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Testosterone Replacement, Low T, HCG, & Beyond
Testosterone Basics & Questions
My Experience On Jatenzo (Oral TRT) Log
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<blockquote data-quote="madman" data-source="post: 217772" data-attributes="member: 13851"><p>Come again?</p><p></p><p><em><strong>*Oral administration of non-esterified T generally results in low bioavailability as it is extensively metabolized through first-pass metabolism</strong></em></p><p></p><p><strong>*Testosterone undecanoate (TU) is a fatty acid ester of T, with a straight carbon chain (alkylated chain with 11 of carbons) ester at the C17 position of the D-ring </strong></p><p></p><p><em><strong>*Oral administration of TU provides a sufficient TU level by lymphatic route absorption through the gastrointestinal tract avoiding the first-pass metabolism, then TU is converted to T by non-specific esterases abundant in the body, overcoming the <u>low oral bioavailability of native T</u></strong></em></p><p><em><strong></strong></em></p><p><em><strong>*Oral administration of TU appears to avoid the serious hepatic adverse effects and fatal complications observed after oral administration of 17-α-methylated T products</strong></em></p><p></p><p></p><p></p><p></p><p></p><p></p><p>[URL unfurl="true"]https://www.excelmale.com/forum/threads/jatenzo%C2%AE-challenges-in-the-development-of-oral-testosterone.24093/[/URL]</p><p></p><p><strong>*PHARMACOLOGY OF ORAL TESTOSTERONE THERAPY</strong></p><p></p><p><em>Oral administration of exogenous TT historically has proven to be unsuccessful. Despite adequate absorption in the gastrointestinal system, this form of testosterone undergoes extensive first-pass metabolism through the liver, and thus requires ingestion of supraphysiological doses to attain therapeutic serum levels [14].</em><strong><em> As a way to circumvent the liver metabolism pathway, research efforts to administer oral testosterone have taken two primary paths: alkylation of testosterone at the carbon-17 position and fatty-acid esterification of testosterone to create a testosterone ester (Fig. 1).</em></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong></strong></p><p><strong>Fig. 1 Molecular structure of testosterone with modifications to improve the tolerability of oral formulations. <u>A</u> Testosterone <u>B</u> 17αmethyltestosterone <u>C</u> Testosterone undecanoate.</strong></p><p><strong><em>[ATTACH=full]19802[/ATTACH]</em></strong></p><p></p><p></p><p></p><p></p><p><em><strong><u>Alkylation of testosterone at carbon 17α</u> results in 17αmethyltestosterone which allows for the ability to bypass the first metabolism in the liver. However, this modification has been linked to significant liver toxicity including cholestasis, hepatitis, and hepatic adenocarcinoma [15–17] and lowering of HDL cholesterol [18, 19].</strong> The effects of methyltestosterone on liver function were first described in the 1940s, with studies of liver function demonstrating elevations in both serum direct and indirect bilirubin levels [19]. Foss and Simpson also described a case series of 42 patients who developed jaundice during methyltestosterone therapy [20]. They noted that the duration of therapy to the onset of jaundice ranged from 8 days to 10 months and withdrawal of methyltestosterone therapy resulted in remission of hepatocellular dysfunction within a few days to weeks.<strong> Recent work has focused on testing the effects of synthetic androgens on liver function utilizing animal models [21] and has corroborated prior work demonstrating direct increases in alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, and sorbitol dehydrogenase. Therefore, methyltestosterone is largely not recommended for the management of male hypogonadism [6, 22].</strong></em></p><p><em><strong></strong></em></p><p><em><strong><u>Esterification of testosterone at carbon 17β yields testosterone esters</u> such as testosterone cypionate, testosterone propionate, and testosterone undecanoate (TU).</strong> <strong><u>Specifically for TU, this modification allows testosterone to be absorbed via the lymphatic system and therefore bypass liver degradation</u>.</strong> An early oral TU formulation (ANDRIOL®) was approved for use in many countries but never in the United States. This formulation is heavily reliant on dietary fat intake as a means of increasing absorption and therefore leads to significant intra- and inter-patient variability in testosterone response [23, 24]. This results in the need to dose hypogonadal men with several capsules three or more times daily affecting compliance. Several studies have also demonstrated both gastrointestinal and liver adverse effects including severe cholestasis and jaundice [25, 26]. Consequently, these oral TU formulations have never been widely utilized to treat TD in the United States although they remain available in many countries</em></p><p></p><p></p><p><strong>*SELF-EMULSIFYING DRUG DELIVERY SYSTEM (SEDDS)</strong></p><p></p><p><em>TU has been formulated in a unique self-emulsifying drug delivery system (SEDDS) that was initially evaluated in multi-institutional placebo-controlled studies in Europe [27]. <strong>SEDDS formulations combine hydrophilic and lipophilic components that enable the solubilization of lipophilic molecules such as TU in the gut (Fig. 2). This promotes intestinal lymphatic absorption of lipophilic testosterone esters, thereby reducing first-pass hepatic metabolism. Furthermore, this formulation allows absorption after oral ingestion with a typical meal as opposed to high-fat content meals required for prior formulations. </strong>Yin et al. showed that this TU with SEDDS resulted in adequate serum testosterone levels within the physiologic range after dosing with just TU 200 mg twice per day in most hypogonadal men [28].</em></p><p></p><p></p><p><strong>Fig. 2 Pictorial representation of TU lymphatic absorption after oral delivery in SEDDS formulation. Reprinted from Swerdloff et al., 2020 [29] with permission from SAGE Publishing.</strong></p><p><em>[ATTACH=full]19803[/ATTACH]</em></p><p></p><p></p><p></p><p></p><p>[URL unfurl="true"]https://www.excelmale.com/forum/threads/a-new-oral-t-tlando-treatment-regimen-without-dose-titration-requirement-for-male-hypogonadism.24793/#post-21681[/URL]</p><p></p><p><em><strong><u>Oral administration of non-esterified T generally results in low bioavailability as it is extensively metabolized through first-pass metabolism</u>.8</strong> Testosterone undecanoate (TU) is a fatty acid ester of T, with a straight carbon chain (alkylated chain with 11 of carbons) ester at the C17 position of the D-ring. <strong>Oral administration of TU provides a sufficient TU level by lymphatic route absorption through the gastrointestinal tract avoiding the first-pass metabolism, then TU is converted to T by non-specific esterases abundant in the body, overcoming the low oral bioavailability of native T.9 <u>Oral administration of TU appears to avoid the serious hepatic adverse effects and fatal complications observed after oral administration of 17-α-methylated T products</u>.10,11 Most marketed TRT products require dose titrations to achieve the eugonadal T levels.</strong> One of the top reasons for discontinuation in TRT is lack of perceived efficacy, possibly related to insufficient T levels within the first 3–6 months of therapy, which may be within dose titration duration.12</em></p><p><em></em></p><p><em><strong>TLANDO is an oral capsule product having 112.5 mg of TU in a unique lipid formulation containing predominantly predigested triglycerides (mono- or di-glycerides). It was designed to enable absorption of TU via the intestinal lymphatic pathway. <u>In a previous 52-week, multicenter, open-labeled, active-controlled study with TLANDO using a dose titration regimen in hypogonadal men (N = 315, NCT02081300), it was found that there is little impact of titration for TLANDO on achieving eugonadal total T levels (300–1140 ng/dl)</u>.13</strong> Titrations in the study were performed two times at weeks 4 and 8 after measuring 24-h pharmacokinetics (PK) at weeks 3 and 7 to identify who should be titrated, then the final PK measuring at week 13 was performed. <strong>As a result, the mean dose for post-titration was 213 mg TU twice daily (426 mg daily) compared to 225 mg TU twice daily (450 mg daily) for pre-titration. <u>PK results at week 3 (no titration) showed 86% of subjects within the normal range and the results at week 13 (post two titrations) showed 87% of subjects within the normal range</u>. </strong>The distributions of Cavg and Cmax were also shown little impact of titration (p = 0.24 for Cavg and p = 0.31 for Cmax). <strong>With the unique formulation and the previous study PK results on the titration regimen of TLANDO, it was hypothesized that the TLANDO treatment regimen (225 mg BID (twice daily)) may not require dose titration to find an appropriate dose for therapeutic T levels. The goal of this study is to validate the TLANDO dosing regimen without titration and evaluate safety and efficacy.</strong></em></p><p><em><strong></strong></em></p><p><em><strong>Here we report the clinical outcomes from this phase III study of oral TU (TLANDO) administered as 225 mg twice daily (450 mg daily) without dose titration.</strong></em></p><p></p><p></p><p></p><p></p><p>[URL unfurl="true"]https://www.excelmale.com/forum/threads/effects-of-the-oral-tu-kyzatrex%E2%84%A2-on-ambulatory-blood-pressure-in-hg-men.23578/[/URL]</p><p></p><p><strong>1 | INTRODUCTION</strong></p><p></p><p>Testosterone replacement therapy for male hypogonadism or androgen deficiency has been administered by intramuscular and subcutaneous injections, transdermal gels and lotions, dermal patches, intranasal gels, and oral delivery.1 <strong><em>Testosterone itself has limited oral bioavailability. Long-chain fatty acid esterification of testosterone to create testosterone undecanoate allows for absorption via the intestinal lymphatic system and bypasses the first-pass metabolism in the liver.2 Testosterone is then liberated from testosterone undecanoate by endogenous non-specific esterases. <u>Oral formulations of testosterone undecanoate have been developed to provide average serum testosterone levels in the eugonadal range (typically 300–1000 ng/dl) and avoid peak concentrations above 1500 ng/dl</u>. </em></strong>During recent studies with both injectable and oral testosterone formulations, increases in both clinic and ambulatory blood pressure (BP) have been observed3,4 but the mechanism of these increases has not been elucidated nor has there been clarity regarding clinical predictors associated with BP increases. <em><strong>In the present BP safety study, we evaluated a new oral testosterone undecanoate therapy using ambulatory BP monitoring performed at baseline and following 120 and 180 days of daily therapy along with standard clinical and laboratory safety parameters</strong></em></p></blockquote><p></p>
[QUOTE="madman, post: 217772, member: 13851"] Come again? [I][B]*Oral administration of non-esterified T generally results in low bioavailability as it is extensively metabolized through first-pass metabolism[/B][/I] [B]*Testosterone undecanoate (TU) is a fatty acid ester of T, with a straight carbon chain (alkylated chain with 11 of carbons) ester at the C17 position of the D-ring [/B] [I][B]*Oral administration of TU provides a sufficient TU level by lymphatic route absorption through the gastrointestinal tract avoiding the first-pass metabolism, then TU is converted to T by non-specific esterases abundant in the body, overcoming the [U]low oral bioavailability of native T[/U] *Oral administration of TU appears to avoid the serious hepatic adverse effects and fatal complications observed after oral administration of 17-α-methylated T products[/B][/I] [URL unfurl="true"]https://www.excelmale.com/forum/threads/jatenzo%C2%AE-challenges-in-the-development-of-oral-testosterone.24093/[/URL] [B]*PHARMACOLOGY OF ORAL TESTOSTERONE THERAPY[/B] [I]Oral administration of exogenous TT historically has proven to be unsuccessful. Despite adequate absorption in the gastrointestinal system, this form of testosterone undergoes extensive first-pass metabolism through the liver, and thus requires ingestion of supraphysiological doses to attain therapeutic serum levels [14].[/I][B][I] As a way to circumvent the liver metabolism pathway, research efforts to administer oral testosterone have taken two primary paths: alkylation of testosterone at the carbon-17 position and fatty-acid esterification of testosterone to create a testosterone ester (Fig. 1).[/I] Fig. 1 Molecular structure of testosterone with modifications to improve the tolerability of oral formulations. [U]A[/U] Testosterone [U]B[/U] 17αmethyltestosterone [U]C[/U] Testosterone undecanoate. [I][ATTACH type="full" alt="1645238898778.png"]19802[/ATTACH][/I][/B] [I][B][U]Alkylation of testosterone at carbon 17α[/U] results in 17αmethyltestosterone which allows for the ability to bypass the first metabolism in the liver. However, this modification has been linked to significant liver toxicity including cholestasis, hepatitis, and hepatic adenocarcinoma [15–17] and lowering of HDL cholesterol [18, 19].[/B] The effects of methyltestosterone on liver function were first described in the 1940s, with studies of liver function demonstrating elevations in both serum direct and indirect bilirubin levels [19]. Foss and Simpson also described a case series of 42 patients who developed jaundice during methyltestosterone therapy [20]. They noted that the duration of therapy to the onset of jaundice ranged from 8 days to 10 months and withdrawal of methyltestosterone therapy resulted in remission of hepatocellular dysfunction within a few days to weeks.[B] Recent work has focused on testing the effects of synthetic androgens on liver function utilizing animal models [21] and has corroborated prior work demonstrating direct increases in alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, and sorbitol dehydrogenase. Therefore, methyltestosterone is largely not recommended for the management of male hypogonadism [6, 22]. [U]Esterification of testosterone at carbon 17β yields testosterone esters[/U] such as testosterone cypionate, testosterone propionate, and testosterone undecanoate (TU).[/B] [B][U]Specifically for TU, this modification allows testosterone to be absorbed via the lymphatic system and therefore bypass liver degradation[/U].[/B] An early oral TU formulation (ANDRIOL®) was approved for use in many countries but never in the United States. This formulation is heavily reliant on dietary fat intake as a means of increasing absorption and therefore leads to significant intra- and inter-patient variability in testosterone response [23, 24]. This results in the need to dose hypogonadal men with several capsules three or more times daily affecting compliance. Several studies have also demonstrated both gastrointestinal and liver adverse effects including severe cholestasis and jaundice [25, 26]. Consequently, these oral TU formulations have never been widely utilized to treat TD in the United States although they remain available in many countries[/I] [B]*SELF-EMULSIFYING DRUG DELIVERY SYSTEM (SEDDS)[/B] [I]TU has been formulated in a unique self-emulsifying drug delivery system (SEDDS) that was initially evaluated in multi-institutional placebo-controlled studies in Europe [27]. [B]SEDDS formulations combine hydrophilic and lipophilic components that enable the solubilization of lipophilic molecules such as TU in the gut (Fig. 2). This promotes intestinal lymphatic absorption of lipophilic testosterone esters, thereby reducing first-pass hepatic metabolism. Furthermore, this formulation allows absorption after oral ingestion with a typical meal as opposed to high-fat content meals required for prior formulations. [/B]Yin et al. showed that this TU with SEDDS resulted in adequate serum testosterone levels within the physiologic range after dosing with just TU 200 mg twice per day in most hypogonadal men [28].[/I] [B]Fig. 2 Pictorial representation of TU lymphatic absorption after oral delivery in SEDDS formulation. Reprinted from Swerdloff et al., 2020 [29] with permission from SAGE Publishing.[/B] [I][ATTACH type="full" alt="1645239177504.png"]19803[/ATTACH][/I] [URL unfurl="true"]https://www.excelmale.com/forum/threads/a-new-oral-t-tlando-treatment-regimen-without-dose-titration-requirement-for-male-hypogonadism.24793/#post-21681[/URL] [I][B][U]Oral administration of non-esterified T generally results in low bioavailability as it is extensively metabolized through first-pass metabolism[/U].8[/B] Testosterone undecanoate (TU) is a fatty acid ester of T, with a straight carbon chain (alkylated chain with 11 of carbons) ester at the C17 position of the D-ring. [B]Oral administration of TU provides a sufficient TU level by lymphatic route absorption through the gastrointestinal tract avoiding the first-pass metabolism, then TU is converted to T by non-specific esterases abundant in the body, overcoming the low oral bioavailability of native T.9 [U]Oral administration of TU appears to avoid the serious hepatic adverse effects and fatal complications observed after oral administration of 17-α-methylated T products[/U].10,11 Most marketed TRT products require dose titrations to achieve the eugonadal T levels.[/B] One of the top reasons for discontinuation in TRT is lack of perceived efficacy, possibly related to insufficient T levels within the first 3–6 months of therapy, which may be within dose titration duration.12 [B]TLANDO is an oral capsule product having 112.5 mg of TU in a unique lipid formulation containing predominantly predigested triglycerides (mono- or di-glycerides). It was designed to enable absorption of TU via the intestinal lymphatic pathway. [U]In a previous 52-week, multicenter, open-labeled, active-controlled study with TLANDO using a dose titration regimen in hypogonadal men (N = 315, NCT02081300), it was found that there is little impact of titration for TLANDO on achieving eugonadal total T levels (300–1140 ng/dl)[/U].13[/B] Titrations in the study were performed two times at weeks 4 and 8 after measuring 24-h pharmacokinetics (PK) at weeks 3 and 7 to identify who should be titrated, then the final PK measuring at week 13 was performed. [B]As a result, the mean dose for post-titration was 213 mg TU twice daily (426 mg daily) compared to 225 mg TU twice daily (450 mg daily) for pre-titration. [U]PK results at week 3 (no titration) showed 86% of subjects within the normal range and the results at week 13 (post two titrations) showed 87% of subjects within the normal range[/U]. [/B]The distributions of Cavg and Cmax were also shown little impact of titration (p = 0.24 for Cavg and p = 0.31 for Cmax). [B]With the unique formulation and the previous study PK results on the titration regimen of TLANDO, it was hypothesized that the TLANDO treatment regimen (225 mg BID (twice daily)) may not require dose titration to find an appropriate dose for therapeutic T levels. The goal of this study is to validate the TLANDO dosing regimen without titration and evaluate safety and efficacy. Here we report the clinical outcomes from this phase III study of oral TU (TLANDO) administered as 225 mg twice daily (450 mg daily) without dose titration.[/B][/I] [URL unfurl="true"]https://www.excelmale.com/forum/threads/effects-of-the-oral-tu-kyzatrex%E2%84%A2-on-ambulatory-blood-pressure-in-hg-men.23578/[/URL] [B]1 | INTRODUCTION[/B] Testosterone replacement therapy for male hypogonadism or androgen deficiency has been administered by intramuscular and subcutaneous injections, transdermal gels and lotions, dermal patches, intranasal gels, and oral delivery.1 [B][I]Testosterone itself has limited oral bioavailability. Long-chain fatty acid esterification of testosterone to create testosterone undecanoate allows for absorption via the intestinal lymphatic system and bypasses the first-pass metabolism in the liver.2 Testosterone is then liberated from testosterone undecanoate by endogenous non-specific esterases. [U]Oral formulations of testosterone undecanoate have been developed to provide average serum testosterone levels in the eugonadal range (typically 300–1000 ng/dl) and avoid peak concentrations above 1500 ng/dl[/U]. [/I][/B]During recent studies with both injectable and oral testosterone formulations, increases in both clinic and ambulatory blood pressure (BP) have been observed3,4 but the mechanism of these increases has not been elucidated nor has there been clarity regarding clinical predictors associated with BP increases. [I][B]In the present BP safety study, we evaluated a new oral testosterone undecanoate therapy using ambulatory BP monitoring performed at baseline and following 120 and 180 days of daily therapy along with standard clinical and laboratory safety parameters[/B][/I] [/QUOTE]
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Testosterone Replacement, Low T, HCG, & Beyond
Testosterone Basics & Questions
My Experience On Jatenzo (Oral TRT) Log
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