MESO-Rx

Anabolic Steroids

Finasteride [5ARI] Induced/Associated Effects

Re: Mainstream media finally realizing Propecia can make you impotent

Michael Scally MD said:
Merck - Merck & Co., Inc.: NYSE:MRK quotes & news - Google Finance - has plenty of money. The chances of Merck investigating this are slim, fat, and none. JMHO

IMO, I think this is an excellent area for investigating epigenomic and downstream AR factors.
Click to expand...

I agree the chances of them doing anything are non-existent just now as it would be an admission of guilt. Could they be forced by a lawsuit to do something, or provide funds for it?
 
Re: Mainstream media finally realizing Propecia can make you impotent

Getting Merck to take responsibility is a two part problem: first, show that the adverse effect is due to an insult to the body, and then try to show that this change is due to the drug in question. In the past, lawyers have been able to win against the drug companies without knowing exactly how the drug causes the adverse effect, but at least the adverse effect was well understood. Look at the lawsuits going on with Accutane and ulcerative colitis / crohn's disease.

IMO the reason why it will be harder in the case of Propecia is because (1) no one is quite sure yet what has changed in these men to cause the impotence, and (2) the number of men experiencing these effects is small. I imagine that Merck's lawyers would try to argue that the impotence was psychological in nature. In the Accutane lawsuits, lawyers were able to rely on medical explanations for what has changed in the digestive tracts of their clients, and needed only to show that it was likely due to the Accutane.
 
Re: Mainstream media finally realizing Propecia can make you impotent

What is this joke man?? People loose their testicles, penises and mind after finasteride use. Where is the difficulty to prove it??

I have blood tests that show a wacked system after using finasteride - or do you think that someone that converts almost no T to dht is normal ?? (unless we belong to this caribbean tribe that have congenital androgen resistance and still don't know it)
I can bring 7-8 ex girlfriends i had in the court to assure that before fin i was a perfect male and now a limp. In all aspects.

Merck will sit for this in court, its a matter of time. We are not 10-20 people theres several thousands allready, and as the drug gets access to more countries more people will be affected. The only problem is that doctors don't report on the side effects. I went to 20 doctors before one actually admitted that these problems could be of finasteride use. They are very reluctant because they get money from those pharmies.
 
Re: Mainstream media finally realizing Propecia can make you impotent

No disrespect intended Shaolin. The fact that it took you 20 doctors is exactly my point --- it is difficult for doctors to say what exactly has happened that has caused the impotence.
 
Re: Mainstream media finally realizing Propecia can make you impotent

New report ?? Wow, and i thought it was only recognised in Sweden..

My dear friend, Structure, it took 20 doctors because i started going from pathologists to urologists to endocrinologists and finally to antiaging. You think i new anything practically about hormones and hypogonadism before using finasteride?? I study endocrinology in med school and the only thing we learned is primary and secondary and those are veeery veeery rarely seen in our university hospital. 90% of the endocrine cases refer to diabetes and thyroid problems and mostly have to do with women. In a whole year of endocrinology training i remember seeing one guy, literally one, with a problem in his testicles and that was because of a tumor.

Today however i see more and more doctors understanding the role of 5-ar inhibitors in causing long lasting sexual problems. Young endocrinologists are aware of it, and i don't really have such a hard time getting proof.
 
Re: Mainstream media finally realizing Propecia can make you impotent

As long as someone can point a finger at you and say you're impotence and depression are because you have a mental illness, winning a court battle will be non-trivial. My 2 cents.

Some doctors take this stance because (1) some people do have depression and impotence due to mental illness, and (2) these doctors don't understand the relationship between finasteride and permanent depression / impotence / loss of libido.

Unless the mechanism by which finasteride causes these problems is better understood, or until a clinical study is done that reaches the conclusion that finasteride can cause these problems, I don't think much cash will be changing hands. Again, my 2 cents, nothing against you Shaolin.

I'm just glad that publications are starting to show up... That is a good first step, and hopefully will inspire more doctors and scientists to look into what is happening.
 
Re: Mainstream media finally realizing Propecia can make you impotent

Good. Now maybe they will also realize that Lipitor (aka Limpitor) can cause the same problem. All I have is anecdotal evidence, but the handful of friends I have who have been on it took themselves off it when they noticed a decline in their ability to have an erection.
 
Re: Mainstream media finally realizing Propecia can make you impotent

Structure said:
As long as someone can point a finger at you and say you're impotence and depression are because you have a mental illness, winning a court battle will be non-trivial. My 2 cents.

Some doctors take this stance because (1) some people do have depression and impotence due to mental illness, and (2) these doctors don't understand the relationship between finasteride and permanent depression / impotence / loss of libido.

Unless the mechanism by which finasteride causes these problems is better understood, or until a clinical study is done that reaches the conclusion that finasteride can cause these problems, I don't think much cash will be changing hands. Again, my 2 cents, nothing against you Shaolin.

I'm just glad that publications are starting to show up... That is a good first step, and hopefully will inspire more doctors and scientists to look into what is happening.
Click to expand...

Adverse Side Effects of 5[]-Reductase Inhibitors Therapy: Persistent Diminished Libido and Erectile Dysfunction and Depression in a Subset of Patients - Traish - 2010 - The Journal of Sexual Medicine - Wiley Online Library

Some highlights from full txt:

To date, the adverse side effects of 5a-RIs on sexual function, gyneco- mastia, and the impact on the overall health have received minimal attention. However, in some patients, these side effects are persistent with regard to sexual function and with an emotional toll including decreased quality of life.

In the brain, the products of 5a-Rs are trans- formed by another group of specific enzymes known as 3a-hydroxysteroid dehydrogenases (3a-HSD), which reduce 5a-DHT to 3a, 5a-androstane 17b-diol (3a-diol) and 5a-DHP to 3a, 5a-tetrahydroprogesterone (allopreg- nanolone). Similarly, 5a-DHDOC is further reduced to 3a, 5a-tetrahydrodeoxycorticosterone (THDOC). These derivatives are thought to func- tion as neurosteroids in the central nervous system (Figure 3), with important physiological functions including modulation of gamma-aminobutyric acid type A (GABAA) receptor, sigma receptor function, nicotinic acetylcholine receptor, voltage- gated calcium channels, and synaptic and brain plasticity. These physiological functions may impact mood, rhythm, stress, sleep, memory, anxiety, and sexual function [11]. 3a-HSD utilizes NADPH as a cofactor, and this reaction is revers- ible [10–12]. In transformation of these 3a, 5a reduced steroids; the 5a-R reaction is the rate-
limiting step [12,13].

The two most investigated inhibitors of 5a-R are finasteride and dutasteride (Figure 1) [10]. Dutasteride is a selective inhibitor of 5a-R1 and 5a-R2 in most tissues examined [9]. Dutasteride approaches maximum inhibition at 1 mg/kg/day, with a peak blood concentration of 140 ng/mL [10], and it reduces serum 5a-DHT by approxi- mately 90% [9,14]. Finasteride is maximally effec- tive at 70 mg/kg/day, with a peak blood level of 7,840 ng/mL in humans [10], and it reduces serum 5a-DHT by approximately 70% [14,15]. Finas- teride is considered mainly an inhibitor of 5a-R2 and is approximately 50 times weaker in inhibiting 5a-R1 than 5a-R2 [9]. Finasteride is thought to cross the blood–brain barrier and inhibits 5a-Rs in the central nervous system [16].

Finasteride was thought to be a competitive inhibitor of both 5a-Rs isozymes, with an inhibi- tor dissociation constant (Ki) varying from 3 to 26 nM [17–19]. Recently, finasteride was shown to catalyze T to 5a-DHT via a mechanism- based inhibitor of 5a-R2, with formation of enolate intermediates. The enzyme/NADP- dihydrofinasteride complex is stable, with a half-life of approximately 1 month, and the reaction produces dihydrofinasteride [20]. 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].

Adverse Effects of 5a-R inhibitor Therapy
A host of adverse effects had been observed in the clinical settings as a result of 5a-RIs therapy; however, some of these adverse events are consid- ered either insignificant or temporary, and may not exhibit long-term effects in patients’ overall health. Other adverse events including sexual dysfunction appear to either become severe or persistent. In the study by Wessells et al. [25], only 50% of patients experienced resolution of their sexual adverse events after discontinuation. Furthermore, Erdemir et al. [26] stated that “While sexual dys- function induced by Finasteride and dutasteride
diminishes over time, resolving completely with discontinuation of therapy and discontinuation due to sexual adverse events occurs in up to 4% of patients.” Additional evidence is found in clinical studies and in the Merck database, which strongly suggest that in some patients, the sexual adverse effects are persistent. In the medicine health care products regulatory agency (MHRA) public assess- ment report on the risk of finasteride published in December of 2009 in Section 4.8 Undesirable Effects, it was stated that “In addition, the following have been reported in post-marketing use: persis- tence of ED after discontinuation of treatment with PROPECIA.” Clearly, the sexual adverse events do not necessarily resolve completely in all patients, who discontinue use of finasteride, again support- ing the premise that in some patients these sexual side effects remain “persistent.” In the proceeding section, we will discuss the impact of these drugs on sexual function, gynecomastia, and depression.
 
Re: Low Libido, numbing, aching and sleeping problems - I quit finasteride 4 months a

Madlib, you have got to get in contact with me so we can discuss some of your Finas sides!! I saw that you get up in the middle of the night wide awake, I got that too! Also you said your heart seemed to be working harder then usual, me too!! You are the first person I could find that had the same issues! Please contact me either on here or my email: timallen45@hotmail.com

Thank you
Tim
 
Theory As To Why Finasteride Causes Permanent Hypogonadism-like Symptoms

Background

Finasteride is sold for hairloss under the brand name Propecia (fincar, finpecia as generics in India). It is a competitive 5alpha Reductase Type 2 inhibitor, it also inhibits 5beta Reductase. As a result it blocks the production of Dihydrotestosterone in the scalp and prostate and elsewhere, it also inhibits the production of all the 5alpha reduced metabolites in the body, including important neurosteroids in the brain. It also inhibits liver enzymes as a result of its actions upon 5beta reductase.

As a result Finasteride alters the hormone profile to be same as 5AR2 deficient pseudohermaphrodites [0]. Low serum DHT and low levels of other 5aR metabolites.

The members of Propeciahelp.com are the real world examples of the post marketing side effects of Finasteride.

Typically someone with issues will experience erectile dysfunction and loss of libido, known side effects of androgen deprevation [00]. After stopping finasteride things typically get worse, a full endocrine 'crash' followed by a host of symptoms normally found in men with low levels of testosterone, these include fatigue, problems concentrating, depression and even muscle loss plus many more. These side effects are permanant and continue despite all and any attempts to allieviate them (even supra-physiological levels of testosterone will not always work). A low quality of life results for those suffering this miserable condition.

It must be accepted that the 'post finasteride syndrome' is a novel form of iatrogenically induced hypogonadism. The underlying mechanism of which is not known.

Blood tests on these individuals show a consistent set of results:

Low to normal Testosterone levels
Normal DHT levels
Very low 3adiolG levels (the actual marker of intracellular DHT activity)
Low ratios of other 5aR reduced metabolites, especially 5a-Tetrahydrocortisol, but not as low as when using Finasteride.
Effects on DHEA-S, Androstenedione and other hormones
Low to normal LH and FSH,
Low Vitamin D

The syndrome is a mystery, why do these symptoms persist despite normal T? Why such low levels of 3adiolG despite normal T and DHT levels?


Some, including serious and educated endocrinologists and neuroendocrinologists (in the USA and Europe) who have seen a number of sufferers have come to the conclusion that they have developed a form of acquired androgen insensitivity.

I think there is one better explination, that reflects the fact such symptoms do not persist in those undergoing full androgen deprevation therapy. I will now provide my own theory.

Feedback is very welcome.



Theory

The 'Phantom DHT' theory or the 'Increased Testosterone Metabolism Theory'


(1) Fin inhibits 5-beta-Reductase, which controls the hepatic cyp3a4 enzyme involved in the metabolism of androgens and xenobiotics [1]. Fin is both a xenobiotic and a synthetic androgen [10], thus the reduced cyp3a4 enzyme is taxed to metabolise it.

(2) As fin inhibits its own metabolism there may be v.high serum levels and higher chances of side-effects, especially if taken with other drugs, alcohol.

(3) When fin usage ends, 5-beta-reductase will regenerate thus creating more cyp3a4 enzyme. I theorise this could lead to permanant increase in the metabolation of androgens as well. (this has been discussed in relation to the gulf war syndrome [9])

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

(4) higher testosterone metabolism will lead to more deactivated hydroxytestosterone (especially 6beta-hydroxy testosterone '6bOHT') in serum. [2]

(5) the body should compensate for metabolism with more T production via LH [3] (possibly resulting in altered LH profile)

(6) 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.

(7) I theorise 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 [7], transport throughout the body)

(8) 6bOHT is an excellent substrate of 5aR.[4] 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.

(9) 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.

(10) I propose the product of 6bOHT and 5aR is: 6b-hydroxy-5a-dihydrotestosterone, a deactivated version of DHT [5]

(11) 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 this paper [5]) and because the normal test for DHT seems insensitive (andractim & proviron also detected as DHT for example[8]). Thus the DHT found in blood tests is a 'Phantom DHT'.

(12) 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.

(13) Blood tests will show inhibition of other 5aR reduced metabolites due to 'competion' over 5aR in the liver.

(14) A urinary or blood test to determine the ratio of Hydroxy-Testosterone to Testosterone will discover if this has happened, or prehaps other markers of cyp3a4 induction.[6]

(15) 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)

A pretty solid theory. Symptoms & Blood tests results match with the theory.

Proof of all of this, apart from the 'theories' claims, in the references below.

[0] C19 and C21 5 beta/5 alpha metabolite ratios in su... [J Clin Endocrinol Metab. 1990] - PubMed result
[1] http://onlinelibrary.wiley.com/doi/1...157.x/abstract
[2] The Contribution of Hepatic Inactivation of Testosterone to the Lowering of Serum Testosterone Levels by Ketoconazole — Toxicol Sci
[3] http://www.ncbi.nlm.nih.gov/pubmed/9...?dopt=Abstract
[4] ScienceDirect - Archives of Biochemistry and Biophysics : Inhibition of steroid 5?-reductase and its effects on testosterone hydroxylation by rat liver microsomal cytochrome P-450*1
[5] http://onlinelibrary.wiley.com/doi/1....tb00389.x/pdf
[6] The increase in urinary excretion of 6 beta-hydrox... [Br J Clin Pharmacol. 1989] - PubMed result
[7] I assume there will be some interference as 6bOHT enters a cells cytoplasm to react with 5aR.
[8] I assume hydroxytestosterone does not show up as normal testosterone in a blood test.
[9] Inhibition and Activation of the Human Liver Microsomal and Human Cytochrome P450 3A4 Metabolism of Testosterone by Deployment-Related Chemicals — DMD
[10] http://www.wiley-vch.de/books/sample/3527306501_c01.pdf
[00] Erdemir F, Harbin A, and Hellstrom WJG. 5-alpha reductase inhibitors and erectile dysfunction: The connection
 
Re: Mainstream media finally realizing Propecia can make you impotent

I only know that my androstanediol glucuronide is 1.24 pg/ml (normal range is 12-18).
I only know that my aromatase is 10x what it used to be in my testicles.

I only know that my testicles have lost 85% of their size and they are around 10ml now. (all this process is going on last 6 months)

I only know that i have quit the drug 7 years ago and still have constistent and new side effects popping up from the obstruction of T metabolism to dht.

I only know there is no way out of this, and i swear i have tried hundreds.

P.S. How is it possible that someone on a full dose of aromasin (25 mg/day) a good dose of DHT 5g/day gel, HcG every other day and high levels of Testo get more and more testicular atrophy and in the speed of light??

How is it possible??

How is it possible that not even a full dose of aromasin and dht does not preven my gyno from growing and growing and growin??

How the fuck am i going to survive when my testicles are gone in a few weeks time?? I already have my gun loaded, just don't know where i am gonna point it to
 
Re: Mainstream media finally realizing Propecia can make you impotent

Shaolin said:
I only know that my androstanediol glucuronide is 1.24 pg/ml (normal range is 12-18).
I only know that my aromatase is 10x what it used to be in my testicles.

I only know that my testicles have lost 85% of their size and they are around 10ml now. (all this process is going on last 6 months)

I only know that i have quit the drug 7 years ago and still have constistent and new side effects popping up from the obstruction of T metabolism to dht.

I only know there is no way out of this, and i swear i have tried hundreds.

P.S. How is it possible that someone on a full dose of aromasin (25 mg/day) a good dose of DHT 5g/day gel, HcG every other day and high levels of Testo get more and more testicular atrophy and in the speed of light??

How is it possible??

How is it possible that not even a full dose of aromasin and dht does not preven my gyno from growing and growing and growin??

How the fuck am i going to survive when my testicles are gone in a few weeks time?? I already have my gun loaded, just don't know where i am gonna point it to
Click to expand...


See: https://thinksteroids.com/community/posts/742639
It is taking far more time than you wish, but the case reports are being published.

As for violence, directed outward or inward will not be of benefit to you or others. Stick with it, contact others so affected, and even contact the researchers for information. In this manner, you can help many others as well as yourself.
 
Re: Mainstream media finally realizing Propecia can make you impotent

Maybe I`m off the rail here , but isnt it well known that DHT inbibitors cause these Sx?. Isnt the real issue whether or not the effects are lasting?
 
Re: Mainstream media finally realizing Propecia can make you impotent

Shaolin said:
I have blood tests that show a wacked system after using finasteride - or do you think that someone that converts almost no T to dht is normal ?? .
Click to expand...

Do you have blood tests from before you took Propecia ?
 
Re: Mainstream media finally realizing Propecia can make you impotent

I am so glad I never took Propecia. I actually had a doctor pushing it on me and claiming there were no side effects to worry about except for hair growth. I think I still have the box of generic Finasteride laying around here somewhere (they don't have Propecia here so I would have to chop up 5mg pills). I did try Rogaine for about a week, but my head turned into a dandruff factory.

I have started using generic Nioxin and it is working wonders for me. After just a couple weeks I started noticing hair was growing back in the thinning areas (my hair is buzzed very short). I have been taking photos semi-daily to document it. It may not work for some, but it is definitely working for me.
 
Re: Mainstream media finally realizing Propecia can make you impotent

I really hope and expect this to be the year that Merck's bs finally gets widespread exposure.
Forget even about post-finasteride syndrome for a moment, the company claims that LESS THAN 2% get sexual side effects, they say it was 1.7% v a placebo of .7%. The reality is more like 20% +, I was told this by a uro who prescribes it for cancer and BPH.

I can't think of any other drug that decimates sexual function so much, and for such a trivial purpose, as propecia. At least with anti-d's they are well known to reduce libido and the stats aren't so fixed. Basically, if any guy uses finasteride and isn't acquainted with the facts from forums like this or even the hair loss boards where there are always loads of guys complaining about sides, he's playing Russian roulette with his sex life without being even remotely informed of this.
 
Re: Theory As To Why Finasteride Causes Permanent Hypogonadism-like Symptoms

I am impressed beyond description.
Evenmoreso if this is indeed your original work.
I have read of the intermediate hormones you mention but have never formed a clear picture of the entire androgen conversion process especially the neural aspect; but your reasoning sounds correct.
However, CYP 3a4 is involved in the metabolism of many common drugs as well as the androgens. Furthermore many common drugs as well as Fin inhibit it.
Did I miss the mechanism that causes the special relationship to Fin and CYP3A4?
Ive been wondering about this for a few years now. Yours is the most complete and sensible theioy I`v encountered.
My hat is off to your Sir: Thank you for the information.
zkt


xeno said:
Background

Finasteride is sold for hairloss under the brand name Propecia (fincar, finpecia as generics in India). It is a competitive 5alpha Reductase Type 2 inhibitor, it also inhibits 5beta Reductase. As a result it blocks the production of Dihydrotestosterone in the scalp and prostate and elsewhere, it also inhibits the production of all the 5alpha reduced metabolites in the body, including important neurosteroids in the brain. It also inhibits liver enzymes as a result of its actions upon 5beta reductase.

As a result Finasteride alters the hormone profile to be same as 5AR2 deficient pseudohermaphrodites [0]. Low serum DHT and low levels of other 5aR metabolites.

The members of Propeciahelp.com are the real world examples of the post marketing side effects of Finasteride.

Typically someone with issues will experience erectile dysfunction and loss of libido, known side effects of androgen deprevation [00]. After stopping finasteride things typically get worse, a full endocrine 'crash' followed by a host of symptoms normally found in men with low levels of testosterone, these include fatigue, problems concentrating, depression and even muscle loss plus many more. These side effects are permanant and continue despite all and any attempts to allieviate them (even supra-physiological levels of testosterone will not always work). A low quality of life results for those suffering this miserable condition.

It must be accepted that the 'post finasteride syndrome' is a novel form of iatrogenically induced hypogonadism. The underlying mechanism of which is not known.

Blood tests on these individuals show a consistent set of results:

Low to normal Testosterone levels
Normal DHT levels
Very low 3adiolG levels (the actual marker of intracellular DHT activity)
Low ratios of other 5aR reduced metabolites, especially 5a-Tetrahydrocortisol, but not as low as when using Finasteride.
Effects on DHEA-S, Androstenedione and other hormones
Low to normal LH and FSH,
Low Vitamin D

The syndrome is a mystery, why do these symptoms persist despite normal T? Why such low levels of 3adiolG despite normal T and DHT levels?


Some, including serious and educated endocrinologists and neuroendocrinologists (in the USA and Europe) who have seen a number of sufferers have come to the conclusion that they have developed a form of acquired androgen insensitivity.

I think there is one better explination, that reflects the fact such symptoms do not persist in those undergoing full androgen deprevation therapy. I will now provide my own theory.

Feedback is very welcome.



Theory

The 'Phantom DHT' theory or the 'Increased Testosterone Metabolism Theory'


(1) Fin inhibits 5-beta-Reductase, which controls the hepatic cyp3a4 enzyme involved in the metabolism of androgens and xenobiotics [1]. Fin is both a xenobiotic and a synthetic androgen [10], thus the reduced cyp3a4 enzyme is taxed to metabolise it.

(2) As fin inhibits its own metabolism there may be v.high serum levels and higher chances of side-effects, especially if taken with other drugs, alcohol.

(3) When fin usage ends, 5-beta-reductase will regenerate thus creating more cyp3a4 enzyme. I theorise this could lead to permanant increase in the metabolation of androgens as well. (this has been discussed in relation to the gulf war syndrome [9])

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

(4) higher testosterone metabolism will lead to more deactivated hydroxytestosterone (especially 6beta-hydroxy testosterone '6bOHT') in serum. [2]

(5) the body should compensate for metabolism with more T production via LH [3] (possibly resulting in altered LH profile)

(6) 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.

(7) I theorise 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 [7], transport throughout the body)

(8) 6bOHT is an excellent substrate of 5aR.[4] 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.

(9) 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.

(10) I propose the product of 6bOHT and 5aR is: 6b-hydroxy-5a-dihydrotestosterone, a deactivated version of DHT [5]

(11) 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 this paper [5]) and because the normal test for DHT seems insensitive (andractim & proviron also detected as DHT for example[8]). Thus the DHT found in blood tests is a 'Phantom DHT'.

(12) 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.

(13) Blood tests will show inhibition of other 5aR reduced metabolites due to 'competion' over 5aR in the liver.

(14) A urinary or blood test to determine the ratio of Hydroxy-Testosterone to Testosterone will discover if this has happened, or prehaps other markers of cyp3a4 induction.[6]

(15) 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)

A pretty solid theory. Symptoms & Blood tests results match with the theory.

Proof of all of this, apart from the 'theories' claims, in the references below.

[0] C19 and C21 5 beta/5 alpha metabolite ratios in su... [J Clin Endocrinol Metab. 1990] - PubMed result
[1] http://onlinelibrary.wiley.com/doi/1...157.x/abstract
[2] The Contribution of Hepatic Inactivation of Testosterone to the Lowering of Serum Testosterone Levels by Ketoconazole — Toxicol Sci
[3] http://www.ncbi.nlm.nih.gov/pubmed/9...?dopt=Abstract
[4] ScienceDirect - Archives of Biochemistry and Biophysics : Inhibition of steroid 5?-reductase and its effects on testosterone hydroxylation by rat liver microsomal cytochrome P-450*1
[5] http://onlinelibrary.wiley.com/doi/1....tb00389.x/pdf
[6] The increase in urinary excretion of 6 beta-hydrox... [Br J Clin Pharmacol. 1989] - PubMed result
[7] I assume there will be some interference as 6bOHT enters a cells cytoplasm to react with 5aR.
[8] I assume hydroxytestosterone does not show up as normal testosterone in a blood test.
[9] Inhibition and Activation of the Human Liver Microsomal and Human Cytochrome P450 3A4 Metabolism of Testosterone by Deployment-Related Chemicals — DMD
[10] http://www.wiley-vch.de/books/sample/3527306501_c01.pdf
[00] Erdemir F, Harbin A, and Hellstrom WJG. 5-alpha reductase inhibitors and erectile dysfunction: The connection
Click to expand...
 
Re: Mainstream media finally realizing Propecia can make you impotent

zkt said:
Did I miss the mechanism that causes the special relationship to Fin and CYP3A4?
Click to expand...

The special relationship is this; Finasteride inhibits 5beta-Reductase (not just 5Alpha-Reductase). 5beta-Reductase controls the CYP450 3A4 enzyme responsible for the metabolization of both xenobiotics and sex steroids.

Finasteride is a xenobiotic (and also a synthetic androgen). Theoretically Finasteride could even inhibit its own metabolism.

When Finasteride usage ends, 5beta-Reductase will regenerate, there will therefore be 'more' CYP450 3A4. I would suggest that the increase in an enzyme that has been both inhibited and heavily taxed to metabolize an androgen could lead to its permanant induction/up regulation. (---remember, something has been permanantly changed---)

If CYP450 3A4 is now metabolizing more testosterone, the effect will not be more testosterone urinated out but more weak/deactivated testosterone in the blood. Enough deactivated testosterone is a natural anti-androgen as it will impede the androgenic activity of normal testosterone by competing for the Androgen Receptor and binding/not binding to SHBG etc.

The result may be a new form of hypogonadism.

This validity of this theory is easy to determine via a blood/urine test.
 
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