Dr. Hideo Uno is one of the leading researchers of hair loss using animal models in the world. He has been involved in many of the early tests of drugs which are the most effective, including Minoxidil, Proscar, and RU58841.

Hideo Uno, MD, PhD
Senior Scientist
Wisconsin Regional Primate Research Center
Adjunct Associate Professor
Department of Pathology and Lataratory Medicine
University of Wisconsin
Madison, Wisconsin

Contents

• Introduction
• Hair Loss and Hair Follicle Abnormality
• The Structure and Cyclic Growth of the Hair Follicle
• Fetal Folliculogenesis
• Cyclic Growth of the Hair Follicle
• Cyclic Dynamics of Hair Follicle Development
• Hair Growth in Normal Development
• Follicular Changes in Male Pattern Baldness (Androgenetic Alopecia)
• Androgenetic Alopecia in Men
• Androgenetic Alopecia in Women
• Androgenetic Alopecia in Stump-tailed Macaques
• Alopecia Areata
• Histological Changes of Hair Follicles
• Alopecia in Abnormal Conditions
• Conclusions
• References

Cyclic Dynamics of Hair Follicle Development

The cyclic change of hair follicles not only replaces an old hair with a new hair but also determines the length of hairs in various body regions. Follicles having a long growth period (anagen phase) produce longer hairs than do follicles with a short anagen phase. Generally, the large terminal follicles have a longer anagen phase than the small vellus follicles. However, the terminal follicles of the scalp have a longer growing phase than the terminal follicles in the facial, axillary, and pubic regions. The duration of the hair follicle cycle in different body regions appears to be determined by genetic factors. However, the normal homeostatic pattern of hair growth is readily altered by hormonal abnormalities, particularly of androgens, or the effects of certain drugs. The transformation of hair follicles from vellus to terminal takes place under various conditions, including the normal developmental process. Thin, silky hairs in the scalp of infants gradually change to thick, coarse hairs as the child grows older; this phenomenon is due entirely to the gradual enlargement of individual scalp hair follicles. Body hairs, how ever, do not thicken or increase in length but remain as short vellus hairs until puberty. There is considerable evidence that the pubertal ele- vation of serum testosterone induces the growth of sex hair in both sexes and of facial and body hair in males. Women with above-normal ovarian or adrenal androgen production show a masculine type of facial hair growth called "hirsutism" Whatever the stimulus, the conver sian of vellus hairs to terminal hairs, in either normal or abnormal physiological conditions, is essentially a result of transformation from vellus to terminal follicles. Microscopically, there is a great size difference between vellus and terminal follicles (Figures 16a,b). The growth of terminal follicles from the small vellus follicles requires many steps of gradual enlargement. Furthermore, anagen follicles have a complicated structure consisting of many highly differentiated cell groups. The only chance for an enlargement of follicular size exists during the follicular growth cycle. When the secondary germ cells grow in the early to mid-anagen (regrowing) phase of a follicle's cycle, the rate of germ-cell proliferation will determine the size of a new anagen phase follicle. If the rate is higher than that of the previous cycle, the new anagen follicle becomes larger than the previous anagen follicle. As mentioned earlier, the cyclic remodeling of hair follicles begins from a small number of the follicular germ cells in the base of a telogen phase follicle, and these undifferentiated multipotential cells rapidly proliferate and eventually produce a complete anagen follicle. Conceivably, any hormones or drugs that stimulate or suppress mitosis may influence the rate of the cell prolif eration of the germinal cells. Thus, the rate of germinal cell proliferation during a follicular cycle plays a major role in follicular enlargement.

Figure 16 Vellus and terminal follicles

Micropholographs showing a comparison of small vellus anagen follicles in the face of a woman (a) and large terminal follicles in the scalp skin (b).

It Is widely known that androgens show dichotomous effects on hair growth. They induce postpubertal sexual and facial hair growth but simultaneously induce alopecia (thinning of hair) in the scalp of bald-trait men and women and some nonhuman primates. Hirsute women often show both masculine facial hair growth and alopecia in the scalp. These data underscore the fact that androgenic actions on hair follicle transformation cause either hyper plastic (hair growth) or hypoplastic (alopecia) effects on those hair follicles that are genetically coded to respond to androgens.

Drugs with potent hypertrichotic effects are known to stimulate mitotic activity of the fol licular germ cells, sheath cells, and perifollicular fibrocytic cells.

In the following sections, follicular transfor mation will be described as it occurs in normal follicular development and in male pattern alopecia.

Figure 17 Development of hair follicles

Scalp hair

Sexual and facial hair; hirsutism

Hair Growth in Normal Development

Scalp Hair

The length and thickness of scalp hairs increase progressively during the juvenile and adolescent periods. By adulthood, the entice scalp is fur nished with long, coarse, pigmented terminal hairs. This gradual change of scalp hairs from childhood to adulthood is a result of a gradual enlargement of the hair follicle. The cyclic interseal of the scalp hair in human neonates is much shorter than in adult scalp hair. Thus, during the childhood and adolescent develop- mental periods, the hair follicles undergo many cyclic turnovers, In each cycle, the new anagen follicle produced from the follicular germ cells in early to mid-anagen phase grows larger than the anagen follicle of the previous cycle. This stepwise enlargement of follicles is an essential mechanism for growth of fetal follicles to adult terminal follicles in the scalp (Figure 17).

Body Hair

Unlike the scalp, the other body regions retain short vellus hairs until puberty (Figure 17), The secondary hair growth in the pubic and surillary region in adolescence begins around the age of 11 in girls and 12 in boys. The vellus hairs over the pubes in preadolescent individuals first show a sparse growth of long, slightly pigmented downy hair at the base of the penis or along the labia. It takes another two to three years to complete the growth of the terminal hairs of both the length and density of adult hair. Thus, the transformation of vellus follicles to terminal follicles, which produces the growth characteristic of secondary hair, occurs over about a three-year period as gradual, stepwise enlargement of the follicles. The speed of the follicular transformation of sexual hair is much faster than the follicular transformation of scalp hair. This difference may be due largely to a shorter cyclic interval of the body vellus follicles than of the scalp follicles. Furthermore, a progressive elevation of serum androgen levels occurs during adolescence in both boys and girls. The apparently androgen-sensitive fol licles in the pubic and axillary regions grow at a rate that corresponds with the level of andro gens. The vellus follicles in the facial region are also sensitive to androgen levels. However, the level of testosterone in women, approxi mately one tenth that of men, is not high enough to stimulate growth of masculine-type hair. This sexually dimorphic pattern of hair growth is readily interrupted by abnormally high or low levels of androgen. In hirsute women an increased rate of androgen production in the skin is also a contributory factor in excessive facial hair growth. Furthermore, dihydrotestosterone is the most potent of the various endogeonus androgens for stimulating the prostate and hair follicle. Although the level of dihydro testosterone in circulating blood is much lower than that of testosterone, an enzyme that converts testosterone to dihydrotestosterone - steroid 5a-reductase - is found in the hair follicles. Therefore, the follicular cells convert circulating testosterone to follicular dihydrotestosterone.

However, androgens not only stimulate hair growth but also induce a regression of hair follicles in the scalp. This postadolescent regres- sive change of the scalp hair is a fundamental cause of male pattern baldness, called "andro genetic alopecia. Although the phenomenon occurs in men and women who have inherited the genetic trait for alopecia, as mentioned previously, androgens have dichotomous actions on the hair follicles: they stimulate an enlarge- ment of the vellus follicles in various body rogions (secondary sexual hair growth) and also cause a regressive atrophy of the terminal follicles in the scalp (male pattern alopecia, Figure 18).

Figure 18 Androgenic hair follicle transformation

Follicular Changes in Male Pattern Baldness (Androgenetic Alopecia)

The modern era of research into male pattern baldness was opened by Dr. James Hamilton in early 1940. As an endocrinological anatomist, his first work strongly supported the androgenic theory of common baldness. His work covered clinical observations of baldness in 104 men with testicular insufficiency, including 20 prepubertal castrates and eunuchoids and 84 postpubectal castrates. None of the 20 men with prepubertal insufficiency showed development of baldness. Four eunuchoids treated with androgens sub- sequently developed a pronounced hair loss in the frontoparietal regions and crowns of their beads. The rate and degree of baldness in patients who had postpubectal castration varied widely, but men castrated at an earlier age (14 to 19 years) showed much less balding than did those castrated at later ages. The incidence of baldness in women was generally much less than that found in men: in addition, among 3,965 persons over the age of 35, the baldness found in women was much milder than that found in men. Hamilton's studies also suggested that there was an obvious correlation of androgenic stimulation and genetic factors in baldness. However, the mechanism of androgenic action in baldness remained an open question. In his histo- logical studies, Hamilton noticed that the bald scalp contained many atrophic hair follicles.

Androgenetic Alopecia in Men

In 1951, Hamilton described his system for the classification of common baldness in Caucasians based on the pattern of distribution of remaining hair (types I to VIII). He also studied sexual and racial differences in the degree and age of studies on baldness stimulated many other inves- tigators to also study this common affliction of humankind. Perhaps the first morphometric study on hair follicles in common baldness was described by Van Scott and Ekel in l958. They found that the size of a hair follicle, particularly the geometric relationships between the matrix of hair bulb and dermal papilla, showed a remarkable proportional reduction in both matrix and papilla in early male baldness when compared with the same type of follicle in the normal hairy scalp. They concluded that bald- nest appears to be due largely to progressive diminution in the size of terminal hairs. In 1959, Montagna stressed that the belief that the bald scalp is devoid of hair is false: instead, the naked scalp has numerous follicles, but they are so small that they produce colorless, prac- tically invisible hairs. He further noted that baldness is not a degenerative phenomenon but a system of progressive changes in which the hair follicles undergo a retrograde type of metamorphosis.

Many investigators recognized that progres- sive thinning of the scalp hair is a result of transformation of the terminal follicle to the vellus type. However, some investigators have believed that the cause of the follicular diminu tion is abnormal dystrophic changes of the hair follicle per se. There are, in fact, many dystro phic follicles in very old persons with advanced baldness, but the vellus follicles in the bald scalp of young and middle-aged adults generally showed no abnormal changes in follicular struc tures and surrounding dermal tissues (Figures 19a,b). The hair follicles in advanced stages of baldness become extremely small, and the bulbs of such small follicles are located in the lower level of the sebaceous gland (Figure 20a) or even above the upper level of the gland (Figure 20b). Sebaceous glands generally are the same size in normal hairy skin and bald skin (Figure 19b). Most investigators now believe that baldness is a phenomenon of retrograde transformation of the hair follicles from terminal to vellus size. However, the question whether the number of hair follicles in the bald scalp is less than that in the hairy scalp is still not fully resolved, despite Giacometti's earlier studies suggesting that the density of hair follicles in the bald scalp is obviously less than that in the nonbald scalp of the same age group. In addition, histological data show a significant reduction in the den- sity of hair follicles in the bald scalp of older (70 to 85 years) compared with that of younger (45 to 70 years) men (Table), There is no doubt that male pattern baldness is a progressive and spontaneously irreversible phenomenon. The hair follicles become pro- gressively smaller as baldness develops, and they may eventually lose their potential for cyclic remodeling. Moreover, the hair follicles in the advanced bald scalp and even in the body of elderly persons often show dystrophic changes associated with abnormal multiple budding, scar-like, dense collagenous accumulation below the follicles, and hyaline degeneration of the dermal papilla (Figures 21a,b). These weary follicles in old skin, as well as in long-standing advanced bald scalp, may eventually disappear. Thus, the phenomenon of male pattern bald ness (androgenetic alopecia) is not a pathological change; after many years the hair follicles may eventually exhaust the potential for cyclic remodeling and become incapable of growing new anagen follicles.

Figure 19 Normal scalp terminal and bald scalp vellus follicles

Microphofographs showing a comparison of normal large ferminal anagen follicles in the hairy scalp of an adult male (a) and small vellus anagen follicles in the bald scalp of an adult male (b).

Figure 20 Bald scalp vellus follicles

Marked reduction of the size of aellus anagen follicles (arrows) in the bald scalp of an adult male. The bases of the follicles are located at the lower level of the sebaceoss gland (a) and above the gland (hi.

Androgenetic Alopecia in Women

As Hamilton noted in 1942, thinning of thc scalp hair in adulthood is not solely an affliction of men. Although the grade of hair loss and its incidence are much less than in men, approxt mately 257 of Caucasian females show bitemporal recession (type I) by the ago of 40.' The thinning of hair continues to progress during aging and extends over the vertex and the frontal hairline, Unlike baldness in men, a severe degree of hair loss is rather rare in women, However, women producing an excess of androgens due to either ovarian or adrenal disorder often show a complete recession of hair on the frontal scalp.

Classification of the types of androgenetic alopecia in women with or without androgen excess was first described by Ludwig. The three grades of thinning of hair represent a progressive degree of hair loss on the crown: grade I, thin ning; grade II, pronounced rarefaction; and grado III, full baldness (total denudation). Severe degrees (grades II and III) of baldness are often seen in women who have excess androgen pro duction or have been treated with a high dose of testosterone, and these women also have a pronounced hirsutism. In 1986 DeVillez and Dunn reported that baldness in women as well as in men can be induced by normal levels of androgens in those individuals genetically predisposed to hair loss. However, their study revealed an increased ratio of 3a,17B-andm- stanediol glucuronide to sex-hormone-binding globulin in women who have varying degrees of baldness. They speculated that this increased ratio may cause increased androgenic action or minimal androgen excess in genetically sensitive hair follicles.

Figure 21 Dystrophic hair follicles

Dystrophic hair follicles in the bald scalp skin of an 84-year-old male: atrophic follicles consist of irregular- shaped upper follicular sheath with aberrant budding (arrowhead) and scarry-collagenous sheath in the adipose tissue (arrows) (a). Hyalinized dermal papilla and vascular wall of the perifollicular blood vessels of an anagen follicle of the bald frontal scalp skin of a 84-year-old female (arrows) (b)

Histologically, the hair follicle changes observed in female androgenetic alopecia may mimic some follicular changes seen in males, but no systematic study has been reported in the literature. We recently observed 20 biopsies of scalp skins from grades I and II female alopecia patients ranging in age from the late 20s to the 6Os. By both gross and microscopic observation, we noticed first that the bald scalp had virtually no, or very few, vellus hairs and that most were long, poorly pigmented, and of very small caliber. Although most women show just noticeable thinning of hair in the vertex, men's bald scalps usually contain many vellus hairs even in the early stage of balding. Unlike baldness in males, female alopecia generally shows later onset, slow progression, and limited severity. Just as female baldness progresses more slowly than male bald- ness, so follicular changes in female alopecia develop more slowly than in male alopecia. The rate of progressive reduction in the diameter of the hair that accompanies aging is greater in balding females than in nonbalding females. The differences in steroid hormone levels between men and women may cause different metamorphic changes of hair follicles particu- larly in women with a normal androgen level or a minimal androgen excess. Additional studies are needed to provide more precise histological observations of female alopecia.

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