What type of persons are more vulnerable to hairloss?

Bryan

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docj077 said:
Bryan said:
Doctor, Stephen is making a different point here and asking a completely different question. He is pointing out that in Uno's stumptailed macaque study which was referenced earlier in this thread, they found that the dermal papillae of juvenile monkeys (pre-pubertal) didn't show any sensitivity to androgens (in the sense of inhibiting the growth of co-cultured keratinocytes), whereas the dermal papillae of post-pubertal monkeys _did_ show such a growth suppression in response to androgens.

Bryan, I believe that you already know how this system works. All you have to do is look at bodybuilders. Resistance training increases testosterone and has been found to increase androgen receptor production in target tissues (I have a study that demonstrates this, by the way). The more androgens you put into the system, the higher the production of androgen receptors will become. You reach a physiological and signal threshold and once that occurs, the follicles are sensitized. This works faster in men with early-onset male pattern baldness, because the receptor allows you to reach that threshold faster.

Michael Barry's point about length of cultivation and androgen action is likely the correct answer. male pattern baldness is a process that takes years for it to realize its full disease potential. You have to upregulate a lot of genes and deposit a lot of collagen.

Ahh....I see. Your answer to the puzzle is that the frontal hair follicles of the juvenile, pre-balding stumptailed macaques DID INDEED have an intrinsic sensitivity to androgens (in the sense that they would suppress the growth of keratinocytes that were co-cultured with them), it's just that the level of androgen receptors in the hair follicles of those youthful monkeys was so low that the suppressive effect wasn't obvious to the researchers.

Doctor, the only problem I have with that is that there was no mention of any such hypothesis from Uno and his colleagues in that study. They seem to be as puzzled by that as the rest of us (other than you and, of course, Stephen Foote! :wink: ) who have discussed this aspect of the experiment from time to time. Doesn't it seem likely that someone as experienced and famous in the field of hairloss research as Hideo Uno would have suggested such an explanation, if he felt it was reasonable? What I get from the text of that study is that the levels of androgen (testosterone) that they used should have been sufficient to produce _some_ kind of a noticeable suppressive effect, even if there were lower levels of androgen receptors in the young monkeys.

BTW, how do you explain Sawaya's claim of finding an "intense upregulation" in the numbers of androgen receptors in the hair follicles of finasteride users? That would appear to contradict what you said above (greater androgenic stimulation upregulates androgen receptors). Furthermore, a separate study ("RNA-Levels of 5a-Reductase and Androgen Receptor in Human Skin, Hair Follicles and Follicle-Derived Cells", Eicheler et al, from the book "Hair Research for the Next Millenium", 1996) found that adding testosterone to cultures of human scalp hair follicle papilla cells DOWN-regulated androgen receptor RNA, which would seem to support Sawaya's findings and contradict the theory that androgens UP-regulate androgen receptors (at least specifically in human scalp hair follicles). Do you have any thoughts on all that?

And Stephen Foote, why have YOU remained silent on this? What do you think of docj's answer to the pre-pubertal macaque puzzle? :)
 

docj077

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Bryan said:
docj077 said:
Bryan, I believe that you already know how this system works. All you have to do is look at bodybuilders. Resistance training increases testosterone and has been found to increase androgen receptor production in target tissues (I have a study that demonstrates this, by the way). The more androgens you put into the system, the higher the production of androgen receptors will become. You reach a physiological and signal threshold and once that occurs, the follicles are sensitized. This works faster in men with early-onset male pattern baldness, because the receptor allows you to reach that threshold faster.

Michael Barry's point about length of cultivation and androgen action is likely the correct answer. male pattern baldness is a process that takes years for it to realize its full disease potential. You have to upregulate a lot of genes and deposit a lot of collagen.

Ahh....I see. Your answer to the puzzle is that the frontal hair follicles of the juvenile, pre-balding stumptailed macaques DID INDEED have an intrinsic sensitivity to androgens (in the sense that they would suppress the growth of keratinocytes that were co-cultured with them), it's just that the level of androgen receptors in the hair follicles of those youthful monkeys was so low that the suppressive effect wasn't obvious to the researchers.

Doctor, the only problem I have with that is that there was no mention of any such hypothesis from Uno and his colleagues in that study. They seem to be as puzzled by that as the rest of us (other than you and, of course, Stephen Foote! :wink: ) who have discussed this aspect of the experiment from time to time. Doesn't it seem likely that someone as experienced and famous in the field of hairloss research as Hideo Uno would have suggested such an explanation, if he felt it was reasonable? What I get from the text of that study is that the levels of androgen (testosterone) that they used should have been sufficient to produce _some_ kind of a noticeable suppressive effect, even if there were lower levels of androgen receptors in the young monkeys.

BTW, how do you explain Sawaya's claim of finding an "intense upregulation" in the numbers of androgen receptors in the hair follicles of finasteride users? That would appear to contradict what you said above (greater androgenic stimulation upregulates androgen receptors). Furthermore, a separate study ("RNA-Levels of 5a-Reductase and Androgen Receptor in Human Skin, Hair Follicles and Follicle-Derived Cells", Eicheler et al, from the book "Hair Research for the Next Millenium", 1996) found that adding testosterone to cultures of human scalp hair follicle papilla cells DOWN-regulated androgen receptor RNA, which would seem to support Sawaya's findings and contradict the theory that androgens UP-regulate androgen receptors (at least specifically in human scalp hair follicles). Do you have any thoughts on all that?

And Stephen Foote, why have YOU remained silent on this? What do you think of docj's answer to the pre-pubertal macaque puzzle? :)


I can't explain the upregulation of androgen receptors in men taking finasteride. There is obviously an increase in androgen receptor numbers in the dermal papillae cells, which I can only explain by a feed forward mechanism. The same mechanism can be seen in the muscle of men taking steroids. However, propecia increases androgen receptor numbers. I can't explain that right now. If I find the answer, I'll let you know. My guess is that it's actually a result of the increase in estrogen locally as a result of the increase in testosterone. The estrogen receptor and the androgen receptor do co-localize and they do work synergistically in the presence of estrogen. However, I can't find a good study that demonstrates estrogen activity and androgen receptor response. I'll keep looking. But, I have found studies that demonstrate that increased estrogen results in increased androgen receptor amounts within the nucleus of the observed cell. So, I don't know how they were measuring the AR concentration in that finasteride study, which means I can't really give you a solid answer. The other response to consider is the decreased action of 5 alpha reductase. By decreasing the action of this enzyme you decrease the conversion of progesterone to its 5-alpha metabolite. Progesterone metabolites other than its 5 alpha metabolite are known to bind to the androgen receptor. I can not find a study that demonstrates that increased progesterone locally increases androgen receptor creation, because such a research article simply doesn't exist. However, it would not be foolish to think that the possible increase in progesterone and estrogen locally should have very interesting effects on the levels of estrogen, progesterone, and androgen receptors.

The bigger question that I have actually involves the dermal fibroblasts and their expression of androgen receptors. Dermal fibroblasts in the presence of minimal collagen seem to express more androgen receptors. The opposite is true in the presence of increasing levels of collagen. As collagen deposition increases, the androgen receptor number is supposed to decrease. However, in male pattern baldness there is obviously a continuously progressive increase in collagen deposition which means that the androgen response is either increasing or the same. What is allowing this?


By the way, the Uno study that you mentioned does demonstrate that androgens have a direct action.

"The inhibitory effects were shown only when bald
frontal dermal papilla cells from postpubertal macaques and
outer root sheath cells were cocultured in the same wells of
multiplates (Table 1)
. The total number of outer root sheath
cells cocultured with either type of dermal papilla cells increased
by more than the sum of the number of dermal
papilla cells and outer root sheath cells cultured alone. Testosterone
(10210 m) significantly decreased the total number
of bald frontal dermal papilla cells and outer root sheath cells
in coculture. RU 58841 antagonized this testosterone-elicited
inhibition. By contrast, the total cell numbers in cocultures of
prebald frontal or occipital dermal papilla cells and outer
root sheath cells were not affected by testosterone
. Testosterone
(10210 m) had no effect on proliferation of outer root
sheath cells cultured alone."




So, obviously cells from the outer root sheath are required, but what this demonstrates is that androgens have a direct action. I don't see what the problem is here. This combined with the study posted early that demonstrated that androgens increase TGF-beta is pretty much enough for me.

Why do you and Foote continue to argue over this when this is yet another study that shows a direct androgen action?

However, I am curious to know what the signal from the outer root sheath is that is required for the inhibition to occur. The dermal papillae and surrounding tissues contain the dermal fibroblasts, so when it comes to keratinocyte inhibition, we have most of the required cells. I'm guessing that there isn't so much a signal, but a lack of energy for the follicle as a result of the loss of those cells. They supply glycogen, and thus the energy, for hair growth.
 

Armando Jose

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Docj077;




It is interesting the study of Valerie Horsley about the Blimp1 gene and its implication in the creation of sebaceous gland and hair. I didn’t know till now but he is one of the aprox. 50 genes implicated. Blimp1, mediating c-my expression, regulates the number of sebocytes and its division rate. Other two growth factors are Bmp6 and FGF18, which are expressed specifically in the bulge area. By the way, this is a very good team and his leader Elaine Fuchs a very brave, cute and interesting person. (http://jcs.biologists.org/cgi/content/full/117/21/4877)

Respect at the progenitory cells of sebaceous gland, Fuchs writes in journal Cell
http://www.rockefeller.edu/pubinfo/news ... 1504_a.php
about the multipotent power of these stem cells and watched them travel either down to the bulb of the hair follicle to form new hair, or up to the surface to create new skin epidermis and sebaceous gland. “The grafted cells, all derived from the, made new hair, skin and sebaceous glands, which excrete oil to lubricate the hair.â€
Then it is possible conclude that sebaceous gland are originated from the same stem cells that dermal papillae cells but, independently, I only want to emphasize the intrinsic relation of hair and sebaceous gland.

The possible sebaceous infiltration into the dermis, the plugging and a massive immune response it is possible but is easier that this same process happen more near from hair follicle.

You say that follicle develops first and the signals the sebaceous unit to develop. I don’t know really what happen but in a work with a good model of human hair, in pig, the author indicate that sebaceous gland is operative in stage 8b, and later in stage 9a the spherical papilla is surrounded by the hair bulb. (Development of hair coat and skin glands in fetal integument, J Anat 144:201-220, 1986)

You point out that sebaceous unit-follicle communication is required for proper formation of the pilosebaceous unit, however once the unit is formed sebum is not required for growth. Have you any reference? I have one study where a correlation between penetration properties, hair growth activity and sebum secretion was found, so they could confirm the hypothesis open and closed follicles as well inactive and active hair follicles. (Follicular penetration and targeting, J Invest Dermatol Proc. 10:301-303, 2005.


As for the genetics, the main issue. You talked very well about a genetic difference between non-balding and balding hair follicle but I didn’t ask it. I asked about the difference between HEALTHY scalp hairs, hairs from the top and around head. My idea is there is not differences between all scalp hairs, no differences between sexes, including prepubertals. I don’t know any study at this respect. So difficult is it, especially when most of investigators point out at this supposed genetic difference between scalp hairs?


To Michael:
According to my theory any strategy to avoid problems with sebum flow (creation&elimination) would be positive to prevent common hair loss, and combing hair backward is one of them, due the increase with physical contact among hairs. I posted a photo with a woman with frontal hair receding due a short fringe combed forward.

Have sebaceous gland operative in hairs from eyelashes, eyebrows, toe or fingers?
Please read in
http://en.wikipedia.org/wiki/Demodex_mite
Demodex folliculorum and Demodex brevis are the only Demodex mites that have been found on humans. D folliculorum is found in hair follicles while D brevis lives in sebaceous glands connected to hair follicles. Both species are primarily found in face, near the nose, the eyelash and eyebrowns, but also occur elsewhere on the body.

On the other hand insulin-resistance is only a theory and don’t explain the higher number of affected persons nowadays.

Respect at fluridil there is a commentary:
Dr. Sowak who did this " study " is a leading official at Interpharma which produces the stuff. Nearly everyone at Biophysica is connected to Interpharma.Nobody in the scientific world took this "study " serious.....
After disappointing sales and the refusal of French authorities to approve it they simply start a new try

Also I don’t see a lot of people using this med. Fluridil is a receptor blocker and would be a good alternative to finasteride. OTOH fluridil have a role in sebaceous gland and disminih the production of sebum. Maybe the supossed good results are connected to sebum regulation?

Another good commentary:
Fluridil started off with alot of promise, but has lost credibility over the years.

They lack any independant studies and the only available studies done were performed by the manufacture of the product themselves. It has been available for a few years now so you would think that someone would take interest in the stuff.

We must also understand that since the product cannot come in touch with water, it makes it a difficult topical to add for those of us who use other treatments such as minoxidil.

On top of this, the product is very high in Isopropyl alcohol which can irritate the scalp and dry out the hair.

Please understand that I am not against Fluridil; I would love it if the stuff worked. However, after being available for as long as it has with no independant studies supporting it, as well as the tepid feedback from this and other sites, makes me a little skeptical about the product.

You know this study, don’t you?, have you any commentary?
Effect of 5alpha-Dihydrotestosterone and Testosterone on Apoptosis in Human Dermal Papilla Cells.Winiarska A, Mandt N, Kamp H, Hossini A, Seltmann H, Zouboulis CC, Blume-Peytavi U.
Department of Dermatology and Allergy, Charite-Universitatsmedizin Berlin, Berlin, Germany.

Pathogenetic mechanisms in androgenetic alopecia are not yet fully understood; however, it is commonly accepted that androgens like testosterone (T) and 5alpha-dihydrotestosterone (5alpha-DHT) inhibit hair follicle activity with early induction of the catagen. Thus, we investigated the influence of T and 5alpha-DHT on proliferation, cell death and bcl-2/bax expression in cultured dermal papilla cells (DPC) from nonbalding scalp regions of healthy volunteers. T and 5alpha-DHT induced apoptosis in DPC in a dose-dependent and time-related manner; in addition a necrotic effect due to T at 10(-5)M was found. Interestingly, bcl-2 protein expression was decreased in T- and 5alpha-DHT-treated cells, leading to an increase in the bax/bcl-2 ratio. In addition, T and 5alpha-DHT induced proteolytic cleavage of caspase 8 and inhibited proliferation of DPC at 10(-5)M. High concentrations of T and 5alpha-DHT were needed to induce apoptotic effects in DPC. These data suggest that DPC from nonbalding scalp regions do have the capacity to undergo apoptosis, but need a high androgen stimulus. The present study provides an interesting new pathogenetic approach in androgenetic alopecia. Copyright (c) 2006 S. Karger AG, Basel.

PMID: 16931898 [PubMed - as supplied by publisher]



Finally,
I “sellâ€, acording to my theory, a totally free preventive method to avoid common hair loss. Allow grow scalp hair to a minimal length. Is so bad? Is it interferering the sales of finasteride, dutasteride, minoxidil, ketoconazole, pirictone olamine? I don’t think so.
And by the way, are you using anyone of the listed meds?, or better what is your prevention choice? Maybe dutasteride or MK8046?. Please note that I ask for a preventive method, not curative.

Armando
 

docj077

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Armando Jose said:
Docj077;

As for the genetics, the main issue. You talked very well about a genetic difference between non-balding and balding hair follicle but I didn’t ask it. I asked about the difference between HEALTHY scalp hairs, hairs from the top and around head. My idea is there is not differences between all scalp hairs, no differences between sexes, including prepubertals. I don’t know any study at this respect. So difficult is it, especially when most of investigators point out at this supposed genetic difference between scalp hairs?

Armando

Armando, there is a very real difference in the scalp between healthy scalp hair and balding scalp hair. Balding scalp hair appears to have higher concentrations of androgen receptors and it also seems to have higher levels of five alpha reductase. Not only is this true, but it also has higher levels of IGF-1 and TGF-beta, which would be expected due to the increased androgen action as a result of more androgen receptors and more androgen production in those follicles.

I do not know if there is an intrinsic difference in the growth rate of scalp hair from the temples vs. the occiput, but I do know that a difference exists when you compare scalp hair to other hair on the human body. Any difference in scalp hair growth rate or inhibition of scalp hair should be supplied by the exogenous production of hormones and their eventual binding and/or conversion within the follicle itself. The difference should be decided by where androgen action is increased the most, which should be where potent androgens are produced the fastest and where they have the greatest opportunity to bind.
 

mumuka

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Armando ,i found this post on another site. It could mean nothing.... i`ll post it just to put a little gas on the fire. :D

The thread starter asks ``to the ppl who add olive oil to their regi........when do u often use it?
and is it effective? ``

Here is Thinmans reply :
Thinman123
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Posts: 88
Joined: Mar 2007
Sunday June 03, 2007 1:07 PM


i have an uncle who uses it everyday!..pure olive oil..he styles his hair with it and spikes his hair up with it..hes been doing it eversincce he was young..and i swear to god his hairline is PERFECT! not one hair lost..he is 42 yrs old by the way and i WISH I had his hair..thick black hair..he is always in a relaxed mood also..always cracking jokes and having a good time..not once have i seen him upset..that might be another factor..by yea, he uses olive oil everyday and he stayed at my house for a couple of months and ive seen him do it.. (he used to get oil stains on the pillow)
 

michael barry

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Unfuckkingbelievable.


I post THREE pictures of FLURIDIL regrowing hair, two of them fairly impressive, and Armando acts as if it doesn't work at all.


Studies on Fluridil. I have posted two new ones in the past few weeks.

Here is a fluridil study, http://www.med.muni.cz/biomedjournal/pd ... /49_58.pdf
The study is for hirsutism and shows a woman who lost a mustache using fluridil.

Here is a womans androgenic alopecia study with fluridil,
http://www.med.muni.cz/biomedjournal/pd ... /35_48.pdf
ALL OF THE WOMEN ARMANDO, had greater hair diameters in the study, and some had 20-percent increases (or very close to that) in hair diameter.


There is no big topical spironolactone study for baldness that Im aware of, but we are pretty certain it works. There are three studies for fluridil.

Fluriil is a pain-in-the-*** because they dont want you shampooing much on it, and people like to shampoo. Its also pricey, and is made by a small company that does not have the money in all probablility to pay universities for large formal trials. Revivogen hasnt had a FDA trail either, but the pics on their website demonstate some efficacy. Since its difficult to use other hypertrichotis with , many are going to shun fluridil. Anti-androgens havent had a track record of generating great regrowth on their own. This will keep people away from fluriil in large numbers in my opinion.



Armando wrote: "On the other hand insulin-resistance is only a theory and don’t explain the higher number of affected persons nowadays"

Thats a gross oversimplification of what I said, however higher T-levels, levels of free T, and higher levels of DHT would indeed explain the higher numbers of men balding in their twenties and thirties. The Japanese docs sure as hell point the finger at the Westernized diet.
 

michael barry

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Unfuckkingbelievable.


I post THREE pictures of FLURIDIL regrowing hair, two of them fairly impressive, and Armando acts as if it doesn't work at all.


Studies on Fluridil. I have posted two new ones in the past few weeks.

Here is a fluridil study, http://www.med.muni.cz/biomedjournal/pd ... /49_58.pdf
The study is for hirsutism and shows a woman who lost a mustache using fluridil.

Here is a womans androgenic alopecia study with fluridil,
http://www.med.muni.cz/biomedjournal/pd ... /35_48.pdf
ALL OF THE WOMEN ARMANDO, had greater hair diameters in the study, and some had 20-percent increases (or very close to that) in hair diameter.


There is no big topical spironolactone study for baldness that Im aware of, but we are pretty certain it works. There are three studies for fluridil.

Fluriil is a pain-in-the-*** because they dont want you shampooing much on it, and people like to shampoo. Its also pricey, and is made by a small company that does not have the money in all probablility to pay universities for large formal trials. Revivogen hasnt had a FDA trail either, but the pics on their website demonstate some efficacy. Since its difficult to use other hypertrichotis with , many are going to shun fluridil. Anti-androgens havent had a track record of generating great regrowth on their own. This will keep people away from fluriil in large numbers in my opinion.



Armando wrote: "On the other hand insulin-resistance is only a theory and don’t explain the higher number of affected persons nowadays"

Thats a gross oversimplification of what I said, however higher T-levels, levels of free T, and higher levels of DHT would indeed explain the higher numbers of men balding in their twenties and thirties. The Japanese docs sure as hell point the finger at the Westernized diet.
 

Bryan

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docj077 said:
I can't explain the upregulation of androgen receptors in men taking finasteride. There is obviously an increase in androgen receptor numbers in the dermal papillae cells, which I can only explain by a feed forward mechanism.

Actually, do we even know for a FACT that there are significantly fewer androgen receptors in pre-pubertal hair follicle cells? It would seem like a fairly safe bet, but nevertheless I'd like to see some actual scientific evidence for it. The only study I've ever heard of having anything at all to do with the general level of androgenic stimulus in scalp hair follicles of pre-pubertal humans is the one Armando cited recently, in which a doctor measured levels of androgens in the hair roots of children. But as far as I know, there was no measurement of androgen receptors.

docj077 said:
The same mechanism can be seen in the muscle of men taking steroids.

I would never assume that all human tissues behave in the same way in that regard. In other words, androgens might upregulate androgen receptors in one tissue, and downregulate them in another.

docj077 said:
However, propecia increases androgen receptor numbers. I can't explain that right now. If I find the answer, I'll let you know. My guess is that it's actually a result of the increase in estrogen locally as a result of the increase in testosterone. The estrogen receptor and the androgen receptor do co-localize and they do work synergistically in the presence of estrogen. However, I can't find a good study that demonstrates estrogen activity and androgen receptor response. I'll keep looking. But, I have found studies that demonstrate that increased estrogen results in increased androgen receptor amounts within the nucleus of the observed cell.

I'm sure that the studies you're referring to are in vitro ones with cell cultures (I'd appreciate if you could cite one or two of those for me...I'd like to take a look at them), but there's an obvious rationale for why that would happen in vivo, assuming that androgens do indeed down-regulate androgen receptors like Sawaya and Eicheler found: giving an animal estrogen would reduce its own indigenous production of androgens by way of suppressing the HPT axis, which in turn should then upregulate ARs in scalp hair follicles (notice that I'm being careful to specify scalp hair follicles...I'm making no assumptions at all about what would happen to levels of androgen receptors in any other body tissue).

docj077 said:
So, I don't know how they were measuring the AR concentration in that finasteride study, which means I can't really give you a solid answer. The other response to consider is the decreased action of 5 alpha reductase. By decreasing the action of this enzyme you decrease the conversion of progesterone to its 5-alpha metabolite. Progesterone metabolites other than its 5 alpha metabolite are known to bind to the androgen receptor. I can not find a study that demonstrates that increased progesterone locally increases androgen receptor creation, because such a research article simply doesn't exist. However, it would not be foolish to think that the possible increase in progesterone and estrogen locally should have very interesting effects on the levels of estrogen, progesterone, and androgen receptors.

I'm still somewhat skeptical that the (alleged and/or assumed) lower level of androgen receptors in pre-pubertal hair follicles, even if it really does exist, really has all that much to do with the concurrent levels of androgens being circulated in the body. What if it's just a kind of "set point" that gets altered during/after puberty, much like the "set point" for androgens themselves gets altered (we still don't the exact reason(s) for the dramatic increase in testosterone production during puberty)? Sawaya's and Eicheler's evidence for the downregulation of ARs in scalp hair follicles by androgens seems so simple and clear-cut, it's difficult for me to think that there's a simple and direct one-to-one positive correspondence between them.

docj077 said:
By the way, the Uno study that you mentioned does demonstrate that androgens have a direct action. {snip}

So, obviously cells from the outer root sheath are required, but what this demonstrates is that androgens have a direct action. I don't see what the problem is here. This combined with the study posted early that demonstrated that androgens increase TGF-beta is pretty much enough for me.

Why do you and Foote continue to argue over this when this is yet another study that shows a direct androgen action?

We continue to argue about it, but it doesn't really have anything to do with whether or not androgens have a "direct" effect. Stephen's specific objection to that part of the study is that nobody has any explanation (other than the one you posted earlier) for why pre-pubertal macaque hair follicles don't seem to be sensitive to androgens, but then become sensitive to them after puberty. He counts that as a major weakness of the accepted theory, which shows just how bereft he is of any evidence at all in support of his own. He has to find some minor reason like that to attack the standard theory.
 

Armando Jose

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Thanks Mumuka. I did read the post about olive oil.

Is another positive case to avoid common baldness. It is in the line of my theory but I would use jojoba oil, or better jojoba oil with different essential oils, instead olive oil due at the special characteristic of the liquid wax of Jojoba.

Armando[/quote]
 

Armando Jose

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Docj077 wrote
Armando, there is a very real difference in the scalp between healthy scalp hair and balding scalp hair. Balding scalp hair appears to have higher concentrations of androgen receptors and it also seems to have higher levels of five alpha reductase. Not only is this true, but it also has higher levels of IGF-1 and TGF-beta, which would be expected due to the increased androgen action as a result of more androgen receptors and more androgen production in those follicles.

Yes, I know the differences in affected hairs, but I want know if this difference exist before hairs are afected. I mean in healthy scalp hairs.
Its clear that the genetical expression of genes is different when a scalp hairs is in a different enviroment.

But, thanks for your effort even you are incapable looking for a suitable study.

I also failled with it.


Armando
 

Armando Jose

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Thank you Michael Barry for the links to studies with fluridil.

I take note but I would like other independent studies about this.

Armando
 

Armando Jose

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Bryan wrote:
Actually, do we even know for a FACT that there are significantly fewer androgen receptors in pre-pubertal hair follicle cells? It would seem like a fairly safe bet, but nevertheless I'd like to see some actual scientific evidence for it. The only study I've ever heard of having anything at all to do with the general level of androgenic stimulus in scalp hair follicles of pre-pubertal humans is the one Armando cited recently, in which a doctor measured levels of androgens in the hair roots of children. But as far as I know, there was no measurement of androgen receptors.

This is an important issue in order to clear all doubts, an study in healthy scalp hairs in prepubertal in both sexes and in two areas of head, including sebum, steroids and androgen receptors. Is it so difficult to make?

Armando
 

Old Baldy

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Guys, are we getting closer to understanding how the genes might influence male pattern baldness?

Does anyone know of a "medication" that might lower the SRY expression locally? Even a little bit?

1: Dermatology. 2007;214(3):199-204. Links
Expression of sex-determining genes in the scalp of men with androgenetic alopecia.Chen W, Yang CC, Tsai RY, Liao CY, Yen YT, Hung CL, Chen KF, Tsai SJ, Zouboulis CC.
Department of Dermatology, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC. wchen@cgmh.org.tw

BACKGROUND: The regulation of the cutaneous steroidogenesis in patients with androgenetic alopecia remains largely unclear. OBJECTIVE: The purpose of this study was to quantify the expression of the sex-determining genes in different scalp areas. METHODS: Paired scalp specimens from frontal and occipital scalp areas of 10 patients were examined by real-time RT-PCR for mRNA expression and of 40 patients (mean age 34.9 years, range twenty-two to fifty-eight) by Western blotting for protein analysis. RESULTS: The SOX-9 mRNA was most abundant in the skin, while SF-1 mRNA was sparsely detected. The protein levels of DAX-1, SRY and WT-1 were significantly higher in the bald scalp (p=0.003, 0.004 and 0.03, respectively). Only the SRY expression showed a positive correlation with the baldness severity in Norwood-Hamilton classification (p=0.024). There was no association between patient's age and the protein levels. Immunostaining of SOX-9 was detected in the outer root sheath keratinocytes of hair follicles but not in the dermal papillae. CONCLUSION: Further study on a larger population, including normal subjects and female patients, is needed to confirm the pathogenic role of sex-determining genes in androgenetic alopecia. Copyright (c) 2007 S. Karger AG, Basel.

PMID: 17377380 [PubMed - indexed for MEDLINE]
Now how do we REDUCE those sex determining genes in our male pattern baldness scalps!!??

What makes our male pattern baldness scalps have more of those sex determining genes?

It appears to be that da** Y chromosome we all have. Some of us express the Y chromosome more in our scalps and, the more they express it, the more baldness they appear to suffer?

If we could somehow lower that expression LOCALLY (or in a "targeted" way) could we cure baldness?

Here's an older study:

071 Transcriptional Regulation of Type II 5á-Reductase in Human Dermal Papilla Cells

Jotaro Nakanishi and Toshihiko Hibino. Shiseido Life Science Research Center, Yokohama, Japan.

Previous studies suggested that type II 5alpha-reductase (5aRII) contributed to androgenetic hair loss. This was supported by the facts that 1) androgenetic alopecia is not observed in patients with 5aRII deficiency, and 2) finasteride, a specific inhibitor of 5aRII, is effective on the treatment of androgenetic alopecia. In spite of its importance, regulatory mechanism of 5aRII is still unclear. In this study, we tried to find out the transcriptional regulation of 5aRII in human dermal papilla cells (hDPCs). First, we isolated a genomic clone containing 6-kb of the 5’-flanking region of 5aRII gene from a human genomic library. In the immediate upstream sequence from the transcription start site between –1 to –200, there are three GC-boxes resembling recognition sites for Sp1/Sp3, but no TATA or CAAT sequences. Analysis of the promoter activity revealed that the second GC-box at –47/–42 was responsible for the minimal promoter activity. Although there are many candidate molecules to control the transcriptional activity of 5aRII, we focused on SRY (sex-determining region Y), a male specific transcriptional factor. Within the –2400/–1850 region, multiple SRY binding sites were obserbed. The mRNA level of 5aRII was in proportion to the expression level of SRY in hDPCs from beard and frontal scalp with androgenetic alopecia. To confirm the function of SRY, hDPCs were transfected with SRY expression plasmid. The expression of 5aRII in the transfected cells was remarkably stimulated as compared with control cells. These results suggest that SRY is a male-specific transcriptional stimulator for 5aRII in hDPCs.

None of this is earth shattering news but has anyone found anything that might work to neutralize this SRY expression? Or is this a "Star Trek" type of question? :)
 

Armando Jose

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Old baldy, nice job.


The more important thing:
CONCLUSION: Further study on a larger population, including normal subjects and female patients, is needed to confirm the pathogenic role of sex-determining genes in androgenetic alopecia.


In my opinion it is neccesary the same study with normal subjects and both sexes, including prepubertal.

By the way, You say:
more they express it, the more baldness they appear to suffer?
If we could somehow lower that expression LOCALLY (or in a "targeted" way) could we cure baldness?


Although it could be a little harsh, in my opinion there is no an actual cure, including the tunning of gene expresion because it is very difficult, but imposible, target extrictly local in certains zones or hairs. So is better, more better, try to find a forceful preventive method. This one demands the knowledge of the first events in common hair loss and then it is neccesary look in healthy persons.

Again, thank you for your find.


Armando
 

Old Baldy

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Yes Armando, maybe it's wishful thinking. :(

It's irritating to know what might initially cause male pattern baldness but we're unable to do a da** thing (i.e., DIRECTLY) about it! :-x
 

docj077

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Bryan said:
docj077 said:
I can't explain the upregulation of androgen receptors in men taking finasteride. There is obviously an increase in androgen receptor numbers in the dermal papillae cells, which I can only explain by a feed forward mechanism.

Actually, do we even know for a FACT that there are significantly fewer androgen receptors in pre-pubertal hair follicle cells? It would seem like a fairly safe bet, but nevertheless I'd like to see some actual scientific evidence for it. The only study I've ever heard of having anything at all to do with the general level of androgenic stimulus in scalp hair follicles of pre-pubertal humans is the one Armando cited recently, in which a doctor measured levels of androgens in the hair roots of children. But as far as I know, there was no measurement of androgen receptors.

docj077 said:
The same mechanism can be seen in the muscle of men taking steroids.

I would never assume that all human tissues behave in the same way in that regard. In other words, androgens might upregulate androgen receptors in one tissue, and downregulate them in another.

If the response is not localized to the tissues, then you are correct when you say it would be due to the HPA.

Here's what I've found regarding androgen receptor expression. In some studies, there seems to be a increase in androgen receptors (ie the finasteride study you mentioned). In other studies, androgens have been found to not increase AR production, but create more stable ARs. That's something that we already know. The higher the potency of the androgen, the more stable the androgen receptor becomes. For example, testosterone binding to the AR creates a less stable configuration than when DHT binds to the AR. The difference in stability is likely what allows DHT and testosterone to initiate the transcription of different genes.


FSH increases AR in sertoli cells (that one is a no-brainer). Growth hormone, prolactin, and epidermal growth factor have all been found to increase AR in prostate. Trans-retinoic acid can downregulate or upregulate AR production depending upon the particular cell line that is being studied.

Also, 17beta-estradiol has been observed to enhance androgen binding to the cytoplasmic androgen receptor in prostate.

The problem that I have with all the above and the problem that you will have, as well, is that most of these observations are not from research involving hair follicles.



I find this entire study to be incredibly interesting. They enjoy making some rather interesting conclusions, but there are a lot of good studies referenced here.

http://edrv.endojournals.org/cgi/reprint/21/4/363.pdf

"In rat preputial sebocytes, androgen receptor expression has been found to increase with sebocyte differentiation (93). Androgen receptor mRNA abundance seems to approach its maximum at the stage at which sebocytes achieve competence for their specific pattern of lipid
accumulation."



"Estrogen prolongs the growth period of scalp hair by increasing
cell proliferation rates and postponing the anagentelogen
transition (214). Estrogen in low dosage stimulates
pubic and axillary hair growth slightly. This is clear from
observations that pubic hair increases upon inducing puberty
in hypogonadal patients with physiological doses of
estradiol alone (215). This occurs without a detectable increase
in plasma androgens. It is possible that this effect of
estrogen on hair growth is mediated in part by induction of
androgen receptors (216), or by increase in IGF-I (217). In late
pregnancy, when estrogen levels are high, a high proportion
of scalp hair follicles remain in anagen (218). Postpartum, a
large number of hair follicles simultaneously advance into
telogen, causing loss of a large number of hairs. This postpartum
telogen effluvium has been postulated to be caused
by the rapid decrease of estrogen at the time of delivery (219).
On the other hand, estrogen directly suppresses sebaceous
gland function (1, 3, 75, 220, 221). An estrogen effect is clear
at ethinyl estradiol doses of 35 mg/day or more (222)"

I can not find any other studies, because they simply haven't been done. I'll keep looking.
 

S Foote.

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Bryan said:
docj077 said:
Bryan said:
Doctor, Stephen is making a different point here and asking a completely different question. He is pointing out that in Uno's stumptailed macaque study which was referenced earlier in this thread, they found that the dermal papillae of juvenile monkeys (pre-pubertal) didn't show any sensitivity to androgens (in the sense of inhibiting the growth of co-cultured keratinocytes), whereas the dermal papillae of post-pubertal monkeys _did_ show such a growth suppression in response to androgens.

Bryan, I believe that you already know how this system works. All you have to do is look at bodybuilders. Resistance training increases testosterone and has been found to increase androgen receptor production in target tissues (I have a study that demonstrates this, by the way). The more androgens you put into the system, the higher the production of androgen receptors will become. You reach a physiological and signal threshold and once that occurs, the follicles are sensitized. This works faster in men with early-onset male pattern baldness, because the receptor allows you to reach that threshold faster.

Michael Barry's point about length of cultivation and androgen action is likely the correct answer. male pattern baldness is a process that takes years for it to realize its full disease potential. You have to upregulate a lot of genes and deposit a lot of collagen.

Ahh....I see. Your answer to the puzzle is that the frontal hair follicles of the juvenile, pre-balding stumptailed macaques DID INDEED have an intrinsic sensitivity to androgens (in the sense that they would suppress the growth of keratinocytes that were co-cultured with them), it's just that the level of androgen receptors in the hair follicles of those youthful monkeys was so low that the suppressive effect wasn't obvious to the researchers.

Doctor, the only problem I have with that is that there was no mention of any such hypothesis from Uno and his colleagues in that study. They seem to be as puzzled by that as the rest of us (other than you and, of course, Stephen Foote! :wink: ) who have discussed this aspect of the experiment from time to time. Doesn't it seem likely that someone as experienced and famous in the field of hairloss research as Hideo Uno would have suggested such an explanation, if he felt it was reasonable? What I get from the text of that study is that the levels of androgen (testosterone) that they used should have been sufficient to produce _some_ kind of a noticeable suppressive effect, even if there were lower levels of androgen receptors in the young monkeys.

BTW, how do you explain Sawaya's claim of finding an "intense upregulation" in the numbers of androgen receptors in the hair follicles of finasteride users? That would appear to contradict what you said above (greater androgenic stimulation upregulates androgen receptors). Furthermore, a separate study ("RNA-Levels of 5a-Reductase and Androgen Receptor in Human Skin, Hair Follicles and Follicle-Derived Cells", Eicheler et al, from the book "Hair Research for the Next Millenium", 1996) found that adding testosterone to cultures of human scalp hair follicle papilla cells DOWN-regulated androgen receptor RNA, which would seem to support Sawaya's findings and contradict the theory that androgens UP-regulate androgen receptors (at least specifically in human scalp hair follicles). Do you have any thoughts on all that?

And Stephen Foote, why have YOU remained silent on this? What do you think of docj's answer to the pre-pubertal macaque puzzle? :)

I have not posted because i have a life outside of these forums, that often restricts the time i have to post.

The basic scientific problem with the argument above, is that it just tries to make results that don't fit with a theory, comform to that theory by using assumptions!

That is why reputable scientists like Hideo Uno just dont raise this kind of unscientiic reasoning :wink:

The simple bottom line is this.

Androgens do not "directly" convert normal scalp follicles into male pattern baldness follicles in "ANY" experiment we have to date!

If you are going to speculate about unfounded mechanisms for this result, the very least you have to do is to "prove" some kind of pre-existing "difference" in follicles in people prone to male pattern baldness, and those not!

After the fact is not good enough! There are many possible external effects that "could" change the growth of follicles, but the "internal" current theory means some kind of pre-existing difference, "REGARDLESS" of androgen levels, receptors etc.

So far the evidence states there is "NO" internal difference in various follicles in the way they "directly" respond to androgens, because androgens "DO NOT" directly change follicle growth rates in known experiments!

In regard to that immuno mice study that used "whole" human balding and non balding follicles.

It doesn't matter that the study did not specificaly mention TGF beta-1, the fact is "Doctor" that "YOU" try to claim TGF beta-1 is the culprit in the cause of male pattern baldness!

So explain to us "Doctor" why when all the same conditions exist in this study for such an influence of TGF beta-1, that these human male pattern baldness follicles grow to the same kind of size as the other scalp follicles? :wink:

S Foote.
 

michael barry

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Stephen,

I know youre going to claim that "its just cells, not whole hairs", however I feel compelled to point out that when you say "we have no experiments showing non-male pattern baldness hairs being converted to male pattern baldness hairs, etc....." to post this:


Effect of 5alpha-dihydrotestosterone and testosterone on apoptosis in human dermal papilla cells.Winiarska A, Mandt N, Kamp H, Hossini A, Seltmann H, Zouboulis CC, Blume-Peytavi U.
Department of Dermatology and Allergy, Charité-Universitatsmedizin Berlin, Berlin, Germany.

Pathogenetic mechanisms in androgenetic alopecia are not yet fully understood; however, it is commonly accepted that androgens like testosterone (T) and 5alpha-dihydrotestosterone (5alpha-DHT) inhibit hair follicle activity with early induction of the catagen. Thus, we investigated the influence of T and 5alpha-DHT on proliferation, cell death and bcl-2/bax expression in cultured dermal papilla cells (DPC) from nonbalding scalp regions of healthy volunteers. T and 5alpha-DHT induced apoptosis in DPC in a dose-dependent and time-related manner; in addition a necrotic effect due to T at 10(-5) M was found. Interestingly, bcl-2 protein expression was decreased in T- and 5alpha-DHT-treated cells, leading to an increase in the bax/bcl-2 ratio. In addition, T and 5alpha-DHT induced proteolytic cleavage of caspase 8 and inhibited proliferation of DPC at 10(-5) M. High concentrations of T and 5alpha-DHT were needed to induce apoptotic effects in DPC. These data suggest that DPC from nonbalding scalp regions do have the capacity to undergo apoptosis, but need a high androgen stimulus. The present study provides an interesting new pathogenetic approach in androgenetic alopecia.

PMID: 16931898 [PubMed - indexed for MEDLINE










Old Baldy, that was excellent information. The type of thing I hoped to encounter on hairloss talk websites. A real find


Armando,
The four universities that completed those two studies (three in Czechoslovakia and one here in California, aren't "owned' by biopharma or whatever little company makes fluridil. They had a picture of a woman with a mustache, and then without a mustache. Thats pretty good proof.
You, Armando, should be all for topical receptor blockers that would reduce sebum secretions anyway. The less sebum that is made, means there is less to make trouble for the philosebaceous unit. Wiping the head with a towel every few hours would also be something that should be good according to what you believe.
 

Bryan

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S Foote. said:
The basic scientific problem with the argument above, is that it just tries to make results that don't fit with a theory, comform to that theory by using assumptions!

Actually, docj presented a hypothesis to explain the observation in pre-pubertal macaques. Do you know the difference between a hypothesis and an assumption?

S Foote. said:
The simple bottom line is this.

Androgens do not "directly" convert normal scalp follicles into male pattern baldness follicles in "ANY" experiment we have to date!

Now YOU are the one presenting a hypothesis. You don't really have any physical evidence for making such a claim. For all we know, docj's hypothesis could in fact be correct in that ALL scalp hair follicles are actually "male pattern baldness follicles", it's just that pre-pubertal ones don't yet have sufficient numbers of androgen receptors to demonstrate it in an obvious fashion.

S Foote. said:
If you are going to speculate about unfounded mechanisms for this result, the very least you have to do is to "prove" some kind of pre-existing "difference" in follicles in people prone to male pattern baldness, and those not!

With this newer study which has been recently re-posted by Armando and Old Baldy, it seems to be becoming increasingly clear that ALL scalp hair follicles are "prone" to male pattern baldness to some degree (quite possibly even pre-pubertal ones), it's just that some are more sensitive to that problem than others.

S Foote. said:
After the fact is not good enough! There are many possible external effects that "could" change the growth of follicles, but the "internal" current theory means some kind of pre-existing difference, "REGARDLESS" of androgen levels, receptors etc.

That's correct. Unfortunately, you're getting back to that fundamental question for which we don't (yet) have an answer, which is why androgens stimulate the growth of most body hair, but suppress the growth of scalp hair.

It's highly amusing to most of us that your whole reason for participating in this forum is just to constantly emphasize and dwell on that one specific lack of information in the current theory of male pattern baldness so that you can push your own eccentric theory; but if that's what floats your boat, go for it! :wink:

S Foote. said:
So far the evidence states there is "NO" internal difference in various follicles in the way they "directly" respond to androgens, because androgens "DO NOT" directly change follicle growth rates in known experiments!

Again, that's purely a hypothesis on your part. It could well be that docj's idea is correct: pre-pubertal scalp hair follicles _might_ show a similar suppression, if only they had the same numbers of androgen receptors as hair follicles from older scalps. But that's something that needs to be tested, it's not something for you to sit back in your armchair and pontificate about! :wink:
 
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