Minoxidil and Insulin

[thin=depressed]

As for the dht effected cells there is clearly a lessened state of metabolism and that in turn can be linked to adenosine which is the sugar responsable for being the catalyst. What I'm saying is have you guys considered the chemical bridge per say and its impact on cell health. This would be an indirect dht cause, not genetics.

 

[S Foote.]

Again i will ask you how an influence of Minoxidil on VEGF, or any other growth factor can increase hair production, when your theory says DHT is shutting down the cells growth response internally?

I've already explained to you numerous times: if androgens are downregulating the internal production of certain critical growth factors, then you can presumably circumvent that by supplying those same growth factors EXTERNALLY. I'll keep repeating that for you until you understand it.

But that is just `NOT' what the theory you support says Bryan! Are you now trying to `modify' your theory with even more speculation?

Let's be clear about this.

The current theory as we are lead to understand it, is that androgens attatch to receptors within follicle cells. This complex then moves into the genetic material at the heart of the cell to change the expression of genes. This change in gene expression at the very heart of the cell then creates a restricted growth response to the available growth factors in the issues.

But now Bryan, you are telling us that DHT is `reducing' the amount of growth factors within male pattern baldness cells!

Do you have any evidence for this, or is this just another wild guess?[/quote]

I have as you well know Bryan, explained my opinion of how contact inhibition `could' be altering the in-vitro response to androgens. I argued this point in our last debate here, using recognised precedents in support of the principle. You may not agree with me Bryan, but please don't try to suggest that i am `unable' to respond to the points.

Oh, you're responding all right, but you're unable to respond WELL to those points! :wink:

Your claim above that you've cited "precedents" is a complete sham, Stephen. I don't care what you think COULD be happening from contact inhibition, all I care about is what is obviously so embarrassing to you; namely, that there is not a shred of evidence that contact inhibition can alter the way that hair follicle cells (ANY kind of cell, for that matter) respond to androgens. That is pure and utter speculation on your part. It's not based on ANY kind of biological "precedent".

On the other hand, despite me asking on many occasions, you are unable to offer any precedent or any other support for your `genetic clock' speculation!

Yep, you're right: we BOTH have things we can't explain in detail! :wink:

Bryan

I don't think i'am the one who is embarrassing themselves here Bryan!

You have the nerve to say i don't respond `well' to points!!

I gave you the precedent for a role of contact inhibition in male pattern baldness, in our last debate.

Very simply, androgens release TGF beta-1 from follicle cells. TGF beta-1 `locks' cells that have been contact inhibited, in that state in-vitro. This explains the in-vitro results in male pattern baldness cells, by a `demonstrated' pathway!

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

You try to claim that follicle cells that have been proven `NOT' to respond directly to androgens, `WILL' given enough time. All the known precedents for hormone/cell interactions, go against your `assumption' Bryan!

There is far more `hard' evidence for a role of contact inhibition in male pattern baldness, than your `magic' explainations 8)

S Foote.

 

[S Foote.]

As for the dht effected cells there is clearly a lessened state of metabolism and that in turn can be linked to adenosine which is the sugar responsable for being the catalyst. What I'm saying is have you guys considered the chemical bridge per say and its impact on cell health. This would be an indirect dht cause, not genetics.

I agree there is a reduced state of metabolism, but the current theory just can't explain how this comes about in the light of Minoxidil.

There is no change in the availability of anything the follicle needs to `grow', so the change must be in the ability of the cells to utilise available growth factors.

Contact inhibition is one recognised way this can happen.

S Foote.

 

[thin=depressed]

[quote="thin=depressed":acc97]As for the dht effected cells there is clearly a lessened state of metabolism and that in turn can be linked to adenosine which is the sugar responsable for being the catalyst. What I'm saying is have you guys considered the chemical bridge per say and its impact on cell health. This would be an indirect dht cause, not genetics.

I agree there is a reduced state of metabolism, but the current theory just can't explain how this comes about in the light of Minoxidil.

There is no change in the availability of anything the follicle needs to `grow', so the change must be in the ability of the cells to utilise available growth factors.

Contact inhibition is one recognised way this can happen.

S Foote.[/quote:acc97]well said, and I agree that dht inhibits via indirect influence. A combination of poor circulation, insulin,bad nutrition,dht equals hair loss.

 

[Old Baldy]

You guys make good points. However, it doesn't appear that you both feel DHT is the main culprit in contracting male pattern baldness.

Our hair loss appears to involve a "cascading" of events that is initially caused by our sensitivity to DHT. We've all known people that eat terribly, get colds and influenza all the time, have high blood pressure, yet don't have male pattern baldness.

It is our genetically inferior follicles that make us negatively sensitive to DHT. That "sensitivity" appears to cause a cascade of events that leads to male pattern baldness. Minaturization appears to be caused by our reaction to DHT. We must remove the influence of DHT first. If we don't do that, we're in BIG trouble IMHO.

You can have poor scalp health and not be afflicted with male pattern baldness. You cannot have an adverse reaction to DHT and avoid male pattern baldness IMHO. I admit scalp health is extremely important but only to those of us that suffer from a sensitivity to DHT. (I mean this only as far as male pattern baldness is concerned. Scalp health is obviously important for everyone if they want their existing hair to look good.)

 

[S Foote.]

You guys make good points. However, it doesn't appear that you both feel DHT is the main culprit in contracting male pattern baldness.

Our hair loss appears to involve a "cascading" of events that is initially caused by our sensitivity to DHT. We've all known people that eat terribly, get colds and influenza all the time, have high blood pressure, yet don't have male pattern baldness.

It is our genetically inferior follicles that make us negatively sensitive to DHT. That "sensitivity" appears to cause a cascade of events that leads to male pattern baldness. Minaturization appears to be caused by our reaction to DHT. We must remove the influence of DHT first. If we don't do that, we're in BIG trouble IMHO.

You can have poor scalp health and not be afflicted with male pattern baldness. You cannot have an adverse reaction to DHT and avoid male pattern baldness IMHO. I admit scalp health is extremely important but only to those of us that suffer from a sensitivity to DHT. (I mean this only as far as male pattern baldness is concerned. Scalp health is obviously important for everyone if they want their existing hair to look good.)

As you know Old Baldy, i don't think the greater body of evidence fits with a `pre-programed' difference in hair follicles themselves to the `direct' influence of DHT.

But i certainly agree that DHT is the `trigger' to male pattern baldness, but that the effect is indirect.

In the Hydraulic theory, the differences in an individuals `triggering' of male pattern baldness, with a certain level of DHT, is linked to the blood `feed' pressure to the head. So in my opinion, DHT `sensitivity' to male pattern baldness in the individual, is related more to vascular `differences' than anything else.

If the Hydraulic theory is correct, trying to maintain good scalp health would help to avoid secondary infections and more inflamation. Basicaly, my theory says that DHT creates lymphedema in the male pattern baldness area. This can be `self' maintaining, and explains why it is that male pattern baldness gets harder to reverse the longer it exists. The immunology and fibrosis in male pattern baldness are already recognised in lymphedema, and i recommend people read the information on this site.

http://www.lymphoedema.org.au/index.htm

I would avoid anything that creates any scalp irritation, and keep the scalp as cool as you can. Wash your hair with water as cool as you can stand, and if you have the time the occasional ice pack treatment is a good thing in my opinion. I suggest these things as i see male pattern baldness as a `swelling' issue, and anything that can reduce the swelling is a good thing.

I think the layout and density of superficial lymph vessels says a lot about androgen related hair growth. Where DHT increases hair growth significantly, there are increased concentrations of superficial lymph vessels, that is close to the follicles, (beard, groin, armpits).

I think this diagram of the lymphatic layout of the head is very interesting. Note how the point at the sides where the main vessels start to go `deep', matches the base of our hair growth, (in front and behind the ears, and on the neck).

http://hometown.aol.co.uk/Stephenfoote/ ... hatics.bmp

Note how these vessels reduce as they reach the male pattern baldness area!

Regards.

S Foote.

 

[Bryan]

But that is just `NOT' what the theory you support says Bryan!

OH REALLY?? Quote me something from a study or a medical textbook that shows that you can't influence hair follicles by supplying growth factors (or growth inhibitors) EXTERNALLY! You're bluffing again, Stephen! :wink:

Let's be clear about this.

The current theory as we are lead to understand it, is that androgens attatch to receptors within follicle cells. This complex then moves into the genetic material at the heart of the cell to change the expression of genes. This change in gene expression at the very heart of the cell then creates a restricted growth response to the available growth factors in the issues.

But now Bryan, you are telling us that DHT is `reducing' the amount of growth factors within male pattern baldness cells!

Do you have any evidence for this, or is this just another wild guess?

I have REPEATEDLY cited for you the studies that are coming out now that discuss the nature of those growth factors and growth inhibitors. Why in the name of God do you keep acting like we haven't already discussed all this??

Here's just one that I _strongly_ recommend you read (there are others, too): "Do Androgens Influence Hair Growth by Altering the Paracrine Factors Secreted by Dermal Papilla Cells?", Valerie A. Randall et al, Eur J Dermatol 2001; 11: 315-20. If you cannot obtain this study, I will be happy to personally mail you a copy of it. Private Message me your postal address, Stephen; this is a serious offer (yes, I know you're over there in England)!

I don't think i'am the one who is embarrassing themselves here Bryan!

You have the nerve to say i don't respond `well' to points!!

I gave you the precedent for a role of contact inhibition in male pattern baldness, in our last debate.

Very simply, androgens release TGF beta-1 from follicle cells. TGF beta-1 `locks' cells that have been contact inhibited, in that state in-vitro. This explains the in-vitro results in male pattern baldness cells, by a `demonstrated' pathway!

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

I already explained that to you in that prior thread! You're twisting it around to try to make it fit your theory, but it won't work. You're avoiding the very important point that _either_ contact inhibition _or_ TGF beta-1 (all by itself) will result in the same suppression of those proteins that they mentioned, in that particular cell line. That has absolutely NOTHING to do with your task at hand, which is to explain why cells would flip-flop in their response to those same androgens. There was NO flip-flop at all in those cells above, they were ALWAYS inhibited by androgens (or contact inhibition, for that matter). In your desperation, you're attempting to read something into it that isn't there at all.

Bryan

 

[Old Baldy]

Here's that study Stephen (look for V.A. Randall study):

http://216.109.117.135/search/cache?p=D ... 1&.intl=us

 

[Bryan]

Wow, excellent find, Old Baldy! The full study, right there for everyone to read!

There ya go, Stephen: start reading and LEARNING...

Bryan

 

[S Foote.]

But that is just `NOT' what the theory you support says Bryan!

OH REALLY?? Quote me something from a study or a medical textbook that shows that you can't influence hair follicles by supplying growth factors (or growth inhibitors) EXTERNALLY! You're bluffing again, Stephen! :wink:

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

I already explained that to you in that prior thread! You're twisting it around to try to make it fit your theory, but it won't work. You're avoiding the very important point that _either_ contact inhibition _or_ TGF beta-1 (all by itself) will result in the same suppression of those proteins that they mentioned, in that particular cell line. That has absolutely NOTHING to do with your task at hand, which is to explain why cells would flip-flop in their response to those same androgens. There was NO flip-flop at all in those cells above, they were ALWAYS inhibited by androgens (or contact inhibition, for that matter). In your desperation, you're attempting to read something into it that isn't there at all.

Bryan[/quote:7b9a7]


First Bryan, don't tell me what my `task at hand' is!! You are not a school teacher talking down to one of his pupils.

Secondly, technicaly speaking, i `DONT' have to explain `ANYTHING' relating to my theory at this point. My theory is not the currently accepted theory in male pattern baldness!!

The theory `YOU' support is the currently accepted theory, and as such it has the responsibility to answer the relevant questions.

I keep asking you these relevant questions, but because you have no idea how to address these questions, you try to distract by constantly refering to my theory! It's the same diversionary tactics every debate we have Bryan, just answer the bloody question!!!

Thirdly, if you can't see the relevance of the contact inhibition/TGF beta-1 study to the in-vitro follicle cell studies, you really shouldn't get involved in these discussions!

The relevance of that study to the `flip flop' androgen response of follicle cells is there for all to see! With all due respect, if you `REALLY' don't get that, you should seriously consider finding another hobby Bryan because science is just not your thing i'am afraid.

Finally, i have just read the full text of the study by Randall et al, thank's Old Baldy.

As usual, it is not so much what is in this kind of study, but what is missing from it! I see this comes from Bradford England, which is quite local to me. I am going to see if i can contact Prof Randall, as there is something i would like his opinion on.

But meanwhile Bryan before i respond to this here, i would like you to go on the record and tell us all how significant you think this study is, and how it answers our questions. In other words what is it `YOU' think `I' should i be `learning' from this?


S Foote

 

[S Foote.]

There are a few interesting points raised in the study refered to above. I cant wait to hear Bryans spin on this, sorry i mean `interpretation'. 8)

There are a number of things i want to say about this, but it will be weekend before i have the time to post. (Got some family issues to deal with at the moment).

S Foote.

 

[Old Baldy]

I should have just pasted the actual study here for everyone to read. I have to reread it a few times. It takes me time to digest these things but ... well, nevermind. Need to reread it again. Time for bed right now. (Old Baldy had a mentally rough few days at work this week.)

Author(s) : V.A. Randall, N.A. Hibberts, M.J. Thornton, A.E. Merrick, K. Hamada, S. Kato, T.J. Jenner, I. De Oliveira, A.G. Messenger, Department of Biomedical Sciences, University of Bradford, Bradford, BD7 1DP, UK..

Summary : Androgens regulate many aspects of human hair growth in both sexes. After puberty they transform tiny vellus follicles in many areas, e.g. the face, to terminal ones producing long, thick, pigmented hairs. In genetically predisposed individuals, androgens also cause the reverse transformation of terminal scalp follicles into vellus ones, causing balding. In the current hypothesis for androgen action, androgens control most follicular cells indirectly acting via the mesenchyme-derived dermal papilla which regulates many aspects of follicular activity. In this model androgens binding to androgen receptors in dermal papilla cells alter their production of regulatory molecules which influence other follicular components; these molecules may be soluble paracrine factors and/or extracellular matrix proteins. This hypothesis is supported by immunohistochemical localisation of androgen receptors in dermal papilla cell nuclei and the demonstrations that androgen receptor content and testosterone metabolism patterns of cultured dermal papilla cells from various body sites reflect hair growth in androgen-insensitivity syndromes. The next question is whether androgens alter the paracrine factors secreted by dermal papilla cells. Cultured dermal papilla cells do release soluble, proteinaceous factors into their media which stimulate the growth of keratinocytes and other dermal papilla cells. This mitogenic potential can cross species from humans to rodents. Importantly, testosterone in vitro stimulates the mitogenic potential of beard cells, but in contrast inhibits production by balding scalp cells reflecting their in vivo androgenic responses. Since androgens in vitro do alter the secretion of paracrine factors the current focus lies in identifying specific factors produced, e.g. IGF-I and stem cell factor (SCF), using ELISA and RT-PCR, and comparing their expression in cells from follicles with varying responses to androgens in vivo or under androgen stimulation in vitro. This should lead to greater understanding of androgen action and enable the development of better treatment for androgen-potentiated disorders.

Keywords : androgens, dermal papilla cells, hair, human, paracrine factors.

Pictures


ARTICLE


Androgens are the main regulator of changes in human hair growth [1]. One of the first signs of puberty in both sexes is the gradual replacement of tiny vellus hairs in the pubic and axillary areas with longer, more pigmented intermediate forms and eventually the large, dark terminal hair characteristic of adulthood [2, 3]. These changes parallel the rise in plasma androgens in both sexes [4, 5]. Later, similar changes occur on the face, chest, upper pubic triangle and the limbs of men readily distinguishing the adult male [6, 7]. In complete contrast, androgens progressively inhibit large terminal scalp follicles in individuals with a genetic predisposition so that they are gradually replaced by tiny vellus ones causing male pattern baldness or androgenetic alopecia [8-11]. The absence of the characteristic increased hair growth in adults or any male pattern baldness in individuals with deficient androgen receptors i.e. androgen insensitivity syndrome confirms the essential role of androgens and androgen receptors in the regulation of human hair growth [12]. The paradoxically different responses of hair follicles to similar circulating levels of androgens (reviewed in [1] and [13]) clearly demonstrated by bald men with bushy beards indicates that the particular effect produced by androgens depends on factors within the individual follicles themselves. How this occurs is not fully understood, but one strong possibility is that androgens alter the paracrine factors produced by dermal papilla cells and hence alter the cellular activity of the follicles various cell types. This is currently the subject of experimental investigation.

Mode of action of androgens in hair follicles
The current hypothesis for the mode of action of androgens in hair follicles focuses on the dermal papilla. The mesenchyme-derived dermal papilla plays an important regulatory role in the follicle, altering many parameters and determining the type of hair produced [14, 15]. This is believed to occur by the production of paracrine growth factors and extracellular matrix proteins. During the beginning of anagen, the growth phase of the hair cycle, hair follicles appear to recapitulate follicular embryogenesis when a new hair is being formed [13]. Since steroids act via the mesenchyme in many developing steroid-dependent tissues such as the prostate [16], Randall has proposed that androgens act on the hair follicle via the dermal papilla [13, 17]. In this hypothesis, summarised in Figure 1, androgens enter the follicle via the dermal papilla's capillaries, bind to androgen receptors within the dermal papilla cells and trigger the expression of hormone responsive genes. This then alters the paracrine factors produced by the dermal papilla cells which regulate the growth and activity of the other cell types in the follicle (Table I). These paracrine factors could be soluble mitogenic factors or extracellular matrix components.

Androgens alter the size of the hair produced and, therefore, the size of the sheaths surrounding the hair and the dermal papilla at its base. In addition hair pigmentation is also altered during responses to androgens and larger follicles require a greater vascular supply. This means that several cell types are potential targets for these factors. They include: the follicular keratinocytes which form the hair itself and the various layers of the outer and inner root sheaths; the melanocytes, which produce the pigment which gives the follicle its colour; and the endothelial cells of the blood vessel capillaries. Factors could also act in an autocrine or paracrine manner on the dermal papilla cells themselves.

This model of androgens acting directly on the regulatory dermal papilla and then indirectly on the other cell types does seem very plausible. Androgens have such widely differing effects on hair follicles even within the same person that it is difficult to conceive of the responses being so well controlled if each cell type had to react directly to androgens.

The hypothesis has received a great deal of experimental support. Androgen receptors have been located in dermal papilla cells of hair follicles by immunohistochemistry, although the distribution reported elsewhere in the follicle varies with a monoclonal antibody detecting no epithelial cell staining [18] while a polyclonal antibody study reported staining also in the outer root sheath [19]. Specific high affinity, low capacity androgen receptors have been identified in cultured dermal papilla cells derived from androgen target follicles such as beard [20] and balding scalp [21].

Studies of androgen metabolism by dermal papilla cells also provide strong corroboration. Beard cells metabolise testosterone to 5alpha-dihydrotestosterone [22, 23] unlike either pubic or axillary cells [24]. This corresponds to the absence of beard growth but presence of axillary and the female pubic pattern hair growth in patients with 5alpha-reductase deficiency [25]. As well as supporting the current hypothesis for androgen action in the hair follicle (Fig. 1), these studies confirm that cultured dermal papilla cells retain characteristics in vitro that reflect the androgen responses of their parent follicle in vivo.

Secretion of mitogenic factors
Currently, research is focussing on the soluble mitogenic factors secreted by dermal papilla cells. A particular aim of our research is to determine whether androgens can alter the production of mitogenic factors produced by dermal papilla cells. A number of bioassays have been carried out involving co-culture of dermal papilla cells and other cell types or collecting media in which dermal papilla cells have been grown, "conditioned media", and assessing the capacity of this conditioned media to promote cell growth in other cells. These have shown that human dermal papilla cells secrete soluble, proteinaceous factors which are mitogenic for other dermal papilla cells [17, 26], outer root sheath cells [27, 28], transformed epidermal keratinocytes [29] and endothelial cells [30]. These mitogenic factors can cross at least some species as human dermal papilla cell media have the capacity to stimulate growth of rat whisker cells [31].

When the effect of androgens on mitogenic capacity was assessed, testosterone was found to stimulate the mitogenic capacity of beard cells for outer root sheath cells [28] and beard dermal papilla cells [26], as would be predicted by the hypothesis. Interestingly, testosterone had no effect on the mitogenic capacity of non-balding scalp cells and only beard dermal papilla cells were able to respond to the factors (Fig. 2). The effect of testosterone was not seen when the same range of testosterone concentrations were added to media previously conditioned by beard cells in the absence of testosterone (Fig. 2). This demonstrates that the androgenic effect was due to the androgen-potentiated synthesis of a mitogenic factor or factors rather than an interaction of testosterone with an existing paracrine factor in the conditioned media. The restriction of the response to beard dermal papilla cells could reflect a different receptor on beard cells or that scalp cells were already responding at their full capacity to the mitogenic factors. This suggests that an autocrine mechanism of producing paracrine factors for beard cells is involved in beard cell growth in response to testosterone. Certainly, the size of the dermal papilla has been shown to be proportional to the size of the hair [32] and this appears to involve an alteration in the number of dermal papilla cell numbers as well as the amount of extracellular matrix present [33]. A need to alter the autocrine production of growth factors after androgen stimulation could account for the slow response of follicles to androgens which often takes many years to have a full effect [6-10].

When dermal papilla conditioned media was assayed on a standard line of keratinocytes, physiological levels of testosterone again stimulated the production of greater mitogenic ability by beard, but not non-balding scalp cells [34]. Interestingly, when dermal papilla cells from androgen-inhibited balding scalp follicles from both men [29] and the stump-tailed macaque [35, 36] were investigated the mitogenic capacity assayed on keratinocytes was inhibited by physiological levels of testosterone. All these markedly contrasting responses to testosterone in vitro reflect the paradoxical in vivo responses and provide further strong support for the model of androgen action (Fig. 1).

Identification of paracrine factors
Research is now focussing on identifying specific paracrine factors secreted by cultured dermal papilla cells and determining whether their production is altered by the androgen responsiveness of the parent follicle in vivo or by androgen in vitro. A range of growth factors and cytokines have been implicated in hair growth (reviewed in [37-39]). Several of these have been shown to be produced by cultured dermal papilla cells from androgen-independent follicles either by measurement of protein production by ELISA of conditioned media or by examining their expression of mRNA by RT-PCR. One of the most studied of these is insulin like growth factor-I, IGF-I [40], a potent mitogen which plays an important role in maintaining anagen in cultured human scalp follicles in vitro [41] and which causes abnormal patterns of growth and differentiation of hair follicles [42] when its effects are blocked in the IGF-I receptor deficient knockout mouse. Itami and colleagues [28] have identified the expression of mRNA for IGF-I in beard dermal papilla cells and confirmed its importance by blocking the mitogenic effect of dermal papilla cells on co-cultured outer root sheath cells with an antibody to IGF-I.

Hepatocyte growth factor, HGF (also known as scatter factor), is a potent mitogen, morphogen and motogen for epithelial cells which is produced by mesenchyme cells during embryogenesis [43]. It is also expressed by dermal papilla cells [44, 45]. HGF also stimulates the growth of mouse hair follicles in culture [46], but the effects reported on isolated human hair growth vary depending on the group [39, 47]. Vascular endothelial growth factor, VEGF, is a major regulator of angiogenesis and vascular permeability which is also secreted [48] and expressed by cultured human dermal papilla cells [49, 50]. So many other growth factors and cytokines have been implicated in hair follicle growth that there is insufficient space to consider them here; they have recently been reviewed elsewhere [37-39, 51]. Studies on factors altered by androgens are more limited, although they are a prime focus in our laboratory. Itami, Takayasu and colleagues have found that physiological levels of testosterone in vitro stimulated increased IGF-I mRNA expression by beard dermal papilla cells [28].

In our studies of human dermal papilla cells we have employed a particular experimental design to investigate the effects of androgens in vivo and in vitro. We have investigated in vivo effects of androgens on androgen potentiated hair growth by comparing beard dermal papilla cells with control, non-balding scalp cells and also the inhibitory effects of androgens by comparing balding scalp cells with non-balding ones. The effects of androgens in vitro have been assessed by incubating dermal papilla cells from the three types of follicles in the presence, or absence, of 10 nM testosterone for 24 hrs.

When HGF was investigated testosterone in vitro had no effect on its expression by any cell type. However, beard cells expressed much more HGF than non-balding scalp cells and expression was virtually undetectable in balding scalp cells. This suggests that HGF could be important in maintaining large follicles and that its levels in androgen-dependent follicles may be altered by exposure to androgens in vivo [45]. Results with the vascular regulator VEGF were markedly different; both beard and non-balding scalp cells secreted the same amounts of VEGF into the media and expressed the same amounts of mRNA [48, 50]. However, this is not too surprising as both types of follicles were producing terminal hairs necessitating a good blood supply.

Since androgens alter the pigmentation of follicles we have also investigated the role of stem cell factor (SCF,
c-kit ligand, steel factor, mast cell growth factor) known to play important roles in the development of epidermal [52, 53] and hair pigmentation [54, 55]. Dermal papilla cells from both non-balding scalp and beard follicles secreted SCF [56] implicating the dermal papilla as the local source of SCF for hair follicle melanocytes. Adult human scalp hair follicle melanocytes do express the receptor for SCF, c-kit [57]. Interestingly, although androgen in vitro had no effect, beard cells secreted more SCF than non-balding scalp which may indicate that androgens had increased the production of SCF by facial dermal papilla cells to cause the darkening of facial hair in the transformation of a boy's vellus facial hair to a full adult beard.

Recently, an interesting study of cultured human dermal papilla cells by Professor Takayasu's group has shown that they express the protease nexin-1 and that its expression by cells from balding follicles is inhibited by androgen in vitro [58]. Protease nexin-1, also known as glia-derived nexin-1, is a potent inhibitor of serine proteases, such as thrombin, urokinase and plasmin, thereby regulating cellular growth and differentiation in many tissues [59]. Since its effect in other tissues is modulated by extracellular matrix components such as type IV collagen [60] which dermal papilla cells also produce [61], alterations in protease nexin-1 production by dermal papilla cells could result in changed production of such extracellular matrix components by the dermal papilla. These could act as paracrine signals between the dermal papilla cells and the other follicular components as proposed in Figure 1 and may play an important role as alterations in the size of the dermal papilla are known to correlate with the size of the hair produced by the follicle [32, 33].

CONCLUSION

The original question being addressed was whether androgens influence hair growth by altering the paracrine factors produced by dermal papilla cells. There is certainly strong experimental support for the hypothesis that androgens alter follicle size by acting via the dermal papilla. Dermal papilla cells from both human and primate follicles secrete paracrine factors in culture which stimulate the growth of many cell types from the follicle. Importantly, androgens in vitro increase or inhibit the production of mitogenic factors by human and macaque cells in line with the parent follicle's response to androgens in vivo. Thus, the evidence so far is that androgens may influence hair growth in this way. The identification of specific growth factors and enzymes, some of which appear to be altered by androgens either in vivo or in vitro supports this view. Further analysis of factors whose production is altered by androgens may lead to the development of novel regimens for the treatment of androgen-potentiated hair disorders.

 

[Bryan]

I keep asking you these relevant questions, but because you have no idea how to address these questions, you try to distract by constantly refering to my theory! It's the same diversionary tactics every debate we have Bryan, just answer the bloody question!!!

Ummm...what question would that be? What question of yours have I not answered (assuming that I actually do HAVE an answer)??

Thirdly, if you can't see the relevance of the contact inhibition/TGF beta-1 study to the in-vitro follicle cell studies, you really shouldn't get involved in these discussions!

I can't help but notice that you haven't addressed the specifics of what I said about that contact inhibition/TGF beta-1 study. Should I assume that you haven't thought of any way to debunk what I said about it, Stephen? :wink:

Finally, i have just read the full text of the study by Randall et al, thank's Old Baldy.

As usual, it is not so much what is in this kind of study, but what is missing from it! I see this comes from Bradford England, which is quite local to me. I am going to see if i can contact Prof Randall, as there is something i would like his opinion on.

FYI: Valerie Randall is a woman.

But meanwhile Bryan before i respond to this here, i would like you to go on the record and tell us all how significant you think this study is, and how it answers our questions. In other words what is it `YOU' think `I' should i be `learning' from this?

Just what we've been talking about for a long time: apparently, androgens adversely affect the growth of balding scalp hair follicles by altering their production of various growth factors and/or inhibitors in the dermal papillae, which then have a paracrine effect on the rest of the follicle. That's it, in a nutshell! That seems increasingly to be the accepted explanation for the effect of androgens on hair follicles.

Bryan

 

[Bismarck]

According to Stephen's theory, one could do a hair transplant by taking a graft and putting it at the same place again ?

 

[Bryan]

HOLY MOLEY!! Excellent point, Bis!

According to Stephen's weird ad hoc rationalizations, guys who get hair transplants don't need to worry about running out of a supply of "donor hair". All they have to do is just extract the follicles in the thinning areas (before they get TOO miniaturized, of course), then put them right back whence they came!

Spread this joyous news in all the hair transplant forums!!

Bryan

 

[Bryan]

Oops...I just remembered that Stephen already has an answer to that: he claims that the scarring that builds up around a transplanted follicle maintains the ORIGINAL pressure around it, whether it's normal pressure or excessive pressure. I'll leave it to all the other readers to decide for themselves if that's a credible theory!

I wonder if Stephen thinks that you could extract one of those thinning follicles, and kinda "drain" the fluid out of it or do something to relieve that internal pressure, then put it right back in the same position?? Wouldn't that be a permanent solution to the problem? How about it Stephen, what do you think of THAT basic methodology? Why wouldn't THAT work, if your theory is correct??

Bryan

 

[Old Baldy]

I'm not sure he says that Bryan and Bis because he stated that when he had scalp reduction surgery, and the hairs on the sides were pulled up into the top area of the scalp, they behaved like male pattern baldness stricken hairs. So their "pressures" took on the "pressures" of the top of the scalp.

But you're right that he has said transplanted follicles set up "protective" type cylinders around the follicles that keep them from being "pressurized".

Kind of a dilemma isn't it? Just transplanting the hairs cures the contact inhibition problem?

The more I think about it Bis.... good point!!

Stephen, where are you?

Btw, Bryan your summary of the Randall et. al., study was great!

 

[S Foote.]

>>I keep asking you these relevant questions, but because you have no idea how to address these questions, you try to distract by constantly refering to my theory! It's the same diversionary tactics every debate we have Bryan, just answer the bloody question!!!<<


Bryan wrote:
Ummm...what question would that be? What question of yours have I not answered (assuming that I actually do HAVE an answer)??<


Well Bryan, i don't think you can answer my question, and that is the real point. Any valid theory is `SUPPOSED' to answer the questions!

This is of course about the `genetic' clock question. The theory you support falls apart without this unprecedented, unheard of, untestable, unlikely `mechanism'. You may as well blame it all on the `follicle fairies'



>>Thirdly, if you can't see the relevance of the contact inhibition/TGF beta-1 study to the in-vitro follicle cell studies, you really shouldn't get involved in these discussions!<<


Bryan wrote:
I can't help but notice that you haven't addressed the specifics of what I said about that contact inhibition/TGF beta-1 study. Should I assume that you haven't thought of any way to debunk what I said about it, Stephen? :wink:<


If you are refering to the `flip flop' issue as you like to call it Bryan, i thought i had addressed that? Try this.

When follicle cells that are known to be `future' male pattern baldness follicles are exposed to androgens in-vitro, nothing happens. Direct exposure of these cells to androgens does `NOT' induce any change in their growth response. When these cells come from `already' balding follicles, this restricted growth characteristic is maintained by androgens in-vitro.

So, what we can be sure of from this, is that androgens are maintaining the `pre-existing' growth characteristics of follicle cells in-vitro, whatever this may be. I think this is the important thing to remember. Androgens are not `directly' changing the growth characteristics of `any' follicle cell samples.

The only candidate `mechanism' for the flip flop in-vitro response to androgens of male pattern baldness cells, is normal contact inhibition Bryan!

Androgens increase the expression of TGF beta-1 in culture. http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract

So TGF beta-1 is androgen inducible from follicle cells.

TGF beta-1 is also known to `MAINTAIN' cell samples in- vitro, in the growth restricted state induced by contact inhibition in-vivo. 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"

This is a `PROVEN' mechanism that explains the observations in the in-vitro testing with male pattern baldness follicle cells! Two and two makes four Bryan, your `magic' genetic clock is not necessary to explain what we are seeing!!


>>Finally, i have just read the full text of the study by Randall et al, thank's Old Baldy.

As usual, it is not so much what is in this kind of study, but what is missing from it! I see this comes from Bradford England, which is quite local to me. I am going to see if i can contact Prof Randall, as there is something i would like his opinion on.<<


Bryan wrote:
FYI: Valerie Randall is a woman.<

>>But meanwhile Bryan before i respond to this here, i would like you to go on the record and tell us all how significant you think this study is, and how it answers our questions. In other words what is it `YOU' think `I' should i be `learning' from this?<<


Bryan wrote:
Just what we've been talking about for a long time: apparently, androgens adversely affect the growth of balding scalp hair follicles by altering their production of various growth factors and/or inhibitors in the dermal papillae, which then have a paracrine effect on the rest of the follicle. That's it, in a nutshell! That seems increasingly to be the accepted explanation for the effect of androgens on hair follicles.<



I have found `her' contact details and i will be posing a few questions. I will post any response i get.

As i said above, there are a few comments i have on this study, and i will post these over the weekend.

S Foote.

 

[S Foote.]

Oops...I just remembered that Stephen already has an answer to that: he claims that the scarring that builds up around a transplanted follicle maintains the ORIGINAL pressure around it, whether it's normal pressure or excessive pressure. I'll leave it to all the other readers to decide for themselves if that's a credible theory!

I wonder if Stephen thinks that you could extract one of those thinning follicles, and kinda "drain" the fluid out of it or do something to relieve that internal pressure, then put it right back in the same position?? Wouldn't that be a permanent solution to the problem? How about it Stephen, what do you think of THAT basic methodology? Why wouldn't THAT work, if your theory is correct??

Bryan

A reasonable attempt at misleading people about what i have said on this issue Bryan, but not good enough i'am afraid!

I have explained to you before Bryan, that it is not the increased fluid pressure itself that is acting `directly' here. It is the effect of this in `pushing' dermal tissue cells in towards the `hollow' space that the enlarging anagen follicle is trying to create.

It is the resistence of the dermal cells `pushed' into the anagen follicle `space' by the increased fluid pressure, that creates a dermal cell resistence to anagen follicle enlargement, and early contact inhibition.

A very simple but very relevant analogy here, is the `pressure' within a party baloon. The pressure within the baloon creates a force behind the surface of the baloon. If you try to form a hollow space in the baloon with your finger, how easy this is depends on the pressure within it. If the pressure is higher, it is harder to force your finger into the baloon.

The same principle applies to the expanding anagen follicle.

For air pressure read dermal fluid pressure. For the skin of the baloon read dermal tissue. For your finger read the growing anagen follicle.

The higher the pressure, the greater the resistence of the dermal tissue, the earlier normal contact inhibition stops follicle growth.

The `scaffold' principle is well known in providing a template for cellular growth.

A scaffold provides protection from `interference' by other structures from preventing cellular growth through normal contact inhibition. The advantages of a scaffold template for cell multiplication is recognised by professional science, and has been discussed in the context of hair multiplication research. http://www.hairsite4.com/dc/dcboard.php ... 2515&page=

My suggestion is that transplanted anagen follicles can survive and cycle, because a natural scarring `scaffold' is created by the healing process during the transplantation procedure.

Yes Bryan, this does mean that you should be able to `auto- graft' pre-balding follicles back into the male pattern baldness area with sucess, and i wish someone would try this!

Your theory would be completely scewed then wouldn't it!!

It is getting late in England, and i will post over the weekend about that study.

Meanwhile Bryan, here's a puzzle for you. This is your `task' for the weekend :wink:

The failure of follicles in the center of the larger grafts is put down to hypoxia, that is a lack of oxygen because of reduced blood supply. http://www.hairtransplantadviser.org/fallacies.htm

But induced hypoxia in the balding scalp, has been shown to improve hair growth according to an article you have quoted! http://www.geocities.com/bryan50001/artery_ligature.htm

So how do you reconcile this paradox with your theory Bryan?

S Foote.

 

[S Foote.]

With regard to the study posted in this thread by Randall et al.

http://www.john-libbey-eurotext.fr/en/r ... =text.html

People should note that the authors of this study, have placed this in the correct context regarding the current thoughts upon a direct action of androgens on follicle cells. This is as a Hypothesis!!!!

Although we argue here about direct and indirect `theories', scientificaly speaking, the current idea of a direct action of androgens on follicle cells is just a `Hypothesis', as the professional scientists who wrote the paper accept.

The proposed Hypothesis is presented, along with in-vitro evidence that `seems' to support it, and i have no problem at all with the presented data. I do have a problem with a primary assumption made in this statement however.

Quote:
" The paradoxically different responses of hair follicles to similar circulating levels of androgens (reviewed in [1] and [13]) clearly demonstrated by bald men with bushy beards indicates that the particular effect produced by androgens depends on factors within the individual follicles themselves."

I would suggest that the greater body of evidence explains this through an `external' action of androgens, more logicaly than any `internal' action, as i have argued here before.

As i said earlier in this thread, it isn't so much what is in this paper, but what isn't?

The paper concentrates upon the in-vivo growth of hair follicles, being `mirrored' by the in-vitro response to androgens. But again this leaves out the all important mechanism of CHANGE!!

We know from the studies that androgens do not `directly' change normal terminal hair producing follicles, into male pattern baldness follicles. This study like all the others just doesn't address this issue!

Bryan would have us believe that this is a `small irrelevant' detail, but understanding the mechanism of change is the most important `core' pursuit of science.

The current `Hypothesis' just can't explain the mechanism of change, without making wild assumptions that have no recognised basis in known physiology. This is akin to the `will of the aliens' discussed in the scientific method.

http://phyun5.ucr.edu/~wudka/Physics7/N ... 0000000000

An indirect action of androgens explains all the observations in androgen related changes in hair growth, based on recognised physiology. A direct action of androgens can only explain these changes in hair growth through an unprecedented `magic' leap of faith. Just like the `alien' example.

The authors of this study propose a `direct' action of androgens on follicle cells, via changes in an autocrine induced paracrine signaling change.

Autocrine means a substance produced within the cell, directly effects the growth characteristics of that cell. Paracrine means a substance produced within a cell, creates growth changes within nearby cells.

So,the Hypothesis as far as male pattern baldness follicle cells go, is that androgens act within the DP cells to induce the production of a substance or substances, that inhibits DP cell growth, and also the growth of other related follicle cells.

This `mechanism' only has two possible ways of working. Either the substance effected by androgens is a growth factor or factors, and androgens are reducing production of this. Or a substance or substances are released from these cells by androgens, that `block' the normal uptake of available growth factors by the follicle cells.

Going back to the original theme of this thread, how could Minoxidil effect this process?

If the androgen effect is to reduce the internaly secreted growth factors, Minoxidil would have to be supplying increased amounts of these growth factors to compensate. If the androgen effect is to produce a substance that prevents normal uptake of available growth factors, Minoxidil would have to be `blocking' the production of this substance or substances.

So either way, Minoxidil should increase follicle cell growth in-vitro if this Hypothesis is correct?

But the original posted study clearly shows that Minoxidil has `NO' such effect in-vitro!!!

We all know that Minoxidil increases hair growth in male pattern baldness. So if it isn't doing this `directly', it just has to be an `indirect' effect.

S Foote.