VASCULAR/ANGIOGENIC RELATED COMPOUNDS

Regaine/Rogaine (minoxidil) 2% has been used worldwide for over 10 years, and is now over the counter (OTC) in the USA. Most recently, Extra Strength 5% Rogaine has hit the OTC shelves in the USA, with approval in November 1997. Pharmacia-Upjohn has sole rights to being the only manufacturer for the next 3 years for this new version of minoxidil, which is indicated only for men.

Despite lack of understanding of the distinct mechanism of action, in women it has been shown to increase the non-vellus hairs when using it for 32 weeks or more2. One potential drawback to minoxidil therapy is that spontaneous reversal to the pretreatment state that can be expected one to three months after cessation of therapy, indicating minoxidil has a direct effect on the hair follicle, sensitizing it and making it dependent on the drug for future growth. The mechanism of action although still unclear, seems to open potassium channels and increases proliferation and differentiation of epithelial cells in the hair shaft2.

Serum concentrations after topical application of 2% minoxidil, used twice a day are generally about 5% of those with oral minoxidil, and with the 5% solution they are about 10% of those treated with the oral drug. Minoxidil is metabolized in the liver and excreted in the urine.

With respect to effectiveness, four unpublished 32 to 48 week studies presented to the FDA compared the effects of placebo, 2% minoxidil and 5% minoxidil by counting the net gain in hairs in 1 cm2 areas of the scalp. As described2, two studies in women did not find statistically significant differences between 2% and 5% minoxidil. A 32-week study in men found that the mean increase from baseline in hairs/cm2 was 5 with placebo, 30 with 2% minoxidil and 39 with 5% minoxidil. A 48-week study in men found a mean increase in hairs/cm2 of 3.9 with placebo, 12.7 with 2% minoxidil and 18.5 with 5% minoxidil. Previous studies have shown that when the drug is stopped, all of the newly regrown hair falls out6. Despite these reports the new advertisements claim 45% more effective hair growth than regular strength 2%, with regrowth occurring as early as 2 months with overall 5 times more hair regrowth than placebo, with no major safety concerns.

Most physicians and lay people who have been using minoxidil for many years are not concerned about safety aspects, since most feel it to be a very safe product. Concerns are more on the "effectiveness" of the product in promoting and maintaining hair growth. The new 5% Extra Strength brings about a new glimmer of hope in showing improved hair growth for individuals that may not have seen results with 2% minoxidil.

Adverse effects noted with oral minoxidil include tachycardia, angina pectoris and fluid retention. When taken orally during pregnancy, minoxidil has been associated with hypertrichosis of the fetus and congenital anomalies. One double blind study in 35 balding men found that topical use of 2% minoxidil caused small but statistically significant increases in left ventricular end-diastolic volume, cardiac output and left ventricular mass2. Infrequently, dizziness and tachycardia have been reported with 2% solution, with advice given to patients to reduce frequency of application which helps in eliminating these side effects. Local irritation, itching, dryness and erythema may occur with the use of topical minoxidil, most likely due to the vehicle formulation of alcohol and propylene glycol.

The conclusion on minoxidil 5% and 2% solutions are that they can produce a modest increase in hair on scalps of young men with mild to moderate hair loss, with continuous application for years to maintain the effect. Questions as to use of 5% Extra Strength in women are being posed, with some clinicians already giving this to young women with early hair loss, even though it is only indicated by the manufacturer Pharmacia-Upjohn for use in men.

Many patients may be asking their physicians now and in the future about using both topical Extra Strength 5% Rogaine along with oral 1 mg Propecia, which many believe may be beneficial working together synergistically, however further human clinical trials are needed to verify this, since the only previous study was performed in the Macaque monkey model, which did show benefit when used together7.

Although other vasodilatory/angiogenic related compounds are progressing through the development pipeline1, it is difficult to ascertain their effectiveness until human clinical trials are performed. Many compounds that mimic minoxidil in vasodilatory properties, fail to show the same results, hence there may still be a unique mode of action about this compound that is yet to be fully uncovered. Unpublished investigations have suggested minoxidil to have oxidative-reductive potential to facilitate cofactor reactions necessary in side chain steps for hair follicle growth, as well as other suggestions of stimulating some of the keratin genes of hair matrix cells for synthesis of hair shaft keratins, producing thin, fine, indeterminate hairs, often seen with continued use of minoxidil.

MEDICATIONS AS AN ADJUVENT TO SURGERY

Currently available medications should prove to be useful adjuncts to surgical hair restoration for a number of reasons.

Medications work best in the younger patient who may not yet be a candidate for hair transplantation.
Medications are less effective in the front part of the scalp, the area where surgical hair restoration can offer the greatest cosmetic improvement.
Medications can regrow, or stabilize hair loss, in the back part of the scalp where hair transplantation may not always be indicated.
Although medications are of little use in patients who have extensive baldness, these patients are often ideal candidates for hair transplantation.
If medications are shown to be safe and effective in the long-term, they will allow the hair restoration surgeon the ability to creat more density in the needed areas (such as the frontal hairline), since keeping reserves for future hair loss will be less of a concern.
With different medical options now available, patients must be educated as to their choices, advised as to how these agents work, educated to the fact that these drugs need to be used continuously throughout life in order to be of benefit, and be aware that long-term risks are not yet known. Most importantly, they must be provided with realistic expectations regarding the inability, at the present time, for medications to regrow substantial amounts of hair in the average patient. As newer, more effective agents are developed, it is certain that they will play a more expanded role in the hair restoration process.

REFERENCES
Sawaya ME: Alopecia - the search for novel agents continues. Expert Opinion in Therapeutic Patents 7(8):859-872, 1997.
Abramowicz M (Ed): Propecia and Rogaine Extra Strength for alopecia, In: The Medical Letter 40(1021):25-27, 1998.
Kaufman K: Clinical studies on effects of oral finasteride, a type 2 5a-reductase inhibitor on scalp hair in men with male pattern baldness. Proceedings from First Tricontinental Meeting of Hair Research Societies 1995.
Kaufman K: Updates of clinical phase III trial data and results presented at the American Academy Dermatology Meeting, San Francisco, CA, March 1997, as well as the World Congress Meeting, Australia, June 1997.
Bramson HN, Hermann D, Batchelor KW, ET AL: The unique preclinical characteristics of GG745, a potent dual inhibitor of 5AR. J Pharmacotics and Experimental Therapy, 1997.
Kidwai BJ, George M: Hair loss and minoxidil withdrawal. Lancet 340:609-610, 1992.
Diani AR, Mulholland MJ, Shull KL, et al: Hair growth effects of oral administration of finasteride, a steroid 5-alpha reductase inhibitor, alone and in combination with topical minoxidil in the balding stumptail macaque. J Clin Endocrinol Metab 74(2):345-350, 1992.
Cloning
In August 1967, R.F. Oliver published a paper titled The Experimental Induction of Whisker Growth in the Hooded Rat by Implantation of Dermal Papillae1, in which he described - as the title implies - the growth of a whisker hair from the implantation of only dermal papillae cells. Prior to this paper he had demonstrated that implantation of the lower third of the vibrissa follicle wall would produce a hair, but the implantation of the upper two thirds of the follicle would not2. The August 1967 report took the study one step further by showing that even the lower third of the follicle was unnecessary and that dermal papilla cells alone were sufficient to produce hair growth. Other authors have shown that there is an inductive role of the dermal papilla during the ontogeny of pillage and vibrisae follicles3.

The implications of these results in rats, with regard to human subjects with Male Pattern Baldness (MPB), can easily be discerned. If we were able to culture human dermal papilla cells (DPC) from a "permanent" hair-bearing donor area in a patient with MPB, and implant them into the bald area of the same patient and grow hair, we could potentially have an unlimited supply of donor hair with which to treat that patient. Thus any hair density and coverage would be made possible in any patient after harvesting a single small piece of donor skin.

With cloning, those portions of hair transplant surgery during which donor tissue is anesthetized, excised, and divided into grafts would no longer be necessary. In addition, the handling of donor tissue during sectioning and insertion into the recipient area that can potentially result in decreased hair survival, could be reduced or eliminated. In effect, many of the time consuming, skill dependent, potentially damaging and costly aspects of hair transplanting could be avoided if a technique for successful culturing and transplanting of DPC could be perfected. Lastly, the need for more invasive surgical procedures such as Alopecia Reduction, Scalp Expansion and Extension, and scalp flaps could be eliminated.

In the summer of 1997, Professor Dan Sauder, chief of the Department of Dermatology at the University of Toronto, Gulnar M. Shivji, Shabana Shahid, and Dr. Walter Unger, met and decided on a series of steps for the investigation of cloning in humans. Their work is summarized as follows:

Identify and Grow Hair Dermal Papilla Cells (DPC) in culture.
Perfect techniques to grow large numbers of DPC quickly i.e. ideal culture media and nutrients.
Introduce the DPC into athymic mice or SCID mice and grow hair.
Introduce DPC into the human donor skin and grow hair.
Devise optimal methods of introduction of DPC into the human donor.
Learn how to grow hair with uniform density, with growth in the correct direction and at the correct angle.
Although it was initially thought that accomplishing the first two steps would be relatively easy, nearly a year was spent completing that task. Table #1 outlines the process of identification and characterization of human DPC. The first step in obtaining DPC involves dissecting the dermal papilla from a small graft containing one or more hairs in the anagen phase of growth. The dermal papilla is carefully excised from the remaining hair structure and placed into a tissue culture dish containing medium. These cells may or may not be DPC, and one must learn how to

distinguish between them and epithelial cells or endothelial cells, which inhabit the same area of the follicle. Once the cells grow in culture, their true identity as DPC are confirmed with three different types of tests. The first is a morphological comparison, the second is confirmation using antibody stains that specifically react with components of only DPC, and the third is electron microscopy in which the ultrastructure is studied and confirmed to be that of DPC rather than epithelial or endothelial cells.

It should be clear from the above, that the task is not as simple as many of us clinicians would believe. Cells can be incorrectly thought to be DPC, primary cultures are easily contaminated by bacteria, the cells of some patients seem to grow far more easily than others, and finally propagating cells by sub-culturing is sometimes successful and sometimes not. In addition, the morphologic characteristics of DPC tend to change as their passage numbers are increased and they also will probably ultimately prove to be less effective in producing hair when they are finally introduced into the test animals.

Despite the above, we are very positive that we can now get millions of functioning DPC cells from one cell in most patients and that we will probably be able to do this successfully in all patients with further development of our expertise. Studies on athymic mice will begin as soon as approval has been received from the ethics committee of the University of Toronto.

After further refining laboratory studies, we will eventually be ready to introduce the cells into the human donor from which they came. Should we be successful in growing hair, the remaining two stages - that of devising the optimal methods of introducing the DPC into the donor and learning how to grow these hairs with a uniform density, in the correct direction and at the correct angle remain as large clinical barriers we have to overcome.

REFERENCES
J. Embriol: Exp. Morph. August 1967; 8(1): 43-51.
Oliver R.F.: Ectopic Regeneration of Whiskers in the Hooded Rat from Implanted Lengths of Vibrissa Follicle Wall. J. Embriol. Exp. Morph. 1967; 17: 27-34.
Embryonic Papillae, Edward J. Kollar: The Induction of Hair Follicles. The Journal of Investigative Dermatology 1970; 55(6): 374-378.

Genetic Therapies for Androgenetic Alopecia

Imagine that in your practice in the year 2010, in the corner of the room stands a futuristic incubator full of tiny plastic dishes with living, growing human dermal papilla cells from anonymous donors with a whole spectrum of different hair colors and textures. Each of the dermal papilla micro-cultures was already genetically engineered with an ensemble of genes known to control the growth, cycling and color of the hair for a lifetime. In addition, the grafts were engineered to be universal donors, by de-programming their immune imprint and re-setting the imprint to that of the recipient. Your patient enters the room, prepared for today’s "treatment", which involves filling your gene gun with papilla micro-cultures, and permanently implanting engineered cells into the scalp. These magical cells have the ability to perfectly recapitulate the individual’s entire genetic hair program, for the rest of the recipient’s life. Should your patient need a little fine-tuning, no problem - a topically applied growth factor cream to selectively activate and silence the artificial ensemble of genes will do the trick.

Sounds like science fiction? Think again. For the first time ever, Dermatologic scientists have begun to take aim at a genetic understanding of androgenetic alopecia (AGA), and if the current pace keeps up, we will have a good handle on the genes governing the human hair cycle in the next few years. The first human gene known to be involved in control of hair cycle regulation is called "hairless". It was cloned in our laboratories earlier this year, and proven to be the genetic cause of a simple form of inherited atrichia1. We anticipate it will be the first of many genes which work together to drive the hair cycle. With discoveries like this, we will soon be in a position to design rational cell-based and gene-based therapies for hair loss, in contrast to the currently available treatments. If all of this sounds just around the corner, however, we must pause and realize that the identification of susceptibility genes for AGA is still a few years away, not to mention the translation of those genes into a meaningful and rational cellular or genetic therapy.

If we look back in history, it is clear that we are poised for a genetic revolution in our understanding of hair growth at its most fundamental level. Here, we outline our current thinking of AGA as a complex genetic trait, and discuss our strategies to identify susceptibility genes for AGA. It is never too early to imagine what the practice of dermatology will be like in the year 2010, and we believe the future holds great promise for the application of this knowledge in the clinical setting.

THE HISTORICAL PERSPECTIVE
Correspondence shows that John D. Rockefeller Sr.’s problem with hair loss began in 1886 at the age of forty-seven, when he began ordering bottles of hair restorative. In 1893, his alopecia worsened as he struggled with digestive problems and fretted over the University of Chicago’s finances. Alopecia totalis, or the total loss of body hair, has been attributed to many causes, ranging from genetic factors to severe stress, but remarkably little is known for certain. In March of 1901, his symptoms worsened markedly, his moustache began to fall out, and all the hair on his body had followed by August.

The change in his appearance was startling. He suddenly looked old, puffy, stooped, and all but unrecognizable. He seemed to age a generation. Without hair, his facial imperfections grew more pronounced. His skin appeared parchment dry, his lips too thin, his head large and bumpy. Soon after losing his hair, Rockefeller went to a dinner thrown by J.P. Morgan (one of the few public dinners he ever attended) and sat down next to a mystified Charles Schwab, the new president of U.S. Steel. "I see you don’t know me, Charley, " said Rockefeller.

"I am Mr. Rockefeller".

Coming on the eve of the muckraking era, Rockefeller’s alopecia had a devastating effect on his image: It made him look like a hairless ogre, stripped of all youth, warmth and attractiveness, and this played powerfully on people’s imaginations. For a time, he wore a black skullcap, giving him the impressively gaunt physiognomy of a Renaissance prelate. One French writer wrote "under his silk skull-cap he seems like an old monk of the inquisition such as one sees in the Spanish picture galleries."

The alopecia dealt a blow to Rockefeller’s morale. The psychological effect is crushing for most people, and he dabbled restlessly in remedies. His physician started him on a hair-restoration regimen in which he took phosphorus six days a week and sulfur on the seventh. When such remedies failed, Rockefeller decided to buy a wig. Self-conscious at first and reluctant to wear it, he tested it one Sunday at the Euclid Avenue Baptist Church. Before the service, he stood in the pastor’s office, nervously adjusting it and telling a listener what an ordeal it would be to wear it in the church. When the wig met with a good reception, he was almost boyishly elated. Soon, he grew to love this wig, telling daughter Edith, "I sleep in it and play golf, and I am surprised that I went so long without it, and think I made a great mistake in doing so."

He became so fond of wigs that he started to wear rotating wigs of different lengths to give the impression of his hair growing and then being cut. He even had wigs styled for different occasions: golf, church, short walks, and so on. For all his wealth, however, Rockefeller could never find the ideal wig. Starting out with a fashionable wig maker on the Rue Castiglione in Paris, he grew disillusioned when springs in the framework pushed up through the hair. He then switched to a Cleveland wig maker whose product had another maddening defect: The foundation fabric would shrink, making the wig suddenly slide across his bald pate.

What God had taken away, it seems, could never be perfectly restored.

- excerpted from Titan by Ron Chernow, 19982

This passage from a recent biography of John D. Rockefeller, Sr. captures the essence of living with alopecia from the standpoint of the patient2. We empathize with his fruitless searching for remedies, we are humbled and moved by the erosion of his self-esteem, we are chilled by the description of his ghoulish appearance, we cheer when his wig is met with approval in the church, we laugh and cry with him at the tales of him searching the globe for the perfect hairpiece, and we are intrigued by the observation revealed later in the book that his mother suffered from the same condition.

Equally chilling, however, is the observation that in the 100 years since Rockefeller’s alopecia began, at least three things remain unchanged: the devastation of its victims, the absence of a cure, and importantly, the profound lack of scientific knowledge about its pathogenesis.

A century later, with the advent of modern genomics, we stand uniquely poised to bring an end to all three.

THE ANSWERS ARE IN OUR GENES

Alopecia areata (AA) affects approximately 1.7% of the United States population, or approximately 4.6 million individuals, including males and females of all ages and ethnic groups3, 4. A second, more common form of hair loss, androgenetic alopecia (AGA), also known as male pattern baldness, affects 50% of all males over age 50 in the United States, and a large percentage of women, generating a combined figure of nearly 40 million individuals who suffer from some form of inherited hair loss5-7, most of whom spend billions of dollars each year on ill-designed treatments, not cures, to combat their disease. While it is clear that AGA is a hormonally-modulated phenotype, it is clearly not due to single gene mutations in a single gene, such as the 5ða-reductase genes8, 9, and it fits the criteria to be modeled and analyzed as a primary polygenic disorder for the first time.

In men with AGA, the reported effects of hair loss are: considerable preoccupation, stress, anxiety, and coping efforts10, 11. These effects are more pronounced in men with extensive hair loss, and among younger, single men, and those with an early onset of hair loss. Relative to control subjects, balding men had less body-image satisfaction yet were comparable in other personality indexes. Although most men regard hair loss to be an unwanted and distressing experience that damages their body image, many balding men actively cope and generally retain the integrity of their personality functioning10, 11.

In contrast, similar research revealed strikingly deleterious psychosocial effects of AGA in women12, 13. The vast majority reported that their hair loss engendered considerable anxious preoccupation, helplessness and feelings of diminished attractiveness. Women worried that others would notice their hair loss and that the condition would progress and become more socially apparent. Such stresses also gave rise to active coping efforts. Many have sought information and selective social support, struggled to control their disruptive negative thoughts and feelings about their condition, tried to conceal their hair loss with altered hairstyles, and engaged in compensatory grooming activities to try to restore their body-image integrity. AGA was clearly more disturbing to affected women than a control group of women with less visible cutaneous disorders, and the psychological impact of androgenetic alopecia was found to be two-fold higher in women than in men12, 13.

The authors of these studies emphasize that physicians should recognize that the pathology of AGA goes well beyond the physical aspects of hair loss and growth10-13. As has been observed in other appearance-altering conditions, they noted that patients’ psychological reactions to hair loss were less related to the clinician’s ratings than to the patient’s own perceptions of the extent of their hair loss. Even in patients with minimal hair loss, that loss carries significant emotional and psychological meaning that the physician should not minimize. The losses pertain not only to hair, but profoundly impact the quality of life, the ability to function in society, the preservation of self-esteem, and can lead to psychological disturbances as profound as suicide. One recent statistic quoted that 45% of men with AGA would sacrifice 5 years of their life span for a full head of hair14.

The two prescription drugs currently available for AGA are largely unsatisfactory, and were serendipitously found to grow hair in men taking these drugs for other indications, including hypertension and prostate hypertrophy. Astonishingly, neither of these treatments arose from primary research on the genetic mechanisms driving the hair cycle. Similarly, a rationally designed treatment for AA based on a fundamental understanding of the disease process is sorely lacking. Desperate patients spend tens of millions of dollars a year for remedies, yet all of this is in vain in the absence of a basic knowledge of hair loss as a genetically controlled process. Only genetic therapies targeting the hair cycle itself will lead to a cure for hair loss, in contrast to the available treatments which ineptly address only downstream effects.

For the first time in history, we are in a position to address these devastating dermatologic diseases from their foundation, as complex genetic disorders. With the promise of completion of the Human Genome Project in 2005, these studies are timely in a way not possible up to now, and will likely lead to the identification of candidate susceptibility genes by the end of the five years15.

We present a strategy for the identification of candidate genes in the control of the hair cycle, starting with simple Mendelian forms of inherited alopecia, and expanding into genome-wide linkage studies in complex genetic diseases including AGA. These studies will pinpoint candidate genes for the first time, lead to an understanding of the interactions of these genes with each other and with other variables such as the immune system and hormonal differences, and ultimately illuminate potential rational therapeutic targets for the future.

MALE PATTERN BALDNESS AS A COMPLEX TRAIT DISORDER

Mendelian forms of diseases such as inherited alopecias are rare, clear cut, black-and-white examples of disease segregation: a family member can either be affected or unaffected. Mendelian traits ’run in families’ (segregate) in clear and reproducible patterns, usually autosomal recessive or dominant.

The term "complex trait", in contrast, refers to a more common genetic disorder that appears as a spectrum of shades of gray, rather than black and white. This term is used to describe any phenotype that does not exhibit classic Mendelian recessive or dominant inheritance attributable to a single gene locus15-18. The genes contributing to the phenotype can exist in such a way that they confer either additive or multiplicative degrees of susceptibility to developing disease15. The genetic analysis of complex non-Mendelian traits is most efficiently and powerfully studied using a technique known as Affected Sib Pair (ASP) analysis19-25. For two parents considered jointly, the two offspring can either share 0, 1, or 2 alleles with an average of 1 under no linkage. Testing for linkage amounts to determining whether the observed number of alleles shared over many ASPs is significantly higher than expected by chance, a phenomenon known as IBD, or identity by descent.

Once a complex trait has been mapped to several susceptibility loci, the formidable task of identifying the responsible gene still remains. Up to now, this has proven the greatest challenge in complex trait analysis, however, the timeliness of this proposal is reflected in the promise of the Human Genome Project to make a tremendous contribution to the positional cloning of complex traits by eventually providing a complete database of all genes in a given region15. Upon its completion near the year 2004, the Human Genome Project will facilitate the rapid and systematic evaluation of candidate genes in inherited alopecias.

The starting point for the genetic dissection of complex traits lies in the demonstration that genes are indeed an important part of whether an individual is at increased risk for disease predisposition. The observation that a trait ’runs in families’ (aggregates) in an ill-defined pattern is not sufficient evidence to make the a priori assumption that its etiology is genetic, since families may share predisposing environments as well as genes. With this starting point in mind, we present the following arguments in favor of polygenic inheritance model in AGA.

IS ANDROGENETIC ALOPECIA GENETIC?

It has been widely cited in the Dermatologic literature that AGA is caused by a single autosomal dominant gene with reduced penetrance in women3, 6, 12, 26. Amazingly, there exists only a single extensive family study published by Dorothy Osborn in 1916, where she studied the pattern of hair growth in 22 families and concluded that AGA is an autosomal dominant phenotype in men and a recessive phenotype in women27. She believed that a single gene dosage (Bb) causes AGA in men, where a double dose (BB) would be necessary in women. She gave no details regarding the methods of her examination, and weakened the validity of her data by stating that she had simply omitted the symptom-free women in her pedigrees27, 28. Nonetheless, her conclusions were adopted, cited, and re-cited until the present, by many writers in both the dermatologic and genetic literature.

While careful family studies of AGA are still lacking, in 1984, Küster and Happle reconsidered the autosomal dominant model of AGA, and put forth several arguments against a simple mode of Mendelian inheritance. What they did, in fact, was to meticulously define AGA as a classic example of a polygenic trait28.

First Argument: Prevalance of the AGA Trait

It is common knowledge that AGA is widespread in all populations, yet it is difficult to determine the exact frequency of the trait. Numbers in the literature vary, however, a generally accepted rule of thumb is that approximately 50% of 50-year old men will have AGA, thus, affecting approximately 30 million men in the U.S.3, 12, 26.

Hereditary traits due to a single gene rarely occur with a frequency higher than 1:1000. If AGA were a dominant trait resulting from a single gene, then it would be predicted that only 270, 000 individuals in the U.S. would be affected. As a general rule, inherited traits with a higher prevalence are due to more than one gene, therefore, the prevalence of AGA is a strong argument in favor of polygenic transmission28.

Second Argument: The Normal Gaussian Curve of Distribution

There is no generally accepted borderline between "normal" men and individuals with AGA. Any attempt to draw the line would be arbitrary, and in fact, all stages ranging from full hair growth to complete baldness are found in the population, with the transitions between these stages being fluid. The prevalence of AGA corresponds to a normal gaussian (bell) curve of distribution, typical of polygenic traits. If AGA were due to a single gene, there would be a clear-cut difference between the phenotypes, and we would expect a curve with two or more peaks28.

The distribution of AGA is best explained by a model of polygenic inheritance with a threshold effect. Individuals on the far left of such a curve represent those who carry only a few predisposing genes, and therefore enjoy a lifelong full head of hair. For those in the middle curve, there is a threshold for the manifestation of the trait, and the threshold is lowered by the presence of circulating androgens28. The essential role of androgens in the development of AGA is reflected in the nomenclature "andro" "genetic", since it is believed that androgens alone cannot produce AGA without an inherited predisposition, and the inherited predisposition cannot produce AGA in the absence of androgens5, 28.

Third Argument: Risk Increases with the Number of Family Members Already Affected

In 1946, Harris examined 900 men and found a "premature baldness" in 120 of them29. In this group, he determined the number of affected brothers in families with an affected father, as well as in families with an unaffected father. He showed that the number of affected brothers was higher in families that also had an affected father. If AGA were due to a single autosomal dominant gene, there should be no difference between the two groups. In contrast, a model of polygenic transmission would suggest that there should be a difference, since the risk of an individual developing AGA would increase with the number of family members already affected28.

Fourth Argument: Severely Affected Women Carry More Predisposing Genes that Mildly Affected Women

In 1964, Smith and Wells studied the first-degree relatives of 56 women with AGA30. Eighteen of these women had severe AGA, and interestingly, these 18 women had more affected first-degree relatives as compared to the entire group of 56 women. Smith and Wells postulated that the severely affected women were homozygous for a dominant gene, but they emphasized that this would not explain the fact that only 33% and not 100% of the fathers of these women were affected. This observation argues against the assumption of simple Mendelian inheritance, and also cannot be explained by the auxiliary hypotheses of diminished penetrance and variable expressivity. However, the model of polygenic inheritance provides an explanation for the results obtained by Smith and Wells: In the severely affected women, the number of predisposing genes is higher than in the mildly affected women, and therefore, more first-degree relatives will be affected28.

Fifth Argument: Affected Women Carry More Predisposing Genes Than Affected Men

In 1890, Jackson examined 1, 200 individuals with "premature baldness", consisting of 410 men and 790 women31. In the group of 410 men, he found a genetic influence from the father’s side in 236 cases, from both parents in 27 cases, and from the mother’s side in 9 cases. In the group of 790 women, he found 131 affected fathers and 240 affected mothers. This would be consistent with the assumption that for affected women, the maternal predisposition is more important than the paternal predisposition. However, the threshold concept provides an explanation that is more plausible than assuming homozygosity in severely affected women. Due to the higher androgen threshold present in women, an affected woman would carry a higher number of predisposing genes than a man affected to the same degree, and therefore, she would transmit a higher number of predisposing genes to her offspring28.

SUMMARY
The discovery of genes directly implicated in the pathogenesis of inherited hair loss will have far-reaching implications for the treatment of affected individuals. Ultimately, it is hoped that discovery and modulation of the genes for inherited hair loss will provide novel therapeutic targets, and eventually eliminate these psychologically devastating disorders.

REFERENCES
Ahmad, W., Ul Haque, M. F., Brancolini, V., Tsou, H. C., Ul Haque, S., Lam, H., Aita, V. M., Owen, J., deBlaquiere, M., Frank, J., Cserhalmi-Friedman, P. B., Leask, A., McGrath, J. A., Peacocke, M., Ahmad, M., Ott J., Christiano, A. M.: Alopecia Universalis Associated with a Mutation in the Human Hairless Gene. Science 1998; 279: 720-724.
Chernow, R.: Titan: The Life of John D. Rockefeller, Sr. Random House, New York 1998; 192: 407-408.
Sawaya, M.E., Hordinsky, M.K.: Advances in Alopecia Areata and Androgenetic Alopecia. Adv. Dermatol 1992; 211-226.
Schwartz, R.A., Janniger, C.K.: Alopecia Areata. Cutis 1997; 59: 238-241.
Kaufman, K.D.: Androgen Metabolism as it Affects Hair Growth in Androgenetic Alopecia. Dermatol. Clin. 1996; 14: 697-711.
Roberts, J.L.: Androgenetic Alopecia in Men and Women: An Overview of Cause and Treatment. Dermatol. Nurs. 1997; 9:379-386.
Drake, L.A., Dinehart, S.M., Farmer, E. R., Goltz, R.W., Graham, GAF., Hordinsky, M.K., Lewis, C.W., Pariser, D.M., Webster, S.B., Whitaker, D.C., Butler, B., Lowery, B.J., Price, V.H., Baden, H., DeVillex, R.L., Olsen, R., Shupack, J.L.: Guidelines of Care for Androgenetic Alopecia. American Academy of Dermatology. J. Am. Acad. Dermatol. 1996; 35: 465-469.
Sawaya, M.E., Price, V.H.: Different Levels of 5 Alpha-Reductase Type I and II, Aromatase and Androgen Receptor in Hair Follicles of Women and Men with Androgenetic Alopecia. J. Invest. Dermatol. 1997; 109: 296-300.
Ellis, J.A., Stebbing, M., Harrap, S.B.: Genetic Analysis of Male Pattern Baldness and the 5ða-Reductase Genes. J. Invest. Dermatol. 1998; 110: 849-853.
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A History Lesson 1

In 1983, at a hair replacement symposium in Los Angeles, a single case report of transplanting only ten two-haired micrografts to refine an abrupt standard grafted hairline was presented. The speaker was careful to mention that harvesting and planting 10-15 micrografts in each standard grafting session, and placing them on the part-side only, would add only ten or fifteen minutes of additional time to the length of each surgical session.

No sooner had the presentation ended when a distinguished dermatologic surgeon rose from his seat and announced to the other three hundred members of the audience, "This lecture was the greatest waste of time I have ever been forced to sit and listen to. The hair transplant procedure is tedious and time-consuming enough without adding another fifteen minutes for only fifteen more hairs. Besides my patients are already very happy with their results. I hardly think a few more isolated single hairs would make any difference to them." No one in the room rose to refute him.

One year later that presentation was published in the Journal for Dermatologic Surgery!2 Dr. Art Ulene, then the medical correspondent for the Today Show, read it, contacted the speaker, filmed the process, and broadcasted it to a national television audience. The rest, as they say, is history. Apparently those legions of supposedly "happy patients" concluded quite independently from their doctors, that those "few isolated single hairs" just might make them even happier that they already were! Unlike their surgeons, they saw a great deal of difference, indeed. Protestations of additional time and tedium meant nothing to them…that was the doctor’s problem. They cared only how they looked.

The future of hair replacement surgery will be determined, not by the doctor, but by the patient. The fully informed patient, the educated, savvy hair consumer is the most feared and powerful species in the free enterprise jungle of surgical hair replacement. His power comes from his knowledge. Comfortable and complacent surgeons should be wary. Though Dr. Art Ulene has retired, it will only be a matter of time before some other enterprising investigative, reporter decides once again to educate the "happy" hair consumer. Then, as in 1983, the rest will be history, and those who cannot remember it will be condemned to repeat it.

REFERENCES
Marritt, E: Full text to be published in Hair Transplant Forum International.

Marritt, E: Single-hair Transplantation for Hairline Refinement: A Practical Solution. Journal for Dermatologic Surgery and Oncology Dec’84; 10(12): 962-66.

Acknowledgment: The authors would like to thank Rebecca Sipala, Nazia Rashid and Marie Rassman for their assistance in the preparation of this manuscript.

Reprint Requests:

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