Liver Enzymes can deactivate Testosterone and DHT

General Discussion
#21

I dont think that accutane has alot to do with our problem, other than epigenetic/methylation type trouble. If it inhibits 5ar1 this is surely only peripheral to its main methods of action.

To Summarise This Liver Problem Theory.

1. Finasteride is chemically very similar to Testosterone, this is why it works so well. viewtopic.php?f=8&t=1053

2. Sex hormone agonist and antagonists such as Finasteride and Testosterone (and DHT) are metabolised and deactivated by the same liver enzyme; Cytochrome p450 3A4. en.wikipedia.org/wiki/CYP3A4#CYP3A4_substrates

3. An increase in the activity of this liver enzyme may effect the metabolism of testosterone, a xenobiotic may cause this to be permanent (see the studies posted above). This means testosterone metabolism in permantly increased. Metabolism = deactivation.

4. A scenario where testosterone is being metabolised faster than normal would not effect serum testosterone levels. (again, see the studies above).

5. More metabolism of testosterone creates higher levels of deactivated testosterone such as 6β-hydroxytestosterone.

6a. 6β-Hydroxytestosterone is an excellent substrate of 5a-Reductase. This would inhibit Dihydrotestosterone production and create a new useless product, the same way as Nandralone converts to NOR-DHT, dihydronandrolone, and creates DecaDick.
6b. This could occur whilst using finasteride & may have the same effect as taking Dutasteride.

7. Raised 3A4 enzyme may only create a negative effect after quitting Fin, (as it is now clearing Testosterone, DHT instead of Finasteride)

8. As a result there is a permanant effect on Testosterone homeostasis: More metabolism of Testosterone and DHT in the body and more hydroxytestosterones inhibiting the production of DHT and therefore less 3adiolG.

Problems…

1. Increased metabolism of Testosterone may not be a problem at all since the studies show that the body will compensate with higher production, however, “Maintaining hormonal balance relies upon a number of variables including rate of hormone synthesis, interactions among hormones, and rates of secretion, transport, and metabolism” (see study above, also there are no human studies on this to know what happens)

2. Normal DHT levels. Just about everyone has this. It is a leap of faith, but the unusual product of the hydroxysteroid and 5a-Reductase could show up on the blood tests as DHT {prehaps in a similar way to a synthetically produced T shows up on a blood test}

3. Application of DHT (&T). This may work but may become increasingly less effective at low doses as 3A4 enzymes are invoked to clear it (DHT can also be cleared by glucuronidation too ergogenics.org/anabolenboek/index11en.html)

4. I dont know what the cure would be. Testing for this would possibly mean advanced blood testing, mass spectrometry etc. Which is difficult/impossible for a layman.

So thats my weak theory! I have invented a way that a man can be hypogonadal despite normal blood results!

#22

good Oscar
ok P450 will work after Testosterone has been produced so how would you describe weak dick and shrunken Testicles? So we should try to lower P450 now?

sps

#23

This may evolve but it’s a very clear and excellent picture. I agree about the mechanism here but again its a question of how tomfix it.

#24

Liver enzymes are a fairly standard test as i understand. Shouldn’t be too difficult to get a doctor to have this tested.

#25

Some liver enzymes are easy to test, others we may not even know about, especially the downstream metabolites.

#26

We have to remember there are more hormones involved than just DHT for sexual function. And that P450 is directly involved in those processes as well.

#27

I don’t think the enzymes themselves are out of whack, meaning elevated levels. Possibly just the way they handle the metabolism as suggested. But that could actually be a secondary issue of something else. Would never know until a test is performed though.

#28

alot of people are complaining about sides from Alcohols on this forums.Maybe liver theory carries some weight.
Awor if you are reading this thread what is your response? You have been on HRT before and after propecia.what difference did you notice between now and before (before propecia) from alcohol use? I know this very confusing when there are so many possibilities for the sides to occure.

#29

Guys,

I already have mentioned this several times here. Sorting the liver issues sorts out a lot of hormone metabolism problems. Repairing liver is not within the realms of western medicine. You dont need to go test liver enzyms or anything.

I would simply visit an unani or ayuverda doctor. The whole system will need to be worked on, adrenals, thyroid, testes, pituarty, hypothalamus and ofcourse liver. It will take time but slowly these organs will be brought back to health and optimum functioning. Then your symptoms will start to resolve. I been through it all.

Liver tests mean nothing, you could have cirrhosis and still have okay liver results. The ficroscan can detect liver cirrhosis. However, i would simply work on improving liver, as living in a toxic world we all need liver help anyway so there is nothing to lose.

#30

This is an EXCELLENT POINT! Cirrhosis of the liver can not be accurately diagnosed with blood tests. Doctors usually do biopsies, which means they need to physically see a piece of the liver to tell.

Extrapolate this to our liver enzymes determining liver function and the conclusion is blood tests CANNOT be a full picture of liver function.

#31

We have been focussing on 5AR as beeing the root cause but maybe 5AR is basically changed our liver metabolism capacity. I have seen two cases exactly like ours. One guy got hypogonadal after using Metformin and other (actully I believe there are many) from using Tribulus Teristiris. Now I am not sure about Metformin but Tribulus is not 5AR inhibitor. He is on Musclechatroom.com and have been on HRT for almost 8 months and he got no benefits at all. He is just like some chaps over here who are on HRT. HE is having same musclepain, joint pain etc although using good doses of T injection. His blood is showing good level of T but he is constantly complaining. I read another case history ( which I will post here) of young man who got gyno and got it repeatedly removed but it was recurring untill his DR discovered he was on Tribulus. He was taken off and got normal. His LH and FSH were < 1 in 0.+ and T was 1 or 3. After discontineuing HE got FSH ,LH and T in normal range. Maybe his liver recovered. Alcohol and aggravation in our symptoms are going hand in hand, showing something wrong with liver. our low vit D are point in this direction too but We don’t know weak liver is the cause of effect of low Testosterone.

#32

“Testosterone in males is produced primarily in the testicles, but also in the adrenal glands.” -Wikipedia (you probably were already aware, but I did not know testosterone was also produced in the adrenal glands, just putting out the info as many feel adrenal issues relate to this syndrome…)

“Finasteride also inhibits 5b-reductase [21]. 5b and 5a-reductases are involved in hepatic steroid metabolism, and thus finasteride might affect liver function [21]. Inhibition of 5b-reductase may impair CYP3A4 activity [21], which is the enzyme responsible for finasteride metabolism [22]. Dutasteride also involves a two-step mechanism and is a time- dependent inhibitor of 5a-R2 [23,24].” - member 19 post

Above quote initiated my search of the CYP3A4 enzyme and it’s activity, the link below provides some info and drug interactions. It seems, if I’m reading correctly, that if one is taking a substrate and an inhibitor it can be very dangerous.

pharmacytimes.com/issue/pharmacy/2008/2008-09/2008-09-8687

(info about CYP3A4 activity and its substrates, inhibitors and inducers.)

question is, does destruction or harm to this enzyme interfere with the liver processing of hormones? (specifically testosterone) and if so…how can it be restored? is there a lab test that can be used to determine CYP3A4 activity? just wondering if any of the researchers who monitor this site think this is a reasonable thing to look at? Just trying to help, sorry if it seems like it wouldn’t be useful.

#33

I just read that metformin causes the same hypogonadism how ? maybe possible this way

Metformin inhibits hepatic glucose production, thereby reducing the androgen production of theca cells.
books.google.com/books?id=7SVFDF0_v…5&ct=result

#34

Saudi Med J. 2002 Aug;23(8):934-7.

Effects of short term metformin administration on androgens in normal men.

Shegem NS, Nasir AM, Jbour AK, Batieha AM, El-Khateeb MS, Ajlouni KM.

National Center for Diabetes Endocrinology and Genetics, Jordan University Hospital, Amman, Jordan.

OBJECTIVE: To study the effect of metformin on androgens in normal men. METHODS: A total of 12 healthy males volunteered to participate in the study. A blood sample was obtained from each of them and analyzed for the following: Testosterone (total and free), sex hormone binding globulin dehydroepiandrosterone sulphate, 17-hydroxyprogesterone, luteinizing hormone, and follicle stimulating hormone. In addition, each participant was subjected to a glucose tolerance test and his insulin level was measured. Metformin 850 mg twice daily for 2-weeks was given to each subject after which the above tests were repeated. A paired t-test was used to assess the statistical significance of any observed differences before and after metformin. RESULTS: After metformin administration, there was a significant reduction in serum level of total testosterone (p=0.0001), free testosterone (P=0.002), and 17 hydroxyprogesterone (p=0.0001). There was also a significant increase in serum level of sex hormone binding globulin (p=0.009) and dehydroepiandrosterone sulphate (P=0.0008). Serum levels of luteinizing hormone and follicle stimulating hormone showed no significant changes. Similarly, there were no changes in fasting plasma glucose, fasting serum insulin, weight, or blood pressure. CONCLUSION: Metformin administration was associated with a reduction in total testosterone, free testosterone, and 17-hydroxyprogesterone and an increase in sex hormone binding globulin and dehydroepiandrosterone sulphate in normal males.

#35

Please read the following thread. Guys here are blaming liver for low TT after metformin use, possibley metformin decreases 3beta -hydroxysteroid dehydrogenase (3beta-hsd) the enzyme responsible for the conversion.
Note they also conclued even clomid can not fix the issues b/c problem is in the liver enzymes.

mindandmuscle.net/forum/index.php?showtopic=35802

#36

I think the question that needs to be addressed by this theory is how could it explain our clinically hypogonadal state? I’m not discounting it but love to hear thoughts on this.

CYP3A4 and its function is interesting as doxycycline is metabolised partially through this but how does that correlate with symptoms. Doxy has helped me. But I can’t think why CYP3A4 would help.

Finasteride is metabolised by this too. It acts as a substrate.

pharmacytimes.com/issue/pharmacy/2008/2008-09/2008-09-8687

"Unfortunately, many CYP3A4 substrates have substantial toxicity, and some patients may develop severe toxicity when CYP3A4 inhibitors are taken concurrently. " (I imagine this is because the drug is not metabolised properly therefore leading to raised levels of the drug causing problems)

“CYP3A4 inducers are drugs that increase the activity of CYP3A4. Note that the CYP3A4 enzyme is particularly susceptible to enzyme inducers, and marked reductions in the plasma concentrations of CYP3A4 substrates may occur. For example, a patient taking the potent CYP3A4 inducer rifampin may have a roughly 90% reduction in serum concentrations of CYP3A4 substrates, such as buspirone, triazolam, and verapamil.”

The following are inducers:

Aminoglutethimide
Bexarotene
Bosentan
Carbamazepine
Dexamethasone
Efavirenz
Fosphenytoin
Griseofulvin
Modafinil
Nafcillin
Nevirapine
Oxcarbazepine
Phenobarbital
Phenytoin
Primidone
Rifabutin
Rifampin
Rifapentine
St. John’s wort

If you believe inducing the enzyme will help then taking any of these should help. I’d like to hear if anyone has and if there was any effect.

#37

Doxy induces p450 enzymes, as stated on it’s own wikipedia article. I think that explains the anecdotal partial recovery response, but may only contribute to a limited improvement while taking the antibiotic. Meaning it is only a booster and not a potential cure or anything. And since the effects don’t last, I’d assume you’d have to take it indefinitely to stave off the symptoms.

This doesn’t mean for sure p450 enzymes are the culprit, it just means you can possibly feel better by inducing them. Sorry, I don’t want to get anyone’s hopes up for something that may not be of benefit in the long term.

That said, Oscar’s theory is good and shouldn’t be discounted at all.

#38

Oscar, what governs the liver enzymes metabolism? Is it still the HPTA? Shouldn’t that feedback loop detect a problem still?

#39

I don’t mean to discount the theory. As I ask on the epigenetic thread we should bash the theories and see if they still make sense after we try and find holes in them. We should work together to plug the holes. I am just asking why would it affect our androgen response?

If the metabolism of testosterone was affected then why are DHT levels normal in some of us? Why did levofloxacin have a similar effect to doxycycline in me when it is not metabolised in the liver?

Also if you’re saying the testosterone gets swept up then flooding our systems with testosterone will mean our livers can’t compensate and there would be a reversal of symptoms. Very few respond to testosterone.

#40

Actually I think it is metabolized in the liver by CYP2D6. Which I believe is a P450 enzyme. Also, test by itself isn’t the only thing that we need. It’s metabolites DHT, E2, etc. also have to be at correct levels, as you are probably aware. Not to mention the myriad of other hormones that are processed by those liver enzymes as well.