Hair Loss

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Androgenetic Alopecia-- Aka, "Pattern Balding" or "Seborrheic alopecia" )

Nomenclature

Dawber (1) summarizes it best: " The contemporary nomenclature is confusing. In some countries " seborrheic alopecia " is favored. This term is unfortunate in that it has misleading aetological connotations.* " Male pattern alopecia " is perhaps the most widely-used term, but is descriptively misleading when applied to androgenetic alopecia in women. " Pattern baldness " is unobjectionable but has not found favor. The preferred term is androgenetic alopecia which stresses both the hormonal and genetic basis."

• Incidence of battern balding in males roughly corresponds to age (i.e., at age 35, about 35% of males show hair loss). Incidence of baldness and hair loss in women half to third this, at least before menopause, when the incidence of hair loss greatly increases. The inheritance of pattern hair loss is complicated. Possibly: "autosomal dominant with mixed penetrance". Translation: you can inherit pattern balding from mom or dad and hair loss expresses itself variably.

• Increased Androgen uptake, conversion to more active forms, receptor sites may be involved in balding.



• Four major androgens may be involves in balding: Androstenedione. DHT is the most potent-- but, DHEA from adrenals is important in women and possibly men. Likewise, androstenedione in men may play a key role in hair loss.

Anatomy of Balding

In balding, the hair follicle progressively " miniturizes " or becomes smaller. The hair that grows from it also miniaturizes, loses its pigmentation and decreases the amount of time it spends in the Anagen or growth phase, which goes from 2-4 years to a month or two for really fine " vellous " hair. The last stage in balding involves atrophy and fibrosis ( scaring ) of the hair follicle. Interestingly, the SOD's noted below reverse fibrosis in some experimental systems and there is reason to think they do this in pattern baldness also.

As the follicle miniaturizes, the oil gland attached to it becomes progressively larger and produces more oil or " sebum ". The resulting increase in scalp sebum accounts for one alternative name for balding, " seborrheic alopecia " ( latin: alopecia seborrheica or seborrhoeica = " fatty hair loss " ). This is not to be confused with alopecia due to seborrheic dermatitis, which may also contribute to the balding process.

Emerging Model for Pattern Balding (after Kligman, others )

Balding begins when male sex hormones do "something " to the scalp hair follicle which causes it to be read as a "foreign body". Your immune system then mounts an attack on the hair folllicle. The main damage in pattern hair loss is probably immunologically-mediated. Damage to lining of blood vessels, which produces hair growth factors, makes the balding process worse.

• Hormonal factors:

Castration, lack of DHT-receptors/enzymes (testicular feminization) , feminine status block the progression of balding and hair loss. However, women and castrated males have other sources of androgens and can still experience pattern loss.

• Immunological factors:

Microscopically, balding looks like organ rejection. That is, increased number of immune system cells clustor round the base of the scalp hair follicle. Interestingly, lessor numbers of immune system cells normally cluster around the hair follicle. These may have a role in the normal hair cycle.

• Organ rejection drugs ( e.g., cyclosporin ) reverse balding better than antiandrogens. This gives a rough indication of the relative importance of hormonal verses immunological factors in maintaining the balding state. Conversely, cyclosporin and similar agents may also have a "phenytoin-like" action on follicles which induces hair regrowth, separate from their immunosuppressive properties.

Antibodies to hair follicles are also present in blood in some cases of pattern hair loss.

Blood Vessel Lining in Pattern Hair Loss

Minoxidil, other agents apparently imitate hair growth factors ( nitric oxide radical, etc. ) produced by vessel lining. For a paper on this, go here. In diseases involving damage to vessel lining (e.g., atherosclerosis) production of these hair regrowth factors decreases. Such diseases are associated epidemiologically with severe balding. Also, decreases in circulation reported in balding scalp may reflect local damage to vessel linings. Alternately, some deficit in both the blood vessel and the hair follicle produces coincidental deterioration in both organs, producing hair loss. Again, a good candidate is the nitric oxide/superoxide system.

Regrowth of Hair Loss

Aside: Forget looking in the medical literature for new hair loss treatment drugs and hair regrowth agents. Because of the commercial potential of hair regrowthstimulators, everyone (including me) goes after patents. Most drug companies want to keep things secret as long as possible and so often don't publish on a new drug until commercial release.

BTW, when developing a drug such as for hair regrowth, the first place a PhD pharmacologist ( the guys who really develop drugs ) looks is in the patent literature. Most physicians and nonpharmacologists biomedical researchers do not know about patents, so you will rarely see them quoted. Most media. writers don't know about patents either, so they often get surprised by new products..

Even if a researcher is just interested in basic mechanisms of hair loss and balding, this is a bad mistake. For example, several patents indicate that superoxide dismutases or "SODases" stimulate hair growth and have hair regrowth properties. Still another patent from the Procter and Gamble company indicates that an SODase inhibitor blocks hair growth.

The implication is that superoxide radical ( an important messenger in many biological systems ) also modulates hair regrowth. Similarly, another patent claims that inhibitors of the systhesis of nitric oxide ( the "natural minoxidil" ) also inhibit hair regrowth. There is no hint of this in the "open" biomedical literature.

Besides, at last count, over several hundred us and foreign patents are issued in the areas of baldness treatment, hair loss, and hair regrowth. Probably most work at least some to reverse hair loss. But few if any of these hair regrowth agents have been published.

Antiandrogens: E.g.: Propecia (Finasteride), Cyoctal, spironolactone.

These agents have significant hair-loss treatment and regrowth properties.. They are also useful as adjuvants to other hair loss treatment where they 1) make it work better 2) Help prevent tolerance. Every few years, a new antiandrogen will be presented as the ultimate "solution for balding". This has yet to work out. E.g., clinical trials with cyoctal, arguably the most potent topical antiandrogen, were terminated because of lack of effectiveness. Likewise, the dual 5-AR inhibitor dutasteride ("Avodart") appears to work only a litte better (if that) than finasteride. So clinical trials with dutasteride were also stopped. Even castration, the commonly used treatment for prostate cancer, generally doesn't do a lot for balding and hair loss.
Arguably, the most promising antiandrogen is Propecia ( finasteride), from Merck. Tho the weakest antiandrogen on paper, it seems to be as effective as the others in baldness treatment. My experience is that oral finasteride works about as well as topical spironolactone, about a 50% response rate, at one year. Some individuals take even longer to respond.

BTW, I have prime patents in this area ( for growth stimulators plus antiandrogens ). In fact, because of the publication of our patents, the combination of a hair growth stimulator plus and antiandrogen is now " obvious " and thus unpatentable. I sure wish antiandrogens worked better.

Possible explaination: Male hormones only initiate balding. Further, whatever hormones do seems to be mostly irreversible. The main damage to the hair follicle seems to be done by other factors, especially immunological. But I reserve the right to change my mind about this.

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Nitroxides: Minoxidil, nicorandil

These are blood vessel dialating hair regrowth stimulators. OTOH, most dialating agents don't stimulate hair regrowth. So, vessel dilatation is not directly related to hair regrowth.

Possible explaination: Nitrovasodialators mimic some natural messenger substance coincidentally mediating both bloos vessel dialatation and hair growth. Currently, the best candidate is nitric oxide ( aka, EDRF or NO ). For a paper summarizing the evidence that minoxidil is an artificial form of nitric oxide, go here.

Nitric oxide is a very important messenger molecule. e.g., the 1998 Nobel Prize in Medicine was awarded to the scientists who first worked out the nitric oxide system in blood vessels.

NO is a ubiquitous transmitter which has identical effects to minoxidil on blood vessels. The action of both these agents and nitric oxide seems to be secondary to opening "K-channels", important for regulating a variety of cellular processes.

Whenever you see NO ( as in miNOxidil or naNO ) in the name of a drug, it probably has the nitric oxide chemical group in it. Similarly, as you might expect if nitric oxide is an important stimulator of hair regrowth, inhibitors of NO production reduce hair growth. See: "Reduction of Hair Growth", US pat# 5,463,478.

For a good review of the chemistry and the myriad biological functions of NO (with emphasis on its messenger functions for stuff like neurotransmission, blood pressure maintenance, blood clotting, etc.) go here

Also, not only is nitric oxide now has its own home page:

Nitric oxide Homepage.

Superoxide Dismutase Mimetics: ( more )

e.g.-- Prazotide copper (Procyte corporation) and Copper-Binding Peptide (Procter and Gamble). Also, a peptone-derived copper binding peptide was recently patented by Loren Pickart, who did the work with prazotide. It is marketed as "Folligen". A form of Prazotide copper, Graftcyte, recently received FDA approval for preventing hair loss in hair transplant surgery.

In the late 70's, we found that SODase prevents stress-induced hair loss in experimental animals. This was an incidental observation while we were trying to prevent diabetic cataract in rodents with the copper/zinc peptide antiinflammatory agent Orgotein, a purified SODase. BTW, Orgotein is FDA-approved in the US as the veterinary drug Palosein . Such diabetic animals undergo massive hair loss.

Orgotein didn't provent diabetic cataract. But, quite unexpectedly, it did prevent the hair loss. Go here to see a picture. From evidence like the antiinflammatory activity of Orgotein, we know that superoxide is a messenger for inflammation, among other things.. So, this suggested that superoxide might also be a natural messenger regulating hair fallout. Superoxide also seems to inhibit hair regrowth in the normal hair cycle.

TEMPOL is another SODase. Researchers at the National Cancer Institute report that TEMPOL stimulates the regrowth of hair in experimental hair loss following radiation. I own the patent for TEMPOL and other similar nitroxide spin labels and spin traps as ahir regrowth stimulating agents. These may have uses in many other degenerative diseases such as age-related neurological disorders like Parkinsons disease and Altzheimers. The may also be useful in the amelioration of sepsis, tissue ischemia, and reperfusion injury.

Because of our early discoveries, the US patent office issued me the dominant patent on using SODases and other metal-binding peptides for hair loss and hair regrowth.. This covers all the others. Other radical scavengers are also effective to induce regrowth or hair loss. So are hair growth stimulating Pyridine-N-oxides such as NANO and its esters, for which there are patents to both a Japanese drug company and myself for hair regrowth and the treatment of hair loss..

In fact, this technology is so mature that the Procter and Gamble corporation has a US patent on a well-known SODase inhibitor ( DDTC ) to prevent hair regrowth.

SODases destroy superoxide free radical: Superoxide reacts with nitric oxide ( the putative "natural" minoxidil ) to produce other toxic products. So these hair loss treatment agents probably stimulate hair growth either by increasing nitric oxide levels or by destroying these reactive hair growth inhibitors..

Peroxynitrite may be the most important of these hair growth blocking compounds.. From work with Parkinson's Disease, Altzheimers, as well as many other human diseases, a picture is emerging indicating SODases protect against peroxynitrite production. For example superoxide and nitric oxide may interact in heart attack to produce peroxynitrite, which may actualy cause much of the damage. For more information, go to the Peroxynitrite home page.

Hair regrowth stimulators may interfere with the immunological component in hair growth. Active oxygen species, which seem to mediate hair loss and inhibit hair regrowth, are also the most important mediators of cell-mediated immunity. BTW, a mild infiltrate of immune cells develops around the normal follicle as the hair cycle progresses. This may be the source of the superoxide that tells hair not to regrow..

Significantly, nitric oxide and superoxide have opposing "yin-yang" effects on a number of bodily systems. Examples include blood-vessel dialatation ( nitric oxide dialates, superoxide constricts ), blood clotting, hair regrowth, etc. Also, nitric oxide and superoxide react with each other to form toxic nitroperoxynitrite.

Most likely, the apparent superior effectiveness of the SODase growth-stimulators over the nitric oxide-like growth stimulators is due to such multiple actions.

Superoxide and nitric oxide may be the most ubiquitous paired transmitter substances around. Apparently, nitric oxide is the transmitter that initiates and maintains hair growth and hair regrowth in the hair cycle. Similarly, superoxideinhibits hair growth and regrowth. It also may cause hair to transition from the growth phase to the loss phase in the hair growth cycle. Also, superoxide reacts with nitric oxide to form toxic products. These may be important in mediating the immune attack.

Interestingly, such processes may play a role in other disorders such as Altzheimer's disease. Here, the pathogenic mechanisms are worked out in some detail. For a recent review of this, see:

"Altzheimer's Disease, A Radical Vascular Connection", J. S. Stamler, in Nature, vol 380, p108 ( March 14, 1996 ).

A Superoxide / nitric oxide interaction may also figure in high blood pressure: E.g.:

Tschudi, et al. Direct in situ measurement of nitric oxide in mesenteric resistence arteries. Increased decomposition by superoxide in hypertension. Hypertension, vol 27, p.32, (Jan. 1996 ).

The mechanism is probably rather similar to what happens in balding and hair loss, as well as other degenerative diseases. E.g., the first article even suggests treating Altzheimers with SODases,

1) Dawber, R., Diseases of the Hair and Scalp, Blackwell Science, Oxford (1997) p101.

This is spider bait: Ignore it. NANO superoxide dismutase and antiandrogens. Other aspects of drug treatment comprise alopecia hair follicle scalp stop scalp hair proctor disorders hair care chemotherapy problems m We also treat follicle scalp disorders and stop hair loss problems products hair prevention. The various treatments for hair replacement include minoxidil propecia finasteride proscar inoxidil propecia finasteride proscar superoxide dismutase proctor hair loss prevention replacement hairloss.

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