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Safety Aspects and Rational Use of Testosterone Undecanoate in the Treatment of Testosterone Deficiency: Clinical Insights (2023)
Katherine Campbell, Akhil Muthigi, Armin Ghomeshi, Kyle Schuppe, Max D Sandler, Ranjith Ramasamy
Abstract
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 (TU) 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 TU 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.
Introduction
Testosterone deficiency is recognized as the deficiency of testosterone (T) production by the testes. This deficiency results in a pathologically low systemic testosterone concentration, as well as the concentrations of its bioactive metabolites dihydrotestosterone (DHT) and estradiol (E2).1 Testosterone deficiency may affect up to 10% of men worldwide and 40% of men over the age of 45.2,3 Signs and symptoms of testosterone deficiency include characteristic physical changes such as regression of secondary sex characteristics, decreased lean muscle mass, and cognitive changes.3–5 The restoration of serum testosterone to physiologic, or eugonadal, levels has been shown to alleviate some of the symptoms of testosterone deficiency and provide significant improvement in quality of life.6 Multiple treatment options for testosterone deficiency exist, most commonly consisting of testosterone therapy (TT) with exogenous testosterone. Specifically, testosterone undecanoate (TU) is an 11-carbon-long androgen ester derivative of testosterone that comes in an injectable or oral formulation. Recently, we have seen a rapid increase in the available FDA-approved TU forms of T. Herein, we present a focused review on testosterone undecanoate and its various formulations, as well as a practical guide for prescribers.
What is Testosterone Deficiency
As per American Urologic Association guidelines, testosterone deficiency is diagnosed with a serum testosterone level below 300 ng/dL on two separate occasions, with both conducted in the early morning in combination with symptoms.
Recent studies suggest that 300 ng/dL may not be an appropriate cutoff for a diagnosis of testosterone deficiency, and thus the diagnosis should be made by a trained physician based on serum biochemical (testosterone and sex hormone binding globulin) and clinical symptoms given the specific patient’s concomitant medical conditions.8 Regardless of primary or secondary etiology, testosterone deficiency is associated with characteristic physical changes, including gynecomastia, regression of secondary sex characteristics, and sexual dysfunction.5,7 Testosterone deficiency is also associated with musculoskeletal changes such as decreased bone mineral density and muscle mass.5 In addition, obese or overweight men have been shown to have higher rates of secondary testosterone deficiency than their normal-weight counterparts.9 Psychological disturbances such as low motivation, poor concentration, and diminished energy are also frequent concerns of men with low T.5,10 Of the symptoms, diminished energy is the most reported hypogonadal symptom in men younger than 40 years old.11
Why Do We Treat Testosterone Deficiency?
Testosterone therapy can improve mood, libido, and sexual function, as well as increase muscle mass and bone density, elevate hematocrit from anemic levels, and reduce body fat.7,12,13 Despite less conclusive evidence, many patients also report significant improvements in their energy level and cognitive function with TT.14 Currently, studies have shown conflicting results as to the reproducibility and mechanism of these improvements in energy and cognition, and, as such, the 2018 AUA Guidelines do not recognize improvements in energy and cognition as known benefits of TT.7
Treating patients with testosterone deficiency not only improves immediate symptoms but also minimizes long-term sequelae of T deficiency itself. T deficiency is a known risk for cardiovascular disease and is associated with hypertension, dyslipidemia, obesity, and diabetes.7,12 A 2018 meta-analysis of seven observational studies indicated that men with testosterone deficiency have an increased risk of myocardial infarction and pooled analysis of 12 studies demonstrated an increased risk of cerebrovascular accidents compared to men with normal T levels.7
Due to a lack of long-term prospective studies, it is unclear whether testosterone therapy in deficient patients will ameliorate all these risks, and prescribers must balance the potential benefits against risks of TT, including the well-described effects of polycythemia, hypertension, and a decrease in sperm count. This is especially true in those at high risk of these adverse events and those with baseline poor health status. Patients with elevated hemoglobin/hematocrit (>50%) should delay testosterone therapy to avoid further polycythemia.15 Patients wishing to conceive must also be informed that 10% of men failed to recover sperm in their ejaculate until two years after stopping TT and some may become permanently oligospermic or azoospermic after treatment with TT.16 Ironically, despite the association between testosterone deficiency and cardiovascular risk, exogenous T may have cardiovascular risks of its own. The 2018 AUA Guidelines recognized this risk but, since then, a systematic review of over 50 trials showed that testosterone therapy was not associated with an increased risk of cardiovascular events.17 Due to this conflicting evidence, an individualized and patient-centered approach must include a discussion of these risks, alongside the benefits, before testosterone therapy is to be prescribed.
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) applications (Table 1). Testosterone Undecanoate (TU) is a testosterone ester that has a long half-life compared to other esters.18 TU is also the only available formulation of oral TT (Table 2). Pharmacokinetic studies demonstrate that TU injections (Table 3) can return serum T levels to the eugonadal range 7–14 days after injection with a slow decline back to the hypogonadal range by 10 weeks.19–21 Compared to testosterone enanthate and cypionate, TU is a longer-acting form of testosterone and therefore requires less frequent administration to achieve clinical benefits.22 As a result, patients experience more stable T levels between injections and report significantly fewer fluctuations in mood and sexual function.23 Furthermore, a prospective study showed a maximal TU effect on erectile function after 9 years of therapy, suggesting continued benefits over a long period of time.24
Oral Testosterone Undecanoate Formulations
Andriol
-History and Development
-Efficacy
-Dosing
-Adverse Effects
Jatenzo
-History and Development
-Efficacy
-Dosing
-Adverse Effects
Tlando
-History and Development
-Efficacy
-Dosing
-Adverse Effects
Kyzatrex
-History and Development
-Efficacy
-Dosing
-Adverse Effects
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 T 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 T when compared to other forms of TT.51,52 Clearly, patients with dysphagia or other impediments to using 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
Aveed
-History and Development
-Efficacy
-Dosing
-Adverse Effects
Nebido
-History and Development
-Efficacy
-Dosing
-Adverse Effects
Patient Selection for Injectable Testosterone Undecanoate
Intramuscular injections of testosterone have been the most commonly prescribed form of TT since their development in the 1930s.64 IM formulations of TT remain the most cost-effective and most frequently covered by insurance, making them an ideal option for those wishing for cost-effective treatment. IM injections of T often require dose optimization based on body habitus and individual metabolism; therefore, dosing may vary and should be guided by an individual’s serologic and symptomatic response. Though IM injections are commonly used, and generally safe, this formulation may not be a suitable option for patients who are averse to self-injecting the medication. Additionally, those with physical or cognitive impairment that prevents them from drawing up testosterone from a small vial and then injecting it may not be candidates for IM TT.
Conclusions
Low testosterone is an ongoing problem for men and can cause detrimental physiological and psychological effects. Various pharmacological interventions exist, and TU is currently a promising treatment modality. TU 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 the absorption of these drugs must be taken into consideration before the prescription. Traditional injectable formulations of TU continue to provide a cost-effective strategy for TT. The decision to start treatment with oral or injectable TU must be the result of an individualized conversation between a patient and their physician. Overall, clinicians may offer TU as part of a personalized treatment regimen based on patient goals and preferences.
Katherine Campbell, Akhil Muthigi, Armin Ghomeshi, Kyle Schuppe, Max D Sandler, Ranjith Ramasamy
Abstract
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 (TU) 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 TU 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.
Introduction
Testosterone deficiency is recognized as the deficiency of testosterone (T) production by the testes. This deficiency results in a pathologically low systemic testosterone concentration, as well as the concentrations of its bioactive metabolites dihydrotestosterone (DHT) and estradiol (E2).1 Testosterone deficiency may affect up to 10% of men worldwide and 40% of men over the age of 45.2,3 Signs and symptoms of testosterone deficiency include characteristic physical changes such as regression of secondary sex characteristics, decreased lean muscle mass, and cognitive changes.3–5 The restoration of serum testosterone to physiologic, or eugonadal, levels has been shown to alleviate some of the symptoms of testosterone deficiency and provide significant improvement in quality of life.6 Multiple treatment options for testosterone deficiency exist, most commonly consisting of testosterone therapy (TT) with exogenous testosterone. Specifically, testosterone undecanoate (TU) is an 11-carbon-long androgen ester derivative of testosterone that comes in an injectable or oral formulation. Recently, we have seen a rapid increase in the available FDA-approved TU forms of T. Herein, we present a focused review on testosterone undecanoate and its various formulations, as well as a practical guide for prescribers.
What is Testosterone Deficiency
As per American Urologic Association guidelines, testosterone deficiency is diagnosed with a serum testosterone level below 300 ng/dL on two separate occasions, with both conducted in the early morning in combination with symptoms.
Recent studies suggest that 300 ng/dL may not be an appropriate cutoff for a diagnosis of testosterone deficiency, and thus the diagnosis should be made by a trained physician based on serum biochemical (testosterone and sex hormone binding globulin) and clinical symptoms given the specific patient’s concomitant medical conditions.8 Regardless of primary or secondary etiology, testosterone deficiency is associated with characteristic physical changes, including gynecomastia, regression of secondary sex characteristics, and sexual dysfunction.5,7 Testosterone deficiency is also associated with musculoskeletal changes such as decreased bone mineral density and muscle mass.5 In addition, obese or overweight men have been shown to have higher rates of secondary testosterone deficiency than their normal-weight counterparts.9 Psychological disturbances such as low motivation, poor concentration, and diminished energy are also frequent concerns of men with low T.5,10 Of the symptoms, diminished energy is the most reported hypogonadal symptom in men younger than 40 years old.11
Why Do We Treat Testosterone Deficiency?
Testosterone therapy can improve mood, libido, and sexual function, as well as increase muscle mass and bone density, elevate hematocrit from anemic levels, and reduce body fat.7,12,13 Despite less conclusive evidence, many patients also report significant improvements in their energy level and cognitive function with TT.14 Currently, studies have shown conflicting results as to the reproducibility and mechanism of these improvements in energy and cognition, and, as such, the 2018 AUA Guidelines do not recognize improvements in energy and cognition as known benefits of TT.7
Treating patients with testosterone deficiency not only improves immediate symptoms but also minimizes long-term sequelae of T deficiency itself. T deficiency is a known risk for cardiovascular disease and is associated with hypertension, dyslipidemia, obesity, and diabetes.7,12 A 2018 meta-analysis of seven observational studies indicated that men with testosterone deficiency have an increased risk of myocardial infarction and pooled analysis of 12 studies demonstrated an increased risk of cerebrovascular accidents compared to men with normal T levels.7
Due to a lack of long-term prospective studies, it is unclear whether testosterone therapy in deficient patients will ameliorate all these risks, and prescribers must balance the potential benefits against risks of TT, including the well-described effects of polycythemia, hypertension, and a decrease in sperm count. This is especially true in those at high risk of these adverse events and those with baseline poor health status. Patients with elevated hemoglobin/hematocrit (>50%) should delay testosterone therapy to avoid further polycythemia.15 Patients wishing to conceive must also be informed that 10% of men failed to recover sperm in their ejaculate until two years after stopping TT and some may become permanently oligospermic or azoospermic after treatment with TT.16 Ironically, despite the association between testosterone deficiency and cardiovascular risk, exogenous T may have cardiovascular risks of its own. The 2018 AUA Guidelines recognized this risk but, since then, a systematic review of over 50 trials showed that testosterone therapy was not associated with an increased risk of cardiovascular events.17 Due to this conflicting evidence, an individualized and patient-centered approach must include a discussion of these risks, alongside the benefits, before testosterone therapy is to be prescribed.
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) applications (Table 1). Testosterone Undecanoate (TU) is a testosterone ester that has a long half-life compared to other esters.18 TU is also the only available formulation of oral TT (Table 2). Pharmacokinetic studies demonstrate that TU injections (Table 3) can return serum T levels to the eugonadal range 7–14 days after injection with a slow decline back to the hypogonadal range by 10 weeks.19–21 Compared to testosterone enanthate and cypionate, TU is a longer-acting form of testosterone and therefore requires less frequent administration to achieve clinical benefits.22 As a result, patients experience more stable T levels between injections and report significantly fewer fluctuations in mood and sexual function.23 Furthermore, a prospective study showed a maximal TU effect on erectile function after 9 years of therapy, suggesting continued benefits over a long period of time.24
Oral Testosterone Undecanoate Formulations
Andriol
-History and Development
-Efficacy
-Dosing
-Adverse Effects
Jatenzo
-History and Development
-Efficacy
-Dosing
-Adverse Effects
Tlando
-History and Development
-Efficacy
-Dosing
-Adverse Effects
Kyzatrex
-History and Development
-Efficacy
-Dosing
-Adverse Effects
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 T 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 T when compared to other forms of TT.51,52 Clearly, patients with dysphagia or other impediments to using 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
Aveed
-History and Development
-Efficacy
-Dosing
-Adverse Effects
Nebido
-History and Development
-Efficacy
-Dosing
-Adverse Effects
Patient Selection for Injectable Testosterone Undecanoate
Intramuscular injections of testosterone have been the most commonly prescribed form of TT since their development in the 1930s.64 IM formulations of TT remain the most cost-effective and most frequently covered by insurance, making them an ideal option for those wishing for cost-effective treatment. IM injections of T often require dose optimization based on body habitus and individual metabolism; therefore, dosing may vary and should be guided by an individual’s serologic and symptomatic response. Though IM injections are commonly used, and generally safe, this formulation may not be a suitable option for patients who are averse to self-injecting the medication. Additionally, those with physical or cognitive impairment that prevents them from drawing up testosterone from a small vial and then injecting it may not be candidates for IM TT.
Conclusions
Low testosterone is an ongoing problem for men and can cause detrimental physiological and psychological effects. Various pharmacological interventions exist, and TU is currently a promising treatment modality. TU 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 the absorption of these drugs must be taken into consideration before the prescription. Traditional injectable formulations of TU continue to provide a cost-effective strategy for TT. The decision to start treatment with oral or injectable TU must be the result of an individualized conversation between a patient and their physician. Overall, clinicians may offer TU as part of a personalized treatment regimen based on patient goals and preferences.
