The hype around PGD2 in male pattern baldness.

[S Foote.]

I have not posted on the forums for a long time. But given the latest hype about PGd2 in male pattern baldness, i wish to point out something i think has been overlooked in the debate.

If PGD2 is significant in male pattern baldness, why do transplants survive in this sea of PGD2 in the bald area? The human samples used in the study came from areas not considered to be growth restricted by the androgen pathway. There is no evidence of any differences in how follicles react to PGD2, so how can this possibly be significant in male pattern baldness?

What happened to any responsible peer review of this paper? The problem with this kind of latest "cure" hype we get ever now and then, is the reaction of people on hair loss forums. People start to self medicate with often dangerous drugs. In my opinion, this is just another example of the poor science that has been the norm for many years in male pattern baldness research.

In my opinion male pattern baldness research has reached a dead end, simply because it has been based upon an untested assumpion. I dont want to seem negative here, but the only way forward is to be critical about the traditional assumptions that have got us nowhere in many years of trying.

Some here may remember my posts about my ideas relating to changes in follicle size based on evolution. This got to the point where i could go no further without professional scientific support, something that is not in the interest of anyone in the field. However developments continue to add weight to my argument.

I have recently written an updated article about my arguments involving hair growth, and a test proposal, This is linked on the Node website here:

http://thenode.biologists.com/a-consideration-of-mammalian-dermal-evolution/discussion/

In this i argue the case against some of the traditional assumptions that have been made in male pattern baldness, that continue to hold back progress towards better treatments. One recent study in particular effectively refutes the long held notion of the androgen pathway in male pattern baldness, reference 16 in my article.

 

[maher]

This PGD2 "hype" was about 3 years ago

If PGD2 is significant in male pattern baldness, why do transplants survive in this sea of PGD2 in the bald area?

Thats because mast cells from back of the scalp are immuno-inactive.

 

[benjt]

In this i argue the case against some of the traditional assumptions that have been made in male pattern baldness, that continue to hold back progress towards better treatments. One recent study in particular effectively refutes the long held notion of the androgen pathway in male pattern baldness, reference 16 in my article.

Can you please paste the relevant text sections for this? The title and abstract of reference 16 themselves do not say that. On the contrary to your hypothesis here, the interpretation one could draw up from reference 16 is closer to supporting that PGD2 plays a huge role.

 

[S Foote.]

OK let me expand upon the immunology assosiation in male pattern baldness, and the other known factors.

Benjt the immune-mouse study has its own thread here, this has been debated before.

The main issue is one of scientific parsimony. If it is going to be argued that DHT effects hair follicle size through immunology, where's the "opposite" action in beard/body follicle enlargement? Also it is a strange immune action that does not damage the follicle, just reduces its size. Remember miniaturised follicles still grow hair, just not as much as we would like.

I think the various factors in male pattern baldness have traditionaly just been cherry picked to suit a particular argument. You have to try to put all the relavant data together in a logical cause and effect sequence.

In terms of scientific parsimony, there is a very simple cause and effect pathway in male pattern baldness. This explains follicle miniaturisation, sebaceous gland hyperplasia (swelling), the changes in immunology, and the relative hypoxia and fibrosis.

The follicles get smaller because of androgen induced lymphedema in the area. The link here and its purpose in evolution, are described in my article.

The increased local tissue fluid pressure also causes swelling of the sebaceous glands. The raw material of any secreating gland is tissue fluid, the gland then processes this into the required secretion. Increased fluid pressure will swell secreating glands, including of course the prostate.

Increased fluid levels or edema has other recognised effects in tissues. These include hypoxia and fibrosis, and the kind of changes in local immunology noted in male pattern baldness.

http://qjmed.oxfordjournals.org/content/95/12/803

http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0030254#close

http://www.lymphnotes.com/article.php/id/569/

The evidence is that the changes in immunology are an associated factor in male pattern baldness, and not causal.

My views upon transplantation are in my article. The only logical difference in the immune deficient mouse study, is the lack of a fibrotic barrier to follicle enlargement.

It should be noted that tissue edema and inflammation, are two sides to the same coin. One can cause the other and vise versa. In edema the inflammatory processes this causes are known to further increase edema, and make the situation worse. I think this is why some male pattern baldness treatments that target inflammation, do have a positive effect.

Androgen induced lymphedema as the initial change in the scalp, is the only action that can logicaly link all the recognised data together in male pattern baldness.

- - - Updated - - -

Let me be more specific about the consequences of that immune-mouse study, for the traditional claims of donor dominance.

According to the claims of direct sensitivity to androgens of male pattern baldness follicles, the results of that study are just not possible. According to this claim. everything necessary to maintain those follicles in a miniaturised state was transplanted within them. There was also more that enough androgens present in the mice to feed these follicles, according to the claim of direct sensitivity.

To try to claim now that androgens must act via immunology, goes against the initial claim and is just bad science. There was also no immune component in the in-vitro tests, that were claimed to prove direct androgen effects in follicles in the first place. So either way the direct sensitivity notion fails to explain the actual observations.

 

[Swoop]

There isn't a hype, and never was for me at least regarding PGD2. Perhaps of your lack of visiting the forums or reading studies you have missed the latest consensus. Androgenetic Alopecia has never been more clear than it is currently, and it hasn't reached an dead end, we are just actually finally getting started imo. I suggest you to read this;

http://www.hairlosstalk.com/interact/showthread.php/89309-Understanding-Androgenetic-Alopecia

 

[Fbalding84]

S FOOTE, in a few Simple sentences what's the cause and what is the cure?

 

[benjt]

If it is going to be argued that DHT effects hair follicle size through immunology, where's the "opposite" action in beard/body follicle enlargement?

... and where is it for the hair in the horse shoe pattern? Doesn't prove anything regarding either the PGD2 or the androgenetic pathway. Also, just saying "there was a thread on this here once" doesn't prove anything, as in many threads many wrong things were said.

Also it is a strange immune action that does not damage the follicle, just reduces its size. Remember miniaturised follicles still grow hair, just not as much as we would like.

This is not strange given how the follicle itself doesn't have ARs, but only the DP has. In the DP, both the DP cells and the DSC cells get damaged from the PGD2 that is released downstream somewhere in the course of events which is triggered by DHT docking to the DP's ARs.

The link here and its purpose in evolution, are described in my article.

It's a hypothesis of yours and by no means proven. The same argument of "cherry-picking to support your view" applies. I'm not saying it's wrong, nor am I saying it's true - I'm just saying it's a mere hypothesis without any support in actual findings, and that you are refuting things on a very, very thin basis. Your refutal of the androgen pathway is, by the way, downright wrong. Just because you are not able to explain it doesn't mean that it isn't there. Galileo also noticed the existence of the circular movements of the planets before they could be explained.

Increased fluid levels or edema has other recognised effects in tissues. These include hypoxia and fibrosis, and the kind of changes in local immunology noted in male pattern baldness.

... which can be equaylly explained by PGD2's effects.

Androgen induced lymphedema as the initial change in the scalp, is the only action that can logicaly link all the recognised data together in male pattern baldness.

Most certainly not. And don't always say "it's explained in my article". It's 24 pages. When you cite something you don't say "can be found in book XYZ". For the sake of your reader's comprehension, at least explain the claim of yours you refer to in one or two sentences. Nobody can just look for the sentence you might or might not refer to.

Lastly, there was work that has shown that the major difference in follicles from the back vs top of scalp is whether the DP exhibits ARs. So yes, this explains things perfectly.

 

[bushbush]

Based on recent findings, male pattern baldness is 'only' linked to the immune system by the implication of mast cells. This also fits quite nicely with the PGD2 theory and the role of androgens.

Larson, Allison R., et al. "A prostaglandin D-synthase-positive mastcell gradient characterizes scalp patterning." Journal of cutaneous pathology 41.4 (2014): 364-369.

Finds evidence of a PGD2 gradient (importantly, in the familiar 'horseshoe' pattern) in mast cells.

Some other papers:

Mast cells actively de-granulate in Androgenetic Alopecia areas of scalp:

JAWORSKY,CHRISTINE, A. M. Kligman, and G. F. Murphy. "Characterization of inflammatory infiltrates in male pattern alopecia: implications for pathogenesis." British Journal of Dermatology 127.3 (1992):239-246.

-Which (de-granulation) may:

Mayo,Juan C., et al. "Androgen-dependent mast cell degranulation in the Harderian gland of female Syrian hamsters: in vivo and organ culture evidence." Anatomy and embryology 196.2 (1997):133-140.

-or may not (depending on where you look):

Chen, WenChieh, et al. "Human mast cells express androgen receptors but treatment with testosterone exerts no influence on IgE-independent mast cell degranulation elicited by neuromuscular blocking agents." Experimental dermatology 19.3 (2010):302-304.

- be regulated by mast cell androgen receptors.

-Significantly greater numbers of mast cells were present in subjects with Androgenetic Alopecia (contrary to the lack of a statistically significant difference in the above Larson et al., 2014 paper):

Won, Chong Hyun, et al. "Dermal fibrosis in male pattern hair loss: a suggestive implication of mast cells." Archives of dermatological research 300.3 (2008): 147-152.

Given what we know about the (causal, not just correlative) effects of PGD2 on hair growth (see: Garza et., 2012 Prostaglandin D2 inhibits hair growth and is elevated in bald scalp of men with androgenetic alopecia.) and how PGD2 is in turn an androgen dependant transcript that is present in a 'horseshoe' pattern gradient within the scalp: the hype is justified.

If PGD2 is significant in male pattern baldness, why do transplants survive in this sea of PGD2 in the bald area?

Hairs are transplanted with a small amount of surrounding tissue. It is possible that this acts as a protective buffer.

 

[Quantum Cat]

Good to see you again here Mr. Foote. Did you know Bryan passed away?

Hope you plan to stick around - I always found your contributions interesting. (don't get deterred by some of the rude/hostile people here such as Maher)

 

[S Foote.]

Hi Quantum cat, yes i heard about Bryan.


I take on board everything people have said here about PGD2, but in my opinion non of this is relevant to the primary cause of follicle miniaturisation in male pattern baldness. I contacted Dr Cotsarelis about these issues a while back, if he decides to reply i will post it.

We can argue for evermore about the intepretation of one particular piece of data, and i dont intend to get into this kind of pointless cherry picking thats common on the forums. Lets go straight to the bottom line.

As an experienced systems engineer i have to consider the whole body of data relating to the function of the system, and what is and is not relevant at the functional level. In science this is described as the rule of parsimony.

https://archosaurmusings.wordpress.com/2008/06/15/the-principle-of-parsimony-in-science/

In my opinion this is where any significant influence of PGD2 and other claims fail, because they dont take account of all the systems data and parsimony.

In the case of androgen related hair loss/growth, the ideal in scientific parsimony would be this.

There would be "ONE" initial action of DHT, that would explain the pathway of hair loss and growth and all the known associated factors. It would do this using recognised physiology, without making any mechanistic assumptions. This initial action of DHT should also be falsifiable by experiment. I would personaly add that in the case of biology, there should also be a demonstration of purpose in evolution.

There is only one initial action of DHT that can meet this requirement. This is that DHT increases lymphatic pumping efficiency.

This action of DHT could be easily tested by those in a position to do this. If this action was confirmed, it would be very important for effective future treatments for male pattern baldness, and in other areas of gender related physiology.

This test is the simple bottom line of my argument. In my experience to date there are other consequenses to this test, that make professional scientists very reluctant to get involved. But thats the politics and not the science.

So if anyone would like to see me proven wrong, i suggest they should support the testing of this question.

 

[bushbush]

I take on board everything people have said here about PGD2, but in my opinion non of this is relevant to the primary cause of follicle miniaturisation in male pattern baldness.

How were they not relevant? This paper: http://stm.sciencemag.org/content/4/126/126ra34.short (which I cited) is dedicated to explaining the role of PGD2 in Androgenetic Alopecia. You should read this (in full text) before being dismissive.

I don't see how your theory is any less based on "untested assumption" than currently accepted lines of research. In fact, what evidence, if any, is there that MBP is caused by "increase[d] lymphatic pumping efficiency"?

I would personaly add that in the case of biology, there should also be a demonstration of purpose in evolution.

Not so simple. If you consider MBP as a pathology, there are plenty of examples of conditions that serve no evolutionary "purpose" yet they persist in populations because they manifest after reproductive age (e.g. Alzheimer's disease) or they do not sufficiently handicap the individual that their fitness is reduced (e.g. Short-sightedness). In both cases, 'defective' genes can be maintained and propagate without being advantageous to the carrier. Regardless, such theory is of little importance when elucidating the molecular mechanisms that underpin this particular process (if what you ultimately care about is a therapeutic intervention).

So if anyone would like to see me proven wrong, i suggest they should support the testing of this question.

To be taken seriously, you first need more evidence. Good research should be hypothesis driven, but still not without grounding.

 

[S Foote.]

How were they not relevant? This paper: http://stm.sciencemag.org/content/4/126/126ra34.short (which I cited) is dedicated to explaining the role of PGD2 in Androgenetic Alopecia. You should read this (in full text) before being dismissive.

I don't see how your theory is any less based on "untested assumption" than currently accepted lines of research. In fact, what evidence, if any, is there that MBP is caused by "increase[d] lymphatic pumping efficiency"?



Not so simple. If you consider MBP as a pathology, there are plenty of examples of conditions that serve no evolutionary "purpose" yet they persist in populations because they manifest after reproductive age (e.g. Alzheimer's disease) or they do not sufficiently handicap the individual that their fitness is reduced (e.g. Short-sightedness). In both cases, 'defective' genes can be maintained and propagate without being advantageous to the carrier. Regardless, such theory is of little importance when elucidating the molecular mechanisms that underpin this particular process (if what you ultimately care about is a therapeutic intervention).



To be taken seriously, you first need more evidence. Good research should be hypothesis driven, but still not without grounding.

Good points.

First I have read the studies about PGD2 and the proposed role in male pattern baldness. I have no problem with the technical aspects of these studies or their results, but as with all in-vitro studies the results can be misleading. What you have to do is to compare in-vitro results with known in-vivo conditions to see how these fit. If the results make sense in terms of the recognised in-vivo data, you may be on to something.

But in this case to claim that PGD2 is significant in male pattern baldness, just adds another layer of complication. A bad sign in terms of the scientific method. Extra complication can only be justified if there is no other more simple explanation. Given the whole body of evidence in male pattern baldness, there is a more simple explanation.

male pattern baldness is a pathology in humans. But a consideration of hair follicles in terms of evolution could be useful in trying to understand the possible factors that can cause hair loss. This is what my article explored.

The hypothesis this generated was that hair follicle structure and the hair cycle, evolved to adjust follicle size in response to changes in local tissue fluid pressures. This has important advantages in mammalian evolution. What this means is that any pathology that changes local fluid pressures in humans, will change the local hair growth.

The grounding as you put it, is already accepted human physiology. Once you make the connection with hair growth and local fluid pressures, accepted physiology does the rest. It is the order of events that comes from this that predicts DHT initially increased lymphatic efficiency in men.

When it comes to the rules of evidence, the traditional assumptions would do well to try to obey them. I think at this time a serious review of the historic hair loss research is overdue, and I will post on this tomorrow.

PS
In regard to your comment.

" Regardless, such theory is of little importance when elucidating the molecular mechanisms that underpin this particular process (if what you ultimately care about is a therapeutic intervention). "

I think it is a mistake to believe that manipulating molecular mechanisms is going to be the answer here. There are other levels of functional interactions in biology.

In this scenario the molecular mechanisms that underpin the male pattern baldness process, are those linked to normal tissue growth controls described here.

http://www.pnas.org/content/111/15/5586.abstract

The last thing we want to do is to try to change this process. In my opinion this is why the cell based research continues to fail, and if it ever does succeed long term it will be just too dangerous to ever be licenced.

Far easier cheaper and safer to change the external forces that cause this natural reaction in the follicles in the first place.

 

[maher]

Ok Mr foote. interesting hypothesis. So, whats the solution? besides genetic engineering.. Releasing lymph pressure in the scalp tissue? more efficient lymph drainage?

 

[Fena2000]

So how is it minoxidil is effective then, doesn't it dilate the capillaries so there is more bloodflow in the tissue, wouldn't it put more strain on the lymph vessels to drain the fluid.

 

[S Foote.]

Ok Mr foote. interesting hypothesis. So, whats the solution? besides genetic engineering.. Releasing lymph pressure in the scalp tissue? more efficient lymph drainage?

You've got it.

I intend to talk about the possible treatment options shortly.

- - - Updated - - -

So how is it minoxidil is effective then, doesn't it dilate the capillaries so there is more bloodflow in the tissue, wouldn't it put more strain on the lymph vessels to drain the fluid.

I think peoples complaints about minoxidil on the forums tells the story. The wrinkles and dark patches around the eyes.

Minoxidil changes the tissue fluid balance in tissues, reducing fluid at the level of the follicles. The wrinkles and dark patches are a sign of this.

Ref.

Topical minoxidil: cardiac effects in bald manF. H. H. LEENEN, D. L. SMITH & W. P. UNGERHypertension Unit, Department of Medicine, Toronto Western Hospital, and Departments of Medicine andPharmacology, University of Toronto, Toronto, Ontario, Canada.

 

[Fena2000]

S foote, your theory makes sense to me. Wonder if replicel thought about this.

I've always thought the lymphvessels played part in this. But what do you think about the cappilaries , maybe weak cappilaries play part in this too.

I've asked this already in another post, is there a link between rosacea/SD and Androgenetic Alopecia. In rosacea the bloodvessels are malfunctioning, they are weak and aren't able to constrict. This causes constant bloodflow in the tissue, and lymphvessels aren't able to drain the excess fluid, which eventually causes a malfunction in the lymphvessels (edema). That's maybe why I have extreme hair loss since Ive been dealing with rosacea/SD.
Could the burning sensations come from the blood pooling in the tissue and the poor drainage of the lymphvessels, and the DHT of course.

I really believe if the excess fluid in the skin could be drained by well functioning lymphvessels, our problem will be solved or almost solved .

But what I don't understand is , how is it that hair transplants survive in that kind of environment.

 

[bushbush]

First I have read the studies about PGD2 and the proposed role in male pattern baldness. I have no problem with the technical aspects of these studies or their results, but as with all in-vitro studies the results can be misleading. What you have to do is to compare in-vitro results with known in-vivo conditions to see how these fit. If the results make sense in terms of the recognised in-vivo data, you may be on to something.

If you have read the study in question then you will know that it did indeed demonstrate inhibition of hair growth in vivo.

But in this case to claim that PGD2 is significant in male pattern baldness, just adds another layer of complication. A bad sign in terms of the scientific method.

Not if it can be explained scientifically, with evidence.

I think it is a mistake to believe that manipulating molecular mechanisms is going to be the answer here. There are other levels of functional interactions in biology.

Said interactions are an interplay between genetics (including their expressed products) and the environment. male pattern baldness has a molecular basis, therefore any functional 'cure' (bar transplanting complete cells or follicles) also will. Finasteride does, as does minoxidil, either directly or indirectly. By understanding the mechanisms better drugs can be designed. Higher level biological systems still have a molecular basis---they just might be poorly understood or have not yet been fully investigated on that level.

So how is it minoxidil is effective then, doesn't it dilate the capillaries so there is more bloodflow in the tissue, wouldn't it put more strain on the lymph vessels to drain the fluid.

This is a common misconception, there is no evidence to suggest that minoxidil is effective due to increased blood flow.

 

[S Foote.]

S foote, your theory makes sense to me. Wonder if replicel thought about this.

I've always thought the lymphvessels played part in this. But what do you think about the cappilaries , maybe weak cappilaries play part in this too.

I've asked this already in another post, is there a link between rosacea/SD and Androgenetic Alopecia. In rosacea the bloodvessels are malfunctioning, they are weak and aren't able to constrict. This causes constant bloodflow in the tissue, and lymphvessels aren't able to drain the excess fluid, which eventually causes a malfunction in the lymphvessels (edema). That's maybe why I have extreme hair loss since Ive been dealing with rosacea/SD.
Could the burning sensations come from the blood pooling in the tissue and the poor drainage of the lymphvessels, and the DHT of course.

I really believe if the excess fluid in the skin could be drained by well functioning lymphvessels, our problem will be solved or almost solved .

But what I don't understand is , how is it that hair transplants survive in that kind of environment.

Understanding why transplants survive, is central to understanding the real mechanisms of male pattern baldness.

Over the Christmas period I intend to start a thread about reviewing the historic research into male pattern baldness, from the perspective of the whole body of evidence we have today.

Briefly, my proposal here involves external resistance of the dermal tissue controlling anagen follicle size. This being modified by the fluid pressure.

In the successful transplants (small grafts), the large transplanted follicles get a tough fibrotic matrix formed around them (scarring). This then preserves this large follicle space for future anagen enlargements.

I will go into this more in the new thread, but it will be weekend at least before I can get round to it.

- - - Updated - - -

If you have read the study in question then you will know that it did indeed demonstrate inhibition of hair growth in vivo.



Not if it can be explained scientifically, with evidence.



Said interactions are an interplay between genetics (including their expressed products) and the environment. male pattern baldness has a molecular basis, therefore any functional 'cure' (bar transplanting complete cells or follicles) also will. Finasteride does, as does minoxidil, either directly or indirectly. By understanding the mechanisms better drugs can be designed. Higher level biological systems still have a molecular basis---they just might be poorly understood or have not yet been fully investigated on that level.




This is a common misconception, there is no evidence to suggest that minoxidil is effective due to increased blood flow.

I think most people on the forums are aware by now, that hair growth in-vivo in mice is a lot different than hair growth in-vivo in the human male pattern baldness scalp. Clearly something else is significant in human male pattern baldness.

You state quote " male pattern baldness has a molecular basis, therefore any functional 'cure' (bar transplanting complete cells or follicles) also will".

This is clearly wrong. Inflammation has a molecular basis, the ice pack that reduces this significantly has not.

You are also assuming that there is a molecular difference within the follicles involved in male pattern baldness, compared to other follicles. I will elaborate on the evidence against this in the new thread I refer to in my post above..

 

[Fena2000]

Understanding why transplants survive, is central to understanding the real mechanisms of male pattern baldness.

Over the Christmas period I intend to start a thread about reviewing the historic research into male pattern baldness, from the perspective of the whole body of evidence we have today.

Briefly, my proposal here involves external resistance of the dermal tissue controlling anagen follicle size. This being modified by the fluid pressure.

In the successful transplants (small grafts), the large transplanted follicles get a tough fibrotic matrix formed around them (scarring). This then preserves this large follicle space for future anagen enlargements.

I will go into this more in the new thread, but it will be weekend at least before I can get round to it.

- - - Updated - - -



I think most people on the forums are aware by now, that hair growth in-vivo in mice is a lot different than hair growth in-vivo in the human male pattern baldness scalp. Clearly something else is significant in human male pattern baldness.

You state quote " male pattern baldness has a molecular basis, therefore any functional 'cure' (bar transplanting complete cells or follicles) also will".

This is clearly wrong. Inflammation has a molecular basis, the ice pack that reduces this significantly has not.

You are also assuming that there is a molecular difference within the follicles involved in male pattern baldness, compared to other follicles. I will elaborate on the evidence against this in the new thread I refer to in my post above..

So so it's like digging a little hole and planting a big plant into it, the roots won't be able to grow and the plant will die. So in transplants you can compare it to digging a big hole to put the plant in, now the plant has the ability to grow.

But in the long run this follicle will die too because of the excessive fluid build up or not.

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I'm using rosacea again, since this skin disorder is caused by weakened capillaries , which in the long run also causes the lymphvessels to fail. In Russia , there's a doctor (dr syrokomskyy) who claims to cure rosacea by constantly attacking and damaging the skin (and afterwards his patients have to use a topical for a certain amount of time).0n the rosacea site a guy went to Russia to get this procedure done, he explained he actually peeled the skin layer by layer.
This reminds me of the guy who burned himself and his hair grew back. I think the skin regenerates the bloodvessels and lymphvessels, which are now not defect anymore, and therefore hair can regrow in a new healthy environment. I Do believe lymphvessel drainage plays a big part in it.

just curious S foote, how do you know so much about this?

 

[BrightonBaldy]

Interesting Fena.

Who here is willing to peel off a few layers of skin on their head though? lol

What else could be done to test this?