Liver Enzymes can deactivate Testosterone and DHT

General Discussion
#41

I dont know why liver enzymes should permanantly change. But, according to the studies, if more testosterone is being metabolised by the liver and excreted, the body will compensate with increased testosterone production to maintain a study serum level. This is why testosterone levels remain within range for most. (So maybe this shouldnt even cause a problem…maybe, maybe not see the studies i posted?)

Saying that, I also think it would also explain why some have a notable and consistently low testosterone levels - increased metabloism.

However another problem here is that LH should be increased as a result. Which it isnt. Unless the LH pulses are now more frequent and as a result the actual pulse spike is lower.

The two big problems with this theory are, firstly, the fact that DHT is being produced in the body. If there was a testosterone problem this should not be the case. But consider this… Testosterone is metabolised by Cytochrome p450 3A4 to 6β-hydroxytestosterone (70-80%) which is then further metabolised by 5a-reductase.

Testosterone —> P450 3A4 (deactivation) —> 6β-hydroxytestosterone —> 5a-Reductase —> ???

What is the product of 6β-hydroxytestosterone & 5a-reductase??? Not DHT. But prehaps it shows up on a blood test like other DHT derivatives such as Proviron and Andractim will.

A bit crazy? Well prehaps checking if the blood tests are accurate (DHT is DHT!) should be the first step before assuming that a blood test that shows normal DHT and low 3adiolG means androgen insensitivity (which i dont discount btw).

The second big problem is why testosterone supplementation (T or DHT) doesnt work. Metabolism of androgens may be increased when more androgens are added (resulting in a the repeated ‘fade’ and short term successes). I’m not sure how many people have actually pushed their T levels to supra-physiological levels or wether the successes/failures here can be attributed to any of the ideas i have mentioned. (see viewtopic.php?f=4&t=3250)

One last thought…

If testosterone production is increased to compensate for more deactivation/metabolisation, then the body should create more testosterone from its precursors by upregulating 17β-HSD etc. If this happens wont there be altered levels of DHEA and Androstenedione and Androstenediol? Sounds familiar…

#42

Interesting stuff man. So, is there a way to distinguish real DHT from metabolites that may “mimic” DHT values in a lab test?

#43

If androgens were being metabolized faster wouldn’t that show up as higher levels of metabolites in a 24 hour urine panel?

#44

Not sure how much docs are looking for that, or what “normal” would be considered in my limited knowledge. But I would assume the same thing mariobros.

#45

Well there must be! Its called ‘Mass-Spectrometry’. This is the method used by scientists to determine the exact chemical structure of a compound. Unfortunately only a University will have access to such equipment. So it requires your doctor to be sympathetic (and connected enough) to check why you have apparantly normal ‘DHT’ but low 3aDiolG with a University’s science dept.

I dont know how to really prove/disprove this theory. Or even if it would really effect the body by creating symptoms of hypogonadism anyway. You would prehaps expect levels of testosterone metabolites found in urine to differ in quantity from serum levels of testosterone (T and DHT in urine is the deactivated version).

So one way may be to measure serum T and DHT and compare with the amount of urine metabolites; T, DHT, Epitestosterone, Androstadienone, total Androsterone and total Etiocholanolone. This is a complete guess…

#46

Finasteride also inhibits 5-beta-Reductase, and 5-beta-Reductase controls the liver enzyme CYP3A4, it has been proposed that Finasteride may prevent its own metabolism (see viewtopic.php?f=8&t=2703 ). It may be in fact the regeneration of 5bR and the subsequent rise in CYP3A4 that leads to the ‘crash’ as well as the rest of this theory, as the reduced enzyme was taxed to reduced the synthetic androgen which Fin is…

…anyway the way to test this theory would seem to be to test CYP3A4 activity. This can be done by testing the 6 Beta-Hydroxycortisol ratio to cortisol.

“The concentration of 6 Beta-Hydroxycortisol reflects the activity of the hepatic cytochrome P450 enzyme (CYP3A4) involved in the metabolism of endogenous steroids and approximately one-third of prescribed oral medications. An increase in the ratio of 6 Beta-Hydroxycortisol to urinary free cortisol suggests the patient has induced activity of CYP3A4.”

nicholsinstitute.com/TestDetail.aspx?TestID=254

cebp.aacrjournals.org/content/1/7/567.abstract
ncbi.nlm.nih.gov/pubmed/19959402
ncbi.nlm.nih.gov/pubmed/2590599

#47

Some more thoughts on this…
I may now call this the ‘Phantom DHT’ theory, or the ‘Increased Testosterone Metabolism Theory’.

b[/b] Fin inhibits 5-beta-Reductase, which controls the cyp3a4 enzyme involved in the metabolism of androgens and xenobiotics. Fin is both a xenobiotic and a synthetic androgen, thus the reduced cyp3a4 enzyme is taxed to metabolise it.

b[/b] As fin inhibits its own metabolism = v.high serum levels and higher chances of side-effects.

b[/b] When fin usage ends, 5-beta-reductase will regenerate thus creating more cyp3a4 enzyme. I theories this could lead to permanant increase in the metabolation of androgens as well.

(metabolism = deactivation before being made water soluble for urination. Androgens can also be made water soluble for urination w/out deactivation from cyp3a4)

b[/b] higher testosterone metabolism will lead to more deactivated hydroxytestosterone (especially 6beta-hydroxy testosterone ‘6bOHT’) in serum.

b[/b] the body should compensate for metabolism with more T production via LH

b[/b] the sudden metabolism and gap before T production catches up could lead to the ‘crash’. If T production never catches up T levels will be permanantly lowered.

b[/b] I theories that a higher serum ratio of hydroxytestosterone/testosterone could interfere with the heomeostatis of testosterone in the body leading to symptoms of hypogonadism. (ie competing for the androgen receptor, transport throughout the body)

b[/b] 6bOHT is an excellent substrate of 5aR. Thus higher levels of this will also inhibit normal production of dihydrotestosterone throughout the body. High levels of 6bOHT will create higher serum levels which interfere with 5aR throughout the body, not just the liver.

b[/b] 6bOHT is NOT an inhibitor of 5aR. Thus its reduction via 5aR will only take place where T normally produces its metabolites. It will NOT inhibit 5aR conversions of neurosteroids in the brain for example, or stop other 5ar metabolites.

b[/b] I propose the product of 6bOHT and 5aR is: 6b-hydroxy-5a-dihydrotestosterone, a deactivated version of DHT (see onlinelibrary.wiley.com/doi/10.1111/j.1432-1033.1968.tb00389.x/pdf )

b[/b] I theorise that 6b-hydroxy-5a-dihydrotestosterone is detected in the blood as normal DHT. Due to the fact it is a difficult chemical to determine due to its unique properties (as was found in the paper/link above) and because the normal test for DHT seems insensitive (andractim & proviron also detected as DHT for example). Thus the DHT found in blood tests is a ‘Phantom DHT’.

b[/b] The result of point (11) is apparantly normal DHT but v. low 3adiolG (lower even than when on fin) due to both T AND DHT being effected.

b[/b] Blood tests will show inhibition of other 5aR reduced metabolites due to ‘competion’ over 5aR in the liver.

b[/b] A urinary or blood test to determine the ratio of Hydroxy-Testosterone to Testosterone will discover if this has happened.

b[/b] Also…this enzyme, cyp3a4, will also increase metabolism of androgens such as DHEA and Androstendione as well as T (although T is metabolised most).
The body will compensate with LH to create more T & Androstendione from the testes and ACTH to create more DHEA from the adrenals. However, since each are also steps in the steroid pathway, this disruption can lead to altered levels (particularly DHEA as it has only one precursor and comes before Androstendione & T)

See other papers posted in the thread for proof of all of this, apart from the ‘theories’ claims.

Ta-da. A pretty solid theory. now with its own thread viewtopic.php?f=27&t=4695

#48

sorry I could not understand the theory. If it is just fast metabolism by the liver then our balls should not be shrunken and soft, they should be busys days and night, full,firm and big.LH and FSH should be very high twice or three times the high end but they are in the gutter for most of us.In my opinion P450 is slower than normal not faster.

1 Like
#49

Herbal medicines are widely used in the world and are generally considered effective and safe, although many studies have demonstrated their potential toxic effects, particularly for the liver. We present a case of a woman, who developed a mixed cholestatic/hepatocellular liver injury due to herbal products. Firstly, she was admitted to Division of Surgery for right upper abdominal pain and jaundice and, for the suspect of biliary obstruction, she underwent to cholecystectomy. For persistence of liver enzymes elevation, she was admitted to our Gastroenterology Unit. We excluded every etiologies of hepatitis and, after an intensive dialogue with the patient, we obtained a history of herbal medicines use. Then, we performed a liver biopsy which was compatible with hepatotoxic injury. Therapy with ursodeoxycholic acid (UDCA) was started. Liver function tests returned to normal in two months. We describe this clinical case to encourage the communication doctor/patient in phytotherapy area and physician knowledge about efficacy and side effects of herbal medicine to avoid delayed diagnosis.

PMID: 21222373 [PubMed - in process]

#50

Its not simple.
Basically the theory goes that the liver is deactivating more testosterone than it should.
Turns out deactivated testosterone is a natural anti-androgen (My discovery! :slight_smile:)

Unless the production of testosterone in turn creates a high amount of deactivated testosterone which is a natural antiandrogen (6beta Hydroxy Testosterone) which also inhibits 5aR activity.

Im not saying I have all the answers, you are correct- the fact LH isnt high does not fit in with this theory.

LH is produced in pulses. Prehaps the number of pulses has increased but the amount in each pulse has not.

Or prehaps blood tests and the pituitary both detect deactivated testosterone as normal testosterone (unlikely).

Completed theory has now moved here —> viewtopic.php?f=27&t=4695

#51

Hey Oscar

Could you elaborate when you say “Turns out deactivated testosterone is a natural anti-androgen” and as to it inhibiting 5 alpha reductase. Do you have a source I can read? Thanks.

19

#52

See here —> viewtopic.php?f=27&t=4695&p=32310#p32310

#53

Alpha lipoic acid has fixed the liver of people dying from liver disease. any one wants to try? honestmedicine.com/2009/03/burt-berkson-md-phd-talks-with-honest-medicine-about-his-work-and-our-medical-system-the-interview-t.html

#54

I honestly think our livers are fine…

#55

It is quite hard to fathom that anyone could think this to be honest(I am not specifically picking on you just this widespread mindset); and, consequently, I don’t believe that anyone who reads the mounting literature implicating the liver as a hormonal control centre; and, as a corollary: the pertinent issue of drug metabolism believes it truly. I think there is a tendency to side skirt issues that are not conducive to quick fixes: that is human nature. The problem with acceptance stems from deprivation; in that, we don’t have a concise and effective course of action to remedy a faulty/damaged liver; but, that does not mean we should stick our heads in the sand. We can all tweak sub-standard hormones; and, in fact argue about what constitutes optimal hormone levels ad nauseam; it will not make a great difference

#56

Oscar, I am all for liver implication in PFS, but could you please highlight the proof for indefinite over expressed liver cyp3a4 enzyme in the scientific literature. I agree with you in theory that it could be over expressed temporarily; but you seem to go further and say there could be indefinite long term over expression. Again, I am not being unsupportive, but there seems to be quite a leap there.

#57

There is none.

However, I carried on developing this idea in another thread and eventually found scientific literature that clearly states that this would cause my symptoms - viewtopic.php?f=27&t=4695&p=34053#p34053

But indefinite long term over expression without the use of exogenous drugs? No, its not in the literature - not that I could find anyway. But whatever the hell I have wrong with me isnt in the literature anywhere either.

#58

Cool, that is fine; I just wanted to make sure I was not missing anything. I appreciate yours efforts battling this nightmare. You might be quite close.

#59

I still think that the only way this is possible (long lasting side effects is if the liver(steroid hormone degeneration) has been slowed down.

I posted a study that revealed women have slower liver cyp3a4 than men and they concluded that it was due to estrogen.

So heres my spin

  1. We take finasteride.

  2. Estrogen increases, liver enzymes are slowed. No big problem for some, at this stage.

  3. Continue to take fin, now speaking for people who gain sides or crash on drug and never recover.
    Testerosterone/estrogen get higher, body sensors to much hormone so down regulates (Shuts down) (lh, fsh, adrenal hormones, vit d)

  4. Others quit fin, make full recovery testosterone starts getting converted back to DHT rather than estrogen. Liver enzymes are still slow. Body sensors way to much steroid hormone as it is not being degraded fast enough, so it regulates hormone levels by “shutting down”.

  5. cyp3a4 inhibitors may give us a brief boost, due to an increase of hormone before the body regulates again, potentially making us worse ie Milk Thistle, some antibiotics, marijuana.

  6. Testosterone boosters may help, TRT, Clomid, because you will get a boost of testosterone, then the body regulates.

  7. So the slow liver metabolism of steroid hormones has caused an increase in blood levels which the body has sensored and then regulated, which is actually to low.

The degree of shut down can be explained by the degree of sides, how badly each individual is effected.

jpet.aspetjournals.org/content/311/2/728.full

dmd.aspetjournals.org/content/30/5/534.full.pdf

#60

Regulates what, how? I think we can rule out TRT shutting down production and therefore causing problems, especially if you have regular blood tests (or had hypogonadism before taking Fin).

Then that should be detected in a blood test and corrected with TRT. Isnt this just called secondary hypogonadism?

The idea I EVENTUALLY developed was that the end metabolism (not production) of testosterone could cause our problems, but this must be due to an increase of enzymes activity. This is supported by the medical literature - in fact it has been used as a way to shrink prostates of rats.

Although it is in fact a new form of hypogonadism I know of no disease states can cause this to happen.