madman
Super Moderator
ABSTRACT
Introduction: Testosterone deficiency (TD) is defined as low serum testosterone associated with symptoms and signs. There has been an increasing prevalence of TD in recent decades, especially in males aged 15–39. Many of these men will require long-term testosterone therapy (TT). Although the end goals for all treatments are essentially the same, strategies for increasing serum testosterone should be decided individually.
Areas covered: This review focuses on the pharmacological management of TD in adults which includes TT with different routes of administration, such as transdermal, buccal, intramuscular, and subcutaneous injections, pellets, nasal gel, and oral (pills). The authors review the options for TT available in the USA with emphasis on newer therapies. Furthermore, they examine the efficacy of these therapies with a comparison between potential advantages or disadvantages related to dosing, administration method, and adverse events.
Expert opinion: Treating TD can be difficult due to the wide range of available medications, diverse side effects related to testosterone replacement and route-of-administration, and the necessity for long-term therapy. The combination of pharmacological and non-pharmacological therapies can improve symptoms of TD and patient satisfaction. Each patient should be managed individually, and clinicians should consider available treatment regimens based on the route of administration, efficacy, safety, and cost based on a shared decision-making approach.
1. Introduction
Testosterone is the primary male sex hormone that plays an integral role in many facets of physiology including embryologic development, spermatogenesis, and development and maintenance of secondary sexual characteristics throughout puberty and adulthood. Testosterone deficiency (TD) is defined as insufficient production of testosterone combined with symptoms of low serum total testosterone such as decreased muscle mass, osteoporosis, poor erythropoiesis, diminished energy, low libido, and erectile function [1–6]. Etiologically, TD can be separated into primary and secondary TD. Primary TD occurs when there are problems with testosterone production at the level of the testes, whereas secondary TD involves defects in the production of gonadotropin hormones from the hypothalamus or pituitary [7]. Although this review focuses mainly on the treatment of TD from a primary etiology, the principles and medications can be used with any patient that presents with TD. Diagnosing TD can be challenging because of the heterogeneity of symptoms experienced by different individuals but the current definition relies on two criteria: having low serum testosterone defined by two separate early morning testosterone levels <300 ng/dL as well as manifestations of the aforementioned symptoms. TD is incredibly common among the general population. A recent study estimated the prevalence of TD in the elderly population to be as high as 2.1% [8]. Another study examining testosterone levels from 2000 to 2016 also demonstrated an increasing prevalence of decreasing serum levels in adolescents and young males over time [9]. This can possibly be due to the increasing prevalence of obesity and elevated BMI which are associated with low testosterone levels [8]. As such, physicians are now frequently seeing patients with this pathology. TD is treated with various forms of testosterone therapy (TT) with the goals of improving symptoms and increasing serum testosterone to physiologic levels in the range of 450–600 ng/dL [10]. Many options for TT have been approved by the FDA with each formulation having unique advantages and disadvantages. Available routes of administration include transdermal, buccal, nasal, IM injections, implants, and, most recently, oral pills. This article will review treatment options available in the USA for TT in adult men with an emphasis on novel, more recently developed medications.
2. Non-exogenous TT options
3. Transdermal
3.1. Androderm®
3.2. Androgel®
3.3. Testim®
3.4. Fortesta®
3.5. Vogelxo®
3.6. Testavan®
3.7. Axiron®
4. Buccal
5. Intramuscular depot
5.1. Testosterone cypionate
5.2. Testosterone enanthate
5.2.1. Xyosted™
5.3. Testosterone undecanoate
6. Subdermal pellets
7. Nasal gel
8. Oral formulations
8.1. Jatenzo®
9. Conclusion
TD can cause a variety of symptoms that can be treated with the administration of exogenous testosterone. The current landscape for TT includes a plethora of options with different modes of application, each with its own unique advantages and disadvantages. To ensure high-quality care, we recommend that providers and patients use a shared decision-making approach based on patient preference and functionality, dosing interval, treatment burden, cost, and side effect profile in choosing the appropriate form of TT.
10. Expert opinion
The management of TD is very complex because of the wide variety of options (transdermal, IM and subcutaneous injections, subdermal pellets, oral, nasal gel, and buccal tablet). In addition, many of the causes of TD are irreversible which necessitates long-term treatment, rendering patient compliance a critical factor for successful treatment. Many of the drugs require frequent administration or have unique side effects which can be an issue for many users. Although management is focused on maintaining testosterone levels in the normal range (450–600 ng/dL), treatment often leads to sub and supraphysiological levels of testosterone after drug administration and absorption [10]. For example, males receiving TE and TC injections every 2–4 weeks may have fluctuating levels of serum testosterone, with up to 50% of the time below the treatment target [74]. These large fluctuations may be responsible for mood swings, decreased libido, and fatigue by the end of the cycle. It has also been demonstrated that supraphysiological levels of serum testosterone, especially those common with intramuscular injections, are the most important cause of many of the side effects (elevated hematocrit, endothelial dysfunction, acne, breast enlargement) [75]. Together, these factors can make TD a difficult disease process to manage. To highlight this, one study demonstrated that up to 25% of the men discontinue TT within 6 months after imitation, and 24% switch to another form of TT [76]. As such, it is imperative to treat men with TD individually through a shared decision-making process to determine the optimal TT regimen.
There are several areas of current research that focus on improving reliability, ease of use, patient compliance, and cost. Many patients seeking TT commonly ask for a ‘pill to solve their problems.’ However, oral testosterone has long been a nonviable option due to hepatotoxicity and variable absorption. Jatenzo (testosterone undecanoate capsules) appears to be promising as an oral testosterone option in providing resolution of symptoms and normal range serum testosterone levels. Subdermal pellets also represent an excellent option with a uniform response; however, Testopel is often expensive with many payers denying coverage. Currently, an ongoing trial is investigating the efficacy of long-term subdermal generic pellets after 4 months versus Testopel. This would provide evidence for an affordable alternative that may allow the implantation of pellets to become more ubiquitous [58].
Another area of research involves the treatment of TD while preserving fertility. As exogenous testosterone disrupts the HPG axis through a negative feedback loop, males will universally have compromised spermatogenesis. With TD becoming even more common, especially in young males and adolescents, novel methods for TT that preserve male infertility are imperative [9]. The authors believe in two major lines of future research in this arena. First, the use of Leydig stem cells (LSC) appears to be promising in restoring the production of serum testosterone while simultaneously preserving the HPG axis. Previous studies have shown the feasibility and safety of subcutaneous autografting of a combination of Leydig cells, Sertoli cells, and peritubular myoid cells in rats. The ectopic site could not only produce testosterone but also respond to hypothalamic-pituitary signaling, corroborating in-vitro findings [77,78]. Future clinical trials should focus on evaluating the efficacy, security, and applicability of LSC autograft in humans with primary testosterone deficiency. Second, very short-acting testosterone has the theoretical potential to preserve the HPG axis by providing short bursts of testosterone which allow for periods of recovery. A single-arm clinical trial evaluating Natesto, very short-acting testosterone, demonstrated patients had preserved gonadotropin levels and spermatogenesis at 6 months [79]. Further research should focus on short-acting testosterone and its effect on male infertility.
Introduction: Testosterone deficiency (TD) is defined as low serum testosterone associated with symptoms and signs. There has been an increasing prevalence of TD in recent decades, especially in males aged 15–39. Many of these men will require long-term testosterone therapy (TT). Although the end goals for all treatments are essentially the same, strategies for increasing serum testosterone should be decided individually.
Areas covered: This review focuses on the pharmacological management of TD in adults which includes TT with different routes of administration, such as transdermal, buccal, intramuscular, and subcutaneous injections, pellets, nasal gel, and oral (pills). The authors review the options for TT available in the USA with emphasis on newer therapies. Furthermore, they examine the efficacy of these therapies with a comparison between potential advantages or disadvantages related to dosing, administration method, and adverse events.
Expert opinion: Treating TD can be difficult due to the wide range of available medications, diverse side effects related to testosterone replacement and route-of-administration, and the necessity for long-term therapy. The combination of pharmacological and non-pharmacological therapies can improve symptoms of TD and patient satisfaction. Each patient should be managed individually, and clinicians should consider available treatment regimens based on the route of administration, efficacy, safety, and cost based on a shared decision-making approach.
1. Introduction
Testosterone is the primary male sex hormone that plays an integral role in many facets of physiology including embryologic development, spermatogenesis, and development and maintenance of secondary sexual characteristics throughout puberty and adulthood. Testosterone deficiency (TD) is defined as insufficient production of testosterone combined with symptoms of low serum total testosterone such as decreased muscle mass, osteoporosis, poor erythropoiesis, diminished energy, low libido, and erectile function [1–6]. Etiologically, TD can be separated into primary and secondary TD. Primary TD occurs when there are problems with testosterone production at the level of the testes, whereas secondary TD involves defects in the production of gonadotropin hormones from the hypothalamus or pituitary [7]. Although this review focuses mainly on the treatment of TD from a primary etiology, the principles and medications can be used with any patient that presents with TD. Diagnosing TD can be challenging because of the heterogeneity of symptoms experienced by different individuals but the current definition relies on two criteria: having low serum testosterone defined by two separate early morning testosterone levels <300 ng/dL as well as manifestations of the aforementioned symptoms. TD is incredibly common among the general population. A recent study estimated the prevalence of TD in the elderly population to be as high as 2.1% [8]. Another study examining testosterone levels from 2000 to 2016 also demonstrated an increasing prevalence of decreasing serum levels in adolescents and young males over time [9]. This can possibly be due to the increasing prevalence of obesity and elevated BMI which are associated with low testosterone levels [8]. As such, physicians are now frequently seeing patients with this pathology. TD is treated with various forms of testosterone therapy (TT) with the goals of improving symptoms and increasing serum testosterone to physiologic levels in the range of 450–600 ng/dL [10]. Many options for TT have been approved by the FDA with each formulation having unique advantages and disadvantages. Available routes of administration include transdermal, buccal, nasal, IM injections, implants, and, most recently, oral pills. This article will review treatment options available in the USA for TT in adult men with an emphasis on novel, more recently developed medications.
2. Non-exogenous TT options
3. Transdermal
3.1. Androderm®
3.2. Androgel®
3.3. Testim®
3.4. Fortesta®
3.5. Vogelxo®
3.6. Testavan®
3.7. Axiron®
4. Buccal
5. Intramuscular depot
5.1. Testosterone cypionate
5.2. Testosterone enanthate
5.2.1. Xyosted™
5.3. Testosterone undecanoate
6. Subdermal pellets
7. Nasal gel
8. Oral formulations
8.1. Jatenzo®
9. Conclusion
TD can cause a variety of symptoms that can be treated with the administration of exogenous testosterone. The current landscape for TT includes a plethora of options with different modes of application, each with its own unique advantages and disadvantages. To ensure high-quality care, we recommend that providers and patients use a shared decision-making approach based on patient preference and functionality, dosing interval, treatment burden, cost, and side effect profile in choosing the appropriate form of TT.
10. Expert opinion
The management of TD is very complex because of the wide variety of options (transdermal, IM and subcutaneous injections, subdermal pellets, oral, nasal gel, and buccal tablet). In addition, many of the causes of TD are irreversible which necessitates long-term treatment, rendering patient compliance a critical factor for successful treatment. Many of the drugs require frequent administration or have unique side effects which can be an issue for many users. Although management is focused on maintaining testosterone levels in the normal range (450–600 ng/dL), treatment often leads to sub and supraphysiological levels of testosterone after drug administration and absorption [10]. For example, males receiving TE and TC injections every 2–4 weeks may have fluctuating levels of serum testosterone, with up to 50% of the time below the treatment target [74]. These large fluctuations may be responsible for mood swings, decreased libido, and fatigue by the end of the cycle. It has also been demonstrated that supraphysiological levels of serum testosterone, especially those common with intramuscular injections, are the most important cause of many of the side effects (elevated hematocrit, endothelial dysfunction, acne, breast enlargement) [75]. Together, these factors can make TD a difficult disease process to manage. To highlight this, one study demonstrated that up to 25% of the men discontinue TT within 6 months after imitation, and 24% switch to another form of TT [76]. As such, it is imperative to treat men with TD individually through a shared decision-making process to determine the optimal TT regimen.
There are several areas of current research that focus on improving reliability, ease of use, patient compliance, and cost. Many patients seeking TT commonly ask for a ‘pill to solve their problems.’ However, oral testosterone has long been a nonviable option due to hepatotoxicity and variable absorption. Jatenzo (testosterone undecanoate capsules) appears to be promising as an oral testosterone option in providing resolution of symptoms and normal range serum testosterone levels. Subdermal pellets also represent an excellent option with a uniform response; however, Testopel is often expensive with many payers denying coverage. Currently, an ongoing trial is investigating the efficacy of long-term subdermal generic pellets after 4 months versus Testopel. This would provide evidence for an affordable alternative that may allow the implantation of pellets to become more ubiquitous [58].
Another area of research involves the treatment of TD while preserving fertility. As exogenous testosterone disrupts the HPG axis through a negative feedback loop, males will universally have compromised spermatogenesis. With TD becoming even more common, especially in young males and adolescents, novel methods for TT that preserve male infertility are imperative [9]. The authors believe in two major lines of future research in this arena. First, the use of Leydig stem cells (LSC) appears to be promising in restoring the production of serum testosterone while simultaneously preserving the HPG axis. Previous studies have shown the feasibility and safety of subcutaneous autografting of a combination of Leydig cells, Sertoli cells, and peritubular myoid cells in rats. The ectopic site could not only produce testosterone but also respond to hypothalamic-pituitary signaling, corroborating in-vitro findings [77,78]. Future clinical trials should focus on evaluating the efficacy, security, and applicability of LSC autograft in humans with primary testosterone deficiency. Second, very short-acting testosterone has the theoretical potential to preserve the HPG axis by providing short bursts of testosterone which allow for periods of recovery. A single-arm clinical trial evaluating Natesto, very short-acting testosterone, demonstrated patients had preserved gonadotropin levels and spermatogenesis at 6 months [79]. Further research should focus on short-acting testosterone and its effect on male infertility.
