What is the recommended testosterone replacement therapy (TRT) protocol (100 mg intramuscular testosterone enanthate or cypionate twice weekly) for an adult male with documented hypogonadism, including dosing schedule, baseline and follow‑up monitoring, and alternative regimens?

Testosterone Replacement Therapy: 100 mg Twice Weekly Protocol

Recommended Dosing Regimen

For adult males with documented hypogonadism, initiate intramuscular testosterone enanthate or cypionate at 100 mg weekly rather than 100 mg twice weekly, as the twice-weekly schedule exceeds standard FDA-approved dosing and increases the risk of supraphysiologic testosterone levels and erythrocytosis. 1

The FDA-approved dosing range for testosterone cypionate and enanthate is 50–400 mg every 2–4 weeks, with weekly dosing at 50–100 mg representing the upper frequency limit of evidence-based practice. 2 A regimen of 100 mg twice weekly (200 mg/week total) substantially exceeds this standard and will likely produce testosterone concentrations well above the therapeutic target range of 450–600 ng/dL. 2, 1

Evidence-Based Dosing Alternatives

Weekly Dosing (Preferred)

• Start with 50–100 mg intramuscular weekly of testosterone enanthate or cypionate, which provides more stable serum testosterone levels compared to biweekly administration while remaining within guideline-recommended parameters. 1, 3
• Weekly injections minimize the "roller coaster" effect of fluctuating testosterone levels that occurs with less frequent dosing. 4
• This schedule achieves steady-state testosterone concentrations in the mid-normal range (450–600 ng/dL) when measured midway between injections. 2, 1

Biweekly Dosing (Alternative)

• 100–200 mg every 2 weeks is the traditional FDA-approved regimen that has been used for decades. 1, 3
• Peak serum testosterone occurs 2–5 days after injection, with return to baseline by days 10–14. 4, 2
• This schedule produces greater fluctuation in testosterone levels compared to weekly dosing but remains clinically effective. 4

Long-Acting Injectable (Third-Line)

• Testosterone undecanoate 750 mg initially, repeated at 4 weeks, then every 10 weeks provides the most stable long-term testosterone levels with the fewest injections per year. 1, 5
• This formulation must be administered as a gluteal intramuscular injection only and requires a maximum volume of 3 mL per injection site. 1

Baseline Requirements Before Initiating Therapy

Diagnostic Confirmation

• Two separate fasting morning (8–10 AM) total testosterone measurements both < 300 ng/dL are mandatory to establish biochemical hypogonadism; single measurements are insufficient due to diurnal variation and assay variability. 2, 6
• Measure serum LH and FSH after confirming low testosterone to differentiate primary (elevated LH/FSH) from secondary (low/normal LH/FSH) hypogonadism, as this distinction directs treatment choice and fertility counseling. 2, 6
• Assess for qualifying symptoms—specifically diminished libido and erectile dysfunction—as these are the only symptoms with proven testosterone responsiveness. 2 Fatigue, low energy, and mood complaints show minimal to no improvement even with confirmed hypogonadism. 2

Mandatory Pre-Treatment Laboratory Tests

• Baseline hematocrit/hemoglobin: Hematocrit > 54% is an absolute contraindication to starting testosterone therapy. 2, 6
• PSA level in men > 40 years: PSA > 4.0 ng/mL (or > 3.0 ng/mL in high-risk groups) requires urologic evaluation and documented negative prostate biopsy before initiating therapy. 2, 6
• Fasting glucose and HbA1c to exclude diabetes. 2
• Lipid profile as part of baseline metabolic assessment. 2
• TSH to exclude thyroid dysfunction that can mimic hypogonadal symptoms. 2

Pituitary Imaging Indications

• Order pituitary MRI when testosterone < 150 ng/dL with LH/FSH < 1.5 IU/L (regardless of prolactin level), or when prolactin exceeds 1.5 × the upper limit of normal, or when visual field defects or anosmia are present. 2

Monitoring Protocol

Initial Follow-Up (2–3 Months)

• Measure total testosterone midway between injections (days 5–7 for weekly dosing, days 7–10 for biweekly dosing), targeting mid-normal values of 450–600 ng/dL. 2, 1, 6
• Repeat hematocrit/hemoglobin to screen for erythrocytosis. 2, 6
• Repeat PSA in men > 40 years. 2, 6
• Assess clinical response, particularly improvement in sexual function and libido. 2
• Adjust dose if symptoms persist with suboptimal hormone levels or if testosterone exceeds the target range. 2

Ongoing Monitoring (Every 3–6 Months During Year 1, Then Annually)

• Repeat total testosterone, hematocrit, and PSA at each visit. 2, 6
• Perform digital rectal examination to assess for prostate abnormalities. 2, 6
• Withhold treatment if hematocrit > 54% and consider phlebotomy in high-risk cases. 2, 6
• Refer to urology if PSA rises > 1.0 ng/mL within the first 6 months or > 0.4 ng/mL per year thereafter. 2, 6

Absolute Contraindications

• Active desire for fertility preservation: Testosterone therapy causes prolonged azoospermia; gonadotropin therapy (hCG + FSH) is mandatory instead. 2, 6
• Breast or prostate cancer. 6
• Hematocrit > 54%. 2, 6
• Untreated severe obstructive sleep apnea. 6
• Recent cardiovascular events (myocardial infarction or stroke within the past 3–6 months). 2, 6
• Uncontrolled heart failure. 6

Expected Treatment Outcomes

Proven Benefits

• Small but statistically significant improvement in sexual function and libido (standardized mean difference ≈ 0.35). 2
• Modest quality-of-life improvements, primarily in sexual function domains. 2
• Potential improvements in metabolic parameters, including insulin resistance, triglycerides, and HDL cholesterol. 2

Minimal or No Benefit

• Little to no effect on physical functioning, energy, vitality, depressive symptoms, or cognition, even with confirmed hypogonadism. 2
• Fatigue and low energy show clinically insignificant improvement (standardized mean difference ≈ 0.17). 2
• Mood disturbances exhibit less-than-small improvement (standardized mean difference ≈ −0.19). 2

Formulation-Specific Risks

Injectable Testosterone (Enanthate/Cypionate)

• Erythrocytosis occurs in approximately 43.8% of patients receiving intramuscular injections, compared to 15.4% with transdermal patches. 4, 7
• Supraphysiologic peak testosterone levels 2–5 days after injection increase the risk of adverse effects, particularly erythrocytosis. 4, 7
• Cost advantage: Annual cost of approximately $156 for intramuscular formulations versus $2,135 for transdermal preparations. 2

Transdermal Testosterone (Alternative First-Line)

• Transdermal testosterone gel 1.62% at 40.5 mg daily is the preferred first-line formulation due to more stable day-to-day testosterone levels and lower erythrocytosis risk (15.4% vs. 43.8% with injectables). 2, 7
• Erythrocytosis risk is dose-dependent: 2.8% at 5 mg/day delivered, increasing to 17.9% at 10 mg/day delivered. 2
• Main disadvantage: Significantly higher cost and potential for transfer to partners or children through skin-to-skin contact. 2, 1

Critical Pitfalls to Avoid

• Do not diagnose hypogonadism on a single testosterone measurement or on symptoms alone; require two fasting morning values < 300 ng/dL plus specific sexual symptoms. 2
• Never omit LH/FSH testing after confirming low testosterone; the primary vs. secondary distinction guides therapy and fertility counseling. 2
• Never initiate testosterone without confirming the patient does not desire fertility, as exogenous testosterone causes prolonged azoospermia. 2, 6
• Do not prescribe testosterone for weight loss, general energy enhancement, or athletic performance, as these are not evidence-based indications. 2
• Do not continue supraphysiologic dosing (such as 100 mg twice weekly) even if the patient reports feeling well, as this increases adverse event risk, particularly erythrocytosis. 2
• Do not ignore mild erythrocytosis (hematocrit 50–52%) in elderly patients or those with cardiovascular disease, as even modest elevations increase blood viscosity and thrombotic risk. 2
• Do not draw testosterone levels at the peak (days 2–5 after injection), as this will show supraphysiologic levels that do not reflect average exposure and may lead to inappropriate dose reduction. 2
• Do not draw levels at the trough (days 13–14 after injection), as testosterone may have returned to baseline or below, potentially leading to unnecessary dose escalation. 2

Practical Administration Details

Injection Supplies

• 18-gauge needle for drawing testosterone from the vial. 1
• 21–23 gauge, 1–1.5 inch needle for intramuscular injection. 1
• 1–3 mL syringe (3 mL most common for typical 100–200 mg doses). 1
• Alcohol prep pads, gauze pads, adhesive bandages, and sharps container. 1

Injection Sites

• Anterolateral thigh (vastus lateralis) for self-administration. 1
• Gluteal muscle (ventrogluteal or dorsogluteal) for administration by another person; maximum volume 3 mL per injection site. 1
• Subcutaneous injection is an emerging alternative with comparable efficacy to intramuscular administration and may offer easier self-administration with less discomfort. 2, 8

Reevaluation and Discontinuation Criteria

• At 12 months: If sexual function has not improved despite achieving target testosterone levels, discontinue testosterone therapy to prevent unnecessary long-term exposure to potential risks without benefit. 2
• Persistent erythrocytosis (hematocrit > 52%) despite dose reduction and formulation change warrants reevaluation of whether the patient is experiencing meaningful clinical benefit, given the small improvements in sexual function and minimal to no benefit for energy, physical function, or mood. 2