What is a suitable treatment plan for a male patient with hypogonadism (low testosterone levels) seeking microdosing testosterone replacement therapy (TRT)?

Microdosing Testosterone Replacement Therapy (TRT)

Microdosing TRT refers to administering smaller, more frequent doses of testosterone—typically weekly or twice-weekly injections rather than the traditional every 2-3 week schedule—to minimize peak-trough fluctuations and maintain more stable physiologic testosterone levels. 1

What is Microdosing TRT?

Traditional intramuscular testosterone cypionate or enanthate injections are administered at 100-200 mg every 2-3 weeks, resulting in peak serum levels 2-5 days post-injection (often supraphysiologic) and return to baseline by days 10-14. 1 This creates a "roller coaster" effect where patients experience high testosterone symptoms early (acne, mood changes, fluid retention) and low testosterone symptoms late in the cycle (fatigue, decreased libido). 1

Microdosing splits the total biweekly or monthly dose into smaller, more frequent administrations—for example, 50-100 mg weekly or 25-50 mg twice weekly—to achieve more stable day-to-day testosterone levels similar to transdermal preparations. 1 This approach mimics the pharmacokinetic advantage of testosterone gel (which provides stable levels) while maintaining the cost advantage and patient preference benefits of injectable therapy. 1

Treatment Plan for Microdosing TRT

Pre-Treatment Requirements

Confirm biochemical hypogonadism with morning total testosterone <300 ng/dL on two separate occasions, measured between 8-10 AM. 2, 1 If borderline, measure free testosterone by equilibrium dialysis and sex hormone-binding globulin (SHBG), especially in men with obesity or diabetes where low SHBG may artificially lower total testosterone. 1

Measure LH and FSH to distinguish primary (elevated LH/FSH) from secondary (low-normal LH/FSH) hypogonadism, as this has critical treatment implications for fertility preservation. 1 Men with secondary hypogonadism desiring fertility must receive gonadotropin therapy (hCG plus FSH), not testosterone, as exogenous testosterone causes azoospermia. 2, 1

Obtain baseline laboratory tests before initiating therapy: 1

• Hematocrit/hemoglobin (withhold if >54%)
• PSA level and digital rectal examination in men >40 years
• Fasting glucose and lipid panel
• Prolactin if loss of libido is prominent

Absolute contraindications include: 1

• Active desire for fertility preservation
• Active or treated male breast cancer
• Hematocrit >54%
• Prostate cancer on active surveillance or androgen deprivation therapy
• Untreated severe obstructive sleep apnea

Microdosing Protocol

Starting regimen: Testosterone cypionate or enanthate 50-100 mg intramuscularly weekly, or 25-50 mg twice weekly (every 3.5 days). 1 The total weekly dose should approximate 100-200 mg biweekly divided by frequency. For example, if a patient would receive 200 mg every 2 weeks traditionally, microdosing would be 100 mg weekly or 50 mg twice weekly.

Injection sites: Deltoid, ventrogluteal, or vastus lateralis muscle. 1 Deltoid injection allows for self-administration and improves patient autonomy. 1

Target testosterone levels: Mid-normal range of 450-600 ng/dL. 1 This avoids both supraphysiologic peaks and subtherapeutic troughs.

Monitoring Schedule

Initial monitoring at 2-3 months after treatment initiation or dose adjustment: 1

• For weekly injections: Draw testosterone levels 3-4 days after injection (mid-cycle)
• For twice-weekly injections: Draw levels on day of injection before administering (trough level)
• Target mid-normal testosterone 500-600 ng/dL
• Check hematocrit/hemoglobin (withhold if >54%)
• Check PSA in men >40 years

Once stable levels confirmed, monitor every 6-12 months: 1

• Testosterone level
• Hematocrit (withhold if >54%, consider phlebotomy in high-risk cases)
• PSA (refer for urologic evaluation if increase >1.0 ng/mL in first 6 months or >0.4 ng/mL per year thereafter)
• Digital rectal examination
• Clinical symptom response (sexual function, libido, energy)

Dose Adjustments

If testosterone >750 ng/dL: Decrease weekly dose by 25 mg (or 12.5 mg per injection if twice-weekly). 1

If testosterone 350-750 ng/dL and clinical response adequate: Continue current dose. 1

If testosterone <350 ng/dL or inadequate clinical response: Increase weekly dose by 25 mg (or 12.5 mg per injection if twice-weekly). 1

Maximum dose should not exceed 200 mg weekly total (100 mg twice weekly). 1

Expected Treatment Outcomes

Testosterone therapy produces small but significant improvements in sexual function and libido (standardized mean difference 0.35) and modest quality of life improvements, primarily in sexual function domains. 1 These are the primary indications for treatment—diminished libido and erectile dysfunction. 1

Testosterone therapy produces little to no effect on physical functioning, energy, vitality, depressive symptoms, or cognition, even in confirmed hypogonadism. 1 Patients must understand these realistic expectations before initiating therapy. 1

Additional potential benefits include: 1

• Improved bone mineral density in men with osteoporosis
• Increased lean body mass and decreased visceral adiposity
• Improvements in insulin sensitivity, fasting glucose, triglycerides, and HDL cholesterol in men with metabolic syndrome or diabetes
• Correction of mild anemia

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

Advantages of Microdosing Over Traditional Dosing

More stable day-to-day testosterone levels minimize the peak-trough fluctuations associated with traditional biweekly or monthly injections. 1 This reduces early-cycle symptoms (acne, mood swings, fluid retention from supraphysiologic peaks) and late-cycle symptoms (fatigue, decreased libido from subtherapeutic troughs). 1

Lower risk of erythrocytosis compared to traditional injectable dosing, as sustained supraphysiologic peaks drive red blood cell production. 2, 1 Injectable testosterone carries higher erythrocytosis risk than transdermal preparations, with rates up to 44% in some studies. 1

Maintains cost advantage over transdermal testosterone gel (annual cost $156 for intramuscular vs. $2,135 for transdermal), while providing pharmacokinetic stability closer to gel formulations. 1

Patient preference varies: Some prefer weekly or twice-weekly injections for stable symptom control, while others prefer less frequent traditional dosing despite fluctuations. 1 Shared decision-making should guide formulation choice based on cost, convenience, and tolerance of fluctuations. 1

Critical Pitfalls to Avoid

Never initiate testosterone without confirming the patient does not desire fertility, as exogenous testosterone suppresses spermatogenesis and causes prolonged azoospermia that may take months to years to reverse after discontinuation. 2, 1

Never diagnose hypogonadism based on symptoms alone without confirmed low testosterone on two separate morning measurements. 1 Approximately 20-30% of men receiving testosterone in the United States do not have documented low testosterone levels before treatment initiation, violating evidence-based guidelines. 1

Never draw testosterone levels at peak (days 2-5 after injection) or trough (days 13-14) with traditional dosing, as this will show supraphysiologic or subtherapeutic levels that do not reflect average exposure and may lead to inappropriate dose adjustments. 1 For microdosing, draw mid-cycle for weekly injections or trough for twice-weekly injections.

Never continue testosterone therapy beyond 12 months without documented improvement in sexual function, as this is the primary evidence-based indication. 1 Continuing therapy for non-responsive symptoms (fatigue, mood, cognition) exposes patients to risks without proven benefit. 1

Never use testosterone in eugonadal men (normal testosterone levels) for weight loss, muscle building, cardiometabolic improvement, cognition, vitality, or physical strength, as this violates guidelines and lacks evidence for benefit. 1, 3

Safety Monitoring and Risk Mitigation

Monitor hematocrit at every visit and withhold treatment if >54%. 1 Consider phlebotomy in high-risk cases with persistent erythrocytosis. 1 Microdosing may reduce this risk compared to traditional dosing by avoiding sustained supraphysiologic peaks. 1

Monitor PSA levels in men >40 years before initiating therapy and periodically during treatment. 1 Refer for urologic evaluation if PSA increases >1.0 ng/mL in first 6 months or >0.4 ng/mL per year thereafter. 1

Counsel patients about cardiovascular risk: The FDA issued a safety announcement in 2015 regarding possible increased risk of heart attack and stroke with testosterone therapy, though evidence is conflicting. 2 Multiple large retrospective studies show contradictory results, and most level 1 trials found no difference in cardiovascular adverse events compared to placebo. 2 Patients starting or currently prescribed TRT should be advised of these possible risks. 2

For men with obesity-associated secondary hypogonadism, attempt weight loss through low-calorie diets and regular exercise before initiating testosterone, as this can improve testosterone levels without medication. 2, 1 Excessive aromatization of testosterone to estradiol in adipose tissue causes estradiol-mediated negative feedback suppressing pituitary LH secretion. 1