Oral testosterone agents mark important paradigm shift

Arthur L. Burnett II, MD, MBA

Burnett, a member of the Urology Times® Editorial Council, is professor of urology at Johns Hopkins University School of Medicine, Baltimore, Maryland.

The reports of clinical trial results for 2 novel oral testosterone undeconoate agents for use as testosterone replacement therapy bring forward a major advance in the management of testosterone deficiency. The introduction of these agents represents a paradigm shift in this clinical space for sexual medicine practice (see articles, pages 6-7).

Historically, an oral option for testosterone replacement therapy was unavailable because of risks of liver toxicity, including cholestasis and jaundice, associated with earlier developed 17-alpha-alkylated oral analogues. A host of testosterone delivery routes including transdermal (gels, creams, or patches), buccal, intranasal, intramuscular, and subcutaneous options have been in use, but each preparation has potential limitations and all are more onerous to administer than the simple mode of oral treatment.

These novel oral agents offer a new entry to the testosterone replacement therapy armamentarium by addressing the liver toxicity issue. They feature specialized formulations that avoid adverse hepatic effects. In clinical trials, both oral agents were found to produce no significant adverse effects on liver function tests. Rather, there is evidence reportedly of improved markers of liver disease.

The rigorous study and promising clinical availability of oral therapy for testosterone deficiency are flash points in the current era, in which the utility of testosterone therapy is under critical review. Recent concern regarding the proper indications for testosterone replacement therapy has prompted regulatory agency requirements and medical society recommendations to assist practitioners in clinical practice. A simpler oral treatment for testosterone deficiency presents another variable to be fully defined in exercising its appropriate prescription and use.

These trials provide early reassurance of safety, although ongoing studies may further elucidate safety aspects across cardiovascular, hematologic, and genitourinary systems of regular clinical concern associated with testosterone replacement therapy. It will also be valuable to investigate further the efficacy of oral therapies across conditions of testosterone deficiency, including adult-onset hypogonadism-related diabetes mellitus, testicular dysfunction as a complication of prior radiation or chemotherapy, HIV infection status, and other conditions characterized by low testosterone function.

The new oral therapies are a welcome advance for managing testosterone deficiency and will certainly prompt thorough review and positioning in process-of-care therapeutic algorithms. Assuredly, current guidance for evaluation and monitoring schemes for testosterone replacement therapy will remain operable. Recommendations for lifestyle modifications to improve health outcomes, which may then modify the role for testosterone interventions, should remain in force.

An ongoing limitation of exogenous testosterone therapy having potential adverse effects on normal spermatogenesis that compromises fertility remains relevant with use of oral therapies. This latter concern underscores the purpose of ongoing studies in men’s health to foster interventions that normalize male andrologic function and optimize natural wellness.