I'm looking for a crazy study....

[docj077]

This is bulls**t.

Both you and Bryan are deliberately trying to avoid the simple point here :roll:

Hey, watch what you say, Stephen! :-x I tried to explain your point to docj, but for some reason that escapes me, he hasn't addressed that in his last couple of posts. So don't be trying to say that _I_ am avoiding your point.


Bryan

Wait....what question did I miss? I'm trying to study for a test and skim these forums, so I might be missing pieces of discussions. What's the question I need to answer?

 

[docj077]

This is bulls**t.

Both you and Bryan are deliberately trying to avoid the simple point here :roll:

Hey, watch what you say, Stephen! :-x I tried to explain your point to docj, but for some reason that escapes me, he hasn't addressed that in his last couple of posts. So don't be trying to say that _I_ am avoiding your point.


Bryan

Wait....what question did I miss? I'm trying to study for a test and skim these forums, so I might be missing pieces of discussions. What's the question I need to answer?

Oh, the question about whether or not androgens directly cause male pattern baldness follicles to undergo miniaturization or how a normal follicle becomes a male pattern baldness follicle.

Well, that study that I just posted a couple of posts back took non-male pattern baldness areas (at least areas not exhibiting male pattern baldness tendencies) and basically bombarded the follicles with high levels of androgens causing them to be growth inhibited.

According to that study anyway, all that is needed for growth inhibition is androgens and it's androgens that promote the change from being nonsusceptible to susceptible.

I do not believe that anyone knows the exact mechanism of how a normal follicle becomes a male pattern baldness follicle. All that is known is that androgens are required, they act directly to inhibit growth (through pro-apoptotic factors), and their downstream effectors cause androgens to act indirectly to cause an unhealthy follicular environment histologically. There is no evidence of contact inhibition in that study. Only androgen exposure and growth inhibition.

 

[Bryan]

Docj, I'm going to explain this again more carefully, so you can understand Stephen's point very clearly:

The stumptailed macaque study that Stephen always refers to showed that when androgens are added to cultured dermal papilla cells, they apparently release soluble growth inhibitors of some sort (or stop releasing growth stimulants, or both) which stunt the growth of the co-cultured keratinocytes. That, of course, is presumed to be an important step in the balding process.

However, they also found something else that was very interesting: androgens added to PRE-PUBERTAL (non-balding) dermal papillae didn't have that same effect. That is, they didn't cause them to stunt the growth of the co-cultured keratinocytes.

So the obvious question is this: assuming that the same thing is true for humans, what actually CAUSES scalp hair follicles to go from being UNaffected by androgens to being affected by them? Stephen has been harping on that simple question for a long long time. Because the standard theory of male pattern baldness has no clear explanation for that phenomenon, he points to that as being a major problem with the overall theory. He suggest that contact inhibition itself (surprise, surprise) is what CAUSES that change in hair follicles (becoming sensitive to androgens), although I've had lots of fun by pointing out to him that he can produce no evidence of such a thing happening anywhere else in biology! :wink:

Bryan

 

[docj077]

Hmm...

Well, I know that taking a hair follicle with no signs of male pattern baldness and exposing it to a certain concentration of androgens for a certain period of time has a direct influence upon its growth. Even when this follicle is taken from a non-balding area.

It is quite likely that there is a feedback mechanism we need science to discover for us. Perhaps, androgen receptor binding and internalization causes the production of more androgen receptors and thus a stronger response over a period of time with the signal eventually becoming strong enough to induce a pro-apoptotic environment through the production of enough gene product to alter cellular capabilities. I'll have to do some more research.

I have seen no evidence for contact inhibition in any study that I've seen posted on this website. No molecule, no ligand, and no cellular change secondary to such a process.

 

[S Foote.]

Hmm...

Well, I know that taking a hair follicle with no signs of male pattern baldness and exposing it to a certain concentration of androgens for a certain period of time has a direct influence upon its growth. Even when this follicle is taken from a non-balding area.

It is quite likely that there is a feedback mechanism we need science to discover for us. Perhaps, androgen receptor binding and internalization causes the production of more androgen receptors and thus a stronger response over a period of time with the signal eventually becoming strong enough to induce a pro-apoptotic environment through the production of enough gene product to alter cellular capabilities. I'll have to do some more research.

I have seen no evidence for contact inhibition in any study that I've seen posted on this website. No molecule, no ligand, and no cellular change secondary to such a process.

Well at least there now seems to be some recognition of the issue, so i will elaborate a bit more.

I am on the record as stating that i think the in-vitro tests are dangerously misleading. I have posted a reference to such a study that showed estrogen reduced follicle cell growth, yet we know this is not so in the real world in-vivo.

The latest study you posted Doctor is quite obviously "NOT" what happens in-vivo is it! This is yet another in-vitro study that shows how misleading they can be as i said.

Androgens may well effect hair growth from the traditional "non male pattern baldness area" over very long periods of time. We know the wreath can thin out and receed in the neck area. But this is way out of the time scales of these in-vitro studies, so basic common sense tells us it is "WRONG" in true in-vivo terms!

You can "directly" effect any cell type in-vitro if you bombard it with artificial levels of "anything"! That doesn't mean these "direct" reactions are truly reflecting what happens in-vivo!

The only value of the in-vitro studies is that you can "compare reactions" on a level playing field. You can see if various samples are reacting in the same way, or differently?

So the only reliable thing to come out of the in-vitro studies, is that known "future" male pattern baldness cells are "NOT" directly changed into male pattern baldness follicles by androgens. Because they remain growth uneffected just like the alledged androgen resistent cells from other scalp follicles!

So you are still left with the problem of the evidence we have, being against the direct theory Doctor!

The thing is, you can speculate all you like about the downstream molecular effects, but these are not necessarily related to a "direct" androgen trigger? These downstream effects and changes can be more logicaly linked to "indirect" effects of androgens given the larger body of evidence.

It is important to know for sure if the androgen effect is direct or indirect, because this will make all the difference to designing effective future treatments.

The direct theory makes a very clear claim, that follicles are inherently different at the molecular level. This is why they respond to androgens "differently".

So if you claim the direct theory is correct Doctor, you have to provide proof of this different follicle "pre-programing"?

The in-vitro studies show "no difference", so to date the hard evidence is against you!

At this time you have no evidence for this claim, and what real evidence there is contradicts you!


Bryan, i apologise!

It seems you have explained my case to Doctor better than i did! But i think you still misunderstand one important factor?

You seem to still believe that once follicles are "converted" into male pattern baldness follicles, that they are then maintained "directly" by androgen inducable TGF beta-1 as in the in-vitro studies?

You are clearly claiming here that follicles "DO" become directly sensitive to androgens, regardless of the "how" correct?

I don't think for a moment that follicles "become" directly sensitive to androgens at any time!

I point out above the flaws with the in-vitro tests. But apart from this if male pattern baldness follicles did become subject to "direct" androgen inducable TGF beta-1 as in the test tube, they would have remained miniaturised in that mouse study we talked about!

No immunology in the test tube, no immunology in those mice. Androgen inducable TGF beta-1 growth restriction in the test tube, "just the opposite" of follicle re-growth in those mice!

So no Bryan, again the hard "real world" in-vivo evidence is against any "direct" action of androgens, either in the conversion of follicles "TO" male pattern baldness, or the maintainence "OF" male pattern baldness follicles!

A few comments about contact inhibition.

Doctor wrote quote:

"I have seen no evidence for contact inhibition in any study that I've seen posted on this website. No molecule, no ligand, and no cellular change secondary to such a process."

No one yet knows the "FULL" details of the growth restriction process involved in normal contact inhibition, but it is a safe bet that this involves recognised negative cell growth factors like TGF beta-1!

In fact this study proves that both contact inhibition and TGF beta-1 effect the same molecular pathway.

http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract

Quote:

"Expression of p45 reappeared 12 h after release from contact inhibition and 6-8 h after release from TGF-beta 1, while TGF-beta 1 prevented release from contact inhibition and maintained suppression of both p45 and cyclin D2. Additionally, cyclin D2 phosphorylation and its associated kinase activity were strongly inhibited by contact inhibition and TGF-beta 1. Thus suppression of p45, cyclin D2/Cdk-4, and cyclin B1/Cdc-2 expression and/or activities is targeted both by contact inhibition and by TGF-beta 1 and may define common mechanisms through which these negative growth signals are integrated."

I have also posted the link below in this thread already, perhaps people should have read this more carefully!

http://www.hairsite4.com/dc/dcboard.php ... ting_type=

Quote:


"In alopecia skin, tha abnormal streamers underneath the follicles appear to be a structural barrier for the down-growth of anagen follicles. Moreover, severe inflammatory involvement in the streamers causes suppressive growth of the follicular bulb and dermal papilla cells (see Figure 8a). Dense collagenous or hyalinized scarring streamers block the growth of follicles (Figure 8b and c). These follicular structures naturally resist any therapeutic effect for follicular growth. Moreover, associations of focal perivascular and perofollicular inflammatory cell infiltrations are often seen in alopecic skin."

The follicles have not got the ability to just "force" through these scarring steamers, why?

Because of a basic control of cell growth called "contact inhibition"!

It stands to reason that "ANY" other factor that increases resistence of surrounding tissue to anagen enlargement, would also stop follicle growth by normal contact inhibition, including increased pressure.

Contact inhibition as the primary in-vivo control of follicle size, "ALSO" makes sense of "ALL" the other related factors in male pattern baldness, as i have described before!

Professor Fuch's research showed that manipulating the WNT's and b-catenin pathways in mice, greatly increased follicle size and hair growth.

http://www.hhmi.org/fuchs/index.html

Both these pathways are known to be related to the contact inhibition pathway.

http://www.springerlink.com/content/r453v21l0r4321n2/

Fuchs also noted that tumor formation was increased in these mice. Again, this is a known effect when the factors involved in "normal" contact inhibition are "messed" with!

All the clues relating to contact inhibition and follicle size, already exist in the research. You just have to open your eyes!

S Foote.

 

[michael barry]

Docj077,

Over the past couple of years of questioning Stephen about his theory, and witnessing and participating in, the debates Bryan and Stephen have had...................even though I doubt its true, I have respect for the amount of search engine work and study reading Stephen has done.

So, just in case his theory is perhaps partially correct..........I always rinse my head after shampooing with very cold water and wait a few minutes before completely drying it. I also do Tom Hagerty's scalp excercises in the shower and for at least a few minutes while on the computer (they make your scalp pump up with blood, and would improve lymph flow). If you, Docj077, think applepoly would be good for your hair..............it would almost certainly be great if Stephen's theory was in any way correct. It contracts on your scalp (I have about 4 months of a supply of this left, and like some of the ingredients which I'll go into below for you). Those first two things, which require very little effort, would probably keep a man in hair if Stephen was correct. Thats why I dont worry too much about his theory. I already do two things that would help in case he's right.


About the apple poly...........it has abscorby palmitate (also in prox-N) which is a natural stimulant.

It has aloe leaf juice, which helps get nitric oxide released if I remember correctly (which would modulate lymphatic vasomotion)

It has B-2, B-3 (barley), and C-1 (grape seed) proanthocyanidns

It has retinyl palmitate and tocopherol (I cant remember if thats a PKC inhibitor or TNF-alpha inhibitor).

Thats it.


It struck me when I read the ingredients when I got the bottles of the stuff that "wow, I could make this myself..............pretty much". It also smells pleasant.


I think Dave001 is right about making one's own topicals. He linked a site that has ingredients where we could concievably even make our own shampoos.


Ive been interested for a while to mix up beta sis, borage seed oil, arginine, barley extract, green apple extract, grape seed extract, abscoryl palmitate, and possibly blueberries with a little vodka for a homemade topical. One could concievably add this topical to a shampoo also. Id use folligen about every other night after it. I'd love for some of the RSG's on these forums to come up with a layman's recipie for a homemade topical with all that. This topical, with its prostaglandin E-1 analogue (the GLA in the borage seed oil), the NO-releaser in arginine, and its (what I think) estrogen-mimicking compound (my pine oil experiment is beginning to show fruit......................there is less hair on the back of my hand vs. the other) would help as per Stephen's idea or the direct theory.

I hate to see men have to spend a fortune on trying to keep their damned hair.............................Boy I hope those phase two intercytex trials go well. Im ready not to think about hair anymore.

 

[docj077]

Hmm...

Well, I know that taking a hair follicle with no signs of male pattern baldness and exposing it to a certain concentration of androgens for a certain period of time has a direct influence upon its growth. Even when this follicle is taken from a non-balding area.

It is quite likely that there is a feedback mechanism we need science to discover for us. Perhaps, androgen receptor binding and internalization causes the production of more androgen receptors and thus a stronger response over a period of time with the signal eventually becoming strong enough to induce a pro-apoptotic environment through the production of enough gene product to alter cellular capabilities. I'll have to do some more research.

I have seen no evidence for contact inhibition in any study that I've seen posted on this website. No molecule, no ligand, and no cellular change secondary to such a process.

I am on the record as stating that i think the in-vitro tests are dangerously misleading.

No, in vitro tests give us the drugs we have today. In vivo studies give us the ability to give them to patients.

The latest study you posted Doctor is quite obviously "NOT" what happens in-vivo is it! This is yet another in-vitro study that shows how misleading they can be as i said.

Prove it. Find a study where they either inject testosterone or use an androgen topical and show me the evidence that states that neither inhibits hair growth in a human volunteer


Androgens may well effect hair growth from the traditional "non male pattern baldness area" over very long periods of time. We know the wreath can thin out and receed in the neck area. But this is way out of the time scales of these in-vitro studies, so basic common sense tells us it is "WRONG" in true in-vivo terms!

How are the time scales wrong? In vitro testing involves high concentrations of androgen exposure for specific time periods. Such concentrations do not necessarily coincide with the concentrations of androgens in the hair follicle meaning what takes a lab days, weeks, or even a few months can take an adult male years as one inhibitory molecule does not correlate with total inhibition of hair growth.

You can "directly" effect any cell type in-vitro if you bombard it with artificial levels of "anything"! That doesn't mean these "direct" reactions are truly reflecting what happens in-vivo!

That's a crap response and pretty much a non-sequitor in this debate. Congrats.


So the only reliable thing to come out of the in-vitro studies, is that known "future" male pattern baldness cells are "NOT" directly changed into male pattern baldness follicles by androgens. Because they remain growth uneffected just like the alledged androgen resistent cells from other scalp follicles!

I just posted a study above that says quite differently. Hair taken from non-balding regions of volunteers was clearly growth inhibited with high concentrations of testosterone in vitro. Try again.

The thing is, you can speculate all you like about the downstream molecular effects, but these are not necessarily related to a "direct" androgen trigger? These downstream effects and changes can be more logicaly linked to "indirect" effects of androgens given the larger body of evidence.

Again, the previous study shows direct effects and other in vitro and in vivo studies I've posted clearly demonstrate the increase in TGF-beta activity and the corresponding fibroblast activation and tissue remodeling that occurs.

It is important to know for sure if the androgen effect is direct or indirect, because this will make all the difference to designing effective future treatments.

Which have already been designed and include topical TGF-beta II antagonists and TGF-beta receptor antagonists, as well as, topical macrolide antibiotics that inhibit TNF-alpha function.

The direct theory makes a very clear claim, that follicles are inherently different at the molecular level. This is why they respond to androgens "differently".

All cells in the human body, other than gametes, are all molecularly identical and gene regulation is the only molecular process that makes them phenotypically different. The androgen receptor complex is one such gene regulator and there are numerous factors that can influence the transcription of a gene and the production of a gene product. Believing that a simple difference exists between the types of hair follicles is idiocy as its finest.

So if you claim the direct theory is correct Doctor, you have to provide proof of this different follicle "pre-programing"?

I don't need to. All cells in the human body have the exact same genetic sequence. It's all based on gene regulation and how the androgen/androgen nuclear receptor functions once it enters the nucleus of a cell. That's how a nuclear receptor functions.

The in-vitro studies show "no difference", so to date the hard evidence is against you!

You don't ever read anything I post, do you? There is an upregulation of TGF-beta mRNA and protein production, as well as, an increase in procollagen I production. There is also an increase in pro-apoptotic factors within dermal papillae cells, growth inhibition of keratinocytes, and extracellular remodeling by fibroblasts secondary to previously mentioned factors. The in vivo proof that these molecules cause this action is the in vitro evidence that minoxidil inhibits all apoptotic pathways in the DPCs to cause its in vivo effects. Topical procyanidins prevent TGF-beta mediated fibrosis and that Hydrangea macrophylla, a TGF-beta inhibitor, inhibits catagen induction in mouse models.

At this time you have no evidence for this claim, and what real evidence there is contradicts you!

Nope. Try again.


You seem to still believe that once follicles are "converted" into male pattern baldness follicles, that they are then maintained "directly" by androgen inducable TGF beta-1 as in the in-vitro studies?

A simplistic response and completely lacking all necessary mediators, but that's what you do best. TGF beta II is also required as is the expresssion of procollagen I.

You are clearly claiming here that follicles "DO" become directly sensitive to androgens, regardless of the "how" correct?

Prove that they don't with an in vivo study.

I don't think for a moment that follicles "become" directly sensitive to androgens at any time!

Then you'd be wrong as the follicles obviously increase the number of androgen receptors, which means that hormonal action of androgens is increased in male pattern baldness follicles relative to the conc. of androgens in the general circulation.

J Endocrinol. 1998 Jan;156(1):59-65.
Balding hair follicle dermal papilla cells contain higher levels of androgen receptors than those from non-balding scalp.Hibberts NA, Howell AE, Randall VA.

TGF-beta1 and beta II both inhibit hair growth in vitro.

Procyanidin B-3, isolated from barley and identified as a hair-growth stimulant, has the potential to counteract inhibitory regulation by TGF-beta1.Kamimura A, Takahashi T.

"Addition of TGF-beta1 to hair epithelial cell cultures dose-dependently decreased the cell growth, and addition of procyanidin B-3 to the culture neutralized the growth-inhibiting effect of TGF-beta1. From these results, it is concluded that procyanidin B-3 can directly promote hair epithelial cell growth in vitro, has the potential to counteract the growth-inhibiting effect caused by TGF-beta1 in vitro, and has potential to stimulate anagen induction in vivo."

A few comments about contact inhibition.

Doctor wrote quote:

"I have seen no evidence for contact inhibition in any study that I've seen posted on this website. No molecule, no ligand, and no cellular change secondary to such a process."

No one yet knows the "FULL" details of the growth restriction process involved in normal contact inhibition, but it is a safe bet that this involves recognised negative cell growth factors like TGF beta-1!

In fact this study proves that both contact inhibition and TGF beta-1 effect the same molecular pathway.

http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract

Quote:

"Expression of p45 reappeared 12 h after release from contact inhibition and 6-8 h after release from TGF-beta 1, while TGF-beta 1 prevented release from contact inhibition and maintained suppression of both p45 and cyclin D2. Additionally, cyclin D2 phosphorylation and its associated kinase activity were strongly inhibited by contact inhibition and TGF-beta 1. Thus suppression of p45, cyclin D2/Cdk-4, and cyclin B1/Cdc-2 expression and/or activities is targeted both by contact inhibition and by TGF-beta 1 and may define common mechanisms through which these negative growth signals are integrated."


Wrong tissue. Try again. One can not assume that all tissues have the same receptors and respond the same to similar molecules. That's a fallacy of science to those that even consider it.

I have also posted the link below in this thread already, perhaps people should have read this more carefully!

http://www.hairsite4.com/dc/dcboard.php ... ting_type=

Quote:


"In alopecia skin, tha abnormal streamers underneath the follicles appear to be a structural barrier for the down-growth of anagen follicles. Moreover, severe inflammatory involvement in the streamers causes suppressive growth of the follicular bulb and dermal papilla cells (see Figure 8a). Dense collagenous or hyalinized scarring streamers block the growth of follicles (Figure 8b and c). These follicular structures naturally resist any therapeutic effect for follicular growth. Moreover, associations of focal perivascular and perofollicular inflammatory cell infiltrations are often seen in alopecic skin."

The follicles have not got the ability to just "force" through these scarring steamers, why?

No, because of collagen deposition and fibrosis. I've told you before, collagen makes up bone, cartilage, and basement membranes. With androgen inhibition, TGF-beta inhibition, and decreased nutrients and area for growth or even the ability to grow, hair follicles will remain dormant and miniaturized.


Because of a basic control of cell growth called "contact inhibition"!

Still, no evidence for contact inhibition. No ligand, no receptor, and no initiating molecule to start the process has been provided.


It stands to reason that "ANY" other factor that increases resistence of surrounding tissue to anagen enlargement, would also stop follicle growth by normal contact inhibition, including increased pressure.

Contact inhibition as the primary in-vivo control of follicle size, "ALSO" makes sense of "ALL" the other related factors in male pattern baldness, as i have described before!

Professor Fuch's research showed that manipulating the WNT's and b-catenin pathways in mice, greatly increased follicle size and hair growth.

http://www.hhmi.org/fuchs/index.html

Not a medically relevant website.

Both these pathways are known to be related to the contact inhibition pathway.

http://www.springerlink.com/content/r453v21l0r4321n2/

Not relevant to this discussion and I don't even think you understand the molecular biology being discussed here.

Fuchs also noted that tumor formation was increased in these mice. Again, this is a known effect when the factors involved in "normal" contact inhibition are "messed" with!

All the clues relating to contact inhibition and follicle size, already exist in the research. You just have to open your eyes!

I disagree. All the research necessary to conclude that androgens induce growth inhibition followed by indirectly causing cellular apoptosis, collagen deposition, and fibrosis through secondary molecular mediators also exists.

S Foote.

 

[Old Baldy]

Does anyone know if pre-puberty males have the same level of androgen receptors as adult males? I couldn't find anything answering that question.

Do androgen receptors increase in number when we are going through puberty?

For us laymen, here's a good, brief article on AR's, however, it doesn't answer my question (I think it doesn't - LOL!):

http://www.johnberardi.com/articles/hor ... drogen.htm

This article seems to indicate we are born with AR's but I don't know if AR's increase as we get into puberty?

If we do increase AR's as we get into puberty, maybe they reach a "threshold level" that causes DHT to damage our follicles.

Prior to puberty, is it possible AR levels are low enough to answer Stephen's concerns relative to androgens not affecting pre-puberty follicles?

http://www.jco.org/cgi/content/full/20/13/3001


Doctor: A little something you should know about Stephen.

A while back I asked Stephen what treatments should be used to treat male pattern baldness. His advice was VERY mainstream (i.e., counter the effect of DHT and androgens and improve scalp health with what we know can help).

His main thrust falls into the "scalp health" category as I, as a layman, like to categorize it.

He has a point. I MUST do something to remove/treat what I like to call this "rubberized callous" on top of my head! LOL!

You know, eliminate (1) the fibrosis and (2) the excess "concrete" like skin deposits that so many of us male pattern baldness suffers experience. Like I said, I jokingly call it the "rubberized callous".

I see nothing wrong with diving head first into that area of male pattern baldness treatment. Dr. Proctor agrees with that "diving" and, Stephen and Bryan have never criticized me for calling my scalp a rubberized callous.

Now what comes first, DHT effects or fibrosis, etc., effects? I ain't saying because I can conviently(sp?) avoid such arguments by falling back on my "layman's" status!!

Although, I do lean fairly heavily towards androgens having some god da** direct effect. Either way, Stephen's recommended treatment protocol is extremely mainstream. Keep that in mind.

 

[Bryan]

Hmm...

Well, I know that taking a hair follicle with no signs of male pattern baldness and exposing it to a certain concentration of androgens for a certain period of time has a direct influence upon its growth. Even when this follicle is taken from a non-balding area.

Yes, it seems more plausible to me to think that ALL scalp hair follicles are sensitive to androgens (in the male pattern baldness-way of being "sensitive"), but some are much more sensitive than others; I could accept the notion that ALL scalp follicles would be adversely affected by androgens, if the level of exposure to them were sufficiently high.

A more problematical scenario to explain, of course, would be if scalp hair follicles at some (early?) point are actually stimulated by androgens, but then something eventually causes them to make a transition to being adversely affected by them.

It is quite likely that there is a feedback mechanism we need science to discover for us. Perhaps, androgen receptor binding and internalization causes the production of more androgen receptors and thus a stronger response over a period of time with the signal eventually becoming strong enough to induce a pro-apoptotic environment through the production of enough gene product to alter cellular capabilities. I'll have to do some more research.

What bothers me about all that is that androgenic feedback loops, if anything, seem to have a penchant for being NEGATIVE feedback, not POSITIVE feedback. I suspect that the reason for the increase in sensitivity to androgens in scalp hair follicles lies somewhere else, in some other type of "timed" mechanism that begins during puberty.

Bryan

 

[S Foote.]

OK Doctor, have it your own way.

I think you are wrong on many cause and effect levels, but this debate is never going to resolve the questions.

I am not going to be able to post for a few days, but there is a point i would like to raise that people should consider?

The section of the follicle that gets miniaturised in male pattern baldness, is the lower section below the stem cell bulge. This dies altogether at one point in the hair cycle, and is rebuilt by follicle stem cells at the start of the next anagen period.

So if the cells in different follicles produced in this process are pre-programed "differently" as is claimed, the stem cells these arise from "must" also be pre-programed differently.

But what makes stem cells "stem cells", is the very fact that they "do not" have any pre-dispositions!!

If it is going to be argued that somewhere along the line, androgens directly effect follicle cells "differently", there just has to be a difference in the follicle stem cells!

But that goes against the whole notion of pluripotent stem cells, so you see the paradox?

The direct theory has to explain this paradox?

S Foote.

 

[Bryan]

The latest study you posted Doctor is quite obviously "NOT" what happens in-vivo is it! This is yet another in-vitro study that shows how misleading they can be as i said.

Androgens may well effect hair growth from the traditional "non male pattern baldness area" over very long periods of time. We know the wreath can thin out and receed in the neck area. But this is way out of the time scales of these in-vitro studies, so basic common sense tells us it is "WRONG" in true in-vivo terms!

I don't understand what your point is here. The in vitro studies clearly show that androgens stunt the growth of scalp hair follicles. They don't DESTROY them in a period of only a week or two, they just inhibit their growth. So what does the difference in "time scales" have to do with anything?? It's intuitively quite sensible: androgens (be they endogenous in a human scalp, or exogenous in a test-tube) inhibit the growth of scalp hair follicles in the short-term (days or weeks), and ultimately wither them away and destroy them in the long-term (years). I see no problem whatsoever with that, and I don't think any other reasonable person does, either.

You can "directly" effect any cell type in-vitro if you bombard it with artificial levels of "anything"! That doesn't mean these "direct" reactions are truly reflecting what happens in-vivo!

Oh, so I suppose that it's just a big COINCIDENCE that both types of hair follicles (body hair, and scalp hair) show the very same response to androgens in vitro that they do in vivo?

So the only reliable thing to come out of the in-vitro studies, is that known "future" male pattern baldness cells are "NOT" directly changed into male pattern baldness follicles by androgens.

No. Not over a period of just a week or two. But it's still an open question whether or not something like that could happen slowly over a period of YEARS. I've had to explain this to you numerous times, Stephen.

I actually tend to favor the idea that it's not the actual continuous exposure to androgens that's causing the change, but some other type of timing mechanism.

The thing is, you can speculate all you like about the downstream molecular effects, but these are not necessarily related to a "direct" androgen trigger? These downstream effects and changes can be more logicaly linked to "indirect" effects of androgens given the larger body of evidence.

But (as we say here in Texas) your theory is as bare of evidence as a hound's *** is bare of honey!

You are totally unable to cite any evidence for us that androgen receptors exist in lymphatic vessels, so you can't explain how androgens would supposedly make edema in the scalp worse by adversely affecting pumping efficiency. You haven't been able to think of any excuse to explain why the Nordstrom study found that transplanted balding follicles continue to bald at exactly the same rate. You tried to claim that contact inhibition causes hair follicles to become sensitive to androgens, but you are unable to find ANY example of such a thing happening anywhere else in biology.

All you can come up with are excuses, hypotheses, rationalizations, "what-if's", and "maybe's" to try to keep your theory afloat. You are utterly lacking in any scientific EVIDENCE for it.

The direct theory makes a very clear claim, that follicles are inherently different at the molecular level. This is why they respond to androgens "differently".

Yes. And they DO respond to androgens differently. There's plenty of scientific evidence for that.

Bryan, i apologise!

It seems you have explained my case to Doctor better than i did!

I accept your apology. While you and I don't agree on the causes of balding, I certainly don't want to obfuscate your theory. I want what you're saying to be crystal-clear, so that other people can judge your theory on its own merits! :wink:

But i think you still misunderstand one important factor?

You seem to still believe that once follicles are "converted" into male pattern baldness follicles, that they are then maintained "directly" by androgen inducable TGF beta-1 as in the in-vitro studies?

I'm not quite clear what you mean by "maintained" in this context. Do you mean maintained in their miniaturized state, or maintained as being sensitive to androgens? Or both? Or neither? You need to be more precise in your language.

You are clearly claiming here that follicles "DO" become directly sensitive to androgens, regardless of the "how" correct?

Yes, of course. There can be no doubt of that. How many different studies and experiments do you require before you can believe that??

I don't think for a moment that follicles "become" directly sensitive to androgens at any time!

I point out above the flaws with the in-vitro tests.

I don't see any "flaws" in the in vitro tests. The objections you mentioned above have been answered.

I thought you admitted at one point that follicles DO become sensitive to androgens (by way of contact inhibition), although you still maintained that that's not what actually causes balding. Are you changing your tune on that?

But apart from this if male pattern baldness follicles did become subject to "direct" androgen inducable TGF beta-1 as in the test tube, they would have remained miniaturised in that mouse study we talked about!

No immunology in the test tube, no immunology in those mice. Androgen inducable TGF beta-1 growth restriction in the test tube, "just the opposite" of follicle re-growth in those mice!

You keep going back to that mouse study, and I keep pointing out to you that it raises more questions than it answers. First of all, it hasn't been duplicated by any other group. Second of all, they never measured or tested the level of androgens in those mice, so we really don't have much of an idea what was going on with those transplanted hair follicles. Until that can be clarified, it remains an interesting study, but we really can't draw any firm conclusions about it.

A few comments about contact inhibition.

No one yet knows the "FULL" details of the growth restriction process involved in normal contact inhibition, but it is a safe bet that this involves recognised negative cell growth factors like TGF beta-1!

In fact this study proves that both contact inhibition and TGF beta-1 effect the same molecular pathway.

http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract

Yes, but so what?? That doesn't prove that contact inhibition is what's affecting the growth of hair follicles.

All the clues relating to contact inhibition and follicle size, already exist in the research. You just have to open your eyes!

You have to do more than just propose a new rationale for what causes balding. Blaming that on contact inhibition is nothing more than just a simple hypothesis. you have to provide EVIDENCE for such a link, and you haven't done that.

Bryan

 

[S Foote.]

You are totally unable to cite any evidence for us that androgen receptors exist in lymphatic vessels, so you can't explain how androgens would supposedly make edema in the scalp worse by adversely affecting pumping efficiency. You haven't been able to think of any excuse to explain why the Nordstrom study found that transplanted balding follicles continue to bald at exactly the same rate. You tried to claim that contact inhibition causes hair follicles to become sensitive to androgens, but you are unable to find ANY example of such a thing happening anywhere else in biology.

If you are just going to ignore all my previous answers to these questions, there is no point in me constantly repeating them!

Everyone following our debates knows i have answerd these questions before Bryan, so you pretending i haven't isn't scoring you any points here :roll:

Just on the issue of androgen receptors in lymph vessels.

Michael for one knows i posted "WITH" references, that muscle fibers have androgen receptors. Lymphatic vessels have muscle fibers in their walls. So clearly lymphatic vessels have androgen receptors.

But no doubt at some point in the future you will again try to claim i haven't answered this point :roll:

People are not blind to this tactic of yours. :wink:

S Foote.

 

[Bryan]

Everyone following our debates knows i have answerd these questions before Bryan, so you pretending i haven't isn't scoring you any points here :roll:

I'll leave it up to the other readers to decide for themselves whether or not you've answered those questions! :wink:

Bryan

 

[S Foote.]

Everyone following our debates knows i have answerd these questions before Bryan, so you pretending i haven't isn't scoring you any points here :roll:

I'll leave it up to the other readers to decide for themselves whether or not you've answered those questions! :wink:

Bryan

I clearly answered the question on androgen receptors and lymphatic muscle fibers, when you asked me before Bryan.

http://www.hairlosstalk.com/discussions ... &start=210

People can see that you clearly claimed above that i had not!

Congratulations, you have at least proved one thing to the readers now, and that is your clearly a liar 8)

S Foote.

 

[Bryan]

I clearly answered the question on androgen receptors and lymphatic muscle fibers, when you asked me before Bryan.

No you didn't. You clearly FAILED to answer Docj's follow-up questions and objections. You still haven't proposed any mechanism for how androgens supposedly decrease lymphatic drainage in the scalp.

I'm not going to let you slip out of this, Stephen.

Bryan

 

[docj077]

You are totally unable to cite any evidence for us that androgen receptors exist in lymphatic vessels, so you can't explain how androgens would supposedly make edema in the scalp worse by adversely affecting pumping efficiency. You haven't been able to think of any excuse to explain why the Nordstrom study found that transplanted balding follicles continue to bald at exactly the same rate. You tried to claim that contact inhibition causes hair follicles to become sensitive to androgens, but you are unable to find ANY example of such a thing happening anywhere else in biology.

If you are just going to ignore all my previous answers to these questions, there is no point in me constantly repeating them!

Everyone following our debates knows i have answerd these questions before Bryan, so you pretending i haven't isn't scoring you any points here :roll:

Just on the issue of androgen receptors in lymph vessels.

Michael for one knows i posted "WITH" references, that muscle fibers have androgen receptors. Lymphatic vessels have muscle fibers in their walls. So clearly lymphatic vessels have androgen receptors.

But no doubt at some point in the future you will again try to claim i haven't answered this point :roll:

People are not blind to this tactic of yours. :wink:

S Foote.

What I bolded and underlined is incorrect unless you're referring to skeletal muscle, which is susceptible to androgen stimulation and is not present in lymphatic vessels.

Lymphatics of any given size correspond structurally and histologically to, "vessels of similar diameter in the venous system. Lymphatic capillaries are more permiable than blood capillaries and the endothelial cell cytoplasm of lymphatics is extremely thin, the basement membrane is rudimentary or absent, and there are no pericytes. Fine collagenous filaments known as anchoring filaments link the endothelium to the surrounding supporting tissue preventing collapse of the lymphatic lumen."

-Wheater's Functional Histology. Fourth Edition.

Vessels in the venous system also have a reduced amount of elastic and muscular components, which is why their valve systems are so important.

Not only that, but the muscle fibers contained within the walls of vessels are smooth muscle cells and not skeletal muscle cells. If you were to believe that all smooth muscle cells in the human body contained androgen receptors, then all would hypertrophy and blood flow would be decreased to all areas of the body as the lumen would narrow in all vessels. The hypertrophy involves striated muscle fibers, which have no link to the subcutaneous lymphatics that you're using in your theory. The muscles of the scalp are quite deep to the lymphatics that drain the scalp and if indeed this lymphatic flow was obstructed, the result would not be what you so incorrectly describe as "pitting edema". It would massive swelling and severe cutaneous compromise leading to much more than hair loss.

 

[docj077]

It is quite likely that there is a feedback mechanism we need science to discover for us. Perhaps, androgen receptor binding and internalization causes the production of more androgen receptors and thus a stronger response over a period of time with the signal eventually becoming strong enough to induce a pro-apoptotic environment through the production of enough gene product to alter cellular capabilities. I'll have to do some more research.

What bothers me about all that is that androgenic feedback loops, if anything, seem to have a penchant for being NEGATIVE feedback, not POSITIVE feedback. I suspect that the reason for the increase in sensitivity to androgens in scalp hair follicles lies somewhere else, in some other type of "timed" mechanism that begins during puberty.

Bryan

I'm confused, as well. I know that abrupt removal of androgens from a tissue requiring androgen for proper growth will result in increased androgen receptor creation in that tissue (ie prostate tissue during BPH, for instance).

However, I do not understand why more androgen receptors are being created in a tissue that should not need them. It should be negative feedback, but I don't know why the system seems to be working backwards when it comes to hormonal stimulation.

It's as if androgen stimulation causes more androgen receptors to be created, which amplifies the downstream effects of androgens. This could be the reason why male pattern baldness as a disease is so progressive and seems to accelerate or at least progress rapidly once whatever "signal" is given or physiological obstacle is overcome in the non-male pattern baldness follicle.

Foote has a point when he repeatedly says that we need to figure out what the initial "signal" or whatever is. He uses his contact inhibition theory, but I think we need to figure out something that explains the increase in androgen receptors.

Edema really isn't an option, because it's a side effect to a disease process and not the cause of the disease itself. Plus, histological slides just don't show such a process occurring. That's something I'll have to look into more.

 

[Old Baldy]

Yes, it seems the AR's go haywire for some unknown reason. Too many, too sensitive.....? And, you need androgens to make that "haywire" reaction occur.

That's the problem I have with edema also Stephen. It seems to be a "by-product" rather than a cause in diseases I've read about.

It's not that edema like symptoms are irrelevant but.......?

 

[docj077]

Different tissue, but an interesting phenomenon....

Am J Physiol Endocrinol Metab. 2006 Oct 17; [Epub ahead of print]
Estrogen-Induced Up-Regulation of Androgen Receptor (AR) Expression and Enhancement of AR Nuclear Translocation in Mouse Fallopian Tubes in vivo.Shao R, Ljungstrom K, Weijdegard B, Egecioglu E, Fernandez-Rodriguez J, Zhang FP, Kjellberg AT, Bergh C, Billig H.


It's a big leap, but if estrogens secondary to androgen metabolism actually increase androgen receptors in target cells, then that would be bad news for those that are trying to convert androgens to estrogens through herbal or other pharmcological methods.

I will continue to look for this phenomenon is hair studies, but I've found nothing so far. Could simply be tissue specific.

Also,

1: Endocr Rev. 2006 Oct;27(6):677-706. Epub 2006 Jul 28. Links
The hair follicle as an estrogen target and source.Ohnemus U, Uenalan M, Inzunza J, Gustafsson JA, Paus R.

"Besides altering the transcription of genes with estrogen-responsive elements, 17beta-estradiol (E2) also modifies androgen metabolism within distinct subunits of the pilosebaceous unit (i.e., hair follicle and sebaceous gland). The latter displays prominent aromatase activity, the key enzyme for androgen conversion to E2, and is both an estrogen source and target."

That's right out of the abstract, so you'll have to forgive me.

 

[CCS]

Do you know what enzyme in the liver metabolises DHT and which one testosterone? I hope they are not metabolised by the p450 enzyme, which metabolises dutasteride, since I'm inhibiting it with grapefruit.

I wish I knew just how effective estrogen is supposed to be for helping hair, and that Bryan's proof is not based on women having more estrogen and more hair, since they also have less testosterone and DHT.