The ‘Phantom DHT’ theory or the ‘Increased Testosterone Metabolism Theory’
Edit: theory moved to post 6, below.
Theory is based on the one developed in this thread (see viewtopic.php?f=27&t=4260) but i feel is now complete and deserves its own thread (its easier to find too)
A fair theory. One that is easily testable too.
Yes, this is very interesting. So basically what someone would expect to see in a lab setting is higher levels of both 5beta-reductase and CP3A4, coinciding with subsequent increased levels of inactive metabolites, namely 6b-hydroxy-5a-dihydrotestosterone. So what sort of strategy would one use to reverse this problem?
I am currently perfecting this theory to the best of my abilities which I may post as a .pdf.
I dont know. Liver transplant maybe? On the face of it starting fin again would seem to be a solution as it will go back to repressing 5beta-Reductase and therefore cyp3a4 via the pregnane X receptor ( medicine.iupui.edu/clinpharm/ddis/table.asp . But these are pretty serious medications, there may be simpler ones though.
I really do like this idea. I believe it to be a competitor to the more popular AR theory. It is easy to test for too.
I hope that’s a joke.
If it’s simply a means of inhibiting CYP3A4, then grapefruit juice can do that.
From Wikipedia:
Grapefruit juice, and grapefruit in general, is a potent inhibitor of the cytochrome P450 CYP3A4 enzyme, which can impact the metabolism of a variety of drugs, increasing their bioavailability.
en.wikipedia.org/wiki/Grapefruit_juice
So you propose that the permanency of side effects is likely related to “rebound” effect of 5 beta-reductase leading to an altered homeostasis of liver enzyme metabolism? The link to the article for your first reference, regarding the relationship between 5 beta-reductase and CYP3A4 i am not able to access, could you post the relevant information?
This is an interesting theory man, good work. I feel the AR insensitivity theory is at a stage now where it really needs to be taken to the lab for it to be studied further, so i’m happy to discuss this one in the meantime.
On a side note, I also want to say that there seems to be a lot of attitude by some people on this forum about different theories which is very unnecessary, i am not adverse to anyone posting about any theory they believe in, as long as it is backed up by a logical explanation. In the same way if you believe a theory is not plausible you should similarly be able to de-construct it with a logical argument. As spstriken once said to me, “We are here to get better, not to score points”.
Persistent Finasteride Side Effects Idea(as good as i’m going to get it!)
Blood tests show a consistent set of results[1] :
Low to normal Testosterone levels
Normal DHT levels
Very low 3adiolG levels (the actual marker of intracellular DHT activity)
Low ratios of other 5alpha reduced metabolites (especially 5a-Tetrahydrocortisol, but taken together not as low as when using Finasteride)
Low Vitamin D
Effects upon LH
Effects on DHEA-S, Androstenedione and numerous other hormones
The syndrome is a mystery, why do these symptoms persist despite normal Testosterone? Why such low levels of 3adiolG despite normal Testosterone and DHT levels?
Some endocrinologists (in the USA and Europe) who have seen a number of patients with this condition have concluded that they may have developed a form of acquired androgen insensitivity, even going so far as to state so publicly[2].
I think there is an explanation to persistant symptoms; one that reflects the fact such a problem does not persist in a similar fashion through such powerful antiandrogen drugs as Flutamide which do not inhibit 5alpha/beta-Reductase.
Theory
Testosterone can be inactivated/metabolized through hydroxilation by hepatic Cytochrome P450 isozymes[3] . Glucuronosyltransferase and Sulfotransferase can conjugate testosterone directly or subsequent to hydroxylation, to either glucuronic acid or sulfate, making the testosterone water soluble before excretion with urine[4] .
I propose that through the use of Propecia and subsequent to ending this ‘medication’ the ratio of deactivated Hydroxy-Testosterone to active Testosterone can become permanently disturbed. I propose that this can cause symptoms of Hypogonadism by impeding normal androgenic action. Such a permanent change is not known to exist before, but has been discussed by US Government funded papers in relation to the gulf war syndrome[5] .
(1) Finasteride inhibits 5beta-Reductase which controls the hepatic Cytochrome P450 3A4 enzyme involved in the metabolism of androgens and xenobiotics[6] amongst others[7] . Finasteride is both a xenobiotic[8] and a synthetic androgen[9]. It has been proposed that Finasteride may inhibit its own metabolism[10] .
(2) Due to Finasteride’s mechanisms of action there may be increased serum levels relative to competition for hepatic enzymes from other sources, however, Proscar is regularly taken with other medication. Deactivated testosterone can also increase with Finasteride use[11] .
(3) When Finasteride usage ends 5alpha-Reductase regenerates, normally DHT levels return to normal and side effects dissipate.
(4) When Finasteride usage ends, 5beta-Reductase will regenerate affecting the P450 3A4 enzyme. I suggest this could lead to permanent increases in the metabolizing of androgens as well.
(5) Higher testosterone metabolism/deactivation will lead to more deactivated hydroxy-testosterone, especially 6beta-hydroxy testosterone (6bOHT) which is normally 75-80% of all deactivated testosterones[12] .
(6) The body should compensate for increased metabolism with more testosterone production[13] (possibly resulting in an altered LH profile).
(7) The sudden increase in metabolism and gap before testosterone production catches up could lead to the ‘crash’. The rise in DHT production creating negative feedback on the pituitary could also contribute. If testosterone production never catches up with metabolism, levels will be permanently lowered.
(8) I theorize that a higher serum ratio of hydroxy-testosterone/testosterone could further interfere with the homeostasis of testosterone in the body leading to symptoms of Hypogonadism. For example competition for coactivators at a cellular level[14] or androgen transport throughout the body. The properties of hydroxy-testosterones in vivo are relatively poorly understood.
(9) 6bOHT is an excellent substrate of 5alpha-Reductase[15] . Thus higher levels in serum will also inhibit normal production of 5alpha reduced metabolites such as DHT throughout the body.
(10) 6bOHT is NOT an inhibitor of 5alpha-Reductase (although other hydroxy-testosterones may do so[16] ). Thus its reduction via 5alpha-Reductase will only take place where testosterone normally produces its metabolites. It will NOT inhibit 5alpha conversions of neurosteroids in the brain for example, or stop other 5alpha metabolites.
(11) The product of 6bOHT and 5alpha-Reductase has been called 6b-hydroxy-5a-dihydrotestosterone, a deactivated version of DHT[17] .
(12) I theorize that 6b-hydroxy-5a-dihydrotestosterone is detected in the blood as normal, active DHT. There are several reasons for this idea.
Firstly, due to the fact it is a difficult chemical to determine due to its unique properties, as was found in the same paper as above[18] .
Secondly, circumstantial evidence points toward the normal blood testing being insensitive with Mesterolone and/or Drostanolone being detected as DHT.
Thirdly, I should add that in all of this I am assuming that deactivated testosterone is not detected as active testosterone in a normal blood test in the first place, if this does occur it will provide weight to this theory.
(13) The result of (11) is apparently normal DHT but low 3adiolG (possibly lower even than on Finasteride) due to both Testosterone and DHT being affected.
(14) Urine tests may show inhibition of other 5alpha reduced metabolites due to ‘competition’ over 5alpha-Reductase in the liver. Cytochrome P450 3A4 can increase the metabolism of DHEA and Androstendione as well as Estradiol, Cortisone and Progesterone[19] . Such a situation will lead to an unknown cascade of problems throughout the body potentially supporting this theory by the effects upon blood test results.
(15) A diagnosis may be supported by urinary or blood test to determine the ratio of Hydroxy-Testosterones to Testosterone[20] , or perhaps other markers of P450 3A4 induction[21] .
(16) The reason such effects are not noted by men using Proscar or Dutasteride (a 5alpha-Reductase Type 1 & 2 inhibitor) for BPH may be due to their age and general ill health.
It could also be due to the specific effects of a 1mg dose and/or the fact the usage of Finasteride is so widespread that men with rare genetic variations making them susceptible in this way have used it (who may not also be genetically predisposed to prostate cancer). In this theory one such genetic variation is to be found in relation to their liver.
Discussion
This takes a different approach to those strange persistent side effects of Propecia and attempts to answer the puzzle in a novel way, whilst still staying to true to the principles of logic and science. The theory attempts to bring together the symptoms, test results and timeline that many men experience.
This is an attempt to find an answer born out of frustration. There are no papers or text books which mention these problems. The drug manufacturer Merck still continues to deny or obscure the fact erectile dysfunction can be a permanent side effect[22] (the warning labeling changed for Europe but not in North America another example).
The problems with this theory are also clear. The metabolism of Finasteride has been extensively studied[23] . No unusual or permanent side effects are known in studies on Propecia. Nor does this theory explain why some suffer side effects but others do not. Also, most of the important ideas in this theory are speculation and are not known to be true or to have occurred before.
[Size=4][1] propeciahelp.com
[2] Dr Alan Jacobs, MD neuroendocrinology.org
[3] Inhibition and Activation of the Human Liver Microsomal and Human Cytochrome P450 3A4 Metabolism of Testosterone by Deployment-Related Chemicals. (2003).
dmd.aspetjournals.org/content/31/4/384.full
[4] Ibid
[5] Ibid
[6] Cytochromes P450 and metabolism of xenobiotics (2001)
springerlink.com/content/yvaxpqv757jvld86/
[7] Evidence of significant contribution from CYP3A5 to hepatic drug metabolism. (2004). ncbi.nlm.nih.gov/pubmed/15383492
[8] Identification of human cytochrome P450 isozymes responsible for the in vitro oxidative metabolism of finasteride. (1995). ncbi.nlm.nih.gov/pubmed/8654202?dopt=Abstract
[9] Foye’s Principles of Medicinal Chemistry. Fifth Edition. P112.
[10] Inhibition of Human Steroid 5β-Reductase (AKR1D1) by Finasteride and Structure of the Enzyme-Inhibitor Complex. (2009). jbc.org/content/284/30/19786.full
[11] Inhibition of steroid 5α-reductase and its effects on testosterone hydroxylation by rat liver microsomal cytochrome P-450. (1988). dx.doi.org/10.1016/0003-9861(8890386-4
[12] Ibid
[13] Ibid
[14] Due to the ability to enter a cells cytoplasm and interact with 5alpha-Reductase
[15] Inhibition of steroid 5α-reductase and its effects on testosterone hydroxylation by rat liver microsomal cytochrome P-450. (1988). dx.doi.org/10.1016/0003-9861(8890386-4
[16] 7-Alpha-Hydroxytestosterone in Seminiferous Tubules of Rat Testis
informahealthcare.com/doi/abs/10.3109/01485018308990170
[17] Studies on the Metabolism of C19 Steroids in Rat Liver. (1968)
onlinelibrary.wiley.com/doi/10.1111/j.1432-1033.1968.tb00389.x/pdf
[18] Ibid
[19] medicine.iupui.edu/clinpharm/ddis/table.asp
[20] Determination of testosterone and 6β-hydroxytestosterone by gas chromatography
dx.doi.org/10.1016/S0378-4347(9900332-1
[21] The increase in urinary excretion of 6 beta-hydroxycortisol as a marker of human hepatic cytochrome P450IIIA induction. (1989). ncbi.nlm.nih.gov/pubmed/2590599
[22] BBC New Report 21/12/2010 bbc.co.uk/newsbeat/12040303
[23] Identification of Finasteride Metabolites in Human Bile and Urine by High-Performance Liquid Chromatography/Tandem Mass Spectrometry. (2009).
dmd.aspetjournals.org/content/37/10/2008.full#ref-36[/size]
Yep, its worth a go. Although there are stronger drugs. The link i provided names some of those drugs and has links to study papers.
I dont have access to that paper i linked to in my first post. Its a good one tho. Someone else may have posted quotes.
I agree. Im not trying to score points. I dont discount Awors idea.
Good work Oscar.
You’ve tried to explain this in a logical scientific manner and I respect that.
So in order to diagnose this you have to test 6beta-hydroxy testosterone and see how it correlates with testosterone levels. Also would be good to test 6b-hydroxy-5a-dihydrotestosterone.
Things we can try - we can inhibit CYP3A4. Grapefruit juice is a good candidate. There are others. To people that want to try this make sure you check you are not taking a substrate and an inhibitor at the same time. Check with this:
pharmacytimes.com/issue/pharmacy/2008/2008-09/2008-09-8687
Another point to support the liver theory and its pathways is that many people here are sensitive to medications and people build a tolerance to meds like cialis. This could be explained due to the enzyme sweeping it up before the drug can act. However, also it should be said that if the enzyme is preoccupied with other substrates then it will have less time to deactivate testosterone (unless there is loads of the enzyme).
Keep it up Oscar!
Milk Thistle, a Herbal Supplement, Decreases the Activity of CYP3A4 and Uridine Diphosphoglucuronosyl Transferase in Human Hepatocyte Cultures
Abstract
Milk thistle extract is one of the most commonly used nontraditional therapies, particularly in Germany. Milk thistle is known to contain a number of flavonolignans. We evaluated the effect of silymarin, on the activity of various hepatic drug-metabolizing enzymes in human hepatocyte cultures. Treatment with silymarin (0.1 and 0.25 mM) significantly reduced the activity of CYP3A4 enzyme (by 50 and 100%, respectively) as determined by the formation of 6-β-hydroxy testosterone and the activity of uridine diphosphoglucuronosyl transferase (UGT1A6/9) (by 65 and 100%, respectively) as measured by the formation of 4-methylumbelliferone glucuronide. Silymarin (0.5 mM) also significantly decreased mitochondrial respiration as determined by MTT reduction in human hepatocytes. These observations point to the potential of silymarin to impair hepatic metabolism of certain coadministered drugs in humans. Indiscriminate use of herbal products may lead to altered pharmacokinetics of certain drugs and may result in increased toxicity of certain drugs.
Milk thistle gave me a bonner but increased my brain fog
Definitely something to try. I bought some today and have had a few glasses. Did feel a little different at first. Not sure if it will help yet. Can take up to 72 hours to take effect and not sure i’m drinking enough to change hepatic metabolism. Will get back to you soon.
You have to drink quite a bit i think.
ncbi.nlm.nih.gov/pubmed/12953340
Exposure-dependent inhibition of intestinal and hepatic CYP3A4 in vivo by grapefruit juice.
However, increases in the AUCs of CYP3A4 substrates recently associated with the consumption of large amounts of GFJ were similar to those observed with potent inhibitors of hepatic CYP3A4.
Actually this would need to be very likely indeed.
If nothing else becomes of this thread, I have at least discovered that some deactivated/hydroxy-testosterones are indeed natural anti-androgens. 
6beta Hydroxy Testosterone (6bOHT) the most abundant deactivated testosterone (80%) is an anti-androgen because (in large amounts) it will inhibit the normal production of DHT as it is also an excellent substrate of 5aR, see the first study. Other hydroxy-testosterones simply inhibit 5aR full stop, see the bottom study.
It would also follow that if 6bOHT is a substrate of 5aR it can enter a cells cytoplasm and interfere with coregulators at a cellular level, prehaps this interferes with the action of normal testosterone. It may also interfere with the transport of T around the body by binding/not binding to albumin, SBHG. Although these last two facts are only likely, not actually based on studies as deactivated testosterone is not well studied (at all really) in humans.
Inhibition of steroid 5α-reductase and its effects on testosterone hydroxylation by rat liver microsomal cytochrome P-450
dx.doi.org/10.1016/0003-9861(8890386-4
7-Alpha-Hydroxytestosterone in Seminiferous Tubules of Rat Testis
informahealthcare.com/doi/abs/10.3109/01485018308990170
good work Oscar although it doesn’t solve our issues but can explain some possiblities. Oscar what is your back ground not sarcastic but I am interested. you really made some xplaination. Is there some way we can test for 6boht?
sps
my box of viagra says do not take with grapefruit or gf juice, just a fyi. 
Note about grapefruit juice, it as do most other things that we put in our bodies, have multiple effects. I don’t think you can look at taking grapefruit juice as solely blocking one enzyme activity in the liver. It has sugar. We have noted on the forum that we have some similar issues to diabetics. Sugar affects diabetics. I think that we need to look at multiple forms of action.
I do think this theory has some merit.
I considered the liver transplant component a while ago. It’s not worth it.
Correct me if I’m wrong, but doesn’t DHT get converted (deactivated) mostly to 6bOHT in muscle tissue as well? Not really on topic, but it’s the only other place I believe I have heard that steroid mentioned before.
I just found this and posted it in the epigenetic thread but it correlates with this one too.
ncbi.nlm.nih.gov/pubmed/16336225
Anti-epileptic drug phenytoin enhances androgen metabolism and androgen receptor expression in murine hippocampus.
Epilepsy is very often related to strong impairment of neuronal networks, particularly in the hippocampus. Previous studies of brain tissue have demonstrated that long-term administration of the anti-epileptic drug (AED) phenytoin leads to enhanced metabolism of testosterone mediated by cytochrome P450 (CYP) isoforms. Thus, we speculate that AEDs affect androgen signalling in the hippocampus. In the present study, we investigated how the AED phenytoin influences the levels of testosterone, 17beta-oestradiol, and androgen receptor (AR) in the hippocampus of male C57Bl/6J mice. Phenytoin administration led to a 61.24% decreased hippocampal testosterone level as compared with controls, while serum levels were slightly enhanced. 17beta-Oestradiol serum level was elevated 2.6-fold. Concomitantly, the testosterone metabolizing CYP isoforms CYP3A11 and CYP19 (aromatase) have been found to be induced 2.4- and 4.2-fold, respectively. CYP3A-mediated depletion of testosterone-forming 2beta-, and 6beta-hydroxytestosterone was significantly enhanced. Additionally, AR expression was increased 2-fold (mRNA) and 1.8-fold (protein), predominantly in the CA1 region. AR was shown to concentrate in nuclei of CA1 pyramidal neurons. We conclude that phenytoin affects testosterone metabolism via induction of CYP isoforms. The increased metabolism of testosterone leading to augmented androgen metabolite formation most likely led to enhanced expression of CYP19 and AR in hippocampus. Phenytoin obviously modulates the androgen signalling in the hippocampus.
It could be that both this liver idea and the androgen receptor idea are linked. Ideally we would want to test the metabolites of testosterone as you say. This is a very good contender for explaining our problems.
Also viewtopic.php?f=27&t=1400 is interesting. Mew said “Perhaps another area worth investigating and testing… 3α-hydroxysteroid dehydrogenase/3b-hydroxysteroid dehydrogenase levels and function.” I am inclined to agree.
Note in:
informahealthcare.com/doi/abs/10.3109/01485018308990170
“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.”
ncbi.nlm.nih.gov/pubmed/15155549?dopt=Abstract
Silybin inactivates cytochromes P450 3A4 and 2C9 and inhibits major hepatic glucuronosyltransferases.
Silybin, a major constituent of the milk thistle, is used to treat several liver disorders. Silybin inactivated purified, recombinant cytochromes P450 (P450) 3A4 and 2C9 in a mechanism-based manner. The inactivations were time-, concentration-, and NADPH-dependent. The inactivation of the 7-benzyloxy-4-(trifluoromethyl-)coumarin O-debenzylation activity (P450 3A4) was characterized by a K(I) of 32 microM, a k(inact) of 0.06 min(-1), and a t(1/2) of 14 min. Testosterone metabolism to 6-beta-hydroxytestosterone (P450 3A4) was also inactivated with a K(I) of 166 microM, a k(inact) of 0.08 min(-1), and a t(1/2) of 9 min. The 7-ethoxy-4-(trifluoromethyl)coumarin O-deethylation activity of purified human P450 2C9 was inactivated with a K(I) of 5 microM, a k(inact) of 0.14 min(-1), and a t(1/2) of 7 min. Parallel loss of heme was observed with both P450s. Activity of both P450 enzymes was not recovered after removal of silybin either by dialysis or by spin gel filtration. In addition, silybin inhibited the glucuronidation of 7-hydroxy-4-trifluoromethylcoumarin catalyzed by recombinant hepatic UDP-glucuronosyltransferases (UGTs) 1A1, 1A6, 1A9, 2B7, and 2B15, with IC(50) values of 1.4 microM, 28 microM, 20 microM, 92 microM, and 75 microM, respectively. Silybin was a potent inhibitor of UGT1A1 and was 14- and 20-fold more selective for UGT1A1 than for UGT1A9 and UGT1A6, respectively. Thus, careful administration of silybin with drugs primarily cleared by P450s 3A4 or 2C9 is advised, since drug-drug interactions cannot be excluded. The clinical significance of in vitro UGT1A1 inhibition is unknown.
I agree with the 3HSD possibly being one of the biggest players in all this.