madman
Super Moderator
Abstract
Symptomatic male hypogonadism, defined by low serum testosterone with associated clinical symptoms, is increasingly treated with testosterone replacement therapy. Traditional oral formulations were limited by hepatotoxicity and poor bioavailability, leading to reliance on injectable and transdermal routes. Recent advances in oral testosterone undecanoate formulations have introduced safer and more effective options. This review compares Jatenzo, Tlando, and Kyzatrex, highlighting their pharmacology, efficacy, safety, and clinical utility. Clinical trial data demonstrate restoration of eugonadal testosterone levels in most patients (80–88%), with shared risks including hypertension, polycythemia, and lipid changes. Differences in dosing regimens, titration requirements, and insurance coverage influence choice of therapy and patient adherence. Kyzatrex offers flexible titration and self-pay access, Tlando provides a fixed-dose regimen, and Jatenzo combines titratability with established clinical data. Collectively, these agents expand the therapeutic landscape of hypogonadism, offering effective, non-invasive alternatives that support individualized treatment strategies.
This review aims to provide a comprehensive comparison of the newly developed oral testosterone therapies, Jatenzo, Tlando, and Kyzatrex, focusing on their development, effectiveness, and clinical outcomes. By evaluating these therapies, we aim to clarify their respective roles in the management of symptomatic male hypogonadism, highlighting the benefits and challenges associated with each, and informing clinical decision making regarding their use in treatment plans.
Development of Oral Testosterone Therapies
The development of oral testosterone undecanoate marked a significant improvement in TTh and occupies a unique position in the evolutionary timeline of testosterone therapies. Oral TU is the first orally bioavailable formulation with a safety profile distinct from older oral androgens discussed above. Introduced in the 1970s, oral TU leveraged lymphatic absorption, bypassing the portal circulation and reducing first-pass hepatic metabolism and associated hepatotoxicity [5,10].
TTh has undergone significant advancements over the years. Early oral formulations like methyltestosterone and fluoxymesterone faced major drawbacks, including poor bioavailability and hepatotoxicity caused by extensive first-pass metabolism in the liver. These 17 α-alkylated derivates, developed to bypass hepatic metabolism, were linked to significant liver toxicity, ranging from cholestatic jaundice and peliosis hepatitis to benign adenomas and hepatocellular carcinoma [10,13].
The risk was strongly dose- and duration-dependent. In one cohort of 60 patients receiving methyltestosterone (50 mg three times daily), 32% developed abnormal liver function tests and 63% had abnormal liver scans, particularly in those treated for more than one year [14]. Histopathology revealed early peliosis hepatitis, and in one case, hepatic adenoma. Case reports have described hepatic adenomas and hepatocellular carcinoma after 5-11 years of methyltestosterone therapy [15,16,17]. The FDA label for methyltestosterone explicitly warns of rare but serious adverse hepatic reactions, recommending close liver function monitoring [18]. Fluoxymesterone, another α-alkylated androgen, carries a similar risk profile, although less extensively studied. Its use has been discouraged due to reports of hepatic neoplasia and bile acid dysregulation [16,19,20]. However, mechanistically both agents promote oxidative stress and hepatocyte hyperplasia which explains their hepatotoxic profile.
Because of these limitations, the use of methyltestosterone and fluoxymesterone is now infrequent and generally limited to circumstances where the potential benefits outweigh the risks, while always carefully monitoring hepatic function. Their toxicity drove the development of alternative delivery systems, such as injectable esters and transdermal preparations. However, these methods came with their own set of challenges, including fluctuating testosterone levels and difficulties with patient adherence [5,21].
The development of oral testosterone undecanoate marked a significant improvement in TTh and occupies a unique position in the evolutionary timeline of testosterone therapies. Oral TU is the first orally bioavailable formulation with a safety profile distinct from older oral androgens discussed above. Introduced in the 1970s, oral TU leveraged lymphatic absorption, bypassing the portal circulation and reducing first-pass hepatic metabolism and associated hepatotoxicity [5,10].
Prior to this innovation, testosterone therapy had evolved through several delivery routes (Figure 1). Subcutaneous pellets (e.g., Testopel), developed in the 1930s, provided sustained release over 3–6 months but required minor surgical implantation [22]. Injectable testosterone esters (enanthate, cypionate), introduced in the 1950s, became widely adopted, though their pharmacokinetics produced supraphysiologic peaks and subtherapeutic troughs, leading to symptomatic fluctuations [5,6,19]. Transdermal preparations, including patches (1980s) and gels (2000s), provided more physiologic testosterone profiles and greater convenience, though with risks of skin irritation and inadvertent transfer [23,24]. More recently, long-acting injectable TU (e.g., Nebido, Aveed) has been developed, offering more stable serum levels with quarterly dosing and improved adherence [5,6,25]. In parallel, subcutaneous injections gained traction due to ease of administration and comparable pharmacokinetics compared to intramuscular injections [26].
Modern oral TU formulations represent a culmination of these developments. A key breakthrough came with the self-emulsifying drug delivery system (SEDDS), which combines hydrophilic and lipophilic components to solubilize testosterone undecanoate in the gut and promote intestinal lymphatic absorption independent of very high dietary fat intake [27,28]. Clinical trials have shown that these newer oral formulations effectively restore testosterone to eugonadal levels in men with symptomatic hypogonadism, with efficacy and safety comparable to non-oral routes [11].
When administered with dietary fat, oral testosterone undecanoate is absorbed through the intestinal lymphatics via incorporation into chylomicrons, resulting in more stable serum testosterone concentrations and a safety profile free from hepatic complications [10,29]. However, early testosterone undecanoate products such as Andriol (approved in many countries but not in the United States) relied heavily on high-fat meals for absorption, resulting in considerable intra- and inter-patient variability, frequent dosing requirements, and occasional gastrointestinal or hepatic adverse effects [6,10,30].
These advances have bridged the gap between the convenience of oral administration and safety and efficacy of parenteral and transdermal therapies. These new testosterone undecanoate options join the modern therapeutic landscape for symptomatic hypogonadism as a convenient, effective, and safe alternative that improves patient choice and adherence.
2.1 Jatenzo
Jatenzo is the first FDA approved oral testosterone undecanoate in SEDDS form indicated for TTh in adult males with confirmed primary or hypogonadotropic hypogonadism. The recommended starting dose is 237 mg orally twice daily with food, titrated between 158 mg and 396 mg twice daily based on serum testosterone levels measured 6 h after the morning dose.
2.2 Tlando
Tlando is a once-daily oral testosterone undecanoate option for testosterone replacement in adult men with confirmed primary or hypogonadotropic hypogonadism. Unlike Jatenzo, which requires titration, Tlando is administered as a fixed dose of 225 mg twice daily with food, eliminating the need for individualized dose adjustments [9].
2.3 Kyzatrex
Kyzatrex is approved for TTh in adult men diagnosed with either primary or hypogonadotropic hypogonadism, following documentation of low morning serum testosterone on at least two separate days and the presence of clinical symptoms. The recommended starting dose is 200 mg orally twice daily with food, titrated between 100 mg once daily and 400 mg twice daily based on serum testosterone levels measured 3–5 h post-dose [8,29]. Kyzatrex has been approved in three dosage strengths: 100 mg, 150 mg, and 200 mg [8,29].
2.4 Comparison of Kyzatrex, Tlando, and Jatenzo
Kyzatrex, Tlando, and Jatenzo are oral testosterone undecanoate formulations absorbed via the intestinal lymphatic system, bypassing first-pass hepatic metabolism, as illustrated in Figure 2. Kyzatrex is taken with food to optimize absorption, with fat content markedly increasing exposure (area under the curve increased 37–97% vs. fasting); after 90 days, the mean concentration was 393 ng/dL and maximum concentration was 852 ng/dL [8]. Tlando’s bioavailability is also food-dependent but unaffected by fat content, though fasting reduces the maximum concentration and area under the curve by 65% and 38%, respectively; the mean average concentration was 476 ng/dL and maximum concentration was 979–989 ng/dL [9]. Jatenzo absorption is influenced by fat content (15 g fat meal decreases exposure by 25% vs. 30 g), achieving a mean average concentration of 403 ng/dL and maximum concentration of 1008 ng/dL after titration [31]. All share similar distributions (around 40% bound to sex hormone binding globulin), metabolism (ester hydrolysis, testosterone conversion to dihydrotestosterone and estradiol), and excretion pathways (primarily urinary conjugates) [8,9,31].
In the aforementioned clinical trials, eugonadal levels were achieved in 88% (Kyzatrex), 80% (Tlando), and 87% (Jatenzo) of patients, with Jatenzo also demonstrating improvements in psychosexual function and body composition. Safety profiles overlap, with hypertension, polycythemia, and lipid changes as the most common adverse effects; Jatenzo and Kyzatrex both carry boxed warnings for blood pressure elevation. No clinically significant hepatotoxicity has been reported and gastrointestinal symptoms are generally mild.
Tlando’s fixed-dose regimen offers simplicity and may improve adherence, while Kyzatrex and Jatenzo’s titratable dosing allows individualized optimization. Market uptake and insurance coverage vary, with cost considerations likely to influence accessibility across products. Kyzatrex and Tlando are generally priced competitively, with average wholesale prices for a 30-day supply in the several hundred-dollar range, and both offer copay assistance programs to reduce patient costs [8,9]. Coverage for these are available through many commercial insurance plans and select Medicare Part D formularies, although prior authorization is common [9,29]. Jatenzo has historically been the highest priced formulation, with average wholesale prices often exceeding others [31]. Insurers frequently require prior authorization or step therapy, and manufacturer copay assistance is available for eligible patients [10,31]. A summary comparison is provided in Table 1.
3. Challenges and Future Directions
Although oral TU formulations represent a major advance in testosterone replacement therapy, several important challenges and unanswered questions remain. These must be addressed to clarify their long-term role in the management of symptomatic male hypogonadism.
3.1 Blood Pressure and Cardiovascular Safety
3.2 Comparative Effectiveness
3.3 Absorption Variability and Non-Interchangeability
3.4 Symptom Outcomes and Quality-of-Life Measures
4. Conclusions
Oral testosterone undecanoate formulations such as Kyzatrex, Tlando, and Jatenzo offer effective, non-invasive options for restoring eugonadal testosterone levels in men with symptomatic hypogonadism. These oral options fill an important niche for patients who cannot or prefer not to use injections or transdermal forms, expanding patient choice. Clinical trials demonstrate high efficacy and comparable safety profiles for all three agents. In practice, the choice between these therapies should be guided by individualized patient factors, including need for dose titration, adherence preferences, cardiovascular risk, and cost/insurance considerations. Tlando’s fixed-dose regimen may favor simplicity and adherence, while Kyzatrex and Jatenzo allow individualized titration to optimize serum testosterone levels. Finally, if insurance authorization denials is an ongoing battle, Kyzatrex does offer a reasonable self-pay only option for patients. Ongoing research will be essential to inform optimal monitoring strategies and refine their role in personalized management of male hypogonadism.
