What is the role of subcutaneous testosterone (testosterone cypionate or enanthate) injections in treating hypogonadism in males?

Subcutaneous Testosterone for Male Hypogonadism

Subcutaneous testosterone cypionate or enanthate injections are an effective, safe, and well-tolerated alternative to intramuscular injections for treating confirmed male hypogonadism, offering comparable efficacy with less injection site discomfort and the convenience of self-administration. 1, 2

FDA-Approved Indications

Subcutaneous testosterone is indicated for replacement therapy in males with:

• Primary hypogonadism (testicular failure from cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, or orchidectomy) 3, 4
• Secondary hypogonadism (gonadotropin or LHRH deficiency, or pituitary-hypothalamic injury from tumors, trauma, or radiation) 3, 4

Critical caveat: The FDA explicitly states that safety and efficacy in "age-related hypogonadism" have not been established, and oral testosterone formulations are specifically contraindicated for this indication. 3, 4, 5

Diagnostic Requirements Before Initiating Treatment

You must confirm both biochemical hypogonadism and specific symptoms:

• Two separate morning total testosterone measurements <300 ng/dL (drawn between 8-10 AM) 5
• Measure LH and FSH to distinguish primary (elevated LH/FSH) from secondary (low/normal LH/FSH) hypogonadism 5
• Primary symptoms justifying treatment: diminished libido and erectile dysfunction 5
• Secondary symptoms include diminished vitality, though evidence for improvement is weaker 6, 5

Absolute contraindications:

• Men actively seeking fertility (testosterone causes azoospermia; use gonadotropin therapy instead) 5
• Active male breast cancer 5
• Active or treated prostate cancer (though evidence is evolving) 5

Subcutaneous Administration Protocol

Dosing Regimen

Start with 50-75 mg subcutaneous testosterone cypionate or enanthate weekly, adjusting based on week 6 trough levels. 1

• Dose range: 50-150 mg weekly (median effective dose 75-80 mg) 1
• Target trough testosterone: 500-600 ng/dL (mid-normal range) 5
• Effective across wide BMI range (19.0-49.9 kg/m²) 2

Advantages Over Intramuscular Injection

• More stable serum testosterone levels with smaller peak-trough fluctuations compared to IM injections every 2-4 weeks 1, 7
• Virtually painless: >95% of patients report no injection-related pain 1
• Self-administration capability via auto-injector, eliminating need for clinic visits 1
• Strong patient preference: Among patients switched from IM to SC, 91% (20/22) had marked preference for SC, with none preferring IM 2
• Lower risk of supraphysiologic peaks that occur 2-5 days after IM injection 5

Monitoring Schedule

• Measure testosterone at 2-3 months after initiation or dose change (midway between injections for SC) 5, 7
• Once stable, monitor every 6-12 months 5, 7
• Monitor hematocrit periodically; withhold if >54% (SC has lower erythrocytosis risk than IM) 5, 8
• Monitor PSA in men >40 years 5, 8

Expected Clinical Outcomes

Realistic expectations must be discussed upfront:

• Small but significant improvements in sexual function and libido 6, 5
• Modest improvements in quality of life (vitality, social functioning, mental health domains) 6, 5
• Little to no effect on: physical functioning, energy/vitality, depressive symptoms, or cognition 6, 5
• Metabolic benefits in men with diabetes/metabolic syndrome: modest improvements in HbA1c (0.18% at 18 weeks), BMI, waist circumference, and inflammatory markers 6

Discontinue treatment at 12 months if no improvement in sexual function, as continued exposure without benefit increases risk without justification. 5

Comparison with Other Formulations

Cost Considerations

• Intramuscular injections: $156.24 annually (most economical) 8, 7
• Transdermal preparations: $2,135.32 annually 8, 7
• Subcutaneous injections fall between these costs while offering superior tolerability to IM 1, 2

When to Choose SC Over Other Routes

Choose subcutaneous when:

• Patient desires self-administration and convenience 1, 2
• Patient has experienced discomfort with IM injections 2
• More stable testosterone levels are desired compared to IM every 2-4 weeks 1
• Cost is a concern but patient cannot tolerate IM injections 8, 7

Choose transdermal (gel/patch) when:

• Patient prefers daily application over weekly injections 7
• Cardiovascular risk factors are present (gels may have better CV safety profile) 7
• Patient has high risk for erythrocytosis 8, 7

Avoid transdermal when:

• Risk of transfer to partners/children is a concern 7
• Cost is prohibitive 8, 7

Critical Pitfalls to Avoid

• Never start testosterone without confirming the patient does not desire fertility in the next 1-2 years, as recovery of spermatogenesis after cessation can take 6-12 months or longer 5
• Never diagnose hypogonadism based on symptoms alone without two confirmatory morning testosterone measurements 5
• Never use testosterone in eugonadal men (normal testosterone levels) even if symptomatic, as guidelines explicitly recommend against this 5
• Never attempt to diagnose primary vs. secondary hypogonadism while patient is on testosterone; requires 2-4 week washout period 5
• Never use weekly IM dosing (e.g., 200 mg weekly), as this exceeds standard practice and increases risk of supraphysiologic levels and erythrocytosis 5

Special Population: Secondary Hypogonadism in Young Men

For men with secondary hypogonadism who may desire future fertility:

• First-line: Gonadotropin therapy (hCG ± FSH) to stimulate endogenous testosterone production and preserve spermatogenesis 5, 9
• Testosterone is absolutely contraindicated if fertility is desired, as it suppresses the hypothalamic-pituitary-gonadal axis 5
• Consider selective estrogen receptor modulators as alternative 5