What are the potential side effects of testosterone therapy in a young male with hypogonadism?

Side Effects of Testosterone Therapy in Young Males

Testosterone therapy in young males with confirmed hypogonadism carries specific risks that differ from older populations, most notably erythrocytosis (elevated red blood cells), testicular atrophy with potential infertility, and acne, though cardiovascular risks appear neutral based on the most recent high-quality evidence. 1

Critical Distinction: Young Males vs. Older Men

The available evidence predominantly focuses on older men, with very limited data in men aged 18-50 years 1. This is a major knowledge gap that clinicians must recognize when treating young males. The side effect profile may differ substantially in younger populations compared to the extensively studied older cohorts 1.

Most Common and Clinically Significant Side Effects

Hematologic Effects

• Erythrocytosis (elevated hematocrit) is the most common side effect, occurring in up to 44% of patients receiving injectable testosterone 2
• Injectable formulations carry significantly higher risk of erythrocytosis compared to transdermal preparations 3, 2
• Hematocrit should be monitored periodically and treatment withheld if >54%, with consideration of phlebotomy in high-risk cases 3
• This can increase risk of thrombotic events if left unmonitored 4

Reproductive System Effects

• Testicular atrophy occurs due to suppression of the hypothalamic-pituitary-gonadal axis 2
• Testosterone therapy causes azoospermia (absence of sperm) and is absolutely contraindicated in men seeking fertility 3, 5
• This effect can be prolonged even after discontinuation 3
• Young men desiring future paternity should receive gonadotropin therapy (hCG plus FSH) instead of testosterone 3, 5

Dermatologic Effects

• Acne or oily skin is a common side effect, particularly relevant in younger males 2
• This occurs due to increased sebaceous gland activity from androgen stimulation 2

Cardiovascular Considerations

• The 2023 TRAVERSE trial (the highest quality and most recent evidence) found no increased risk of stroke or major adverse cardiac events in men 45-80 years with confirmed hypogonadism receiving transdermal testosterone 1
• However, the FDA previously issued warnings about potential cardiovascular risks, and long-term safety data remains limited, especially in young males 1, 6
• Some testosterone products can increase blood pressure, which theoretically increases myocardial infarction and stroke risk 6

Less Common but Important Side Effects

Fluid Retention and Cardiac Effects

• Edema may occur, with or without congestive heart failure, particularly concerning in patients with pre-existing cardiac, renal, or hepatic disease 4
• Fluid retention is rarely of clinical significance in healthy young males 2

Prostate-Related Effects

• Potential worsening of benign prostatic hyperplasia symptoms, though less relevant in young males 2
• Theoretical risk of stimulating occult prostate cancer, though definitive evidence is lacking 2
• PSA monitoring is recommended in men over 40 years 3

Gynecomastia

• Breast tissue development may occur and occasionally persists in patients being treated for hypogonadism 4
• This results from aromatization of testosterone to estrogen 4

Sleep Apnea

• May worsen sleep apnea in predisposed individuals 1, 2
• Untreated severe obstructive sleep apnea is considered a contraindication by some guidelines 3

Formulation-Specific Risks

Injectable Testosterone (Cypionate/Enanthate)

• Higher risk of erythrocytosis compared to transdermal preparations 3, 2
• Supraphysiologic peak levels occur 2-5 days after injection, potentially increasing side effect risk 3, 2
• More economical but less stable testosterone levels 3

Transdermal Preparations (Gels/Patches)

• More stable day-to-day testosterone levels, potentially reducing side effect burden 3
• Lower risk of erythrocytosis 3
• Skin irritation at application site 3

Critical Monitoring Requirements

• Testosterone levels should be checked 2-3 months after initiation or dose change, then every 6-12 months once stable 3
• Hematocrit must be monitored regularly to detect erythrocytosis early 3, 2
• For injectable testosterone, levels should be measured midway between injections, targeting 500-600 ng/dL 3
• Baseline hematocrit should be documented before starting therapy 3

Special Considerations for Young Males

Fertility Preservation

• This is the most critical consideration in young males that distinguishes them from older populations 3, 5
• Fertility counseling is mandatory before initiating testosterone therapy 3
• Young men should be explicitly warned that testosterone will suppress sperm production 3, 5
• Alternative treatments exist (gonadotropins, selective estrogen receptor modulators, aromatase inhibitors) that preserve fertility 5

Growth and Development

• In adolescents with delayed puberty, bone maturation should be monitored every 6 months by assessing bone age 4
• Androgen treatment may accelerate bone maturation without compensatory linear growth, potentially compromising final adult height 4
• The younger the patient, the greater the risk of compromised adult stature 4

Absolute Contraindications

• Active breast cancer 3
• Men actively seeking fertility (must use gonadotropins instead) 3
• Prostate cancer (though evidence is evolving) 3
• Untreated severe obstructive sleep apnea 3

Common Pitfalls to Avoid

• Do not prescribe testosterone without confirming both low testosterone levels (on two separate morning measurements) AND specific symptoms 3
• Do not use testosterone for "age-related hypogonadism," athletic enhancement, or in eugonadal men even if symptomatic 3, 2, 4
• Do not ignore fertility counseling in young males—this is malpractice given the profound impact on reproductive potential 3, 5
• Do not use weekly dosing of testosterone cypionate—this exceeds standard practice and increases risk of supraphysiologic levels and erythrocytosis 3
• Do not continue therapy if no improvement in symptoms after 12 months 2

Benefits vs. Risks Context

While side effects exist, the benefits of testosterone therapy in young males with confirmed hypogonadism typically outweigh risks 7. Expected benefits include:

• Significant improvement in libido and sexual function 3, 2
• Increased lean body mass and decreased body fat 2
• Improved bone mineral density 2
• Correction of mild anemia 2
• Small improvements in quality of life 1

However, benefits for physical functioning, depressive symptoms, energy, and cognition are limited or absent 1, 3, which is important for setting realistic patient expectations.