The treatment of male hypogonadism is complicated by the multitude of treatments available, the lack of a clear understanding of the differences between treatment modalities, barriers to treatment, and patient misperceptions, unrealistic expectations, and anxieties.
Key Findings
Results
Intramuscular testosterone cypionate and enanthate are the most commonly used injectable testosterone formulations in the United States.
Testosterone cypionate and enanthate are long-acting injectable esters administered every 1-2 weeks
These formulations produce supraphysiologic peaks and subphysiologic troughs in serum testosterone levels
The peak-to-trough variability can cause mood fluctuations and symptom variability in patients
Testosterone undecanoate (Aveed) is a longer-acting injectable given every 10 weeks after initial loading doses, providing more stable serum levels
Results
Topical testosterone gels and solutions are widely used but carry a risk of transference to female partners and children.
Topical formulations include gels, solutions, and creams applied daily to skin
Transference risk requires patients to cover application sites or wash hands thoroughly before contact with others
Topical formulations provide more stable serum testosterone levels compared to short-acting injectables
Dihydrotestosterone (DHT) levels may be elevated with some topical formulations due to 5-alpha reductase activity in the skin
Results
Testosterone pellets implanted subcutaneously provide a long-acting delivery method lasting 3-6 months.
Pellets are implanted subcutaneously, typically in the hip or buttock area
Duration of action is approximately 3-6 months depending on pellet dose and patient metabolism
Complications include pellet extrusion, infection, and fibrosis at the insertion site
Dosing is less flexible compared to other formulations once pellets are implanted
Results
Oral testosterone undecanoate (Jatenzo) was approved by the FDA in 2019 as a novel oral testosterone formulation that avoids first-pass hepatic metabolism.
Jatenzo is absorbed via the intestinal lymphatic system, bypassing hepatic first-pass metabolism
It is taken twice daily with food to optimize absorption
The formulation avoids the hepatotoxicity associated with older 17-alpha alkylated oral androgens
Blood pressure increases were noted as a side effect in clinical trials, leading to an FDA black box warning
Results
Nasal testosterone gel (Natesto) offers a unique intranasal delivery system administered three times daily.
Natesto is applied intranasally three times daily and produces rapid absorption and clearance
Studies suggest Natesto may better preserve sperm production compared to other testosterone formulations
The rapid pharmacokinetic profile results in minimal suppression of the hypothalamic-pituitary-gonadal axis in some patients
Nasal side effects including nasopharyngitis and rhinorrhea have been reported
Results
Testosterone replacement therapy (TRT) is associated with suppression of spermatogenesis, which is a significant concern for hypogonadal men who desire fertility.
Exogenous testosterone suppresses LH and FSH via negative feedback on the hypothalamic-pituitary axis
Suppression of gonadotropins leads to reduced intratesticular testosterone and impaired spermatogenesis
Alternative treatments such as clomiphene citrate or human chorionic gonadotropin (hCG) can be used to treat hypogonadism while preserving fertility
Recovery of spermatogenesis after cessation of TRT can take 6-18 months or longer
Discussion
Patient barriers to testosterone replacement therapy include misperceptions about prostate cancer risk, cardiovascular risk, and concerns about fertility.
Historical concerns about testosterone and prostate cancer risk have been largely refuted by more recent evidence
Cardiovascular safety of TRT remains an area of active investigation and patient concern
Patient education regarding realistic expectations for symptom improvement is critical to treatment satisfaction
Unrealistic expectations and anxieties about TRT contribute to suboptimal treatment adherence