What to do if testosterone level remains at hypogonadism after treatment with testosterone (gel) 20.25mg?

Inadequate Response to Testosterone Gel: Management Algorithm

If testosterone levels remain at zero despite treatment with testosterone gel 20.25mg, you must first verify proper application technique and then escalate the dose or switch to intramuscular injections, as gel absorption can be highly variable and insufficient in some patients. 1

Immediate Assessment Steps

Verify Application Technique

• Confirm the patient is applying the full prescribed dose (20.25mg is only 1 pump actuation, which is below the recommended starting dose of 40.5mg) 2
• Check that application is to clean, dry, intact skin of the upper arms and shoulders only (not abdomen, genitals, chest, or other sites where absorption differs) 2
• Ensure the patient waits minimum 2 hours before showering or swimming after application 2
• Verify hands are washed immediately after application and application sites are covered with clothing once dry 2
• Confirm the pump was properly primed (3 actuations discarded before first use) 2

Rule Out Absorption Issues

• Gel absorption is highly variable between patients, with some experiencing inconsistent testosterone replacement 1
• Application of moisturizing lotion or sunscreen can alter absorption (increases levels by 8-17%), but this doesn't explain zero levels 2
• Consider whether the patient has skin conditions affecting the application site that could impair absorption 1

Dose Escalation Protocol

Increase to Therapeutic Starting Dose

• The current dose of 20.25mg is subtherapeutic—the FDA-approved starting dose is 40.5mg (2 pump actuations) 2
• Increase immediately to 40.5mg daily and recheck testosterone levels at 14 days 2
• If levels remain below 350 ng/dL at 14 days, increase by 20.25mg increments up to maximum of 81mg (4 pump actuations) 2
• Target testosterone levels should be in the mid-normal range of 450-600 ng/dL 1

Monitoring Timeline

• Measure pre-dose morning testosterone at 14 days and 28 days after starting treatment or dose adjustment 2
• Continue periodic assessment every 3-6 months for the first year, then yearly 1
• Also monitor hematocrit/hemoglobin, PSA, and perform digital rectal examination at each visit 1

Switch to Alternative Formulation

When to Switch from Gel to Injections

• If maximal recommended gel dose (81mg) fails to achieve adequate serum testosterone levels, switch to intramuscular injection therapy 1
• Intramuscular testosterone (cypionate or enanthate) administered every 2-3 weeks offers more reliable absorption than gels 1, 3
• Injections are significantly more cost-effective ($156.24 annually vs $2,135.32 for transdermal) and advantageous for patients with reduced disease-management skills 1, 3
• For injection therapy, measure testosterone levels midway between injections, targeting 500-600 ng/dL 1, 3

Alternative: Testosterone Patches

• Patches minimize variable absorption issues seen with gels but have higher rates of skin irritation (up to 66% vs 5% with gels) 1
• Consider if patient has difficulty with injection compliance but needs more reliable delivery than gel 1

Consider Secondary Causes

Evaluate for Obesity-Related Pseudo-Hypogonadism

• If the patient has obesity (BMI >30), measure morning free testosterone by equilibrium dialysis and sex hormone-binding globulin (SHBG) 1
• Low total testosterone with proportionately low SHBG but normal free testosterone indicates pseudo-hypogonadism of obesity, not true hypogonadism 4
• In this scenario, weight loss is more effective than testosterone treatment—clinically significant weight loss substantially reverses obesity-related testosterone reductions 4

Distinguish Primary vs Secondary Hypogonadism

• Measure serum LH and FSH to differentiate testicular failure (primary) from pituitary-hypothalamic dysfunction (secondary) 1, 3
• If LH/FSH are low with low testosterone (secondary hypogonadism), evaluate for pituitary pathology with prolactin, iron saturation, and consider MRI of sella turcica 1

Alternative Pharmacotherapy

Clomiphene Citrate for Secondary Hypogonadism

• For men with secondary hypogonadism who wish to preserve fertility or cannot tolerate testosterone, clomiphene citrate 25-50mg daily is an effective alternative 5, 6
• Clomiphene stimulates endogenous testosterone production without suppressing spermatogenesis 5, 6
• Particularly valuable in obesity-related hypogonadism where increased aromatization suppresses LH 5
• Not effective for primary hypogonadism—check baseline LH/FSH first 5
• Monitor response at 3 months; if no improvement, switch to testosterone replacement 5

Critical Pitfalls to Avoid

• Do not continue ineffective gel therapy indefinitely—if levels remain suboptimal after dose escalation to 81mg, switch formulations 1
• Do not apply gel to abdomen or other non-approved sites attempting to improve absorption—this alters pharmacokinetics unpredictably 2
• Do not assume treatment failure without first confirming proper application technique and adequate dosing 2
• Do not overlook reversible causes like obesity, uncontrolled diabetes, sleep apnea, or medications that suppress testosterone 1, 4
• Counsel regarding lifestyle modifications concurrently—weight loss and increased physical activity can increase testosterone levels 1