Subcutaneous Testosterone Administration in Hypogonadism

Yes, Subcutaneous Testosterone is Effective and Increasingly Preferred

Subcutaneous (subQ) testosterone injection is an effective, safe, and well-accepted alternative to intramuscular (IM) administration for men with confirmed hypogonadism and transgender men, offering comparable efficacy with greater convenience, less discomfort, and easier self-administration. 1, 2, 3

Diagnostic Confirmation Required Before Initiating Therapy

Before prescribing any testosterone formulation, confirm the diagnosis:

Two separate fasting morning total testosterone measurements (8–10 AM) must both be < 300 ng/dL to establish biochemical hypogonadism 4, 5
Measure LH and FSH after confirming low testosterone to distinguish primary (elevated LH/FSH) from secondary (low/normal LH/FSH) hypogonadism, as this distinction is critical for treatment selection and fertility counseling 4
Document specific symptoms—primarily diminished libido and erectile dysfunction—as these are the only symptoms with proven testosterone responsiveness 6, 4
Fatigue, low energy, depressed mood, and reduced physical function show minimal or no improvement with testosterone therapy, even when hypogonadism is confirmed 6

Subcutaneous Dosing Regimen

Initial Dosing

Start with testosterone cypionate or enanthate 50–100 mg subcutaneously once weekly 5, 1, 7
This weekly dosing provides more stable testosterone levels compared to biweekly IM administration 5

Dose Titration

Measure testosterone levels 2–3 months after initiation or any dose change 4, 5
Target mid-normal serum testosterone concentrations of 450–600 ng/dL 4, 5
Adjust dose based on serum levels and clinical response; the effective dose range is 50–150 mg weekly 1, 7
Therapy is effective across a wide range of body mass index (19.0–49.9 kg/m²) 1

Long-Term Monitoring

Once stable levels are achieved, monitor every 6–12 months 4, 5
Continue to target mid-normal testosterone levels (450–600 ng/dL) 4, 5

Injection Technique and Administration Sites

Recommended Injection Sites

Abdomen (most common site for subQ injections) 1, 3
Anterior thigh (allows for easy self-administration) 5, 1
Rotate injection sites to minimize local reactions 1

Injection Supplies

18-gauge needle for drawing testosterone from the vial 5
25–27 gauge, ½-inch needle for subcutaneous injection 1, 7
1 mL insulin syringe (0.5–1 mL capacity is sufficient for typical weekly doses) 3, 7
Alcohol prep pads, gauze pads, adhesive bandages, and a sharps container 5

Self-Administration Advantages

SubQ testosterone is relatively painless and easy to self-inject, allowing for the convenience and economy of patient self-administration 2, 3
In a study of 22 patients who switched from IM to subQ, all 22 preferred subQ injections (20 marked preference, 2 mild preference); none preferred IM 1

Pharmacokinetics and Stability

Serum Testosterone Stability

Serum testosterone concentrations remain stable between weekly subQ injections, with mean total testosterone of 627 ± 206 ng/dL and free testosterone of 146 ± 51 pg/mL across the dosing interval 2
This stability contrasts with IM injections, where peak levels occur 2–5 days post-injection and return to baseline by days 10–14 4
The more consistent day-to-day levels with subQ administration may reduce adverse effects, particularly erythrocytosis 5, 8

Dose Proportionality

SubQ testosterone demonstrates dose-proportional pharmacokinetics, meaning doubling the dose approximately doubles serum testosterone levels 7

Safety Profile and Adverse Effects

Local Reactions

Minor and transient local reactions (mild erythema, induration) occur in approximately 14% (9/63) of patients but are generally well-tolerated 1
No serious local reactions or abscesses have been reported in clinical studies 1, 2, 3

Erythrocytosis Risk

Injectable testosterone (IM) carries a significantly higher risk of erythrocytosis (43.8% of users) compared to transdermal preparations (15.4%) 4, 5
SubQ administration may have a lower erythrocytosis risk than IM due to more stable serum levels, though direct comparative data are limited 8
Monitor hematocrit at each visit; withhold treatment if > 54% and consider phlebotomy in high-risk cases 4, 5

Cardiovascular Safety

The 2023 TRAVERSE trial found no significant increase in major adverse cardiac events or stroke with transdermal testosterone in men with pre-existing cardiovascular risk 4
Injectable testosterone may carry greater cardiovascular risk than transdermal preparations due to fluctuating levels, but this remains uncertain 5

Contraindications

Absolute Contraindications

Active desire for fertility preservation—testosterone suppresses spermatogenesis and causes prolonged azoospermia; use gonadotropin therapy (hCG + FSH) instead 4
Active or treated male breast cancer 4
Hematocrit > 54% 4, 5
Untreated severe obstructive sleep apnea 4
Prostate cancer (though evidence is evolving) 4

Relative Contraindications

Recent myocardial infarction or stroke within 3–6 months 4
Severe/decompensated heart failure 4

Monitoring Requirements

Baseline Assessments

Hematocrit/hemoglobin (contraindication if > 54%) 4, 5
PSA in men > 40 years (PSA > 4.0 ng/mL requires urologic evaluation and negative prostate biopsy before initiating therapy) 4
Fasting glucose and HbA1c to exclude diabetes 4
Lipid profile 4
TSH to exclude thyroid dysfunction 4

Follow-Up Monitoring

2–3 months after initiation: measure testosterone, hematocrit, and PSA 4, 5
Every 3–6 months during the first year: repeat testosterone, hematocrit, PSA, lipid profile, and digital rectal examination 4
Annually thereafter: continue the same panel once stable 4

PSA Monitoring Thresholds

Refer to urology if PSA increases > 1.0 ng/mL within the first 6 months or > 0.4 ng/mL per year thereafter 4

Expected Treatment Outcomes

Sexual Function

Small but significant improvements in sexual function and libido (standardized mean difference 0.35) 6, 4
This is the primary indication for testosterone therapy 6, 4

Limited or No Benefit

Little to no effect on physical functioning, energy, vitality, depressive symptoms, or cognition 6, 4
Fatigue and low energy show minimal improvement (standardized mean difference 0.17) 4
Depressive symptoms show less-than-small improvement (standardized mean difference -0.19) 4

Metabolic Effects

Modest improvements in insulin sensitivity, triglycerides, and HDL cholesterol may occur 4
Modest improvements in bone mineral density (3.2% increase at lumbar spine, 1.4% at femoral neck) 4

Discontinuation Criteria

If no improvement in sexual function after 12 months, discontinue therapy to prevent unnecessary long-term exposure to potential risks without benefit 4

Comparison: SubQ vs. IM vs. Transdermal

Subcutaneous Advantages

Easier self-administration with less discomfort 1, 2, 3
More stable serum testosterone levels than IM biweekly injections 2, 8
Lower cost than transdermal preparations (annual cost: IM/subQ ≈ $156 vs. transdermal ≈ $2,135) 4, 5
Marked patient preference over IM injections 1

Transdermal Advantages

Lowest erythrocytosis risk (15.4% vs. 43.8% with IM) 4, 5
Most stable day-to-day testosterone levels 4, 5
No injection required 5

Transdermal Disadvantages

Significantly more expensive than injectable formulations 4, 5
Risk of transfer to partners or children through skin contact 5
Skin reactions occur in 5% of gel users (vs. 66% with patches) 5

Special Populations

Transgender Men

SubQ testosterone is effective and preferred in transgender men, with the same dosing regimen (50–150 mg weekly) 1, 2
Target trough testosterone levels of 300–1,000 ng/dL (mid-normal 450–600 ng/dL preferred) 9
All 63 transgender patients in one study achieved therapeutic levels with subQ administration 1
51 of 53 premenopausal patients achieved amenorrhea with subQ testosterone 1

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 activity plus resistance training 2–3 times/week) 4
A 5–10% weight loss can significantly increase endogenous testosterone production 4
If lifestyle modification fails after 3–6 months and the patient does not desire fertility, testosterone therapy can be initiated 4

Common Pitfalls to Avoid

Do not diagnose hypogonadism on a single testosterone measurement—require two separate morning values < 300 ng/dL 4
Do not prescribe testosterone without measuring LH and FSH—the distinction between primary and secondary hypogonadism is critical for treatment selection and fertility counseling 4
Do not initiate testosterone in men desiring fertility—use gonadotropin therapy (hCG + FSH) instead 4
Do not expect meaningful improvements in energy, physical function, or mood—these symptoms show minimal or no response to testosterone therapy 6, 4
Do not continue therapy beyond 12 months if sexual function has not improved—this is the only proven benefit of testosterone therapy 4
Do not ignore hematocrit monitoring—erythrocytosis is a common and potentially serious adverse effect 4, 5
Do not assume all testosterone formulations are interchangeable—subQ, IM, and transdermal preparations have different pharmacokinetics, adverse effect profiles, and costs 5, 8

Clinical Algorithm for SubQ Testosterone Initiation

Confirm diagnosis: Two morning testosterone < 300 ng/dL + specific sexual symptoms (diminished libido, erectile dysfunction) 4
Measure LH/FSH to distinguish primary vs. secondary hypogonadism 4
Confirm patient does not desire fertility—if fertility is desired, use gonadotropin therapy instead 4
Obtain baseline labs: hematocrit, PSA (if > 40 years), fasting glucose, lipid profile, TSH 4
Exclude contraindications: hematocrit > 54%, active breast/prostate cancer, recent MI/stroke, severe heart failure 4
Prescribe testosterone cypionate or enanthate 50–100 mg subQ weekly 5, 1, 7
Provide injection supplies: 18-gauge draw needle, 25–27 gauge ½-inch injection needle, 1 mL syringes, alcohol pads, sharps container 5, 3, 7
Teach self-injection technique: abdomen or anterior thigh, rotate sites 1, 3
Follow-up at 2–3 months: measure testosterone (target 450–600 ng/dL), hematocrit, PSA; adjust dose if needed 4, 5
Long-term monitoring: every 6–12 months once stable 4, 5
Reassess at 12 months: if no improvement in sexual function, discontinue therapy 4

Can testosterone be administered subcutaneously in men with confirmed hypogonadism or transgender men, and what are the appropriate dosing regimen, injection technique, contraindications, and monitoring requirements?

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