Prostate biopsy?

[Enden]

Would anyone here volunteer to do this? The sample(s) could probably be used to analyze the 5AR Type 2 enzymes - to see if they’re still working, or are defect.
I’m sure the community will finance it.

I’ve been reading some more about dihydrofinasteride, and it worries me. Mostly because my experiments suggest that there is a problem with the conversion of testosterone to DHT - which leads to a severe problem with estrogen dominance. Propecia is obviously a steroidal drug, and the reductase enzymes converts finasteride to dihydrofinasteride. The result is an enzyme/NADP-dihydrofinasteride complex, and it has a half-life of 30 days in body temperature. The complex decomposes over time, and dihydrofinasteride appears to be the only thing that’s left. It sounds like finasteride is a suicide inhibitor - which means that the body has to produce new reductase enzymes. Now, the question is whether or not the body produces new enzymes at a constant rate, or if the enzymes which are damaged have to decompose before they’re replaced with new enzymes. The metabolism is individual, and maybe the process is a lot slower in those who develop PFS. If that’s the case, we should investigate compounds that are able to speed up the process, maybe by disrupting the membrane - as it’s referred to as a membrane-bound enzyme inhibitor complex.

What is known about dihydrofinasteride, btw? How does it affect the body?

[spstriken]

@Enden

Would anyone here volunteer to do this? The sample(s) could probably be used to analyze the 5AR Type 2 enzymes - to see if they’re still working, or are defect.
I’m sure the community will finance it.

I’ve been reading some more about dihydrofinasteride, and it worries me. Mostly because my experiments suggest that there is a problem with the conversion of testosterone to DHT - which leads to a severe problem with estrogen dominance. Propecia is obviously a steroidal drug, and the reductase enzymes converts finasteride to dihydrofinasteride. The result is an enzyme/NADP-dihydrofinasteride complex, and it has a half-life of 30 days in body temperature. The complex decomposes over time, and dihydrofinasteride appears to be the only thing that’s left. It sounds like finasteride is a suicide inhibitor - which means that the body has to produce new reductase enzymes. Now, the question is whether or not the body produces new enzymes at a constant rate, or if the enzymes which are damaged have to decompose before they’re replaced with new enzymes. The metabolism is individual, and maybe the process is a lot slower in those who develop PFS. If that’s the case, we should investigate compounds that are able to speed up the process, maybe by disrupting the membrane - as it’s referred to as a membrane-bound enzyme inhibitor complex.

What is known about dihydrofinasteride, btw? How does it affect the body?

Good. I this is what should have been asked 12 years back. Yes this biopsy will give pin pointed answers.

[Enden]

What’s a bisubstrate analog inhibitor, btw? An abstract to a study, said that the complex is an extremely potent bisubstrate analog inhibitor.

[Enden]

In clinical trials, the efficacy of finasteride far exceeded expectations based on its perceived potency against the human prostate enzyme, for which finasteride was first thought to be a simple, rapidly-reversible inhibitor with Ki =26 nM. For instance, circulating concentrations of finasteride comparable to this Ki actually reduced levels of dihydrotestosterone to values approaching those found in individuals genetically deficient in the prostate isozyme, and as long as two weeks were required for dihydrotestosterone to return to basal levels after withdrawal of finasteride (Stoner, J. Steroid. Biochem. Molec. Biol. 37: 375-378 (1990) and Gormley et al., J. Clin. Endocrinol. Metabol. 70: 1136-1141 (1990)). A closer evaluation of the interaction of finasteride with the human prostate (type 2) isozyme led to appreciation that finasteride and certain analogs thereof are slow-binding inhibitors, such that their potency had been mistakenly underrated in standard fixed-time assays (Harris et al., Proc. Natl. Acad. Sci. U.S.A., 89: 10787-10791 (1992)). Independently, Faller et al., also recognized the inconsistency. Faller et al., have recently described in detail the slow-binding behavior of finasteride, reaching the conclusion that finasteride binds to the human prostate isozyme with a rate constant of 2.7×105 M-1 s-1 to form an essentially irreversible enzyme-inhibitor complex with a Ki <<1 nM (Faller et al., Biochemistry 32: 5705-5710 (1993)).

(…)

The enzyme-inhibitor complex decomposes spontaneously with a half life of about 1 month, and the dihydro-3-oxo-4-azasteroid inhibitor is the only product recovered.

(…)

The method of the present invention provides for an inhibitor which displays the characteristics of a suicide inhibitor without covalently modifying the enzyme. Generally, “suicide inhibitors” are inhibitors that deactivate the enzyme by covalent modification of the enzyme protein. Such “suicide inhibitors” are not favored as pharmaceutical agents because the covalently-modified enzyme may be recognized by the immune system of the treated organism as foreign matter and trigger an undesirable immunological response. The non-protein bound adduct of the present invention eliminates the possibility of such an undesirable immunological response.

The long-lived enzyme-bound 3-oxo-4-azasteroid-NADP adduct of the present invention provides further advantages in clinical settings. The method of the present invention provides for sustained inhibition of 5α-reductase even when the dose regimen is interrupted and the levels of the 3-oxo-4-azasteroid drug having a 1,2-double bond drop, as when the patient misses a dose. In this situation of interrupted dosing, 5α-reductase that had been inhibited cannot recover from the inhibition and additional drug is required to inhibit only the 5α-reductase that has been newly synthesized by the patient.

(…)

In practice, the halflife of the enzyme-inhibitor complex is so long that the inhibition is for all intents irreversible, and release of the inhibitor probably occurs by death of the enzyme rather than turnover to regenerate catalytically competent enzyme.

This is from a Merck patent filed in 1997, labeled Irreversible inhibition of human 5α-reductase

So it’s not a traditional suicide inhibitor, but it destroys the enzymes. It’s mentioned that the DHT level returns to baseline value within 2 weeks, which suggest that reductase enzymes should be produced at a constant rate, but what if this doesn’t happen in our case?

[Enden]

People are supposed to recover within 2 weeks after stopping the treatment with Propecia.
Slow metabolism (synthesis of new reductase enzymes) may explain why some people recover months or years later without a proper explanation.

If this is the case, I imagine that a prostate biopsy would reveal a ratio between functional and defect 5AR Type 2 enzymes. It would probably be different in every member in here. The ratio would tell us how badly affected each one of us are, and a series of biopsies, would give an estimation of how long it takes to recover in each case. Treatments to speed up the recovery process can be investigated, if this turns out to be the root cause.

[jeff12]

This is all very interesting and definitely worth a shot, however the damage that could result from a biopsy would need to be looked at before someone is willing to be put under the knife. I wouldn’t even feel right in asking the worst sufferers to do so.

However, there are users on here that do not have DHT levels that are below or above range. This would imply that their 5 alpha reductase enzymes have been replaced and are functioning correctly, would it not? I think the sexual side effects are all centered around the prostate so maybe in doing the biopsy it would be worthwhile testing for pathogens and anti-bodies deep within the tissue…that’s where I think the real value will come from this…would be able to give a definitive answer to whether this is related to prostatic inflammation.

Just my 2 c…

I just hope one day there will be an answer to this god awful syndrome!

[Enden]

They’re using a device with a tiny needle to collect samples. I don’t think it’ll cause any problems.

No one, or at least only a few people knows what their baseline DHT level is. It’ll most likely be within the “normal range”, but it can still be a lot lower than it should in your case. Keep in mind that 5AR Type 1 is responsible for around 30% of the DHT level.

[Brainbug]

@Enden

They’re using a device with a tiny needle to collect samples. I don’t think it’ll cause any problems.

No one, or at least only a few people knows what their baseline DHT level is. It’ll most likely be within the “normal range”, but it can still be a lot lower than it should in your case. Keep in mind that 5AR Type 1 is responsible for around 30% of the DHT level.

I had my DHT levels before and after. Now they are totaly like before… and the more they went up, the worse I feel. Anyway, the only thing that counts is the reaction on the cell and the DNA.

Er du fra Norge? Hilsen fra Tyskland

[Mark_Benson]

Does this have a prostitis angle to it?

Mark

[jeff12]

I think it could be useful in providing a lot of answers, in terms of enzyme activity and prostatitis etiology…

This really could provide the answer but if everything is given the OK then we are back to square one! I would suggest more than one biopsy is required to give any definitive answers.

[Enden]

So, who would volunteer to be a test subject? I’m currently testing another hypothesis with drug treatment, but I will do a prostate biopsy as a last resort. I’m mainly interested in the 5AR Type 2 enzymes, because I know that I have a problem with DHT deficiency. We could test for everything that comes to mind, but it may require a lot more subjects…

I believe that the prostate holds some answers to PFS.

[Enden]

Keep in mind that the intracellular level of DHT may be too low, despite the fact that serum DHT level is within the normal range. DHT is a paracrine hormone…

Abstract
Androgen action in sexual tissues, especially skin and the prostate, is expressed by dihydrotestosterone (DHT) acting at the nuclear level. Dihydrotestosterone in the circulation and target tissues is almost solely derived from the peripheral conversion of secreted testosterone (T) in men and androstenedione in women. The general pathway is testosterone----DHT in equilibrium with androstanediol (3 alpha diol). However, a number of studies suggest that blood DHT or 3 alpha diol are not reliable indicators of peripheral DHT formation. This is particularly suggested by discrepancies in the specific activity of DHT in blood and urine following infusion of labeled DHT, suggesting that total body DHT formation is not reflected by blood levels. Thus, DHT should be thought of as a paracrine hormone formed and acting primarily in target tissues. 3 alpha androstanediol glucuronide (3 alpha diol G) is a major metabolite of DHT. An important site of its formation is the skin. Levels in blood and urine are increased in hirsutism and acne, and blood levels closely parallel pubertal development. 3 alpha diol G levels are especially increased in adrenal disorders of androgenicity such as andrenogenital syndrome; it is also a good marker of response to therapy. Levels are reduced in various forms of male pseudohermaphroditism. 3 alpha androstanediol glucuronide appears to be the best marker available of DHT formation in target tissues such as skin.

Dihydrotestosterone is a peripheral paracrine hormone.

Most people here have low 3a-diol-g…

[mlb]

This wouldn’t explain low T levels though, would it?

[Mark_Benson]

I think this is interesting and so long as its safe< I am ready to volunteer. My DHT serum levels are at top of the limit but under it - 3400 on a scale of 700 - 3404 …Is there a way to check 3 G diol in Canada?

Mark

[Enden]

@mlb

This wouldn’t explain low T levels though, would it?

Yes it would. DHT is an important estrogen antagonist. Estrogen has a strong, negative effect on the HPTA. The DHT- and estradiol level raises along with the testosterone level. If you have a lot of defect 5AR Type 2 enzymes, DHT won’t be able to keep up, and when estradiol activity increases too much in relation to DHT activity, it’ll exert negative feedback and cut the testosterone production before it should. I guess that people who developed secondary hypogonadism have more defect enzymes than those who didn’t. However, DHT deficiency will still cause symptoms of hypogonadism; 1) because it’s a powerful androgen. 2) it’s an important estrogen antagonist. 3) it affects the free testosterone level.

We have to stop looking at the serum DHT level, because it won’t tell us anything about intracellular activity - which probably is the issue here. 3a-diol-g is a good marker if I remember correctly, and most people here have a low level due to DHT deficiency. I’ve just done an experiment which proved that there isn’t a problem with the DHT = 3a-DIOL conversion.

[Enden]

@Mark_Benson

I think this is interesting and so long as its safe< I am ready to volunteer. (…) Is there a way to check 3 G diol in Canada?

Mark

Good! A blood test of androstanediol glucuronide is used to diagnose hirsutism, and it should be available in any clinic.

[NewYorker]

This seems like and old thread, but has anyone as of yet preformed a prostate biopsy? Do we know of any tests of this, even on mice, before I ask my doctor to refer me for this test?

[Scott.H]

This is an amazing read: http://www.freepatentsonline.com/5962442.html

Detailed breakdown on how finasteride works from the horses mouth.
So is it safe to say that our 5a enzyme has been permanently altered by the drug? We did not snap back to normal after 2 weeks. There must be a way to reverse this.

[Baz44uk]

From reading that information i can’t help but assume a prostate biopsy Could be a valuable way to determine the mechanism behind persistent / permanent side effects of Finastetide.
I also have my own theories too that the problem is to do with the auto immune system.
I’ve come across a few people that have persistent side effects and have auto immune system issues which can be determined by genetic markers via blood tests.
The reality is the whole problem is far to complex for the average Joe to solve.
The human is so complex its is still baffling scientists today.
It’s a strange World really we can create so many cures for disease that by cureing one disease we sometimes create another.
One of the biggest problems finasteride sufferers face is that the side effects tend to have sexual impacts on people which alot of guys struggle discussing at the best of times now add the fact that alot of guys cycle steroids or drink heavily smoke heavily or smoke take snort or inject one of a number of recreational drugs that Could lead to sexual problems it easy to dismiss this innocent pill for physical or even psychological issues.
One day all will known .

[NewYorker]

Thank you. Would you know what blood tests would identify the genetic markers would identify the auto immune issues?