madman
Super Moderator
When it comes to elevated hematocrit everyone is still so caught up on peak T levels!
As I have been preaching for years on here running too high a trough/steady-state FT will have a big impact here!
* While the precise mechanism underlying secondary polycythemia in the setting of TTh is still debated, it is likely that a longer duration of supraphysiological testosterone levels drives erythrocytosis.
* Testosterone undecanoate (TU), developed in the 1970s, provided a solution by utilizing lymphatic absorption to bypass hepatic metabolism. The Andriol formulation was the first to use a lipid-based vehicle to promote gut lymphatic uptake. Despite validating the approach, Andriol faced clinical challenges, including variable serum levels, the need for frequent dosing 3-4 times per day, a short shelf life and the need to be taken with a high fat meal. Newer oral TU formulations—Jatenzo (2019), Tlando (2022), and Kyzatrex (2022)—have addressed these limitations by using distinct lipid excipients to enhance the pharmacokinetic profile of the drugs, leading to improved bioavailability and dosing convenience. These formulations differ in their oil vehicles—Jatenzo’s principal oil is seed based, while Tlando and Kyzatrex utilize glyceryl and propylene glycol, respectively.
* Beyond the convenience, the safety profile of oral TU is superior to other formulations. The rate of erythrocytosis (Hematocrit >50%) for short acting injectable testosterone enanthate and cypionate was as high as 66.7%, while the corresponding rates for transdermal testosterone and subcutaneous pellets were 12.8% and 35.1%, respectively.1 In contrast, the prevalence of increasing hematocrit ranged from 4.3% to 4.8% for the three new generation oral TU drugs. While the precise mechanism underlying secondary polycythemia in the setting of TTh is still debated, it is likely that a longer duration of supraphysiological testosterone levels drives erythrocytosis. As such, the more stable serum concentrations of oral TU and the dosing regimen that more closely mimics endogenous production, results in a lower prevalence of increased hematocrit.
The effective use of oral testosterone therapy has long been hindered by first-pass hepatic metabolism, which renders unmodified oral testosterone largely inactive. Early attempts to overcome this involved 17α-methyltestosterone, a formulation that prevented degradation by the liver but carried a significant risk of hepatotoxicity, particularly with chronic use or high doses.
Testosterone undecanoate (TU), developed in the 1970s, provided a solution by utilizing lymphatic absorption to bypass hepatic metabolism. The Andriol formulation was the first to use a lipid-based vehicle to promote gut lymphatic uptake. Despite validating the approach, Andriol faced clinical challenges, including variable serum levels, the need for frequent dosing 3-4 times per day, a short shelf life and the need to be taken with a high fat meal. Newer oral TU formulations—Jatenzo (2019), Tlando (2022), and Kyzatrex (2022)—have addressed these limitations by using distinct lipid excipients to enhance the pharmacokinetic profile of the drugs, leading to improved bioavailability and dosing convenience. These formulations differ in their oil vehicles—Jatenzo’s principal oil is seed based, while Tlando and Kyzatrex utilize glyceryl and propylene glycol, respectively.
The new generation of oral testosterone therapy (TTh) offers practical, as well as biochemical advantages for patients. Unlike traditional forms of TTh, there is no risk of transference, nor need for frequent injections. Moreover, patients are highly familiar with the concept of twice daily (BID) oral pharmaceuticals, eliminating any learning curve that may be associated with injections. These new formulations can be easily added to BID regimens for other medications in men with testosterone deficiency with metabolic syndrome diagnoses such as diabetes and hypertension. The oral approach is also much more conducive to travel.
Beyond the convenience, the safety profile of oral TU is superior to other formulations. The rate of erythrocytosis (Hematocrit >50%) for short acting injectable testosterone enanthate and cypionate was as high as 66.7%, while the corresponding rates for transdermal testosterone and subcutaneous pellets were 12.8% and 35.1%, respectively.1 In contrast, the prevalence of increasing hematocrit ranged from 4.3% to 4.8% for the three new generation oral TU drugs. While the precise mechanism underlying secondary polycythemia in the setting of TTh is still debated, it is likely that a longer duration of supraphysiological testosterone levels drives erythrocytosis. As such, the more stable serum concentrations of oral TU and the dosing regimen that more closely mimics endogenous production, results in a lower prevalence of increased hematocrit. Beyond polycythemia, the FDA announced this year that all testosterone products are required to include a warning about the risk of hypertension in its prescribing information. Compared to traditional formulations, the rates of hypertension, as well as increases in PSA, are favorable with the new oral TU options. FDA prescribing information across drugs is enumerated in Table S1.
Endogenous testosterone production in healthy younger men is influenced by pulsatile release of luteinizing hormone (LH) that drives testosterone production, following a diurnal pattern. Twice daily oral TU more closely mimics the circadian variation and as a result, is believed to promote only incomplete inhibition of the HPG axis. As a result, spermatogenesis may be maintained. In one trial, 40% of participants maintained normal levels of gonadotropins while on Tlando.2 In another, only a modest reduction of LH and FSH was noted while on Kyzatrex.3 In contrast, it has been well documented that the use of other formulations of testosterone (IM injection, topical gels, subcutaneous pellets) leads to the ablation of FSH and LH, with subsequent downregulation of spermatogenesis. Additionally, early data evaluating the use of Tlando in one cohort of men previously on TTh via injectionsor gels and another, naïve to all TTh, demonstrated a unique biochemical profile; across both groups, sex hormone-binding globulin (SHBG) significantly decreased and dihydrotestosterone (DHT) increased without increased DHT-mediated adverse effects.4
The pharmacokinetics (PK) of the new oral TU formulations are generally similar; Tlando and Kyzatrex reach peak serum testosterone concentrations∼5 h. Jatenzo is slightly quicker in onset, reaching peak between 2 and 4 h. The dosing schedule enables a safe and steady average serum testosterone; 24 h PK measures of Tlando show a mean serum concentration of 476 ng/dL, with maximum concentrations reaching 989 ng/dL, avoiding excursions in supratherapeutic ranges. Absorption is best with Jatenzo and Kyzatrex with higher fat meals. For Jatenzo specifically, there is comparable absorption with 30 g fat, 45 g fat, and high fat meals. However, when taken with a 15 g fat meal, there is a 25% lower testosterone exposure. Tlando’s absorption is steady across low, medium,and high fat meals. However, all three require administration with food, as mean serum testosterone in fasting cohort only increased minimally. Dosing schedules, titration options, and efficacy data are enumerated in Table S2. Labs should be monitored in the first few months. This should include checking prolactin prior to initiation and after 3 months of use with Tlando, as 6% of patients may have resultant hyperprolactinemia, with a mean rise of prolactin of 7 ng/mL from baseline. The recommendation by manufacturers is to obtain serum laboratory levels on treatment, for Jatenzo at 6 h and Kyzatrex at 3–5 h after the morning dose is administered. However, expert recommendations are to check levels at peaks to prove absorption and satisfy patients.
The biochemical and pharmacokinetic profiles of these new generation TU formulations facilitate unique clinical applications; given that oral TU seems to decrease SHBG more than other formulations, in men with high SHBG, these medications are particularly potent at improving free testosterone levels. Oral TU may even be used as an adjunct to a patient’s current TTh; in men reliant on high doses of injectable TTh due to high SHBG, adjunctive oral TU can allow the provider to lower intramuscular TTh doses, thus decreasing the risk of erythrocytosis. Further, for men interested in fertility preservation, early data showed a regimen of Clomiphene citrate combined with oral TU once daily appears to avoid HPG suppression. Other clinical pearls include BID dosing of oral TU at breakfast and lunch, rather than breakfast and dinner. This permits an extended daytime peak serum testosterone concentration rather than an afternoon lull and subsequent second peak during sleep. In our practice, we also recommend trending free testosterone as well as DHT, as DHT elevation may be the primary driver mediating symptomatic benefits in oral TU patients.
As I have been preaching for years on here running too high a trough/steady-state FT will have a big impact here!
* While the precise mechanism underlying secondary polycythemia in the setting of TTh is still debated, it is likely that a longer duration of supraphysiological testosterone levels drives erythrocytosis.
* Testosterone undecanoate (TU), developed in the 1970s, provided a solution by utilizing lymphatic absorption to bypass hepatic metabolism. The Andriol formulation was the first to use a lipid-based vehicle to promote gut lymphatic uptake. Despite validating the approach, Andriol faced clinical challenges, including variable serum levels, the need for frequent dosing 3-4 times per day, a short shelf life and the need to be taken with a high fat meal. Newer oral TU formulations—Jatenzo (2019), Tlando (2022), and Kyzatrex (2022)—have addressed these limitations by using distinct lipid excipients to enhance the pharmacokinetic profile of the drugs, leading to improved bioavailability and dosing convenience. These formulations differ in their oil vehicles—Jatenzo’s principal oil is seed based, while Tlando and Kyzatrex utilize glyceryl and propylene glycol, respectively.
* Beyond the convenience, the safety profile of oral TU is superior to other formulations. The rate of erythrocytosis (Hematocrit >50%) for short acting injectable testosterone enanthate and cypionate was as high as 66.7%, while the corresponding rates for transdermal testosterone and subcutaneous pellets were 12.8% and 35.1%, respectively.1 In contrast, the prevalence of increasing hematocrit ranged from 4.3% to 4.8% for the three new generation oral TU drugs. While the precise mechanism underlying secondary polycythemia in the setting of TTh is still debated, it is likely that a longer duration of supraphysiological testosterone levels drives erythrocytosis. As such, the more stable serum concentrations of oral TU and the dosing regimen that more closely mimics endogenous production, results in a lower prevalence of increased hematocrit.
The effective use of oral testosterone therapy has long been hindered by first-pass hepatic metabolism, which renders unmodified oral testosterone largely inactive. Early attempts to overcome this involved 17α-methyltestosterone, a formulation that prevented degradation by the liver but carried a significant risk of hepatotoxicity, particularly with chronic use or high doses.
Testosterone undecanoate (TU), developed in the 1970s, provided a solution by utilizing lymphatic absorption to bypass hepatic metabolism. The Andriol formulation was the first to use a lipid-based vehicle to promote gut lymphatic uptake. Despite validating the approach, Andriol faced clinical challenges, including variable serum levels, the need for frequent dosing 3-4 times per day, a short shelf life and the need to be taken with a high fat meal. Newer oral TU formulations—Jatenzo (2019), Tlando (2022), and Kyzatrex (2022)—have addressed these limitations by using distinct lipid excipients to enhance the pharmacokinetic profile of the drugs, leading to improved bioavailability and dosing convenience. These formulations differ in their oil vehicles—Jatenzo’s principal oil is seed based, while Tlando and Kyzatrex utilize glyceryl and propylene glycol, respectively.
The new generation of oral testosterone therapy (TTh) offers practical, as well as biochemical advantages for patients. Unlike traditional forms of TTh, there is no risk of transference, nor need for frequent injections. Moreover, patients are highly familiar with the concept of twice daily (BID) oral pharmaceuticals, eliminating any learning curve that may be associated with injections. These new formulations can be easily added to BID regimens for other medications in men with testosterone deficiency with metabolic syndrome diagnoses such as diabetes and hypertension. The oral approach is also much more conducive to travel.
Beyond the convenience, the safety profile of oral TU is superior to other formulations. The rate of erythrocytosis (Hematocrit >50%) for short acting injectable testosterone enanthate and cypionate was as high as 66.7%, while the corresponding rates for transdermal testosterone and subcutaneous pellets were 12.8% and 35.1%, respectively.1 In contrast, the prevalence of increasing hematocrit ranged from 4.3% to 4.8% for the three new generation oral TU drugs. While the precise mechanism underlying secondary polycythemia in the setting of TTh is still debated, it is likely that a longer duration of supraphysiological testosterone levels drives erythrocytosis. As such, the more stable serum concentrations of oral TU and the dosing regimen that more closely mimics endogenous production, results in a lower prevalence of increased hematocrit. Beyond polycythemia, the FDA announced this year that all testosterone products are required to include a warning about the risk of hypertension in its prescribing information. Compared to traditional formulations, the rates of hypertension, as well as increases in PSA, are favorable with the new oral TU options. FDA prescribing information across drugs is enumerated in Table S1.
Endogenous testosterone production in healthy younger men is influenced by pulsatile release of luteinizing hormone (LH) that drives testosterone production, following a diurnal pattern. Twice daily oral TU more closely mimics the circadian variation and as a result, is believed to promote only incomplete inhibition of the HPG axis. As a result, spermatogenesis may be maintained. In one trial, 40% of participants maintained normal levels of gonadotropins while on Tlando.2 In another, only a modest reduction of LH and FSH was noted while on Kyzatrex.3 In contrast, it has been well documented that the use of other formulations of testosterone (IM injection, topical gels, subcutaneous pellets) leads to the ablation of FSH and LH, with subsequent downregulation of spermatogenesis. Additionally, early data evaluating the use of Tlando in one cohort of men previously on TTh via injectionsor gels and another, naïve to all TTh, demonstrated a unique biochemical profile; across both groups, sex hormone-binding globulin (SHBG) significantly decreased and dihydrotestosterone (DHT) increased without increased DHT-mediated adverse effects.4
The pharmacokinetics (PK) of the new oral TU formulations are generally similar; Tlando and Kyzatrex reach peak serum testosterone concentrations∼5 h. Jatenzo is slightly quicker in onset, reaching peak between 2 and 4 h. The dosing schedule enables a safe and steady average serum testosterone; 24 h PK measures of Tlando show a mean serum concentration of 476 ng/dL, with maximum concentrations reaching 989 ng/dL, avoiding excursions in supratherapeutic ranges. Absorption is best with Jatenzo and Kyzatrex with higher fat meals. For Jatenzo specifically, there is comparable absorption with 30 g fat, 45 g fat, and high fat meals. However, when taken with a 15 g fat meal, there is a 25% lower testosterone exposure. Tlando’s absorption is steady across low, medium,and high fat meals. However, all three require administration with food, as mean serum testosterone in fasting cohort only increased minimally. Dosing schedules, titration options, and efficacy data are enumerated in Table S2. Labs should be monitored in the first few months. This should include checking prolactin prior to initiation and after 3 months of use with Tlando, as 6% of patients may have resultant hyperprolactinemia, with a mean rise of prolactin of 7 ng/mL from baseline. The recommendation by manufacturers is to obtain serum laboratory levels on treatment, for Jatenzo at 6 h and Kyzatrex at 3–5 h after the morning dose is administered. However, expert recommendations are to check levels at peaks to prove absorption and satisfy patients.
The biochemical and pharmacokinetic profiles of these new generation TU formulations facilitate unique clinical applications; given that oral TU seems to decrease SHBG more than other formulations, in men with high SHBG, these medications are particularly potent at improving free testosterone levels. Oral TU may even be used as an adjunct to a patient’s current TTh; in men reliant on high doses of injectable TTh due to high SHBG, adjunctive oral TU can allow the provider to lower intramuscular TTh doses, thus decreasing the risk of erythrocytosis. Further, for men interested in fertility preservation, early data showed a regimen of Clomiphene citrate combined with oral TU once daily appears to avoid HPG suppression. Other clinical pearls include BID dosing of oral TU at breakfast and lunch, rather than breakfast and dinner. This permits an extended daytime peak serum testosterone concentration rather than an afternoon lull and subsequent second peak during sleep. In our practice, we also recommend trending free testosterone as well as DHT, as DHT elevation may be the primary driver mediating symptomatic benefits in oral TU patients.
