| The article below is by Dr.
Richard De Villez, one of the original physicians helping to coordinate Upjohn's Minoxidil
FDA trials. He is one of the leading experts on hair loss in the United States.
Richard L. De ViIIez, MD
Associate Professor
Division of Dermatology
University of Texas Health Science Center
San Antonio, Texas
Contents
In some animal species, such as rats and mice, all hairs are apparently in
the same state of activity, and all cyclic changes are synchronized.26 In
humans, however the cycle of each follicle occurs independently from that of
neighboring follicles, exhibiting a mosaic pattern. Hair cycles are divided
into three stages: (1) anagen, a growing or active phase, (2) catagen, a
regressive stage, and (3) telogen, a resting stage.22-29 The relative
duration of these phases varies with the individual's age, nutritional
status, hormonal factors, and other physiologic and pathologic factors. Fully
formed anagen follicles produce hair that is firmly fixed within the
follicle. As soon as the growth phase is complete, degeneration begins
(Figure 6).
The catagen stage exhibits bulbar involution and destruction of the lower part of
the follicle. The onset of catagen is defined as an interruption of medullary
mitotic activity and the simultaneous cessation of the melanogenesis by the
melanocyte of the bulb. While the cortex continues to grow, the hair becomes
thin and white as the transfer of pigment granules becomes defective. Cellular
proliferation of the matrix is reduced and interrupted. The original glassy-
smooth membrane, which divides the epithelial cells of the follicle from the
connective- tissue layer develops folds and increases enormously in size. The
inner root sheath disintegrates and disappears while the cells of the external
root sheath form a sac at the base enclosing the germ cells of the follicle. The
structure of the bulb disappears, and the dermal papilla is separated from the
follicle. The cells of the bulb migrate to the keratogenic zone and surround the
base of the nongrowing hair. The outer root sheath (together with the hair) shifts
to the upper zone of the follicle. It subsequently atrophies, partially rolls up, and
forms an epithelial envelope around the hair's root. A few layers of cells are
then formed from this thin column.
Some of these cells are mitotically active and are in contact with the mesodermal
papilla. The hair club is surrounded by a capsule of partially keratinized cells
and becomes bound to the unkeratinized cells at the base of the sac. As soon as
the glassy membrane has disintegrated and becomes nearly resorbed, catagen is
complete; and the follicle enters the telogen, or resting phase of the hair cycle.25
The telogen follicle is short, and its base terminates in the vicinity of the
sebaceous gland. It has a wide infundibulum; and here, the cells of the basal
layer of the preserved part of the outer root sheath undergo the same mitotic
and keratinization changes as occur in epidermal cells. The walls of the follicle
firmly adhere to the stalk of the hair club, which has a frayed, brush-like base
surrounded by the cell mass of the destroyed bulb. The telogen follicle is only
seemingly quiescent, however because the germ of the new follicle is already
beginning to form at its base.
The sequence of events in anagen is similar to that of the original morphogenesis
of follicles in fetal skin.6-11 In stage one of anagen, the cells of the dermal
papilla increase in size and show increased RNA synthesis; simultaneously,
germ cells at the base of the sac undergo vigorous mitotic activity. In stage
two of anagen, the lower part of the follicle grows down into the dermis and
partially encloses the dermal papilla. In the matrix ring that surrounds the
dermal papilla, differentiation of cells commences and represents the various
layers of the hair and the inner root sheath. This differentiation of cells
is a distinctive feature of stage three. In stage four of anagen, the melanocytes
that line the papilla develop dendrites and begin to form melanin. Although
the hair has formed, it is still within the cone of the internal root sheath
and ends at the base of the original clubbed hair The keratogenous zone
becomes established just below the level of the sebaceous duct. In stage
five, the hair emerges from the cone of the external root sheath and forces
its way to the surface along the original hair shaft, which gets pushed
aside, and eventually the clubbed hair is discharged. Stage six begins as
soon as the hair emerges at the skin surface and continues until the onset of
catagen.
figure 6. Phases of hair growth
Hair growth is regulated by several factors.27,29 The influence of
innervation on the growth of hair has been studied in animals, and the
experimental methods that were used involve total denervation, sympathetic
denervation, and excision in follicle transplantation. Experience in hair
growth in humans originated with auto- grafts during hair transplantation.
Here, the excision of tissue severs its innervation. In all such experiments,
transplanted hairs continue to grow to the same extent and with the same
thickness as they did at their original location. Questions about the
relationship of the nervous system to hair growth remain unresolved, but the
prevailing view today is that hair growth is not directly controlled by the
nervous system.
The significance of vascularization is likewise not altogether clean Of course, hair
will not grow without an adequate supply of blood to furnish the follicle with
necessary metabolites. Also, large anagen follicles are vascularized better than
the small ones, and hairs located over large vascular anomalies are frequently
thicker and longer than adjacent hairs in the same area. Many attempts have
been made to stimulate hair growth in alopecic skin by increasing blood flow by
massage methods and by topical administration of vasodilators.30 With the
exception of a few recent studies,31,32 all such attempts have been
unsuccessful. Much like the association of hair growth to the innervation of the
follicle, the relationship of vascularization to hair growth has not been
completely resolved. It is generally thought that vascularization by itself does
not stimulate follicular activity but that the active follicle determines its own
blood supply from the dermal vascular plexus.
There is no doubt that sex hormones play an important role in the growth,
distribution, and pigmentation of human hair. During puberty, secondary hair
develops in the pubic and axillary regions. In males, the beard starts to grow
and, on a smaller scale, terminal hairs appear on the trunk and limbs. With
various endocrinopathies associated with overproduction of androgens,
hypertrichosis is a significant feature. The different effects of circulating
androgens on various groups of human hairs in various locations lead to the
hypothesis that differences exist in the metabolism of hormones in follicular
tissue.
The conversion of testosterone to the more active dihydrotestosterone
(DHT) in certain target cells depends upon the presence of the enzyme
5-a-reductase.33,34
The DHT combines with a cytosol receptor to form a complex that enters the
nucleus and joins with chromatin to initiate protein synthesis (Figure 7).
Androgen metabolism in cells can be impaired either by decreased conversion of
testosterone to DHT or by the cell's inability to accumulate DHT because of the
absence of the cytosol-receptor protein. The primary catabolic product of
androgen metabolism in either growing or resting hair follicles is
androstenedione.35 The conversion of testosterone to androstenedione via 17-(l-
hydroxysteroid dehydrogenase is tenfold the rate of the 5-a-reductase system
that yields DHT.
figure 7. Mechanisms of protein synthesis
The effects of androgens on sexual-hair growth and scalp-hair loss might
be mediated through changes in intracellular concentrations of cyclic
AMP (cAMP) (Figure 8). The "second messenger" theory of cAMP states that the
first messenger (a hormone) is carried to the plasma membrane of its target
tissue where adenyl cyclase recognizes only the specific first messenger
Simultaneously, a catalytic subunit of adenyl cyclase produces cAMP which
initiates a specific physiologic function.35
The effects of various sex hormones on the activities of adenyl cyclase in the
follicles of scalp hair indicate that dihydrotestosterone produces inhibition but
that testosterone does not. Increased adenyl cyclase activity is observed when
estrone is added to hair follicles. However estradiol (an active estrogen) does not
activate adenyl cyclase. The intracellular concentration of cAMP is determined
by the relative concentrations of synthetic enzymes, such as adenyl cyclase, and
degenerative enzymes, such as cAMP phosphodiesterase.
figure 8. Mechanisms of changing intracellular concentrations of cyclic AMP
Presumably, dihydrotestosterone inhibits energy production by keeping
phosphodiesterase relatively inactive and by suppressing various protein
(enzyme) synthetases. A relatively high concentration of cAMP may cause
premature termination of the growing stages of hair follicles. Repetition of such
processes over several years presumably transforms terminal follicles to vellus-
type follicles and ultimately causes baldness. The diverse biologic effects of
cAMP are mediated through activation of a family of protein kinases, which
consist of a regulatory (R) and a catalytic (C) subunit; and when bound,
these kinases are not active. Cyclic AMP binds to the R subunit, (a binding
protein) for cAMP and subsequently releases the C subunit to form an active
enzyme. Therefore, the more cAMP available in the androgen-sensitive hair
follicles, the stronger the activation of the protein kinase. An increase in
cAMP concentrations in hair follicles would produce diverse effects on
various enzymes and reaction pathways. Inhibition of glycolysis - by the
action of the active C subunit on the enzyme phosphofructokinase - decreases
the energy available for the cell to maintain its metabolic functions (Figure
9). The same active subunit effectively slows posttranslational protein
synthesis and interferes with cell cycles at the C1 and S phases.36 These
combined effects of high cAMP concentrations could result in premature
completion of the anagen stage; and this, in turn, could yield follicles that are
thinner and shorter than those of normal terminal hair.35 Apparently, the
differences in sensitivities for androgens of various types of hair follicles reside
in the cAMP protein-kinase system. However; the specific effects of the cAMP
system on the metamorphosis of terminal hair to vellus hair must be studied
further.
It is common knowledge that undernourishment slows the growth rate of hair;
and extreme starvation may render people totally alopecic. Basic amino acids,
fats, and vitamins are all necessary for the growth of healthy hair. Generally,
poor states of health lead to complicated processes that result in disturbed
metabolic and endrocrine interrelationships. Individuals who are on diets that
are unsuitable for weight loss, children who are starving and who have
kwashiorkor disease, and adolescents who are suffering from anorexia nervosa
all grow hair that is fine, short, and either unpigmented or copper colored.
Marasmus is accompanied by reduction of anagen hairs and an increased
number of clubbed hairs.37,38 In contrast to those of the preceding conditions,
these hairs are short and very brittle.
Unlike inductive factors, inhibitory factors affect anagen follicles, reduce or
completely suppress mitotic activity of the matrix, and impair keratinization.
Hair growth can be inhibited by radiation, chemicals, heavy metals, cytotoxic
agents, anticoagulants, large doses of vitamin A, and agents that block
cholesterol synthesis.
The growth of hair in humans is controlled by complicated mechanisms that can
differ among various locations on the body. Most of these mechanisms are only
partially understood.
figure 9. Inhibition of glycolysis by active catalytic subunit
Hair follicles develop in the skin of fetuses early in their developmental
phase. From that time on, i.e., throughout one's entire life, these follicles
undergo many cycles of degeneration and regrowth. During the neonatal period
and throughout adolescence, scalp hairs progressively thicken because their
follicles gradually enlarge with each new cycle. Body hairs, however, remain
short. This suggests that their cyclic changes do not lead to enlargement of
new follicles. The biologic effects of androgens cause postpubertal
thickening of axillary, pubic, and facial hairs in men and cause hirsutism in
women.
High rates of testosterone uptake and metabolism occur in scalp-hair
follicles of men and women. Scalp hair is androgen independent. In hair
follicles from scalps that have balding traits, the androgen hormone causes
metamorphosis of terminal hair to vellus hair by shortening the cell cycle
that leads to premature senescence of the follicles. It also exhausts further
mitotic activity of the matrix cells. The pathogenesis (and androgenetic
alopecia) is probably the same in men and women.
Perhaps further studies that involve metabolic controls of matrix cells of the hair
bulb, and their interaction with the dermal papilla, will improve our treatment
of hair-growth disorders.
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