Anyone who follows the hairloss forums will be aware of the slow progress towards effective treatments for male pattern baldness, and the regular dissapointment of the claimed breakthroughs. I think it is time to review the evidence for the historical claims, that continue to get us little in terms of effective treatments. So what entitles me to an opinion on the subject? I am a systems engineer, with over forty years experience of building and trouble shooting complex mechanical systems. I have had to consider real world scientific principles in the function of systems, every day of my working life. These are physical laws that apply to the function of any system, be it mechanical or biological. This is intended to review the historical body of evidence relating to male pattern baldness, and the issues with its interpretation. The emphasise being upon how claims made at the molecular level, dont hold up in terms of the systems function. I also suggest there is a systems interaction going on that very simply explains follicle miniaturisation in male pattern baldness, and what could be done about this. The initial work of Hamilton is credited with establishing the link with androgens and male pattern baldness. Further research established that it is the androgen DHT that is the significant trigger to the male pattern baldness process. DHT being converted from T, in the dermal system largely in hair follicle DP cells by 5AR type 2. http://www.ncbi.nlm.nih.gov/pubmed/11397903 Subsequent hair transplantation studies lead to the notion of donor dominance. The survival of follicles transplanted into the male pattern baldness area, and certain in-vitro studies lead to the following conclusion. This is that follicles have a different internal molecular make up, that leads to different direct androgen effects on follicle size. All the treatment research since in male pattern baldness, has been aimed at targeting or avoiding a direct androgen action in male pattern baldness. There are some serious issues with this conclusion however, and so far male pattern baldness treatments based upon this have just not delivered. The problems begin when you consider this direct action, in terms of the actual in-vivo observations. If this is correct, it means that follicles have to be feed androgens for long periods, before there is any direct response at all. The androgen induced hair growth that developes from the ears and nostrils of middle aged men, apparently takes 20 to 30 years to realise its androgen dependent. We all know that male pattern baldness can take years to develope after the initial increase in androgens at puberty, again indicating a delayed response that varies widely in individuals. It also seems that once follicles do become directly sensitive to androgens in male pattern baldness, they become very sensitive indeed. In male pattern baldness castration removes over 90% of the available androgen stimulus, but it does not reverse male pattern baldness. http://press.endocrine.org/doi/abs/10.1210/jcem-20-10-1309 The actual real life observations in male pattern baldness, go against everthing we know about direct hormone actions upon target cells. http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/basics/hormones.html There is a very important point about the claim that male pattern baldness is caused by a direct hormone action. If this was true, male pattern baldness would be easy to prevent and treat. We just block the follicle androgen receptors with a topical antagonist, or anti-androgen. Topical hormone medications are effective in many conditions, and there is no technical reason that the same size antagonist molecule should have penetration issues. In fact hair follicles are recognised as being effective channels for such topicals. http://www.inetce.com/articles/pdf/221-146-04-054-h01.pdf The market for a topical with no systematic effects that treated male pattern baldness, and prevented it in people with a family history would be worth billions. So where is this simple fix? The experience on hair loss forums tells a different story. We know that any effect at all of topical anti-androgens only happens where there is some systematic effect. People make all kinds of excuses for the factors refered to so far. All these so called explainations have to add complication upon complication. You can explain anything you like by adding complication, but this is not how genuine science works. http://math.ucr.edu/home/baez/physics/General/occam.html Also the action of androgens in male pattern baldness, has to explain all the recognised changes. The direct action notion cannot do this without adding even more complication. There are many other factors in the male pattern baldness scalp, that demonstrate differences compared to hairy scalp. These include increased levels of DHT, increased levels of inflammatory related activity, fibrosis and a relative hypoxia. There are also significant changes in sweating capacity, and sebaceous gland hyperplasia (swelling). There are suggestions that an increased inflammatory activity triggered by androgens, is significant in follicle miniaturisation in the male pattern baldness area. The latest being the hype about PGD2. So far we are all aware that what happens in mice and tissue culture, means very little when it comes to human male pattern baldness. On the surface the process of male pattern baldness seems very complex, with many associated factors. In my experience with complex systems, you have to look for the common factor. If you can find a common factor, this usually makes sense of and gives order to the events and changes. This can sort out what is causal in a change, and what are just downstream effects. I think we need to take another look at the early data that generated this direct androgen action, and the different response of follicles notion. The key here is hair transplantation, and why some methods succeed, while others fail. Understanding the real mechanisms of this, is the key to the future of male pattern baldness treatment. Continued below. - - - Updated - - - The early hair transplantation studies used large grafts by todays standards. The original Orentreich study used grafts of four milimeters diameter. This is a good historical article on hair transplantation. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2840892/ The initial studies that used these large grafts ran for up to two years, and the results generated two possibilities. The survival of terminal follicles transplanted into the male pattern baldness area, was either because of internal follicle differences or effects very close to the follicles. Further testing could have established which of the two possibilities it was, but such testing was just not done. Instead hair transplantation moved largely into the commercial field, along with the assumption that the follicles were different than the originals in the male pattern baldness area. What is important about the studies with the early large grafts, is what was not seen. Nowadays there are clinics that specialise in the repair of problems assosiated with the early large grafts. One problem being the loss of hair in the center of these, leaving only terminal hair growing around the circumference of the grafts. http://www.bernsteinmedical.com/res...spects-of-repair-and-basic-repair-strategies/ This common hair loss in grafts from 3-5 mm diameter, is not seen in modern smaller grafts. The reason offered for this is hypoxia, or poor oxygen supply before proper healing and restoration of graft blood supply. The big problem with this, is that there was no mention of this hair loss in the early studies that ran for up to two years. If as now accepted this was common in the then most used 4 mm grafts, why wasn't this apparent during the period of treatment sessions? As it was these large grafts continued to be used from the 1950's right up to the early 80's. If this was an early effect, customer complaints alone would have driven the move to smaller grafts far earlier. Any unbiased review of the limited data about large grafts, would conclued that this hair loss is longer term and consistent with the continuation of male pattern baldness in these grafts. The question should be why does hair continue to grow long term around the edges? More recent studies have questioned the early assumptions, and demonstrated an influence of the surrounding tissue upon transplanted hair growth. http://newhair.com/pdf/mp-2002-donor-dominance.pdf One recent study effectively refutes the claim that follicles survive in transplantation, because of internal factors. Quote: "Balding Hairs Grow Long and Thick on Immunodeficient Mice" Because immunodeficient mice do not reject foreign tissues, they will accept transplants of human hairs that can then be studied. We transplanted both miniaturized and normal hair follicles from scalp affected by common balding. Our study found that miniaturized hair follicles can quickly regenerate once removed from the human scalp; in fact they grew as well as or better than the transplanted normal, non-balding hair follicles as assessed by their diameter and length achieved at 22 weeks. Krajcik RA, Vogelman JH, Malloy VL, Orentreich N. Transplants from balding and hairy androgenetic alopecia scalp regrow hair comparably well on immunodeficient mice. Journal of the American Academy of Dermatology 48(5):752-59, 2003." According to the direct action and androgen sensitivity claim, this result is just not possible. There were more than enough androgens in those mice to feed the alledged direct within the follicle process, and sensitivity of male pattern baldness follicles. There was also no immunology present in the historical in-vitro studies, that claimed to prove opposite direct actions of androgens on follicle cells. No immune mediated direct action of androgens excuse then, for the results of this study. The really inportant thing about this study is it demonstrates that human male pattern baldness follicles can recover, and that the in-vivo action is external. Again we must look for the common factor in all this apparent complication. Going back to the original alternative explaination, of an effect very close to the follicles in transplantation. There is one external action that links together the transplantation data, and all the recognised conditions in human male pattern baldness. This involves the structure of hair follicles, and the recognised changes during the hair cycle. This external influence is based upon the original function of hair as an insulator in mammalian evolution. Continued below. - - - Updated - - - The core problem in male pattern baldness is one of tissue growth. The anagen enlargement of the follicles is cut short, and the follicles fail to enlarge further. The smaller follicles then produce less hair. Basic physics dictate that in order for the follicles to enlarge, the surrounding tissue has to move out of the way, two things cannot occupy the same space at the same time. So there has to be a resistence factor of the surrounding tissue to follicle enlargement. I will make a simple analogy. Anagen follicle enlargement is like trying to inflate a balloon under water. The higher the water pressure, the harder it is to inflate the balloon. If the pressure inflating the balloon is a constant, changing the external pressure will change the ultimate size the balloon can reach. It has been demonstrated that normal tissue growth is subject to spacial constraints. Increasing external pressure restricts tissue growth. Reducing external pressure allows increased tissue growth. http://www.pnas.org/content/111/15/5586.abstract This physical connection when considered in terms of general dermal physiology, generates the following hypothesis. This is that the hair producing structure in mammals evolved as a re-cycling pocket, to read and respond to the prevailing external resistence. This allows follicle size and hair growth, to automaticaly adjust in line with the mammals primary thermal control system. This and other advantages of the pocket structure of hair follicles in evolution, are detailed in my pdf article with diagrams linked here. http://thenode.biologists.com/a-consideration-of-mammalian-dermal-evolution/discussion/ In the described original function the different timing of anagen in follicles, and the distortion of follicles already in anagen, creates shedding and thinning of hair when neccesary. According to this, anagen follicle size is determined by the resistence factor of the local tissue. Any significant change in follicle size, being caused by changes in local tissue fluid pressures created by whatever mechanism. In male pattern baldness rising fluid pressures over time in the areas concerned, would account for the shedding and thinning patterns and ultimate baldness. There is evidence that DHT has a significant effect upon tissue fluid pressures and levels, based upon evolution. There is also evidence that in some individuals, DHT can create increased fluid pressure in the male pattern baldness area. The details of how this happens, are for another discussion. The point here being, is increased scalp fluid pressure the actual cause of follicle miniaturisation in male pattern baldness? DHT induced scalp lymphedema as the primary cause of male pattern baldness, is the only thing that makes sense of and gives order to all the associated scalp conditions. Changes in immunology, fibrosis, and hypoxia are all recognised downstream effects of lymphedema. http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0030254#close The increased sweating capacity and sebaceous gland swelling, is also easily explained by the local increase in tissue fluid pressures. The scalp tightness and taut shiny skin, are something we all know about. There are also increased levels of DHT in bald scalp tissue, despite a drastic reduction in the local production capacity. Most dermal DHT production is from many DP cells in large follicles. Most of this is lost in miniaturised follicles. However increased tissue fluid levels, also means increased amounts of substances transported in this fluid. This includes DHT. There is a paradox concerning hypoxia in the bald scalp, that supports increased fluid pressure as the mechanism of male pattern baldness. Some claim hypoxia itself has a causal role in the male pattern baldness process. http://www.ncbi.nlm.nih.gov/pubmed/8628793 But there is another study that demonstrates that surgicaly induced scalp hypoxia, significantly increases hair growth? http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2536995/ What tells the story is how the hypoxia is produced. In lymphedema, the reduced fluid drainage and stagnation reduces oxygen levels in the tissue. In the the surgical procedure, the limited blood feed reduces the oxygen levels. Lymphedema increases tissue fluid pressure, whilst reduced blood supply reduces tissue fluid pressure. This is the important difference, and the common link with the changes in hair growth. So how does this explain the results of hair transplantation, and more to the point what can we do to treat male pattern baldness? Continued below. - - - Updated - - - The principle here is that hair follicle enlargement, is controled by the prevailing external tissue resistence. It has already been sugested that the fibrotic tissue that forms over time in male pattern baldness, is a barrier to follicle re- enlargement. This has been suggested as one of the reasons that it is harder to treat male pattern baldness, once it has been established. The reverse principle must also apply. In transplantation, large follicles are transplanted into the bald area. In the modern small grafts, the healing process results in fibrotic scar tissue around the grafts. Now instead of being a barrier to the enlargement of small follicles, fibrosis becomes a barrier to the external tissue moving in on the large follicles space. This conserves this space for future large anagen follicles. This would explain why the only large follicles to survive long term in the old large grafts, are those around the edges. That is within the scarring zone. This also explains the paradox of male pattern baldness follicles re-enlargeing in the quoted mouse study. The lack of immunology in these mice, fails to produce this fibrotic cage around the follicles during healing. The transplanted miniaturised follicles, are then free to re-enlarge within the low resistence conditions in the mouse tissue. The common factor in the treatments that have a positive effect in male pattern baldness, is that they have some effect on reducing scalp tissue fluid pressures and levels. We are all aware of these treatments. Reducing levels of DHT with finasteride etc, reduces the primary effect that results in scalp lymphedema. Minoxidil stimulates the local microcirculation, reducing surface fluid levels (demonstrated by wrinkles). http://www.ncbi.nlm.nih.gov/pubmed/6239893 Latanoprost was developed to reduce tissue fluid pressure in the eyes. note the lymphatic drainage link. http://www.ncbi.nlm.nih.gov/pubmed/24049723 Low level laser light, has now been approved for treating lymphedema. http://www.breastcancer.org/treatment/lymphedema/treatments/laser Anti-inflammatory drugs do just that. They help to reduce tissue effects, that increase and maintain edema. We then have all the anecdotes. There have been all sorts of methods proposed to increase the blood supply to follicles, that claim to have some effect. Scalp exercises, hanging upside down, massage etc. It is not increasing blood supply that matters, it is improving the scalp circulation to reduce fluid levels. So what can we do to increase the effectiveness of male pattern baldness treatment? The quoted mouse study demonstrates that there is nothing basicaly "wrong" with the follicles in male pattern baldness, and given the right conditions they can re-enlarge. So we need to provide the right conditions. The fluid pressure in tissue is a function of the feed and drainage equation. In this senario, DHT is reducing the drainage side of the equation. So we obviously need to address this. There is the feed side also, and i think the evidence suggests that this can make a significant difference in men who are prone to male pattern baldness. So we need to increase scalp fluid drainage, reduce scalp fluid feed, and address the scalp fibrosis that increases scalp tissue rigidity. Continued below. - - - Updated - - - On the drainage side of the equation and DHT. Again without going into detail here about fluid dynamics, and the complex "plumbing" of the human head. The evidence is that there is to much local production of DHT, in the large follicles of the whole scalp and beard area. This is why topical 5ARI inhibitors on the bald area itself have little effect, and why the systematic drugs like finasteride have a better treatment effect. But i dont think it is neccessary to use systematic drugs here. People were supprised by the treatment effect of shampoo's that have some action upon reducing DHT production. I suggest this is simply because they are treating the whole scalp. So ideally for convinience of use, we need shampoo's and face washes that topicaly reduce local DHT production effectively. To maximise the increased drainage, we must also address the other side of the equation. This could be more important that the drainage side in reversing male pattern baldness. With reduced scalp drainage, a higher blood pressure feed is far more likely to create higher scalp fluid pressure. This is in line with the recent study that confirmed a link with coronary heart disese, and vertex balding in male pattern baldness. The common factor being implicated here, is a higher core blood pressure in the individual. http://bmjopen.bmj.com/content/3/4/e002537.short?g=w_open_current_tab There have also been anecdotes on the forums, about bald men who have had accidents involving scalp detachment. I cannot find the posts, but the claim is that after scalp re-attachment hair started to regrow. The only difference now being the reduced blood supply to the re-attached scalp. According to this factor the scalp arterial ligature procedure referenced above, should make a big difference in combination with local DHT reduction. This would of course need to be properly studied first for safety, and wider effects upon core blood pressure etc in the male pattern baldness application. But a one off reversable procedure like this, could be much more effective and preferable than any other surgery for male pattern baldness. Then we are left with dealing with the scalp fibrosis that developes in male pattern baldness. Here again a common factor links male pattern baldness and lymphedema. In male pattern baldness some claim a good massage technique has a positive edffect. In lymphedema such techniques are used to reduce the fluid levels, and breakdown the fibrotic tissue. Lasers we know show a positive effect in male pattern baldness, and they are also used in lymphedema to again reduce fluid levels and fibrosis. Such things should not be needed long term once the right fluid balance in achieved in the male pattern baldness area. Somethings to avoid would be heating the scalp, and external irritants that create inflammation. Cold is good, and cool or lukewarm water only should be used for washing the hair. The external connection here, also explains why the cell based research for male pattern baldness has not gone as expected. Over the last twenty years or so, we have seen these companies come and go. The same thing seems to happen in all these procedures. Initial results seem promising, but then they just dont develope. I think the problem is these procedures do not address the actual problem. It would be perfectly possible to create new follicles initialy, but these then have to survive the scalp conditions as described above. Without some kind of external protective matrix, they will suffer the same fate as the original follicles. I think that is why these procedures are failing to develope. We could always mess with the normal tissue growth controls, to make follicles overcome the external resistence. But this would be a very bad idea, and one that would certainly not be licensed in humans. In my opinion these kinds of procedures would be expensive, not effective long term, and potentialy dangerous. If we can change the external condition that cause follicle miniaturisation, these procedures would not be neccessary anyway.