What is the recommended protocol for initiating testosterone replacement therapy with intramuscular testosterone enanthate (or cypionate) 50 mg twice weekly in an adult male with confirmed hypogonadism, including baseline evaluation, monitoring schedule, dose adjustments, and contraindications?

Testosterone Replacement Therapy: 50 mg Twice Weekly Protocol

Recommended Starting Protocol

For adult males with confirmed hypogonadism, initiate testosterone cypionate or enanthate at 50–100 mg intramuscularly once weekly rather than 50 mg twice weekly, as weekly dosing provides more stable serum levels while reducing injection frequency. 1, 2

Why Weekly Dosing Is Preferred Over Twice-Weekly

• Weekly administration (50–100 mg) produces more stable testosterone concentrations compared to bi-weekly regimens, minimizing the "roller-coaster" effect of supraphysiologic peaks and subtherapeutic troughs. 1, 2
• Serum testosterone peaks at 2–5 days post-injection and returns toward baseline by days 10–14, so twice-weekly dosing (every 3.5 days) prevents full trough recovery and may cause cumulative elevation. 1
• Injectable testosterone carries a 43.8% risk of erythrocytosis (hematocrit >52%), significantly higher than the 15.4% seen with transdermal preparations, and more frequent dosing may amplify this risk. 1

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Baseline Evaluation Before Initiation

Diagnostic Confirmation (Mandatory)

• Obtain two separate fasting morning (8–10 AM) total testosterone measurements, both <300 ng/dL, to establish biochemical hypogonadism; single measurements are insufficient due to diurnal variation and assay variability. 1
• Measure serum LH and FSH after confirming low testosterone to differentiate primary (elevated LH/FSH) from secondary (low/normal LH/FSH) hypogonadism—this distinction is critical for treatment selection and fertility counseling. 1
• In borderline cases (total testosterone 231–346 ng/dL) or obese patients, measure free testosterone by equilibrium dialysis and sex hormone-binding globulin (SHBG) to distinguish true from functional hypogonadism. 1

Symptom Assessment

• Therapy is justified only when diminished libido and/or erectile dysfunction are present; these are the sole symptoms with proven testosterone responsiveness (standardized mean difference ≈0.35). 1
• Do not initiate therapy for fatigue, low energy, depressed mood, or cognitive complaints, as testosterone produces little to no benefit in these domains even with confirmed hypogonadism. 1

Pre-Treatment Laboratory Tests

• Hematocrit/hemoglobin – absolute contraindication if >54%; document baseline to monitor for erythrocytosis. 1
• PSA and digital rectal examination in men >40 years – PSA >4.0 ng/mL requires urologic evaluation and negative prostate biopsy before starting therapy. 1
• Prolactin – if LH/FSH are low/normal, measure prolactin; if >1.5× upper limit of normal, order pituitary MRI to exclude prolactinoma. 1
• Fasting glucose and HbA1c – screen for diabetes. 1
• Lipid profile – baseline metabolic assessment. 1
• TSH – exclude thyroid dysfunction mimicking hypogonadal symptoms. 1

Pituitary Imaging Indications

• Order MRI immediately if testosterone <150 ng/dL with LH <1.5 IU/L and FSH <1.5 IU/L, even without hyperprolactinemia, to rule out non-functioning adenoma. 1
• MRI is also indicated for prolactin >1.5× ULN, visual field defects (bitemporal hemianopsia), or anosmia. 1

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Absolute Contraindications

• Active desire for fertility preservation – testosterone causes prolonged azoospermia; use gonadotropin therapy (hCG + FSH) instead for secondary hypogonadism. 1
• Active or treated male breast cancer. 1
• Hematocrit >54% – withhold therapy and consider phlebotomy. 1
• Recent cardiovascular events (MI or stroke within 3–6 months). 1
• Untreated severe obstructive sleep apnea. 1

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Dosing and Administration

Injectable Testosterone Cypionate or Enanthate

• Start at 50–100 mg intramuscularly once weekly (or 100–200 mg every 2 weeks if weekly dosing is not feasible). 1, 2
• Injection sites: deep gluteal muscle (provider-administered) or anterolateral thigh (self-administration). 2
• Needle specifications: 18-gauge to draw medication; 21–23 gauge, 1–1.5 inch for intramuscular injection. 2
• Maximum safe volume per gluteal injection site is 3 mL; typical testosterone doses require 0.5–1 mL. 2

Supplies to Prescribe

• 1–3 mL syringes (3 mL most common for 100–200 mg doses). 2
• 18-gauge drawing needles. 2
• 21–23 gauge, 1–1.5 inch injection needles (longer for gluteal, shorter for thigh in lean patients). 2
• Alcohol prep pads, gauze pads, adhesive bandages, sharps container. 2

Subcutaneous Alternative (Off-Label but Effective)

• Subcutaneous testosterone enanthate 50–100 mg weekly achieves therapeutic levels equivalent to intramuscular administration with less discomfort and easier self-injection. 3, 4, 5, 6
• Subcutaneous dosing is associated with lower post-therapy estradiol and hematocrit compared to intramuscular cypionate, potentially offering a preferable safety profile. 3
• Inject into anterolateral thigh or abdomen using a shorter needle (5/8 inch, 27-gauge). 4

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Target Testosterone Levels

• Aim for mid-normal serum testosterone of 450–600 ng/dL when measured midway between injections (days 5–7 for weekly dosing). 1, 2
• Do not draw levels at peak (days 2–5), as supraphysiologic values may lead to inappropriate dose reduction. 1
• Do not draw at trough (days 13–14), as low values may prompt unnecessary dose escalation. 1

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Monitoring Schedule

Initial Follow-Up (2–3 Months)

• Measure total testosterone (midway between injections), hematocrit, and PSA; assess clinical response (improvement in libido and erectile function). 1
• Adjust dose if symptoms persist with suboptimal levels; if clinical response is adequate, no change is needed even if testosterone is low-normal. 1

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

• Repeat testosterone, hematocrit, PSA, lipid profile, and digital rectal examination at each visit. 1
• Withhold therapy if hematocrit >54%; consider therapeutic phlebotomy in high-risk patients (elderly, cardiovascular disease). 1
• Refer to urology if PSA rises >1.0 ng/mL in first 6 months or >0.4 ng/mL per year thereafter. 1

Discontinuation Criteria

• If no improvement in sexual function at 12 months, discontinue therapy to avoid unnecessary long-term exposure without benefit. 1

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Dose Adjustment Algorithm

• If clinical response is suboptimal AND testosterone levels are low-normal or below, increase dose (e.g., from 50 mg to 75–100 mg weekly). 1, 2
• If testosterone levels are >1,000 ng/dL, reduce dose by approximately 50% (e.g., from 100 mg to 50 mg weekly) to minimize erythrocytosis risk. 2
• If maximal transdermal dose fails to achieve adequate levels, switch to intramuscular injections. 2

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Expected Treatment Outcomes

• Small but significant improvement in sexual function and libido (standardized mean difference 0.35). 1
• Modest quality-of-life gains confined to sexual-function domains; no meaningful impact on energy, physical function, mood, or cognition. 1
• Potential metabolic benefits: improved insulin resistance, triglycerides, and HDL cholesterol. 1

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Critical Pitfalls to Avoid

• Do not diagnose hypogonadism on a single testosterone measurement or symptoms alone; require two morning values <300 ng/dL plus specific sexual symptoms. 1
• Do not omit LH/FSH testing after confirming low testosterone; the primary vs. secondary distinction directs therapy and fertility counseling. 1
• Never initiate testosterone without confirming the patient does not desire fertility, as therapy causes prolonged azoospermia. 1
• Do not prescribe testosterone for weight loss, energy enhancement, or athletic performance—these are not evidence-based indications. 1
• Do not continue therapy beyond 12 months without documented improvement in sexual function. 1
• Do not ignore mild erythrocytosis (hematocrit 50–52%) in elderly or cardiovascular patients, as even modest elevations increase thrombotic risk. 1

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Formulation Selection: Injectable vs. Transdermal

• Transdermal testosterone gel (1.62%, 40.5 mg daily) is first-line due to stable serum levels and lower erythrocytosis risk (15.4% vs. 43.8% with injectables). 1, 2
• Injectable testosterone is a cost-effective alternative (annual cost $156 vs. $2,135 for transdermal) but requires intramuscular injection and carries higher erythrocytosis risk. 1, 2
• Weekly injectable dosing (50–100 mg) reduces fluctuation compared to bi-weekly regimens (100–200 mg every 2 weeks). 1, 2

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Special Populations

Obesity-Associated Secondary Hypogonadism

• First-line treatment is weight loss through hypocaloric diet (500–750 kcal/day deficit) and structured exercise (≥150 min/week moderate-intensity aerobic + resistance training 2–3×/week), as 5–10% weight loss can markedly increase endogenous testosterone. 1
• Testosterone therapy may be considered if lifestyle modification fails, but never use testosterone for weight loss alone. 1

Men Desiring Fertility Preservation

• Gonadotropin therapy (recombinant hCG + FSH) is mandatory for secondary hypogonadism with fertility concerns; testosterone is absolutely contraindicated. 1
• Combined hCG + FSH restores both testosterone production and spermatogenesis. 1

Elderly Men or Cardiovascular Risk

• Target mid-range testosterone (350–600 ng/dL) in elderly patients or those with chronic illness. 1
• Use transdermal preparations preferentially to minimize erythrocytosis risk. 1
• Avoid initiation within 3–6 months of MI or stroke. 1