My Experience On Jatenzo (Oral TRT) Log

[Systemlord]

Was ur energy at the same level as before donating blood, or was it higher than before?

The energy levels are the same regardless of hematocrit and hemoglobin levels, however erections are better after the phlebotomy.

This is the second time my erections have gotten better on day two after a phlebotomy.

 

[Nelson Vergel]

Ive made now my top priority fixing my NAFLD which by the way seems Ive had since being a little kid.

Oral Prodrug of Testosterone Fast-Tracked for Nonalcoholic Steatohepatitis

https://www.empr.com/home/news/drugs-in-the-pipeline/oral-prodrug-of-testosterone-fast-tracked-for-nonalcoholic-steatohepatitis/ The Food and Drug Administration (FDA) has granted Fast Track designation to LPCN 1144 for the treatment of noncirrhotic nonalcoholic steatohepatitis (NASH). LPCN...

www.excelmale.com

Novel oral testosterone therapy shows liver health benefits

The treatment improves markers of nonalcoholic fatty liver disease, an investigator reports.

www.urologytimes.com

 

[Systemlord]

A word to anyone considering Jatenzo, if you have low potassium levels or you have digestive issues, your T mileage will suffer greatly on Jatenzo and you may even have identical trough and peak levels.

I tested my levels at 6 and 12 hours, T levels where within a few single digits.

I just found out I have a potassium deficiency which can interfere with digestion do to muscle spasms in the colon and GI tract making it difficult to properly absorb food and medicine.

Update: The results are in, I have a vitamin D deficiency (@ 15) as well probably do to the change in weather, lack of sunlight and obviously a lack of vitamin D in my diet only sufficient for warmer months where I spend more time at the beach.

 

[duramax]

I wanted to start a thread detailing my personal experience with Jatenzo (oral TRT) which is remarkable in how quickly it has shown results when compared with injections. The first week on Jatenzo was very pleasant unlike my experience after dosing changes on injections, all with minimal swings and I felt things stabilize on day 7 which is where things felt consistent.

The first few days on Jatenzo my glucose levels were the lowest, then over the next two and a half weeks I would see glucose levels fluctuate wildly and at the end of week three a return to those same lower fasting and lower peak glucose I saw in the beginning of treatment.

I started with a fasting glucose in the 220-260 range, peak glucose in the 369 range after meals and now I'm seeing 140's fasting, and 140's 1-2 hours after meals all in three weeks time! When I started Jatenzo I had cypionate half-lives built up in my system which is almost completely out of my system and things are still progressing in the same direction.

The strongest perceived benefits thus far is wellbeing and sexual function being the most notable improvements and I notice a connection between lowering of glucose and erectile function.

I have started feeling erectile sensitivity during the daytime if only briefly like a lightswitch flickering on and off which is pretty intense. I'm going to be drawing labs soon to see what kind of numbers I'm getting on 158mg twice daily which is the lowest dosage for Jatenzo.

My blood pressure is well controlled and am seeing it decrease every so often (120/65) and resting heart rate in the low 60-70's. My veins are very noticeable in my hands, arms and legs.

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I will continue to update this log and detail my experience going forward.

I have been following your post and am very interested in trying Jatenzo. I have struggled with every option available. I think my main problem with TRT is I have low SHBG. Just curious where your SHBG levels are at? I do a daily creme/injection now. Think this stuff might work for me? thank you.

 

[Systemlord]

Just curious where your SHBG levels are at?

My SHBG is 16.

 

[Nocalves]

New update on my progress on Jatenzo, in the beginning I was taking Jatenzo once daily and starting feeling not as good after starting twice daily dosing. When I excersise mildly about 15 minutes later I start to feel strange in my head and feel run down.

I actually thought my levels were going to end up low and took double the dosage and it took the unwell feeling to the next level confirming my levels are already too high. I'm going to split the capsule in three quarters or by half and store the remainder in a glass vial for in the evening.

My A1C decreased 1.5% in less than five weeks and fasting this morning was 132. Just for some reference, when my Total T is 600 my Free T is 30+ and I believe this is driving the hematocrit upwards and can only imagine where my Free T is when at 989.

I also become extremely irritable and moody after my evening Jetanzo dosing. These higher Total T levels are also dragging my ferritin levels down at a time when they were on an upwards trajectory before starting Jetanzo. My SHBG is also suppressed to 14 and believe the higher Total T to be the reason, on injections (469 ng/dL) SHBG was 24.

Jetanzo dosing on 158 twice daily.

Total T = 989 -> 2 hours after in the morning
Total T = 668 -> 6 hours after
Total T = 250 -> 12 hours after in the morning before my Jetanzo
Hematocrit = 56.1
Hemoglobin = 18.1
Triglycerides 331-> 196
A1C 9.5-> 8.0

What si the estradiol convertion vs. injection?

 

[Systemlord]

What si the estradiol convertion vs. injection?

I'm unsure but is has to be lower since levels are not constant.

 

[Fortunate]

@Systemlord, I have been following your experience with Jatenzo peripherally, but just took a closer look. It sounds like your struggled with troubleshooting for much of 2021. Would you agree? I have been slightly interested in Jatenzo (I struggle with everything except Natesto), but the thought of taking months and months to figure out how to maximize results doesn't sound appealing.

Just curious, did you know anyone else taking Jatenzo before you tried it?

Is anyone else here besides @Systemlord using Jatenzo?

 

[Systemlord]

@Systemlord, I have been following your experience with Jatenzo peripherally, but just took a closer look. It sounds like your struggled with troubleshooting for much of 2021. Would you agree?

My doctor didn't start me out on the recommended starting dosage of 237mg and therefore my levels were low for much of 2021.

My progress accelerated once I got on 237mg twice daily.

Just curious, did you know anyone else taking Jatenzo before you tried it?

No there isn't anyone else I know of that is on Jatenzo.

 

[JA Battle]

My doctor didn't start me out on the recommended starting dosage of 237mg and therefore my levels were low for much of 2021.

My progress accelerated once I got on 237mg twice daily.


No there isn't anyone else I know of that is on Jatenzo.

I’m on oral testosterone base
It costs me 25$ per month.
Orally has roughly the same bioavailability of testosterone undecanoate, roughly same half life, and regardless of meal status maintained the same bioavailability.

 

[JA Battle]

Oh I’m also on test prop daily too. Never have I had such erections while on trt and libido has been much better. This is saying something because I’ve tried just about every hormone, combinations of hormones, dosing routine and route of administration.

 

[JA Battle]

Big thumbs up for oral testosterone. Be it jatenzo, or testosterone. We think nothing of eating pregnenolone, dhea, or progesterone. But since pharma controls testosterone there has been little talk of consuming it orally until jatenzo. So for jatenzo I’m grateful. Most will not be able to swing the cost. And I don’t see the need to pay for big pharma when to me it seems esterless testosterone is better doe to being 48x less costly and need not be taken with a meal. The downside is that one will have to resort to non American supply to get it.

 

[madman]

I’m on oral testosterone base
It costs me 25$ per month.
Orally has roughly the same bioavailability of testosterone undecanoate, roughly same half life, and regardless of meal status maintained the same bioavailability.

Come again?

*Oral administration of non-esterified T generally results in low bioavailability as it is extensively metabolized through first-pass metabolism

*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

*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

*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

JATENZO®: Challenges in the development of oral testosterone

Testosterone therapy (TT) for the treatment of testosterone deficiency (TD) can be administered via several routes of administration. Due to a variety of concerns such as hepatotoxicity, an oral formulation has long been absent in the United States. Recently, JATENZO® (testosterone undecanoate)...

www.excelmale.com

*PHARMACOLOGY OF ORAL TESTOSTERONE THERAPY

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]. 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).




Fig. 1 Molecular structure of testosterone with modifications to improve the tolerability of oral formulations. A Testosterone B 17αmethyltestosterone C Testosterone undecanoate.

Alkylation of testosterone at carbon 17α 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]. 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. 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].

Esterification of testosterone at carbon 17β yields testosterone esters such as testosterone cypionate, testosterone propionate, and testosterone undecanoate (TU). Specifically for TU, this modification allows testosterone to be absorbed via the lymphatic system and therefore bypass liver degradation. 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


*SELF-EMULSIFYING DRUG DELIVERY SYSTEM (SEDDS)

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]. 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. 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].


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.

A new oral T (TLANDO) treatment regimen without dose titration requirement for male hypogonadism

A new oral testosterone (TLANDO) treatment regimen without dose titration requirement for male hypogonadism (2022) Anthony DelConte, Kongnara Papangkorn Kilyoung Kim Benjamin J. Bruno Nachiappan Chidambaram Mohit Khera Irwin Goldstein Tobias S. Kohler Martin Miner Adrian S. Dobs Mahesh V. Patel...

www.excelmale.com

Oral administration of non-esterified T generally results in low bioavailability as it is extensively metabolized through first-pass metabolism.8 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. 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 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.10,11 Most marketed TRT products require dose titrations to achieve the eugonadal T levels. 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

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. 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).13 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. 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. 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. The distributions of Cavg and Cmax were also shown little impact of titration (p = 0.24 for Cavg and p = 0.31 for Cmax). 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.

Effects of the oral TU Kyzatrex™ on ambulatory blood pressure in HG men

Abstract Testosterone replacement therapies have been shown to increase blood pressure (BP) in hypogonadal men. We studied the effects of a new formulation of testosterone undecanoate (Kyzatrex™) on ambulatory blood pressure (ABP) and heart rate, in 155 men with hypogonadism (mean age, 50.5...

www.excelmale.com

1  | INTRODUCTION

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 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. 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. 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. 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

 

[madman]

Big thumbs up for oral testosterone. Be it jatenzo, or testosterone. We think nothing of eating pregnenolone, dhea, or progesterone. But since pharma controls testosterone there has been little talk of consuming it orally until jatenzo. So for jatenzo I’m grateful. Most will not be able to swing the cost. And I don’t see the need to pay for big pharma when to me it seems esterless testosterone is better doe to being 48x less costly and need not be taken with a meal. The downside is that one will have to resort to non American supply to get it.

But since pharma controls testosterone there has been little talk of consuming it orally until jatenzo

Search the literature it has been discussed numerous times.


And I don’t see the need to pay for big pharma when to me it seems esterless testosterone is better doe to being 48x less costly and need not be taken with a meal.

Need to sit back and think this through.

 

[JA Battle]

Come again?

*Oral administration of non-esterified T generally results in low bioavailability as it is extensively metabolized through first-pass metabolism

*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

*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

*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

JATENZO®: Challenges in the development of oral testosterone

Testosterone therapy (TT) for the treatment of testosterone deficiency (TD) can be administered via several routes of administration. Due to a variety of concerns such as hepatotoxicity, an oral formulation has long been absent in the United States. Recently, JATENZO® (testosterone undecanoate)...

www.excelmale.com

*PHARMACOLOGY OF ORAL TESTOSTERONE THERAPY

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]. 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).




Fig. 1 Molecular structure of testosterone with modifications to improve the tolerability of oral formulations. A Testosterone B 17αmethyltestosterone C Testosterone undecanoate.
View attachment 19802




Alkylation of testosterone at carbon 17α 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]. 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. 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].

Esterification of testosterone at carbon 17β yields testosterone esters such as testosterone cypionate, testosterone propionate, and testosterone undecanoate (TU). Specifically for TU, this modification allows testosterone to be absorbed via the lymphatic system and therefore bypass liver degradation. 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


*SELF-EMULSIFYING DRUG DELIVERY SYSTEM (SEDDS)

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]. 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. 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].


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.
View attachment 19803

A new oral T (TLANDO) treatment regimen without dose titration requirement for male hypogonadism

A new oral testosterone (TLANDO) treatment regimen without dose titration requirement for male hypogonadism (2022) Anthony DelConte, Kongnara Papangkorn Kilyoung Kim Benjamin J. Bruno Nachiappan Chidambaram Mohit Khera Irwin Goldstein Tobias S. Kohler Martin Miner Adrian S. Dobs Mahesh V. Patel...

www.excelmale.com

Oral administration of non-esterified T generally results in low bioavailability as it is extensively metabolized through first-pass metabolism.8 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. 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 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.10,11 Most marketed TRT products require dose titrations to achieve the eugonadal T levels. 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

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. 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).13 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. 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. 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. The distributions of Cavg and Cmax were also shown little impact of titration (p = 0.24 for Cavg and p = 0.31 for Cmax). 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.

Effects of the oral TU Kyzatrex™ on ambulatory blood pressure in HG men

Abstract Testosterone replacement therapies have been shown to increase blood pressure (BP) in hypogonadal men. We studied the effects of a new formulation of testosterone undecanoate (Kyzatrex™) on ambulatory blood pressure (ABP) and heart rate, in 155 men with hypogonadism (mean age, 50.5...

www.excelmale.com

1  | INTRODUCTION

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 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. 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. 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. 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

Interesting, I’m looking more into this. It seems as though I have misspoke. What do you make of these?

Serum-testosterone during oral administration of testosterone in hypogonadal men and transsexual women - PubMed

Testosterone tablets of crystal size 2-5 micrometer were administered orally for 10 dags to 3 human subjects with low endogenous serum testosterone (se-T) levels. Fifty mg testosterone increased se-T slightly, while one daily dose of 200 mg maintained the se-T level within normal range for men...

www.ncbi.nlm.nih.gov

Bioavailability of oral testosterone in males - PubMed

Twenty-six male volunteers received a single oral dose of testosterone as free crystals or as the undecanoate ester. The latter was given either in crystalline form or in arachis oil. All preparations were tested three times in the same individual, whilst fasting on 2 days and on one day...

www.ncbi.nlm.nih.gov

THERAPEUTIC EFFECTIVENESS OF ORAL TESTOSTERONE

200 mg. of free testosterone (2-5 μ particles compressed into conventional tablets) produced normal male serum-testosterone levels for 5-7 hours in four subjects without testicular function. Serum-testosterone levels were still at least five times higher than initial values 6-8 hours after...

www.thelancet.com

LONG-TERM ORAL TESTOSTERONE AND LIVER FUNCTION

www.thelancet.com

[ON 2 CASES OF ASCITES DUE TO HEPATIC CIRRHOSIS IN SUBJECTS OPERATED ON BY SPLENECTOMY AND PRESENTING PORTA OBLITERATION--CLINICAL RECOVERY FOLLOWING TREATMENT WITH HIGH DOSES OF TESTOSTERONE AND VITAMIN B 1] - PubMed

[ON 2 CASES OF ASCITES DUE TO HEPATIC CIRRHOSIS IN SUBJECTS OPERATED ON BY SPLENECTOMY AND PRESENTING PORTA OBLITERATION--CLINICAL RECOVERY FOLLOWING TREATMENT WITH HIGH DOSES OF TESTOSTERONE AND VITAMIN B 1]

www.ncbi.nlm.nih.gov

[Possible clinical cure in a high percentage of cases of liver cirrhosis with a treatment based on high doses of testosterone and vitamin B 1] - PubMed

[Possible clinical cure in a high percentage of cases of liver cirrhosis with a treatment based on high doses of testosterone and vitamin B 1]

www.ncbi.nlm.nih.gov

[THERAPY OF LIVER CIRRHOSIS WITH TESTOSTERONE AND VITAMIN B 1] - PubMed

[THERAPY OF LIVER CIRRHOSIS WITH TESTOSTERONE AND VITAMIN B 1]

www.ncbi.nlm.nih.gov

Dihydrotestosterone prevents spontaneous adenocarcinomas in the prostate-seminal vesicle in aging L-W rats - PubMed

Slow-release implants of DHT administered to L-W rats at age 12 months reduced by 50% the development of spontaneous P-SV tumors by age 24 months.

www.ncbi.nlm.nih.gov

 

[madman]

Interesting, I’m looking more into this. It seems as though I have misspoke. What do you make of these?

Serum-testosterone during oral administration of testosterone in hypogonadal men and transsexual women - PubMed

Testosterone tablets of crystal size 2-5 micrometer were administered orally for 10 dags to 3 human subjects with low endogenous serum testosterone (se-T) levels. Fifty mg testosterone increased se-T slightly, while one daily dose of 200 mg maintained the se-T level within normal range for men...

www.ncbi.nlm.nih.gov

Bioavailability of oral testosterone in males - PubMed

Twenty-six male volunteers received a single oral dose of testosterone as free crystals or as the undecanoate ester. The latter was given either in crystalline form or in arachis oil. All preparations were tested three times in the same individual, whilst fasting on 2 days and on one day...

www.ncbi.nlm.nih.gov

THERAPEUTIC EFFECTIVENESS OF ORAL TESTOSTERONE

200 mg. of free testosterone (2-5 μ particles compressed into conventional tablets) produced normal male serum-testosterone levels for 5-7 hours in four subjects without testicular function. Serum-testosterone levels were still at least five times higher than initial values 6-8 hours after...

www.thelancet.com

LONG-TERM ORAL TESTOSTERONE AND LIVER FUNCTION

www.thelancet.com

[ON 2 CASES OF ASCITES DUE TO HEPATIC CIRRHOSIS IN SUBJECTS OPERATED ON BY SPLENECTOMY AND PRESENTING PORTA OBLITERATION--CLINICAL RECOVERY FOLLOWING TREATMENT WITH HIGH DOSES OF TESTOSTERONE AND VITAMIN B 1] - PubMed

[ON 2 CASES OF ASCITES DUE TO HEPATIC CIRRHOSIS IN SUBJECTS OPERATED ON BY SPLENECTOMY AND PRESENTING PORTA OBLITERATION--CLINICAL RECOVERY FOLLOWING TREATMENT WITH HIGH DOSES OF TESTOSTERONE AND VITAMIN B 1]

www.ncbi.nlm.nih.gov

[Possible clinical cure in a high percentage of cases of liver cirrhosis with a treatment based on high doses of testosterone and vitamin B 1] - PubMed

[Possible clinical cure in a high percentage of cases of liver cirrhosis with a treatment based on high doses of testosterone and vitamin B 1]

www.ncbi.nlm.nih.gov

[THERAPY OF LIVER CIRRHOSIS WITH TESTOSTERONE AND VITAMIN B 1] - PubMed

[THERAPY OF LIVER CIRRHOSIS WITH TESTOSTERONE AND VITAMIN B 1]

www.ncbi.nlm.nih.gov

Dihydrotestosterone prevents spontaneous adenocarcinomas in the prostate-seminal vesicle in aging L-W rats - PubMed

Slow-release implants of DHT administered to L-W rats at age 12 months reduced by 50% the development of spontaneous P-SV tumors by age 24 months.

www.ncbi.nlm.nih.gov

Regarding oral native T, this is where it stands as of now.

DITEST™- Oral Native Testosterone

https://www.diurnal.com/Investor/news/successful-outcome-of-oral-testosterone-clinical-study DITEST™ In addition to its hydrocortisone products, Diurnal’s is also developing a novel formulation of testosterone for the treatment of hypogonadism. Male hypogonadism is defined as testosterone...

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*Diurnal’s is also developing a novel formulation of testosterone for the treatment of hypogonadism

*Diurnal’s DITEST™ product is a formulation of unmodified testosterone that seeks to avoid the issues of poor bioavailability by using a PROPRIETARY, oil-based excipient mixture

Oral testosterone supplements can avoid these issues of transference, although they make up a smaller portion of the market. Currently available oral products use an undecanoate ester of testosterone, which dramatically improves bioavailability over uncodified testosterone by avoiding first-pass metabolism. However, testosterone undecanoate has a substantial food effect: for instance, Jatenzo must be taken with a high-fat meal (30g of fat or more) to ensure complete absorption and this must be done twice a day. For reference, a tablespoon of butter has 12g of fat. Moreover, Jatenzo has a black box warning for cardiovascular side effects.

Diurnal’s DITEST™ product is a formulation of unmodified testosterone that seeks to avoid the issues of poor bioavailability by using a proprietary, oil-based excipient mixture. It has not been reported on how this excipient mixture avoids the issue of first-pass metabolism, but Diurnal has reported results from a Phase I study (n=25, 24 completed treatment) that showed similar pharmacological parameters to testosterone undecanoate, but without the food effect.

Oral native testosterone

Abstract Context: There is no licensed oral Native Testosterone (NT) because of challenges in the formulation. Licensed oral formulations of the ester, testosterone undecanoate (TU), require a meal for absorption and generate supraphysiological dihydrotestosterone (DHT) levels. Objective: To...

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*There is no licensed oral testosterone because of challenges in formulation





Significance Statement

There is no licensed oral testosterone because of challenges in formulation, and the oral formulations of the ester, testosterone undecanoate, require a fatty meal for absorption and generate supraphysiological dihydrotestosterone levels. We have overcome the design challenges and formulated oral native testosterone which can be taken with or without food and provides physiological levels of testosterone and dihydrotestosterone in hypogonadal men. This formulation, DITEST, has the potential advantage of being oral for patients who don’t tolerate injections and less risk of adverse events that might theoretically be associated with elevated dihydrotestosterone levels. Future studies will need to define the dosing regimen for replacement in hypogonadal men.




Introduction

Testosterone was isolated, named, and synthesized in 1935 (1), but to date, no oral native testosterone has been licensed for testosterone replacement therapy. The reason being that oral native testosterone, although absorbed through the intestine, undergoes extensive presystemic metabolism along the gastrointestinal tract (2), as well as rapid first-pass metabolism in the liver (3). The oral absorption of testosterone is also dependent on the dosing vehicle, wherein a lipophilic vehicle may increase the proportion of testosterone absorbed via the lymphatic route (4). It is thus difficult to achieve adequate bioavailability of testosterone in order to maintain consistent physiological testosterone levels via the oral route. To address this, different routes of administration for testosterone have been used and native testosterone replacement therapy has been licensed as implants, transdermal, transbuccal, and intranasal therapies (5).

Oral 17α-alkylated androgens such as methyltestosterone and oxymetholone were proved to be effective androgen replacement therapies but were associated with severe liver damage including the development of jaundice, peliosis hepatis, and liver tumors (6). This toxic effect on the liver appears to be specific to oral modified (i.e. non-native) testosterones, particularly methylated testosterone, and was not seen with native testosterone in animal models assessing liver toxicity (7). Testosterone undecanoate (TU) is an ester prodrug of testosterone and has a mid-chain length fatty acid at the 17β position and when given orally undergoes absorption in part through the intestinal lymphatic pathway, so circumventing some of the first-pass metabolism through the liver (4). Oral testosterone undecanoate is presented as an oily capsule and has been available in Europe since the 1970s (1); however, TU has to be taken with a meal two or three times daily, has an unpredictable absorption pattern, and generates high dihydrotestosterone (DHT) to testosterone ratio (8-10). An oral self-emulsifying formulation of TU has recently been approved in the US (Jatenzo®, Clarus Therapeutics Inc., USA). The formulation promotes solubilization and intestinal lymphatic absorption of the lipophilic testosterone ester. Deesterification of TU by nonspecific esterases in liver, blood, and tissue results in the production of testosterone. The liberated undecanoic acid moiety is metabolized via beta-oxidation. 5-Alpha reduction of testosterone undecanoate in the gut produces dihydrotestosterone undecanoate (DHTU) and DHT (11). The testosterone undecanoate formulation has to be taken with food, patients have higher than normal DHT levels on treatment and the label is associated with a black box warning regarding an increase in blood pressure (12). These data support the need for new developments in this area.

Various oral formulations of native testosterone have been tested in man although none have been licensed (13-20). Soon after testosterone’s identification and characterization, oral testosterone administration was disregarded as a viable route of administration and replacement because of poor oral absorption (21). In the 1970s, a micronized form of free testosterone was demonstrated to be absorbed in hypogonadal men but absorption was not reliable enough to progress as therapy (14). Further research, particularly by Amory and coworkers, showed that native testosterone administered as a suspension in oil, provided potentially therapeutic levels of testosterone in healthy men (15), and combined with 5αreductase inhibitors provided physiological testosterone levels both in the fasted and fed state (16). Native testosterone is practically insoluble in water and in fatty oil vehicles (22), and the challenge has been to develop a solution formulation that contains sufficient testosterone concentration to provide reproducible physiological testosterone levels in hypogonadal men. Building upon the previous observations, we have developed a lipidic solution formulation of native testosterone and have tested it in dogs and humans in the fasted and fed state.




Formulation: Lipidic Native Testosterone (NT) formulations were developed and assessed in vitro for dispersion behavior in gastric and intestinal media and for physical stability. A single formulation of NT, DITEST, was selected to take forward into pre-clinical trials (Table 1). The formulation used digestible lipids (oils with carbon chain length > 10 carbons atoms) with the addition of short-medium chain oils and ethanol as a polar co-solvent to assist with solubilization. The formulation was encapsulated in size 00 soft gelatin capsules with 40mg per capsule inside an aluminum foil blister pack and was stable for 2 years at ambient temperature (25°C).

 

[madman]

This is going to be huge!


Significance Statement

There is no licensed oral testosterone because of challenges in formulation, and the oral formulations of the ester, testosterone undecanoate, require a fatty meal for absorption and generate supraphysiological dihydrotestosterone levels. We have overcome the design challenges and formulated oral native testosterone which can be taken with or without food and provides physiological levels of testosterone and dihydrotestosterone in hypogonadal men. This formulation, DITEST, has the potential advantage of being oral for patients who don’t tolerate injections and less risk of adverse events that might theoretically be associated with elevated dihydrotestosterone levels. Future studies will need to define the dosing regimen for replacement in hypogonadal men.

 

[sammmy]

It looks like Jatenzo did not invent the wheel since oral unesterified testosterone at the huge dose comparable to Jatenzo works just as effectively. It was forgotten in the history of testosterone because injectables provide much higher level at much lower injectable doses:

Pharmacology of testosterone preparations Review from 2004 by Wang et al.:

14.3.1 Oral administration
14.3.1.1 Unmodified testosterone
Unmodified testosterone as physiologically secreted by the testes would appear to
be the first choice when considering substitution therapy.When ingested orally in
its unmodified form testosterone is absorbed well from the gut but is effectively
metabolized and inactivated in the liver before it reaches the target organs (“firstpass-effect”). Only when a dose of 200 mg is ingested which exceeds 30fold theamount of testosterone produceddaily by a normal man, is the metabolizing capacityof the liver overcome. With such doses an increase in peripheral testosterone blood levels becomes measurable and clinical effects can be observed

In hypogonadal men with normal liver function, 400–600 mg testosterone must
be administereddaily if the patient is to be substituted by oral testosterone (Johnsen
1978; Johnsen et al. 1974), a dose exceeding the testosterone production of a normal man almost 100fold. Aside from being uneconomical, the possibility of adverse
effects of such huge testosterone doses cannot be excluded, especially when given
over long periods of time as required for substitution therapy. However, in a small
group of patients treated for as long as seven years with oral testosterone no serious
side-effects were observed (Johnson 1978). Nevertheless, oral administration of
unmodified testosterone has not become a generally accepted method for therapeutic
purposes.

 

[madman]

It looks like Jatenzo did not invent the wheel since oral unesterified testosterone at the huge dose comparable to Jatenzo works just as effectively. It was forgotten in the history of testosterone because injectables provide much higher level at much lower injectable doses:

Pharmacology of testosterone preparations Review from 2004 by Wang et al.:

post #41

Better Libido/Sexual Function with different esters?

If your going to go that route, why not just try oral raw test base? Seeing esters are designed to be cleaved off in the blood, wouldn't they be useless orally?, might be able to get by with much less with the base. The Fda is just in it for the money, and cannot patent straight testosterone. I...

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[madman]

I’m on oral testosterone base
It costs me 25$ per month.
Orally has roughly the same bioavailability of testosterone undecanoate, roughly same half life, and regardless of meal status maintained the same bioavailability.

post #41

Better Libido/Sexual Function with different esters?

If your going to go that route, why not just try oral raw test base? Seeing esters are designed to be cleaved off in the blood, wouldn't they be useless orally?, might be able to get by with much less with the base. The Fda is just in it for the money, and cannot patent straight testosterone. I...

www.excelmale.com

*In hypogonadal men with normal liver function, 400–600 mg testosterone must be administered daily if the patient is to be substituted by oral testosterone (Johnsen 1978; Johnsen et al. 1974), a dose exceeding the testosterone production of a normal man almost 100fold. Aside from being uneconomical, the possibility of adverse effects of such huge testosterone doses cannot be excluded, especially when given over long periods of time as required for substitution therapy. However, in a SMALL GROUP of patients treated for as long as seven years with oral testosterone, no serious side effects were observed (Johnson 1978). Nevertheless, oral administration of unmodified testosterone has not become a generally accepted method for therapeutic purposes.


*Historically, oral administration of physiological testosterone (Figure 1A) has been proven unsuccessful due to extensive first-pass metabolism through the liver despite having good gastrointestinal absorption. Ingestion of supra-physiological doses was required to overcome this and allow for measurable amounts in the serum




From a previous thread:

post #355

Progesterone Dose for Men

Can someone help me on the nightly dosing of progesterone oil? I bought Progestelle brand skin oil referenced in this thread. 1 dropperful contains 20 mg of progesterone. What dose should I target if starting off conservatively? What is the typical absorption rate? I have read 10% for...

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You stated:

I’m currently not on estradiol. I’m not sure where my e2 sits but I presume it is on lower end. My most recent experiment involves 12mg of prop daily and 150mg of oral t base every 8ish hours (3 times daily)

Erectile quality skyrocketed for first time since being on trt. Still seeing whether or not this is honeymoon or not.