Oral Testosterone Replacement Therapy: What’s Available and What Took so Long?
By: Babak K. Azad, MD, University of California, Irvine; Faysal A. Yafi, MD, FRCSC, University of California, Irvine | Posted on: 19 Sep 2023
The field of testosterone replacement therapy (TRT) has witnessed remarkable growth and demand in recent years. While injectable and topical forms remain popular, other types of TRT including oral testosterone have been rapidly growing. Studies in cancer treatment have shown patients exhibiting an overall preference for oral therapy over other regimens, as oral TRT offers a convenient alternative that might improve various aspects of patients’ lives.1
Innovations in Oral Testosterone Formulations
Over the years, researchers have developed various oral testosterone formulations aimed at ensuring reliable absorption into the system. Traditional methyltestosterone, belonging to the previous generation of oral testosterone, raised serious concerns of liver toxicity associated with 17-alkylated testosterone delivery through the portal system. Consequently, oral nonalkylated undecanoate testosterone entered the scene, utilizing intestinal and lymphatic absorption routes to avoid the first pass. Despite the presence of insurance coverage issues in some cases and reports of gastrointestinal intolerance with the new generation, the primary limitation stems from unstable bioavailability. Formulations of this type enable the solubilization of highly lipophilic molecules absorbed after oral ingestion with food, and to optimize efficacy, patients are advised to consume the oral testosterone pill with a meal containing at least 19 g of fat.2
Tracing the Evolution of Undecanoate Oral TRT: From the Past to Present
This article delves into the evolution of undecanoate oral TRT, exploring notable formulations and their corresponding findings. By examining the journey from the release of the first medication to the current state, we aim to shed light on the latest understanding and offer insights into the future of oral TRT options.
The Emergence of Oral TRT
In the early 1970s, the concept of oral TRT began to take shape. However, its availability in the United States was limited due to frequent dosing requirements and concerns for liver toxicity. Over time, researchers and pharmaceutical companies made remarkable progress, leading to the development of formulations that showed promising results.
One of the groundbreaking developments in oral TRT came with the introduction of Jatenzo. In a randomized study conducted by Swerdloff et al in 2018, Jatenzo was compared to a topical testosterone product in hypogonadal men aged 18 to 65.3 The study revealed that 87% of patients in both groups achieved mean serum testosterone levels within the eugonadal range (mean±SD 489 ±155 ng/dL). Safety profiles were similar, except for a slight increase in systolic blood pressure (3 to 5 mm Hg) associated with oral testosterone undecanoate.
Another notable formulation, Tlando, is a lipophilic molecule primarily absorbed into the lymph system after oral administration. Following an initial dose-finding study, a dose validation study was conducted using a fixed dose of 225 mg twice daily of Tlando, with 80% of subjects attaining testosterone levels within the eugonadal range (mean±SD 476 ±184 ng/dL) while maintaining an impressive overall mean compliance of 99.7%. A blood pressure box warning was similarly issued for Tlando, and this drug has been associated with increases in prolactin (cause unknown).4
Incorporating phytosterol esters in gelatin capsules, Kyzatrex offered a starting dose of 200 mg twice daily, with subsequent dose adjustments on days 28 and 56. Studies demonstrated that nearly all subjects achieved mean 24-hour total testosterone levels within the normal range (222-800 ng/dL). Additionally, while the mean change from baseline in systolic blood pressure was minimal (1.7 mm Hg), this also led to a blood pressure box warning.5
The market now boasts a wide range of commercially available TRT options, including novel oral formulations with favorable safety profiles and no liver toxicity concerns. However, it remains crucial to monitor blood pressure in patients prescribed oral TRT.
- Eek D, Krohe M, Mazar I, et al. Patient-reported preferences for oral versus intravenous administration for the treatment of cancer: a review of the literature. Patient Prefer Adherence. 2016; 10:1609-1621.
- Schnabel PG, Bagchus W, Lass H, Thomsen T, Geurts TP. The effect of food composition on serum testosterone levels after oral administration of Andriol® Testocaps®. Clin Endocrinol (Oxf). 2007;66(4):579-585.
- Swerdloff RS, Wang C, White WB, et al. A new oral testosterone undecanoate formulation restores testosterone to normal concentrations in hypogonadal men. J Clin Endocrinol Metab. 2020;105(8):2515-2531.
- DelConte A, Papangkorn K, Kim K, et al. A new oral testosterone (TLANDO) treatment regimen without dose titration requirement for male hypogonadism. Andrology. 2022;10(4):669-676.
- White WB, Bernstein JS, Rittmaster R, Dhingra O. Effects of the oral testosterone undecanoate Kyzatrex™ on ambulatory blood pressure in hypogonadal men. J Clin Hypertens. 2021;23(7):1420-1430.