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"How can hair be revived?"

Mechanism behind alopecia has been elucidated medically and hair science including pharmacotherapy and physical therapy has made significant progress. We had a round table discussion between Dr. Kuwana who strives for antiaging of hair, engaging himself in research and development of Mulberry Root Extract and Dr. Kurata who is well versed in the cutting edge of science on hair growth about the "where we are" and where we are going on medical science of hair.

There were few doctors interested in hair both in clinical and research fields around in 1990. It was an era when it was said that thinning hair could not be even treated.

Dr. Ryuichiro Kuwana who graduated from Nagoya University School of Medicine at that time started incubation experiment on hair follicle cells singlemindedly in the research building of Department of Research and Development of the National Hospital Organization Nagoya Medical Center.

On the other hand, Dr. Sotaro Kurata went to the University of Wisconsin in the United States for study in the early 1990s. He was surprised to learn that basic research on pharmacotherapy for hair thinning has dramatically progressed, which inspired him to start research on how minoxidil*1 was absorbed in hair follicle cells.

As typified by research of these two physicians, the mechanism of hair growth, transitional and resting phases in human, the so-called existence of hair follicle stem cells and mechanisms behind androgenic activity had been elucidated in 1990s. Several ingredients which work directly on cells have been identified accordingly. It was an era when androgenic alopecia had a rosy future for ahead of one.

What relationship is there between androgenic alopecia and androgenic hormone or heredity?

Ryuichiro Kuwana

Ryuichiro Kuwana:When I started research on hair loss, immunoenzymatic techniques in which lymphocytes considered to cause hair loss in alopecia areata were separated into helper T-cells*2 or NK cells*3 emerged. Then, I thought that cells might be different between patients who had alopecia areata progression and those whose alopecia areata were cured and asked some patients with alopecia areata to have a part of their skin removed.Then, I investigated them at the laboratory and found no relationship. Then, I changed my research to culture of hair follicle cells and started experiments to investigate whether addition of several substances might speed up cell division or extend the lifespan of cultured cells. When I heard that collagen was effective for cell cultivation, I would go to the slaughterhouse to get bovine eyeballs (containing collagen) and store them (laughing).

Sotaro Kurata:We can now purchase collagen for research and use collagen dissolved in plate. Now, I can remember that collagen researchers did so previously. In the laboratory I belonged to, I remember that bovine eyeballs were on the shelves of the refrigerator together with beer cans (laughing).

Kuwana:I continued the research without giving it up and was finally successful in cultivating hair follicle cells, staring from proteolytic enzyme, trypsin, that acts to degrade protein and gradually making progress. Based on these experiments, when I produced a hair growth product and used it clinically, I found that it was more effective than the conventional ones.

Kurata:When Dr. Kuwana was engaged in cell culture research, basic research had also progressed in Japan leading to the advancement of biomechanical properties of cells. I started the research on alopecia one or two years later than Dr. Kuwana did. In my case, I embarked the research on relationship between skin and hormones imagining alopecia.

Kuwana:As research on biomechanical properties of cells began, it sounded right to me a little. To tell you the truth, this type of research did not go well easily.

Kurata:In order to elucidate the relationship between androgenic hormone and androgenic alopecia, a pathological study was started from further back. The same androgenic hormone has different effects on hair and beard, that is, the hormone cause hair to fall out while it acts to grow beard. Thus, this was the subject we tried to elucidate. Research conducted by Oita University Faculty of Medicine with which I worked and research on androgenic alopecia related to the relationship between androgenic hormone and skin were a part of such research. As a result, we learned a lot about the relationship. When an androgenic hormone, testosterone, enters in dermal papilla cells which inhibits hair growth, it is converted into a substance called as dihydrotestosterone (DHT), more potent androgen by a certain enzyme. The DHT affects one of epithelial cells called as hair matrix cells by binding to androgen receptors in the cells. As a result, it causes beard growth while it sends signals that inhibit hair growth to the front or the top of the head. Like this, we now know that the different phenomena occur although it is the same androgen.

As we began to learn the mechanism, we came up with the idea that it was able to eradicate the root cause of alopecia if we could block actions of this enzyme in order to prevent hair loss. Finally, we were successful in the development of “finasteride*1” as a drug for alopecia, which led to tremendous progress in the treatment of hair loss. Before finasteride, minoxidil was already commercially available.

Kuwana:Minoxidil was not originally designed for the treatment of hair loss. The drug is a vasodilator and thus it is still unaccountable for the drug to exert effects of growing hair. There is a possibility that vascular endothelial cells are proliferated. However, the drug is developed for the treatment of hypertension and is an oral one. The clear mechanism has not been found. For example, if the drug is used before hair falls out in castrated men, alopecia will not progress, while it is used after hair falls out, it stops the progression of hair loss and does not help hair growth.

Kurata:This study was conducted in the United States in 1942. You found two things when investigating background of castrated men. One thing is that androgenic hormone induced alopecia and that hair loss stops if no androgen exists. Another thing is heredity as a precondition. If a man has a family history of thinning hair, his thinning hair will worsen when androgenic hormone has some impact. Thus, when he becomes castrated, his thinning hair will not progress because androgen will no longer be released. Even though a person has a family history of thinning hair, his thinning hair may not progress. The study results made us learn these two conditions. This is why this article meant a lot.

Kuwana:None of us are exactly alike because of genetics.

Kurata:When a patient comes to you and he has a distant family history of thinning hair, “He may suffer from androgenic alopecia”. On the other hand, when he has no family history of thinning hair in his all relatives, you can say with confidence, “You will not suffer from androgenic alopecia”. So, you do not need to worry.

Kuwana:If a man is castrated, androgen is decreasing in amount leading to the stop of hair loss progression but hair will never grow. When looking at the amount of androgen, the amount of 10 originally may drop to 1 or 3. If there are 3 left, it may not cause its progression but may not grow hair. Although it may help improve moderately, it may progress if hair is thinning.

   
Research on women’s hair loss and usefulness of Mulberry Root Extract

Sotaro Kurata

Kurata:The adrenal glands produce weaker androgen before converting into testosterone. As testosterone is produced in adrenal glands, women have around ten times lower testosterone than that of men. Thus, women also develop pimples or armpit odor (hircismus). It is not that only men have androgens but that women have them causing women’s alopecia.

Kuwana:Lower level of androgen is better in terms of hair loss. However, even though a man has androgen but its androgen receptor protein does not work well, the androgen will not work despite Y chromosome. However, in such a case, thinning hair occurs in women. Thus, I think that the cause is not only androgen.

Also, there is a reverse hypothesis. For example, in an experiment of estrogen (female hormone) using mice, no hair grew. Thus, hair may not grow easily in human as well if estrogen exists. Does androgen have a negative effect or does female hormone do? Do both hormones do wrong? You can bet that a small child with neither androgen nor estrogen will not lose hair.

Kurata:In case of women, it is complicate. Even in a woman, there is a case where androgenic alopecia occurs. There are a fraction of cases where hair loss occurs if the amount of androgen is decreased. Other than that, you cannot determine because you do not know.

The peak in hair thickness and volume in women is in their late twenties to their middle thirties. Since then, hair begins to thin in most of women as well as decrease in number of hairs. Thus, the fact that a symptom emerges in those ages makes you imagine that it is caused by the decrease in estrogen. It is not known whether it will progress to the point where it is regarded as alopecia. It is the age when their hair feels volumeless or frizzy.

Kuwana:Some of hairs begin to thin in a woman after she has her first menstrual period or menopause occurs, or she gets pregnant or gives a birth. In case of women, it is especially difficult to find causes for hair loss because they have several turning points in their lives. Because the progression of hair loss should stop when a woman enters menopause if female hormone causes hair loss.

Kurata:When a woman reaches her sixties, her hair begins to thin for sure as a symptom of aging. For this purpose as well, development of a hair growth product for alopecia in women has made a significant social contribution. One of successful cases is Mulberry Root Extract although it was difficult to develop it.

Kuwana:I started research by getting mulberry roots when I belonged to Tokushima University. Mulberry Root Extract is a natural ingredient extracted from a mulberry’s root bark. In mice experiments, hair grew faster even in the resting phase. In addition, hair grew only region where Mulberry Root Extract was applied. When adding to cultured cells, it also showed effects of cell proliferation.

Kurata:Mulberry Root Extract has tremendous effects, doesn’t it? It induces cell growth factors. It is favorable in that it exerts its effects without injecting the skin directly. Recently, a method in which necessary ingredients are directly injected has popularity.

Kuwana:Stem cells have some beneficial effects.

Kurata:They are the ones by collecting and extracting culture supernatants from adipose-derived stem cells and are injected as a drug. Mulberry Root Extract is a medication that makes its own cells produce important cell growth factors having hair growth effects and induces them. There are some methods including injection. A variety of alternative induction methods have attracted attention.

 
How far did treatment for thinning hair go?
 

Kurata:They include iontophoresis which can deliver large molecules not permeating the skin barrier and electroporation which gives a special strong electrical pulse in short time to the scalp to create temporary pores in cell membranes through which substances can pass into the bottom layer of the dermis. Also, a physical method which attracts attention is narrow-band red LED light irradiation. The safety of LED light has been established and thus it is expected to be a useful method.

Kuwana:Does LED light have clear effect? Does LED light irradiation grow hair?

Kurata:We conducted a clinical study in dozens of patients. Although we did not perform definite statistical analysis, 70% of patients undergoing the procedure answered that it was good.

Kuwana:Did patients have some response?

Kurata:Yes. It has been confirmed to be fairly good. I think that this type of therapy can be an important option leading to greater satisfaction if a person dissatisfied with one treatment undergoes several types of treatments in combination because it can be used in combination with other treatments including oral drugs.

Kuwana:Laser hair growth device has been increasingly used widely in recent years.

Kurata:Laser for hair removal acts strongly on melanin pigments momentarily. It is a laser treatment which destroys melanin and damages thermally hair follicles leading to less hair growth. On the other hand, in case of mild laser irradiation, it stimulates the scalp mildly and it could grow hair. Thus, there are some reports that hair grew despite irradiation of depilation laser.

Kuwana:For laser treatment, hair grows in some people and it is effective for alopecia areata in others.

Kurata:It is difficult to set the wavelength and its conditions and thus I also use excimer laser. We need to proceed with research on what reaction occurs by which wavelength or which intensity.

You could often get something through a windfall profit in this world (laughing).Regarding the very minoxidil, when a hypertension person used it, his hair grew. It holds true for latanoprost and bimatoprost as eyelash growth serum.These drugs are eye drops for glaucoma. When a glaucoma patient used it, her bottom eyelashes grew thicker. An ophthalmologist published that it was a side effect of the drug. When a hair researcher heard of it, he thought, “It may be good”, started an experiment and observed hair growth.

Where is a new treatment for thinning hair heading for?
 

Kurata:We may expect hair restoration using cells as a treatment for thinning hair although I do not know it may occur in near feature or it will take longer time. Taking its risks into account, the treatment may be difficult to be used widely in reality. On the other hand, it is a promising treatment scientifically.

Kuwana:There are two different types of regenerative therapies which can deal with alopecia. One is a method for producing hair by extracting iPS cells from skin cells in the area where hair grows, which is now difficult to materialize. Another is a method in which hair follicle stem cells and dermal papilla cells which produce hair are used, which can make clinical application possible earlier. However, I guess that it will take 5 years or longer.

Kurata:Hair restoration using cultured cells is possible technically. When injecting hair follicle stem cells and hair mesenchymal cells at the same time, it is certain that hair grows.

Interviewer/writer: Akiyoshi Sato Photographer: Naoyuki Tamura

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