Testosterone deficiency is diagnosed by a serum total testosterone level below 300 ng/dL in combination with symptoms such as decreased energy and libido. These symptoms can be ameliorated by restoring serum testosterone to the physiologic range with testosterone therapy (TT). There are numerous forms of testosterone therapy, such as injectable, transdermal, nasal, and subcutaneous applications. There are also multiple formulations of injection, such as testosterone cypionate, testosterone enanthate, and testosterone undecanoate. Testosterone undecanoate is a long-acting ester formulation of testosterone that can be provided in an injectable or oral form. Oral testosterone undecanoate is marketed as Andriol, Jatenzo, Tlando, and Kyzatrex. Oral Testosterone undecanoate provides a convenient option for many patients, which may increase compliance with TT. Injectable testosterone undecanoate is marketed as Aveed and Nebido. Injectable TT remains the most cost-effective therapeutic option and is appropriate for most patients as an initial therapy. This review describes the pharmacokinetics of these testosterone undecanoate products and provides a guide for prescribers using these medications. While many forms of testosterone are appropriate for TT, a patient-centered discussion focused on goals of care should best guide physician prescription of these medications.[1]

Common Treatment Options for Testosterone Deficiency

Many formulations and modalities of testosterone therapy exist. Exogenous testosterone modalities include injections, subcutaneous pellets, topical, and mucosal (nasal and buccal) application. Testosterone Undecanoate (Testosterone undecanoate) is a testosterone ester that has a long half-life compared to other esters. Testosterone undecanoate is also the only available formulation of oral TT. Pharmacokinetic studies demonstrate that Testosterone undecanoate injections can return serum T levels to the eugonadal range 7–14 days after injection with a slow decline back to hypogonadal range by 10 weeks. Compared to testosterone enanthate and cypionate, Testosterone undecanoate is a longer acting form of testosterone and therefore requires less frequent administration to achieve clinical benefits. As a result, patients experience more stable T levels between injections and report significantly fewer fluctuations in mood and sexual function. Furthermore, a prospective study showed maximal Testosterone undecanoate effect on erectile function after 9 years of therapy, suggesting continued benefits over a long period of time.

Oral Testosterone Undecanoate Formulations

In the 1970s, when it was found that the esterification of testosterone allowed for its intestinal lymphatic absorption via chylomicrons, oral TT became a possibility. The first oral Testosterone undecanoate formulation has been marketed for use outside the United State as Andriol, and is available in more than 80 countries around the world. Initial studies of Andriol showed a modest rise in plasma testosterone levels and a substantial rise in dihydrotestosterone when compared with placebo and non-esterified oral testosterone, which established efficacy of the formulation as early as 1975. Additional randomized controlled trials confirmed improvement in quality of life scores as compared with placebo. Few adverse events were found in the trials, and those that did were considered minor, such as headache and gastrointestinal upset. Dosing of Andriol is simple, with 40 and 80 mg capsules available and a starting dose of 120–160 mg divided into a twice-daily administration.[2]

Patient Selection for Oral Testosterone Undecanoate

American Urologic Association guidelines do not specify which modality of testosterone therapy is most appropriate, therefore physicians should take a patient-centered approach to the prescription of TT. Oral formulations provide a convenient and easy to use option for patients with Testosterone undecanoate deficiency. Though these drugs are newer, studies have shown that patients with chronic conditions impacting mobility such as rheumatoid arthritis and multiple sclerosis prefer oral medications and demonstrate improved compliance with oral Testosterone undecanoate when compared to other forms of TT. Clearly, patients with dysphagia or other impediments to use of an oral medication are not good candidates for oral TT. Additionally, patients who cannot take oral medications twice per day are poor candidates for treatment with Jatenzo, Tlando, or Kyzatrex.

Injectable Testosterone Undecanoate Formulations

As early as 1995, preclinical, animal studies were performed to investigate the potential role of Testosterone undecanoate as an alternative injectable form of TT. Subsequent pharmokinetic studies in humans showed that mean serum T levels reached or exceeded the eugonadal range within the first week after injection and slowly returned to the patient’s hypogonadal baseline over the following 8 weeks, accompanied by improvement in quality of life scores. This is likely due to the slow metabolism of the saturated aliphatic fatty acid undecanoic acid. Unlike TE and TC, which require injection every 2 weeks, Testosterone undecanoate showed a favorable pharmokinetic profile and allowed a longer duration between injections, thus decreasing yearly injections from 26–52 to only 5–10 and increasing patient satisfaction.

Unique to the intramuscular (IM) injection of testosterone esters in an oil medium, is a concerning but non-life-threatening adverse effect pulmonary oil microembolism (POME). In contrast to a life-threatening venous thromboembolism, POME is defined by the acute onset of a non-productive cough sometimes accompanied by a sensation of flushing, faintness, or anxiety which resolves in minutes after the injection. These events are rare but did lead to a black box warning on the US formulation of the drug. The mechanism for these events is unclear and may be related to improper injection technique, therefore patients require monitoring after each injection.[3]

Summary

Low testosterone is an ongoing problem for men and can cause detrimental physiological and psychological effects. Various pharmacological interventions exist, and Testosterone undecanoate is currently a promising treatment modality. Testosterone undecanoate has increased compliance due to the option of oral intake and a pharmacokinetic profile that allows for far less frequent dosing compared to other exogenous testosterone compounds. While oral formulations provide a promising new option to expand access to TT, potential liver toxicity and fat consumption necessary for absorption of these drugs must be taken into consideration before prescription. Traditional injectable formulations of Testosterone undecanoate continue to provide a cost-effective strategy for TT. The decision to start treatment with oral or injectable Testosterone undecanoate must be the result of an individualized conversation between a patient and their physician. Overall, clinicians may offer Testosterone undecanoate as part of a personalized treatment regimen based on patient goals and preferences

References

[1] Trabado S, Maione L, Salenave S, et al. Estradiol levels in men with congenital hypogonadotropic hypogonadism and the effects of different modalities of hormonal treatment. Fertil Steril. 2011;95(7):2324–2329.e3.

[2] Anaissie J, DeLay KJ, Wang W, Hatzichristodoulou G, Hellstrom WJ. Testosterone deficiency in adults and corresponding treatment patterns across the globe. Transl Androl Urol. 2017;6(2):183–191. doi: 10.21037/tau.2016.11.16

[3] Rochira V. Hypogonadism in systemic diseases. In: Vitti P, Hegedus L, editors. Thyroid Diseases. Endocrinology. Springer International Publishing; 2017:1–51. doi: 10.1007/978-3-319-29456-8_28-1