The control of hair growth
From the Center for clinical and experimental pharmacology
Clinical Hospital Centre, Kragujevac, Serbia, Yugoslavia.
The hair follicle is one of a few human tissues containing stem cells. The stem cells are interspersed within the basal layer of the outer root sheath and in an area called the bulge. From this reservoir stem cells migrate to hair matrix and start to divide and differentiate. Their behavior is controlled by numerous cytokines produced by cells of the dermal papilla. Dermal papilla cells and some cells of the inner and outer sheaths of the follicle from androgen-dependent hairs have androgen receptors in their cytoplasm and nucleus. Androgens indirectly control hair growth by influencing the synthesis and release of cytokines from the dermal papilla cells. Drugs affecting hair growth belong to one of the following groups: cytotoxic drugs, antiandrogens and drugs acting on potassium channels. Further development of drugs selective for certain steps in the process of hair growth will enable more successful therapy of hair growth disorders.
During fetal life the skin is covered with lanugo hairs. Around the eighth month of development this hair is usually shed. A second generation of lanugo hairs then starts growing and lasts until the first three or four months of extrauterine life are completed. After all lanugo hairs have disappeared, two types of hair emerge: vellus and terminal. Vellus hairs are thin (< 0,1 mm), occasionally pigmented, and short (< 2 cm). All skin is covered with vellus hairs with the exception of skin on the palms, soles, volar side of fingers, penile glans and labia minora et majora (only on internal side). Under the influence of diverse local and systemic factors vellus hairs are in certain regions transformed to terminal hairs. Terminal hairs are thick (up to 0,6 mm), long (> 2 cm), pigmented and medullated.Hair and Follicle Morphology
The portion of hair protruding above the level of the epidermis is called the hair shaft, and the portion within the follicle is the hair root. While terminal hairs are composed of medulla, cortex and cuticle, vellus hairs lack a medulla.[2[ A few rows of the incompletely keratinized cells form medulla, which is in the middle of the hair shaft. The cortex is built with several rows of completely keratinized fusiform cells; it gives strength to the hair. Cortex is covered with cuticle: one row of flat, keratinized cells arranged like tiles on the roof.
The root of the hair is contained in the follicle. The hair follicle is composed of epithelial and connective tissue sheaths. The epithelial sheath, which is in close contact with the hair root, has two layers: inner and outer. The inner layer is composed of three sublayers: (a) an inner layer, the cuticle, which is similar and in close contact with the hair cuticle; (b) a middle layer (Huxley's layer) made of a few rows of square cells; and (c) an outer, Henle's layer, made of one row of polygonal, flattened cells. The outer epithelial layer is considered to be a downgrowth of epidermis, with the spinous layer inside and the basal layer and basal lamina outside. The basal lamina is thickened and known as the vitreous membrane. A connective tissue sheath is an extension of the dermis: it has two layers, inner papillary and outer reticular.
The bottom of the hair root is enlarged and made of cells with high potential for division and differentiation. These cells comprise what is known as the hair matrix. The hair matrix cells divide and move up the follicle, differentiating into either hair cells or inner epithelial sheath cells. Among matrix stem cells there are melanocytes producing pigment of the hair. The pigment is synthesized from the amino acid tyrosine (catalysed by the enzyme phenol-oxydase) and transformed through dopa to dopaquinon. Further transformation of dopaquinon proceeds in two directions: either spontaneous transformation to indolquinon or through the addition of the amino acid cystein. Polymerization of indolquinon only produces the dark pigment, melanin. Polymerization of indolquinon and dopaquinon with added cystein produces the yellow pigment, pheomelanin. Matrix cells during their differentiation ingest (by phagocytosis) melanin or pheomelanin from dendritic elongations of melanocytes. This is how hair assumes its color: black if melanin is dominant, and yellow or red if pheomelanin is the major pigment. The portion of connective tissue root sheath that is in intimate contact with the hair matrix is known as the dermal papilla. It has a major regulating role in hair growth.Hair Growth
Hairs grow in cycles which are not synchronized in human beings; each hair enters phases of the growth cycle at a different time. There are three phases of the hair growth cycle: anagen, catagen and telogen. Anagen is the phase of active hair growth - approximately 900f all hairs are in anagen. It lasts from 2 to 6 years, depending on skin region. After anagen is completed, the hair enters catagen; during this short phase (2 - 3 weeks) the matrix cells gradually stop dividing and eventually keratinize. When full keratinization is achieved, the hair enters the last phase of the cycle, telogen. During the telogen phase (3 - 4 months) keratinized hair falls out, and a new matrix is gradually formed from stem cells in basal layer of outer epithelial root sheath bulge. A new hair starts to grow and the follicle is back in anagen phase.Factors Influencing Hair Growth
Stem cells of the hair follicle are gathered in the basal layer of the outer root sheath bulge. It is from these cells that matrix cells are formed. Growth and differentiation of the matrix cells are under the influence of substances produced by cells of the dermal papilla. On the other hand, the secretory activity of the dermal papilla is controlled either by substances produced in cells of the spinous layer of the outer root sheath or by hormones. Cells of the spinous layer produce peptides greater than 3000 daltons which increase the number of papilla cell mitoses two to five times. It was recently discovered that basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) potentiate the growth of dermal papilla cells. It is proposed that these proteins increase the synthesis of stromelysin (an enzyme, matrix metalloproteinase) which acts on the papilla cells and accelerates their growth. Another cytokine, transforming growth factor beta (TGF- ), inhibits mitogen - induced dermal papilla cell proliferation. On the other hand, dermal papilla cells produce numerous cytokines which influence proliferation of hair matrix cells. Some of them are stimulators, and some inhibitors. Interleukin 1- (IL-1 ) inhibits growth of hair and follicle, but only after 2-4 days of latency. The increase of IL-1 concentration in extracellular fluid during inflammation could be one of the reasons for alopecia following certain infectious diseases. Apart from IL-1alpha, both fibroblast growth factor (FGF) and epidermal growth factor (EGF) inhibit growth of the hair and hair follicle. Fibroblast growth factor type 5 (FGF5) is an especially potent inhibitor. Receptors for these ligands were found by immunohistochemical methods on papilla cells, matrix cells and stem sells in the bulge region of the hair follicle.[11,12] Another cytokine produced by cells of the dermal papilla, keratinocyte growth factor (KGF), induces extensive hair growth in murine models of alopecia. Receptors for KGF were found on keratinocytes in the basal epidermis and throughout developing hair follicles of rat embryos and neonates. Insulin-like growth factor I (IGF-I) accelerates, in a concentration-dependent manner, growth of hair and hair follicles. The actions of IGF-I are modulated by proteins produced in dermal papilla cells which bind IGF (insulin-like growth factor-binding proteins: IGFBPs); the exact mechanism of modulation has not yet been resolved. However, it has been shown that IGFBP-3 (which is the most abundant IGFBP type in dermal papilla cells) forms a complex with free IGF-I to reduce the concentration of IGF-I available for stimulation of hair elongation and maintenance of the anagen phase. Retinoids and glucocorticoids stimulate production of IGFBP-3 in dermal papilla cells. Insulin itself has the same effect as IGF-I; it has been observed that body hair in patients with hyperinsulinism has a male distribution pattern.[17,18] On the other hand, growth hormone (somatotropin) has no direct influence on follicle and hair growth.
Animal studies have shown that substance P induces transition of hair from telogen to anagen phase. The same effect has been observed with the active principle of chili peppers, capsaicin, which releases substance P from nerve endings in skin. Substance P also binds receptors on C-type afferent nerve fibers, producing pain.
Substances regulating the homeostasis of calcium and phosphorous may also be involved in control of hair growth. Parathyroid hormone (PTH) and PTH-related peptide inhibit hair growth and epidermal cell proliferation. 1,25 - dihydroxyvitamin D3 (1,25/OH/D3) in low concentration (1-10nM) stimulates, and in high concentration (100nM) and after longer contact inhibits hair and hair follicle growth. These actions of PTH and 1,25/OH/D3 require direct contact with hair follicles.Androgen-dependent Hair
Androgens have diverse effects on hair in different body regions. Effects vary from essentially nonexistent (e.g. on eye-lashes), weak (on temporal and suboccipital region hair), moderate (on extremity hair), or strong (on facial, parietal region, pubic, chest, and axillary hair). Androgens bind to receptors both in the cytoplasm and nuclei of dermal papilla cells and some cells of the sheaths of the follicle, but only if the hair is in anagen or telogen.[23,24] Two molecular forms of androgen receptors have been proposed: active (protein-monomer, 62 kDa) and inactive (protein-tetramer, with four subunits, total molecular weight 252 kDa). The monomer form has much greater affinity for androgens (dissociation constant for dihydrotestosterone is 2.9 nM). Four monomer molecules aggregate to form a tetramer in a reversible reaction. Necessary factors are glutathione and the enzyme, endogenous disulfide converting factor. The complex of androgen hormone-receptor moves to the cell nucleus and there enables expression of genes coding cytokines. Cells of the dermal papilla synthesize and secrete cytokines which control growth and differentiation of hair matrix cells.[25,26,27,28] In most hair the released cytokines stimulate matrix cell division and differentiation, however for hair of the parietal region the cytokines act as inhibitors, leading to follicle atrophy.
Numerous factors affect the number and activity of androgen receptors in dermal papilla cells. Retinoic acid (vitamin A derivative), if used for a long time, may reduce the number of androgen receptors by 30 - 40 percent. Vitamin B6 reduces by 35-40% the extent of protein synthesis observed after androgen receptor activation. A polypeptide with molecular weight of 60 kDa, analogous to an intracellular calcium-binding protein called calreticulin, prevents binding of the androgen-receptor complex to DNA and also results in the production of calreticulin.
Among all androgens, dermal papilla cells are most affected by 5- -dihydrotestosterone (5 -DHT). It is synthesized in these cells from testosterone under catalytic action of the enzyme 5- -reductase. This enzyme exists in two forms (isoenzymes) - type I and type II .[33,34] 5- -dihydrotestosterone is further reduced to 3- -androstanediol which, after conjugation with glucuronic acid, is excreted in urine. Plasma and urine levels of 3- -androstanediol glucuronide are the most precise clinical indicators of the extent of testosterone transformation to 5- -DHT). They are elevated in hirsute women.
Growth of androgen-dependent hairs can be influenced in several ways: (a) by decreasing androgen production, (b) by blocking testosterone transformation to 5- -DHT or (c) by blocking androgen receptors. Androgen production can be decreased either surgically (removal of hormone-producing ovarian or adrenal tumor) or with drugs. If increased production of androgens is the consequence of adrenal cortex hyperplasia, it can be suppressed with cortisone. Exogenous cortisone will inhibit release of ACTH from the hypophysis, and this in turn will decrease hyperplasia. If increased androgen production is caused by polycystic ovarian dystrophy, it can be reduced by inhibition of hypophyseal release of gonadotropins. Continuous administration of gonadorelin analogs (leuprolide, goserelin, decapeptyl, etc.) is a very efficient tool for achieving this goal. However, administration of these drugs is accompanied by significant adverse effects that result from decreased estrogen and progesterone production. Menstrual irregularities, flushes and osteoporosis are commonly observed (36). These adverse effects can be reduced by simultaneous administration of estrogen (during the first 21 days of the menstrual cycle) and progesterone (from 12th to 21st days of the cycle).
Transformation of testosterone to 5- -DHT can successfully be interrupted with inhibitors of 5- -reductase. One of them, finasteride, is already used clinically with significant efficacy  without disturbance of sex hormone plasma levels. Finasteride only inhibits type II 5- -reductase. There are other 5- -reductase blockers (so-called azasteroids), that have a steroid nucleus with an attached 4-methyl-4-azo moiety and a long hydrophobic side chain on C-17. The most efficient among them is 17 -N,N-diethylcarbamyl-4-methyl-4-aza-5 -androstan-3-one, which has a greater effect on in-vitro hair follicle cultures than finasteride.
One way to suppress the growth of androgen-dependent hairs is by the blockade of androgen receptors. The competitive androgen receptor blocker flutamide has already been approved for human use. Women with idiopathic hirsutism taking flutamide experienced a 30% reduction of hair diameter without disturbance of plasma levels of gonadotropins, testosterone, androstenedione or dehydroepiandrostenedione. Treatment should consist of daily administration of 375 mg for several months. Compared to spironolactone (a diuretic with androgen receptor blocking activity), flutamide is about 3 times more effective [41,42] with less adverse effects (menstrual irregularities).
Several blockers of androgen receptors with non-steroid chemical structure were synthesized recently. They are N-substituted arylthiohydantoins: RU 59063, RU 56187 and RU 58841.[43,44] These are very potent substances. Their affinity for androgen receptors is three times higher than the affinity of testosterone. One of them, RU 58841, is active when applied locally, which is of great benefit considering the significant adverse effects observed after systemic administration. One of the imidazole antimycotics, ketoconazole, is an inhibitor of androgen biosynthesis and also an androgen receptor blocker, however its affinity for androgen receptors is low. Systemic administration of ketoconazole for the treatment of hirsutism requires high doses and is associated with a high incidence of adverse effects.Adverse Effects of Drugs on Hair
Many drugs have significant effects on hair growth in humans. Besides the above-mentioned drugs with affinity for androgen receptors, may drugs affect both androgen-dependent and androgen-independent hair. They produce either hair loss or increased growth.
The hair follicle has a treasure of control mechanisms which influence its growth. Many are under the influence of androgens, while the others are highly autonomous. Thanks to the very long chain of factors controlling hair growth we have the opportunity to intervene in a number of ways. Hirsutism, as well as hair loss, are serious psycho-social problems for affected persons. With the recent advances in the study of hair growth, design of both selective and safe drugs for solving these major problems should be only a matter of time.
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