Back to the roots: Causes and effects of elevated DHT

[benjt]

There is much abuzzin about many things these days: Derma rolling, DKK-1 inhibition, prostaglandine inhibition. From PGD-2 on and downstream, the hairloss process has been pretty much figured out (PGD-2 is an immunue response, leading to inflammation, leading to fibrosis, leading to the squeezing of the hair papilla and cutting off of the lower stem cell reservoir).

All of the treatments that we discuss here, though, are only working on the downstream effects of DHT (except for DKK1 which I still havent quite figured out. If somebody could link a good study on the basic scince, that's be great). Thus, they address only the symptoms, but not the cause.

I want to use this thread for collection of information regarding two big mysteries:

1. What exactly the elevated DHT in our scalp causes directly (completely ignoring indirect causes down the road, as they have been studied to great extent), i.e. the missing link between DHT elevation and PGD-2 elevation
2. What causes DHT to be overproduced en masse in/directly around our follicles in the first place.

Any input, especially on 2., would be greatly appreciated.

And before somebody says that DKK-1 upregulates DHT: That is a common misconception that has unfortunately spread quite a bit. In fact, it is the other way around:

DKK1 is one of the most upregulated genes in androgen-potentiated balding, with DKK-1 messenger RNA upregulated a few hours after DHT treatment of hair follicles

It seems that, when present, DHT leads to DKK-1 activation, rather than the other way around. Then again, DKK-1 could be the missing link in the chain DHT -> ? -> PGD-2, but I dont want to make any unconfirmed statements here.

 

[KeepMovin]

Hi benjt nice topic.

On 2... From what I gather so far, it seems elevated local 5AR can play a big part.
Then I wonder - why elevated 5ar - and then you look at modern life and see
many reasons why — inflammation.

Finding the cause of inflammation seems to be tricky, and it seems
many people give up (not sure i blame them) trying to figure it all out.

Another thing that interests me is how more men bald with age, yet testosterone
drops and estrogen rises with age. Then there is SHBG levels as well.

I can't help but think that aiming to keep testosterone levels
optimized is a good thing to do for hair.

 

[shivers20]

There is much abuzzin about many things these days: Derma rolling, DKK-1 inhibition, prostaglandine inhibition. From PGD-2 on and downstream, the hairloss process has been pretty much figured out (PGD-2 is an immunue response, leading to inflammation, leading to fibrosis, leading to the squeezing of the hair papilla and cutting off of the lower stem cell reservoir).

All of the treatments that we discuss here, though, are only working on the downstream effects of DHT (except for DKK1 which I still havent quite figured out. If somebody could link a good study on the basic scince, that's be great). Thus, they address only the symptoms, but not the cause.

I want to use this thread for collection of information regarding two big mysteries:

1. What exactly the elevated DHT in our scalp causes directly (completely ignoring indirect causes down the road, as they have been studied to great extent), i.e. the missing link between DHT elevation and PGD-2 elevation
2. What causes DHT to be overproduced en masse in/directly around our follicles in the first place.

Any input, especially on 2., would be greatly appreciated.

And before somebody says that DKK-1 upregulates DHT: That is a common misconception that has unfortunately spread quite a bit. In fact, it is the other way around:

It seems that, when present, DHT leads to DKK-1 activation, rather than the other way around. Then again, DKK-1 could be the missing link in the chain DHT -> ? -> PGD-2, but I dont want to make any unconfirmed statements here.

DHT-> PGD2-> DKK-1?

I have read studies where PGE2 reduced DKK-1 by a significant amount in dermal fibroblasts, wonder if PGD2 is having the opposite effect, increasing DKK-1

 

[DesperateOne]

I don't think the entire link has been found. All those rat studies are very missleading because there are several rat studies where balding mice regrow hair simply by inhibiting some protein or something. Since balding seems to be very much tied to the immune system, I have been searching for shops where they do bee sting therapy. I know is a bit off topic but I would like to see people try this as well.

 

[Koga]

Hi benjt nice topic.

On 2... From what I gather so far, it seems elevated local 5AR can play a big part.
Then I wonder - why elevated 5ar - and then you look at modern life and see
many reasons why — inflammation.

Finding the cause of inflammation seems to be tricky, and it seems
many people give up (not sure i blame them) trying to figure it all out.

Another thing that interests me is how more men bald with age, yet testosterone
drops and estrogen rises with age. Then there is SHBG levels as well.

I can't help but think that aiming to keep testosterone levels
optimized is a good thing to do for hair.

1) People are not balding more/faster than a few decades ago.
2) I believe the androgen receptors get more and more sensitive with age: in fact I think they get more sensitive in proportion to the drop in testosterone and DHT. Result? More balding men/hair loss.

 

[Armando Jose]

It is clear that DHT make grow hair,..., in body and sexual hair, but what in scalp hair??? why is different? Maybe the amount of DHT?
we have not yet all the keys.

Regarding point 2, Sebaceous gland is a part, as hair, of the hair follicle, or better pilosebacous unit, and the important DHT is the locally fabricated, in the words of Bryan

[FONT=&quot]"How on earth can DHT levels in the blood not affect the follicles? Please explain that to me, how all this nice, fresh new DHT doesn't just make it's way up there and attach to the androgen receptors?
I'm going to single-out this one point from your post to address, because it's always interested me for years; I may reply to the rest of your post separately.

For years back on alt.baldspot, Dr. Proctor always used to tell us that the consensus among endocrinologists is that DHT only has an effect (a significant effect?) in the tissues where it's actually produced. I never really understood _why_ that would be the case, I just made a mental note of it whenever he would say that.

Nowadays I've come to fully believe that claim, and it makes perfect sense to me. It's based not only on LOGIC, but also on actual physical experiments. For example, topical 5a-reductase inhibitors have been shown to have a "local" effect where they're applied, and that's in both humans and animals. Topical gamma-linolenic acid (GLA) in that hamster study of topical fatty acids was shown to have an effect that was starting to approach what you get with castration on the flank-organ to which it was applied, but not on the opposite flank-organ. A similar effect on a human volunteer was found by the same researchers who did the hamster study: topical GLA on his forehead significantly reduced sebum production where it was applied. The point of all this is screamingly obvious: if serum DHT were much of a factor, why didn't it keep the topical GLA from having an obvious DHT-suppressing effect in the human and in the hamsters where it was applied?

If you do a little reading, it really shouldn't be that surprising that DHT only seems to have a significant effect where it's actually produced. I was reading an interesting article in a medical journal a long time ago (sorry, I didn't even bother to write it down for later citation) that said that the great majority of DHT molecules that are manufactured inside cells (by 5a-reductase, of course) go on to bind to androgen receptors in those same cells, and produce their usual androgenic effects RIGHT THERE WHERE THEY WERE PRODUCED. Only a relatively small number of the DHT molecules "leak out" of the cell and into the bloodstream (according to the article).

Furthermore, DHT in the bloodstream is eliminated rather rapidly, with a "half-life" of a couple of hours. From a study that I've quoted many times over the years ("A Model for the Turnover of Dihydrotestosterone in the Presence of the Irreversible 5a-Reductase Inhibitors GI198745 and Finasteride", Gisleskog et al, Clin Pharmacol Ther 1998;64:636-47): (page 641) "...The elimination rate of DHT, k(OUT), was relatively high, corresponding to an elimination half-life of 2 hours."

So let's sum it all up this way:

1) Only a (small?) minority of DHT molecules make it into the bloodstream in the first place, compared to all the ones that stay inside the cells and do their dirty work right away;

2) The ones that DO make it into the bloodstream are eliminated rather rapidly, before they have a chance to do much mischief;

3) Actual physical experiments with humans and animals verify that serum DHT seems to have no significant effect as an androgenic stimulus. In other words, DHT isn't much of an endocrine hormone, it's mainly an autocrine hormone.How on earth can DHT levels in the blood not affect the follicles? Please explain that to me, how all this nice, fresh new DHT doesn't just make it's way up there and attach to the androgen receptors?[/FONT]

[FONT=&quot]I'm going to single-out this one point from your post to address, because it's always interested me for years; I may reply to the rest of your post separately.

For years back on alt.baldspot, Dr. Proctor always used to tell us that the consensus among endocrinologists is that DHT only has an effect (a significant effect?) in the tissues where it's actually produced. I never really understood _why_ that would be the case, I just made a mental note of it whenever he would say that.

Nowadays I've come to fully believe that claim, and it makes perfect sense to me. It's based not only on LOGIC, but also on actual physical experiments. For example, topical 5a-reductase inhibitors have been shown to have a "local" effect where they're applied, and that's in both humans and animals. Topical gamma-linolenic acid (GLA) in that hamster study of topical fatty acids was shown to have an effect that was starting to approach what you get with castration on the flank-organ to which it was applied, but not on the opposite flank-organ. A similar effect on a human volunteer was found by the same researchers who did the hamster study: topical GLA on his forehead significantly reduced sebum production where it was applied. The point of all this is screamingly obvious: if serum DHT were much of a factor, why didn't it keep the topical GLA from having an obvious DHT-suppressing effect in the human and in the hamsters where it was applied? [/FONT][FONT=&quot]

[/FONT][FONT=&quot]

If you do a little reading, it really shouldn't be that surprising that DHT only seems to have a significant effect where it's actually produced. I was reading an interesting article in a medical journal a long time ago (sorry, I didn't even bother to write it down for later citation) that said that the great majority of DHT molecules that are manufactured inside cells (by 5a-reductase, of course) go on to bind to androgen receptors in those same cells, and produce their usual androgenic effects RIGHT THERE WHERE THEY WERE PRODUCED. Only a relatively small number of the DHT molecules "leak out" of the cell and into the bloodstream (according to the article).

Furthermore, DHT in the bloodstream is eliminated rather rapidly, with a "half-life" of a couple of hours. From a study that I've quoted many times over the years ("A Model for the Turnover of Dihydrotestosterone in the Presence of the Irreversible 5a-Reductase Inhibitors GI198745 and Finasteride", Gisleskog et al, Clin Pharmacol Ther 1998;64:636-47): (page 641) "...The elimination rate of DHT, k(OUT), was relatively high, corresponding to an elimination half-life of 2 hours."

So let's sum it all up this way:

1) Only a (small?) minority of DHT molecules make it into the bloodstream in the first place, compared to all the ones that stay inside the cells and do their dirty work right away;

2) The ones that DO make it into the bloodstream are eliminated rather rapidly, before they have a chance to do much mischief;

3) Actual physical experiments with humans and animals verify that serum DHT seems to have no significant effect as an androgenic stimulus. In other words, DHT isn't much of an endocrine hormone, it's mainly an autocrine hormone.[/FONT]

 

[DesperateOne]

Well if serum DHT doesn't do anything it is because pgd2 was not over expressed on those test subjects. Once DHT starts, it just becomes a chain reaction and very little can be done. One point to make is that after a person goes bald, if they cut their balls, he won't throw hair. The damage has been done and on key thing that people don't pay enough attention is the fat we lose due to fibrosis. I believe that Dr. Cot will make his final result just that, the realization of the fat to maintain and regrow hair.

 

[KeepMovin]

"1) People are not balding more/faster than a few decades ago.
2) I believe the androgen receptors get more and more sensitive with age: in fact I think they get more sensitive in proportion to the drop in testosterone and DHT. Result? More balding men/hair loss."

Koga i dont mean decades ago-
Modern i mean last 100 years.

Maybe the receptor does get more sensitive, and if this is due to low test...like i said - inflammation.
Inflammation lowers test.

Also about the serum dht, that is not the relation.
The relation is the salivary dht.

 

[Sparky4444]

Also about the serum dht, that is not the relation.
The relation is the salivary dht.

hmmm...explain??

 

[KeepMovin]

I dont fully understand it. But it seems high serum dht isnt a problem. But high salivary dht is another matter and is linked to male pattern baldness.
I personally dont think dht should be feared etc... High 5 alpha reductase i would try to balance.

like benjt is getting at, theres something missing...

 

[I.D WALKER]

I really appreciate both the academic tone and bright articulate exchange of ideas here. These earnest and intelligent contributions collectively represent the clear and forward qualities entirely essential for better understanding this enigma. I will thank you in advance for uncovering the mystery.

 

[liquidfirex]

Serum DHT isn't that important, as it's been shown that follicles can metabolize cholesterol into sex hormones locally.
Igf-1 is also another factor, as it's the mediator in thickening body hair in response to dht binding, is also does the opposite in the balding scalp follicles.

 

[KeepMovin]

Benjt what are your thoughts so far? Im agree with you dht isnt the "problem" here. There is a missing link definitely.

 

[shivers20]

1) People are not balding more/faster than a few decades ago.
2) I believe the androgen receptors get more and more sensitive with age: in fact I think they get more sensitive in proportion to the drop in testosterone and DHT. Result? More balding men/hair loss.

This.

The role of DHT is to increase growth in the body. It causes sebaceous hyperplasia, gingivial hyperplasia, hypertrichosis, benign prostate hyperplasia to name just a few. It goes against everything its designed to do, doesnt make sense, why it would cause apoptosis of Dermal papilla cells.

 

[KeepMovin]

Its massively complicated.
I think the body is reacting wrongly to dht "for some reason"...something is causing this reaction. a hyper sensitive AR makes sense, "why" its sensitive is currently seen as genetic.
Although the increase in male pattern baldness usually with age yet the androgen levels drop and estrogen increase. This leads me to think there is some kind of estrogen that is also at play.

 

[benjt]

Benjt what are your thoughts so far?

No progress unfortunately. I had read an article in December 2013 or early January 2014 reporting some viable theory regarding the whole matter but I couldnt find it again :-( This was also the reason for me creating this thread. I had hoped somebody else read either the article I read or even the underlying publication.

The role of DHT is to increase growth in the body.

Sorry, but this is completely wrong. Please read the Wikipedia article on DHT. Growth of some selected features is only a very small subset of DHT's role.

Its massively complicated.
I think the body is reacting wrongly to dht "for some reason"...

As I had discussed with princessRambo when he was still around, the body might in fact not react wrongly to DHT at all. The only wrong thing, so we theorized, is the amount of DHT being produced in the scalp. DHT is linked to natural hair cycling by promoting PGD-2, which also has its role in natural hair cycling (for controlled hair death and renewal).
The main problem is not the DHT itself, but its local overproduction. Too much DHT (i.e. DHT is supposed to be there, just in much smaller amounts) leads to too much PGD-2, which then does not only fulfill its task of hair cycling, but instead keeps hair dead permanently (as opposed to temporarily during normal hair cycling) and, by massive overspilling into adjacent tissue, causing fibrosis (which is also a natural role of PGD-2 - it should should not occur around follicles). This is why scientists speak of perifollicular fibrosis.

 

[Ventures]

But if scalp or salivary DHT is crucial problem for scalp hair follicles, why topical DHT inhibitors(azelaic acid, topical finasteride and dutasteride) don't show significant success ?

My logic explanation about reduced effectiveness of topical treatments ( including topical DHT inhibitors, or topical androgen receptor blockers(CB0301, RU), they don't penetrate deep in epidermis and reach dermal papila ? I remember an advice I heard once from a forum member: It doesn't only matter what you put on your scalp, but how you put it.




Dermarolling would cause more apsorbtion in scalp, but in the same time contribute to more systematic absorption.

 

[KeepMovin]

Benjt, do you think it is dht or the receptor sensitivity? I think local 5ar is definitely not good, and looking at food or supplements may help lower this are usually all going to have good effects on overall health.

Ive been looking into oxidative stress recently and how this all ties in, and i think it definitely does.
One things that is becoming clear to me is this, i see no evolutionary argument that makes sense.

 

[benjt]

why topical DHT inhibitors(azelaic acid, topical finasteride and dutasteride) don't show significant success ?

Because these inhibitors are not necessarily administered in their bioactive form. Minoxidil, for example, is almost not bioactive at all. The body needs to metabolsie it into mixodil sulfate for it to have any effect. The same might (havent done a lot of research into topical DHT inhibitors) be true for topical finasteride and dutasteride. Usually, they are ingested and the enzymes available in our stomach are completely different from the ones available in our scalp. When ingested the enzymes convert them to bioactive substances, while when applied topically there simply are not enzymes there to do that.
Another theory is that the skin barrier blocks finasteride and dutasteride. And no, skin absorbtion does not only depend on molar mass. This cannot be stated clearly enough.

My logic explanation about reduced effectiveness of topical treatments ( including topical DHT inhibitors, or topical androgen receptor blockers(CB0301, RU), they don't penetrate deep in epidermis and reach dermal papila ? I remember an advice I heard once from a forum member: It doesn't only matter what you put on your scalp, but how you put it.

That advice is definitely true. Topical finasteride and dutasteride being ineffective can be because they are not properly absorbed, but as I said, I have no knowledge about this. Someone else might be able to shed some light on this.

Dermarolling would cause more apsorbtion in scalp, but in the same time contribute to more systematic absorption.

If absorbtion is the issue and not enzymes. Then again, systemic absorbtion will be lower with DR + topical application than with taking pills.

Benjt, do you think it is dht or the receptor sensitivity?

I think that receptor sensitivity is not the primary issue, if at all. 5ar inhibitors work because they lower the DHT production, not the AR sensitivity.

looking at food or supplements may help lower this are usually all going to have good effects on overall health.

Wouldnt say so. finasteride and dutasteride can have very bad side effects. Tea, in high amounts, has also been linked to prostate cancer.

Ive been looking into oxidative stress recently and how this all ties in, and i think it definitely does.

I did so at one point too. The problem with oxidative stress is, though, that it is responsible for all kinds of decay and can thus be linked to pretty much every decay that occurs over time in our body. Androgenetic Alopecia/male pattern baldness however are only so negligibly dependent on oxidative stress as a primary factor that I do not consider it to be of major importance. Look at biopsies of Androgenetic Alopecia/male pattern baldness struck scalps: What you see is hair sheaths being crushed between the bottom and top reservoir by fibrotic skin. That has nothing to do with oxidative stress, but only with fibrosis as a downstream effect of PGD-2. Another downstream effect is a halt of angiogenesis and loss of fat tissue.

One things that is becoming clear to me is this, i see no evolutionary argument that makes sense.

As I have recently stated in another thread, Androgenetic Alopecia/male pattern baldness does not make evolutionary sense and it does not have to. The fact alone that it still exists means that it is not enough of a disadvantage for finding a mating partner to be eradicated from the gene pool.

 

[Ventures]

Because these inhibitors are not necessarily administered in their bioactive form. Minoxidil, for example, is almost not bioactive at all. The body needs to metabolsie it into mixodil sulfate for it to have any effect. The same might (havent done a lot of research into topical DHT inhibitors) be true for topical finasteride and dutasteride. Usually, they are ingested and the enzymes available in our stomach are completely different from the ones available in our scalp. When ingested the enzymes convert them to bioactive substances, while when applied topically there simply are not enzymes there to do that.
Another theory is that the skin barrier blocks finasteride and dutasteride. And no, skin absorbtion does not only depend on molar mass. This cannot be stated clearly enough.

But why do you think finasteride isn't administered in bioactive form when applied locally or orally ? For instance Propecia pill contains active ingredient (finasteride) and sugar and other stuff which form film coton. I don't exactly understand biochemistry behind mechanisms and how exactly finasteride inhibit 5ard. Is finasteride decomposed / converted to other enzymes or substances which then bind or adhere to 5ard molecules or ?

Can someone who studied and understand biochemistry shed light how exactly is 5ard inhibited by finasteride, does that mean binding (attaching) to 5ard which results in changing of electro-chemical properties (chemical signature is changed, and T doesn't recognise 5ard any more, hence it is disabled to receive two hydrogen atoms to form DHT)