FINASTERIDE: PFS MECHANISM (detailed)

[PAS]

Don't think anyone posted this yet
Finasteride - A Patient Case Exploring the Downstream Effects of a 5α-Reductase Inhibitor

Finasteride in relation to NADPH while bound to 5-beta-reductase, note the distance between the hydride on NADPH (purple) and the sp2 hybridized carbon on finasteride (green).
Finasteride reduces intraprostatic and serum DHT, reducing the growth rate, halting growth completely, or even reducing the size of the prostate.2 The downstream effect of 5α-R inhibition by finasteride results in altered gene expression resulting in a reduction of the expression and thus the number of androgen receptors in prostate epithelial cells. The reduction of androgen receptor expression is also correlated with prostatic epithelial cell atrophy which may be contributory to BPH relief, specifically a decrease in size.

The conversion enzyme 5α-R has three isozymes identified as 5α-R1, 2, and 3 with each performing similar functions in different tissues.4 The 5α-R2 enzyme is shown to be responsible for a majority of DHT synthesis, as opposed to the other isozymes.4
Originally, it was thought that finasteride was a competitive inhibitor with affinity for 5-α-reductase type 2, but it has been recently shown that it acts as a mechanism-based inactivator of 5α-R2. 5 This mechanism works by NADPH donating a hydride to the 1,2-ene double bond of finasteride, which then allows NADP+ to covalently bind to dihydrofinasteride at the enzyme active site, forming a NADP+ - dihydrofinasteride complex. 5 It is this bisubstrate that has affinity for 5α-R2. 5 Refer to Figure 3 for a stepwise diagram showing the mechanism-based inactivation of 5α-R2 by finasteride.

After exploring the mechanism of action of finasteride, there are possible areas of improvement in order to decrease side effects. The downstream side effects could potentially be reduced by increasing specificity for 5α-R2 so there are fewer interactions with 5α-R1. The most direct means of improving specificity would be to obtain an x-ray crystallography structure of finasteride in a 5α-R2 enzyme. The binding of finasteride to 5β-R does not result in a reduction reaction, while the binding of finasteride to 5α-R does result in a reduction reaction. As these two enzymes utilize the same cofactor, these differences in reactivity must be due to differences in enzyme structure. As the names of the two enzymes suggest, they both reduce double bonds, but add hydrogens to distinct faces of the steroid skeleton. Obtaining a structure of 5α-R in complex with finasteride and cofactor may elucidate the interaction between finasteride and 5α-R.5 This would allow for specific investigation of molecular changes that could be made to finasteride in an effort to improve specificity for this enzyme.

Finasteride binds selectively to 5α-R2 significantly reducing the number of adverse side effects seen. One area of improvement may be in reducing the effects of sexual dysfunction including decreased libido, impotence, and ejaculation disorder. These side effects may occur because 5α-R2 inhibits the conversion of testosterone to DHT. A secondary explanation of side effects may be the ability for small amounts of finasteride to cross the blood brain barrier. In keeping the effectiveness of the drug, changing selectivity of binding in the prostate is not a good idea. However, one proposed alteration to the molecular make up of finasteride to reduce these side effects may be to add a more polar group or steric bulk to the amide nitrogen on finasteride. In doing so, it would potentially decrease the drug's ability to cross the blood brain barrier leading to less binding in the hypothalamus, pituitary and cerebral cortex.

Summary
The affinity of finasteride with 5-beta-reductase is a result of the orientation of finasteride in the enzyme active site and H-bond interactions between finasteride and 5-Beta-reductase. Finasteride binds several reductase enzymes, with the significant clinical effects deriving from 5-alpha-reductase enzymes. The side effects of sexual dysfunction, and hypotension must be weighed against the benefit of the medication when determining its use in patients with BPH.

This is amazing! We are finally understanding the mechanism of these substances! I suggest everybody to read this. On a sidenote, the authors talk about altering fin in such a way that it doesnt cause side effects when new people take it. I hope they devise a way to heal people already suffering from the syndrome.

Also I hope somebody starts looking into isotretinoin. I dont see any research being conducted into that.

 

[IHateFin]

This is amazing! We are finally understanding the mechanism of these substances! I suggest everybody to read this. On a sidenote, the authors talk about altering fin in such a way that it doesnt cause side effects when new people take it. I hope they devise a way to heal people already suffering from the syndrome.

Also I hope somebody starts looking into isotretinoin. I dont see any research being conducted into that.

i read that accutane is a retinoid (i think i spelled that right) a type of Vitamin A. im sure thats nothing new, but it blew my mind.

 

[PAS]

Yeah its related to vitamin A. people figured out that vit A overdose kills acne but in the process it kills the person also. Isotretinoin is the answer to killing acne without killing the person. Don't quote me though I am pretty sure it has killed many haha

 

[IHateFin]

Yeah its related to vitamin A. people figured out that vit A overdose kills acne but in the process it kills the person also. Isotretinoin is the answer to killing acne without killing the person. Don't quote me though I am pretty sure it has killed many haha

i actually read that someone did die after taking accutane 12 hours later. not sure which drug is worse, but both seem to have taken lives technically even if the lives fin takes are at the hands of the user

 

[PAS]

I meant it killed people by causing PAS but once I read in 2010 that a teen got blind after taking it (ofcourse no proof), so your case might be true . Bro can you confirm that 4AD is androstenedione. Did it cause any benefits because I have only seen you talking about androsterone

 

[IHateFin]

I meant it killed people by causing PAS but once I read in 2010 that a teen got blind after taking it (ofcourse no proof), so your case might be true . Bro can you confirm that 4AD is androstenedione. Did it cause any benefits because I have only seen you talking about androsterone

its said to be 4-Androstènediol which i believe converts to 5 androstenedione? i read this before in detail, but i cant find the place i read it in so i cant confirm right now. its altered DHEA which i think normally converts to 4 androstenedione and 4AD converts to 5 androstenedione.

this is my third Randro cycle and first time i have added 4AD with it, but the effects are day n night and seem much more natural as far has actual feeling of homeostasis goes. my log hasnt been updated for like a week, but it details some of the differences i felt. some benefits were like more natural libido, feeling super gym hungry, HUGE mood bosts and empathy and stress management feelings. like i would brush things off like they were nothing just as i used to prefin. also arm hair changes and increases also mitigated the reduction of arm hair that Randro givers me. stuffg like that. today will most likely be my last day taking them and its been about 2 1/2 weeks on them.
maybe too early to hop off, but Randro ramps my metabolism way too much and i know im being suppressed more than usual with just an Randro cycle.

 

[jacknap]

has anyone had benefits these days from pregnenalone? anyone try that post ru?

never used RU. But I used preg. Preg when I was at my worst helped me sleep better and also gives energy. Nothing for libido though. At higher doses 150mg I got aggression but sweet spot for me was 60mg

Tubzy used to use it as well. Gbold says not to use it if I recall correctly because it saps your iron like crazy.

 

[ruprmurdoch]

I'm not Pfs, but for me, finasteride/accutane/vitamin a can cause empty sella syndrome/idiopathic intracraniall hypertension (feeling like somthing pressure / explode inside you head) in the same way like injected testosterone or Progestin IUD. You pituitary stop work and beacuse of that there is more space for cerebrospinal fluid, which in some people is hard to remove during transverse sinus stenosis. Myself have lumbar puncture drop this year, and change is significant.I feel 50% better. I think one more with addition of pine pollen and will be cured.

 

[IHateFin]

guys check this out:

Do not stop finasteride cold turkey! A strong argument to taper to very low doses.

"
I'm going to expand on 3. first because this will explain why tapering might do anything at all:

I apologise for the endocrinology 101 stuff but it's important:

The most studied hormonal axis in man is the hypothalamic-pituitary axis (HPA axis) and it acts as a good model for other axes like the hypothalamic-pituitary-gonadal axis (HPG axis).

Simple pictures of both below will show you how similar the mechanics are.



For the HPA axis, the hypothalamus secretes CRH which stimulates the pituitary gland to produce ACTH which in turn stimulates the adrenal gland to produce cortisol (CORT). Levels are roughly maintained by feedback inhibition of cortisol to the adrenal gland and hypothalamus.






For the HPG axis, the hypothalamus secretedGnRH which stimulated the pituitary toproduce LH and FHS which in turnsimulated the testes to produce a number of gonadal hormones includingtestosterone. Testosterone and other gonadal hormones (like dihydrotestosterone(DHT)) produce feedback inhibition to the pituitary and hypothalamus.

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Glucocorticoids (drugs that act like cortisol which is the human glucocorticoid) are amongst the most widely used drugs in medicine. When people have inflammatory disorders – like severe arthritis or severe asthma they often receive glucocorticoids (because it is a potent anti-inflammatory). These glucocorticoids (like prednisone or dexamethasone - there are many different trade names) are man-made and are more potent versions of cortisol.

So they do what cortisol does only stronger. The beneficical part of this is they strongly suppress inflammation (good treatment for the arthritis, asthma etc). They also produce a number of side effects.

But the main thing of interest here is that these synthetic glucocorticoids strongly suppress the HPA axis. That is, they strongly inhibit the secretion of CRH and ACTH at the hypothalamus and pituitary and therefore shut down the secretion of cortisol from the adrenal gland. That is totally fine because you have a huge amount of these glucocorticoids in your body when you're being treated so you don't need your own supply.

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But when you stop it’s a different story.

It has been known for years (since the 1960s) that if you stop these synthetic glucocorticoids abruptly then the HPA axis tends to stay shut down. Studies vary as to what percentage of people will experience this - some suggest 100% (for at least a small period of time if the dose has been big enough for long enough).

What varies between people is how long the axis stays shutdown for. For some people there is recovery in a couple of weeks, others four weeks, some it takes as long as months.

What influences this? How high the dose of glucocorticoids were, how long they were given for, how abruptly they were stopped.

Ok, so what's this got to do with finasteride?

Finasteride lowers levels of DHT so if anything it should increase the activity of the HPG axis (because there is less feedback inhibition), right?

There probably is an upregulation of the sensitivity of the HPG axis while you are on the drug (this is why those studies of androgen receptors in foreskin tend to show increased levels of androgen receptors, etc).You have levels of DHT that are around 20-30% of usual levels meaning there is less signal hitting the system and hormonal systems normally upregulate to make up for this (this is how biochemistry generally works).

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OK, but what's this got to do with dexamethasone?

When you stop finasteride, your levels go back to approximately normal over 2-4 weeks (see graph below).

This is a study that shows men being given different doses of finasteride each day for two weeks. At day 14 they stopped getting the drug. Their serum DHT levels were measured (at intervals) for the 14 days of receiving the drug and for 16 days after stopping, giving a total of 30 days.

You can see that after day 14 their levels of DHT rise back towards normal over this period. Extrapolating the graph you might guess that their levels of DHT would return to normal in about another 2 weeks, meaning they would probably get back to normal about 4 weeks after stopping the drug.





That sounds good, right? It is and that is why people likely report feeling a lot better a week or so after quitting (probably the time taken for enough DHT to be back in the system for people to be able to feel the difference) and report their side effects diminishing and then disappearing. In fact, some people report feeling fantastic.

One thing to point out here is that hormone levels (like DHT) coming back from their reduced levels is not the same 80% increase as on the way down. Now you are going from 20-30% of normal levels back up to 100%. This is actually a four or five fold increase. That is a massive increase in hormone levels. It is kind of like getting a big dose of dexamethasone - only this affects your hpg axis.

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It is plausible that this rapid increase in DHT (not forgetting all the other hormones that are influenced by 5AR) has the same effect on the HPG axis as dexamethasone has on the HPA axis. That is, the surge in DHT causes shut down of the HPG axis.

This would fit with the improvement felt by men coming off it over 7-14 days (approx) followed shortly after by a 'crash'.

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What I am suggesting is that the coming off finasteride might be an important factor in causing the post-finasteride syndrome.

Logically speaking there are basically two broad possibilities for what causes this syndrome:
(1) Something the drug does to you while you are on it (affects neurosteroids, the androgen receptor, etc, etc, hypotheses abound)
(2) Something that happens upon stopping it

(or perhaps a combination of (1) and (2))

The reason why (2) seems to be plausible is the time line of events that most men report -

- experiencing side effects while on the drug
- a resolution of side effects a few days after stopping
- followed by a 'crash' a few days or weeks after this
- the symptoms following this 'crash' are variable in severity and variable in how long it takes to resolve. They also seem to be worse than the side effects experienced on the drug AND they seem to have a different hormonal signature (ie in post-finasteride syndrome men seem to have a hypogonadotrophic hypogonadism, while men on the drug have low DHT (of course) and a slightly higher than normal testosterone and basically normal LH and FSH)


This time line of symptoms seems to fit the shutdown of the axis cause by a surge in returning hormones.

I think (1) is important because it probably increases the sensitivity of the system to DHT and other hormones, thus creating a perfect storm - a rapid and large increase in hormone affecting an already overly sensitive system; making it more likely to be shut down."

 

[Aflac94]

How could we accurately tapper Finasteride if low doses inhibit the enzyme non-reversably (non-competitively)

 

[Aflac94]

For the people with HPA suppressed by taking steroids then stopping cold turkey. They would just get back on the steroids and taper down slowly. Would be a nice idea for us. But one we are all scared (appropriately) and two Finasteride inhibits an enzyme non-comparatively and therefore drops DHT and other downstream metabolites by a fixed percent even at pretty low doses. So to take Finasteride again at 1 mg, then half, then a fourth would be tapering the pill but the hormone levels would not be slowly returning even they you are taking less. Because the enzyme is blocked the same at all those dosages. You have to get really low .15mg, then .2, then .02, etc. but would it actually gradual increase in the hormone levels? Or just stop inhibiting enzyme at such a low dose. So you see we don’t know or cannot achieve the doses required for a taper. Plus how may days apart to take the dose since it blocks enzyme for certain number of days. I would try this at some point if we could figure out a dose plan if I never recover with this other stuff

 

[Helen]

Some people have high dht and highish and normal testosterone after quitting. We have 2 groups here, one with low dht and one with high dht. and high testosterone.

If the body were too sensitive to DHT why would it keep DHT high. It would just kill the axis. Unless body upregulated pentose like crazy and keep pushing NADPH on you after quitting Fin. And even without LH, body producing testosterone and DHT. In this cases taking NADPH would downregulate everything. but the only NADPH for sale which I saw was on alibaba.

I mean if Fin kills NADPH. then to undo this you take NADPH.

I agree that finasteride shouldn't be just dropped

 

[Yura]

In this case simple DHT would work to make DHT less sensitive. Why go on fin at all. ( it will lower DHT again when you go on it) Just increase NADPH and be done with it. Huge doses of b1 and b3.

FIn binds NADPH. NADPH converts testosterone to DHT and also converts cholesterol to pregnenolone ( this is stumulated by LH) So to undo fin , you just could just increase NADPH a lot and drop it . What is in the body increases NADPH = pentose. What does it work on. NAD and thiamine

Also , HPG is not supressed in all cases/ if you have constantly high DHT levels and testoterone in 50% cases. If HPG were suppressed you would have low testosterone and low DHT. And we have 2 cases here. one group of people has high testesterone and high DHT. ( nothing is suppressed in this group) Another group has low testosterone and low dht.( NADPH is still down)

I guess all this depends on which enzyme fin suppressed more, 5 beta or 5 alpha. And you just do the opposite after quitting.

What are huge doses of B1 and B3? Also is form of the vitamin important? Is thiamine hcl and inositol hexanicotinate ok?

 

[Helen]

What are huge doses of B1 and B3? Also is form of the vitamin important? Is thiamine hcl and inositol hexanicotinate ok?

I deleted this message LOL. You dont have post finasteride.

100 mg is enough dosages. I rec to you to do a hairtest. otherwise you will be trying stuff for 10 years.

Sometimes you need to give NADPH to downregulate NADPH production. This is probably true with people with high DHT and high testosterone

Or you can try stuff that needs NADPH to downregulate NADPH. like andro, or xylitol stuff like that. This will down regulate pentose and will cause NADPH to be produced less.

If people take steroids. they usually downregulate NADPH production. |But if fin is what binds NADPH,( makes it inactive) then I would assume body will try to upregulate NADPH production

 

[freeflow]

I deleted this message LOL. You dont have post finasteride.

100 mg is enough dosages. I rec to you to do a hairtest. otherwise you will be trying stuff for 10 years.

Sometimes you need to give NADPH to downregulate NADPH production. This is probably true with people with high DHT and high testosterone

Or you can try stuff that needs NADPH to downregulate NADPH. like andro, or xylitol stuff like that. This will down regulate pentose and will cause NADPH to be produced less.

If people take steroids. they usually downregulate NADPH production. |But if fin is what binds NADPH,( makes it inactive) then I would assume body will try to upregulate NADPH production

Could you suggest another steroid which could be taken for this goal and which is not androsterone? I really feel shit, worst of the worst when i take r andro but i had the snap back so i know its helping. But the depression from the low estrogen it causes is unbelievable. Water fasting is easier compared to this state when im on r andro.

 

[Helen]

Could you suggest another steroid which could be taken for this goal and which is not androsterone? I really feel shit, worst of the worst when i take r andro but i had the snap back so i know its helping. But the depression from the low estrogen it causes is unbelievable. Water fasting is easier compared to this state when im on r andro.

I thought you loved r andro. You have POIS right? Why dont you try to take 2-5mg of vitamin B1 daily. And see how your POIS is doing

 

[freeflow]

I thought you loved r andro. You have POIS right? Why dont you try to take 2-5mg of vitamin B1 daily. And see how your POIS is doing

The r andro snap back was awesome but being on it is horrible. Yes i have POIS as i crashed from orgasm but i took finasteride for 1.5 years. Then i recovered from my crash for 2 days and crashed with orgasm again. I can try the b1 daily but i want to cure myself finally. The r andro snap back gave me back a lot of motivation and enjoyement but slowly faded away.

 

[Helen]

The r andro snap back was awesome but being on it is horrible. Yes i have POIS as i crashed from orgasm but i took finasteride for 1.5 years. Then i recovered from my crash for 2 days and crashed with orgasm again. I can try the b1 daily but i want to cure myself finally. The r andro snap back gave me back a lot of motivation and enjoyement but slowly faded away.

Try 2-5 mg Vitamin B1. for a week. and dont take anything else. And tell me how is your motivation after that. And how is your POIS

 

[freeflow]

Try 2-5 mg Vitamin B1. for a week. and dont take anything else. And tell me how is your motivation after that. And how is your POIS

I will report back, can start this on tuesday. I will do nothing else just healthy eating and exercise.

 

[r4ndom]

Finasteride is a progestin which does not convert to cortisol or metabolites like progesterone does. Since it does not convert to metabolites as progesterone it lowers NADPH. This takes down 5 alpha reductase. Also since progestin does not convert into cortisol, it puts pressure on cortisol and this weakly inhibits the enzyme that breaks down cortisol which is 5 beta reductase. Most of the symptoms while on fin are coming from inhibiting 5 beta reductase enzyme. the higher dosage of Fin , the more you inhibit this enzyme. and the higher cortisol goes.. 5 beta reductase is the enzyme which is responsible for bile acids. This is why progestins stop bile production. Actually progesterone in certain cases could do the same.

So while you are taking finasteride, you lower NADPH and you lower NADP , you stop 5alpha reductase and you stop 5 beta reductase. Most of the symptoms come from 5 beta reductase . And the higher fin dose the more you inhibit this enzyme. This is why if you found the optimal dosage not to inhibit this enzyme you would be only inhibiting 5 alpha reductase and would not have problems while on fin.


Now. After you come off fin. I assume. your NADPH production spikes back up really high. Since fin was blocking it. while you were on it. . This is why you see high DHT in some of the PFS guys. This high NADPH inhibits 5 beta reductase even further. Since 5 alpha reductase works on NADPH, but 5 beta reductase's end product is NADPH. SO when you come off fin, your NADPH production is high , and 5 beta gets inhibited even more. Your bile acids are zero now. your fat solubles are zero, and also your cortisol is high and aldo is high , since 5 beta reductase does not break them down. You are in alkalosis. and your fat digestion is zero.

So once again. When you are on fin , since fin raises metabolism but does not convert to cortisol like progesterone should have. It lowers both 5 alpha and 5 beta reductase.

But when you go off fin, this increases 5 alpha back to normal and beyond , but it totally inhibits 5 beta even more since NADPH decreases 5 beta


This is why andro works( inhibits 5 alpha) , 5 alpha inhibitors work, licorice works( increases cortisol) and this pushed 5 beta higher, dexamethasone , and progesterone. amino acids, zinc finger , RU lowers metabolism and increases cortisol and 5 beta increased . they all decrease need for cortisol and this increases 5 beta reductase.

So PFS is a imbalance between NADP and NADPH after you come off FIN. NADPH is what 5 alpha works on, and NADP is what 5 beta works on. NADPH is also made out of NADP. So this makes 5 beta and 5 alpha 2 enzymes that go opposite of each other. NADP to NADPH ratio. when NADP high 5 beta is higher, when NADPH is high , 5 beta is lower.


We will be trying many things to put 5 beta back online.





This is basically more precise explanation of the receptor theory but from enzymes view.

For those who are still taking fin, you can always adjust dosage so you dont inhibit 5 beta reductase too much , and this way you will be on fin with minimal sides . If you adjust the dosage lower, this will grow even more hair since you wont be experiencing protein wasting hairloss like in hyperthyroidism. Fin is just uncontrollable progesterone. Fin does not convert to cortisol, but causes the rise of metabolism. When metabolism rises progesterone converts to cortisol to make more sugar and aminos. But fin cant convert , and if you take too high of a dose it is like being hyperthyroid. Puts too much pressure on cortisol and closes down 5 beta reductase with bad sides coming from 5 beta reductase

IF you test your 5 beta reductase and make sure it is good, you can stay on fin without sides


For people who went off the fin . @TubZy and I are trying different protocols to fix this situation more precise. But you have many ways to manipulate NADP NADPH ratio, knowing this mechanism that we outlined above

I hope this explains why people feel bad on anything that increases 5 alpha reductase.

and for those who still think what andro does - just look a this chart. Hormonal Charts & Pathways
as you can see andro inhibits 5 alpha reductase. Because androstenedione converts to androsterone via 5 alpha reductase.


@mattyb

ive gotten my aldosterone tested, it is not high, it is low