children must avoid contact with unwashed or unclothed application sites due to risk of virilization 3

Preferred Option 2: Intramuscular Testosterone

• Testosterone cypionate or enanthate 100-200 mg every 2 weeks intramuscularly 1, 2, 4, 6
• More cost-effective option with annual cost of $156 1, 2
• Peak levels occur at days 2-5, return to baseline by days 10-14 1
• Higher risk of erythrocytosis compared to transdermal preparations 1, 2

Choose intramuscular injections if cost is a primary concern; choose transdermal gel if the patient prefers convenience and more stable testosterone levels. 1, 2

Expected Treatment Outcomes

Benefits You Can Promise

• Small but significant improvements in sexual function and libido with standardized mean difference of 0.35 7, 1, 2, 6
• Improvements in fasting plasma glucose, insulin resistance, triglyceride levels, and HDL cholesterol 7, 1
• Increased lean body mass and decreased visceral adiposity 7, 8
• Improved bone mineral density 1, 8, 5

Limited or No Benefits

• Little to no effect on physical functioning, energy, vitality, or cognition even with confirmed hypogonadism 7, 1, 2
• Minimal improvements in depressive symptoms (SMD -0.19) 7, 1
• The American College of Physicians explicitly recommends against initiating testosterone to improve energy, vitality, physical function, or cognition 7

Monitoring Protocol

Initial Monitoring (First 3 Months)

• Measure testosterone levels at 2-3 months after treatment initiation or dose adjustment 1, 5, 6
• For injectable testosterone, measure levels midway between injections (days 5-7), targeting mid-normal values of 500-600 ng/dL 1, 2
• For transdermal gel, measure pre-dose morning levels at 14 and 28 days, targeting 350-750 ng/dL 3
• Monitor hematocrit at each visit—withhold treatment if >54% and consider phlebotomy 1, 2, 5, 6

Ongoing Monitoring (After Stabilization)

• Testosterone levels every 6-12 months once stable 1, 5, 6
• Hematocrit every 3-6 months 2, 5, 6
• PSA levels in men over 40 years—refer for urologic evaluation if PSA increases >1.0 ng/mL in first 6 months or >0.4 ng/mL per year thereafter 1, 2, 5, 6
• Digital rectal examination to assess for prostate abnormalities 1, 5, 6

Treatment Reassessment

• Reevaluate symptoms at 12 months and discontinue testosterone if no improvement in sexual function to prevent unnecessary long-term exposure without benefit 1, 2

Absolute Contraindications

Do not initiate testosterone therapy if the patient has: 1, 2, 5, 6

• Active or treated male breast cancer 1, 2, 5, 6
• Prostate cancer or PSA >4 ng/mL (>3 ng/mL in high-risk men) without urologic evaluation 5, 6
• Active desire for fertility preservation—testosterone causes azoospermia; use gonadotropin therapy (hCG plus FSH) instead 1, 2, 6, 9
• Hematocrit >50-54% 5, 6
• Untreated severe obstructive sleep apnea 5, 6
• Uncontrolled heart failure 5, 6
• Myocardial infarction or stroke within the last 6 months 6
• Palpable prostate nodule or induration without urologic evaluation 5, 6

Critical Fertility Consideration

If the patient desires fertility now or in the near future, testosterone therapy is absolutely contraindicated. 1, 2, 6, 9

• Exogenous testosterone suppresses the hypothalamic-pituitary-gonadal axis, causing azoospermia that can persist for months after discontinuation 1, 9
• For men with secondary hypogonadism seeking fertility, use recombinant hCG plus FSH instead, which stimulates the testes directly and restores both testosterone production and spermatogenesis 1, 9
• Men with primary hypogonadism cannot benefit from gonadotropin therapy as their testes cannot respond 1

Special Populations

Men with Obesity-Associated Hypogonadism

• Attempt weight loss through low-calorie diets and regular exercise before initiating testosterone, as this can improve testosterone levels without medication 7, 1
• Obesity causes low sex hormone-binding globulin and increased aromatization of testosterone to estradiol, resulting in secondary hypogonadism 7
• Free testosterone measurement by equilibrium dialysis is essential in this population 7, 1

Men with Diabetes

• Testosterone therapy may improve insulin resistance, glycemic control, and HbA1c by approximately 0.37% 1
• Consider intensifying diabetes therapy concurrently with GLP-1 receptor agonist or SGLT2 inhibitor for cardiovascular benefits 1

Common Pitfalls to Avoid

• Never diagnose hypogonadism based on symptoms alone without confirmed low testosterone on two separate morning measurements 1, 2, 5, 6
• Never start testosterone without confirming the patient does not desire fertility, as this causes irreversible suppression of spermatogenesis 1, 2
• Never draw testosterone levels at peak (days 2-5) or trough (days 13-14) for injectable testosterone—measure midway between injections 1
• Never assume age-related decline justifies treatment—the FDA has not approved testosterone for age-related hypogonadism, and evidence shows minimal benefit for non-sexual symptoms 7, 3
• Never attempt to diagnose primary vs. secondary hypogonadism while the patient is on testosterone therapy—the results will be misleading due to suppression of the hypothalamic-pituitary axis 1