Are higher does of Minoxidil more effective?

[Bryan]

Triplet repeat mutations are not associated with hyperfunction. They are associated with loss of function. I can't think of any diseases with triplet repeat mutations that are associated with an increase in the function of any protein. Insertion of amino acids into a protein will cause it to be misfolded and force it to function poorly or not at all.

Whatever is happening with the androgen receptor is due to its inability to accomplish its physiological role...

Are you sure about all that, docj?? How on earth can you explain the fact that men with that specific androgen receptor mutation certainly have all the normals sign of virility, IN ADDITION to an increased risk for balding?

Bryan

 

[Bryan]

5ar1 is predominant in the scalp yet 5ar1 inhibitors do nothing for hair loss. 5ar2 is predominantly in the follicle and 5ar2 inhibitors have an effect on hair loss. so why does anyone still think scalp dht is important?

But the follicle is PART of the scalp, as is the sebaceous gland! The complaint I always have when people start talking about "scalp DHT" is not that they're talking about something unrelated to balding, it's that they're not using enough SPECIFICITY in their speech. The term "scalp DHT" includes both follicular DHT (strongly related to balding) and sebaceous gland DHT (only mildly related to balding). I want people to be more specific in what they say.

Bryan

 

[IDOASIS]

I should point out one issue here which you appear to have overlooked: I suppose it's within the realm of possibility that azelaic acid might help fight balding by some mechanism OTHER than inhibiting 5a-reductase. You went on and on and on about that small study on azelaic acid and alopecia areata, without acknowledging that I have always been very careful to specify that what I'm talking about is whether or not azelaic acid reduces DHT. So I guess it's vaguely possible that azelaic acid is useful for male pattern baldness, but very likely not for the reason that you think.

It could be Bryan ,I have never claimed it does inhibit 98% DHT at
3 mmol/l (5%) ,like the vitro study have claimed.

Losing your hair makes you BOLD? Cool!

I'm not sure what did you mean by that .
I didnt understand what Doctor claimed , how could it be both increasing hair count and at the same time going bald.

You meant to say LONGER triplet regions, didn't you?

Yes I did ,my mistake.


Bryan do you believe finasteride inhibits the same amount of
follicular DHT and serum DHT?

 

[IDOASIS]

As for your last question, I believe that increases in IGF-1 have been seen both in vitro and in vivo.

How many participants in the vivo study?

Doctor ,I repeat my question.

5ar1 is predominant in the scalp yet 5ar1 inhibitors do nothing for hair loss. 5ar2 is predominantly in the follicle and 5ar2 inhibitors have an effect on hair loss. so why does anyone still think scalp dht is important?

I dont believe its true.
0.5 mg dutasteride inhibits approximately 98% of 5ar2 and 50% 5ar1.
1 inch diameter circle increased by about ~96 hairs with 0.5mg Dutasteride (after six month).


1 inch diameter circle increased by about ~108 hairs with 2.5mg Dutasteride .

Do you really think the extra 2% can explain the diffrences?

I think MK386 did not show benefit for hair loss because inhibiting
only 5ar1 is not enough ,but it would benefit as additional to 5ar2.

 

[powersam]

hah

 

[docj077]

Triplet repeat mutations are not associated with hyperfunction. They are associated with loss of function. I can't think of any diseases with triplet repeat mutations that are associated with an increase in the function of any protein. Insertion of amino acids into a protein will cause it to be misfolded and force it to function poorly or not at all.

Whatever is happening with the androgen receptor is due to its inability to accomplish its physiological role...

Are you sure about all that, docj?? How on earth can you explain the fact that men with that specific androgen receptor mutation certainly have all the normals sign of virility, IN ADDITION to an increased risk for balding?

Bryan

Well, from the perspective of known human diseases, if the x chromosome has a defect in it, the results are normally catastrophic for whatever gene is affected and the severity of the disease is directly proportional to the number of triplet repeats within the gene.

There is a possibility that a particular number of repeats in the androgen receptor yields a hyperactive protein capable of binding androgen more efficiently or performing another function at an accelerated rate, but I've never heard of that with any x-linked condition. Normally, triplet repeats correspond to defective protein, and thus, defective physiology in the sense that the results are not linked to one particular area.

As you've so kindly mentioned in the past, there is no reason why a defective androgen receptor in the scalp shouldn't be spread throughout the body with the same defect. A man only inherits one x chromosome and if it has the defect, then every single cell with an androgen receptor should have a defective androgen receptor, but this doesn't seem to be true and embryological patterning will not make a difference. At least, I've never seen a study comparing androgen receptors in the scalp to androgen receptors in another part of the body. X-linked mosaicism doesn't work in men, because they only have one x chromosome, so whatever is going on with the androgen receptor in the scalp is either an in vivo mutation manifesting itself later in life or there really isn't a mutation at all and the triplet repeats simply correlate with the functionality of the receptor within the entire male body and something far worse is going on behind the scenes.

Triplet mutations do not explain male pattern baldness, because they don't explain the difference in functionality between a scalp androgen receptor and body androgen receptor. They only explain why some downstream mechanism is either not functioning or why it's functioning too well.

That's my opinion anyway.

Personally, I think the disease is more related to the mechanism from the website below and I'm not even totally sure it's a defect anymore:

http://www.jimmunol.org/cgi/content/full/171/7/3855

 

[Bryan]

Bryan do you believe finasteride inhibits the same amount of follicular DHT and serum DHT?

Don't know for sure, but I would guess that it "inhibits" even more follicular DHT than serum DHT (you're forcing me to use that popular vulgarity! ).

Bryan

 

[Bryan]

Triplet mutations do not explain male pattern baldness, because they don't explain the difference in functionality between a scalp androgen receptor and body androgen receptor. They only explain why some downstream mechanism is either not functioning or why it's functioning too well.

That's my opinion anyway.

Well, I _think_ I'm in agreement with you, despite what seems to be some slightly mixed signals I'm getting.

The triplet mutations clearly don't cause a loss of function for androgen receptors in this case; in fact, they apparently enhance it, because they increase the risk of male pattern baldness. And I would never ever suspect them of being the explanation for the difference in response between scalp follicles and body follicles. That's obviously a farther "downstream" effect. The study you cited a while back is very compelling...the one where even non-balding scalp follicles were shown to be sensitive to androgens, if you get the dose high enough. That fits right in with the idea that the triplet mutations increase the STRENGTH of the net androgenic response, but not the KIND of response to it.

Bryan

 

[IDOASIS]

Don't know for sure, but I would guess that it "inhibits" even more follicular DHT than serum DHT (you're forcing me to use that popular vulgarity! ).

Bryan

Just curios, what make you think that?

 

[docj077]

Triplet mutations do not explain male pattern baldness, because they don't explain the difference in functionality between a scalp androgen receptor and body androgen receptor. They only explain why some downstream mechanism is either not functioning or why it's functioning too well.

That's my opinion anyway.

Well, I _think_ I'm in agreement with you, despite what seems to be some slightly mixed signals I'm getting.

The triplet mutations clearly don't cause a loss of function for androgen receptors in this case; in fact, they apparently enhance it, because they increase the risk of male pattern baldness. And I would never ever suspect them of being the explanation for the difference in response between scalp follicles and body follicles. That's obviously a farther "downstream" effect. The study you cited a while back is very compelling...the one where even non-balding scalp follicles were shown to be sensitive to androgens, if you get the dose high enough. That fits right in with the idea that the triplet mutations increase the STRENGTH of the net androgenic response, but not the KIND of response to it.

Bryan

What I'm thinking is that current male pattern baldness research shouldn't be focusing on how to stop the process with a mutated androgen receptor. Current research should be focusing on how the rest of the body seems to deal with a mutated androgen receptor with little difficultly while maintaining a sense of normal physiology (i.e. all men with male pattern baldness don't have Hirsutism, for example).

There must be something downstream of the androgen receptor in other areas of the body that allows it to function with its repeats.

It's pretty obvious that the androgen receptor isn't hyperfunctional everywhere in the body or else men with male pattern baldness would have incredible secondary sex characteristics.

So, what we need to find is the molecule that takes a hyperfunctional androgen receptor in the body and tones down the signal enough to make the process somewhat normal.

It's obviously not androgen mediated hypertrophy of muscles causing lymphedema, because there is no proof that there is either edema, hypertrophy of muscles, loss of functionality of lymphatics, or muscular hypertrophy/the same processes occurring in other parts of the body. There is no reason for such a process to be localized as there are plenty of places with less blood flow and poorer lymphatic drainage that are working against gravity that still have hair.

The only thing that would make it any different or localized to the scalp would be an infection, inflammation secondary to an applied substance, or an immune system response secondary to a previous infection/damage (sunburn).

I really can not think of why there is a difference in the biochemistry of this process in the scalp when compared to the rest of the body. The cells may be patterned differently embryologically, but there would have to be another mutation somewhere in another molecule causing the difference.

 

[Bryan]

Don't know for sure, but I would guess that it "inhibits" even more follicular DHT than serum DHT (you're forcing me to use that popular vulgarity! ).

Bryan

Just curios, what make you think that?

The relative distribution of the two 5a-reductase enzymes within hair follicles has been controversial, and the results of studies looking at that have been conflicting. However, I tend to believe the more recent ones showing that in the dermal papilla, the type 2 enzyme apparently is present almost exclusively. The type 1 enzyme may be present in other parts of the hair follicle, but the impression I get from what I've read is that it's there probably in only a relatively small proportion. For those reasons, I personally would expect finasteride to reduce DHT to a more significant extent inside the hair follicle than it does in the body as a whole, but that's only my own hunch. I could be wrong.

Bryan

 

[Guest]

So docj077, what your saying is that Testosterone also signals TGF-B the same way DHT does. So both T and DHT cause hairloss? And this would mean that Fina. and to a greater extend Dutasteride wouldn't stop hairloss because of the extra T with some people?

In vitro, testosterone has the same effects, but DHT is still the main molecule of concern as it has the highest binding affinity for the androgen receptor. DHT also seems to induce a much stronger conformational change in the androgen receptor allowing it to produce downstream effects at a faster rate and with an overall stronger response.

Testosterone ability to possibly cause male pattern baldness, as well, is most concerning to me as it could be one of two reasons why drugs like propecia and avodart prove useless in the long run as some DHT still binds and testosterone will always be there to keep the disease progressing. But, that's just my opinion.

Doctor, Bryan, anyone, feel free to answer. I'd prefer if anyone who wanted to answer my post chime in. NOW Do we know yet that most people who take Avodart will end up progressing? Dutasteride has only been out 5 years. I have posted about this before but while Propecia may knock out 85% of the type II 5-ar, Avodart knocks out 98.5% of it at the daily dose of 0.5 mg. So that leaves 1.5% of original DHT levels. There is still the testosterone to deal with but doesn't DHT have 30 times the potency of regular t? So it would have a greater affinity for the androgen receptors than plain old T does. So it seems to me like even though the disease will still progress after a time on Avodart, it will progress incredibly slowly, and the progression may not even be noticeable for decades.

What do you think about that? Even with strong hair loss genes working against the person it still seems likely that if it would take someone 5 years to progress one Norwood scale(say III to IV) without any meds, then it may take them 25 years to progress that same amount on dutasteride. We're talking about 1.5% of original circulating DHT in the follicles and t levels remaining the same, compared to no meds with 100% of original circulating DHT in the follicles and t levels MAYBE slightly increased. It's cutting it by 98.5%. Don't you think this ought to slow it rather dramatically?

Also, how much do you think adding topical spironolactone to the hairline in addition to oral Avodart will stop the progression, if any? Most people on here think that the front is far more susceptible to other non-dht androgens than the back is, meaning that people on Avodart may get no worse than NW3, keeping dense hair in the mid anterior region and in the crown.

I'm going to post this graph again which I'm sure you've seen. This is the Propecia 5 year graph. Naturally, we would expect the Avodart graph to be even better because it's knocking out production of 98.5% of type II DHT compared to 80% or whatever with Propecia:

Look at the Propecia line compared to Placebo. From years 3-5, the person on Propecia goes from 60 hairs above baseline in the test area, to 49 hairs above baseline, then 38. Losing about 11 hairs in that area per year. The guy on placebo, on the other hand? He's losing about 80 hairs per year. It is not unreasonable to expect that Propecia line to at least continue its current slope. The line is getting flatter and flatter meaning that, extrapolating it out, the average Propecia user will still be 5 hairs above BASELINE after 8 years on the drug. And I haven't even mentioned Avodart, we don't have an Avodart chart, but I don't think it's too ridiculous to estimate that the average Avodart user could stay above baseline for 12 years, and then start that slow average decline, which will probably be a lot slower than the Propecia decline even, maybe only losing hair at 5% of the rate that a Placebo user would.


What do you think about that, Doctor?

You're a knowledgeable guy so I'm interested to hear your thoughts. Again, I don't think anyone is arguing that male pattern baldness will not continue to progress, but that the progression may be so ridiculously slow on Avodart as to not even be noticeable to the naked eye for decades, meaning that someone who starts taking Avodart at NW2 could stay NW3 or below for their entire life. I think college said that castration takes care of 95% of DHT. So would someone on Avodart be able to add topical spironolactone to their hair to take care of enough of the test to not progress?

Again, I just find it difficult to believe that the test and the miniscule amount of DHT production left by Avodart will move male pattern baldness along at more than a snail's pace in most people.

 

[IDOASIS]

NOW Do we know yet that most people who take Avodart will end up progressing?
.

No we dont ,we have no evidence.

I have posted about this before but while Propecia may knock out 85% of the type II 5-ar, Avodart knocks out 98.5% of it at the daily dose of 0.5 mg. So that leaves 1.5% of original DHT levels.

Do not forget ,5ar1 also has a role in male pattern baldness
though less important than 5ar2.

 

[powersam]

idoasis do you have any proof that 5ar1 plays a role in male pattern baldness? theres quite a lot to show that it doesnt.

 

[Guest]

idoasis do you have any proof that 5ar1 plays a role in male pattern baldness? theres quite a lot to show that it doesnt.

i think 5ar in the sebaceous glands(which is primarily type I, no?) could contribute a bit to hair loss, although not as much as type II.

 

[IDOASIS]

i think 5ar in the sebaceous glands(which is primarily type I, no?)

True.

Two isoenzymes of 5AR exist: Type 1 and Type 2.1 Type 1 is most abundant in the liver and skin, but is found, to a lesser degree, in the prostate as well. It is also the dominant isoform in sebaceous glands. Type 2 is the dominant isoenzyme in the prostate, and is minimally present in the liver and skin. Their primary function is to convert testosterone to DHT. Finasteride has proven to selectively inhibit the Type 2 isoenzyme whereas dutasteride competitively inhibits both forms of the enzyme. This is significant because DHT is a primary androgen and is believed to be important in the development and progression of benign prostatic hyperplasia (BPH).2

Results of a phase II, double-blind, placebo-controlled, comparative dose-ranging trial of dutasteride and finasteride clearly demonstrated that serum DHT suppression was significantly greater with dutasteride (0.5 mg daily) than with finasteride (5 mg daily).3 The mean reduction in baseline DHT concentration in patients receiving 0.5 mg dutasteride daily was 94.7 ± 3.3% and for patients receiving finasteride 5 mg daily was 70.8 ± 18.3%, respectively (P < .001) (Figure 2). In non-comparative clinical trials, chronic therapy with dutasteride (0.5 mg daily) for up to 2 years in patients with BPH resulted in median reductions in serum DHT of 93%.4 In contrast, therapy with finasteride (5 mg daily) suppressed serum DHT concentrations by approximately 70% for up to 4 years in patients with BPH.5 These observations raise the question whether the pharmacologic differences in DHT suppression between a selective versus a dual inhibitor of 5AR results in clinically significant differences in the treatment of BPH.

idoasis do you have any proof that 5ar1 plays a role in male pattern baldness? theres quite a lot to show that it doesnt.

0.5 mg dutasteride inhibits approximately 98% of 5ar2 and 50% 5ar1.
1 inch diameter circle increased by about ~96 hairs with 0.5mg Dutasteride (after six month).


1 inch diameter circle increased by about ~108 hairs with 2.5mg Dutasteride .

Do you really think the extra 2% can explain the diffrences?

I think MK386 did not show benefit for hair loss because inhibiting
only 5ar1 is not enough ,but it would benefit as additional to 5ar2.

How else could you explain the diffrences?

 

[docj077]

What do you think about that, Doctor?

You're a knowledgeable guy so I'm interested to hear your thoughts. Again, I don't think anyone is arguing that male pattern baldness will not continue to progress, but that the progression may be so ridiculously slow on Avodart as to not even be noticeable to the naked eye for decades, meaning that someone who starts taking Avodart at NW2 could stay NW3 or below for their entire life. I think college said that castration takes care of 95% of DHT. So would someone on Avodart be able to add topical spironolactone to their hair to take care of enough of the test to not progress?

Again, I just find it difficult to believe that the test and the miniscule amount of DHT production left by Avodart will move male pattern baldness along at more than a snail's pace in most people.

I totally agree that if you use avodart as a preventative early enough, you should have little progression with regards to your present vs. your future norwood classification.

However, what concerns me is the people that think that going from a NW4 or NW3 to a NW2 or better on Avodart will be a permanent solution to their hair loss. If indeed these 5AR inhibitors are merely blocking androgens and raising the concentration of growth stimulatory molecules in the hair follicle unit, then what is happening is not reversal of hair loss, but simply stimulated regrowth.

I do not know of any studies that clearly demonstrate that 5AR administration reverses perifollicular fibrosis. I know that they move the hair back into deeper tissues to promote the growth of hair with larger diameters, etc. But, if a person makes progress while on these drugs, they will almost certainly revert back to their original norwood or worse unless they are able to remodel the extrafollicular region around the hair follicle and reverse the balding process while keeping their hair active.

Even with testosterone hair loss can progress and without a means to combat the inflammation, fibrosis, and in some cases, "immune response" that accompanies hair loss, a person will not keep all their hair for the duration of their lifetime. It may be subtle and it may be a progression from a NW2 from regrowth to a NW3, but it may not happen for 30 years and you'll either have to live with that or wait for the next best drug to come out and save you.

Also, getting on these drugs before fibrosis or inflammation ever begins (which is why dermatologists should do biopsies on everyone with possible male pattern baldness or allow prescription drugs at the first sign of male pattern baldness) is the only sure way to prevent accelerated progression through the norwood scale. If you want to halt it completely, then one must use a 5AR inhibitor internal with an androgen receptor blocker topical and a possible anti-fibrotic drug topical once they hopefully come out on the market. Right now, such a regimen pretty much happens to be the big three. But, ketoconazole and minoxidil do a pretty crappy job and are really not target specific.

You would never go bald if you start early enough with such a regimen.

 

[docj077]

idoasis do you have any proof that 5ar1 plays a role in male pattern baldness? theres quite a lot to show that it doesnt.

i think 5ar in the sebaceous glands(which is primarily type I, no?) could contribute a bit to hair loss, although not as much as type II.

Type I can contribute through the production of sebum and the possible pro-inflammatory fatty acids that can be created by bacteria.

 

[Bryan]

I totally agree that if you use avodart as a preventative early enough, you should have little progression with regards to your present vs. your future norwood classification.

Agreed.

However, what concerns me is the people that think that going from a NW4 or NW3 to a NW2 or better on Avodart will be a permanent solution to their hair loss. If indeed these 5AR inhibitors are merely blocking androgens and raising the concentration of growth stimulatory molecules in the hair follicle unit, then what is happening is not reversal of hair loss, but simply stimulated regrowth.

I don't really see much of a distinction between those two concepts. Stimulated regrowth by the reduction of androgens IS reversal of hair loss, in my book.

I do not know of any studies that clearly demonstrate that 5AR administration reverses perifollicular fibrosis. I know that they move the hair back into deeper tissues to promote the growth of hair with larger diameters, etc. But, if a person makes progress while on these drugs, they will almost certainly revert back to their original norwood or worse unless they are able to remodel the extrafollicular region around the hair follicle and reverse the balding process while keeping their hair active.

I personally wouldn't make such an assumption, unless presented with some serious evidence for it. To date, all we have in the case of finasteride is just the 5-year study by Merck showing a slow degradation of haircounts after reaching the 1-year peak. No long-term dutasteride data at all. Too bad we'll probably never have such an experiment performed with dutasteride, meaning that this speculation will go on for years! :-x

Bryan

 

[powersam]

ideoasis then how do you explain the fact that specific type 1 inhibitors have absolutely no effect on hair loss whatsoever? what you point out is not proof merely supposition.