Liver Enzymes can deactivate Testosterone and DHT

[Oscar]

I have developed a theory based on Google.

http://en.wikipedia.org/wiki/Testosterone#Metabolism

testosterone and DHT may be deactivated or cleared by enzymes that hydroxylate at the 6, 7, 15 or 16 positions

http://www.mesomorphosis.com/articles/pharmacology/enzymatic-conversions-and-anabolic-steroids.htm

P450 enzymes (various)

A number of enzymes of the P450 class can hydroxylate steroids at various positions on the molecule by adding OH groups. This will deactivate the steroid, and the added hydroxy group also provides a position for further metabolism to make the steroids water soluble and more easily excreted. While some have suggested the idea of inhibiting P450 enzymes to get more “bang for the buck” from a given amount of steroid, the idea is a poor one, since there are many P450 enzymes that can act in this manner on steroids, and these enzymes are important for metabolism of many things other than steroids. Where there might be some relevance is if a drug is taken which greatly increases amount of some P450 enzymes; for example, rifampin. This would probably reduce the effectiveness of steroids by speeding their rate of metabolism.

http://www.anagen.net/glaxo7.htm

Both finasteride and dutasteride undergo extensive hepatic metabolism primarily via the cytochrome P450 3A4 (CYP 3A4) isoenzyme system.

Theory: The increase in hepatic p450 enzymes involved in the metabolism in finasteride resulted in their upregulation leading to increased percentage of deactivation of sex hormones. The cytochrome P450 3A4 is involved in the metabolism of testosterone also.

This may explain the ‘dynamic’ way in which the treatments with T seem to work for a short while but then their effects fade. The body increases enzymes to counteract the rise. it may also explain the poor liver results many sufferers have.

Also: I realise that this isnt much of a theory, more of a cobbled together bunch of facts. I would appreciate any insight anyone else can offer - thanks.

[tim1911]

Nice one

[martinM]

Agreed about the cause, the final effect however can differ, for example sex hormones may not be directly affected. It could be any of thousands of things, like preventing T4 to T3 conversion in the liver, etc. It’s clear that the liver enzymes were supra increased to eliminate fin which has a downstream effect on the body, but the question is how to identify the exact cause and how to treat exactly? I’m hopeful and tending to think that speeding up metabolism back to it’s original point will allow the hepatic enzymes their proper time and eliminate buildup.

[spstriken]

ok liver can deactivate sex harmones but liver can not make your balls mushy and smaller.

[toadstool]

@spstriken

ok liver can deactivate sex harmones but liver can not make your balls mushy and smaller.

perhaps from the lack of hormones?

[spstriken]

@toadstool

@spstriken

ok liver can deactivate sex harmones but liver can not make your balls mushy and smaller.

perhaps from the lack of hormones?

ok, can liver enzymes lower your LH and FSH too?
I have severe most side effects but liver enzymes ideal. Not elevated at all in all tests.

[martinM]

@spstriken

@toadstool

@spstriken

ok liver can deactivate sex harmones but liver can not make your balls mushy and smaller.

perhaps from the lack of hormones?

ok, can liver enzymes lower your LH and FSH too?
I have severe most side effects but liver enzymes ideal. Not elevated at all in all tests.

Some of your enzymes may be ideal, but medical science does not have full comprehension of what the liver does, so you cannot exclude it. Btw, when people get liver transplants many get improved sexual function and libido. Everything you eat gets converted into usable energy in the liver.

You ever eat pure honey, not the kind mixed with high fructose corn syrup? With wax? I get a huge surge of energy from this including libido, just doesn’t last long. Honey is a pure energy that the liver doesn’t need to spend much energy converting.

Also, if the liver doesn’t create an essential protein needed for nervous system functioning we will have the same problems.

[troubledfinuser2]

So the clearence rate of sexsteroids would be upregulated. If this is true and everything else still worked as it should the body would upregulate lh no in order to get more hormones into the system again. That is quite the opposite of what seem to be happening when ppl drop Propecia.

The lh goes low, this is what we c in here from the labs. The most logical explaination would ofcourse be that the body senses all the extra dht and shut down production of T.
Why is it that we try so hard to find another reason than the most logical one?

[spstriken]

@troubledfinuser2

So the clearence rate of sexsteroids would be upregulated. If this is true and everything else still worked as it should the body would upregulate lh no in order to get more hormones into the system again. That is quite the opposite of what seem to be happening when ppl drop Propecia.

The lh goes low, this is what we c in here from the labs. The most logical explaination would ofcourse be that the body senses all the extra dht and shut down production of T.
Why is it that we try so hard to find another reason than the most logical one?

yes I agree.I wrote before and maybe posted a link where some people got their liver screwed up after using Spalmetto but none of them suffered from low TT or ED. I even sent them emails privately and they were surprised when I asked them these questions. To me it looks their mal functioning liver indeed saved them from ill effects of Saw palmetto. It was not broken down and could not exert its piosionous effects on their nerveous system.
Further more we have one accutan users who is suffereing for 15 or 20 years and many fin users for 10 years, kemangd for 8 years after using SP none of these despite repeated liver tests showed any liver problems. yes enzymes are elevated but that happens with many drugs, but that does not really mean they are screwed up sexually as well.
sps

[Oscar]

The lack of Vitamin D (25-hydroxy vitamin D) may also be due to a liver problem as the liver is a major step in its synthesis via Vit D 25-Hydroxlase.

en.wikipedia.org/wiki/Vitamin_D_25-hydroxylase

Vitamin D 25-hydroxylase is a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This enzyme is a microsomal vitamin D hydroxylase that converts vitamin D into 25-hydroxyvitamin D (calcidiol), which is the major circulatory form of the vitamin.

en.wikipedia.org/wiki/Calcifediol

Calcifediol (INN), also known as calcidiol, 25-hydroxycholecalciferol, or 25-hydroxyvitamin D (abbreviated 25(OH)D),[1] is a prehormone which is produced in the liver by hydroxylation of vitamin D3 (cholecalciferol) by the enzyme cholecalciferol 25-hydroxylase.

en.wikipedia.org/wiki/Hydroxylation

Hydroxylation is a chemical process that introduces a hydroxyl groups (-OH) into an organic compound. In biochemistry, hydroxylation reactions are often facilitated by enzymes called hydroxylases. Hydroxylation is the first step in the oxidative degradation of organic compounds in air. It is extremely important in detoxification since hydroxylation converts lipophilic compounds into water-soluble (hydrophilic) products that are more readily excreted. Some drugs (e.g. steroids) are activated or deactivated by hydroxylation.

[Oscar]

Prolonged ethanol consumption increases testosterone metabolism in the liver
sciencemag.org/content/191/4227/563.abstract

Abstract
Male alcoholics often suffer from features of hypogonadism related to abnormal metabolism of sex steroids. Since the activity of testosterone reductases is rate limiting for testosterone metabolism in the liver, the effect of prolonged ethanol consumption by rats and human volunteers on the activities of these microsomal and cytosolic enzymes was studied. In rats, long-term ethanol ingestion doubled microsomal 5alpha-testosterone reductase activity, a major pathway for testosterone metabolism, while in human volunteers the activity was increased two- to fivefold. These changes may play a role in the altered androgenic activity of the chronic alcoholic.

Inhibition and Activation of the Human Liver Microsomal and Human Cytochrome P450 3A4 Metabolism of Testosterone by Deployment-Related Chemicals
dmd.aspetjournals.org/content/31/4/384.full

Maintaining hormonal balance relies upon a number of variables including rate of hormone synthesis, interactions among hormones, and rates of secretion, transport, and metabolism. P450s are a major controlling element in the maintenance of proper steroid hormone levels in mammalian systems. Exposure to foreign compounds can exert changes in endocrine function both directly (hormone agonists or antagonists) or indirectly (altering circulating levels of hormones by influencing rates of hormone synthesis or metabolism) that can severely affect steroid hormone action (Wilson and LeBlanc, 1998). Steroids such as TST (testosterone) are hydroxylated by P450 in a regioselective and stereoselective manner (Waxman et al., 1988). It follows that perturbation of the P450 system by xenobiotics may in turn affect the subsequent metabolism and disposition of TST. Perturbations in TST metabolism may affect levels of circulating TST with possible reproductive and other consequences, including further modulation of the expression of some P450 proteins.
…
However, no studies have been carried out to examine the induction or inhibition potential of these or related compounds on human P450-mediated metabolism of steroid hormones, such as TST. An understanding of how Gulf War related chemicals affects the metabolism of TST could aid in the evaluation of the possible role that these chemicals may play in deployment-related illnesses.
…
Endogenous steroids, such as TST, always exist in vivo, and considerable amounts of these steroids are metabolized by the P450s expressed in the human liver, where foreign compounds are mainly metabolized. If xenobiotics substantially affect TST metabolism, it may alter the rate of TST metabolism, which may ultimately disrupt TST homeostasis

[Oscar]

Metabolism of Testosterone, Dihydrotestosterone, Estrone and Estradiol
ergogenics.org/anabolenboek/index11en.html

The metabolism of testosterone and dihydrotestosterone takes place for 90% in the liver
…
Chemists also can change the structure of the steroid a bit so that metabolism is slowed down or prevented. These possibilities have been investigated extensively and have been directed toward the development of orally active anabolic steroids.

6β-HydroxyTestosterone
caymanchem.com/app/template/Product.vm/catalog/10008519/a/z

6β-hydroxy Testosterone is a major metabolite produced from testosterone by the actions of CYP3A4 and CYP3A5, accounting for 75-80% of all metabolites formed from testosterone. The biological effects of 6β-hydroxy testosterone have been poorly studied.

The Contribution of Hepatic Inactivation of Testosterone to the Lowering of Serum Testosterone Levels by Ketoconazole
toxsci.oxfordjournals.org/content/54/1/128.full

Hepatic biotransformation processes can be modulated by chemical exposure and these alterations can impact the biotransformation of endogenous substrates. Furthermore, chemically mediated alterations in the biotransformation of endogenous steroid hormones have been implicated as a mechanism by which steroid hormone homeostasis can be disrupted.
…
Testosterone is metabolically inactivated in the liver by some of the same hepatic enzymes responsible for the detoxification of xenobiotics. It is well established that the expression of these hepatic enzymes is differentially susceptible to induction or suppression due to xenobiotic exposure (Gonzalez, 1989; Guengerich and Shimada, 1991; Kulkarni and Hodgson, 1984). As a result, alterations in hepatic enzyme activity due to chemical exposure can lead to concomitant changes in the biotransformation of endogenous substrates such as testosterone. It has been further suggested that changes in the rate of inactivation and elimination of testosterone, as a consequence of chemical exposure, can alter the levels of circulating testosterone and thereby disrupt steroid hormone homeostasis
…
Circulating testosterone levels are maintained by a dynamic system that ensures androgen homeostasis. In simplest terms, this system can be considered a balancing act between the rate of testosterone synthesis and the rate of its metabolic inactivation/elimination. If this system is truly a balancing act, then both the rate of synthesis and the rate of metabolic inactivation/elimination impact the maintenance of circulating testosterone levels, and chemically induced disruptions in either process can potentially modify circulating testosterone levels.
…
In CD-1 mice, testosterone is inactivated/metabolized in the liver by four primary pathways. First, cytochrome P450 isozymes can monohydroxylate testosterone in a characteristic manner that is both region specific and stereospecific (Waxman et al., 1983). Second, testosterone can be dehydrogenated to produce androstenedione through P450-mediated pathways (Waxman, 1988), and also through the action of 17β-hydroxysteroid dehydrogenase (Bloomquist et al., 1977). Although the production of androstenedione can contribute to the androgen precursor pool in the body, we focused primarily on its role as an inactivation product. Third and fourth, UDP-glucuronosyltransferase and sulfotransferase can conjugate testosterone directly or subsequent to hydroxylation to either glucuronic acid or sulfate, respectively. These pathways generally produce more polar products that can then be eliminated from the body.
…
Exposure to some xenobiotics can result in increased activity of some hepatic biotransformation enzymes, leading to increased clearance of testosterone (Wilson and LeBlanc, 1998). Again, this effect on biotransformation and elimination did not impact serum testosterone levels. Gonadal testosterone secretion is regulated through serum testosterone levels by feedback control processes (Wilson and Foster, 1985). Although increased clearance of testosterone due to induction of biotransformation elimination processes may result in an initial decrease in serum testosterone levels, this decline would be detected and compensated for by an increase in gonadal testosterone secretion
…
As noted in the introduction, there are many instances in the scientific literature where xenobiotic-mediated changes in the rate of steroid hormone biotransformation and inactivation are presumed to lead to alterations in circulating hormone levels. Our results indicate that this assertion should not be made without careful investigation.

Alteration in sexually dimorphic testosterone biotransformation profiles as a biomarker of chemically induced androgen disruption in mice.
ncbi.nlm.nih.gov/pubmed/10210693?dopt=Abstract
Endosulfan elevates testosterone biotransformation and clearance in CD-1 in mice

ncbi.nlm.nih.gov/pubmed/9465275?dopt=Abstract

Toxicant-mediated induction of hepatic biotransformation enzymes is a mechanism by which endogenous steroid hormone metabolism and elimination may be altered
…
The increase in androgen clearance was associated only with a small, nonsignificant decrease in serum testosterone levels. Results indicate that increases in testosterone biotransformation from endosulfan exposure can result in increases in the elimination of the steroid. However, homeostatic processes apparently compensate for the effect and minimize any consequences on serum hormone levels.

[spstriken]

ok. if liver are screwed up then why Awor did not get any help from DHT. He applied and nothing happened. Othere people got the same experience by applying DHT ( I believe proviron).

thanx

sps

[Oscar]

One last study…

Inhibition of steroid 5α-reductase and its effects on testosterone hydroxylation by rat liver microsomal cytochrome P-450
http://dx.doi.org/10.1016/0003-9861(88)90386-4

4-MA completely inhibited steroid 5α-reductase activity without inhibiting the pathways of testosterone oxidation catalyzed by liver microsomes
…
Evidence is presented that 4-MA increases the accumulation of hydroxytestosterones by two mechanisms. First, 4-MA inhibited the 5α-reduction of those metabolites (such as 6β-hydroxytestosterone) that were found to be excellent substrates for steroid 5α-reductase. In the absence of 4-MA, these metabolites eventually disappeared from incubations containing liver microsomes from mature female rats. Second, 4-MA inhibited the formation of 5α-dihydrotestosterone, which otherwise competed with testosterone for oxidation by cytochrome P-450. This second mechanism explains why 4-MA increased the accumulation of metabolites (such as 7α-hydroxytestosterone) that were found to be poor substrates for steroid 5α-reductase.

7-Alpha-Hydroxytestosterone in Seminiferous Tubules of Rat Testis
informahealthcare.com/doi/abs/10.3109/01485018308990170

Production of 4-androstene-7α, 17β-diol-3-one (7α-hydroxytestosterone) from testosterone was measured in seminiferous tubule and interstitial fractions of rat testis. In adults, specific activity of the 7α-hydroxylase was about 10 times higher in interstitial cells than in seminiferous tubules, but tubule production was a significant portion of the total. Seminiferous tubule 7α-hydroxylase was not detectable in weanlings. Also, we confirmed that 7α-hydroxytestosterone inhibits the activity of the 5α-reductase and 3α-hydroxysteroid dehydrogenase active on testosterone and suggest a role in maturational changes.

[spstriken]

But still I don’t get answer for DHT appication failure. Further some have very high DHT but still impotent. how would you explain that?

[bostonusa2009]

I think it could always be a valid explanation for some guys, but I personally don’t believe this is the source of my problems.

One important thing we are missing here is, many of us ended up in the worst situation when we quit the drug. That does not provide a valid explanation of how the liver could be tied into this. At least, unless someone could provide a reasonble theory as to how that could be the case.

I believe it’s important to look at some of the side effects separately at least in my case, because I had all of the sexual sides prior to quiting. However, I had no issues with building muscle and loss of energy and the complete breakdown of the body before quiting.

That seems more like skewed hormones than an issue with the liver. It seems to point more towards the HPTA axis and a problem with the Pituitary/Hypothalmus. This provides a better explanation for the neurological problems that most of us experience.

One of the key questions is how many of us experienced what I experienced? When you quit, did you experience the crash? Loss of muscle, complete loss of energy, loss of interest in everything? Esssentially a whole new seperate set of side effects? If the majority of us fall into this camp, we need to put more emphasis on this point.

Theortically, there could be a couple of different problems going on at the same time. Maybe this liver issue that you bring up or a kidney problem and a HPTA axis issue with communication to the Pituitary. I know we all hate to think there isn’t simply one issue causing all of the problems, but it just doesn’t explain how a whole new set of sides begin when quiting.

[Mew]

Men have been diagnosed with tertiary hypogonadism (hypothalamic failure – pituitary no longer responding to GnRH or hypothalamus no longer outputting pulsatile GnRH), and remain unresponsive to treatments designed to restore the HTPA and androgenic response in the body.

Why Finasteride caused this after quitting, is still the mystery we are trying to figure out.

[spstriken]

Mew

Is accutane 5 AR inhibitor? I could not find any info on the net yet found that it alters DNA and causes cell death. It is a chemo therapy med. same is true for Fin. So they acutally caused cell death or DNA mutation in our muscles.
about HPTA I am not sure if it is a cause. I thought before but when read other stuff have to change my opion. you once qouted about Chris11’s HPTA shutdown. But when I saw his all posts his HPTA had restarted some how. LH had increased and his TT jumped from 9.1 to 16.6 please see viewtopic.php?f=4&t=755&hilit=chris although in his GP’s words “He has tertiary hypogonadism-hypothalamic…” Unfortunately he post last time on Thu Mar 20, 2008.

sam with me here. My LH has been around 1-2 for 16 months but in a recent test it upped to 5. So maybe problem is not in HPTA itself, but rather some enzymes or protines etc are regulating HPTA.

What I see on wikipedia about accutane’s permanent sides

Permanent side effects
The following adverse effects have been reported to persist, even after discontinuing therapy: alopecia (hair loss), arthralgias, decreased night vision,[37][38] inflammatory bowel disease,[39][40][41][42] degenerative disc disease, keloids, bone disease, dry eyes,[38] dry skin[citation needed]. High dosages of isotretinoin have been reported to cause rosacea (a disease of severe facial skin redness and irritation)[citation needed]. It is not known how these side effects can be permanent but several studies have shown that Isotretinoin induces apoptosis (cell death) in various cells. A recent study[43] about how pharmaceuticals have epigenetic effects (for example DNA methylation) mentions Isotretinoin.

Maybe it is cell death or altered DNA at receptors level? our DHT is not being consumed so there is backlog and result is an increased production of Estradiol, prgestrone and other all un-wanted hormones which signal our HPTA to downregulate LH and FSH?

How can you explain that a woman can respond to a Testosteron injection perfectly and will get manly but we, once perfect males have no response now?
To me Awor is right about his methylation theory.
Finally also read this please

Drugs may alter epigenetic homeostasis by direct or indirect mechanisms. Direct effects may be caused by drugs which affect chromatin architecture or DNA methylation. For example the antihypertensive hydralazine inhibits DNA methylation. An example of an indirectly acting drug is isotretinoin, which has transcription factor activity. A two-tier mechanism is postulated for indirect effects in which acute exposure to a drug influences signaling pathways that may lead to an alteration of transcription factor activity at gene promoters. This stimulation results in the altered expression of receptors, signaling molecules, and other proteins necessary to alter genetic regulatory circuits. With more chronic exposure, cells adapt by an unknown hypothetical process that results in more permanent modifications to DNA methylation and chromatin structure, leading to enduring alteration of a given epigenetic network.

here is the link ncbi.nlm.nih.gov/pubmed/19501473

If this all is true ,man we are toast.

sps

[Oscar]

sps, that post should be in methylation thread. That study has already been posted viewtopic.php?f=5&t=3901&start=80 , by me and others. Finasteride isn’t a chemotherapy drug. Accutane isn’t a 5 AR inhibitor (or not a very strong one at least).

[Mew]

Accutane isn’t a 5 AR inhibitor (or not a very strong one at least).

Actually, it is, however moreso 5AR1. I don’t have the studies in front of me but there are many confirming retinoic acid inhibits 5AR activity, DHT and 3a-diol G.