The Dark Side of 5α-Reductase Inhibitors' Therapy: Sexual Dysfunction, High Gleason G

[cthulhu2.0]

From an interesting article I read:
Stephen E. Wolverton, MD, a professor of clinical dermatology in the Department of Dermatology at Indiana University School of Medicine, conducted a review of finasteride studies in order to determine the accuracy of the new studies reporting permanent sexual side effects and was not able to come to as definitive a conclusion. In particular, Dr. Wolverton looked at a study by McClellan and Markham (1999) that included nearly 1,900 men between 18 and 41 years of age randomized to either finasteride or placebo.[SUP]3[/SUP]
According to Dr. Wolverton, the study by McClellan and Markham demonstrated that there was a slightly increased risk of sexual side effects in patients taking finasteride for male pattern baldness, including decreased libido, erectile dysfunction and ejaculation disorders, but, he adds, there are a couple of points in the article that are particularly important to the current debate about long-term side effects.
“One is that sexual adverse effects ‘resolved in many men who reported them but remained on therapy and in all men who discontinued therapy because of these adverse events,’”[SUP]3[/SUP] explains Dr. Wolverton. “So, in other words, things in any of those three categories went back to normal, even while they were still taking the drug. The other statement was that sexual adverse events resolved ‘in all men who discontinued therapy because of these adverse events.’”[SUP]3[/SUP]
The body of literature on finasteride does consistently support the existence of sexual side effects that begin while patients are on the drug, but the reports also demonstrate that, for the most part, these side effects resolve either when the drug is withdrawn or over time as therapy continues. In a report from the Finasteride Male Pattern Hair Loss Study Group, a slightly higher proportion of finasteride users compared to patients on placebo reported drug-related adverse events (AEs) that related to sexual function, but only 11 men (1.4%) treated with finasteride and 8 men (1.0%) treated with placebo discontinued the study due to these side effects.[SUP]6[/SUP] In addition, the side effects resolved in patients who discontinued finasteride and in most patients who reported them but remained on the drug.[SUP]6[/SUP] Another study published in the Journal of the American Academy of Dermatology (JAAD) concluded that no adverse events were seen significantly more often with finasteride compared to placebo.[SUP]7[/SUP] This study inJAAD also demonstrated that the side effects cleared in men who stopped taking finasteride and in most men who remained on the drug.[SUP]7[/SUP]
[SUP]I acknowledge that certain people may have continued sexual disfunction after stopping finasteride, but they are in an incredibly small minority.[/SUP]

 

[xRedStaRx]

Do you know the levels inhibition of tissue/scalp type 2 DHT in different meds and doses? For ex: .2mg vs 1mg finasteride, .5mg dutasteride

It's very difficult to measure, so you'd likely get different values from various studies.

Concurrently, the level of DHT inside hair tissue is more important than scalp tissue, since this is what causes male pattern baldness in the first place.

It went something like this if I remember correctly.

0.2 mg 18% Finasteride
1 mg 21% Finasteride
5 mg 25% Finasteride
0.5 mg 48% Dutasteride
2.5 mg 75% Dutasteride

 

[cthulhu2.0]

It's very difficult to measure, so you'd likely get different values from various studies.

Concurrently, the level of DHT inside hair tissue is more important than scalp tissue, since this is what causes male pattern baldness in the first place.

It went something like this if I remember correctly.

0.2 mg 18% Finasteride
1 mg 21% Finasteride
5 mg 25% Finasteride
0.5 mg 48% Dutasteride
2.5 mg 75% Dutasteride

Seems about right

 

[Ventures]

It's very difficult to measure, so you'd likely get different values from various studies.

Concurrently, the level of DHT inside hair tissue is more important than scalp tissue, since this is what causes male pattern baldness in the first place.

It went something like this if I remember correctly.

0.2 mg 18% Finasteride
1 mg 21% Finasteride
5 mg 25% Finasteride
0.5 mg 48% Dutasteride
2.5 mg 75% Dutasteride

Do these values apply to scalp DHT or follicular DHT ?

I think we must resolve that male pattern baldness is mostly caused by 5-ard-II produced inside hair follicles and dermal papilla. This DHT is called follicular DHT (produced by 5-ard-II). We agree this type of DHT is the most significant, and there is also consensus among many researchers and individuals regarding this . Next in line is salivary DHT (produced in sebaceous glands by 5-ard-I). Scalp DHT consists both of follicular DHT and salivary DHT.

When members in online communities post data/results from different studies it must be pointed out what exactly is referred by that term/ notion.

So, I think these values correspond to scalp DHT (both follicular and salivary) right ? Since, you mentioned that dose of 0.25 mg finasteride inhibits roughly all amount of 5-ard-II available in average male ? There is only type I DHT left after administration of 0.25 mg dose (In most men) ? And dutasteride is superior since it inhibits 5-ard-I and therefore DHT-type 1 which also, but in weaker way causes male pattern baldness.

 

[xRedStaRx]

Do these values apply to scalp DHT or follicular DHT ?

I think we must resolve that male pattern baldness is mostly caused by 5-ard-II produced inside hair follicles and dermal papilla. This DHT is called follicular DHT (produced by 5-ard-II). We agree this type of DHT is the most significant, and there is also consensus among many researchers and individuals regarding this . Next in line is salivary DHT (produced in sebaceous glands by 5-ard-I). Scalp DHT consists both of follicular DHT and salivary DHT.

When members in online communities post data/results from different studies it must be pointed out what exactly is referred by that term/ notion.

So, I think these values correspond to scalp DHT (both follicular and salivary) right ? Since, you mentioned that dose of 0.25 mg finasteride inhibits roughly all amount of 5-ard-II available in average male ? There is only type I DHT left after administration of 0.25 mg dose (In most men) ? And dutasteride is superior since it inhibits 5-ard-I and therefore DHT-type 1 which also, but in weaker way causes male pattern baldness.

Scalp DHT. Finasteride can still lower scalp DHT concentrations through lower follicular DHT.

I've never heard of the term salivary DHT before.

0.25 mg every day lowers serum DHT roughly 88% of the plateau range (which is ~65-75%). But is even lower in hair count effectiveness at around 80% effectiveness of that of the plateau range as well. I'd say that the flat dose-response curve for 5-AR II inhibition starts somewhere around ~0.5 mg ED. But it can be much lower in some people. It's still a safe estimate 99% of the time.

Yes 5-AR I might be involved just a little in male pattern baldness. But even using selective 5-AR I inhibitors did not improve hair condition, like accutane for example. It's still up for debate on whether non-targeted DHT, or even serum DHT might have an effect on male pattern baldness, and if so, how big is it. The long half life of dutasteride may also be a factor at how effective it can inhibit 5-AR II enzymes inside the hair follicle compared to finasteride, based on their respective IC50s and steady state concentrations.

 

[cthulhu2.0]

If they are able to prove that a topical finasteride forumation involving lipid nanoparticles works not only in mice/vitro but in humans, than that would be huge.

 

[xRedStaRx]

If they are able to prove that a topical finasteride forumation involving lipid nanoparticles works not only in mice/vitro but in humans, than that would be huge.

It should work in humans just the same. Why wouldn't it?

 

[Ventures]

Scalp DHT. Finasteride can still lower scalp DHT concentrations through lower follicular DHT.

I've never heard of the term salivary DHT before.

0.25 mg every day lowers serum DHT roughly 88% of the plateau range (which is ~65-75%). But is even lower in hair count effectiveness at around 80% effectiveness of that of the plateau range as well. I'd say that the flat dose-response curve for 5-AR II inhibition starts somewhere around ~0.5 mg ED. But it can be much lower in some people. It's still a safe estimate 99% of the time.

Yes 5-AR I might be involved just a little in male pattern baldness. But even using selective 5-AR I inhibitors did not improve hair condition, like accutane for example. It's still up for debate on whether non-targeted DHT, or even serum DHT might have an effect on male pattern baldness, and if so, how big is it. The long half life of dutasteride may also be a factor at how effective it can inhibit 5-AR II enzymes inside the hair follicle compared to finasteride, based on their respective IC50s and steady state concentrations.

But if 0.25 mg finasteride ED inhibits almost all amount of 5-ard-II available (in average male), then why researchers in MERCK clinical trials haven't came to this conclusion. I mean, why did they decide to produce Proscar in 5 mg dose, instead of 0.25 or at least 0.5 mg ? Is there any other reason why is 5 mg recommended dose for BPH ? Maybe higher doses allow better absorption of the drug ?

And what is IC50s ? Wiki says it is quantitative measure which indicates how much of a particular drug or other substance (inhibitor) is needed to inhibit a given biological process (or component of a process, i.e. an enzyme, cell,cell receptor or microorganism) by half.

Problem is that relations and transformations in pharmacology are not linear, if we assume that quantity Q of a certain drug X inhibits concentration of enzyme Y in individual person by 100 %. Does that mean that quantity Q/2 should inhibit concentration of enzyme Y in same person by 50 %. If we draw a graph of inhibition of that drug, and put percentage of inhibition in vertical -y axis, and quantity of the drug in horizontal-x axes.

Would the graph be the line (linear function) or something more complex ? in this case we analiysed same person which means, quantity of an enzyme is constant, and when we monitor large groups we would find different concentrations / quantities in each person.
Can you be kind and give your own explaination.

 

[xRedStaRx]

But if 0.25 mg finasteride ED inhibits almost all amount of 5-ard-II available (in average male), then why researchers in MERCK clinical trials haven't came to this conclusion. I mean, why did they decide to produce Proscar in 5 mg dose, instead of 0.25 or at least 0.5 mg ? Is there any other reason why is 5 mg recommended dose for BPH ? Maybe higher doses allow better absorption of the drug ?

And what is IC50s ? Wiki says it is quantitative measure which indicates how much of a particular drug or other substance (inhibitor) is needed to inhibit a given biological process (or component of a process, i.e. an enzyme, cell,cell receptor or microorganism) by half.

Problem is that relations and transformations in pharmacology are not linear, if we assume that quantity Q of a certain drug X inhibits concentration of enzyme Y in individual person by 100 %. Does that mean that quantity Q/2 should inhibit concentration of enzyme Y in same person by 50 %. If we draw a graph of inhibition of that drug, and put percentage of inhibition in vertical -y axis, and quantity of the drug in horizontal-x axes.

Would the graph be the line (linear function) or something more complex ? in this case we analiysed same person which means, quantity of an enzyme is constant, and when we monitor large groups we would find different concentrations / quantities in each person.
Can you be kind and give your own explaination.

Because when it comes to a disease such as BPH, you cannot make mistakes with drug doses. 5 mg was a safe margin of safety to reduce prostate size. In fact, 5 mg does a slightly better job at reducing prostate size than 1 mg, even though they inhibit almost the same amount of serum DHT. I could dig up that study if needed.

IC50 is like what you said. In the case of 5ARIs, the concentration required to inhibit half of 5-AR enzymes. In pharmacology, the logarithmic relationship was found almost universally present, at different concavities depending on the drug and person. Even in cultural cells and bacteria, they all experienced some sort of log relationship in their experiments. It's a quite common graph in biology.

Another point to consider with regard to the relative efficacy of a specific finasteride dose and resultant concentration in plasma and tissue is that the IC50 for finasteride in prostate and scalp homogenates was reported to be 5.9 and 310 nM, respectively. Keeping in mind that a 5 mg finasteride dose produces a peak plasma concentration of finasteride of around 94 nM. So even though finasteride inhibits almost the same serum DHT at doses of and above 0.2 mg, the concentrations differ with regards to the scalp and hair follicle. I'd assume the IC50 of the DP is less than that of the scalp judging by better blood flow and being predominantly 5-AR II.

That also explains why 1 mg of finasteride does better at increasing hair counts than 0.2 mg (25% better) while only doing 13% better at decreasing serum DHT. The same was found using 5 mg, which did slightly better than 1 mg, even though theoretically, the same amount of DHT was inhibited in the blood. Which is another reason why I mentioned that serum DHT does not mean much, if anything in terms of male pattern baldness.

Hope this helps.

 

[Ventures]

Because when it comes to a disease such as BPH, you cannot make mistakes with drug doses. 5 mg was a safe margin of safety to reduce prostate size. In fact, 5 mg does a slightly better job at reducing prostate size than 1 mg, even though they inhibit almost the same amount of serum DHT. I could dig up that study if needed.

Maybe patients who suffer BPH have increased levels of both local (prostate tissue) DHT and serum DHT more than average Androgenetic Alopecia sufferer, and higher doses are required to inhibit same percentage; more molecules of active finasteride ingredient are required to inhibit more 5-ard-II units. It's simple math, right ? That's why Bryan recommended higher doses of finasteride in cases individual has very high DHT activity which is manifested as high libido, lot of body hair, acne, sebum, oily scalp etc...

So, in your opinion, based on your knowledge and reading scientific articles and studies, 0.25 mg of finasteride ED is the golden dose for maintenance ? Especially if we are young, and in our 20s (25, 26 years old). There is no need to jump on 1 mg or 1.25 mg ?

But if there is no huge difference regards to level of 5-ARD-II inhibition between 0.25, 1 and 1.25 mg doses, that means we won't be able to avoid sides on lower doses, since side effects are result from level of DHT supression.
What I wanted to ask you, if someone starts to experience loss of libido on 1.25 mg dose, then if he lowers the dose to 0.25 mg (according to your theory there would be the same level of local 5-ard-II inhibition), would he still experience side effect ?

 

[Python]

It should work in humans just the same. Why wouldn't it?

Because rat studies are typically not Telogen Effluvium same as human trials. We know that basically anything grows hair in mice. We are tired of rat studies

 

[xRedStaRx]

Maybe patients who suffer BPH have increased levels of both local (prostate tissue) DHT and serum DHT more than average Androgenetic Alopecia sufferer, and higher doses are required to inhibit same percentage; more molecules of active finasteride ingredient are required to inhibit more 5-ard-II units. It's simple math, right ? That's why Bryan recommended higher doses of finasteride in cases individual has very high DHT activity which is manifested as high libido, lot of body hair, acne, sebum, oily scalp etc...

So, in your opinion, based on your knowledge and reading scientific articles and studies, 0.25 mg of finasteride ED is the golden dose for maintenance ? Especially if we are young, and in our 20s (25, 26 years old). There is no need to jump on 1 mg or 1.25 mg ?

But if there is no huge difference regards to level of 5-ARD-II inhibition between 0.25, 1 and 1.25 mg doses, that means we won't be able to avoid sides on lower doses, since side effects are result from level of DHT supression.
What I wanted to ask you, if someone starts to experience loss of libido on 1.25 mg dose, then if he lowers the dose to 0.25 mg (according to your theory there would be the same level of local 5-ard-II inhibition), would he still experience side effect ?

Finasteride is extremely effective at almost any dose. Even 0.05 mg of finasteride is enough to inhibit close to half of 5-AR II enzymes in an adult male. I've already explained why Proscar is 5 mg while Propecia is 1 mg. Technically, Androgenetic Alopecia sufferers would benefit more proscar more, and BPH should experience no significant disadvantage with Propecia.

I don't recommend Bryan saying that. And if he did, he'd be clearly wrong.

0.25 mg ED is enough to maintain just fine, unless you have aggressive male pattern baldness, in which case 0.5-0.625 mg ED should be a slightly better option for maintenance.

Side effects don't result really result from DHT suppression, rather the consequence of such inhibition on other hormonal values. Not to mention, 5-AR enzymes have other roles besides DHT reduction.

That greatly depends on the source of side effects. Usually, less doses or more infrequent ones tend to help with any side effects according to public anecdote. And I believe their true.

 

[Ventures]

Finasteride is extremely effective at almost any dose. Even 0.05 mg of finasteride is enough to inhibit close to half of 5-AR II enzymes in an adult male. I've already explained why Proscar is 5 mg while Propecia is 1 mg. Technically, Androgenetic Alopecia sufferers would benefit more proscar more, and BPH should experience no significant disadvantage with Propecia.

Side effects don't result really result from DHT suppression, rather the consequence of such inhibition on other hormonal values. Not to mention, 5-AR enzymes have other roles besides DHT reduction.

That greatly depends on the source of side effects. Usually, less doses or more infrequent ones tend to help with any side effects according to public anecdote. And I believe their true.

You have mentioned that 5 mg of finasteride is still a safe margin dose, and if it is true that even 0.25 mg can block all 5-ard-II enzymes than it would make no sense to use higher doses. Especially keeping in mind, as you mentioned by yourself, 5-ard enzymes (I, II and III) have other roles, and if you swallow 5 mg pill, than only little portion of that dose 0.25 - 0.5 mg should block 5-ard-II, and the rest (4.75 - 4.5 mg) would be unused and float freely in blood serum and maybe interfere (inhibit, bind) with other similar enzymes and cause additional changes in hormonal levels.

In my opinion, reasons why higher doses should act better are:

(a) higher doses start to work faster, and there is maybe better distribution of active ingredient (finasteride) in all tissues of body; including scalp.Maybe steady state concentration of finasteride in blood serum is more stable with higher doses, likely because

(b) finasteride molecules tend to bind to other enzymes / hormones not, just 5-ard-II, so effective finasteride concentration attenuates very fast.

And if this is true higher doses are required in order to provide sufficient number of finasteride. molecules since some parentage get scattered /absorbed by other substrates/enzymes and that portion is lost and not able to do it's job - block only 5-ard -II.

 

[xRedStaRx]

You have mentioned that 5 mg of finasteride is still a safe margin dose, and if it is true that even 0.25 mg can block all 5-ard-II enzymes than it would make no sense to use higher doses. Especially keeping in mind, as you mentioned by yourself, 5-ard enzymes (I, II and III) have other roles, and if you swallow 5 mg pill, than only little portion of that dose 0.25 - 0.5 mg should block 5-ard-II, and the rest (4.75 - 4.5 mg) would be unused and float freely in blood serum and maybe interfere (inhibit, bind) with other similar enzymes and cause additional changes in hormonal levels.

In my opinion, reasons why higher doses should act better are:

(a) higher doses start to work faster, and there is maybe better distribution of active ingredient (finasteride) in all tissues of body; including scalp.Maybe steady state concentration of finasteride in blood serum is more stable with higher doses, likely because

(b) finasteride molecules tend to bind to other enzymes / hormones not, just 5-ard-II, so effective finasteride concentration attenuates very fast.

And if this is true higher doses are required in order to provide sufficient number of finasteride. molecules since some parentage get scattered /absorbed by other substrates/enzymes and that portion is lost and not able to do it's job - block only 5-ard -II.

Finasteride molecules have the highest affinity towards 5-AR enzymes on the prostate, judging by their low IC50 values compared to the scalp, although as I mentioned earlier, that might be due primarily to the over-abundance of 5-AR type I, so I'd assume it's not that far off.

1 mg and 5 mg doses for BPH patients showed insignificant differences between prostate volume and PSA concentrations, but urinary symptoms was slightly better. I'd assume this was due to more inhibition of 5-AR type I at the higher dose.

Finasteride works best at binding to type II and III, and since only a small amount is required to effectively inhibit most of them, then 1 mg/day was judged as optimal. Some doctors prescribe BPH patients with only 1.25 mg, or 5 mg 3x/week instead with satisfactory results.

What you should conclude from all this is the amount of finasteride and the frequency in which you take it is largely irrelevant, since it is very effective on a broad scale. The higher doses might still be superior to lower doses (up to a point anyway), but the difference is usually insignificant when you look at how close the plateau level is compared with the smallest dose people actively take (normally 0.2 mg), and the large diminishing returns with every increment.

In short, anything from 0.2-0.625 mg ED, or 0.625-1.25 mg EOD should give you the most of what you need, and I'd say this is the optimal dose-effect range for people with male pattern baldness. Anything higher than that would be too insignificant to account for. Anything lower will still give you good results.

 

[chuckycheese888]

I was on finasteride for 3 years and gave it up. My Doctor recommended cutting the finasteride pill into 4s, and taking them over a 5 day period -- i.e. take one quarter for four days over a five-day period.

First, I was fine. It wasn't until about a year after use that I started to feel different. It got to a point where I was unable to perform sexually consistently. I got self conscious which only made it more difficult to maintain an erection. It ruined my relationship with 2 different women over that period.

After I gave it up in September of last year, I still just didn't have libido back for months. It is only in recent weeks where I feel "kind of" back to where I used to be. Part of the lower sex drive may just be normal aging (I am 35) but for sure the finasteride had an effect. I simply lost sensation down there and while my mind may feel excited or stimulated, but rarely experienced the "rush" in my groin that led to full arousal. Even when having sex, it just didn't feel good as it used to as my erections weak and sensations dull.

I think new patients definitely need to think twice.

 

[xRedStaRx]

I was on finasteride for 3 years and gave it up. My Doctor recommended cutting the finasteride pill into 4s, and taking them over a 5 day period -- i.e. take one quarter for four days over a five-day period.

First, I was fine. It wasn't until about a year after use that I started to feel different. It got to a point where I was unable to perform sexually consistently. I got self conscious which only made it more difficult to maintain an erection. It ruined my relationship with 2 different women over that period.

After I gave it up in September of last year, I still just didn't have libido back for months. It is only in recent weeks where I feel "kind of" back to where I used to be. Part of the lower sex drive may just be normal aging (I am 35) but for sure the finasteride had an effect. I simply lost sensation down there and while my mind may feel excited or stimulated, but rarely experienced the "rush" in my groin that led to full arousal. Even when having sex, it just didn't feel good as it used to as my erections weak and sensations dull.

I think new patients definitely need to think twice.

There certainly is more to finasteride than we know.

For now, I'm trying to play it safe with ingesting the least amount of finasteride and maintaining hair results. Although I'm not sure if that's helpful, since it's very potent at even micro doses.

 

[supermusic]

I dont care. I only want my hair.

 

[Hairbackpls]

I dont care. I only want my hair.

+1

 

[Notcoolanymore]

+2

This isn't propeciahelp part 2, this is hairlosstalk. This stuff just scares guys into not treating their hair loss.

 

[isishearmyplea]

+2

This isn't propeciahelp part 2, this is hairlosstalk. This stuff just scares guys into not treating their hair loss.

technically you typing +2 is wrong, unless you are proxying for someone else