How should Adrogel (testosterone gel) be dosed and titrated in adult men with confirmed hypogonadism, and what monitoring is needed?

AndroGel Dosing and Titration in Adult Men with Confirmed Hypogonadism

Start with transdermal testosterone gel 1.62% at 40.5 mg daily (2 pump actuations) applied once in the morning to clean, dry, intact skin of the shoulders and upper arms—this is the preferred first-line formulation due to more stable day-to-day testosterone levels and significantly lower erythrocytosis risk (15.4%) compared to injectable testosterone (43.8%). 1, 2

Diagnostic Confirmation Required Before Initiating

Before prescribing any testosterone formulation, you must confirm both biochemical hypogonadism and specific symptoms:

• Two separate morning total testosterone measurements (8-10 AM) must be below 300 ng/dL 3, 1, 4, 5
• Measure free testosterone by equilibrium dialysis if total testosterone is borderline or if the patient has obesity or diabetes (conditions that lower SHBG and may artificially reduce total testosterone while free testosterone remains normal) 1
• Obtain LH and FSH levels to distinguish primary from secondary hypogonadism—this distinction is critical because men with secondary hypogonadism who desire fertility must receive gonadotropin therapy (hCG plus FSH), not testosterone 1, 4
• Qualifying symptoms are diminished libido and erectile dysfunction—these are the only symptoms with proven benefit from testosterone therapy 3, 1, 4

Critical pitfall: Do not prescribe testosterone for fatigue, low energy, depressed mood, reduced physical function, or cognitive complaints—testosterone produces little to no effect on these domains even in confirmed hypogonadism. 3, 1, 4

Starting Dose and Application Technique

AndroGel 1.62% starting dose: 40.5 mg testosterone (2 pump actuations) applied once daily in the morning 4, 5

Application Instructions (FDA-Mandated)

• Apply to shoulders and upper arms only—do not apply to abdomen, genitals, chest, armpits, or knees 5
• Apply to clean, dry, intact skin 5
• Allow gel to dry completely (approximately 5 minutes) before dressing 5, 6
• Wash hands immediately with soap and water after application 5
• Cover application sites with clothing after gel has dried to prevent secondary transfer 5
• Wash application site thoroughly with soap and water before any anticipated skin-to-skin contact with women or children 5

Critical safety warning: Virilization has been reported in children secondarily exposed to testosterone gel—children must avoid contact with unwashed or unclothed application sites. 5

Dose Titration Algorithm

Measure serum testosterone at 14 days and 28 days after starting treatment or after any dose adjustment, then periodically (every 6-12 months) once stable. 1, 4, 5

• Draw testosterone level any time of day for transdermal gel (unlike injectable testosterone, which requires midcycle timing) 1
• Target mid-normal testosterone levels: 500-600 ng/dL 1, 4

Dose Adjustment Based on Testosterone Levels

AndroGel 1.62% can be adjusted between 20.25 mg (1 pump actuation) and 81 mg (4 pump actuations) daily: 5

• If testosterone <350 ng/dL: Increase by 20.25 mg (1 pump actuation) 5
• If testosterone 350-750 ng/dL: Continue current dose 3, 5
• If testosterone >750 ng/dL: Decrease by 20.25 mg (1 pump actuation) 5

The 2023 TRAVERSE trial—the highest-quality evidence available—used transdermal 1.62% testosterone gel with dose adjustments targeting levels between 350 and 750 ng/dL in 5,246 men with confirmed hypogonadism and found no increased risk of stroke or major adverse cardiac events. 3

Mandatory Monitoring Requirements

Baseline (Before Starting Testosterone)

• Hematocrit/hemoglobin—hematocrit >54% is an absolute contraindication to starting therapy 1, 4
• PSA level and digital rectal examination in men over 40 years 1, 4
• Confirm patient does not desire fertility—testosterone causes azoospermia and is absolutely contraindicated in men seeking fertility preservation 1, 4

Ongoing Monitoring

• Testosterone levels: At 2-3 months after initiation or dose change, then every 6-12 months once stable 1, 4
• Hematocrit: At each visit—withhold treatment if >54% and consider phlebotomy in high-risk cases 1, 4
• PSA: 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
• Digital rectal examination: At each visit to assess for prostate abnormalities 1

Expected Treatment Outcomes

Set realistic expectations with patients before starting therapy:

Proven Benefits (Small but Significant)

• Sexual function and libido: Standardized mean difference 0.35—this is the primary indication for therapy 3, 1, 4
• Quality of life: Modest improvements, primarily in sexual function domains 1, 4
• Metabolic effects in men with diabetes: HbA1c reduction of approximately 0.37%, improved insulin resistance 1, 4

Minimal or No Benefit

• Physical functioning, energy, vitality: Standardized mean difference 0.17—too small to be clinically meaningful 1
• Depressive symptoms: Standardized mean difference -0.19—less than small improvement 1
• Cognition: No significant effect 3, 1

Reevaluate symptoms at 12 months and discontinue testosterone if no improvement in sexual function is seen—this prevents unnecessary long-term exposure to potential risks without benefit. 1

Absolute Contraindications

Do not prescribe testosterone if any of the following are present:

• Active desire for fertility preservation—use gonadotropin therapy (hCG plus FSH) instead 1, 4
• Active or treated male breast cancer 1, 4
• Prostate cancer (though evidence is evolving) 1
• Hematocrit >54% 1, 4
• Untreated severe obstructive sleep apnea 1

Formulation Comparison: Why Gel Over Injectable Testosterone

Transdermal testosterone gel is strongly preferred over injectable testosterone for the following evidence-based reasons:

Erythrocytosis Risk

• Injectable testosterone (cypionate/enanthate): 43.8% develop hematocrit >52% 2
• Transdermal gel: 15.4% develop erythrocytosis—nearly 3-fold lower risk 2

This difference directly impacts cardiovascular morbidity and mortality, as elevated hematocrit increases blood viscosity and thrombotic risk. 2

Testosterone Level Stability

• Injectable testosterone: Produces supraphysiologic peaks 2-5 days after injection, followed by subtherapeutic troughs by days 10-14—this fluctuation causes mood and sexual function shifts in some men 3, 1, 2
• Transdermal gel: Provides stable day-to-day testosterone levels with minimal fluctuation 3, 1, 2

Evidence suggests injectable testosterone may carry higher cardiovascular event risk than transdermal preparations due to time spent in both supratherapeutic and subtherapeutic ranges between injections. 3, 2

Cost Consideration

The primary disadvantage of transdermal gel is cost: approximately $2,135 annually versus $156 for intramuscular formulations. 3, 2 However, 71% of patients prefer topical gel over injections for convenience, ease of use, and non-staining of clothes. 1, 2

If cost is a primary concern and the patient has no cardiovascular risk factors, intramuscular testosterone cypionate or enanthate 100-200 mg every 2 weeks is acceptable, but requires closer hematocrit monitoring. 3, 1

Special Populations

Elderly Men (>65 Years)

• Transdermal preparations are strongly preferred over injections due to more stable levels and lower erythrocytosis risk 4
• Target mid-range testosterone levels (350-600 ng/dL) rather than upper-normal 1
• Use easily titratable formulations (gel, spray, or patch) to allow dose adjustment 1

Men with Cardiovascular Disease

• Avoid testosterone in men with recent myocardial infarction or stroke within the past 3-6 months 1, 2
• In men with congestive heart failure, use caution due to risk of fluid retention and target mid-range testosterone levels (350-600 ng/dL) 1
• The 2023 TRAVERSE trial provides reassurance that testosterone gel does not increase stroke risk in men 45-80 years with confirmed hypogonadism and either preexisting CVD or high CVD risk 3

Men with Obesity-Associated Secondary Hypogonadism

Attempt weight loss through low-calorie diets (500-750 kcal/day deficit) and regular exercise (minimum 150 minutes/week moderate-intensity aerobic exercise plus resistance training 2-3 times weekly) before initiating testosterone—this can reverse the condition by improving testosterone levels and normalizing gonadotropins. 1, 4

If lifestyle modification fails after 3-6 months and the patient has persistent symptoms, testosterone therapy can be initiated using the standard algorithm above. 1

Men with Diabetes

• Testosterone therapy may improve insulin resistance, glycemic control, and HbA1c (reduction approximately 0.37%) 1, 4
• Consider intensifying diabetes therapy concurrently with testosterone, such as adding a GLP-1 receptor agonist or SGLT2 inhibitor for cardiovascular benefits 1
• Continue statin therapy as indicated—testosterone may improve lipid profile 1

Alternative Transdermal Formulations

If AndroGel 1.62% is not tolerated or preferred, other transdermal options include:

• AndroGel 1%: 50-100 mg/day (25 mg in 2.5-g packet) 3
• Testim 1% gel: 50-100 mg/day (50 mg in 5-g packet) 3
• Fortesta 2% gel: 10-70 mg/day (metered-dose pump, 10 mg per actuation) 3
• Axiron 2% solution: 30-120 mg/day (metered-dose pump, 30 mg per actuation, applied to axilla) 3
• Testosterone patches (Androderm): 2-6 mg/24-hour patch applied to back, abdomen, upper thighs, or upper arms 3, 2

Patches have the advantage of no risk of secondary transfer to others but higher rates of skin irritation and poor adherence. 3, 2

Pharmacokinetic Data Supporting Once-Daily Dosing

Long-term pharmacokinetic studies demonstrate that transdermal testosterone gel achieves steady-state serum testosterone levels within 48-72 hours of first application, with stable levels maintained over 180 days of daily application. 6 The gel dries within 5 minutes, and approximately 9-14% of applied testosterone is bioavailable. 6 Serum testosterone rises rapidly into the normal adult male range on day 1 with first application and remains stable with continued daily use. 7, 6

Application site matters: testosterone absorption is highest when applied to arms/shoulders, followed by chest/abdomen, then calves/legs. 8 The FDA-approved application site for AndroGel 1.62% is shoulders and upper arms only. 5