Significant decrease in SHBG with the use of Oral TU (JATENZO)

[madman]

SIGNIFICANT DECREASE IN SEX HORMONE-BINDING GLOBULIN WITH USE OF TESTOSTERONE UNDECANOATE CAPSULES (JATENZO) IN MEN WITH HYPOGONADISM (2022)
Alyssa Yee*, Maria Uloko, Irwin Goldstein, San Diego, CA


INTRODUCTION AND OBJECTIVE: Jatenzo (Clarus Therapeutics) which consists of the highly lipophilic prodrug, testosterone undecanoate (TU), in a self-emulsifying drug delivery system (SEDDS), is the first FDA-approved (2019) oral testosterone replacement therapy (TRT) for adult males with primary or secondary hypogonadism. The SEDDS allows TU to avoid first pass hepatic metabolism by being absorbed into the enteric lymphatics, then entering the left subclavian vein to be activated to testosterone (T) by esterases. T is subsequently bound to sex hormone-binding globulin (SHBG), a hepatic synthesized protein whose level is increased, in part, by hepatic conditions (e.g. fatty liver, non-alcoholic steatohepatitis, cirrhotic liver) and whose level is decreased, in part, by improvement in these hepatic conditions. We wished to study the effect of Jatenzo on SHBG including downstream changes to calculated free T and dihydrotestosterone (DHT) values.

METHODS: We reviewed the charts of our first 50 patients using TU capsules. T, SHBG, and DHT were measured 7 days after the patient started his optimum dose, defined as the value of TU that resulted in a mid-range T (425-970 ng/dl).

RESULTS: The mean age of our study group was 60.29 ±9 years. 75% of patients were on TRT previously. The mean testosterone value for these patients prior to TU capsule use was 486 ng/dl, a value higher than clinical trial data because patients were not required to wash out prior to starting TU. SHBG lowered from 41.5 nmol/L at baseline to 26.6 nmol/L post-treatment (156% decrease). This resulted in changes in free testosterone values from 17.0 ng/dl at baseline to 34.6 ng/dl post-treatment (204% increase) and DHT values from 12.8 ng/dl at baseline to 34.1 ng/dl post-treatment (267% increase). No increase in hematocrit or blood pressure severe enough to require a change in patient treatment was reported.

CONCLUSIONS: Our initial experience with TU capsules for the treatment of hypogonadism shows a decrease in SHBG resulting in increases in free T and DHT. In contrast to the hepatotoxic effects of previous methylated oral T products, oral TU (Jatenzo) may decrease SHBG by improving liver health. Further research is needed.

 

[madman]

 

[Systemlord]

So does Jatenzo decrease SHBG more than injections?

 

[Cataceous]

... T is subsequently bound to sex hormone-binding globulin (SHBG), a hepatic synthesized protein whose level is increased, in part, by hepatic conditions (e.g. fatty liver, non-alcoholic steatohepatitis, cirrhotic liver) and whose level is decreased, in part, by improvement in these hepatic conditions. ...

Doesn't the correlation run the other way with non-alcoholic fatty liver? Kind of important to get this right given that most fatty liver is the non-alcoholic type. "About 5% of people in the U.S. have [alcoholic fatty] liver disease. ... Nonalcoholic fatty liver disease ... affects one in three adults and one in 10 children in the United States."[R]

In both men and women, lower SHBG levels were associated with NAFLD.​

https://www.medigraphic.com/pdfs/hepato/ah-2017/ah173l.pdf

Basal SHBG was negatively associated with NAFLD development​

Serum SHBG Is Associated With the Development and Regression of Nonalcoholic Fatty Liver Disease: A Prospective Study - PubMed

Serum SHBG concentration is associated with the development and regression of NAFLD; moreover, it can be a potential biomarker for predicting NAFLD progression, and also a novel preventive and therapeutic target for NAFLD.

pubmed.ncbi.nlm.nih.gov

These results demonstrate that SHBG levels were negatively associated with the presence of NAFLD in middle-aged and elderly Chinese adults.​

Association of sex hormone-binding globulin with nonalcoholic fatty liver disease in Chinese adults - PMC

Sex hormone-binding globulin (SHBG), a glycoprotein synthesized by hepatocytes, has been linked to insulin resistance and hepatic lipid metabolism and is suggested to be associated with nonalcoholic fatty liver disease (NAFLD). This study aimed to ...

www.ncbi.nlm.nih.gov

 

[madman]

Doesn't the correlation run the other way with non-alcoholic fatty liver? Kind of important to get this right given that most fatty liver is the non-alcoholic type. "About 5% of people in the U.S. have [alcoholic fatty] liver disease. ... Nonalcoholic fatty liver disease ... affects one in three adults and one in 10 children in the United States."[R]

In both men and women, lower SHBG levels were associated with NAFLD.​

https://www.medigraphic.com/pdfs/hepato/ah-2017/ah173l.pdf

Basal SHBG was negatively associated with NAFLD development​

Serum SHBG Is Associated With the Development and Regression of Nonalcoholic Fatty Liver Disease: A Prospective Study - PubMed

Serum SHBG concentration is associated with the development and regression of NAFLD; moreover, it can be a potential biomarker for predicting NAFLD progression, and also a novel preventive and therapeutic target for NAFLD.

pubmed.ncbi.nlm.nih.gov

These results demonstrate that SHBG levels were negatively associated with the presence of NAFLD in middle-aged and elderly Chinese adults.​

Association of sex hormone-binding globulin with nonalcoholic fatty liver disease in Chinese adults - PMC

Sex hormone-binding globulin (SHBG), a glycoprotein synthesized by hepatocytes, has been linked to insulin resistance and hepatic lipid metabolism and is suggested to be associated with nonalcoholic fatty liver disease (NAFLD). This study aimed to ...

www.ncbi.nlm.nih.gov

*T is subsequently bound to sex hormone-binding globulin (SHBG), a hepatic synthesized protein whose level is increased, in part, by hepatic conditions (e.g. fatty liver, non-alcoholic steatohepatitis, cirrhotic liver) and whose level is decreased, in part, by improvement in these hepatic conditions.



Lower SHBG levels are associated with NAFLD (non-alcoholic fatty liver disease).

NASH (non-alcoholic steatohepatitis) and liver cirrhosis can increase SHBG.

Present Clinical Data on oral T (LPCN 1144) at 2022 NASH-TAG Conference

https://www.sec.gov/Archives/edgar/data/1535955/000149315221026815/ex99-4.htm LPCN 1144 IMPROVES BODY COMPOSITION IN BIOPSY-CONFIRMED NASH PATIENTS Background: Non-alcoholic Steatohepatitis (NASH) is a common cause of liver disease and rapidly rising to be the leading indication for liver...

www.excelmale.com

*increase in Sex Hormone Binding Globulin (SHBG) is reported with the progression of NASH

 

[madman]

So does Jatenzo decrease SHBG more than injections?

A New Oral Testosterone Undecanoate Formulation Restores Testosterone to Normal Concentrations in Hypogonadal Men (2020)
Ronald S. Swerdloff, Christina Wang, William B. White, Jed Kaminetsky, Marc C. Gittelman, James A. Longstreth, Robert E. Dudley, and Theodore M. Danoff6


Data analyses

Efficacy/pharmacokinetic analyses. Efficacy was assessed based on the percentage of treated patients whose T Cavg was in the eugonadal range. The T Cavg was separately summarized for those receiving oral TU and topical T, respectively, without a formal comparison between the treatment groups. The Cavg was calculated by non-compartmental PK methods using actual sample collection times relative to dosing using a modified intent-to-treat population (mITT). In the efficacy analysis, patients who dropped out prior to the final study day due to a possible treatment-related cause (e.g., an AE), were counted as treatment failures, while patients who dropped out for other causes (e.g., site closure not related to study conduct) had their T Cavg imputed using last observation carried forward (LOCF) methodology. A 95% Clopper-Pearson binomial confidence interval (CI) for the proportion was reported along with the estimated proportion.

Standard descriptive PK for the oral TU and topical T, as calculated using non-compartmental methods, were presented for total T, free T (calculated), DHT, and estradiol. In addition, changes from the pretreatment baseline to the end-of-study were presented for the endogenous molecules LH, FSH, and SHBG.




Changes in calculated free T, SHBG, Estradiol, DHT, LH, and FSH after oral TU

Effects of oral TU and topical T on calculated free T, DHT, estradiol (E2), LH, FSH, and SHBG are depicted in Fig. 6. As expected in both treatment groups, T administration caused significant elevations from baseline in free T, DHT, and estradiol and decreases in, LH, FSH, and SHBG. The magnitude of effects observed in oral TU patients paralleled those seen in patients treated with topical T and the differences in responses between the treatment groups were not statistically different. However, there was a trend toward higher free T concentrations in oral TU patients compared to topical T patients and a greater mean decline in SHBG in oral TU patients. The greater increase in free T from baseline for the oral TU group was partly a function of a 36% decrease in mean SHBG from 28.6 ± 14.7(SD) to 17.0 ±7.6 nmol/L in the oral TU group compared to essentially no change in the topical T group from 26.8 ± 10 to 26.4 ± 11.7 nmol/L. However, both baseline and final mean SHBG concentrations remained within the normal range for eugonadal men (10.8 to 46.6 nmol/L) at the final study visit in both groups.

Over the course of the study, mean estradiol levels increased to slightly above the upper end of the eugonadal range in both treatment groups [oral TU: 32 ± 14 pg/mL (117 ± 51 pmol/L) and topical T: 33 ± 18 pg/mL (121 ± 66 pmol/L]. Plasma DHT concentrations for the oral TU- and topical T-treated patients were essentially identical at all PK visits and at the final visit [73 ng/dL (2.5 nmol/L) were slightly above the normal upper limit of 65 ng/dL (2.2 nmol/L). Mean change from baseline in the serum concentrations of LH and FSH at end of the study (AM pre-dose concentration) in the oral TU and topical T patients showed an approximately 70% decrease from mean baseline values.


Figure 6. Effect of oral TU and topical T on LH, Free T, DHT, FSH, estradiol, and SHBG over course of T therapy.

My reply from a previous thread:

Injecting higher doses of androgens would have a larger impact on driving down SHBG but even then it depends on the individual as some may notice a larger drop and others not so drastic.

Far from common that one would notice an absurd drop in SHBG using therapeutic doses of T.

Depending on dose T used/injection frequency it is not a given that SHBG will be driven down as some will only notice a slight drop or it stays around pre-trt levels.

To be honest the c-17 alpha-alkylated orals such as methyltestosterone, oxandrolone, stanozolol, methandrostenolone, fluoxymesterone, and oxymetholone would have the biggest impact on driving down SHBG.

 

[madman]

 

[Cataceous]

...
Lower SHBG levels are associated with NAFLD (non-alcoholic fatty liver disease).

NASH (non-alcoholic steatohepatitis) and liver cirrhosis can increase SHBG.
...

According to Wiki, NAFLD includes NASH: "The term NAFLD encompasses a continuum of liver abnormalities, from non-alcoholic fatty liver (NAFL, simple steatosis) to non-alcoholic steatohepatitis (NASH)." Also confusing is that occasionally NAFLD progresses to NASH. Does the inverse correlation with SHBG not exist in this subset from the beginning, or does it exist and flip during the progression? "One debated mechanism proposes that hepatic steatosis progresses to steatosis with inflammation following some further injury, or second hit. Oxidative stress, hormonal imbalances, and mitochondrial abnormalities are potential causes of this "second hit" phenomenon."[R]

 

[Nelson Vergel]

All testosterone products do this. The degree of SHBG decrease is dose dependent and it correlates with total T. The same can be said with increases in DHT.

 

[Wilson7]

So does Jatenzo decrease SHBG more than injections?

In Bhasin's 2005 study of graded T dosing in older men there was no significant change in SHBG in dosing up to and including 600 mg/wk that resulted in a total T of 3286 ng/dl. If you compared the change in the means, while not significant there was a 15 - 25% decrease in SHBG with all dosing 25 - 600 mg/wk, lots of variability and no control comparison. No change in LFTs at any dose and a decrease in HDL only with the 600 mg/wk but not 300 mg/wk dosing. C-17 androgens and SARMs are notorious for crushing SHBG as well as HDL.

 

[sammmy]

No proof that the SHBG decreased by exogenous androgens indicates "increased liver health".

 

[Cataceous]

No proof that the SHBG decreased by exogenous androgens indicates "increased liver health".

The authors were trying too hard to put a positive spin on the lower SHBG and crossed the line into being misleading. They also repeat the myth that lower SHBG is boosting free testosterone, when it's actually the exogenous testosterone doing the job.

 

[sammmy]

The article sounds like a marketing scam for Jatenzo. I can't understand how this passed peer review, unless the reviewers don't read at all.

Quite comically, it tries to convince the reader that Jatenzo is SO MUCH! better than topical T and then proceeds to target the group that wants to "decrease SHBG to boost free T". These are usually people with normal T and free T but high SHBG, like me. The article sounds like it's trying to sell Jatenzo to those.

Then follows the astonishingly elementary idea that low SHBG indicates liver help. News flash: low SHBG is correlated with diabetes II, obesity, and aging. I guess liver health increases with aging and diabetes LOL

 

[Systemlord]

My SHBG increased to 11->24 on injections and Jatenzo due to improvement in glycemic control.