How much scalp DHT is made in the scalp?

[CCS]

And how much gets there from the blood supply bringing DHT from the body? I may have enough information to calculate this with a mass balance, but I'd rather someone just send me a link. I'm asking because I want to know how effective topical dutasteride would be. If a lot of the DHT in the scalp comes from the testes through the blood, then a topical dutasteride would not be nearly as effective as if the vast majority were just produced locally. Also, if the local DHT is inhibited, we need to know how much testes DHT must be inhibited to get the 80 or 90% of scalp DHT inhibited. My goal is have greater than 80% scalp DHT inhibition, and less than 40% body DHT inhibition.

Because high testosterone levels can age skin, an androgen receptor blocker in the scalp would be needed too. Nizoral is just an anti-fungal. The active ingredient needs systemic absorption to lower testosterone levels. Even if it lowers them 10%, your body feels this first, and this is nothing compared to the 154% gain in the scalp. We need a low dose topical that would destroy (react with) scalp testosterone, rather than block it or decrease its production.

Oh, and in partial answer to my first question since scalp testosterone levels climb much higher than serum testosterone levels even when less DHT is inhibited in the scalp, this suggests...I'm going to bed. Someone figure out what that says about the mobility of testoterone in small blood vessels.

 

[Bryan]

And how much gets there from the blood supply bringing DHT from the body? I may have enough information to calculate this with a mass balance, but I'd rather someone just send me a link.

That's a very interesting question which understandably has been the subject of a fair amount of lively debate over the years on hairloss sites. I don't think anybody knows the answer to that question for sure, and I'd be curious to know exactly how YOU would go about trying to calculate it.

I've said for years that in my own opinion, serum DHT plays a relatively minor role in hairloss, and by that I mean (wild guess) less than 10% or so. I base that on various circumstantial pieces of evidence, including the following points:

1) Most endogenous molecules of DHT that are generated within cells go on to bind to androgen receptors (I read that in a medical journal article a long time ago, sorry I can't cite it anymore!).

2) Serum DHT is metabolized and excreted fairly rapidly, according to the Gisleskog et al studies, so it can't have very much of an endocrine effect, compared to those endogenous DHT molecules that are formed within the target cells themselves (see #1 above).

3) Experiments with both humans and animals have shown that certain truly effective topical 5a-reductase inhibitors (GLA is a good example) are in fact able to have a significant effect at inhibiting the local sebaceous glands, which obviously implies that the DHT in the blood must not be having very much of an effect at keeping those glands going. It must in fact be the endogenous DHT within those cells which is by far the major factor.

I'm asking because I want to know how effective topical dutasteride would be.

Oh, I think IN THEORY it would work fine, but the main problem you have is simply whether or not dutasteride itself lends itself well to a topical formulation. For example, can you make sure that it's absorbed well into hair follicles and, more importantly, make it STAY there, and not go right into the bloodstream and spread to all the rest of the body? :wink:

I'm not very optimistic for dutasteride's chances as a topical 5a-reductase inhibitor, mainly because of finasteride's very mixed record in that regard. The results of various topical finasteride studies have been all over the map, and I don't know why topical dutasteride would be any different.

Because high testosterone levels can age skin, an androgen receptor blocker in the scalp would be needed too. Nizoral is just an anti-fungal. The active ingredient needs systemic absorption to lower testosterone levels.

Ketoconazole has also been shown to have antiandrogenic (androgen receptor blocker) properties, which I believe to be the most likely explanation for its apparent beneficial effect on male pattern baldness.

Even if it lowers them 10%, your body feels this first, and this is nothing compared to the 154% gain in the scalp.

I wouldn't take those numbers too seriously, if I were you.

Oh, and in partial answer to my first question since scalp testosterone levels climb much higher than serum testosterone levels even when less DHT is inhibited in the scalp, this suggests...I'm going to bed. Someone figure out what that says about the mobility of testoterone in small blood vessels.

I don't know if they "climb much higher", or not. I take those numbers with a grain or two of salt.

Bryan

 

[CCS]

Thanks for the information

That fact about the sebacious gland was very compelling. If my skin dries out, I'll reduce the dose. Yes, I don't know if it will go straight into the blood and leave or if it will build up and linger for a while. I need a scalp test to figure that out. I'll apply it to one part 4 hours before and another similar part 30 minutes before the test, and see how much the concentration changed. I need to ask a Doctor where I can get the test. As for me calculating it:

I have a graph that shows how much serum DHT is inhibited with at each concentration of dutasteride, for the population average.

I also have a graph that shows what fraction of DHT is produced by type I or II at each concentration of dutasteride.

I have another graph that shows the blood concentration of dutasteride for 5 different doses from days 1 to 180.

I don't have the webpage I saved the pics from, but I can upload them on to myspace and send you the link to the profile with the pics.

I know that only 60% is absorbed in the gut. I also know that it is metabolized in the liver or excreted to a lesser extent, so any dutasteride in the scalp must leave the scalp if more comes in, once steady state is achieved.

I don't know how fast AR5 is manufactured under various conditions, but I do know that once dutasteride binds to it, it does not let go.

I also have the information on this site:
http://www.regrowth.com/hairloss-remedy ... esults.cfm

I know where type I and II are found in the body.

I also know that balding scalp has twice as much DHT as non-balding scalp, on average.

I don't know if this is enough information to calculate it, but I think I can do mass balance, and apply my equilibrium chemistry skills. I'll attempt it later tonight and post my results and calculations. If it can't be solved with this information, I'll find out what info is needed to solve it, and maybe that info can be looked up or measured.

I read that bald men's scalp circulation is on average 2.6 times less than normal men's circulation. That could help keep the dutasteride in place.

 

[CCS]

Another approach

We know that oral dutasteride inhibits serum DHT far more than scalp. You say that most DHT is made in the scalp, and little comes from the body. But since the only way Dutasteride can reach the scalp is through the blood, it is logical testosterone and DHT could follow a similar path. Both are very similar to dutasteride, except dutasteride is bigger and less water soluble. Testosterone made in the testes (and petuitary gland?) has no trouble making it to the muscles. Perhaps DHT does not travel as fast as dutasteride because DHT gets caught on many androgen receptors along the way. I wonder if poor scalp circulation, or large AR5 sources near the gut getting first access, cause less dutasteride to reach the scalp, and that cause the smaller DHT lowering effects. I know that the concentrations in the body and the scalp are published somewhere for DHT. You can probably find it for dutasteride, if not on the same pages. If there is a lower dutasteride concentration in the scalp than the body, that could explain the difference in DHT inhibition and make a topical very useful. If the lower response rate of AR5 type 1 is the main reason, a topical could still over power this if it stayed around long. I want to know how fast AR5 is replenished after dutasteride takes it out. I also want to know what the scalp concentration of DHT in eunics is, since that would mean they have none coming from the testes. Unfortunately, I read that there were two identical twins, one of whom was crazy and castrated. The non-castrated one went bald. the other did not, until his psych, doing and experiment, injected him with testosterone, and he lost his hair. I don't know how trustworthy the source was, but it seems that the DHT from the testes played a big part here. If so, I'd say that DHT uptake along the way, and maybe circulation, are to blame for the difference. Even then, a topical would flip the ratio, but it would prevent all DHT from entering.

I also read that milk hormones from injections may trigger some androgen receptors. i don't know if that is true though, but propecia would not stop this if it is true.

 

[Bryan]

Re: Thanks for the information

I don't know how fast AR5 is manufactured under various conditions, but I do know that once dutasteride binds to it, it does not let go.

Dutasteride and finasteride are BOTH irreversible inhibitors of the type 2 enzyme. Dutasteride doesn't inhibit the type 1 form irreversibly.

You can read the Gisleskog et al studies which I've cited here numerous times in the past to see their measurements of the production rate of both 5a-reductase enzymes.

I don't know if this is enough information to calculate it, but I think I can do mass balance, and apply my equilibrium chemistry skills. I'll attempt it later tonight and post my results and calculations. If it can't be solved with this information, I'll find out what info is needed to solve it, and maybe that info can be looked up or measured.

I don't think that's anywhere nearly enough information to "calculate" it. There's a LOT of speculation and guesswork involved with this question. I think the only way to get a reasonable idea of it is to consider experiments like the ones I suggested (with topical inhibitors).

Bryan

 

[Bryan]

Re: Another approach

We know that oral dutasteride inhibits serum DHT far more than scalp.

Maybe, maybe not. I'm not too sure about that. There's rather conflicting information on that in published studies, so I don't think we can say for sure.

You say that most DHT is made in the scalp, and little comes from the body. But since the only way Dutasteride can reach the scalp is through the blood, it is logical testosterone and DHT could follow a similar path. Both are very similar to dutasteride, except dutasteride is bigger and less water soluble. Testosterone made in the testes (and petuitary gland?) has no trouble making it to the muscles.

Yes, but that's not my main point! I'm saying that blood levels of DHT are much smaller than blood levels of testosterone, because the relatively few molecules of DHT that manage to escape from cells and "leak out" into the bloodstream get eliminated fairly rapidly. In other words, all those DHT molecules that _do_ latch onto androgen receptors within cells where they're actually produced undoubtedly have a much stronger influence than the small number of DHT molecules that may happen to drift back into the cell from the bloodstream at a later time. Do you see what I'm saying?

Perhaps DHT does not travel as fast as dutasteride because DHT gets caught on many androgen receptors along the way. I wonder if poor scalp circulation, or large AR5 sources near the gut getting first access, cause less dutasteride to reach the scalp, and that cause the smaller DHT lowering effects.

You DO know that 5a-reductase and androgen receptors are intra-cellular proteins, right?

I know that the concentrations in the body and the scalp are published somewhere for DHT.

I've never seen those numbers published anywhere. And if I did, I'd be suspicious of them.

I want to know how fast AR5 is replenished after dutasteride takes it out.

I don't have that information right at hand, but I'll look it up in the Gisleskog studies and post it here later.

I also want to know what the scalp concentration of DHT in eunics is, since that would mean they have none coming from the testes...it seems that the DHT from the testes played a big part here.

I find it interesting that you keep referring to DHT made in the testes! Most people consider the DHT made by the prostate to be the most important source of what's found in the bloodstream. And indeed, it's probably the most prolific DHT-producer of all (for its size).

Bryan

 

[CCS]

My biology knowledge is very limited

I'm a general chemistry and math guy, not a biology expert. I think I did plenty research into dutasteride stability and skin absorpion. I did not know that AR5 and AR recepters were intracellular proteins. Thank you for educating me. I assumed that since most finasteride is bound to plasma proteins, where it breaks off as needed, that the reaction with AR5 took place in the plasma, not the cells. I will google that study you sighted. I have not read it yet, though it sounds very promising.

Do researchers have to biopsy the scalp to measure the important DHT levels, or can they just take a little blood? You are probably right that I can't calculate the production levels, especially if i don't know what is being measured (blood or cell levels) in the scalp. I also was wrong about testes production instead of prostate production. I think that study will be very educational, if it states how AR5 is produced.

I'm not letting a Doctor biopsy my scalp. So you said there is a way using topical androgen inhibitors to make measurements. I must have missed that. I'll look over your posts and see if I can find where that is. I still think people should be squirting 2-4 capsules in their minoxidil each month while we figure this out. It is too cheap to hurt.

 

[CCS]

I think I found it.

http://www.blackwell-synergy.com/doi/pd ... ookieSet=1

I found a few other sites. Is this the one you read?

And i just remembered that 0.1mg has the same effect as finasteride, 65-70% serum, 38-45% scalp. If that is accurate, then my graph reading of 50% was off. This is probably because I took a guess at the steady state concentration in the first place, but it could also bring the graphs into question.
http://img.photobucket.com/albums/v297/ ... alysis.jpg
That is the steady state graph. Found it on http://www.iregrewmyhair.com
http://smg.photobucket.com/albums/v297/ ... utast4.gif
Here is the other chart.

http://www.iregrewmyhair.com/hair-loss- ... ng-charts/
On this page, he says he got the charts from a "very knowledgeable Bryan Shelton" at hairsite.com.

 

[Felk]

Re: My biology knowledge is very limited

I still think people should be squirting 2-4 capsules in their minoxidil each month while we figure this out. It is too cheap to hurt.

Unless it works like finasteride, and any benefit you get from applying it topically is most likely from systematic absorption. In this case, it's like taking the drug, and Avodart isn't approved for hair loss.

 

[CCS]

I'm reading it now.

I'll read more tomorrow. At least I know not to try that mass balance tonight. You saved me some time.

I do have some good news, though. I looked at some extreme close ups of a NW4 or 5's scalp. In the areas where it looked extremely thin, there were plenly of tiny hairs in the same numbers as in the thickest areas. They were just much smaller. I saw the far away shot with a circle on his head in different areas, and then zoomed way in on the circle. This means that unless you are slick super shiny bald and been that way for a while, a super combo of the right meds applied the right way may regrow all your hair. I really think topical dutasteride, minoxidil, and fluridil combined can do this. I still have some peach fuzz in front, and I hope it is more than just normal fuzz, but old hair. Topical dutasteride would be so much cheaper than oral dutasteride.

 

[Bryan]

Re: My biology knowledge is very limited

I'm a general chemistry and math guy, not a biology expert. I think I did plenty research into dutasteride stability and skin absorpion. I did not know that AR5 and AR recepters were intracellular proteins. Thank you for educating me. I assumed that since most finasteride is bound to plasma proteins, where it breaks off as needed, that the reaction with AR5 took place in the plasma, not the cells.

Yes, 5a-reductase is tightly bound to certain membranes within the cell, and doesn't appear anywhere else outside of cells. In fact, I've read that biochemists have been frustrated for years in their attempts to isolate and purify the substance, because it's so difficult to get to. They've been largely unsuccessful.

Androgen receptors are mobile proteins that exist in the cytoplasm of cells. Some people have the mistaken impression that they are surface receptors on the outside of the cellular membrane, but they are wrong. Androgen receptors sort of "float" around inside the cell's cytoplasm!

Do researchers have to biopsy the scalp to measure the important DHT levels, or can they just take a little blood?

Well, if you want to measure DHT inside hair follicle cells, then you're going to have to take a biopsy. A blood test won't prove anything about what's inside cells.

You are probably right that I can't calculate the production levels, especially if i don't know what is being measured (blood or cell levels) in the scalp. I also was wrong about testes production instead of prostate production.

I didn't mean to imply that you were WRONG about the testes, I was just curious about why you were so interested in that specific source!

The DHT that you measure in the blood is obviously the total of ALL the various tissues around the body that each make their small contributions. Not only the prostate and testes contribute, but also hair follicles, sebaceous glands, sweat glands (I believe), the liver, kidneys, etc.

I'm not letting a Doctor biopsy my scalp. So you said there is a way using topical androgen inhibitors to make measurements. I must have missed that. I'll look over your posts and see if I can find where that is.

No no, you misunderstood me. What I meant is that to get _some_ idea of the relative importance of locally produced DHT versus blood DHT, about all you can do is consider various pieces of evidence like the I mentioned earlier; namely, the fact that certain topical 5a-reductase inhibitors seem to be quite effective at shutting down sebaceous glands, suggesting that blood DHT isn't very much of a factor for them.

Bryan

 

[Bryan]

http://www.blackwell-synergy.com/doi/pd ... ookieSet=1

I found a few other sites. Is this the one you read?

Hey, cool! You found a link to an online source for that one!

That's ONE of the Gisleskog studies on dutasteride/finasteride. There is also another "companion" study by the same researchers that they published at the same time. It has additional excellent charts and graphs. If you can find a source for that one, too, it would be great.

http://smg.photobucket.com/albums/v297/ ... utast4.gif

Here is the other chart.

Heh. That graph is a modified version of one that appeared in one of the Gisleskog studies. I personally added the three vertical dashed lines corresponding to daily oral doses of 0.1, 0.5, and 2.5 milligrams. I did that so that people can get an approximate idea of blood levels of the drug and degree of DHT reduction from those three rather well-known doses. I only wish that whoever it was that posted that had made a note to that effect. I want people to be aware that those are MY estimates, not Gisleskog's, just in case I'm a little bit off on them! :wink:

http://www.iregrewmyhair.com/hair-loss- ... ng-charts/

On this page, he says he got the charts from a "very knowledgeable Bryan Shelton" at hairsite.com.

I'm flattered!

Bryan

 

[not me!]

Bryan's posts have been helping me out for years so it was the least I could do to credit him for his work.

Thanks, Bryan, for not minding me showing those charts on my blog!

 

[Armando Jose]

I'm wondering if scientist test with a biopsy the DHTconcentration in scalp hairs of prepubertal childs.

My idea is:
HORMONES BEFORE PUBERTY


A healthy hair needs a functional sebaceous gland associated.

Sebaceous gland needs hormones in order to work correctly.

Our hair is in very good conditions when we are children, ex. between 3 and 10 years.

Therefore, it should be deduced that androgens should exist when we are children.

How is it possible?

The dermatology treaties don't indicates this possibility and they only speak of the influence of the hormones starting from the puberty.

It is possible that androgens only exist in the neighbouring of pilosebaceous unit over the scalp, don’t circulating in blood flow.
The scalp hair biology can admit it. The asynchronous mechanism of human scalp hair allows this supposition. There exist all necessary enzymes to synthesize testosterone (T) and dihydrotestosterone (DHT) from cholesterol.

Comments are wellcome

Armando

 

[Bryan]

Armando, how do you explain the fact that people with complete androgen-insensitivity syndrome (they have defective, non-functioning androgen receptors) have luxuriant amounts of scalp hair, even though they have essentially no sebum production at all? Isn't that a problem for your theory?? :wink:

Bryan

 

[Armando Jose]

Dear Bryan;

I think that COMPLETE androgen-insensitivity syndrome is not real. The study in polymorphism in androgen receptor is not yet completed.

By the way, have you evidence of the no-existence of hormones in scalp hairs before puberty. I think that a simple biopsy could be very informative.

regards
Armando

 

[powersam]

Bryan have you read the study about the Asebia mice?

"The sebaceous gland has an important role in hair biology1. The asebia (ab) mutant mouse has rudimentary sebaceous glands and develops alopecia2, 3; here we elucidate the genetic basis for this recessive phenotype. Histopathological studies of abJ(ABJ/Le abJ/abJ; ref. 3) and recently discovered ab2J(DBA/1LacJ -ab2J/ab2J; J.P.S., unpublished data) allelic mice indicate that the hair shaft in these mice, which is unable to shed its sheath, grows in reverse toward the subcutis, leading to chronic foreign body inflammatory reactions followed by follicle loss and dermal scarring in adult mutant mice."

taken from http://www.nature.com/ng/journal/v23/n3 ... 9_268.html

 

[CCS]

i'm convinced that the majority of dht follicle damage is caused by dht synthesised by those cells. However, I still wonder if nearby sebum gland dht has a 10% or 20% effect on this, and how to measure this. we can't do a long hair loss study with 100% type 1 reduced since that would be dangerous. Also, one could argue that it did lower cellular dht levels 10%, but that 10% is not enough no make a difference with hair loss. This, then, is where we can have a test. Lets lower dht in the cell by 20% see if it makes a difference, only we must inhibit 25% of 5ar2 by assumption that some 5ar1 is entering. If that has no effect on hair growth, then that means the dht from type 1 is not affecting the hair loss. But this does not follow for people on propecia, who have 70% of dht from 5AR1 inhibited, and are questioning the effect of inhibiting another 10 or 20%. Actually, we know the difference between proscar and propecia is about that much (I think) and that leads to propecia growing 83% as much hair as proscar does. So we know dht concentration does matter. but now we are back to not knowing how much dht from 5ar1 diffuses into the cell compared to how much is in there. we know that all the dht exiting cells is diluted into the blood and non-dht generating cells, and exiting concentrations are smaller than internal concentrations, so I would think that the DHT in the blood is at a much lower concentration than the amount exiting the follicles, so by diffusion, i doubt even 5% in follicles is from the outside. there has to be a way to look at the graphs and figure out some actual numbers though.

 

[wangho75]

I have an idea. Since you are saying dutasteride and finasteride travel the bloostream of the body and less of it hits the scalp where the majority of DHT is within the scalp, what do think about hanging upside down for 30 minutes or so so the blood flows to the scalp and saturates the follicles with the dutasteride (or finasteride) enriched blood?????

 

[Bryan]

Dear Bryan;

I think that COMPLETE androgen-insensitivity syndrome is not real. The study in polymorphism in androgen receptor is not yet completed.

If it's not absolutely 100% complete, it's damned CLOSE to being complete! Like maybe 99% complete! Do you really think that would make much of a difference, Armando?

By the way, have you evidence of the no-existence of hormones in scalp hairs before puberty. I think that a simple biopsy could be very informative.

No, I've never heard of scalp biopsies being done in children just for experimental purposes like that. I agree that it would be quite interesting, though.

Bryan