Testosterone undecanoate was introduced in China for use by injection and in the European Union for use by mouth in the 1970s.[17][18] It became available for use by injection in the European Union in 2004–2005 and in the United States in 2014.[19][20] Formulations for use by mouth are approved in the United States.[3][4][21] Along withtestosterone enanthate,testosterone cypionate, andtestosterone propionate, testosterone undecanoate is one of the most widely used testosterone esters.[15][6][10] However, it has advantages over other testosterone esters in that it can be taken by mouth and in that it has a far longer duration when given by injection.[22][8][6][7][10] In addition to its medical use, testosterone undecanoate is used toimprove physique and performance.[10] The drug is acontrolled substance in many countries.[10]
Oral administration of testosterone undecanoate is an effective method to achieve therapeutic physiological levels of serum testosterone in patients with hypogonadism. In addition, oral therapy has been found to have a positive impact in these patients on quality of life factors such as sexual function, mood, and mental status, as documented in various studies.[23]
Testosterone undecanoate isindicated for testosterone replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone.[3][4][5]
Side effects of testosterone undecanoate includevirilization among others.[10] Specifically, injectable formulations of testosterone undecanoate carry a rare risk of pulmonary oil microembolism (POME).[24]
Testosterone undecaondate has very low bioavailability when taken orally, only about 3-7% in men and 4-10% in women.[28][29][30] This bioavailability is increased with food, especially foods containing fat, thus it is typically recommended to be taken with a meal.[31][32][33][34] It is absorbed through the lymphatic system (90-100%) and peak serum levels are reached after about 3-5 hours.[29][35][36] From there, plasma levels decline, typically reaching pre-dose levels after 6-12 hours. The elimination half-life via the oral route has been stated to be 1.6 hours, with amean residence time of 3.7 hours.[6] However, there is a large amount of individual variability in its duration of action.[37] For this reason it is often dosed twice or even three times a day.[37][35]
Testosterone undecanoate is metabolized partially in the intestinal wall into 5-alpha-dihydrotestosterone undecanoate (DHTU).[38] In the blood, non-specific esterases metabolize testosterone undecanoate into testosterone and DHTU intodihydrotestosterone (DHT).[38] Thus, testosterone undecanoate increases plasma levels of both testerone and DHT. The fact the conversion happens in the blood complicates the accurate measurement of blood levels of testosterone induced by the drug, as the conversion continues to occur while blood samples are being prepared for assay. Ideally, enzyme inhibitors should be used to properly assay the blood testosterone levels induced by testosterone undecanoate.[38]
The first commercialized preparation of oral testosterone undecanoate had it dissolved in oleic acid.[37] This formulation had to be refrigerated in the pharmacy for reasons of stability and would only last about three months at room temperature.[37] A newer more stable pharmaceutical formulation withcastor oil andpropylene glycol laurate has since been developed.[37] This new formulation can be stored at room temperature for three years.[37] A novelself-emulsifying formulation of oral testosterone undecanoate in 300-mg capsules for use once per day has been under development.<[41]
In November 2003, Nebido, an injectable testosterone undecanoate formulation made bySchering AG, received its initial European approval in Finland. This was followed by the completion of the European mutual recognition procedure in July 2004. It was released in a phased commercial launch starting in Finland and Germany in late 2004, with expansion into other European markets continuing through 2005.[19][20]
The USFood and Drug Administration (FDA) has approved several formulations of testosterone undecanoate for the treatment of hypogonadism in men. The first of these, an injectable form marketed as Aveed, received approval in March 2014.[44] It experienced three previous rejections in 2008, 2009, and 2013 due to safety concerns regarding anaphylaxis and pulmonary oil microembolism (POME).[45][46] The fourth attempt at approval was successful when the manufacturer agreed to implement aRisk Evaluation and Mitigation Strategy (REMS) to manage these potential respiratory and allergic reactions.[44][47]
Subsequent approvals have focused on oral delivery methods. In March 2019, the FDA approved Jatenzo, the first oral form of testosterone undecanoate.[21][48] This was followed by the approval of Tlando in March 2022.[4] In July 2022, the FDA approved Kyzatrex, another oral capsule formulation of the drug, to Marius Pharmaceuticals.[49][50]
Testosterone undecanoate is thegeneric name of the drug and itsUSANTooltip United States Adopted Name andBANTooltip British Approved Name.[39][40][51][52] It is also referred to astestosterone undecylate.[39][40][51][52]
Testosterone undecanoate is or has been marketed under a variety of brand names, including Andriol, Androxon, Aveed, Cernos Depot, Jatenzo, Kyzatrex,[5] Nebido, Nebido-R, Panteston, Reandron 1000, Restandol, Sustanon 250, Undecanoate 250, and Undestor.[39][40][51][53][52]
Oral testosterone undecanoate is available in Europe, Mexico, Asia, and the United States.[54][55]
Intramuscular testosterone undecanoate has been approved worldwide,[54][10] including the European Union, Russia, and the United States.[10][54][56] Intramuscular testosterone undecanoate is marketed as Nebido in Europe and as Aveed in the United States while oral testosterone undecanoate is marketed as Andriol.[10][54][56]
In 2013, aphase IIclinical trial testing intramuscular testosterone undecanoate for the treatment ofnon-alcoholic steatohepatitis (NASH) was initiated in theUnited Kingdom.[59] In the United States in 2018, Lipocine Inc. began investigating the potential of using an oral testosterone undecanoate formulation, known as LPCN-1144, in patients with NASH.[60]
In 2013, a study aimed to evaluate the efficacy of testosterone undecanoate therapy on bone mineral density (BMD) and biochemical markers of bone turnover in elderly males withosteoporosis and low serum testosterone levels.
They study found that administering low-dose testosterone undecanoate (TU) at a rate of 20 mg per day to elderly men with low serum testosterone and osteoporosis effectively increases bone mineral density in the lumbar spine and femoral neck, and improves bone turnover, similar to the standard-dose TU (40 mg, per day) treatment. The treatment did not exhibit any adverse side effects on the prostate gland, includingprostate-specific antigen. Therefore, low-dose TU appears to be a safe and cost-effective protocol for treating elderly male osteoporosis.[61] However, further clinical trials with larger sample sizes, multiple centers, and long-term follow-ups are required to determine the efficacy and safety of low-dose testosterone undecanoate treatment in elderly male osteoporosis with low serum testosterone.
In 2020, a study that evaluated the effects of testosterone therapy in men with testosterone deficiency and varying degrees of weight (normal weight, overweight, and obesity) on anthropometric and metabolic parameters found that long-term testosterone undecanoate therapy in hypogonadal men, regardless of their weight at the start of the study, led to improvements in several body composition parameters, including body weight, waist circumference, and body mass index. Additionally, testosterone undecanoate therapy was found to lower fasting blood glucose and HbA1c levels and improve lipid profiles in this population.[63]
There have been several studies that evaluate the effect of testosterone therapy on bone density orbone mineral density (BMD). One study concluded that long-term testosterone replacement therapy (TRT) in middle-aged men withlate-onset hypogonadism (LOH) andmetabolic syndrome (MS) led to a significant increase in both vertebral and femoral bone mineral density (BMD) after 36 months of treatment, as measured by dual-energy x-ray absorptiometry. The TRT treatment was shown to induce a 5% per year increase in BMD without changes in body mass index (BMI). The study suggests that long-term TRT could be beneficial for improving bone health in middle-aged men with LOH and MS, even in the absence of osteoporosis.[64]
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^Behre HM, Nieschlag E, Nieschlag S (26 July 2012). "Testosterone preparations for clinical use in males". In Nieschlag E, Behre HM, Nieschlag S (eds.).Testosterone: Action, Deficiency, Substitution. Cambridge University Press. pp. 309–335.doi:10.1017/CBO9781139003353.016.ISBN978-1-107-01290-5.
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^Tschopp E, Meier R (December 1954). "[Triolandren, a mixture of testosterone esters with quick starting and protracted effect]".Schweizerische Medizinische Wochenschrift (in German).84 (50):1392–4.PMID13237946.
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