the 'Phantom DHT' theory

General Discussion
#21

Hydroxylation of testosterone in the human testis Identification of 4-androstene,7,17β-diol-3-one (7-hydroxytestosterone) as a metabolite of testosterone

Homogenates of normal or cryptorchid, human testes were incubated with [3H]testosterone and a NADPH-generating system. [3H]4-andostene,7,17β-diol-3-one (7-OH-testosterone) was isolated and identified from such incubations. To our knowledge this is the first demonstration that 7-OH-testosterone is a metabolite of testosterone in the human testis. 4-Andro-stene,6β,17β-diol-3-one (6β-OH-testosterone) and 4-androstene,16,17β-diol-3-one (16-OH-testosterone) were also identified as testosterone metabolites. The specific activity of both testosterone 6β- and 16-hydroxylase was higher than that of 7-hydroxylase. Pre-pubertal or cryptorchid human testis tissues seem in our study to have higher testosterone 6β- and 7-hydroxylase activity than normal adult testis tissue.

eje-online.org/cgi/content/abstract/93/2/243

#22

Increasing liver metabolism of androgens as a means of androgen deprevation…

Pregnane X receptor as a therapeutic target to inhibit androgen activity
ncbi.nlm.nih.gov/pubmed/20962047?dopt=Abstract

Androgen deprivation by activating the liver X receptor
ncbi.nlm.nih.gov/pubmed/18450964

Modulation of liver X receptor signaling as novel therapy for prostate cancer
ncbi.nlm.nih.gov/pubmed/17372849

#23

Is anyone able to determine if a normal test for testosterone can also include 6beta Hydroxy-testosterone in the result?

There are a number of papers discussing how they determined the quantity of deactivated hydroxy testsosterones (Quantitative analysis of eight testosterone metabolites using column switching and liquid chromatography/tandem mass spectrometry, ncbi.nlm.nih.gov/pubmed/11488629) but I cant find out if a distinction is made or any significant cross-reactivity during a normal assay. Potentially a very important peice of information.

#24

Oscar I think we should keep it simple, inhibition of 5ARs caused starvation of DHT dependent tissues, shrinkage of prostate and penile fibrosis.
The Effect of 5 {alpha}-Reductase Inhibitors on Erectile Function – Canguven and Burnett 29 (5): 514 – Journal of Andrology

"Further evaluation of the role of DHT in the penis has been done at the penile morphologic level. Shen et al (2000) investigated the ultrastructural changes of the penile corpus cavernosum and tunica albuginea in rats representing 3 groups: sham control, castrated, and treated with finasteride. Four weeks later, blood samples were obtained for the determination of serum T and DHT levels, and penile tissues were taken for scanning electron microscopy. The T and DHT levels in castrated rats and the DHT level in finasteride-treated groups were significantly lower than those in the control group. In the castrated animals, there was a high degree of fibrosis in the corpus cavernosum with irregularly arranged collagenous fibers and a marked decrease in smooth muscle fibers, while in the DHT-inhibited group (finasteride-treated), the corpus cavernosum comprised a substantial amount of thick and irregularly arranged collagenous fibers, but the degree of fibrosis was less than that of the castration group (Shen et al, 2000). This work suggests that because finasteride inhibits the action of DHT but not T on the corporal cavernosal tissue, the degree of fibrosis was less in the DHT-inhibited group than in the castration group. In the castration group, the thickness of tunica albuginea decreased significantly and the elastic fibers were mostly supplanted by collagenous fibers, and in the DHT-inhibited group, the elastic fibers were replaced by disorganized and thick collagenous fibers. Since the tunica albuginea plays a major role in the erectile mechanism of the penis, the latter results offer an explanation for the presentation of ED in patients treated with 5ARIs."

I think the effect is very broad spectrum and in all of our body T/DHT dependent fibers either underwent damag or have been replaced by collagenous fibers. Now these collagenous fibers don’t need any T or DHT so even if 5AR returnes to normal level body does not need that much T or DHT now, end result is after short term elevated high TT, T slowly declines and estradiol increases untill it reaches a balance where body sees low T as the normal T sufficient for present Androgen receptors. There are many ex-fin users whose TT kept declining afer stopping fin. Some people saw a huge decline more that 100% just within weeks.

here look another study

asiaandro.com/1008-682X/5/33.htm

Excerpt:

In the normal control group of this study, the elastic fibers in the tunica albuginea were very rich and arranged regularly and undulatedly. In the castration group, the thickness of tunica albuginea decreased significantly and the elastic fibers were mostly replaced by collagenous fibers and in the DHT-inhibited group, the elastic fibers were replaced by disorganized and thick collagenous fibers. These results indicate that androgen is also essential for the maintenance of the normal structures of tunica albuginea.

I think this also explains why some people are having sides years after, even 10 years not only that since once our natural tissues have been replaced by thes scar tissues no DHT or HRT will get us back lost errections. Awor, JN and Whalen are examples being on TRT nothing is working for them.

#25

I disagree entirely with this last post.

First off if this were the case EVERYBODY on finasteride would have permanent erectile dysfunction. Secondly some people do have benefit on TRT even if only briefly. Thirdly the study ends by saying:

andrologyjournal.org/cgi/content/full/29/5/514

We conclude that 5 -reductase inhibitors do not lead to erectile dysfunction to a significant degree, and we support the position that dihydrotestosterone is less relevant than testosterone in erectile function.

Whilst on Fin testosterone rises and DHT falls.

Fourthly some people only took it for a very short period myself included before any real “damage” could have been made. Fifthly it does not explain the “crash” at all after a period of recovery. My sexual problems started after I stopped fin.

We are a subset of patients who have problems…therefore we must have specific attributes that can contribute to this. Also the natural recoveries as in the people who have our symptoms for a week or two - or up to 6 months and then return to normal function - suggests a reversible nature. We may be jealous of these lucky people but keep in mind their recoveries give us hope.

#26

The paper only mentions fibrosis of the penis… because it only happens in the penis.

This thread is an attempt to find an explanation as to why we CRASH and then continue to display varying symptoms of hypogonadism/androgen deprevation.

We can all help to confirm if this theory is true or false by getting your doctor to test for the ratio of hydroxy-testosterone to normal testosterone in a blood/urine test or possibly through a a test of liver enzyme P450 3A4 induction (see the theory post for how to do this). It would also help to find if a normal assay for testosterone distinguishes between deactivated testosterone metabolites such as 6beta hydroxy-testosterone and normal testosterone.

#27

Whilst i agree that fibrosis may be a part of the problem, it is by no means the whole picture. And the idea that we should keep it simple, well, it isn’t simple… If it was simple we’d have figured it out years ago.

I think this idea is very interesting, but i am starting to find it all little confusing to follow with so many metabolites. Perhaps we need to do a map/diagram which demonstrates the relationships between the relevant metabolites, receptors, their interaction with finasteride and/or the 5 a+b reductases.

#28

So 19 you think this all study is baseless? After all what this study then means?
about EVERYBODY on finasteride would have permanent erectile dysfunction, well I would say every body is different. This is why some people did not see any sides for 10 years and some got sides with even only two tablets. Interestingly people whos saw sides after very long time are the ones who got very littles sides and mostly got well within short time. Many here are who got sides with in months and are staying here still.
I used SP first for 4 months during which I felt extremely fatigued. I did internet research but could not find any thing. I was taking SP in the morning and by 4 PM I was very tired and then in the morning was fresh again. after upset stomach and weird feelings I stopped after 4 months but I did not have any sexual problem this time. after one month gap my urine problems came back ( weak stream , urine burning and wake up due to forceful errection came back).So I started SP again and used 3 more months but this time I got severe sotmach upset and very first time got ED ( I was initially happy that I was not waking up due to errections). Once I got ED and impotence I stopped but after feeling well for 2 weeks I did not get well. So it was impotence after which I could not go back,.

#29

I don’t mean to say its baseless just that fibrosis couldn’t possibly explain all the issues at play including fatigue, brain fog, low libido. It may play a part in erectile function but I doubt it plays a huge part.

Mariobros - you’re right. It is getting confusing.

Has anyone else tried grapefruit juice? For a week sort of thing.

#30

So in order to get my head around it i’m sort of looking at pieces at a time.

So according to these articles 7α-Hydroxytestosterone is an inhibitor of 5 alpha reductase’

Production and effects of 7α-hydroxytestosterone on testosterone and dihydrotestosterone metabolism in rat testis

7α-Hydroxytestosterone, a major metabolite of testosterone in mature rat testis, inhibited 5α-reduction of testosterone in cell extracts of mature but not of immature rat testis.

sciencedirect.com/science?_ob=ArticleURL&_udi=B6T1X-47G2T1W-T8&_user=10&_coverDate=07%2F20%2F1977&_rdoc=1&_fmt=high&_orig=search&_origin=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=c2521dda93365fc7576b499294bdec04&searchtype=a

7-Alpha-Hydroxytestosterone in Seminiferous Tubules of Rat Testis

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.

informahealthcare.com/doi/abs/10.3109/01485018308990170

Ok, and according to this article, the inhibition of 5 alpha-reductase leads to increased levels of 7α-hydroxytestosterone, as decreased levels of DHT means more testosterone is metabolized by CYP-450.

Inhibition of steroid 5α-reductase and its effects on testosterone hydroxylation by rat liver microsomal cytochrome P-450*1

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.

sciencedirect.com/science?_ob=ArticleURL&_udi=B6WB5-4DPBW4Y-T&_user=10&_coverDate=08%2F15%2F1988&_rdoc=1&_fmt=high&_orig=search&_origin=search&_sort=d&_docanchor=&view=c&_searchStrId=1613599061&_rerunOrigin=google&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=62b57686d9cc021b593664c7de98856c&searchtype=a

So, could inhibition of 5 alpha-reductase create a cyclical situation: Fin inhibits 5AR > Low DHT leads to increased 7α-hydroxytestosterone > 7α-hydroxytestosterone inhibits 5AR > Low DHT and so it goes on…

The problem i see with this is that prolonged, high dose DHT supplementation (possibly in combination with CYP-450 inhibitor) should be able to brake the cycle. Of course there are other hormones and factors at play… i guess we won’t know until we are able to test these metabolites.

#31

Nice idea but the problem with this is people don’t always have a rock bottom serum DHT.

#32

viewtopic.php?f=4&t=4406&start=20

17A-Hydrotestosterone 8.0 nmol/L (2.0 - 10.5)

#33

A message to me from one of the leading hormone testing labs (my name isnt really Smith, i was undercover…).

So that answers that. If DHT testing is also specific to DHT and not subject to interference by metabolites, this theory is blown out of the water.

#34

I still stick with my prostate shrinkage theory. Has anybody here done any test that measure accurately prostate size? I am not talking of digital rectam exam. The only test we know is cystoscopy. If some body has done and it came normal then my theory will be blown too. I am still thinking our prostates have shrunken a lot, far below the normal size, so people even with normal T and normal DHT or even on HRT can not have normal errections. We know normal males suffer from errections and libido problems after prostate operations ( keep in mind just some interfering tissues are removed). But this all does not answer higher aromatisation rate and non-responsiveness to DHT as Awor reproted. So we come back to Awor’s theory of AR desensitization.

#35

If you think your prostate has shrunk then you should have the test done but you have to ask yourself, if this is the case why is it that your prostate has remained in a shrunken state after being off for so long? If your prostate is small then something else is causing it to remain that way, its not the root cause of the problem. Guys who have been on fin for 5 - 10+ years would likely have prostates of pre-pubescent size and yet many of these guys seem to have no complaints.

If your prostate is still small years after being off fin then it is likely a symptom of a deeper hormonal/epigenetic issue.

#36

mriobros please read my previous posts. this is replacement of elastic fibers with collagenous fibers, in other words scar tissues. we know scar tissue is just filling , non-responsive to any thing heat ,cold ,hormone etc. So what we should do then grow prostate fibers in lab and then replace in our body.
Can we contact some lab which can do biopsy? If this is all true (I don’t know if it is true for mice in vivo then why not be in our case). God forbid if this is the case who can replace all DHT dependent tissues in our whole body. what a mess? it not the same case of typeII diabeteses? I pray I am wrong.

#37

Fibrosis is possibly a contributing cause of some peoples ED. i have extensive fibrosis myself. Possibly another factor is apoptosis. A shrunken prostate will likely cause problems too, certainly that can occur. (These things will likely get worse and worse if hormone problems continue)

All this means physical damage to a persons body can be caused by Fin. But it doesnt explain ‘the crash’ - the way symptoms get worse after quitting - it doesnt explain brain fog it doesnt explain muscle loss it doesnt explain the patterns that are seen in the blood work.

If you do have an idea that connects all these things dont keep it to yourself, start your own theory thread. This thread is for the specific theory that I have developed which does connect those things, the sooner it is proved or disproved the better. This is done by lab tests or a well constructed argument.

Thanks!

#38

I think we really need to try and get a broader picture of what is going on with these metabolites. Two that we have looked at so far have demonstrated some consistent anomalies (11b-OH-Etiocholanolone and 3alpha-androstanediol glucuronide).

Unfortunately, living in Australia i am not able to do this but i feel this 24 hour panel from rheinlabs.com/hp.html would be a beneficial place to start painting a bigger picture.

#39

Ok Oscar I am done, no more posts to your theory.

#40

We still need to establish what is happening to testosterone. This theory still has some relevance. Otherwise we need to determine where along the androgen pathway the problem is.