Abstract
An extensive scientific review of testosterone undecanoate, the longest-acting injectable testosterone ester and the only oral testosterone formulation with established clinical efficacy, covering its unique pharmacokinetics, dual formulation strategies, clinical evidence, and role in modern TRT.
Testosterone undecanoate is a long-chain fatty acid ester of testosterone formed by esterification of the 17-beta hydroxyl group with undecanoic acid (undecylenic acid), an eleven-carbon aliphatic carboxylic acid. This large ester chain produces the most lipophilic of the clinically available testosterone esters, conferring unique pharmacokinetic properties that enable both an extremely long-acting intramuscular depot formulation and an oral formulation that achieves systemic bioavailability through lymphatic absorption. The compound has the molecular formula C30H48O3 and a molecular weight of 456.70 grams per mol. Approximately 63 percent of this molecular weight represents active testosterone, with the undecanoate ester comprising the remaining 37 percent, the highest ester-to-testosterone ratio among commonly used formulations. The CAS registry number is 5949-44-0.
The chemical rationale for the undecanoate ester is dual-purpose. For the intramuscular formulation, the long carbon chain increases the partition coefficient (log P) substantially, causing the ester to preferentially sequester within the oil depot after injection, resulting in extremely slow partitioning into surrounding aqueous tissue fluids and correspondingly prolonged release of the parent hormone. For the oral formulation, the high lipophilicity enables the ester to be absorbed from the gastrointestinal tract into intestinal lymphatics via chylomicron incorporation, thereby bypassing the portal venous system and hepatic first-pass metabolism that would otherwise rapidly inactivate oral testosterone. This lymphatic absorption pathway was first characterized by Horst and colleagues in the 1970s and represents the key pharmacological innovation that makes oral testosterone therapy clinically viable.
The intramuscular formulation of testosterone undecanoate is marketed under the brand names Nebido (Bayer) in Europe, the United Kingdom, and many other countries, and Aveed (Endo Pharmaceuticals) in the United States. The European Nebido formulation contains 1,000 mg of testosterone undecanoate in 4 mL of castor oil with benzyl benzoate as a co-solvent. The US Aveed formulation contains 750 mg of testosterone undecanoate in 3 mL of castor oil with benzyl benzoate. The pharmacokinetic profile following intramuscular injection is characterized by a very long terminal elimination half-life of approximately 21 days (range 18 to 33 days across studies), reflecting the slow release from the large-volume oil depot. After the first injection, serum testosterone levels rise gradually over 7 to 14 days, reaching peak concentrations at approximately 7 to 14 days post-injection. The peak is typically within or modestly above the physiological range (600 to 1,200 ng/dL), considerably lower and broader than the sharp peaks produced by equivalent testosterone content administered as cypionate or enanthate. Testosterone levels then decline gradually over the ensuing weeks, typically remaining within the physiological range for 10 to 14 weeks.
The recommended dosing protocol for intramuscular testosterone undecanoate involves an initial loading phase followed by maintenance dosing. For Nebido, the protocol specifies 1,000 mg as the first injection, followed by 1,000 mg at 6 weeks, and then 1,000 mg every 10 to 14 weeks thereafter. For Aveed, the protocol is 750 mg initially, 750 mg at 4 weeks, and then 750 mg every 10 weeks. The loading phase is necessary because the very long half-life results in slow accumulation, and without the early second dose, testosterone levels may decline to subtherapeutic levels before steady-state kinetics are established. Full steady-state is typically reached after approximately 3 to 5 injection cycles. At steady state, trough testosterone levels average approximately 400 to 500 ng/dL and peak levels average approximately 700 to 900 ng/dL with the Nebido formulation, representing a remarkably narrow peak-to-trough ratio of approximately 1.5:1 to 2:1. This represents the most stable testosterone blood level profile achievable with any injectable testosterone formulation.
The advantage of minimal peak-to-trough fluctuation with testosterone undecanoate translates to several clinical benefits. Studies by Minnemann and colleagues, published in the World Journal of Urology, compared patient-reported outcomes between testosterone enanthate (250 mg every 3 weeks) and testosterone undecanoate (1,000 mg every 12 weeks) in a crossover design. Patients reported significantly better mood stability, more consistent energy levels, and less cyclical variation in libido and sexual function during the testosterone undecanoate phase. The mean satisfaction score was 8.1 out of 10 for testosterone undecanoate compared to 6.4 out of 10 for testosterone enanthate, with the primary driver of preference being the absence of the symptomatic "roller coaster" associated with shorter-acting esters.
The injection frequency of every 10 to 14 weeks (approximately 4 to 5 injections per year) represents a major practical advantage for patient compliance and quality of life compared to weekly or biweekly injection schedules. However, the large injection volume (3 to 4 mL of viscous castor oil) requires intramuscular administration into a large muscle, typically the gluteus maximus, using a relatively large-bore needle (typically 21-gauge, 1.5-inch). The injection must be administered slowly over approximately 2 minutes to minimize pain and the risk of oil microembolism. Post-injection surveillance for 30 minutes is recommended (and is mandatory under the Aveed REMS program in the United States) due to a rare but serious adverse reaction known as pulmonary oil microembolism (POME). POME occurs when small amounts of the oil vehicle enter the venous circulation and travel to the pulmonary vasculature, causing symptoms ranging from cough, dyspnea, and chest tightness to more severe respiratory distress and syncope. The incidence of clinically significant POME events is estimated at less than 1 percent per injection, based on post-marketing surveillance data. The risk is minimized by strict intramuscular injection technique with aspiration before injecting, slow injection speed, and avoidance of injection into the ventrogluteal site where accidental intravenous entry is more likely.
The oral formulation of testosterone undecanoate is marketed under the brand names Andriol (Organon/MSD) in Europe, Australia, and many other countries, and Jatenzo (Clarus Therapeutics) in the United States. Andriol has been available since the 1980s and contains 40 mg testosterone undecanoate per capsule in oleic acid. Jatenzo, approved by the FDA in 2019, is a newer lipid-based formulation containing 158 mg or 237 mg testosterone undecanoate per softgel capsule. The two oral formulations differ substantially in their pharmacokinetics and dosing requirements due to differences in the lipid excipient system.
Andriol (40 mg capsules) has relatively low and highly variable oral bioavailability, typically requiring doses of 120 to 160 mg daily (3 to 4 capsules) taken with a fat-containing meal to achieve adequate serum testosterone levels. The dependence on dietary fat intake for absorption introduces substantial intra- and inter-individual variability, which has been criticized as a limitation. Peak serum testosterone occurs approximately 4 to 5 hours after ingestion, reflecting the time required for intestinal lymphatic absorption through chylomicron formation. The serum testosterone half-life after oral testosterone undecanoate is substantially shorter than after intramuscular injection (approximately 4 to 8 hours), necessitating twice-daily dosing to maintain therapeutic levels throughout the day.
Jatenzo addresses some of the pharmacokinetic limitations of Andriol through an enhanced lipid vehicle formulation that improves and partially de-links absorption from dietary fat intake. The recommended Jatenzo dose is 237 mg orally twice daily, titrated based on serum testosterone levels measured 4 to 6 hours after the morning dose on day 7 or later. Dose adjustments can be made up to 396 mg twice daily or down to 158 mg twice daily. In the pivotal phase 3 trial, Jatenzo restored serum testosterone to the normal range (300 to 1,050 ng/dL) in approximately 87 percent of hypogonadal men based on the average of two 24-hour testosterone concentration profiles measured at days 90 and 180. The proportion of patients achieving the FDA target of Cavg within 300 to 1,050 ng/dL was comparable to injectable testosterone formulations.
Comparison with other testosterone esters highlights the unique niche occupied by testosterone undecanoate. The intramuscular formulation provides the longest injection interval of any testosterone ester (10 to 14 weeks versus 1 to 2 weeks for cypionate/enanthate), the most stable blood levels, and the least frequent clinic visits or self-injection episodes. The oral formulation is the only currently available oral testosterone that does not employ 17-alpha alkylation, the chemical modification used in methyltestosterone and fluoxymesterone that enables oral bioavailability but causes dose-dependent hepatotoxicity. By utilizing lymphatic absorption instead of surviving hepatic first-pass metabolism, oral testosterone undecanoate avoids the liver toxicity concerns associated with 17-alpha-alkylated oral androgens. This is a critically important distinction: testosterone undecanoate does not cause peliosis hepatis, hepatic adenoma, or hepatocellular carcinoma, adverse effects that led to the withdrawal or restriction of methyltestosterone in many countries.
The side effect profile of intramuscular testosterone undecanoate is generally favorable compared to shorter-acting injectable esters. The reduced peak-to-trough fluctuation attenuates peak-dependent adverse effects including erythrocytosis, acne, and mood instability. Long-term safety data from European registries tracking Nebido use over periods exceeding 10 years demonstrate sustained improvements in metabolic parameters (waist circumference, fasting glucose, hemoglobin A1c, lipid profiles) with a favorable safety profile in hypogonadal men receiving ongoing TRT. The POME risk is the most significant ester-specific adverse effect unique to the intramuscular undecanoate formulation.
For the oral formulation, the most notable safety concern raised during the FDA approval process for Jatenzo was a modest dose-dependent increase in systolic blood pressure (mean increase of 3 to 5 mmHg) observed in clinical trials. This effect, which was not seen with the same magnitude for injectable testosterone formulations, led to the inclusion of a boxed warning about blood pressure elevation in the Jatenzo prescribing information. Regular blood pressure monitoring is recommended for patients on oral testosterone undecanoate. Other adverse effects include headache, diarrhea, and increased hematocrit, consistent with the general pharmacology of testosterone replacement.
The clinical evidence base for testosterone undecanoate is extensive, particularly for the intramuscular formulation. The Registry of Hypogonadism in Men (RHYME) study, a multinational observational study enrolling over 1,000 hypogonadal men across Europe, documented real-world outcomes with various testosterone formulations including testosterone undecanoate. A pivotal long-term study by Saad and colleagues tracked 823 hypogonadal men receiving Nebido for up to 12 years, demonstrating sustained improvements in body composition (mean decrease in waist circumference of 9.4 cm), metabolic markers (mean decrease in fasting glucose of 23 mg/dL), and cardiovascular risk factors (mean decrease in total cholesterol of 37 mg/dL) with no increase in cardiovascular events compared to an untreated reference group.
Regulatory status of testosterone undecanoate varies by formulation and jurisdiction. Intramuscular testosterone undecanoate is subject to a restricted distribution program (REMS) in the United States under the Aveed brand, requiring healthcare provider certification, in-office administration, and 30-minute post-injection observation. This REMS requirement, driven by the POME risk, limits the convenience of the formulation compared to its use in other countries where Nebido can be dispensed for self-injection. In the European Union and many other countries, Nebido is available by standard prescription without mandatory in-office administration restrictions, though healthcare provider training on proper injection technique is recommended. Both oral formulations (Andriol and Jatenzo) are prescription medications classified as Schedule III controlled substances in their respective markets. Storage of the intramuscular formulation should be at room temperature (15 to 25 degrees Celsius), protected from light. Oral capsules should be stored at room temperature. Neither formulation should be frozen. The intramuscular castor oil solution may become very viscous at cool temperatures and should be warmed to room temperature before injection to facilitate administration.